3rd Edition 1

Husband&Reznek's

I m a g i n G in
Oncology

Janet E Husband
Rodney H Reznek
 HUSBAND & REZNEK’S

IMAGING in ONCOLOGY
Third Edition

Edited by

Dame Janet E Husband DBE, FMedSci, FRCP, FRCR

Emeritus Professor of Radiology, Institute of Cancer Research and
The Royal Marsden NHS Foundation Trust, London and Surrey, U.K.

and

Rodney H Reznek MB ChB, FRANZCR (Hon), FRCP, FRCR

Professor of Diagnostic Imaging, Cancer Imaging,
Institute of Cancer, Barts and The London School
of Medicine and Dentistry, London, U.K.
© 2010 Informa UK Ltd

First published in the United Kingdom in 2010 by Informa Healthcare, Telephone House, 69-77 Paul Street, London EC2A 4LQ. Informa Healthcare is a trading
division of Informa UK Ltd. Registered Office: 37/41 Mortimer Street, London W1T 3JH. Registered in England and Wales number 1072954.

Tel: +44 (0)20 7017 5000

Fax: +44 (0)20 7017 6699
Website: www.informahealthcare.com

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic,
mechanical, photocopying, recording, or otherwise, without the prior permission of the publisher or in accordance with the provisions of the Copyright,
Designs and Patents Act 1988 or under the terms of any licence permitting limited copying issued by the Copyright Licensing Agency, 90 Tottenham Court
Road, London W1P 0LP.

Although every effort has been made to ensure that all owners of copyright material have been acknowledged in this publication, we would be glad to
acknowledge in subsequent reprints or editions any omissions brought to our attention.

Although every effort has been made to ensure that drug doses and other information are presented accurately in this publication, the ultimate responsibility
rests with the prescribing physician. Neither the publishers nor the authors can be held responsible for errors or for any consequences arising from the use of
information contained herein. For detailed prescribing information or instructions on the use of any product or procedure discussed herein, please consult the
prescribing information or instructional material issued by the manufacturer.

A CIP record for this book is available from the British Library.
Library of Congress Cataloging-in-Publication Data

Data available on application

ISBN-10: 0 415 45167 1

ISBN-13: 978 0 415 45167 3

Book orders
Informa Healthcare
Sheepen Place
Colchester
Essex CO3 3LP
UK
Tel: +44 (0)20 7017 5540
Email: CSDhealthcarebooks@informa.com

Composition by Exeter Premedia Servies Private Ltd., Chennai, India

Printed and bound in Spain by Grafos SA
 Contents

List of Contributors v 18 Bladder Cancer 315

Foreword ix David MacVicar, Janet E Husband, and Dow-Mu Koh
Preface x
19 Prostate Cancer 348
PART I: GENERAL PRINCIPLES Jingbo Zhang, Tvrtko Hudolin, and Hedvig Hricak

20 Testicular Germ Cell Tumors 371

1 Trends in Cancer Incidence, Survival and Mortality 1 S Aslam Sohaib, Dow-Mu Koh, and Janet E Husband
Jacques Estève and Michel P Coleman
21 Ovarian Cancer 395
2 Staging of Cancer 16
S Aslam Sohaib and Rodney H Reznek
Michael Williams
22 Uterine and Cervical Tumors 431
3 Multidisciplinary Treatment of Cancer: Surgery 22
Andrea G Rockall and Rodney H Reznek
Timothy A Rockall and Bruce F Levy
23 Primary Retroperitoneal Tumors 471
4 Multidisciplinary Treatment of Cancer: Chemotherapy 28
Isaac R Francis, Richard H Cohan, Datla GK Varma, and
Matthew Wheater, Sarah Lowndes, and Peter Johnson Sandra Wong
5 Multidisciplinary Treatment of Cancer: Radiotherapy 43 24 Primary Bone Tumors 488
Robert Huddart, Alan Horwich, and Stephen Morris
Steven LJ James, Murali Sundaram, and
6 Assessment of Response to Treatment 50 A Mark Davies
Lawrence H Schwartz and Binsheng Zhao 25 Soft Tissue Sarcomas 507
7 Secondary Malignancies 62 Eleanor Moskovic
Rod Skinner and ADJ Pearson 26 Breast Cancer 528
David MacVicar
PART II: PRIMARY TUMOR EVALUATION 27 Paranasal Sinus Neoplasms 558
AND STAGING Sheila Rankin

8 Lung Cancer 72 28 Tumors of the Pharynx, Tongue, and Mouth 579

Stephen M Ellis and Zelena Aziz Robert Hermans

9 Mediastinal Tumors 95 29 Laryngeal Tumors 609

Jonathan Goldin Robert Hermans

10 Pleural Tumors 116 30 Thyroid Cancer 642

Sujal R Desai and David M Hansell
11 Esophageal Cancer 127
Richard M Gore, Jonathan W Berlin, Frank H Miller,
Uday K Mehta, Kiran H Thakrar, and Geraldine M Newmark
Polly S Richards, Norbert Avril, Ashley B Grossman, and
Rodney H Reznek
31 Primary Tumors of the Central Nervous System 680
Juliet Britton and Matthew Adams

12 Gastric Cancer 159 32 Neuroendocrine Tumors 761

Alison M McLean Andrea G Rockall, Norbert Avril, Ashley B Grossman, and
Rodney H Reznek
13 Colorectal Cancer 186
Gina Brown, Janet E Husband, and Gary Cook
14 Primary Tumors of the Liver and Biliary Tract 216 PART III: HEMATOLOGY MALIGNANCY
Richard L Baron and James V Ferris
33 Lymphoma 792
15 Renal Tumors 245 Sarah J Vinnicombe, Rodney H Reznek, and
Anju Sahdev and Rodney H Reznek Norbert Avril

16 Primary Adrenal Malignancy 280 34 Multiple Myeloma 851

Rodney H Reznek and Priya Narayanan Conor Collins

17 Pancreatic Malignancy 299 35 Leukemia 870

Matilde Nino-Murcia and R Brooke Jeffrey Dow-Mu Koh and Janet E Husband

iii
 contents

PART IV: PEDIATRICS 53 Radiological Manifestations of Acute Complications

of Treatment 1216
36 General Principles in Pediatric Oncology 895 John A Spencer and Bobby Bhartia
David Stringer and Harvey Teo

37 Wilms’ Tumor and Associated Neoplasms PART VII: EFFECTS OF TREATMENT

of the Kidney 905 ON NORMAL TISSUE
Rebecca Leung and Kieran McHugh
54 Effects of Treatment on Normal Tissue: Thorax 1245
38 Neuroblastoma 923 Revathy B Iyer, Harmeet Kaur, Reginald F Munden, and
Marilyn J Siegel Herman I Libshitz
39 Uncommon Pediatric Neoplasms 941 55 Effects of Treatment on Normal Tissue:
Kieran McHugh Bone and Bone Marrow 1259
Lia Moulopoulos
56 Effects of Treatment on Normal Tissue:
PART V: METASTASES
Abdomen and Pelvis 1271
40 Lymph Node Metastases 967 Paul A Hulse, Bernadette M Carrington, and M Ben Taylor
Dow-Mu Koh and Janet E Husband
PART VIII: THE IMMUNOCOMPROMISED HOST
41 Lung and Pleural Metastases 988
Matthew Gilman and Amita Sharma 57 The Immunocompromised Host:
42 Bone Metastases 1005 Clinical Considerations 1298
David Wilson and Gina Allen Jacqueline M Parkin

43 Liver Metastases 1021 58 The Immunocompromised Host:

Central Nervous System 1305
Claus Koelblinger, Gerald Lesnik, Ahmed Ba-Ssalamah, and
Wolfgang Schima Jane Evanson

44 Metastatic Effects on the Nervous System 1048 59 The Immunocompromised Host: Chest 1314
David MacVicar Ioannis Vlahos
60 The Immunocompromised Host: Abdomen and Pelvis 1355
45 Adrenal Metastases 1077
Roger Chinn and Simon Padley
Rodney H Reznek and Anju Sahdev

46 Peritoneal Metastases 1094 PART IX: FUNCTIONAL IMAGING

Zahir Amin and Rodney H Reznek
61 Clinical Applications
47 Spleen 1115 in Molecular Targeted Therapy 1366
S Aslam Sohaib and Rodney H Reznek Timothy A Yap, Debashis Sarker, Stan B Kaye, and
48 Malignant Tumors of the Skin 1124 Johann S de Bono
Guy J Burkill and D Michael King 62 Positron Emission Tomography: Principles and
49 Radiological Investigation of Carcinoma of Clinical Applications 1384
Unknown Primary Site 1146 Niklaus G Schaefer, Thomas F Hany, and
Gustav K von Schulthess
Christopher J Gallagher, Rodney H Reznek, and
Janet E Husband 63 Measurement of Angiogensis: MRI
Principles and Practice 1401
Tristan Barrett, Anwar Padhani, and Peter L Choyke
PART VI: IMAGING AND TREATMENT
64 Measurement of Angiogenesis: CT
50 Interventional Imaging: General Applications 1154 Principles and Practice 1418
Tarun Sabharwal, Nicos Fotiadis, and Andreas Adam Vicky Goh

51 Interventional Imaging: Tumor Ablation 1173 65 Magnetic Resonance: Emerging Technologies

and Applications 1431
Alice R Gillams
Anwar R Padhani
52 Imaging for Radiotherapy Treatment Planning 1191
Vincent Khoo Index I-1

iv
 List of Contributors
Andreas Adam, MBBS(Hon), FRCP, FRCS, FRCR, FFRRCSI(Hon)
Professor of Interventional Radiology, Department of Radiology,
St Thomas, Hospital, London, UK
Matthew Adams, MB, BChir, FRCR
Consultant Neuroradiologist, National Hospital for Neurology and
Neurosurgery, Queen Square, London, UK
Gina Allen, BM, BCh, MRCGP, MRCP, FRCR, MFSEM
Consultant Musculoskeletal Radiologist, St Lukes Hospital, Oxford, UK
Teaching Associate Green Templeton College, University of Oxford,
Oxford, UK
Zahir Amin, MBBS, MRCP, MD, FRCR
Consultant Radiologist, Department of Imaging, University College
Hospital, London, UK
Norbert Avril, MD
Reader in Nuclear Medicine, Department of Nuclear Medicine, Barts and
The London School of Medicine and Dentistry, London, UK
Zelena Aziz, BSc(Hons), MB, BS, MRCP, FRCR
Consultant Radiologist, Department of Diagnostic Imaging, The London
Chest Hospital, Barts and The London NHS Trust, London, UK
Richard L Baron, MD
Professor and Chair, Department of Radiology, University of Chicago,
Chicago, Illinois, USA
Tristan Barrett, MBBS
Senior Radiology Registrar, Department of Radiology, Addenbrooke’s
Hospital, Cambridge University Teaching Hospitals NHS Foundation
Trust, Cambridge, UK
Ahmed Ba-Ssalamah, MD
Associate Professor of Radiology, Department of Radiology, Medical
University of Vienna, Vienna, Austria
Jonathan W Berlin, MD, MBA
Associate Professor of Clinical Radiology, University of Chicago, Evanston,
Illinois, USA
Bobby Bhartia, MB BS, MRCP, FRCR
Consultant Radiologist, Department of Clinical Radiology, St James’
University Hospital, Leeds, UK
Juliet Britton, MB, BS, FRCR, FRCP
Consultant Neuroradiologist, Department of Neuroradiology, Atkinson
Morley Wing, St. George’s Hospital, London, UK
Gina Brown, MB, MD, MRCP, FRCR,
Consultant Radiologist, Department of Diagnostic Radiology,
The Royal Marsden NHS Foundation Trust, London and Surrey, UK
Guy J Burkill, BSc, MRCP, FRCR, MA
Consultant Radiologist, Department of Radiology, The Royal Sussex
County Hospital, Eastern Hospital, Brighton, Sussex, UK
Bernadette M Carrington, MB ChB, MRCP, FRCR
Consultant Radiologist, The Christie NHS Foundation Trust,
Manchester, UK
Roger Chinn, MB BS, MRCP, FRCR
Consultant Radiologist, Department of Radiology, Chelsea and
Westminster Hospital, London, UK
Peter L Choyke, MD, FACR
Molecular Imaging Program, NCI, Bethesda, Maryland, USA
Richard H Cohan, MD
Professor of Radiology, Department of Radiology,
University of Michigan Hospitals, Ann Arbor, Michigan, USA
Michel P Coleman, BA, BM, BCh, MSc, FPHM
Professor of Epidemiology and Vital Statistics,
Non-Communicable Disease Epidemiology Unit,
London School of Hygiene and Tropical Medicine, London, UK
Conor Collins, BSc, FRCPI, FRCR, FFRRCSI
Consultant Radiologist, St Vincent’s University Hospital, Dubin, Ireland
Hon. Senior Clinical Lecturer in Medicine, University College, Dublin, Ireland
Gary Cook, MBBS, MSc, MD, FRCP, FRCR
Consultant Radiologist, Department of Nuclear Medicine,
The Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK
A Mark Davies, MB ChB, FRCR
Department of Radiology, The Royal Orthopaedic Hospital,
Northfield, Birmingham, UK
Johann S de Bono, MB ChB, FRCP, MSc, PhD
Senior Lecturer and Consultant Medical Oncologist, Section of Medicine,
The Institute of Cancer Research, Sutton, Surrey, UK
The Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK
Sujal R Desai, MD, FRCP, FRCR
Consultant Radiologist and Honorary Senior Lecturer, Department of
Radiology, King’s College Hospital NHS Foundation Trust and
Division of Gene and Cell Based Therapy, King’s College, London, UK
Stephen M Ellis, BA MB BCh MRCP FRCR
Consultant Radiologist Department of Diagnostic Imaging, The London
Chest Hospital, Barts and The London NHS Trust, London, UK
Jacques Estève, PhD
Professor of Biostatistics, Service de Biostatistique,
Hospices Civils de Lyon, Lyon, France
Jane Evanson, MRCP, FRCR
Consultant Radiologist, Department of Neuroradiology,
The Royal London Hospital, London, UK
James V Ferris, MD
Associate Professor of Radiology, University of Pittsburgh Medical Center,
Pittsburgh, Pennsylvania, USA
Nicos Fotiadis, MD, FRCR
Consultant Interventional Radiologist, Department of Diagnostic Imaging,
The Royal London Hospital, London, UK
Isaac R Francis, MD
Professor of Radiology, Department of Radiology, University of Michigan
Hospitals, Ann Arbor, Michigan, USA
Christopher J Gallagher, MBBSc, PhD, FRCP
Consultant Medical Oncologist, Department of Medical Oncology,
St Bartholomew’s Hospital, London, UK
Alice R Gillams, MB ChB, MRCP, FRCR
Consultant Radiologist Senior Lecturer, UCL Medical School and
Honorary Consultant, University College of London Hospital, London, UK
v
 list of contributors
Matthew Gilman, MD
Assistant Radiologist, Massachusetts General Hospital and Instructor in
Radiology, Harvard Medical School, Boston, Massachusetts, USA
Vicky Goh, MA, MBBChir, MD (Cantab), MRCP, FRCR
Consultant Radiologist, The Paul Strickland Scanner Centre,
Mount Vernon Hospital, Northwood, Middlesex, UK
Jonathan Goldin, MD, PhD
Thoracic Imaging Research Group, Department of Radiological Sciences,
UCLA, Los Angeles, California, USA
Richard M Gore, MD
Professor of Clinical Radiology, University of Chicago, Evanston,
Illinois, USA
Chief, Gastrointestinal Radiology, Northshore University Health
System, Evanston, Illinois, USA
Ashley B Grossman, BA, BSc, MD, FRCP, FMedSci
Professor of Neuroendocrinology, Centre for Endocrinology,
Barts and The London School of Medicine, London, UK
David M Hansell, MD, FRCP, FRCR
Professor of Thoracic Imaging, National Heart and Lung Institute and
Division of Investigative Science, Imperial College School of Medicine,
London, UK
Department of Radiology, Royal Brompton Hospital, London, UK
Thomas F Hany, MD
Department of Medical Radiology, Division of Nuclear Medicine,
University Hospital, Zurich, Switzerland
Robert Hermans, MD, PhD
Professor, Department of Radiology, University Hospitals Leuven, Leuven,
Belgium
Alan Horwich, PhD, MBBS, FRCP, FRCR
Academic Unit of Radiotherapy and Oncology, The Royal Marsden NHS
Trust and The Institute of Cancer Research, Sutton, Surrey, UK
Hedvig Hricak, MD, PhD
Chairman, Department of Radiology, Memorial Sloan-Kettering Cancer
Center, New York, New York, USA
Robert Huddart, PhD, MBBS, MRCP, FRCR
Academic Unit of Radiotherapy and Oncology, The Royal Marsden NHS
Foundation Trust and Institute of Cancer Research, Sutton, Surrey, UK
Tvrtko Hudolin, MD, PhD
Department of Radiology, Memorial Sloan-Kettering Cancer Center,
New York, New York, USA
Paul A Hulse, BMed Sci, BM BS, MRCP, FRCR
Consultant Radiologist, The Christie NHS Foundation Trust,
Manchester, UK
Janet E Husband, DBE, FMedSci, FRCP, FRCR, FFRRCSI (Hon),
FRCPSG (Hon), FHKCR (Hon), FAMS (Hon)
Emeritus Professor of Radiology, Institute of Cancer Research and The
Royal Marsden NHS Foundation Trust, London and Surrey, UK
Revathy B Iyer, MD
Associate Professor and Associate Division Head for Education,
University of Texas, M.D. Anderson Cancer Center, Houston, Texas, USA
Steven LJ James, FRCR
Consultant Radiologist, Department of Radiology, The Royal Orthopaedic
Hospital, Northfield, Birmingham, UK
vi
R Brooke Jeffrey, MD
Professor of Radiology, Chief of Abdominal Imaging Section,
Department of Radiology, Stanford University School of Medicine,
Stanford, California, USA
Peter Johnson, MA, MD, FRCP
Professor of Medical Oncology, Somers Cancer Research Building,
Southampton General Hospital, Southampton, UK
Harmeet Kaur, MD
Associate Professor, Department of Diagnostic Radiology, University of
Texas, M.D. Anderson Cancer Center, Houston, Texas, USA
Stan B Kaye, MD, FRCP, FRCR, FRSE, FMedSci
Drug Development Unit, The Royal Marsden NHS Foundation Trust,
Sutton, Surrey, UK
The Institute of Cancer Research, Sutton, Surrey, UK
Vincent Khoo, MBBS, FRACR, FRCR, MD
Consultant and Honorary Senior Lecturer in Clinical Oncology,
Royal Marsden NHS Foundation Trust and Institute of Cancer Research,
Chelsea, London, UK
D Michael King, MD, MS
Consultant Radiologist, Department of Radiology, The Royal Marsden
NHS Foundation Trust, Chelsea London, UK
Claus Koelblinger, MD
Department of Radiology, Medical University of Vienna, Vienna, Austria
Dow-Mu Koh, MD, MRCP, FRCR
Consultant in Functional Imaging, Department of Diagnostic Radiology,
The Royal Marsden NHS Foundation Trust, London and Surrey, UK
Gerald Lesnik, MD
Zentralröntgeninstitut, LKH Klagenfurt, Klagenfurt, Austria
Rebecca Leung, MBBS, FRCR
Department of Radiology, Great Ormond Street Hospital for Children,
London, UK
Bruce F Levy, MBChB (Hons), MRCS, MSc.
Research Registrar, MATTU, Postgraduate Medical School,
University of Surrey, Guildford, UK
Herman I Libshitz, MD, FACR
Chestertown, Maryland, USA
Sarah Lowndes, BM BCh, MA, MRCP
Specialist Registrar Medical Oncology, Somers Cancer Research Building,
Southampton General Hospital, Southampton, UK
David MacVicar, MA, MRCP, FRCR
Consultant Radiologist, Department of Diagnostic Radiology,
The Royal Marsden NHS Foundation Trust, London and Surrey, UK
Kieran McHugh, FACR, MRCPI
Consultant Paediatric Radiologist, Great Ormond Street
Hospital for Children, London, UK
Alison M McLean, FRCP, FRCR
Consultant Radiologist, Department of Diagnostic Imaging,
St Bartholomew’s Hospital, London, UK
Uday K Mehta, MD
Assistant Professor of Clinical Radiology, University of Chicago, Evanston,
Illinois, USA
 list of contributors
Frank H Miller, MD
Professor of Radiology, Northwestern University Medical School, Chicago,
Illinois, USA
Stephen Morris, MBBS, MRCP, FRCR
Department of Radiotheraphy, St. Thomas Hospital, London, UK
Eleanor Moskovic, FRCP, FRCR
Consultant Radiologist, Department of Radiology,
The Royal Marsden NHS Foundation Trust, London, UK
Lia A Moulopoulos, MD
Associate Professor, Department of Radiology, Medical School, University
of Athens, Athens, Greece
Reginald F Munden, MD, DMD
Professor and Chairman, Department of Radiology, University of Alabama
at Birmingham, Birmingham, Alabama, USA
Priya Narayanan, BSc(Hons), MB BS(Hons), MRCP FRCR
Consultant Radiologist, Department of Radiology, Chelsea and
Westminster Hospital, London, UK
Geraldine M Newmark, MD
Assistant Professor of Clinical Radiology, University of Chicago,
Evanston, Illinois, USA
Section Head, Body Imaging, Northshore University Health System,
Evanston, Illinois, USA
Matilde Nino-Murcia, MD
Professor of Radiology, Department of Radiology, Stanford University
School of Medicine, Stanford, California, USA
Department of Radiology, Veterans Affairs Palo Alto Health Care System,
Palo Alto, California, USA
Anwar Padhani, MBBS, MRCP, FRCR
Consultant Radiologist and Head of Imaging Research, The Paul
Strickland Scanner Centre, Mount Vernon Hospital, Middlesex, UK
Simon Padley, MB BS, FRCP, FRCR
Consultant Radiologist, Department of Radiology, Chelsea and
Westminster Hospital, London, UK
Jacqueline M Parkin, MBBS, PhD, FRCP
Vice President, Immuno-Inflammation Drug Discovery, Glaxo Smith
Kline, UK
ADJ Pearson, MD
Professor of Paediatric Oncology, Institute of Cancer Research,
Royal Marsden Hospital, Sutton, Surrey, UK
Sheila Rankin, DCH, FRCR
Consultant Radiologist, Guy’s and St. Thomas Foundation Trust, Guy’s
Hospital, London, UK
Rodney H Reznek, MB ChB, FRANZCR(Hon),
FRCP, FRCR, FFRRCSI(Hon)
Professor of Diagnostic Imaging, Cancer Imaging, Institute of Cancer,
Barts and The London School of Medicine and Dentistry, London, UK
Polly S Richards, BA, MBBS, MRCP, FRCR
Consultant Radiologist, Department of Diagnostic Imaging,
St. Bartholomew’s Hospital, West Smithfield, London, UK
Andrea G Rockall, BSc, MBBS, MCRP, FRCR
Professor of Cancer Imaging, Department of Diagnostic Imaging,
St Bartholomew’s Hospital, London, UK
Timothy A Rockall, MB, BS, MD, FRCS
Professor of Surgery, Royal Surrey County Hospital, Guildford, UK
Tarun Sabharwal, FCRSI, FRCR
Consultant Interventional Radiologist, Department of Radiology,
St Thomas’ Hospital, London, UK
Anju Sahdev, MBBS, MRCP, FRCR
Consultant Radiologist, Department of Diagnostic Imaging, St Bartholomew’s
Hospital, London, UK
Debashis Sarker, MD
Clinical Research Fellow, Institute of Cancer Research and
Royal Marsden Hospital, Sutton, Surrey, UK
Niklaus G Schaefer, MD
Nuclear Medicine, Department of Medical Radiology and Medical
Oncology, Department of Internal Medicine, University Hospital,
Zurich, Switzerland
Wolfgang Schima, MD, MSc
Associate Professor of Radiology, Abteilung für Radiologie und bildgebende
Diagnostik, KH Göttlicher Heiland, Vienna, Austria
Lawrence H Schwartz, MD
Director, Magnetic Resonance Imaging (MRI), Memorial Sloan-Kettering
Cancer Center, New York, New York, USA
Amita Sharma, MBBS, MRCP, FRCR
Assistant Radiologist, Massachusetts General Hospital and Instructor in
Radiology, Harvard Medical School, Boston, Massachusetts, USA
Marilyn J Siegel, MD
Washington University School of Medicine, Mallinckrodt Institute of
Radiology, St. Louis, Missouri, USA
Rod Skinner, MB ChB, PhD, FRCPCH, MRCP (UK), DCH
Consultant / Honorary Clinical Senior Lecturer in Paediatric and
Adolescent Oncology / BMT, Department of Paediatric and Adolescent
Oncology, Royal Victoria Infirmary, Newcastle upon Tyne, UK
Children’s BMT Unit, Newcastle General Hospital,
Newcastle upon Tyne, UK
S Aslam Sohaib, BSc, MRCP, FRCP
Consultant Radiologist, Department of Diagnostic Radiology,
The Royal Marsden NHS Foundation Trust, London and Surrey, UK
John A Spencer, MD, FRCR
Consultant Radiologist, Department of Clinical Radiology,
St James’ University Hospital, Leeds, UK
David Stringer, BSc, MBBS, FRCR, FRCPC
Clinical Professor, (National University Singapore), Adjunct Clinical
Professor, (Duke NUS Graduate Medical School), Head of Department,
Department of Diagnostic Imaging, KK Women’s and Children’s Hospital,
Singapore
Murali Sundaram, MBBS, FRCR
The Cleveland Clinic Foundation, Cleveland, Ohio, USA
M Ben Taylor, MRCP, FRCR
Consultant Radiologist, The Christie NHS Foundation Trust,
Manchester, UK
vii
 list of contributors
Harvey Teo, MBBS, FRCR
Adjunct Associate Professor, (National University Singapore), Clinical
Associate Professor, (Duke NUS Graduate Medical School), Deputy Head
of Department, Department of diagnostic Imaging KK Women’s and
Children’s Hospital, Singapore
Kiran H Thakrar, MD
Assistant Professor of Clinical Radiology, University of Chicago, Evanston,
Illinois, USA
Datla GK Varma, MBBS
Professor of Radiology, Department of Radiology,
M.D. Anderson Cancer Center, Houston, Texas, USA
Sarah J Vinnicombe, BSc(Hons), MRCP, FRCR
Consultant Radiologist, Department of Diagnostic Imaging,
St Bartholomew’s Hospital, London, UK
Ioannis Vlahos, B.Sc, MBBS, MRCP, FRCR
Consultant Radiologist, St George’s Hospital, London, UK
Assistant Professor, New York University, New York, USA
Gustav K von Schulthess, MD, PhD
Nuclear Medicine, Department of Medical Radiology,
University Hospital, Zurich, Switzerland
Matthew Wheater, BM, MRCP
CRUK Clinical Research Fellow, Somers Cancer Research Building,
Southampton General Hospital, Southampton, UK
viii
Michael Williams, MD, FRCP, FRCR
Consultant Clinical Oncologist, Oncology Centre,
Addenbrooke’s NHS Trust, Cambridge, UK
David Wilson, MBBS, BSc, MFSEM, FRCP, FRCR
Consultant Musculoskeletal Radiologist,
Nuffield Orthopaedic Centre NHS Trust, Oxford, UK
Senior Clinical Lecturer, University of Oxford, Oxford, UK
Sandra Wong, MD, MS
Assistant Professor of Surgery, Division of Surgical Oncology,
Department of Surgery, University of Michigan, Ann Arbor,
Michigan, USA
Timothy A Yap, BSc(Hons), MBBS, MRCP
Drug Development Unit, The Royal Marsden NHS Foundation Trust,
Sutton, Surrey, UK
The Institute of Cancer Research, Sutton, Surrey, UK
Jingbo Zhang, MD
Department of Radiology, Memorial Sloan-Kettering Cancer Center,
New York, New York, USA
Binsheng Zhao, DSc
Associate Attending Physicist, Departments of Medical Physics and
Radiology, Memorial Sloan-Kettering Cancer Center, New York,
New York, USA
 Foreword
Imaging is fundamental to the management of almost all patients
with cancer. It has important roles in screening of asymptomatic
patients, diagnosis or exclusion of cancer in patients with symp-
toms, determining the extent of disease, selection of appropriate
treatments, targeting of treatments to the right location, moni-
toring of response to treatment and detection of recurrence and
metastasis. In addition, interventional radiology is increasingly
playing a part in the direct treatment of cancer.
Imaging of cancer has developed remarkably during the 30 years
of my career. CT was first introduced in the 1970s, MRI scanning
in the 1980s, PET scanning in the 1990s and more recently the
fusion of functional and anatomic imaging as with PET-CT. In
addition to these major landmarks, incremental improvements in
each technology have been introduced at more frequent intervals.
The knowledge base related to imaging has also grown hugely,
helping to define the optimal use of each modality for different
cancers.
Given the diverse roles of imaging in the management of cancer
and the rapid developments, it is unsurprising that radiologists
are key members of specialist multidisciplinary cancer teams,
working alongside pathologists, surgeons, oncologists, nurse
specialists, palliative care specialists and others. During my train-
ing as a medical oncologist and subsequently as a consultant I was
fortunate to work in several specialist cancer teams. Several of the
authors of this textbook were members of those teams. Through
them I have come to know how vital the expertise of the radiologist
is to high-quality patient care. Equally I know that to undertake
their role fully, radiologists need to keep up-to-date with progress
on cancer generally and particularly with developments in their
own discipline. Other cancer clinicians also need to keep abreast
of developments in cancer imaging.
This third edition of Imaging in Oncology will be of enormous
value both to radiologists and to other members of specialist
cancer teams. The two editors, Janet Husband and Rodney Reznek,
are internationally recognized as leading experts and teachers in
their field. Alongside their own contributions to this textbook
they have brought together a truly impressive array of other
experts from across the world. The text is both authoritative and
highly readable. Each chapter has a valuable introductory section
as well as detailed information on imaging techniques. The illus-
trations are excellent, as are the lists of key points throughout the
text.
In short this is a remarkable textbook. I strongly commend it
both to radiologists working in the field of cancer and to their
colleagues in specialist cancer teams.
Professor Mike Richards
National Cancer Director, England
ix
 Preface
Over the past several years, it has become clear that the optimal
management of patients with cancer is best achieved by healthcare
professionals working in a multidisciplinary team. During this evo-
lution in cancer management, imaging technology has advanced
markedly, largely but not wholly driven by expansion of comput-
ing power. Thus, multidetector computed tomography (CT) has
become standard practice, allowing elegant, accurate 3D displays
of anatomy and pathology, and new software for the accurate
monitoring of treatment response has been introduced. In mag-
netic resonance (MR) imaging, new sequences and faster gradi-
ents have been developed, and in positron emission tomography-CT
(PET-CT) refinements in technology have made a major impact
on cancer assessment. These two latter developments have combined
to make the specialist radiologist central to the multidisciplinary
team; an individual who understands the clinical questions posed
by the clinician, is skilled in cancer imaging interpretation, and is
familiar with all the relevant recent technological advances.
As with previous editions, the aim of Imaging in Oncology is to
provide an up-to-date text that addresses all these aspects of cancer
imaging. All chapters included in the third edition of Imaging in
Oncology have been revised, often extensively, to include the appli-
cation of state-of-the-art imaging and to review its application to
modern approaches in the management of patients with cancer.
References have been updated to provide the reader with a current
bibliography.
As with previous editions, Imaging in Oncology is divided into
nine sections. The first section covers the general principles of the
management of patients with cancer. As allied disciplines have
become more aware of the importance of imaging in patient man-
agement, this section now includes separate chapters on cancer
surgery, chemotherapy, and radiotherapy. Current thinking on
trends in cancer incidence and the development of second malig-
nancies has been addressed and particular focus has been placed
on new developments in the assessment of treatment response.
Section 2, Staging Disease, is the largest section of Imaging in
Oncology.
Each tumor site is dealt with separately in a set format that
includes a diagrammatic illustration of the staging system together
with an explanation followed by an evaluation of the role of
imaging in demonstrating the extent of the disease. As a thorough
understanding of the diagnostic performance of different imaging
techniques is a crucial component of the radiologist’s role in the
multidisciplinary team, this aspect is stressed throughout the text.
The introduction of new and more successful therapies for
many different types of cancer has encouraged earlier recognition
of recurrent disease and therefore each chapter includes a section
on the patterns of recurrence and their characteristic findings.
Equally, with more aggressive management of metastatic disease,
x
great reliance is now placed on imaging for the accurate detection
and delineation of metastases. Hence, this section has been
updated to reflect modern imaging strategies and performance.
Since the second edition of Imaging in Oncology, great strides have
been made in the localized treatment of tumors including targeted
radiotherapy and percutaneous tumor ablation. These topics are
considered in a separate section on “Imaging and Treatment.”
Functional imaging is now becoming established as a valuable
tool in the non-invasive assessment of metabolic and molecular
processes, not only in the measurement of changes in response to
therapy but also in the assessment of tumor aggressiveness and for
targeting local therapies. MR imaging, CT, PET, and contrast-
enhanced ultrasound have all been developed to assess functional
processes, and several protocols are now moving from the research
setting into routine clinical practice where they can be of real
practical benefit. In this edition of Imaging in Oncology the final
section is devoted to the principles of functional imaging because
we believe that it is critically important for all cancer radiologists
to become familiar with functional imaging techniques, and to
have a broad understanding of their current benefits and limita-
tions in the evaluation of various tumor types.
As in previous editions, salient points within the text have been
highlighted as “Key Points” and a short summary is included at the
end of each chapter in the same format as the Key Points. Several
chapters include, where appropriate, color diagrams produced by
Dee McLean to whom we owe a great debt of gratitude for her
outstanding work. No one has worked harder to bring this third
edition to fruition than Mrs. Maureen Watts, Mrs. Julie Jessop,
and Mrs. Janet Macdonald. All found time in their busy working
lives to contribute outstandingly to this project. Mrs. Watts
co-ordinated the project from start to finish for Janet Husband,
Mrs. Jessop did the same for Rodney Reznek. Mrs. Macdonald
scrutinized all the images, working tirelessly to ensure that the
highest possible quality has been achieved throughout the book.
Finally, we would like to acknowledge the enormous contribution
of all the authors, and would like to thank them for sharing with
us their valuable expertise and extensive experience. The high
quality of their work has made the editing of this text informative,
interesting, and a great pleasure.
We hope that this book will build on the previous editions of
Imaging in Oncology to provide a useful reference text for all radi-
ologists interested in cancer imaging. We hope too that it will
make a contribution to the wider understanding of the ever
increasing and constantly changing role that imaging plays in the
management of patients with cancer.
Janet E Husband
Rodney H Reznek
 1 Trends in Cancer Incidence, Survival and Mortality
Jacques Estève and Michel P Coleman
OVERVIEW
Changes over time in the patterns of cancer incidence, survival and
mortality in the whole population are the key to understanding
progress in achieving cancer control. Improvements in prevention,
screening, diagnosis, and treatment will eventually be reflected in
one or more of these public health indicators of the cancer burden.
The clinical benefits of early diagnosis, accurate staging and
optimal treatment of each cancer patient are usually obvious, both
to the patient and his or her family, as well as to the clinical team.
By contrast, public health approaches to cancer often involve
population-based measures such as incidence and mortality rates.
These measures can seem impersonal to clinicians, or too distant
from clinical efforts at the bedside. Worse, they are derived from
routine data collection systems such as cancer registries and vital
statistics systems with which clinicians may be unfamiliar. Finally,
they often involve statistical approaches to estimation that may be
even less intuitive.
At least the concept of cancer survival is well understood by
clinicians from hospital case series or clinical trials, but again,
cancer survival rates that reflect the experience of all cancer
patients often appear unduly low to clinicians who are more
accustomed to hospital survival rates or clinical trial results, and
for that reason they may be seen as unreliable. As a result, population
measures of cancer incidence, survival and mortality are often
ignored by clinicians as daunting or even irrelevant.
This is most unfortunate, because such measures provide the
only objective and quantitative insights we have into the success
or failure of the collective effort made by society to achieve overall
control of cancer in the whole population. Clinical care is obvi-
ously a crucial component of this collective effort, but it is only
one of many. The others include public education about the symp-
toms of cancer and when to seek help from a healthcare profes-
sional; the training of primary care physicians to detect the early
signs of cancer when it is a rare disease in general practice;
efficient referral systems; and the availability of adequate human,
physical and financial resources to deliver optimal investigation,
diagnosis and treatment promptly to all cancer patients.
In this chapter, we will consider some of the available information
on patterns and trends in cancer incidence, survival and mortality.
INTRODUCTION
Trends in cancer incidence and mortality offer a rational basis for
the planning of diagnostic and treatment services and for the eval-
uation of priorities for cancer prevention and control. Trends may
also shed light on the causes of cancer.
In simple numerical terms, the problem is stark. Around the year
2000, some 10 million new cases of cancer were diagnosed world-
wide each year (5.3 million in men and 4.7 million in women), and
there were over six million cancer deaths a year. By the year 2020,
the annual number of new cases may rise to 15 million a year.
This 50% projected increase in the global cancer burden over the
first two decades of the 21st century is the combined result of
several trends, each of which is more marked in developing countries:
an increase in population size, ageing of the population and an
increase in the risks of developing cancer at a given age, particularly
as a result of a rise in the prevalence of tobacco smoking and the
adoption of a Western lifestyle (1).
Previous analyses of trends in cancer, particularly of cancer
mortality in the United States and Europe, have given rise to
diametrically opposed interpretations according to which society
is either “losing the war against cancer” (2) or, alternatively, “clearly
winning the war” (3). That distinguished scientists with access to
the same data could espouse such different views indicates the
lack of consensus over which measures should be used to evaluate
trends in cancer and over how those trends should be interpreted.
Several authors have examined trends in either incidence or mor-
tality for most major cancers within a country or region, and there
have been many reports on trends in particular cancers. Long-term
trends in incidence, survival or mortality for all the major cancers
have now been examined in France (4–6), Italy (7), Sweden (8), the
United Kingdom (9–11), the European Union (12) and the United
States (13,14), but such reports remain relatively uncommon.
Detection of favorable trends in some populations, but not in
others—particularly where those trends are likely to be due to pre-
vention, screening or treatment—should cause us to ask how far
such trends could be emulated in countries where improvements
are either absent or less marked.
The worldwide analysis of trends in cancer incidence and mor-
tality cited in previous editions has not been updated since 1993
(15), so we have chosen to rely on the incidence data available in
the compendium Cancer Incidence in Five Continents, produced
approximately every five years by the World Health Organization’s
(WHO) International Agency for Research on Cancer, Lyon. For
mortality, we have used data taken from the WHO database. For
survival, the only systematic international comparison is that
provided by the EUROCARE study. At the time of going to press,
the most recent publications covered survival for patients in 20
European countries who were diagnosed up to 1999 and followed
up to 2003 (16–18).
Incidence and Mortality Data
Cancer incidence data were selected from 15 populations in 12
countries in Europe, Asia and Oceania, and North America. We
report simple percentage changes in the age-standardized (world)
incidence rates (over the age range 30 to 74 years) between the
five-year periods centered on 1980 and 2000, reported in volumes V
(1978–1982) and IX (1998–2002), respectively, of Cancer Incidence
in Five Continents (19,20).
Cancer mortality data for the same 12 countries were taken from
the database at WHO, Geneva; for some countries, this database now
covers the 50-year period from 1952 to 2002 (21). Mortality data for
1
 general principles
Hungary were added because the trends are particularly striking, even
though no equivalent incidence data are currently available.
CANCER SURVIVAL DATA
The only source of internationally comparable data on cancer
survival in the general population currently available is the
EUROCARE project, the largest cancer survival study to date.
Data from 83 population-based cancer registries include some six
million cancer patients diagnosed between 1978 and 1999 and
followed up to 2003 in 20 European countries. These include 17 of
the 27 European Union member states, together with Iceland,
Norway, and Switzerland. EUROCARE-4 included population-
based cancer data from a total population of 150 million, some
35% of the total European population of 425 million in 1998.
Data were submitted under a common protocol, subjected to
central quality control and correction of errors, and analyzed in a
single center. The CONCORD study has now extended this
approach to cover 31 countries in all five continents (22).
The EUROCARE-4 study recently provided information on
survival for eight common cancers up to five years after diagnosis
for 2.7 million adults diagnosed during 1995–1999 and followed
up to the end of 2003 (18).
Valid international comparisons of survival cannot be made
with simple, ‘observed’ survival rates, because background mortal-
ity varies two-fold between European regions and countries (23).
Relative survival rates are used in such comparisons to take account
of the fact that, whilst cancer patients have an increased risk of
death due to their cancer (particularly in the first few years after
diagnosis), they also remain at risk of dying from other causes, as
do members of the general population who do not have cancer. A
relative survival rate is the ratio between the observed (crude) sur-
vival rate in the cancer patients being studied and the survival that
would have been expected if they had only had the same mortality
as the general population at each age and time period under study
(24). Thus, if 60% of cancer patients of a given age and sex distri-
bution were to survive five years after diagnosis in a given period,
whereas in the same period 90% of the general population of the
same age and sex at that time would have been expected to live for
a further five years, the relative survival is not 60%, but 60/90, or
67%. The relative survival can be simply interpreted as the propor-
tion of patients who survive, after correction for this background
mortality. It reflects the excess mortality among the cancer patients.
Relative survival rates in the EUROCARE study are adjusted for
the differences in background mortality between the participating
countries, and for changes in these mortality rates over time.
The age distribution of patients with a given cancer also varies
widely between countries and, since survival varies considerably with
age, relative survival rates used in international comparisons are also
age-standardized (25), using the entire population of patients with a
given cancer as the standard age distribution. This procedure is simi-
lar to using a standard population for direct age standardization when
comparing cancer incidence or mortality rates.
OBSERVED TRENDS IN INCIDENCE AND MORTALITY
Age-standardized incidence and mortality rates for several major
adult tumors are presented in Table 1.1, for the truncated age range
2
30 to 74 years. The accuracy of death certification in the elderly is
generally lower (26), and cancer trends in very elderly persons are
likely to be less relevant for assessing current priorities in preven-
tion and etiological research (27). Incidence rates are more reliable
than mortality rates at older ages, because the great majority of
cancer registrations, from which they are derived, stem from
pathological confirmation of malignancy. We nevertheless used
the age range 30 to 74 years, to facilitate direct comparison with the
mortality data. We used different age ranges for testicular cancer
(15–64 years) and Hodgkin’s disease (15–74 years).
Trends in lung cancer are generally favorable for men in most
developed countries, especially in Finland and the United Kingdom,
where incidence and mortality have been remarkably high in the
past. The trends for lung cancer among women give rise to con-
cern, and in many countries lung cancer incidence in women is
increasing rapidly. Since lung cancer is particularly lethal, mortality
is rising in close parallel to the trends in incidence (Fig. 1.1).
Cancers of the mouth and upper digestive tract are also increas-
ing in many parts of Europe. In eastern Europe, substantial increases
in both incidence and mortality are occurring for a wide range of
cancers, particularly those linked to tobacco and alcohol.
The remarkable and well-known long-term decline in the inci-
dence and mortality of stomach cancer appears to be worldwide
(28). It is often greater for women than for men. The causes of this
welcome progress and of the difference between the sexes are only
poorly understood.
Malignant melanoma of the skin is increasing rapidly in many
populations, particularly those of Caucasian stock (15).
Colorectal cancer mortality is generally decreasing in northern
and western Europe and in North America, especially in females,
despite the fact that incidence is slightly increasing. Digital exami-
nation and sigmoidoscopy are widely used for early diagnosis in
Germany and the United States, respectively. It is possible that
these practices have had some impact. In the absence of organized
screening programs before 2000, this pattern is consistent with
better management due to earlier diagnosis and/or better treat-
ment. Mass screening with fecal occult blood testing and endos-
copy is now being introduced in Finland, France and the United
Kingdom. This should eventually lead to a decline in the incidence
of invasive colorectal malignancy as a result of the removal of pre-
invasive malignancy in colorectal polyps. Some reduction in inci-
dence among U.S. whites has already occurred (Table 1.1).
More widespread application of screening for cancers of uterine
cervix and breast would be expected to yield substantial benefits.
This has already been seen for cervical cancer in many countries.
The incidence of leukemia and of cancers of the prostate and
testis is also increasing in a number of populations, although
mortality from prostatic and testicular cancers is either declining,
or else not increasing as fast as incidence. The discrepancies are
likely to be due to a change in the nature of recorded disease for
prostate cancer and to improvements in treatment and survival
for testicular cancer. The widespread decline in mortality from
testicular cancer is due to earlier diagnosis and better treatment
after the introduction of cis-platinum chemotherapy in the late
1970s. Survival at five years now often exceeds 90%.
In many countries, the increase in the incidence of prostate cancer
is such that it comprises a large component of the overall increase
in the incidence of all cancers combined among men.
 trends in cancer incidence, survival and mortality

Table 1.1 Trends in Cancer Incidence and Mortality, Selected Common Adult Malignancies and Selected Populations, by Sex and
Calendar Period: Cancers Amenable to Primary Prevention, Screening and Treatment
New cases Deathsa
Males Females Males Females
1980 2000 Change (%) 1980 2000 Change (%) 1980 2000 Change (%) 1980 2000 Change (%)
Selected cancers amenable to primary prevention
Lung
Denmark 115.1 88.0 −23.5 36.1 65.8 82.1 104.4 80.6 −22.8 31.1 57.1 83.8
Finland 145.3 66.0 −54.6 13.7 18.2 33.0 123.9 58.5 −52.8 10.8 14.4 33.3
France, Bas-Rhin 127.1 118.3 −6.9 8.6 23.1 167.7
84.2 90.5 7.5 7.2 15.2 111.3
France, Isère 105.7 98.6 −6.7 9.3 17.8 90.6
Hungary 115.8 166.2 43.6 19.2 43.4 126.1
Italy, Varese 171.6 115.2 −32.9 11.9 21.1 77.9 109.5 87.2 −20.4 11.6 15.5 34.4
Netherlands,
Eindhoven 184.6 113.0 −38.8 11.8 40.8 244.6 145.9 90.2 −38.2 11.8 34.9 194.7
Slovenia 122.1 117.7 −3.6 13.5 27.6 103.8 118.1 103.9 −12.1 14.7 21.9 48.8
U.K., Scotland 178.2 110.5 −38.0 55.6 67.1 20.6
U.K., West 132.1 68.3 −48.3 36.6 37.3 1.9
Midlands 138.4 79.1 −42.9 31.5 38.2 21.2
Japan, Miyagi 56.3 68.5 21.8 17.0 22.5 32.6
43.1 47.3 9.9 12.6 13.5 6.5
Japan, Osaka 64.6 69.7 7.9 18.9 23.6 24.6
Singapore 148.4 88.3 −40.5 44.2 28.2 −36.2 107.4 69.0 −35.7 32.2 23.1 −28.2
Australia, New
South Wales 104.4 69.2 −33.7 24.0 33.7 40.2 91.1 56.2 −38.3 20.1 25.8 28.5
U.S.A.: blacks 211.4 151.9 −28.1 57.4 78.8 37.3
111.4 86.4 −22.5 36.3 50.3 38.5
U.S.A.: whites 128.7 94.7 −26.4 53.4 69.8 30.8
Lip, mouth, and pharynx (C00-14)
Denmark 18.2 24.2 33.3 6.0 9.3 54.5 5.7 9.7 69.6 2.4 3.0 25.3
Finland 16.5 13.9 −16.0 4.9 5.5 13.4 4.2 4.6 9.6 2.0 1.4 −29.9
France, Bas-Rhin 113.6 65.8 −42.1 7.6 11.1 46.2
33.7 20.6 −38.9 2.3 2.6 13.4
France, Isère 67.9 43.9 −35.3 6.7 7.1 5.8
Hungary 15.8 47.4 201.1 1.9 6.7 251.6
Italy, Varese 39.8 28.2 −29.1 4.2 6.3 49.3 12.4 9.3 −24.8 1.6 1.8 15.3
Netherlands,
Eindhoven 11.7 17.6 49.9 3.4 7.7 123.8 3.6 6.0 68.1 1.3 2.4 86.6
Slovenia 46.5 42.0 −9.8 3.9 6.9 78.8 26.3 21.7 −17.5 1.8 1.9 5.6
U.K., Scotland 15.1 24.0 59.3 6.7 9.5 42.0
U.K., West 5.0 5.5 11.3 2.3 2.1 −11.1
Midlands 10.2 13.4 31.6 4.3 6.6 54.6
Japan, Miyagi 8.8 12.9 46.9 3.0 4.1 37.1
3.7 6.1 63.0 1.2 1.4 19.3
Japan, Osaka 10.2 12.9 26.7 3.5 3.7 6.0
Singapore 52.6 40.9 −22.3 21.8 13.1 −40.0 30.0 19.1 −36.3 10.7 4.7 −56.2
Australia, New
South Wales 27.6 26.9 −2.4 8.4 9.8 16.8 8.7 7.0 −19.6 2.4 1.9 −22.1
U.S.A.: blacks 46.5 30.6 −34.3 15.4 9.1 −41.0
9.1 5.6 −38.3 3.0 1.8 −42.1
U.S.A.: whites 29.5 22.4 −23.9 11.5 8.4 −26.6
Selected cancers amenable to screening
Breast
Denmark 136.7 180.9 32.3 50.6 51.1 1.0
Finland 95.1 176.2 85.3 30.8 31.9 3.6
France, Bas-Rhin 128.2 206.9 61.4
37.9 37.8 −0.3
France, Isère 138.8 198.1 42.7
Hungary 41.1 43.5 5.7
Italy, Varese 133.5 197.4 47.8 39.3 35.1 −10.8
Netherlands,
Eindhoven 142.4 196.3 37.9 52.0 46.0 −11.6
Slovenia 84.4 126.9 50.4 43.4 39.3 −9.5
U.K., Scotland 127.6 170.9 33.9
U.K., West 57.8 42.3 −26.9
Midlands 129.2 173.9 34.6
Japan, Miyagi 49.8 95.5 92.0
11.9 17.9 51.1
Japan, Osaka 43.4 71.4 64.4
Singapore 59.6 125.8 111.1 28.3 28.9 2.2

(Continued)

3
 general principles

Table 1.1 Trends in Cancer Incidence and Mortality, Selected Common Adult Malignancies and Selected Populations, by Sex and
Calendar Period: Cancers Amenable to Primary Prevention, Screening and Treatment (Continued)
New cases Deathsa
Males Females Males Females
1980 2000 Change (%) 1980 2000 Change (%) 1980 2000 Change (%) 1980 2000 Change (%)
Australia, New
South Wales 113.4 181.9 60.3 39.1 33.2 −15.1
U.S.A.: blacks 131.7 173.6 31.8
45.5 34.4 −24.4
U.S.A.: whites 156.1 208.5 33.5
Cervix
Denmark 39.3 21.3 −45.8 16.4 7.2 55.9
Finland 11.5 8.0 −30.4 5.4 2.4 −55.0
France, Bas-Rhin 33.1 17.9 −45.9
4.7 3.1 −33.5
France, Isère 31.8 12.9 −59.4
Hungary 15.7 12.2 −21.9
Italy, Varese 20.8 11.1 −46.7 2.2 1.5 −34.2
Netherlands,
Eindhoven 13.6 10.4 −23.6 7.1 3.3 −53.3
Slovenia 27.2 31.0 14.1 8.3 6.7 −19.0
U.K., Scotland 24.0 17.1 −28.8
U.K., West 10.9 4.7 −56.5
Midlands 27.1 15.5 −42.7
Japan, Miyagi 19.9 12.9 −35.1 4.8 4.0 −16.3
Japan, Osaka 37.2 11.7 −68.6
Singapore 38.0 24.9 −34.4 18.4 9.1 −50.4
Australia, New
South Wales 22.5 12.3 −45.3 7.5 3.3 −56.4
U.S.A.: blacks 35.1 17.4 −50.4
6.7 4.3 −35.9
U.S.A.: whites 16.4 12.2 −25.4
Colorectum
Denmark 65.0 69.1 6.3 55.0 53.9 −2.1 37.0 34.1 −7.8 28.9 26.2 −9.4
Finland 35.7 44.2 23.8 29.6 33.7 13.7 17.6 18.1 3.3 13.9 12.2 −11.8
France, Bas-Rhin 74.9 87.1 16.4 45.1 47.3 4.9
29.5 25.1 −15.1 18.0 14.3 −20.6
France, Isère 66.2 72.3 9.3 46.2 44.2 −4.3
Hungary 39.3 56.9 44.9 28.0 29.4 4.9
Italy, Varese 66.9 79.0 18.1 49.7 52.2 5.0 24.7 24.7 0.2 17.3 15.2 −12.0
Netherlands,
Eindhoven 61.8 80.6 30.5 52.1 60.6 16.4 28.7 27.4 −4.6 23.0 18.6 −19.4
Slovenia 44.1 83.7 89.7 32.2 44.6 38.5 33.6 39.2 16.6 20.1 18.7 −7.2
U.K., Scotland 59.7 78.5 31.6 48.3 50.0 3.6
U.K., West 33.5 26.5 −21.0 25.0 15.8 −37.0
Midlands 58.4 68.8 17.8 42.1 43.6 3.5
Japan, Miyagi 41.1 112.9 174.4 34.8 62.1 78.4
21.0 28.1 34.0 15.1 15.7 3.8
Japan, Osaka 41.5 69.6 67.7 27.2 40.4 48.7
Singapore 61.4 82.2 33.8 52.3 55.8 6.7 29.7 30.4 2.2 27.7 22.1 −20.2
Australia, New
South Wales 72.8 88.9 22.2 54.4 63.1 16.0 36.0 29.8 −17.5 26.7 19.3 −27.6
U.S.A.: blacks 75.6 84.4 11.7 64.3 67.4 4.8
30.5 23.4 −23.3 22.4 15.7 −30.0
U.S.A.: whites 77.2 69.5 −9.9 59.4 50.1 −15.7
Selected cancers amenable to treatment
Hodgkin’s disease
Denmark 3.5 3.1 −11.7 2.3 2.3 −1.3 1.4 0.4 −69.9 0.6 0.4 −40.6
Finland 3.8 3.7 −2.4 2.3 3.2 37.9 1.9 0.4 −78.4 1.0 0.3 −67.3
France, Bas-Rhin 3.4 2.9 −14.5 2.9 2.2 −22.8 1.3 0.5 −62.7 0.7 0.3 −60.6
France, Isère 4.9 3.4 −30.9 3.5 2.8 −19.8
Hungary 1.3 0.9 0.8 0.7
Italy, Varese 5.8 4.2 −27.2 3.9 3.7 −3.9 2.3 0.6 −73.8 1.3 0.4 −70.2
Netherlands,
Eindhoven 2.9 3.2 11.9 2.6 2.7 4.2 1.5 0.5 −66.2 0.7 0.3 −59.7
Slovenia 2.6 2.3 −12.2 1.9 2.8 45.8 1.4 0.6 −56.3 0.7 0.4 −50.0
U.K., Scotland 4.0 3.2 −20.2 2.6 2.8 6.9
U.K., West 1.6 0.5 −68.1 0.9 0.3 −62.5
Midlands 4.2 3.3 −20.7 2.5 2.3 −8.4

(Continued)

4
 trends in cancer incidence, survival and mortality

Table 1.1 Trends in Cancer Incidence and Mortality, Selected Common Adult Malignancies and Selected Populations, by Sex and
Calendar Period: Cancers Amenable to Primary Prevention, Screening and Treatment (Continued)
New cases Deathsa
Males Females Males Females
1980 2000 Change (%) 1980 2000 Change (%) 1980 2000 Change (%) 1980 2000 Change (%)
Japan, Miyagi 0.6 0.7 25.0 0.4 0.5 35.1
0.4 0.1 −76.9 0.2 0.0 −77.8
Japan, Osaka 0.8 0.4 −48.1 0.4 0.2 −50.0
Singapore 1.2 1.1 −5.2 0.5 0.6 22.4 0.5 0.4 −20.8 0.3 0.1 −72.7
Australia, New
South Wales 2.9 3.1 5.8 2.1 2.7 27.4 1.1 0.3 −72.1 0.6 0.2 −64.5
U.S.A.: blacks 3.3 3.5 7.7 1.6 2.7 65.6
1.3 0.6 −56.0 0.8 0.4 −52.6
U.S.A.: whites 4.4 4.0 −9.1 3.2 3.5 9.0
Testis
Denmark 12.1 14.5 19.6 0.6 0.7 4.7
Finland 2.2 5.6 158.1 1.0 0.3 −67.3
France, Bas-Rhin 6.9 10.3 49.5
0.7 0.3 −60.6
France, Isère 4.4 7.7 74.6
Hungary 0.8 0.7
Italy, Varese 5.9 10.9 85.7 1.3 0.4 −70.2
Netherlands,
Eindhoven 4.2 8.8 108.5 0.7 0.3 −59.7
Slovenia 4.0 11.8 192.8 0.7 0.4 −49.3
U.K., Scotland 6.8 11.9 76.0
U.K., West 0.9 0.3 −62.5
Midlands 4.9 8.9 81.6
Japan, Miyagi 1.5 3.8 156.8
0.2 0.0 −77.8
Japan, Osaka 1.7 1.6 −8.0
Singapore 1.2 1.2 0.8 0.3 0.1 −84.8
Australia, New
South Wales 5.3 9.0 70.5 0.6 0.2 −64.5
U.S.A.: blacks 1.4 2.2 61.8
U.S.A.: whites 6.6 9.5 43.9 0.8 0.4 −52.6
a
Mortality data are all national. For Slovenia, mortality data and % change cover the period 1987–2000 only; for Denmark, the last data year is 1999; Singapore data
for Hodgkin’s disease are for 2001 and for testis 1999. For the USA, mortality data are for all races combined. Irregular data are italicized. Data for testicular cancer
are for the age range 15–64 years. Data for Hodgkin’s disease are for the age range 15–74 years.

U.S.A., SEER: whites

U.S.A., SEER: blacks
Australia, New South Wales Mortality, females
Singapore: Chinese Mortality, males
Japan, Osaka Incidence, females
Incidence, males
Japan, Miyagi
U.K., West Midlands
U.K., Scotland
Slovenia
Netherlands, Eindhoven
Italy, Varese
Hungary
France, Isère
France, Bas-Rhin
Finland
Denmark
–100 –50 0 50 100 150 200 250
Lung cancer: percentage change in age-standardized rates (30–74 years), 1980–2000
Figure 1.1 Trends in lung cancer, 1980–2000: percentage change in the truncated (30–74 years) age-standardized (world) annual incidence and mortality rates per
100,000: selected regions and countries, by sex. Source : From Refs. 19–21.

5
 general principles

Substantial therapeutic progress has occurred in many countries
for Hodgkin’s disease, cancer of the testis and leukemia in childhood,
although the improvement occurred later in some countries than
others, and in other countries has not yet been observed at all.
The wide geographical variation in the trends for different cancers
gives some ground for optimism. That is because it suggests that
the increases in cancer incidence and mortality that have been
seen in some countries are potentially avoidable.
Trends in the incidence and mortality rates for all cancers com-
bined inevitably represent a weighted average of the sometimes
widely disparate trends for individual cancers, but they are still
broadly instructive. One of the most striking observations is
the divergence between the trends for incidence and mortality,
especially in western Europe (Fig. 1.2).
Key Points: Trends in Incidence and Mortality
■ Trends in lung cancer in men are generally favorable
■ Lung cancer incidence in women is rising rapidly, as is
mortality
■ In eastern Europe, increases in incidence and mortality are
occurring, especially in those cancers linked to tobacco and
alcohol
■ Malignant melanoma is increasing in many populations,
particularly Caucasians
■ Colorectal cancer mortality is decreasing in western Europe
and North America
■ The increase in incidence of prostate cancer represents a
large component of the overall increase in incidence of all
cancers combined in men
INTERNATIONAL DIFFERENCES AND TRENDS
IN CANCER SURVIVAL
The patterns of cancer survival in Europe revealed by the EURO-
CARE study are striking (Figs. 1.3 and 1.4). There is substantial
international variation, especially for cancers where stage at diagnosis
is particularly important. The ranking of countries is not constant,
which suggests that the observed variation is not simply an artifact
of data collection procedures or analysis. For example, although
survival in the United Kingdom is generally lower than the Euro-
pean average for the main epithelial neoplasms, this is much less
marked for Hodgkin’s disease or testicular cancer. For these two
malignancies, there have been major advances in treatment since
the 1970s, and there is much less variation in survival between
European countries. For melanoma of the skin, survival in Scotland
is well above the European average, which may reflect the success of
efforts to ensure earlier diagnosis (29).
Survival for patients diagnosed during 1990–1994 was higher in
women than in men for 30 of the 35 cancers examined that occur
in both sexes (Table 1.2). The survival rates compensate for back-
ground mortality in men and women separately, and they are
standardized to the combined age distribution for men and
women with each cancer, to remove any effect of sex differences in
the age distribution of cancer patients. Differences in survival
between men and women are thus more likely to arise from sex
differences in tumor biology, host defense mechanisms, awareness
of symptoms, stage of disease at diagnosis or access to effective
treatment.
The female survival advantage for individual cancers may be
due to a more favorable sub-site distribution, more favorable

U.S.A., SEER: whites

U.S.A., SEER: blacks
Australia, New South Wales
Singapore: Chinese
Japan, Osaka
Japan, Miyagi
U.K., West Midlands
U.K., Scotland
Slovenia
Netherlands, Eindhoven
Italy, Varese
Mortality, females
Hungary
Mortality, males
France, Isère Incidence, females
Incidence, males
France, Bas-Rhin
Finland
Denmark
–40 –30 –20 –10 0 10 20 30 40
All cancers combined: percentage change in age-standardized rates (30–74 years), 1980–2000
Figure 1.2 Trends in all cancers combined, 1980–2000: percentage change in the truncated (30–74 years) age-standardized (world) incidence and mortality rates per
100,000: selected regions and countries, by sex. Source : From Refs. 19–21.

6
 trends in cancer incidence, survival and mortality

0 20 40 60 80 100 0 20 40 60 80 100
Italy Switzerland
Austria Norway
Belgium Sweden
Germany Belgium
Portugal France
Spain Austria
Finland Malta
Switzerland Germany
France Netherlands
Finland
Iceland
Iceland
Sweden
Italy
Slovenia
Spain
Norway Scotland
Malta England
N Ireland Portugal
Netherlands Wales
Poland N Ireland
Ireland Ireland
England Denmark
Wales Poland
Scotland Slovenia
Denmark Czech Rep.
Europe Stomach (M) Europe Rectum (M)

0 20 40 60 80 100 0 20 40 60 80 100
Iceland Finland
Switzerland Austria
Italy Italy
Finland Switzerland
Austria France
Sweden Norway
Germany Sweden
France Belgium
Netherlands Germany
Norway Netherlands
Belgium Spain
Spain Ireland
N Ireland N Ireland
Portugal Scotland
Wales Portugal
Ireland Malta
Scotland Iceland
England England
Denmark Denmark
Malta Wales
Czech Rep. Czech Rep.
Slovenia Slovenia
Poland Poland
Europe Colon (M) Europe Colon (F)

0 20 40 60 80 100 0 20 40 60 80 100
Belgium Iceland
Iceland Sweden
Switzerland Finland
Austria France
Netherlands Italy
Germany Norway
France Switzerland
Italy Netherlands
Poland Spain
Portugal Austria
Sweden Germany
Spain Denmark
Norway Belgium
N Ireland N Ireland
Ireland England
Slovenia Portugal
Finland Wales
Wales Malta
Breast (F)

Malta Scotland
England Ireland
Denmark Poland
Scotland Slovenia
Czech Rep. Czech Rep.
Europe Lung (M)
Europe

Figure 1.3 Five-year survival (%) in Europe, adults (15–99 years) diagnosed 1995–1999 and followed up till 2003: cancers of the stomach (M), rectum (M), colon (M, F),
lung (M), and breast (F), by country and sex, age-standardized relative survival (%) with 95% confidence interval (tramlines) and weighted European average (vertical bar).
Source: From Ref. 44 and updated with data from Ref. 18.

7
 general principles

0 20 40 60 80 100 0 20 40 60 80 100
Sweden Iceland
N Ireland N Ireland
Switzerland Sweden
Scotland Switzerland
Malta Netherlands
Netherlands Norway
France Scotland
Norway Ireland
Finland Denmark
Germany England
Italy Spain
Denmark Italy
England France
Spain Finland
Austria Austria
Slovenia Portugal

Melanoma (M)

Melanoma (F)
Ireland Germany
Iceland Czech Rep.
Belgium Belgium
Portugal Slovenia
Wales Wales
Czech Rep. Malta
Poland Poland
Europe Europe

0 20 40 60 80 100 0 20 40 60 80 100
Malta Austria
Switzerland Belgium
France Portugal
Norway Switzerland
Netherlands Germany
Sweden Finland
Belgium Iceland
Finland Italy
Italy Netherlands
Denmark France
Austria Sweden
Czech Rep. Spain
Slovenia Norway
Iceland Ireland
Spain Malta
Germany England
Ireland Wales
England Scotland
N Ireland Poland

Prostate
Scotland N Ireland
Portugal Slovenia
Poland Czech Rep.
Wales Denmark
Europe Cervix Europe

0 20 40 60 80 100
Malta
Netherlands
Nordic countries
Spain South and West Europe
Norway U.K. (England, Scotland, Wales, N. Ireland) and Ireland
Belgium Eastern Europe
France Data covering less than 100% of country (see text)
Scotland
Switzerland Stomach, males - Czech Rep. not included
Testis - Wales, Portugal, N. Ireland, Iceland, Germany not included
Sweden
Denmark
England
Poland
Italy
Austria
Finland
Ireland
Testis

Slovenia
Czech Rep.
Europe

Figure 1.4 Five-year survival (%) in Europe, adults (15–99 years) diagnosed 1995–1999 and followed up till 2003: melanoma of the skin (M, F), cancers of the cervix,
prostate, and testis, by country and sex, age-standardized relative survival (%) with 95% confidence interval (tramlines) and weighted European average (vertical bar).
Source: From Ref. 44 and updated with data from Ref. 18.

8
 trends in cancer incidence, survival and mortality

Table 1.2 Five-Year Cancer Survival (%) in Europe, Adults (15–99 years) Diagnosed 1990–1994 and Followed up Till 1999 (EUROCARE-3)
and Those Diagnosed 1995–1999 and Followed up to 2003 (EUROCARE-4): Ranked on EUROCARE-3 Values, Age-Standardized Relative
Survival (%), by Sex
Five-year Men Women
survival (%)
Rank Site Survival (%) Survival (%) Rank Site Survival (%) Survival (%)
1990–1994 1995–1999 1990–1994 1995–1999
Good (50% or more) 1 Lip 92.5 94.4 1 Lip 90.3 94.1a
2 Testis 91.4 90.2 2 Melanoma of skin 84.3 86.7
3 Hodgkin’s disease 75.2 82.5a 3 Thyroid 81.4 84.9
4 Thyroid 71.8 77.4 4 Hodgkin’s disease 81.5 81.8
5 Melanoma of skin 74.8 77.1 5 Breast 76.1 79.3
6 Prostate 65.4 76.5 6 Uterus 76.0 76.4
7 Penis 68.9 74.6a 7 Chronic lymphoid 66.4 73.2
leukemia
8 Bladder 69.5 73.1 8 Bladder 67.1 71.6
9 Chronic lymphoid 62.2 66.7 9 Salivary gland 68.7 70.6
leukemia
10 Larynx 60.7 63.5 10 Larynx 59.4 63.5
11 Soft tissue 54.2 59.3 11 Cervix 62.1 62.8
12 Kidney 54.2 57.6 12 Bone 56.3 62.0
13 Colon 49.2 54.0 13 Soft tissue 54.2 60.1
14 Rectum 45.1 52.5 14 Vulva and vagina 52.2 59.8
15 Bone 53.0 51.2 15 Kidney 57.2 59.5
16 Salivary gland 51.0 50.6 16 Colon 51.0 55.5
17 Rectum 49.6 55.2
18 Non-Hodgkin 53.7 54.3
lymphoma
19 Tongue 52.2 53.8
20 Oral cavity 56.9 52.3
21 Nasopharynx 49.3 51.3a
Moderate (10–49%) 17 Nasopharynx 39.9 49.9a 22 Nasal cavities 48.0 47.7a
18 Non-Hodgkin 47.7 49.4 23 Oropharynx 43.5 47.5
lymphoma
19 Nasal cavities 43.8 46.2 24 Small intestine 39.2 41.6
20 Oral cavity 40.6 44.9 25 Chronic myeloid 36.9 37.8
leukemia
21 Small intestine 37.6 42.1 26 Ovary 36.7 36.8
22 Tongue 34.9 39.1 27 Multiple myeloma 33.0 36.7
23 Acute lymphoid 24.2 30.6a 28 Hypopharynx 32.3 31.6a
leukemia
24 Multiple myeloma 28.5 35.0 29 Acute lymphoid 21.6 28.0a
leukemia
25 Chronic myeloid 30.5 34.5 30 Stomach 25.4 27.5
leukemia
26 Oropharynx 28.7 34.0 31 Brain 18.5 22.1
27 Hypopharynx 23.2 25.2a 32 Acute myeloid 13.4 18.4a
leukemia
28 Stomach 20.0 23.1 33 Esophagus 10.5 14.2
29 Brain 16.4 18.7 34 Lung 9.6 14.2
30 Biliary tract 12.3 16.9 35 Biliary tract 11.6 13.4
31 Acute myeloid 12.7 14.5
leukemia
32 Esophagus 8.5 11.8a
33 Lung 9.7 11.7
Poor (less than 10%) 34 Liver 6.2 9.0 36 Pleura 5.5 9.8a
35 Pleura 4.8 6.6 34 Liver 6.7 8.3a
36 Pancreas 3.8 5.3a 38 Pancreas 4.6 6.5
a
Not age-standardized.

histology (e.g., women have more adenocarcinoma and less
squamous carcinoma of the lung) or a more favorable stage distri-
bution at diagnosis (e.g., for melanoma of the skin and bladder
cancer). It is not yet possible to show which of these explanations
applies, since there have been few international comparisons of
cancer survival by sex, clinical stage, histological type, or anatom-
ical subsite. Special studies within the EUROCARE project are
addressing these questions.
Survival for all cancers combined is substantially better for women
than for men. This is partly because of the survival advantage women

9
 general principles

have for most individual cancers, but also because women have a by a fall in mortality among women aged 20 to 69 years up to
much more favorable distribution of cancer types. Thus while about 1997 (30); better treatment and mammographic screening
half of all cancers in men occur at sites for which prognosis is extremely probably both contributed. Survival improved less quickly in
poor—less than 10% five-year survival—a similar proportion of the eastern European countries in the early 1990s (31) and the gap
cancers in women occur at sites where the prognosis is relatively good, between eastern and western European countries increased,
with a five-year survival of 50% or higher (Table 1.2). but for patients diagnosed during the late 1990s, the gap had
Improvements in breast cancer survival were more marked begun to narrow (18).
in western Europe during the 1990s, and the range of survival Survival from cervical cancer increased in most European countries
rates between the Nordic countries and western Europe has except in eastern Europe, where it remained low (Fig. 1.5). Eastern
been greatly reduced (Fig. 1.5). Survival also improved more European countries do not have organized cervical screening
rapidly in the United Kingdom, and the survival deficit relative programs, but the survival trends also suggest that effective treatment
to other western European countries declined. This is echoed is not sufficiently widely available.

Northern Europe Western Europe Eastern Europe

100 100

Breast (F)
90 90

80 80
Five-year relative survival (%)

70 70

60 60

50 Denmark England France 50

Finland Germany Italy
Iceland Netherlands Scotland
40 Spain Switzerland Estonia Poland 40
Norway
Wales Slovakia Slovenia
Sweden
0 0
1983–85 1986–88 1989–91 1992–94 1995–99 1983–85 1986–88 1989–91 1992–94 1995–99 1983–85 1986–88 1989–91 1992–94 1995–99

100 100

Cervix
90 90

80 80
Five-year relative survival (%)

70 70

60 60

50 50
Denmark England France
Finland Germany Italy Estonia
Netherlands Scotland
40 Iceland Poland 40
Spain Switzerland
Norway Wales Slovakia
Sweden Slovenia
0 0
1983–85 1986–88 1989–91 1992–94 1995–99 1983–85 1986–88 1989–91 1992–94 1995–99 1983–85 1986–88 1989–91 1992–94 1995–99
Calendar period of diagnosis

Figure 1.5 Trends in age-standardized five-year relative survival (%), by country, Europe, selected cancers, patients diagnosed during 1983–1999 and followed up to 2003:
cancers of the breast (F) and cervix. Source: From Ref. 44 and updated with data from Ref. 18.

10
 trends in cancer incidence, survival and mortality

Northern Europe Western Europe Eastern Europe

80
Colorectal (M)
70 70

60 60
Five-year relative survival (%)

50 50

40 40

30 30

20 20
Denmark England France
Finland Germany Italy
10 Iceland Netherlands Scotland 10
Norway Spain Switzerland Estonia Poland
Sweden Wales Slovakia Slovenia
0 0
1983–85 1986–88 1989–91 1992–94 1995–99 1983–85 1986–88 1989–91 1992–94 1995–99 1983–85 1986–88 1989–91 1992–94 1995–99

100 100
Prostate
90 90

80 80
Five-year relative survival (%)

70 70

60 60

50 50

40 40

30 30

Denmark England France

20 20
Finland Germany Italy Estonia
Iceland Netherlands Scotland Poland
10 Norway Spain Switzerland Slovakia 10
Sweden Wales Slovenia
0 0
1983–85 1986–88 1989–91 1992–94 1995–99 1983–85 1986–88 1989–91 1992–94 1995–99 1983–85 1986–88 1989–91 1992–94 1995–99
Calendar period of diagnosis

Figure 1.6 Trends in age-standardized five-year relative survival (%), by country, Europe, selected cancers, patients diagnosed during 1983–1999 and followed up to 2003:
cancers of the large bowel (M) and prostate. Source : From Ref. 44 and updated with data from Ref. 18.

Colorectal cancer survival rose more in western Europe than else- Rapidly increasing use of prostate-specific antigen (PSA) blood
where, particularly in the Netherlands, Italy, and England (Fig. 1.6). tests in some European countries since the 1990s has led to the diag-
These trends may reflect more widespread use of endoscopy for nosis and treatment of many asymptomatic prostatic cancers that
earlier diagnosis, but improved surgical techniques (32) and lower might never have been diagnosed in life. In Denmark, for example,
post-operative mortality (33) probably also contributed. the 50-year increase in prostate cancer incidence is considered real
Prostate cancer survival has increased in most countries, (34), but the Danish Society for Urology evaluated the evidence in
but international differences have widened (Fig. 1.6). Survival 1990 and decided not to advocate PSA testing in asymptomatic
increased rapidly in four of the Nordic countries, but remained men, because the therapeutic benefit was very limited; only
much lower in Denmark. Survival has increased sharply since the symptomatic patients were offered treatment. This may well have
early 1990s in France, Germany, Italy, England, Scotland, and contributed to the divergence from other Nordic countries in
Wales. Trends in eastern European countries have been very diverse, incidence and survival trends. Opportunistic PSA testing was
with a rapid increase in survival in Estonia and a decline in Poland widespread in several western European countries by the early
and Slovakia. 1990s. This has led to a rapid increase in recorded incidence and a

11
 general principles
change in the clinical spectrum of reported disease. Since most PSA-
detected asymptomatic tumors have an inherently excellent progno-
sis, population-based survival rates have also increased rapidly
where PSA testing is widely used.
The sharp trends in prostate cancer survival are not an artifact.
They accurately reflect a rapid and substantial shift in the biological
spectrum of prostate tumors now being detected and treated as a
result of new diagnostic techniques, including imaging techniques.
The trends in diagnostic activity, in conjunction with the rapid
increase in incidence rates, suggest that the international variation
in prostate cancer survival trends mainly reflects changes in the
nature of prostate cancer as it is now diagnosed and treated.
Whether these trends also represent an improvement for prostate
cancer patients is a more difficult question.
Key Points: International Differences and Trends
in Cancer Survival
■ There are wide international differences in survival, espe-
cially for cancers where stage at diagnosis is critically
important
■ Survival of women with cancer is generally higher than men
■ For individual cancers, the female survival advantage may
be due to more favorable histology or more favorable stage
distribution at diagnosis
■ About half of all cancers in men occur at sites for which the
prognosis is extremely poor
■ Prostate cancer survival has increased in most countries but
trends in eastern European countries have been very diverse,
with a decline of survival in Poland and Slovakia
DISCUSSION
Imaging of tumors has improved dramatically over recent years.
This has led to more refined detection and staging of disease, reduc-
ing the need for invasive procedures to establish a diagnosis and
allowing biopsy to be precisely guided to a suspicious lesion (35,36).
As we have seen for prostate cancer, this undoubted clinical advance
has also contributed to renewed difficulty in the interpretation of
recent trends in incidence and survival, but also mortality (37,38).
Thus the rapid increase in the incidence of prostate cancer seen
during the 1990s in many developed countries is partly due to the
impact of improved diagnostic technique (39). The use of more
sensitive and less invasive diagnostic procedures such as PSA,
transrectal ultrasound (TRUS), computed tomography (CT) and
magnetic resonance (MR) imaging has led to the diagnosis of
some tumors that are not lethal and might well not have been
clinically diagnosed at all in the past. Latent prostate cancer is fre-
quently detected in the prostate gland removed for benign hyper-
trophy or at autopsy, and evidence from Japan suggests an increase
in such biologically invasive but clinically latent disease (40). Once
diagnosed, such tumors are often treated and the men included in
population-based survival analyses. Survival would be expected to
increase as a result of the diagnosis of more latent tumors, regard-
less of whether treatment had actually improved (41,42). Such
inference is supported by long-term survival of all men diagnosed
with prostate cancer in Sweden during the period 1960–1988 (43),
12
and more widely by comparative analysis of survival trends in the
20 European countries (including Sweden, Fig. 1.6) covered by the
EUROCARE study (44). Spencer has cautioned that “imaging
techniques for the diagnosis and staging of prostate cancer are
developing faster than our knowledge of their clinical or prognostic
significance” (45).
This remark has significance beyond imaging techniques in gen-
eral and prostate cancer in particular. Future developments in diag-
nostic and staging techniques, such as tumor imaging and the use of
biomarkers, will continue to affect both the clinical characteristics of
the population of cancer patients (earlier and more benign tumors
will be detected) and the precision with which the tumor can be
staged. Such developments can be expected to vary widely between
countries and over time. This will make reliable international com-
parisons of cancer survival more complicated, but this is a problem
that cannot simply be ignored. The same issues arise within a coun-
try, both for time trends in survival and for differences between
geographic regions or other sub-groups of a national population (11).
Improvements in the accessibility of diagnostic imaging to
different sectors of the population may also lie behind an unexpected
trend in brain tumor survival seen in England and Wales during the
1990s. Average survival from brain tumors for both men and women
fell slightly but steadily during the 1990s. The fall was more marked
for affluent patients than deprived patients (46). One explanation
may be improved access to cerebral CT or MR imaging for affluent
patients. If cerebral tumors were diagnosed more often in affluent
patients who presented with rapidly fatal intracranial events during
the 1990s, when these might previously have been diagnosed (and
certified without post-mortem) as a cerebrovascular accident, the
number of affluent patients who were diagnosed with a brain tumor
and had very short survival would increase more than among the
deprived. This would reduce the survival rate for affluent brain
tumor patients more than for deprived groups. This explanation is
supported by the fact that the incidence of brain tumors rose faster
in affluent groups than in deprived groups between 1986 and 1999,
and survival in the first six months after diagnosis fell more (47).
One of the most valuable lessons from the EUROCARE study so
far is that unless clinicians insist on systematically recording not
just the tissue diagnosis and the clinical stage of disease but also the
method(s) by which tumor stage was determined, it will become
increasingly difficult to compare the results of cancer survival anal-
ysis in future. Neither the cancer populations nor their stage distri-
bution will be comparable, and we will not have the information
required to carry out the appropriate adjustments in analysis
(48,49). This applies not only to regional and international com-
parisons of survival, but also to examination of survival trends
over time within a given country or between geographic regions or
other sub-groups of a population. The differences in cancer survival
between such groups are often considerable (49).
Key Point: Accurate Comparison of Cancer
Survival Data
■ Clinicians should systematically record:
 Tissue diagnosis
 Clinical stage
 Methods of staging used (e.g., imaging techniques
should be recorded)
 trends in cancer incidence, survival and mortality
Evaluation of recent progress against cancer has been influenced
by the U.S. National Cancer Institute, after the then U.S. President
Nixon declared a “war on cancer” in the United States in 1971, and
set out to reduce cancer mortality by 50% by the year 2000. Since
1984 there has been a fierce but ultimately uninformative debate
about whether the war against cancer is being won or lost (50).
The pessimistic view has been based largely on cancer mortality
data, almost exclusively from the United States, while the optimistic
view depends on both incidence and mortality data, largely from
western and northern Europe.
The military analogy is itself an obstacle to wider comprehension
of progress against cancer. As in real wars, the debate has been polar-
ized, the protagonists have camped in fortified positions, and a great
deal of important information has been ignored. There is no single,
simple answer to the question: Are we winning the war against can-
cer? There is a substantial body of information on the worldwide
patterns of cancer incidence, survival, and mortality by age, sex, race,
or ethnic group and by country or region, as well as on how those
patterns appear to be changing with time. Assessment of progress
against cancer requires detailed evaluation of all these measures, as
well as of changes in population exposure to risk factors, the uptake
of mass screening programs, and the extent to which all cancer
patients receive treatment according to accepted protocols (51).
Further progress in the control of cancer will depend on several
factors. Primary prevention remains the key. Declines in lung can-
cer incidence in men in most developed countries are encourag-
ing, since they suggest that long-term behavioral change can
achieve long-term reductions in cancer incidence and mortality.
The rapid increases in lung cancer in eastern Europe in men and
the continuing increases in women in many countries, however,
remain a cause for serious concern.
Progress in both early diagnosis and treatment will remain a
high priority, especially for the most common lethal cancers, such
as those of lung, esophagus and pancreas, for which there has been
no substantial improvement in survival.
Continuous surveillance of cancer patterns in the general popula-
tion is an essential component of any rational strategy for cancer
control. This emphasizes the need for a stable network of popula-
tion-based cancer registries providing high-quality information
and research. The information base on which policy decisions are
made about cancer would merit greater long-term investment
(51–53). In an era of increasingly tight controls on the use of iden-
tifiable data without consent for public health purposes, the case for
a statutory requirement to collect this information is strong (54).
At the global level, progress against cancer will require a better
strategy for the reduction of tobacco use (1). This will demand a
coalition of international agencies such as those that have been
developed for the control of AIDS, tuberculosis and dracunculiasis.
Such a coalition of interests could generate a powerful movement
for the reduction of other tobacco-related disease. The admission
by one U.S tobacco manufacturer that tobacco smoking is both
addictive and carcinogenic helped to improve the climate of opin-
ion for such a development in relation to tobacco. The WHO’s
Framework Convention on Tobacco Control should be a positive
influence. The WHO’s International Agency for Research on Cancer
should also place much greater emphasis on countries developing
their own tobacco control programs, including outright bans on
tobacco promotion and bans on smoking in public places.
The outstanding priorities for the control of cancer remain the
prevention of tumors related to known carcinogens, especially to
tobacco and alcohol. Strategies to prevent the increasing number
of cancers linked to viruses should also remain a high priority,
particularly in the developing world, where some 25% of cancers
are attributable to infection (1). Primary liver cancer (hepatitis B
and C) and cancer of the cervix (human papilloma virus) are the
leading candidates, since these are the most common cancers in
many developing countries, and immunization is likely to be an
effective control measure (1).
A coordinated search for other effective strategies for primary
prevention might be especially rewarding, particularly if they could
be applied in countries with relatively limited resources (55).
Summary
■ Trends in cancer incidence and mortality provide a rational
basis for planning diagnostic and treatment services and for
assessing priorities in cancer prevention and control
■ The rising incidence of cancer worldwide results from an
increase in population size, ageing of the population and envi-
ronmental factors such as the prevalence of tobacco smoking
■ The EUROCARE-4 study provided survival data for eight
common cancers up to five years after diagnosis for 2.7 mil-
lion adults diagnosed between 1995 and 1999, and followed
up to the end of 2003
■ Relative survival is the proportion of patients who survive for
a given period after correction for background mortality
■ Incidence rates are more reliable than mortality rates at older
ages
■ In Europe, the incidence of lung cancer in women is rising.
Cancer of the mouth and upper digestive tract is also increasing
in many parts of Europe
■ The incidence of stomach cancer is decreasing worldwide
■ Malignant melanoma of the skin is increasing rapidly in
Europe
■ Although the incidence of colorectal cancer is increasing
slightly, the mortality is decreasing
■ Breast cancer and cervical cancer mortality are decreasing due
to the widespread application of screening programs in western
Europe
■ The incidence of prostate cancer is increasing while the mor-
tality is decreasing in western Europe
■ Imaging has contributed to the difficulty of interpreting
recent trends in incidence of various cancers due to more
accurate diagnosis of early disease
■ Comparison of results of cancer survival analysis will be increas-
ingly difficult in the future unless the methods by which the
tumor is staged are recorded systematically, in addition to tissue
diagnosis and the clinical stage of disease
ACKNOWLEDGMENTS
We are most grateful to the Annals of Oncology and to the EURO-
CARE investigators for permission to reproduce some of the figures
in this chapter. We are also indebted to Dr Manar Abdel-Rahman
for the preparation of Figures 1.3 to 1.6.
13
 general principles
REFERENCES
1. Stewart BW, Kleihues P, eds. World Cancer Report. Lyon: IARC
Press, 2003.
2. Bailar JC, Smith EM. Progress against cancer? N Engl J Med
1986; 314: 1226–32.
3. Doll R. Progress against cancer: are we winning the war? Acta
Oncol 1989; 28: 611–21.
4. Remontet L, Estève J, Bouvier A-M, et al. Cancer incidence and
mortality in France over the period 1978–2000. Rev Épidémiol
Santé Publ 2003; 51: 3–30.
5. Bossard N, Velten M, Remontet L, et al. Survival of cancer
patients in France: a population-based study from the Associ-
ation of French Cancer Registries (FRANCIM). Eur J Cancer
2007; 43: 149–60.
6. Grosclaude PC, Bossard N, Remontet L, et al, eds. Survie des
patients atteints de cancer en France: étude des registres du
réseau FRANCIM [French Cancer Registry Network]. Lyon:
Springer, 2007.
7. Sant M, Gatta G, Valente F, et al. The ITACARE Study. Tumori
1997; 83: 17–24.
8. Pontén J, Adami H-O, Sparén P. Trends in cancer survival and
mortality rates. Med Oncol Tumor Pharmacother 1991; 8:
147–53.
9. Quinn MJ, Babb P, Brock A, Kirby L, Jones J. Cancer Trends
in England and Wales 1950–1999. Studies on Medical and
Population Subjects No. 66. London: Office for National
Statistics, 2001.
10. Coleman MP, Babb P, Damiecki P, et al. Cancer Survival Trends
in England and Wales 1971–1995: Deprivation and NHS
Region. Studies on Medical and Population Subjects No. 61.
London: The Stationery Office, 1999.
11. Coleman MP, Rachet B, Woods LM, et al. Trends and socio-
economic inequalities in cancer survival in England and Wales
up to 2001. Br J Cancer 2004; 90: 1367–73.
12. Bray F. The burden of cancer in Europe. In: Coleman MP,
Alexe DM, Albreht T, McKee CM, eds. Responding to the
Challenge of Cancer in Europe. Ljubljana: Institute of Public
Health of the Republic of Slovenia, 2008: 7–40.
13. Devesa SS, Silverman DT, Young JL, et al. Cancer incidence
and mortality trends among whites in the United States,
1947–84. J Natl Cancer Inst 1987; 79: 701–70.
14. Devesa SA, Blot WJ, Stone BJ, et al. Recent cancer trends in the
United States. J Natl Cancer Inst 1995; 87: 175–82.
15. Coleman MP, Estève J, Damiecki P, Arslan A, Renard H. Trends
in Cancer Incidence and Mortality. IARC Scientific Publications
No. 121. Lyon: International Agency for Research on Cancer,
1993.
16. Berrino F, Sant M, Verdecchia A, eds. Survival of Cancer
Patients in Europe: The EUROCARE Study. IARC Scientific
Publications No. 132. Lyon: International Agency for Research
on Cancer, 1995.
17. Berrino F, Capocaccia R, Estève J, et al, eds. Survival of Cancer
Patients in Europe: The EUROCARE-2 Study. IARC Scientific
Publications No. 151. Lyon: International Agency for Research
on Cancer, 1999.
18. Berrino F, De Angelis R, Sant M, et al. and the EUROCARE
Working Group. Survival for eight major cancers and all cancers
14
combined for European adults diagnosed in 1995–99: results of
the EUROCARE-4 study. Lancet Oncol 2007; 8: 773–83.
19. Muir CS, Waterhouse JA, Mack T, Powell J, Whelan SL, eds.
Cancer Incidence in Five Continents, Vol. V. IARC Scientific
Publications No. 88. Lyon: International Agency for Research
on Cancer, 1987.
20. Curado MP, Edwards BK, Shin HR, et al, eds. Cancer Incidence
in Five Continents, Vol. IX. IARC Scientific Publications No.
160. Lyon: IARC, 2007.
21. World Health Organization. WHO Statistical Information
System (WHOSIS), WHO Mortality Database. 20 April 2008.
[Available from: http://www.who.int/healthinfo/morttables/
en/index.html]
22. Coleman MP, Quaresma M, Berrino F, et al. and the CONCORD
Working Group. Cancer survival in five continents: a worldwide
population-based study (CONCORD). Lancet Oncol 2008; 9:
730–56.
23. Micheli A, Baili P, Mugno E, et al. and the EUROCARE Working
Group. Life expectancy and cancer survival in the EUROCARE-3
cancer registry areas. Ann Oncol 2003; 14 (Suppl 5): 28–40.
24. Ederer F, Axtell LM, Cutler SJ. The relative survival: a statistical
methodology. Natl Cancer Inst Monogr 1961; 6: 101–21.
25. Estève J, Benhamou E, Raymond L. Statistical Methods in
Cancer Research, Vol. IV. Descriptive Epidemiology. IARC
Scientific Publications No. 128. Lyon: International Agency for
Research on Cancer, 1994.
26. Laurenti R, Coleman MP, Aylin P. Accuracy of statements of
the cause of death on death certificates and the international
comparability of mortality statistics. In: Coleman MP, Aylin P,
eds. Death Certification and Mortality Statistics: An Interna-
tional Perspective. London: Office for National Statistics,
2000.
27. Doll R. Are we winning the war against cancer? A review in
memory of Keith Durrant. Clin Oncol 1992; 4: 257–66.
28. Howson CP, Hiyama T, Wynder EL. The decline in gastric
cancer: epidemiology of an unplanned triumph. Epidemiol
Rev 1986; 8: 1–27.
29. MacKie R, Hole DJ. Audit of public education campaign to
encourage earlier detection of malignant melanoma. Br Med J
2003; 304: 1012–15.
30. Peto R, Boreham J, Clarke M, Davies C, Beral V. UK and USA
breast cancer deaths down 25% in year 2000 at ages 20–69 years.
Lancet 2000; 355: 1822.
31. Sant M, Aareleid T, Berrino F, et al. and the EUROCARE
Working Group. EUROCARE-3: survival of cancer patients
diagnosed 1990–94—results and commentary. Ann Oncol
2003; 14 (Suppl 5): 61–118.
32. Martijn H, Voogd AC, van de Poll-Franse LV, et al. for the
Colorectal Cancer Study Group of the Comprehensive Cancer
Centre south (IKZ). Improved survival of patients with rectal
cancer since 1980: a population-based study. Eur J Cancer
2003; 39: 2073–9.
33. Mitry E, Bouvier A-M, Estève J, Faivre J. Benefit of operative
mortality reduction on colorectal cancer survival. Br J Surg
2002; 89: 1557–62.
34. Brasso K, Friis S, Krüger Kjær S, Jørgensen T, Iversen P. Pros-
tate cancer in Denmark: a 50-year population-based study.
Urol 1998; 51: 590–4.
 trends in cancer incidence, survival and mortality
35. Bruneton JN, Balu Maestro C, Raffaelli C, et al. Indications
for hepatic ultrasonography in breast cancer staging and
follow-up. Breast Cancer Res Treat 1996; 37: 115–21.
36. Conant EF, Maidment AD. Breast cancer imaging. Sci Med
1996; 3: 22–31.
37. Hoffman RM, Stone SN, Hunt WC, Key CR, Gilliland FD.
Effects of misattribution in assigning cause of death on
prostate cancer mortality rates. Ann Epidemiol 2003; 13:
450–4.
38. Feuer EJ, Merrill JA, Hankey BF. Cancer surveillance series:
interpreting trends in prostate cancer - Part II: cause of death
misclassification and the recent rise and fall in prostate cancer
mortality. J Natl Cancer Inst 1999; 91: 1025–32.
39. Ménégoz F, Colonna M, Exbrayat C, et al. A recent increase in
the incidence of prostatic carcinoma in a French population:
role of ultrasonography and prostatic specific antigen. Eur J
Cancer 1995; 31A: 55–8.
40. Yatani R, Shiraishi T, Nakakuki K, et al. Trends in frequency of
latent prostate carcinoma in Japan from 1965–1979 to 1982–
1986. J Natl Cancer Inst 1988; 80: 683–7.
41. Black RJ, Sharp L, Kendrick SW. Trends in Cancer Survival in
Scotland, 1968–1990. Edinburgh, Information and Statistics
Division, 1993.
42. Potosky AL, Kessler LG, Gridley G, Brown CC, Horm JW. Rise
in prostatic cancer incidence associated with increased use of
transurethral resection. J Natl Cancer Inst 1990; 82: 1624–8.
43. Helgesen F, Holmberg L, Johansson JE, Bergström R, Adami
H-O. Trends in prostate cancer survival in Sweden, 1960
through 1988: evidence of increasing diagnosis of nonlethal
tumors. J Natl Cancer Inst 1996; 88: 1216–21.
44. Coleman MP, Gatta G, Verdecchia A, et al. and the EURO-
CARE Working Group. EUROCARE-3 summary: cancer
survival in Europe at the end of the 20th century. Ann Oncol
2003; 14 (Suppl 5): 128–49.
45. Spencer JA. Radiology in the diagnosis and staging of prostate
cancer: more questions than answers. Oncol Newsletter 1996;
24: 8–10.
46. Duetz MS, Abel T, Niemann S. Health measures. Differentiat-
ing associations with gender and socio-economic status. Eur J
Publ Hlth 2003; 13: 313–19.
47. Rachet B, Mitry E, Quinn MJ, Cooper N, Coleman MP. Survival
from brain tumours in England and Wales up to 2001. Br J
Cancer 2008; 99 (Suppl 1): 98–101.
48. Berrino F, Estève J, Coleman MP. Basic issues in the estimation
and comparison of cancer patient survival. In: Berrino F, Sant M,
Verdecchia A, et al., eds. Survival of Cancer Patients in Europe:
The EUROCARE study. IARC Scientific Publications No. 132.
Lyon: International Agency for Research on Cancer, 1995.
49. Berrino F. The EUROCARE Study: strengths, limitations and
perspectives of population-based, comparative survival stud-
ies. Ann Oncol 2003; 14 (Suppl 5): 9–13.
50. Jenks S. Cancer program praised and criticized as plans are forged
for the 21st century. J Natl Cancer Inst 1993; 85: 1631–32.
51. Extramural Committee to Assess Measures of Progress Against
Cancer. Measurement of progress against cancer. J Natl Cancer
Inst 1990; 82: 825–35.
52. Department of Health. What will we not know in future if
cancer registration becomes unreliable? Department of Health,
30 October 2003. [Available from: http://www.doh.gov.uk/
cancer/cancer-registries.htm]
53. Department of Health. The NHS Cancer Plan: Three-Year
Progress Report—Maintaining the Momentum. London:
Department of Health, 2003.
54. Coleman MP, Evans BG, Barrett G. Confidentiality and the
public interest in medical research - will we ever get it right?
Clin Med 2003; 3: 219–28.
55. WHO. National Cancer Control Programmes. Geneva: WHO,
2002.
15
 2 Staging of Cancer
Michael Williams
INTRODUCTION
The radiologist has a central role in the anatomical staging of cancer.
It is now possible to determine the local extent of cancers very
accurately and in addition to detect metastatic disease involving
lymph nodes, bone, lung, liver, brain, and other organs.
Staging systems have evolved as imaging has become more sophis-
ticated. In addition, biologically based prognostic indices have been
developed. For example, in testicular germ cell tumors the levels of
blood markers are combined with disease extent determined radio-
logically to allocate patients to risk groups and to guide therapy. In
lymphoma, blood results, performance status, and radiological
extent are combined to derive prognostic indices. It is conceivable
that in the future the anatomical extent of disease will become less
critical in managing patients if the biological potential for dissemi-
nation can be established by analysis of material from the initial
biopsy. By contrast, response assessment using metabolic imaging is
likely to become more sophisticated: there is already evidence that
early assessment of response in lymphoma using positron emission
tomography (PET) gives important prognostic information.
THE PURPOSE OF STAGING
The purpose of staging is to:
• determine the anatomical extent of disease;
• decide on appropriate therapy, e.g., surgery, radiotherapy,
chemotherapy, hormone therapy, palliative care;
• compare results from different institutions;
• compare results over time; and
• stratify patients for entry into clinical trials.
CLINICAL EXAMINATION
Clinical examination has a critical role in the initial assessment of
patients to determine their investigation pathway. It also gives detailed
information about local extent and often provides the opportunity
for biopsy to confirm the diagnosis. Endoscopy permits direct visual-
ization of the tumor and the extent of local intraluminal involvement,
as well as giving an indication of the presence of extraluminal inva-
sion. It is particularly important in gastrointestinal, pelvic, lung, and
head and neck cancers. In some settings clinical findings may be piv-
otal. Recurrent laryngeal nerve involvement may cause hoarseness
and a weak cough. Horner’s syndrome (ptosis, miosis, anhidrosis,
enophthalmos) usually indicates sympathetic chain involvement at
the thoracic inlet. Both are evidence of inoperability in lung cancer.
THE ROLE OF IMAGING
Radiological assessment now has a dominant role in the staging of
cancer patients. Computed tomography (CT) is the most widely
16
used technique for staging solid tumors but other modalities are
preferable for some sites. For example, in rectal cancer, magnetic
resonance (MR) imaging can determine local extent, the exact
T-stage and also the relationship of the tumor to the mesorectal
fascia more accurately than CT (1). PET-CT can define metaboli-
cally active abnormalities and has become an essential, cost-
effective preoperative investigation for non-small cell lung cancer
and colorectal cancer (2).
The involvement of lymph nodes has hitherto been based on
size criteria, using both CT and MR imaging, together with their
internal appearance as demonstrated by lymphography (3,4).
This is now changing as PET allows the identification of meta-
bolic abnormalities (5). Nanoparticle-enhanced MR imaging
allows internal architecture to be determined (6) and this has
been shown to achieve high sensitivity and specificity in pilot
studies (7). For the detection of lymph mode metastases in head
and neck cancer ultrasound guided fine needle aspiration cytol-
ogy is the most accurate imaging modality, but it does have an
invasive element (8).
THE EVOLUTION OF STAGING SYSTEMS
As new modalities of imaging are developed, staging systems must
be adapted and evolved to make best use of the information.
The simplest staging systems are those based on anatomical
extent. They principally relate to the use of local treatment modal-
ities such as surgery, radiotherapy, or other ablative techniques. If
the disease has disseminated to produce distant metastases, then
aggressive local treatment alone will not cure the patient, although
it may still be important in management. The ideal staging system
should fulfill the following criteria:
• Internationally agreed and acknowledged
• Comprehensive and applicable to all oncology scenarios
• Simple, concise, precise, and consistent in its application
• Conveys prognostic information to facilitate best practice
The TNM staging classification of the International Union Against
Cancer (UICC) provides the conceptual framework for many ana-
tomical staging systems and is now widely used as the preferred
staging system for most tumors (9). It describes the status of the
tumor, nodes and metastases. The framework is based on assessing
three categories of tumor extent:
• T category—assessment of primary tumor extent
• N category—assessment of nodal involvement
• M category—assessment of distant metastases
The primary tumor (T) is followed by several standard forms of
notation:
• TX—primary tumor cannot be assessed
• Tis—in situ disease
• T0—no evidence of primary tumor
 staging of cancer

• T1 to T4—increasing degrees of local tumor extent. Table 2.1 TNM Staging Classification of Testicular Tumors, 2002 (9)
These may be subdivided for greater flexibility, e.g., for
carcinoma of the breast: Primary tumor
The extent of the primary tumor is classified after radical orchidectomy (pT)
° T4a implies involvement of the chest wall (ribs, serratus pTX Primary tumor cannot be assessed (if no radical orchidectomy has
anterior, or intercostal muscles)
been performed, TX is used)
° T4b implies involvement of the skin (ulceration, peau pT0 No evidence of primary tumor (e.g., histological scar in testis)
d’orange, satellite nodules) pTis Intratubular germ cell neoplasia (carcinoma in situ)
° T4c involvement of both chest wall and skin pT1 Tumor limited to testis and epididymis without vascular/lymphatic
° T4d is inflammatory carcinoma invasion; tumor may invade into the tunica albuginea but not tunica
vaginalis
Nodal disease is also designated with similar notation, e.g., for pT2 Tumor limited to testis and epididymis with vascular/lymphatic
carcinoma of the rectum: invasion, or tumor extending through tunica albuginea with
involvement of tunica vaginalis
• NX—regional lymph nodes cannot be assessed pT3 Tumor invades spermatic cord with or without vascular/lymphatic
• N0—no regional lymph node metastases
pT4
invasion
Tumor invades scrotum with or without vascular/lymphatic invasion
• N1—up to three regional lymph nodes
• N2—metastases in four or more regional lymph nodes Regional lymph nodes
Clinical involvement
The M category to describe distant metastases has similar anno-
NX Regional nodes cannot be assessed
tation. For example in colorectal cancer is described as follows: N0 No regional lymph node metastasis
N1 Metastasis with a lymph node mass ≤2 cm in greatest dimension or
• MX—distant metastases cannot be assessed multiple lymph nodes none >2 cm in greatest dimension
• M0—no distant metastases N2 Metastasis with a lymph node mass >2 cm but <5 cm in greatest
• M1—distant metastases dimension, or multiple lymph nodes, any one mass >2 cm but ≤5 cm
in greatest dimension
Table 2.1 shows the application of the TNM system to testicular N3 Metastasis with a lymph node mass >5 cm in greatest dimension
cancer. The size criteria for the subdivision of abdominal node Pathological involvement
masses follows that developed in the Royal Marsden Hospital stag- pN0 No regional lymph node metastasis
ing system for testicular tumors shown in Table 2.2 (10). This is a pN1 Metastasis with a lymph node mass ≤2 cm in greatest dimension and 5
system developed by radiotherapists with the intention of selecting or fewer positive nodes, none >2 cm in greatest dimension
patients who were suitable for an attempt at cure by radiotherapy pN2 Metastasis with a lymph node mass >2 cm but ≤5 cm in greatest
dimension; or more than 5 nodes positive, none >5 cm; or evidence
either to the abdominal nodes (Stage I and II) or to the abdominal of extranodal extension of tumor
and thoracic nodes (Stage II and III). The probability of local con- pN3 Metastasis with a lymph node mass >5 cm in greatest dimension
trol and hence cure rates depended on the bulk of disease treated
(11). Before the development of effective chemotherapy, patients Distant metastasis
MX Distant metastasis cannot be assessed
who had three or fewer lung metastases were offered whole lung M0 No distant metastasis
irradiation with a boost to the metastases. Forty percent of these M1 Distant metastasis
highly selected patients were cured by this approach (12). M1a Non-regional lymph node or pulmonary metastasis
Chemotherapy now dominates the management of germ cell M1b Distant metastasis other than to non-regional lymph nodes and lungs
tumors of the testis and there were a number of attempts to cor-
relate the number and site of metastases with tumor marker levels, Table 2.2 The Royal Marsden Hospital Staging Classification
in order to develop prognostic indices which would inform man- for Testicular Germ Cell Tumors (10)
agement decisions. The International Germ Cell Cancer Collabor- Stage Definitions
ative Group (IGCCCG) performed a multivariate analysis on
I No evidence of metastases
5862 patients and developed the staging system shown in Table 2.3. IM Rising serum markers with no other evidence of metastases
This combines the level of the tumor markers, alpha-fetoprotein II Abdominal node metastases
(AFP), human chorionic gonadotrophin (hCG) and lactase dehy- A <2 cm in diameter
drogenase (LDH), with metastases to adverse anatomical sites, i.e., B 2–5 cm in diameter
liver, bone, and brain, to identify three prognostic groups (13). C >5 cm in diameter
III Supradiaphragmatic node metastases
This has been extremely important in providing a reliable frame-
M Mediastinal
work for clinical trials, separating patients with five-year progres- N Supraclavicular
sion-free survival of 89% (good), 75% (intermediate), and 41% O No abdominal node metastases
(poor). Small volume non-pulmonary visceral metastases in criti- ABC Node size defined as in Stage II
cal organs have a significant impact on the patient’s prognosis. Fig- IV Extralymphatic metastases
Lung
ure 2.1 shows a CT scan demonstrating a small liver metastasis
L1 ≤3 metastases
which placed the patient in the poor risk group. L2 >3 metastases, all <2 cm in diameter
Staging for Hodgkin lymphoma has had a similarly complex L3 >3 metastases, one or more >2 cm in diameter
evolution. The Ann Arbor classification was published in 1971 and H+ Liver metastases
was adopted worldwide (14,15). It was developed on the basis of Br+ Brain metastases
Bo+ Bone metastases
the assumption that Hodgkin lymphoma in its early stages spreads

17

Table 2.3 International Germ Cell Tumor Consensus
Conference Classification (13)
Non-seminoma
Good prognosis Testis/retroperitoneal primary
No pulmonary, visceral
metastases and
Good markers—all of:
AFP <1000 ng/ml,
hCG <5000 IU/L and
LDH <1.5 × upper limit of
normal
56% of non-seminoma
5-year PFS = 89%
5-year survival = 92%
Intermediate Testis/retroperitoneal primary
prognosis No non-pulmonary visceral
metastases and
Intermediate markers—any of:
AFP 1000–10,000 ng/ml, or
hCG 5000–50,000 IU/L, or
LDH 1.5–10 × upper limit of
normal
28% of non-seminoma
5-year PFS = 75%
5-year survival = 80%
Poor prognosis Mediastinal primary or
Non-pulmonary visceral
metastases or
Poor markers—any of:
AFP >10,000 ng/ml
hCG >50,000 iu/L
(10,000 ng/ml), or
LDH >10 × upper limit of
normal
16% of non-seminoma
5-year PFS = 41%
5-year survival = 48%
Abbreviations : AFP, α-fetoprotein; hCG, human chorionic gonadotrophin;
LDH, lactase dehydrogenase; PFS, progression free survival.
(A)
Figure 2.1 CT showing a substantial para-aortic mass (A) and a small liver metastasis (B), which placed the patient in the poor risk group. The patient achieved complete
remission with chemotherapy alone.
18
general principles
Seminoma
Any primary site and
No non-pulmonary
visceral metastases and
Normal AFP, any hCG,
any LDH
90% of seminoma
5-year PFS = 82%
5-year survival = 86%
Any primary site and
No non-pulmonary
visceral metastases and
Normal AFP, any hCG,
any LDH
10% of seminoma
5-year PFS = 67%
5-year survival = 72%
No patients classified as
poor prognosis
contiguously along lymphatic pathways; this gave the opportunity
for cure by radiotherapy if all sites of disease and contiguous nodal
areas could be encompassed within an appropriate field (16). The
Ann Arbor classification was subsequently modified by the Cotswolds
group to take account of the use of CT to evaluate lymph nodes, liver
and spleen as shown in Table 2.4 (16). This staging system is still
widely used, but more detailed prognostic information can be
obtained from the Hasenclever index (17) as shown in Table 2.5.
This is a combination of a number of laboratory results which
together with sex, age, and stage allow patients to be placed in prog-
nostic groups. There is also a system based on measuring the total
volume of involved lymph nodes to estimate the total tumor burden
(18): this does give prognostic information but is so labor intensive
that it has not been adopted for routine use. However, it did show
that other prognostic factors correlate with the total tumor burden
and lack independent prognostic significance (18).
In non-Hodgkin lymphoma, the Ann Arbor system (originally
devised for Hodgkin lymphoma) has been widely used, but again
there are now biological systems giving better prognostic informa-
tion. For example, for high grade lymphoma the International
Prognostic Factors Project developed the predictive model shown
in Table 2.6, using clinical, radiological and laboratory findings
(19). Whichever staging system is used, it is critically important that
the radiologist is fully conversant with the system and that the
radiologist works closely with the clinicians. Such close collaboration
has been greatly facilitated by the development of multidisciplinary
team working.
Stage Migration and the Will Rogers Phenomenon
Stage migration is the phenomenon by which a patient’s stage is
changed by the use of improved imaging technology. The impact of
this was first described in lung cancer (20) but there have been
numerous follow-up articles for example in breast cancer (21) and
colonic cancer (22). The classic Will Rogers quote is: “When the
Okies left Oklahoma and moved to California they lowered the
average intelligence level in both states.” In cancer, the reverse is true
(B)
 staging of cancer

and prognosis is improved. The phenomenon is illustrated in group to which they move, as they will have a lower disease burden
Figure 2.2. Those who are upstaged will be those with the worst than average. Stage migration will improve the prognosis of all sub-
prognosis in their initial group and their removal will improve groups. However, despite this miraculous change, overall survival will
prognosis of that group, but they also improve the prognosis of the remain unchanged as this is simply a reclassification phenomenon.
Outcomes can only improve if more effective treatment is given.
Table 2.4 Staging of Lymphoma (Cotswold Classification) (16)
Stage Area of involvement
Key Points: General Considerations
I One lymph node region or extralymphatic site ■ Clinical examination continues to have a critical role in
II Two or more lymph node regions on the same cancer staging
side of the diaphragm
■ Staging systems continually evolve with the development
III Involvement of lymph node region or structures on
both sides of the diaphragm, subdivided thus: of new imaging modalities
III(Ia) With involvement of spleen and/or splenic hilar, ■ Stage migration improves the prognosis of all subgroups
celiac, and portal nodes but the overall survival remains unchanged
III(2a) With para-aortic, iliac, or mesenteric nodes
IV Extranodal sites beyond those designated E
Additional qualifiers RADIOLOGICAL ASSESSMENT AND TREATMENT STRATEGIES
A No symptoms
Just as there are critical elements which can determine a patient’s
B Fever, sweats, weight loss (to 10% of body
weight) stage, clinicians may use other elements of radiological data for
E Involvement of single extranodal site, contiguous clinical decision-making. For example, in pediatric Hodgkin
in proximity to a known nodal site lymphoma, the German–Austrian Pediatric Hodgkin Study
Xa Bulky disease Group stages patients according to the Ann Arbor classification
Mass > 1/3 thoracic diameter at T5
(14,15), but then allocates patients into three therapeutic groups
Mass > 10 cm in maximum dimension
CEa Clinical stage as shown in Table 2.7 (23). The stratification is based on deter-
PSa Pathological stage: PS at a given site denoted by a mining nodal disease (Stages I–III), extralymphatic involvement
subscript, (i.e., M, marrow; H, liver; L, lung; O, (E stage), and Stage IV based on cross-sectional imaging (23).
bone; P, pleura; D, skin) Figure 2.3 shows an example of pleural involvement which would
a
Modifications from Ann Arbor system. have been staged as in-continuity disease with extranodal exten-
sion (E) in the Cotswolds classification (Table 2.4). In the German–
Austrian system this is regarded as an adverse feature which
Table 2.5 A Prognostic Scoring System for Advanced Hodgkin moves the patient to a more intensive treatment group (Table 2.7).
Lymphoma (Hasenclever) (17) Initial centralized review, which ensures the consistent applica-
Risk factor High risk criteria tion of the staging system, has been shown to have a significant
Age >45 years impact on allocation to therapeutic group and thus on individual
Stage IV treatment (23).
Sex Male
Hb <10.5 g/dl
Albumin <40 RADIOLOGICAL REPORTING FOR RADIOTHERAPY
WBC >15
Lymphocytes <8% The interpretation of radiological studies may also be critical for
Score Relapse-free 5-year survival Overall 5-year survival radiotherapy planning. Minor abnormalities may have a substan-
(%) (%)
tial effect on the proposed treatment. Figure 2.4 shows a large
0–1 79 90
2 67 81 antral rhabdomyosarcoma in a child who also had lung metastases.
3 60 78 The patient received initial chemotherapy with response at all
4 51 61 sites. However, the small bilateral involved occipital lymph nodes,
≥5 42 56 the largest of which measured 12 × 5 mm and which responded

Table 2.6 International Prognostic Index for Aggressive Non-Hodgkin Lymphoma (19)
Risk factor >High risk criteria
Age >60 years
PS 2–4
LDH level Elevated
Extranodal involvement >1 site
Stage (Ann Arbor) III–IV
Risk IPI Score Complete response rate (%) Relapse-free 5-year survival (%) Overall 5-year survival (%)
Low 0–1 87 70 73
Low/intermediate 2 67 50 51
Intermediate/High 3 55 49 43
High >4 44 40 26

19
 general principles

Disease burden Good prognosis Poor prognosis

ORIGINAL STAGING

Stage I Stage II Stage III Stage IV TOTAL

Patients 400 200 200 200 1000

Cured 320 120 80 40 560

Cure rate (%) 80 60 40 20 56

REVISED STAGING

Stage I Stage II Stage III Stage IV TOTAL

Patients 300 200 200 300 1000

Cured 258 132 92 78 560

Cure rate (%) 86 66 46 26 56

Figure 2.2 Improvements in staging and the Will Rogers phenomenon. In this example, under the original staging system 56% of all patients were cured. With the
revised staging system more patients are categorized as Stage IV and fewer as Stage I. The boundaries of Stages II and III have also moved. In each of the stage catego-
ries the survival rate has improved by 6%, but the change in the number in each category means that overall survival is unchanged by this reclassification and remains
at 56%.

Table 2.7 German–Austrian Pediatric Hodgkin Study Group

Therapeutic Groups (23)
TG-1 Patients of Stages I A/B and IIA
TG-2 Patients of Stages IEA/B, IIE, IIB and IIIA
TG-3 Patients of Stages IIEB, IIIEA/B, IIIB or IV A/B

Note that extranodal extension (E) is classified as an adverse prognostic factor

which changes the patient’s therapeutic group and thus treatment.

Figure 2.4 Axial T1-weighted fat saturated post-gadolinium MR image in a child

Figure 2.3 Chest CT of a child with Hodgkin’s lymphoma demonstrating a large
mediastinal mass extending into the pleura and anterior chest wall. There is bone
destruction of the rib and an enlarged node in the right axilla. The extent of disease
shown on CT changed the therapeutic group and chemotherapy prescription.
with a rhabdomyosarcoma of the right antral region. There are bilateral involved
occipital lymph nodes, the largest measuring 12 × 5 mm. Following chemotherapy
the disease responded dramatically at all sites, but these initially involved lymph
nodes required irradiation which made the target substantially larger. In the initial
report the lymph nodes were described but the focus was on the local extent of
disease and the lung metastases.

20
 staging of cancer
dramatically, had a critical influence in defining the extent of the
irradiation field as they needed to be included in the treated
volume.
IMAGING AND RESPONSE ASSESSMENT
Radiology has a central role in response assessment to cancer therapy.
Hitherto this has been based on anatomical evidence of response
and of residual masses but, certainly in lymphoma, metabolic
imaging is assuming a burgeoning importance because it can
detect response earlier (24,25).
Summary
■ Imaging has a key role in determining the anatomic extent of
disease for most malignancies
■ The radiologist must be fully conversant with the details of
the staging system being used by clinical colleagues. This is
facilitated by multidisciplinary working
■ Radiotherapy is a locoregional treatment and the details of
local extent and lymph node involvement will influence the
target volume
■ Chemotherapy is more likely to be influenced by the extent
of distant metastases, but local invasion may be considered
of prognostic importance
■ Staging systems are subject to continual change
■ Stage migration and artifactual improvement in sub-group
prognosis is one effect of the application of novel imaging
technologies
REFERENCES
1. Klessen C, Rogalla P, Taupitz M. Local staging of recent cancer:
the current role of MRI. Eur Radiol 2007; 17: 379–89.
2. Facey K, Bradbury I, Laking G, Payne E. Overview of the clinical
effectiveness of positron emission tomography imaging in
selected cancers. Health Technol Assess 2007; 11: iii–iv, xi–267.
3. Lien HH, Stenwig AE, Ous S, Fossa SD. Influence of different
criteria for abnormal lymph node size on reliability of computed
tomography in patients with non-seminomatous testicular
tumour. Acta Radiol Diagn 1986; 27: 199–203.
4. Stomper PC, Fung CY, Socinski MA, et al. Detection of retro-
peritoneal metastases in early-stage nonseminomatous testic-
ular cancer: analysis of different CT criteria. Am J Roentgenol
1987; 149: 1187–90.
5. Moog F, Bangerter M, Diederichs CG, et al. Lymphoma: role
of whole-body 2-deoxy-2[F-18] fluoro-D-glucose (FDG) PET
in nodal staging. Radiology 1997; 203: 795–800.
6. Saokar A, Braschi M, Harisinghani MG. Lymphotrophic nano-
particle enhanced MR imaging (LNMRI) for lymph node
imaging. Abdom Imaging 2006; 31: 660–7.
7. Guimaraes AR, Tabatabei S, Dahl D, et al. Pilot study evaluating
use of lymphotrophic nanoparticle-enhanced magnetic
resonance imaging for assessing lymph nodes in renal cell cancer.
Urology 2008; 71: 708–12.
8. de Bondt RB, Nelemans PJ, Hofman PA, et al. Detection of
lymph node metastases in head and neck cancer: a meta-analysis
comparing US, USgFNAC, CT and MR imaging. Eur J Radiol
2007; 64: 266–72.
9. Sobin LH, Wittekind Ch, eds. UICC: TNM Classification of
Malignant Tumours, 6th edn. New York: Wiley-Liss, 2002.
10. Peckham MJ, Barrett A, Liew KH, et al. The treatment of
metastatic germ-cell testicular tumours with bleomycin, etoposide
and cis-platin (BEP). Br J Cancer 1983; 47: 613–9.
11. Tyrrell CJ, Peckham MJ. The response of lymph node metastases
of testicular teratoma to radiation therapy. Br J Urol 1976; 48:
363–70.
12. van der Werf-Messing B. The treatment of pulmonary metasta-
ses of malignant teratoma of the testis. Clin Radiol 1973; 24:
1213.
13. International Germ Cell Cancer Collaborative Group. Inter-
national germ cell consensus classification: a prognostic
factor-based staging system for metastatic germ cell cancers.
J Clin Oncol 1997; 15: 594–603.
14. Carbone PP, Kaplan HS, Musshoff K, Smithers DW, Tubiana M.
Report of the committee on Hodgkin’s disease staging classifi-
cation. Cancer Res 1971; 31: 1860–1.
15. Rosenberg SA, Boiron M, DeVita VT Jr, et al. Report of the
committee on Hodgkin’s disease staging procedures. Cancer
Res 1971; 31: 1862–3.
16. Lister TA, Crowther D, Sutcliffe SB, et al. Report of a commit-
tee convened to discuss the evaluation and staging of patients
with Hodgkin’s disease: Cotswold Meeting. J Clin Oncol 1989;
7: 1630–6.
17. Hasenclever D, Diehl V. A prognostic score for advanced
Hodgkin’s disease. International prognostic factors project
on advanced Hodgkin’s disease. N Engl J Med 1998; 339:
1506–14.
18. Specht L. Tumour burden as the main indicator of prognosis
in Hodgkin’s disease. Eur J Cancer 1992; 28A: 1982–5.
19. The International Non-Hodgkin’s Lymphoma Prognostic
Factors Project. A predictive model for aggressive Non-Hodgkin’s
Lymphoma. N Engl J Med 1993; 329: 987–94.
20. Feinstein AR, Sosin DM, Wells CK. The Will Rogers phenom-
enon. Stage migration and new diagnostic techniques as a
source of misleading statistics for survival in cancer. N Engl J
Med 1985; 312: 1604–8.
21. Christensen D. The Will Rogers phenomenon: roping the
effects of a new cancer staging system. J Natl Cancer Inst 2003;
95: 1105–6.
22. Shahrier M, Ahnen DJ. Colorectal cancer survival in Europe:
the Will Rogers phemomenon revisited. Gut 2000; 47:
463–4.
23. Dieckmann K, Potter R, Wagner W, et al. Up-front centralized
data review and individualised treatment proposals in a mul-
ticenter pediatric Hogdkin’s disease trial with 71 participating
hospitals: the experience of the German-Austrian pediatric
multicenter trial DAL-HD-90. Radiother Oncol 2002; 62:
191–200.
24. Kostakoglu L, Goldsmith SJ, Leonard JP, et al. FDG-PET after
1 cycle of therapy predicts outcome in diffuse large cell
lymphoma and classic Hodgkin disease. Cancer 2006; 107:
2678–87.
25. Hampson FA, Shaw AS. Response assessment in lymphoma.
Clin Radiol 2008; 63: 125–35.
21
 3 Multidisciplinary Treatment of Cancer: Surgery
Timothy A Rockall and Bruce F Levy
INTRODUCTION
Until relatively recently, surgery has been the only method of curing
solid tumors. Pioneering surgeons in the latter half of the 19th and
early 20th centuries such as Billroth, Wertheim, and Volkmann per-
formed partial or total organ excisions in an attempt at curative
resection and, in 1890, Halstead developed the concept of en bloc
resection of adjacent tissues for the treatment of advanced tumors of
the breast. Oncological developments that can treat microscopic dis-
ease, however, have changed the nature and magnitude of much of
this excisional surgery. Nevertheless, surgery still plays a major role in
the management of most solid organ malignancy, and indeed many
of the common malignancies, with some notable exceptions, are still
only cured by surgical excision with or without adjuvant therapy.
The modern approach to cancer is one of a multidisciplinary
team, but the surgeon remains pivotal and has a role in all aspects
of cancer care including:
• Prevention
• Diagnosis
• Treatment
• Palliation
• Rehabilitation
Imaging is crucial to the multidisciplinary management of many
of these aspects of patient care, in particular screening, staging, and
surveillance but also in treatment and palliation by intervention
and image-guided surgery.
CANCER PREVENTION
Several disease processes (developmental, inherited, or acquired)
convey a high or indeed inevitable risk of malignancy. Good
examples are the development of colorectal cancer in familial
adenomatous polyposis (FAP), testicular cancer in cryptorchidism
and breast, and ovarian cancer in patients with BRAC1/BRCA2
gene mutations (1). For diseases arising in non-vital organs,
surgery can abolish the organ-specific cancer risk in these patients.
Organ excision (e.g., proctocolectomy, orchidectomy, mastectomy,
or oophorectomy) at an appropriate time prevents cancer.
For common malignancies in the population, screening can be
used to detect pre-malignant lesions such as adenomatous polyps
in the gastro-intestinal tract or intraepithelial neoplasia in the
cervix, and thus can be preventative. Alternatively, screening may
attempt to detect early-stage cancer that is more likely to be at a
curative stage than if the cancers are detected only when they
become symptomatic. Examples include breast cancer screening
or endoscopic screening for gastric cancer and colon cancer. Colon
cancer screening studies by occult blood testing and flexible
sigmoidoscopy have both detected an increased proportion of
Duke’s A carcinomas relative to control groups. Screening tests
vary considerably in their sensitivity and specificity. The most
22
established example of a radiological screening program is
mammography. The development of multidetector computed
tomography (MDCT) with lower radiation doses has stimulated
interest in its use for both lung and colon cancer screening.
CT colonography is increasingly being used in the detection of
colorectal cancer. Whilst it has been shown to be extremely useful
when colonoscopy and barium enemas have failed, its exact role in
screening is still being determined. Due to its non-invasive nature,
CT colonography is more acceptable to patients as a screening
tool than colonoscopy which has a poor voluntary uptake (2). For
many patients, a screening colonography is all that is required to
exclude colonic pathology. If a colonic lesion is found, then
further investigation with colonoscopy may be required to assist
in establishing the diagnosis or to implement treatment of the
primary pathology in the case of a colonoscopically resectable
adenoma. CT colonography has the additional benefit of allowing
examination of the extra-colonic intra-abdominal organs (3). The
national screening program in the United Kingdom, however, is
utilizing fecal occult blood testing and colonoscopy (4).
CANCER DIAGNOSIS
A diagnosis of malignancy is often suggested by clinical findings
or imaging but a definitive diagnosis of malignancy is made by
tissue acquisition, either by needle aspiration, core biopsy, inci-
sional biopsy, or excisional biopsy. There are circumstances in
which a diagnosis of malignancy can be accepted without preop-
erative histological proof, especially where attempts at biopsy may
jeopardize a chance of cure. The radiologist has a role in image-
guided needle and core biopsy, and must follow the same principles
as the surgeon in these cases:
• Place the needle track so that it can be removed in any
subsequent definitive surgery so that resection is not
compromised
• Avoid contamination of new tissue planes
• Avoid using the same instrument on multiple lesions
• Avoid hemorrhage
• Choose the correct biopsy technique to give sufficient
material for diagnosis
Where percutaneous techniques are hazardous or where they fail to
acquire adequate tissue, then surgery may be employed. A diagnosis
of lymphoma can usually be made with aspiration cytology and
lymphoma subclassification can be achieved with core biopsy in
about 90% of cases, both during the initial assessment of the disease
and in the assessment of recurrence (5–8). Surgical excision may
need to be employed in the remaining cases where further histo-
logical classification is required that may impact on the treatment.
There are circumstances where biopsy of malignant lesions prior to
a potentially curative resection is contraindicated, because of the
risk of tumor dissemination into a body cavity or along the needle
track. For example, pancreatic carcinoma should not be biopsied
 multidisciplinary treatment of cancer: surgery
percutaneously if curative resection is being considered because of
risk of tumor seeding. Alternative methods of biopsy with a lower risk
of tumor seeding are available such as endoscopic ultrasound-guided
cytology (9). Another example where preoperative biopsy should not
be performed is a resectable solitary colorectal cancer deposit in the
liver detected at the time of or following curative resection of the pri-
mary (10). In these cases, the decision-making process is guided by
clinical and imaging features alone. A lesion that appears malignant
on the preoperative imaging should be treated with a formal hepate-
ctomy and it must not be biopsied preoperatively. Differentiation of
benign liver lesions such as hemangiomas and focal nodular hyper-
plasia from malignancy can be difficult. In these circumstances, which
are commonly complicated by the coexistence of both benign and
neoplastic lesions, multimodal imaging should be used as each
modality provides additional information. Magnetic resonance
imaging of the liver using contrast agents such as gadolidium adds
information in these situations.
The development of functional imaging has been a major devel-
opment that has had a significant impact on the way in which
patients are managed. There are several different functional imag-
ing modalities including single-photon emission computed
tomography (SPECT), positron emission tomography–computed
tomography (PET–CT), and positron emission tomography–
magnetic resonance imaging (PET–MRI). The process of image
acquisition using SPECT is very similar to that used by a planar
gamma camera and hence employs routinely used radioactive
pharmaceuticals, e.g., technetium (Tc-99m). Functional imaging
with 2-[F-18]fluoro-2-deoxy-D-glucose positron emission tomog-
raphy (18FDG PET) may be useful in difficult clinical circum-
stances to delineate the likely malignant nature of the deposit and
help exclude other secondary deposits not visible using other
modalities. Furthermore, it can be used to monitor the response
to therapy; an example being patients undergoing treatment for
non-small cell lung cancer (11).
PREOPERATIVE CANCER STAGING: WHAT THE
SURGEON NEEDS TO KNOW
The information derived from histology and imaging helps deter-
mine the optimal management and, crucially, which patients are
suitable for potentially curative surgery and require preoperative
adjuvant therapy, and which are best managed without surgery or
with palliative surgery alone (including radiological intervention).
Staging preoperatively using a variety of imaging techniques is
advancing all the time and becoming increasingly accurate. This in
turn is reducing the number of inappropriate interventions with its
associated morbidity. Imaging attempts to supply the multidisci-
plinary team with the staging information, the accuracy of which is
measured by comparing this prediction with the histology following
resection. TNM staging is tumor-specific. T stage is usually related to
tumor size, involvement of tissue layers within an organ, presence of
extra-organ involvement, and complications such as perforation or
fistula formation. N stage is related either to the number of involved
lymph nodes or their presence in various levels of the lymph node
chain. M stage details the presence of detectable metastases.
For locally advanced lesions, information pertaining to the
involvement of adjacent organs is important because this
information may either negate surgery or determine the need
for en bloc resection of adjacent organs for potentially curative
resection. Accurate preoperative staging is paramount in malig-
nant diseases where the method of potentially curative surgery is
stage-dependent. A good example is rectal carcinoma.
Carcinoma of the rectum is usually diagnosed by clinical exam-
ination and endoscopic biopsy. The patient is then staged using a
number of imaging modalities including plain radiology, abdominal
ultrasound, transanal ultrasound, CT, and MR imaging.
Basically, the purpose of imaging is to give local staging informa-
tion on resectability and to give information about the presence of
distant metastases, which may alter the surgical approach or negate
it altogether. The initial treatment options for a potentially curable
carcinoma include local resection, rectal resection, or rectal resec-
tion with preoperative chemoradiotherapy for local down-staging.
Endoanal ultrasound and MR are the best modalities to supplement
a clinical examination. The advantage of endoanal ultrasound lies
in its ability to accurately assess the local depth of invasion. It is
more accurate than MR at T staging due to the superior ability of
ultrasound to differentiate between T1 and T2 lesions (12), although
inflammation around the tumor edge can lead to overstaging.
Endoanal ultrasound also gives useful information regarding the
lymph node stage with the additional potential benefit of image-
guided fine needle aspiration of a suspicious lymph node. This is
safe as long as the path of the biopsy needle is distant from the
tumor. However, the use of endoanal ultrasound is highly operator-
dependant and its accuracy after radiotherapy is severely impaired
and should not be relied upon. With the continuing improvement
of MR both modalities can reasonably accurately T stage a tumor
and may additionally identify nodes in the mesorectum. Nodal
involvement can be predicted on size criteria alone but research
into the use of ultrasmall particles of iron oxide (USPIO) may
improve the specificity of MR in identifying malignant nodes.
CT of the chest, abdomen, and pelvis is probably the best single
test for identification of metastases, particularly in the lung and liver.
This may be supported by abdominal ultrasound which can assist in
evaluating poorly characterized lesions demonstrated on CT. How-
ever, CT does not stage the primary tumor well. Transanal resection
(14) is a much less invasive form of therapy, but if curative treatment
is being considered then only T1 lesions are appropriately resected in
this manner. If a lesion is T1, then the risk of lymph node involve-
ment or micrometastases is negligible. Potentially, complete local
excision of T2 lesions can be achieved transanally, but do have a sig-
nificant incidence of lymph node involvement and a much higher
local recurrence rate, and so treatment is reserved for symptomatic
patients with limited life expectancy due either to the disease itself or
a co-morbid process. T3 lesions are appropriately treated by surgery
with or without preoperative radiotherapy depending on local pro-
tocols, and T4 lesions are usually treated with preoperative chemora-
diation for the purposes of local downstaging and to reduce the
likelihood of involved radial resection margins.
SURGERY FOR CANCER STAGING
Staging of some tumors still requires surgery. However, advances
in imaging (including endoluminal ultrasound) have reduced the
need for staging laparotomy in most instances. For example,
laparotomy for the staging of Hodgkin’s lymphoma is now
23
 general principles
obsolete and has been replaced by CT and 18FDG PET (15).
However, with upper gastro-intestinal malignancy (stomach,
esophagus, and pancreas) in particular, laparoscopy and biopsy is
still utilized to exclude or confirm small-volume peritoneal or
nodal disease prior to resection that is not detected on preopera-
tive imaging (16). The benefit of this staging laparoscopy in reduc-
ing morbidity and mortality has been well documented for
patients undergoing hepato-bilary surgery (17,18). The staging
laparoscopy may be undertaken in conjunction with intraopera-
tive ultrasound assessment, which can be accurately performed at
the time of staging laparoscopy with high quality laparoscopic
ultrasound probes and can be introduced through 10 mm ports
(19,20). The major advantage of laparoscopic ultrasound is the
ability to clearly define the pathological liver lesion and, more
importantly, in terms of ensuring a curative resection, is its potential
to assess the proximity of the lesion to the vascular structures.
CANCER TREATMENT
Surgeons may operate on cancer patients for a number of reasons
including:
• Definitive treatment of the primary
• Debulking of certain tumors
• Metastasectomy with curative intent
• Oncological emergencies
• Palliation
• Reconstruction and rehabilitation
Definitive Treatment
The challenge in oncology is to identify patients that can be cured
and to offer local treatment that balances the potential for cure
with the impact of treatment on quality of life. The multidisci-
plinary team must then advise on adjuvant therapy to control
local and distant recurrence or progression. The treatment aim
may be to attempt cure; however, even when the tumor is appar-
ently confined to the organ, up to 70% (depending on cancer
type) will have micrometastases beyond the primary site. Surgery
is usually, therefore, extended to include resection of the draining
lymph nodes. Involvement of these regional nodes is itself a
predictor of distant undetectable metastases.
Local control of solid tumors requiring surgery and the principles
of curative resection include:
• Excision of the organ (or part thereof) utilizing tissue
planes where appropriate and with an adequate margin
• Where adjacent non-vital organs are involved, to excise
them en bloc
• Excision of the lymph node chain draining the organ
• Excision of some isolated metastases where appropriate
What constitutes an adequate margin varies according to the
tumor type. Cutaneous melanoma, for example, used to be excised
with a 5 cm margin where this was technically feasible. A trial
comparing 5 cm with 2 cm margins revealed no difference in local
recurrence rates and a 2 cm margin is now deemed adequate (21).
In rectal carcinoma, a distal resection margin of at least 5 cm is
generally accepted as involved nodes or satellite deposits in the
mesorectum may be present up to 4 cm beyond the tumor (22).
24
However, for low and mid rectal carcinomas, total mesorectal
excision (TME) is undertaken for the same reason, but an ade-
quate longitudinal tumor margin may be as small as 1 cm to allow
for a colo-anal anastomosis, and has reported low rates of local
recurrence (23,24). If a margin of 1 cm cannot be attained then
abdominoperineal resection is usually indicated.
Recurrent disease does not preclude curative surgery. As surgery for
recurrent disease often results in far greater morbidity than primary
surgery, it is imperative that the preoperative staging is as accurate as
possible in order to prevent patients having incomplete resection
margins. One of the factors making recurrent rectal cancer difficult to
treat is disease extension posteriorly and laterally. Whilst posterior
disease extension can be treated with en bloc excision of the sacrum,
spread of the disease laterally is harder to treat due to the irresectabil-
ity of the lateral pelvic side wall that limits adequate margins from
being obtained (25). Furthermore, disease extension along nerves,
e.g., sciatic nerve, can be difficult to diagnose on the preoperative
imaging, but presence of disease in this situation changes the nature
and magnitude of the surgery if curative intent is maintained.
Some tumors require surgery only for biopsy purposes as the
primary therapy is now chemoradiotherapy. A good example of
this is squamous cell carcinoma of the anal canal, previously
treated by abdominoperineal resection (26). Surgery is now
reserved for tumors that fail to respond. Equally, locally advanced
tumors, excision of which might result in involved margins and
inevitable local recurrence, can sometimes be locally downstaged
by adjuvant therapy so as to allow an attempt at curative surgery
(e.g., locally advanced carcinoma of the rectum).
Key Points: Cancer Treatment
■ A multidisciplinary approach is essential
■ Surgery with curative intent must be extended to obtain ade-
quate resection margins and to include the draining lymph
nodes
■ Adherent/involved adjacent non-vital organs must be excised
en bloc
■ Recurrent disease does not preclude curative surgery
Debulking
There are some tumors that cannot be cured by surgery because of
their stage at presentation. Despite the disease progression, sur-
gery is often beneficial as debulking can provide significant symp-
tomatic relief. Debulking of a cerebral metastasis can provide
almost immediate symptomatic relief from obstructing hydro-
cephalus (27). In addition, tumor debulking provides tissue for
accurate histological diagnosis and as some of these tumors are
chemosensitive or radiosensitive, the efficacy of this further treat-
ment may be increased once the tumor mass is reduced. This is
true of ovarian carcinoma, in particular (28).
Pseudomyxoma peritonei is another example where benefit can be
obtained from tumor debulking. Pseudomyxoma peritonei is a
malignant condition characterized by the progressive accumulation
of mucin within the peritoneal cavity. The tumor accumulates at
sites of relative stasis, whilst the peristaltic small bowel is commonly
spared. The compressive symptoms arise due to the unremitting
production of mucin that eventually produces mechanical obstruc-
tive effects (e.g., of bowel and inferior vena cava). Transcutaneous
 multidisciplinary treatment of cancer: surgery
peritoneal drainage is not possible due to the high viscosity of the
mucinous fluid. Whilst low-grade lesions may be monitored by serial
CT, high-grade lesions need either tumor debulking or cytoreductive
surgery, followed by intraperitoneal chemotherapy. Debulking sur-
gery leads to symptomatic improvement but with time the residual
disease causes further symptoms and repeated surgery to debulk the
tumor becomes increasingly difficult (29). The current definitive
treatment is cytoreductive surgery and intraoperative chemotherapy
(20). The cytoreductive surgery often involves a right hemicolectomy
and an anterior resection as these areas are most commonly affected
due to the relatively static surrounding mucin.
Colonic neoplasms can be debulked using endoscopic-guided
laser therapy or it can be “debulked” in terms of reducing the
“colonic intraluminal volume of tumor” when a metallic stent is
expanded. Approximately 60% of the cases presenting with large
bowel obstruction are due to colorectal cancer (30). Occult malig-
nancy has often resulted in a protracted period of debilitation
prior to admission, which magnifies the severity of the illness
when the patient presents acutely with large bowel obstruction.
Joint management between endoscopists and radiologists can
prevent patients undergoing surgery whilst they are acutely unwell.
This is important, as the magnitude of the corrective surgery in
the acute phase is reflected in the high mortality rates which are
markedly reduced by stenting (31). Furthermore, emergency sur-
gery commonly results in the production of a stoma, with a two-
stage procedure being required if bowel continuity is to ever be
restored. The placement of a stent across the colonic lesion is often
possible with a multidisciplinary approach.
Concern has been raised regarding the possibility of altering the
stage of the disease, thereby converting a potentially curative into
a non-curative situation, but no significant difference has been
found in the follow up studies (32). Colonic stents are most com-
monly placed in the left hemicolon. Rectal stents result in tenes-
mus and may be used as a bridge to surgery but are unsuitable for
longer-term palliation. Stenting of lesions proximal to the splenic
flexure is challenging and often unsuccessful with an increased
risk of perforation. Not all the cases stented are followed up with
surgery and stent placement is sometimes the final palliative pro-
cedure. In these cases, potential complications in the longer term
are stent migration and reocclusion due to tumor growth.
Although endoscopic laser treatment is less commonly used
than primary placement of metallic stents, it is useful in maintain-
ing colonic patency in a surgically unfit patient with threatened
obstruction. It has also been used in the management of blocked
expandable metallic stents that have become occluded by tumor
ingrowth (33). The disadvantage of endoscopic laser treatment is
the higher perforation rate at the time of laser debulking and the
higher rate of re-obstruction due to tumor growth over the
following months when compared with primary stenting.
Key Points: Debulking
■ For some tumors, debulking improves the efficacy of onco-
logical treatments
■ May provide symptomatic relief
■ Stenting of the gastro-intestinal/urinary tract can be used to
relieve obstruction
■ Stenting may prevent surgery in the acutely unwell patient
Metastasectomy
Some malignancies are associated with metastases that are
isolated to one organ and few in number. Resection of these
(either in conjunction with excision of the primary, delayed,
or upon discovery of metastases in follow-up) can result in
cure. Some sarcomas, and increasingly colorectal recurrences
in the lung and liver, are amenable to resection and in this
case may result in a 25% to 40% cure rate (34,35). Isolated
brain metastases can also be excised, but obviously options are
limited by site and functional sequelae. Isolated metastases in
non-vital organs such as the spleen can be excised relatively
simply. In vital organs such as the liver, the metastases have
to be placed so that resection can be technically achieved and leave
adequate organ function postoperatively. The commonly held
criterion for resectability is one to three resectable metastases
in one lobe of the liver, but many hepatic surgeons are extend-
ing their indications. To consider hepatic resection for colorec-
tal metastases, the ideal candidates would have the following
characteristics:
• Histologically suitable tumor (e.g., adenocarcinoma of
the colon)
• Fit to undergo surgery
• Potentially curative resection of the primary tumor
• Metastases isolated to the liver (although lung metastases
may also be excised in the same patient)
• Good hepatic function
• Metastases few in number
• Metastases positioned to allow resection by lobectomy
or segmentectomy with adequate margin of excision
• Sufficient hepatic capacity remaining post-resection
The timing of metastasectomy is debated and may be carried out
immediately when identified simultaneously with the primary. In
keeping with the current management of colonic liver metastases,
they are commonly resected following three to four months of
chemotherapy and with intensive restaging in order to select out
those with rapidly progressive disease who are unlikely to benefit
from surgery. Whilst the practice and benefit of hepatic resec-
tion for colonic liver metastases has been well established for
some time, the use of hepatic resection for other metastatic non-
colorectal, non-neuroendocrine liver malignancies such as breast
and genito-urinary cancers have been shown to be both safe and
effective provided there is no extrahepatic disease on preoperative
staging and adequate liver margins can be surgically obtained
(36,37).
A radiological approach is often required in cases where the
residual volume of hepatic parenchyma after a liver resection
would be insufficient to meet the normal metabolic requirements.
Preoperative portal vein embolization using coils produces sig-
nificant hyperplasia of the normal liver parenchyma, thereby per-
mitting sufficient liver tissue to be resected, which ensures that
complete excision of the margins is obtained whilst having reduced
the risk of developing hepatic insufficiency (38).
Metastases not curable by surgery may nevertheless be amenable
to ablative therapies administered under image-guidance using
ultrasound, CT or MR. Ablation of liver tumors has been shown in
some studies to improve quality of life and improve survival (35)
(see chap. 52).
25
 general principles
Key Points: Metastasectomy
■ Non-vital organs with metastases can be excised completely
■ Vital organs need partial excision ensuring adequate margins
■ Portal vein embolization may be required to stimulate liver
hypertrophy prior to surgery in cases with a predicted
insufficient residual liver volume
Emergency Surgery
Surgeons and radiologists are not infrequently involved in the
management of surgical oncological emergencies. Hemorrhage
may necessitate angiography and embolization or surgical interven-
tion (which may also represent definitive oncological therapy).
Perforation of gastro-intestinal or genito-urinary tracts may result
in peritonitis or abscess formation, which again may require surgical
intervention or percutaneous-guided drainage. Obstruction of the
biliary, gastro-intestinal and genito-urinary tracts due to malignancy
has traditionally been dealt with by surgical decompression or
bypass, or indeed by definitive excisional surgery. However, where
advanced disease is evident, or where the patients are deemed to ben-
efit from recovery of organ function prior to any definitive surgery,
then radiology has an important role in the placement of drains and
stents. Spinal metastases with cord compression is an emergency
because of the potential for rapid and permanent loss of function.
Imaging with MR, in particular, is most often utilized, and emergency
radiotherapy or surgical decompression can be instituted.
Cancer Palliation
Surgery is often used to palliate what is known to be incurable
disease. Defunctioning stomas of the gastro-intestinal tract, palli-
ative bypass procedures, palliative excision and surgically placed
stents are all widely used. Interventional radiology is used in the
same way, with stenting of tubular organs becoming increasingly
available. Guided ablation of metastases using ultrasound, CT,
and MR are all potentially used to improve quality and length of
life in patients with incurable disease.
Cancer Rehabilitation
Rehabilitation of patients after surgery is an important aspect of
the overall management of the cancer patient and contributes both
to the functional recovery and emotional wellbeing of the indi-
vidual. The surgeon is only part of a team, which might also include
physiotherapists, occupational therapists, and psychologists. Breast
reconstruction after mastectomy, limb prosthesis after amputation,
grafting of skin or muscle following disfiguring resection of head
and neck cancers, are all good examples of where surgery is used
in order to regain lost function and improve cosmesis.
CONCLUSION
Oncology is a rapidly advancing specialty and represents the epit-
ome of multimodal therapy. Surgery, however, with some notable
exceptions, remains pivotal in the majority of malignant condi-
tions for both cure and palliation. The decision-making processes
are often complex and are made more so by the increasingly large
amount of preoperative diagnostic information available to the
multidisciplinary team. The most significant changes in surgical
26
management are a result of the major improvements in preopera-
tive imaging, which allow surgeons to select those patients who
are most likely to be cured by their intervention and reduce the
number of operative interventions that result in neither cure nor
improved quality of life for the patient.
Summary
■ Cancer surgery can be undertaken for prevention, diagnosis,
treatment, palliation, or rehabilitation
■ Cancer preventive surgery is undertaken where genetic data
indicate a high or inevitable risk of cancer, or premalignant
lesions are detected on screening
■ Surgical treatment for cancer can be definitive, involve deb-
ulking, removal of metastases, or be used in an emergency
(as in hemorrhage)
■ The most significant changes in surgery come as a result of
improvements in preoperative imaging allowing a better
informed selection of the appropriate form of surgery
REFERENCES
1. Easton DF, Ford D, Bishop DT. Breast and ovarian cancer
incidence in BRCA1-mutation carriers. Breast Cancer Linkage
Consortium. Am J Hum Genet 1995; 56: 265–71.
2. Svensson MH, Svensson E, Lasson A, Hellstrom M. Patient
acceptance of CT colonography and conventional colonos-
copy: prospective comparative study in patients with or
suspected of having colorectal disease. Radiology 2002; 222:
337–45.
3. Pickhardt PJ, Hassan C, Laghi A, et al. Cost-effectiveness of
colorectal cancer screening with computed tomography
colonography: the impact of not reporting diminutive lesions.
Cancer 2007; 109: 2213–21.
4. West NJ, Poullis AP, Leicester RJ. The NHS Bowel Cancer
Screening Programme—a realistic approach with additional
benefits. Colorectal Dis 2007; Oct 23 [Epub ahead of print]
5. de Kerviler E, Guermazi A, Zagdanski AM, et al. Image-guided
core-needle biopsy in patients with suspected or recurrent
lymphomas. Cancer 2000; 89: 647–52.
6. Whelan JS, Reznek RH, Daniell SJ, et al. Computed tomogra-
phy (CT) and ultrasound (US) guided core biopsy in the man-
agement of non-Hodgkin’s lymphoma. Br J Cancer 1991; 63:
460–2.
7. Pappa VI, Hussain HK, Reznek RH, et al. Role of image-guided
core-needle biopsy in the management of patients with lym-
phoma. J Clin Oncol 1996; 14: 2427–30.
8. Demharter J, Muller P, Wagner T, et al. Percutaneous core-
needle biopsy of enlarged lymph nodes in the diagnosis and
subclassification of malignant lymphomas. Eur Radiol 2001;
11: 276–83.
9. Palazzo L. Imaging and staging of bilio-pancreatic tumours:
role of endoscopic and intraductal ultrasonography and
guided cytology. Ann Oncol 1999; 10(Suppl 4): 25–7.
10. Rodgers MS, Collinson R, Desai S, Stubbs RS, Mccall JL. Risk
of dissemination with biopsy of colorectal liver metastases.
Dis Colon Rectum 2003; 46: 454–9.
 multidisciplinary treatment of cancer: surgery
11. Cerfolio RJ, Ojha B, Mukherjee S, et al. Positron emission
tomography scanning with 2-fluoro-2-deoxy-d-glucose as a
predictor of response of neoadjuvant treatment for non-small
cell carcinoma. J Thorac Cardiovasc Surg 2003; 125: 938–44.
12. Meyenberger C, Huch Boni, RA Bertschinger P, et al. Endo-
scopic ultrasound and endorectal magnetic resonance
imaging: a prospective, comparative study for preoperative
staging and follow-up of rectal cancer. Endoscopy 1995; 27:
469–79.
13. Koh DM, Brown G, Temple L, et al. Rectal cancer: mesorectal
lymph nodes at MR imaging with USPIO versus histopatho-
logic findings—initial observations. Radiology 2004; 231:
91–9.
14. Steele RJ, Hershman MJ, Mortensen NJ, Armitage NC,
Scholefield JH. Transanal endoscopic microsurgery—initial
experience from three centres in the United Kingdom. Br J
Surg 1996; 83: 207–10.
15. Menzel C, Dobert N, Mitrou P, et al. Positron emission tomog-
raphy for the staging of Hodgkin’s lymphoma—increasing the
body of evidence in favor of the method. Acta Oncol 2002; 41:
430–6.
16. de Graaf GW, Ayantunde AA, Parsons SL, Duffy JP, Welch NT.
The role of staging laparoscopy in oesophagogastric cancers.
Eur J Surg Oncol 2007; 33: 988–92.
17. Conlon KC, Brennan MF. Laparoscopy for staging abdominal
malignancies. Adv Surg 2000; 34: 331–50.
18. Conlon KC. Value of laparoscopic staging for upper gastroin-
testinal malignancies. J Surg Oncol 1999; 71: 71–3.
19. John TG, Wright A, Allan PL, et al. Laparoscopy with laparo-
scopic ultrasonography in the TNM staging of pancreatic car-
cinoma. World J Surg 1999; 23: 870–81.
20. Finch MD, John TG, Garden OJ, Allan PL, Paterson-Brown S.
Laparoscopic ultrasonography for staging gastroesophageal
cancer. Surgery 1997; 121: 10–7.
21. Cohn-Cedermark G, Rutqvist LE, Andersson R, et al. Long
term results of a randomized study by the Swedish Melanoma
Study Group on 2 cm versus 5 cm resection margins for
patients with cutaneous melanoma with a tumor thickness of
0.8–2.0 mm. Cancer 2000; 89: 1495–501.
22. Heald RJ, Husband EM, Ryall RD. The mesorectum in rectal
cancer surgery—the clue to pelvic recurrence? Br J Surg 1982;
69: 613–6.
23. Andreola S, Leo E, Belli F, et al. Adenocarcinoma of the lower
third of the rectum surgically treated with a <10 mm distal
clearance: preliminary results in 35 N0 patients. Ann Surg
Oncol 2001; 8: 611–5.
24. Kuvshinoff B, Maghfoor I, Miedema B, et al. Distal margin
requirements after preoperative chemoradiotherapy for distal
rectal carcinomas: are < or = 1 cm distal margins sufficient?
Ann Surg Oncol 2001; 8: 163–9.
25. Weiser MR, Landmann RG, Wong WD, et al. Surgical salvage
of recurrent rectal cancer after transanal excision. Dis Colon
Rectum 2005; 48: 1169–75.
26. Buroker TR, Nigro N, Bradley G, et al. Combined therapy for
cancer of the anal canal: a follow-up report. Dis Colon Rec-
tum 1977; 20: 677–8.
27. Gurol ME, St Louis EK. Treatment of cerebellar masses. Curr
Treat Options Neurol 2008; 10: 138–50.
28. Wong RJ, Decosse JJ. Cytoreductive surgery. Surg Gynecol
Obstet 1990; 170: 276–81.
29. Yan TD, Black D, Savady R, Sugarbaker PH. Systematic review
on the efficacy of cytoreductive surgery combined with peri-
operative intraperitoneal chemotherapy for peritoneal carci-
nomatosis from colorectal carcinoma. J Clin Oncol 2006; 24:
4011–9.
30. Law WL, Chu KW, Ho JW, et al. Self-expanding metallic stent
in the treatment of colonic obstruction caused by advanced
malignancies. Dis Colon Rectum 2000; 43: 1522–7.
31. Martinez-Santos C, Lobato RF, Fradejas JM, et al. Self-
expandable stent before elective surgery vs. emergency
surgery for the treatment of malignant colorectal obstructions:
comparison of primary anastomosis and morbidity rates. Dis
Colon Rectum 2002; 45: 401–6.
32. Saida Y, Sumiyama Y, Nagao J, Uramatsu M. Long-term prog-
nosis of preoperative “bridge to surgery” expandable metallic
stent insertion for obstructive colorectal cancer: comparison
with emergency operation. Dis Colon Rectum 2003; 46:
S44–9.
33. Xinopoulos D, Dimitroulopoulos D, Tsamakidis K, Apostoli-
kas N, Paraskevas E. Treatment of malignant colonic obstruc-
tions with metal stents and laser. Hepatogastroenterology
2002; 49: 359–62.
34. Liu LX, Zhang WH, Jiang HC. Current treatment for liver
metastases from colorectal cancer. World J Gastroenterol 2003;
9: 193–200.
35. Sugarbaker PH. Repeat hepatectomy for colorectal metastases.
J Hepatobiliary Pancreat Surg 1999; 6: 30–8.
36. Okaro AC, Durkin DJ, Layer GT, Kissin MW, Karanjia ND.
Hepatic resection for breast cancer metastases. Ann R Coll
Surg Engl 2005; 87: 167–70.
37. Reddy SK, Barbas AS, Marroquin CE, et al. Resection of non-
colorectal nonneuroendocrine liver metastases: a comparative
analysis. J Am Coll Surg 2007; 204: 372–82.
38. Giraudo G, Greget M, Oussoultzoglou E, et al. Preoperative
contralateral portal vein embolization before major hepatic
resection is a safe and efficient procedure: a large single insti-
tution experience. Surgery 2008; 143: 476–82.
39. Vogl TJ, Muller PK, Mack MG, et al. Liver metastases: inter-
ventional therapeutic techniques and results, state of the art.
Eur Radiol 1999; 9: 675–84.
27
 4 Multidisciplinary Treatment of Cancer: Chemotherapy
Matthew Wheater, Sarah Lowndes, and Peter Johnson
INTRODUCTION
Whilst there have been many advances in the surgical and
radiotherapeutic control of primary tumors in the last 20 years,
unfortunately in many cases metastatic spread has already
occurred at the time of diagnosis. Further improvements in
survival, therefore, can only be achieved by the introduction of
better systemic treatments for metastases. Chemotherapy is able
to cure advanced disease in some uncommon tumors such as
childhood cancers, teratomas, and lymphomas. In other more
common cancers, such as breast and colorectal cancer, chemo-
therapy and endocrine therapy can cause significant tumor regres-
sion, symptom palliation, and modest improvements in survival
for advanced disease (Table 4.1). When using chemotherapy, a
balance has to be struck between the desire to cure and the inevi-
table side-effects of treatment. In situations where there is a
reasonable chance of cure, modest toxicity and expense may be
acceptable. In the palliative setting, however, the potential benefits
must be weighed carefully against unwanted side-effects.
The first cytotoxic agents to become available were the alkylating
agents, developed after the observation that soldiers exposed to
mustard gas in the First World War developed pancytopaenias.
Clinical trials of a related compound, nitrogen mustard, found that
these agents were capable of causing significant regression in lym-
phomas. This was soon followed by production of the antifolates,
aminopterin, and methotrexate. Since 1965, numerous new anti-
metabolites, alkylating agents, and antibiotics with significant
activity have been developed, many of which are related to the par-
ent molecules discovered over 20 years ago. Examples of important
drugs introduced into clinical practice in the last 15 years include
etoposide (germ cell tumors and small cell lung cancer), platinum
analogues (lung cancer, germ cell tumors, ovarian cancers, and
bone sarcomas) and taxoids (breast and ovarian cancer).
THE RATIONALE OF CHEMOTHERAPY
Tumor Cell Growth
It is necessary to understand the basic characteristics of tumor cell
growth in order to understand why it may be difficult to cure
more cancers with systemic treatment. Chemotherapy drugs are
developed for their potential to cause a greater proportion of cell
death among tumor cells as compared to normal cells. As with
normal tissues, tumors have a heterogeneous population of cells,
some proliferating and some lying dormant in the G0 phase. All
proliferating cells must pass through a cell cycle (Fig. 4.1). The
total duration of the cycle in malignant cells can vary between
under 10 and over 40 hours. For aggressive, highly proliferative
tumors, the cell cycle is shorter and for slower-growing, more
indolent tumors, longer. This leads to considerable variation in
the speed with which different tumors increase in size.
28
The time taken for a tumor to double in size, however, is longer than
the cycle time of its constituent cells. This is because only a proportion
of cells are in cycle at any one time and some gains are compensated
by a high rate of cell death. That only 20% to 30% of cells are cycling
in tumors at any one time is of particular relevance, as most cytotoxic
drugs are most effective against cells that are dividing.
Gompertzian Growth and Fractional Cell Kill
In order to understand the response of tumors to chemotherapy
and the mechanism of relapse, various theories of tumor growth
have been developed. The rate of proliferation of a tumor is thought
not to be constant. In the early stages, growth is exponential and
the growth fraction, the percentage of cells proliferating, is high. As
the tumor enlarges, the growth rate slows and the growth fraction
falls. This pattern of growth, known as Gompertzian, dictates the
effect of chemotherapy: As the tumor grows, fewer cells remain
in cycle and the inherent resistance to chemotherapy increases,
making the disease harder to cure (Fig. 4.2).
In the early 1960s, the effects of chemotherapy were investigated
on leukemia cell lines (1). The results suggested that cell destruc-
tion by anticancer drugs follows log-kill kinetics, such that a given
dose of a cytotoxic drug kills a proportion of cells and is not a
given number. Thus, if a particular dose of an individual drug kills
99% of cells and there are initially 1010 cells, the tumor burden will
be reduced to 108 cells; the same dose used at a tumor burden of
105 will reduce the tumor burden to 103 cells. The cell kill is, therefore,
proportional regardless of the tumor burden.
These principles imply that tumors are best treated when they
are small in volume when fewer exposures to drugs will be required
and there is less chance of resistance emerging. The Gompertzian
model also predicts that when a tumor is small, its growth fraction
will be at its largest, and the proportional cell kill higher. These
principles form the basis of adjuvant chemotherapy strategies.
Tumor Regression and Cure
The smallest tumor that is likely to be clinically detectable by
either physical or conventional radiologic assessments is approxi-
mately 1 cm in diameter and will contain 108 to 109 cells. Such a
tumor will have undergone approximately 30 doublings, if it is
clonally derived from a single transformed cell, and will usually
weigh about 1 g. Growth to a potentially lethal mass of 1 kg of
tumor requires only a further 10 doublings. Therefore, the period
of tumor growth that is clinically apparent is only a relatively short
episode in the total life history of a tumor.
This demonstrates both the potential for micrometastases to
develop before detection of the primary tumor and why it is dif-
ficult to cure patients with chemotherapy. If the patient starts che-
motherapy with a tumor population numbering 1011 and the
treatment given over four months achieves a cell kill of three logs,
then the tumor will be reduced from 1011 to 108 cells. At this point
the patient would have no clinically detectable tumor and would
 multidisciplinary treatment of cancer: chemotherapy

Table 4.1 Varying Response of Different Tumors to Chemotherapy appear to be cured. In fact there would still be over 100 million
tumor cells remaining in the body and relapse is inevitable. Even
High cure, high Some cure, No cure, some Low response assuming a linear response to continued treatment, eradication
response good response response
would require a further 12 months of therapy. In practice, the
ALL AML Breast Non-small cell selection of chemoresistant tumor cells and cumulative normal tis-
(metastatic) lung cancer sue toxicity limit what can be achieved. Conversely, in those tumors
Hodgkin’s Non- Hodgkin’s Ovary Stomach that can be cured by chemotherapy, there are likely to be other
lymphoma lymphoma Myeloma Pancreas
Testicular Small cell lung Colorectal Glioma
mechanisms involved such as the development of host immunity.
cancer Bladder Esophagus
Choriocarcinoma Osteosarcoma Melanoma Key Points: The Rationale of Chemotherapy
Childhood cancers Breast (primary) Renal cell
Burkitt’s cancer ■ Chemotherapy drugs are developed for their potential to
lymphoma cause a greater proportion of cell death among tumor cells as
Abbreviations: ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia. compared to normal cells
■ Cytotoxic drugs are most effective against dividing cells—
usually only 20% to 30% of cells in a tumor
■ As a tumor enlarges, the percentage of proliferating cells falls
and the tumor becomes more resistant to chemotherapy. This is
G0
G1 known as Gompertzian growth
■ By the time a tumor becomes detectable, it contains 109 cells.
Chemotherapy regimens must continue after the tumor
appears radiologically “cured” in order to eradicate the
remaining tumor cells

INDICATIONS FOR CHEMOTHERAPY

M Chemotherapy is given in three clinical settings: adjuvant therapy,
primary (neo-adjuvant) therapy, and therapy for metastatic dis-
ease. In some cases, particularly the primary treatment of epithelial
tumors, the combination of chemotherapy with synchronous
irradiation is increasingly used.
S
Adjuvant Chemotherapy
When chemotherapy was first discovered, it was used only in
G2 advanced disease when other treatment modalities had failed.
However, as discussed above, there are reasons to believe that
chemotherapy may be more effective against subclinical micro-
metastatic disease. Following the resection of an operable cancer,
many patients will develop local or distant recurrence, even if no
evidence of spread is found at operation or during preoperative
Figure 4.1 The cell cycle. After cell division the cell spends a variable period in the
growth phase G1, during which RNA and protein are produced. On entry into S
investigations. It is, therefore, logical to use cytotoxic chemotherapy
phase, the DNA content is doubled. The G2 phase follows and the cell then passes as an adjuvant to surgery in the aim of eradicating micrometastases
into mitosis, M, in which the pairs of chromosomes separate and the cell divides. rather than waiting until a clinical recurrence is apparent and
when the tumor will almost certainly be beyond cure. This
approach has been very effective in sensitive pediatric tumors such
as Wilms’ tumor, Ewing’s sarcoma, and rhabdomyosarcoma. It is
1012 now established that modest but definite improvements in survival
Clinically detectable
tumor may be obtained with adjuvant chemotherapy in some common
Threshold for adult tumors. Thus, adjuvant therapy is of proven value in premeno-
109 tumor detection
Tumor cells

pausal women with breast cancer (2) and in colorectal cancer (3),
and is under investigation in several other tumor types.

106 Linear Primary (Neo-adjuvant) Chemotherapy

Gompertzian It has been suggested that chemotherapy might be given as a primary
103 treatment prior to surgical removal of a tumor. This treatment has
been called neo-adjuvant chemotherapy and is given with the aim of
Time both tumor shrinkage, enabling surgery to be carried out more eas-
Figure 4.2 Gompertzian growth curve. ily, and control of any occult metastases. In addition, this strategy

29
 general principles
often includes irradiation of the primary tumor. Neo-adjuvant therapy
has the advantage that it can be given immediately, whereas adjuvant
treatment may be delayed through postoperative complications, by
which time any micrometastases will have increased in size and be
less easy to eradicate. The main disadvantage of this approach is that
not all tumors will be sensitive to the drugs given, so that in some
instances there is a risk in delaying surgery and in exposing the
patient to unnecessary toxicity. Studies have suggested a benefit for
neo-adjuvant chemotherapy in esophageal cancer (4), osteogeneic
sarcoma, and head and neck cancer.
Metastatic Disease
Most chemotherapy is given in the setting of metastatic disease. In
rare tumors such as testicular cancer and lymphoma, chemotherapy
can be curative even in this context. In most situations, however,
the aim of treatment is to palliate symptoms and to prolong life.
In cancers such as those of the breast and ovary, although they are
rarely curable with chemotherapy, complete remissions are
common, with absence of detectable tumor for periods of months
to years. Less sensitive tumors such as colorectal cancer and
non-small cell lung cancer (NSCL) have a low response rate to
chemotherapy, but such treatment can nonetheless palliate the
symptoms of advanced malignancy. Despite the many theories of
tumor growth, it remains unclear as to why some malignancies are
generically responsive and others relatively resistant to chemotherapy.
Key Points: Indications for Chemotherapy
■ Adjuvant chemotherapy is given to eradicate micrometasta-
ses after an operable tumor has been eradicated
■ Primary (neo-adjuvant) chemotherapy given to shrink
tumors and to eradicate occult metastases is of benefit in
esophageal cancer, osteogenic sarcoma, and head and neck
cancers
■ Chemotherapy for metastatic disease is given in most cases
to palliate symptoms and to prolong life, and only with
curative intent in a few tumors such as testicular cancer and
lymphoma
CHEMOTHERAPY SCHEDULES
Dose Intensity
The corollary of the Gompertzian model of tumor growth is that
as the mass of disease is reduced so the growth fraction may rise.
This, together with the assumed selection of resistant subclones,
underlies the idea that tumor eradication is dependent upon the
delivery of treatment at adequate dose intensity. If doses are too
small or too infrequent the fractional cell kill can be expected to
decline, and optimal treatment may require a progressive
increase in intensity. Unfortunately, this is rarely practicable
owing to normal tissue toxicity, although strategies such as high-
dose therapy with peripheral blood progenitor cell rescue have
been used in some tumor types to good effect, where the active
agents have marrow depression as their rate-limiting toxicity.
There is some evidence to support a relationship between dose
and response in chemotherapy, although much of this evidence is
derived from studies in cell lines carried out more than 20 years
ago. Few clinical trials have adequately tested this relationship,
30
and many of those that did so have proven negative. The intensifi-
cation of treatment which can be achieved even with progenitor
cell support is relatively modest, perhaps one log at best, and it is
likely that the relationship of dose to response is non-linear for
most tumor types. This means that a threshold may be reached
beyond which further intensification is of little benefit, whilst
below this level a reduction in dose intensity results in inferior
outcomes. Many years of clinical experimentation have sought to
determine which tumor types have such a threshold, and whether
this is reached by the cytotoxics now available.
Combination Chemotherapy
Populations of cells within a tumor are more genetically unstable
than normal cells and have a high rate of random mutation, which
may lead to resistance to cytotoxic agents (5). These spontaneous
mutations occur at such a rate that, by the time the tumor becomes
detectable it is likely to have several drug-resistant clones. This
explains the common clinical scenario of a tumor responding ini-
tially to chemotherapy only to relapse later when the resistant
clones expand. Some tumors, such as metastatic melanoma, are
resistant to cytotoxic chemotherapy agents even when they pres-
ent with a relatively small tumor volume. One possible explana-
tion is that slow-growing tumors may have gone through more
cell-doublings owing to the amount of cell loss in achieving that
size, leading to a higher number of spontaneous mutations and
hence drug-resistant clones. There are, however, many other
potential mechanisms of drug resistance (Table 4.2).
The rationale of combination chemotherapy is that a tumor
cell, which is resistant to one drug with a particular mode of
action, might be susceptible to a different agent with an alterna-
tive form of cytotoxicity. Combining drugs with different mecha-
nisms of cell kill should circumvent as many resistance mechanisms
as possible. Clinical trials in a variety of malignancies confirmed
the value of combination chemotherapy; for example, in advanced
breast cancers, cyclophosphamide and 5-fluorouracil (5-FU) each
have a response rate of 25% but when combined have a response
rate of over 50%. In some instances, combining two agents has
resulted in synergy, the results of treatment being better than
would have been expected from adding the effect of the two drugs
used singly.
Table 4.2 Mechanisms of Resistance to Anticancer Drugs
Mechanism Drugs involved
Efflux of drug via multi-drug resistance protein Anthracyclines, etoposide,
vinca alkaloids
Decreased intracellular glutathione Alkylating agents
Increased production of target molecule:
Dihydrofolate reductase Methotrexate
O6-Alkyltransferase Nitrosoureas
Increased DNA repair Alklyating agents
Antibody formation Asparaginase
Decreased drug activation (pro-drugs) 5-FU, 6-MP
Increased intracellular breakdown Cytosine arabinoside,
methotrexate
Bypass biochemical pathways Methotrexate, 6-MP, 5-FU,
asparaginase
Tumor hypoxia and decreased growth fraction All drugs
Abbreviations: 5-FU, 5-fluorouracil; 6-MP, mercaptopurine.
 multidisciplinary treatment of cancer: chemotherapy
There are general principles guiding the selection of drugs for
use in effective combination chemotherapy regimens (Table 4.3).
Intermittent Chemotherapy
The majority of chemotherapy is given intermittently, often every
three weeks. The aim of this treatment is to exploit the diminished
capacity of tumors for repair and repopulation after injury com-
pared with normal tissues. If a treatment is given at such intervals
that the normal tissue has had time to repair and regenerate, but
the tumor has not, it is in theory possible to eradicate the tumor
without jeopardizing the normal stem cell population. In humans,
the tissues most damaged by chemotherapy are the gut and bone
marrow, both of which regenerate quickly in comparison with
most cancer tissues. If the time between treatments is too short,
toxicity to normal tissues will be too great, resulting in doses being
omitted. If the interval between treatments is too long, this will
allow increases in the tumor cell population between courses
(Fig. 4.3). This is a simplistic model, as for reasons discussed
previously, the tumor cell growth fraction may increase as the
overall tumor size decreases with treatment. Intermittent therapy
does, however, allow treatment to be continued for much longer
periods thereby increasing the chance of cure.
Single-Agent Continuous Chemotherapy
Chemotherapy can also be given orally or as an infusion using
implantable venous catheters and portable infusion pumps. The
theoretical aim is to prolong tumor exposure to the drug so that it
is present when the tumor cell is at a sensitive phase of the cell
cycle, whatever the cycle length. The concentration of drug in the
plasma is much lower than the peaks seen with bolus treatment,
theoretically minimizing toxicity if this is mediated by intermit-
tent high levels. For many drugs this mode of delivery has proved
ineffective or toxic, but a notable exception is 5-FU, where toxicity
Table 4.3 Selection of Drugs for Use in Combination
Each drug should have activity against the tumor when used alone, with those
drugs with maximal efficacy most preferable
Drugs should have different mechanisms of action
Drugs should have minimal overlapping toxicities, where possible, in order to
decrease the risk of potentially life-threatening cumulative toxicity to the
same organ system
Each drug in a combination should be used in its optimal dose and schedule
Normal cells
Tumor cells (log)
Tumor cells
Time
Figure 4.3 The effect of intermittent chemotherapy on normal and tumor cell
populations.
is reduced and efficacy is increased when given as a continuous
intravenous infusion rather than by intermittent boluses (6). A
new fluoropyrimidine, capecitabine, has been developed that can
be given orally for the same indications with similar side-effects
and equal efficacy (7).
Key Points: Chemotherapy Schedules
■ Eradication of tumor depends on an adequate dose intensity,
but this is limited by toxicity to normal tissues
■ Combination chemotherapy is given to circumvent as many
resistant tumor cell lines as possible and therefore achieve
maximal cell kill
■ Chemotherapy is usually given intermittently to allow nor-
mal tissue to repair but not the tumor
Route of Administration
Traditionally, chemotherapy agents have largely been given intra-
venously due to erratic oral absorption and problems with compli-
ance. When administered parenterally, many of the drugs are
sclerosant and require concurrent intravenous fluids to be admin-
istered. They can be given as boluses, short infusions, or protracted
infusions through indwelling central venous catheters. The desire
to move cancer treatment to an outpatient setting, together with a
growing body of information showing higher antitumor activity or
lower systemic toxicity with dosing regimens that produce pro-
longed exposure to some cancer agents, suggests that oral cancer
chemotherapy may be of increasing interest in the future. This has
already led to the evaluation of oral administration of anticancer
drugs that have been available for many years (e.g., etoposide) as
well as novel strategies for oral use of anticancer drugs traditionally
given intravenously, for example the oral fluoropyrimidines (7).
Subcutaneous and intramuscular routes are rarely employed
because large volumes of diluent are required and they are often
highly toxic to tissues in the extravascular compartments. Metho-
trexate or cytosine arabinoside can be administered intrathecally
to palliate or prevent meningeal disease because systemic chemo-
therapy penetrates the blood–brain barrier poorly. Intra-arterial
administration of drugs via the hepatic artery to achieve high doses
of drug locally has also been attempted. However, in metastatic
colorectal cancer, hepatic arterial infusion of 5-FU did not confer
increased survival when compared to standard intravenous infu-
sional 5-FU and was associated with substantial toxicity (8). Other
routes of cytotoxic chemotherapy administration include chemo-
embolization strategies; intra-arterial administration in isolated
limb perfusion in melanoma or sarcoma; intravesical administra-
tion in superficial bladder cancers; and intraperitoneal administra-
tion to small tumor nodules on the peritoneal surface.
DRUG DEVELOPMENT
Many chemotherapy agents have been discovered largely by serendip-
ity. New agents are still often discovered by chance, although active
agents are also being developed as a result of increased understanding
of the biochemical and biological behavior of cancer cells. Design of
inhibitors to known molecular targets is the focus of investigation for
the immediate future, exploiting advances in structural biology and
combinatorial chemical libraries to identify compounds which may
31
 general principles

produce specific effects in critical pathways. New agents are discovered Table 4.4 Classification of Cytotoxic Agents
as novel chemical entities due to knowledge of the molecular basis of
Alkylating agents Mitotic spindle poisons
their action, or by chemically modifying an existing agent for improved
potency or decreased toxicity. Examples of successful analogues are Mustine Vincristine
epirubicin (from doxorubicin), carboplatin (from cisplatin), and Cyclophosphamide and ifosfamide Vinblastine
Chlorambucil Vinorelbine
topetecan (from camptothecin). Once an agent has been identified, it Melphalan Vindesine
undergoes in vitro and in vivo evaluation followed by toxicology Dacarbazine Paclitaxel
studies, and finally, clinical development. BCNU and CCNU Docetaxel
Busulphan
Clinical Development Platinum analogues Topoisomerase inhibitors
Phase I studies are the first trials of a new agent in humans after pre- Cisplatin Etoposide
clinical investigations have suggested the appropriate dose schedule Carboplatin Yopotecan
and the likelihood of any particular toxicities. The main aim of a Oxaliplatin Irinotecan
Phase I trial is to discover the maximal tolerated dose by using a dose Antimetabolites Miscellaneous
escalation protocol and to document the toxicities associated with Methotrexate Procarbazine
the drug. As a result, clinical response rates in Phase I trials are often 5-Fluorouracil Hydroxyurea
low. The patients who take part in such studies normally have disease Cytosine arabinoside l-asparaginase
that is refractory to standard therapy. Phase I trials incorporate phar- 6-Mercaptopurine
macokinetic and pharmacodynamic studies and assessment of bio- 6-Thioguanine
Fludarabine
logical end-points are often included, e.g., inhibition of a target
Antitumor antibiotics
enzyme. Once the maximum tolerated dose has been reached, the
previous lower dose level is generally expanded to a larger cohort of Doxorubicin
Epirubicin
patients and becomes the chosen dose for further studies.
Daunorubicin
Phase II trials are conducted using the dose and schedule identi- Mitoxantrone
fied from Phase I trials, with the aim of assessing the efficacy of Actinomycin-D
the drug and taking the response rate as the primary end-point. Bleomycin
The patients are less heavily pretreated and need to have measur- Abbreviations: BCNU, 1,3-bis(2-chloroethyl)-1-nitrosourea; CCNU, 1-(2-chloroethyl)-3-
able disease in order to assess whether there has been a response. cyclohexyl-1-nitrosourea.

The tumor types investigated in Phase II trials depend on data

from preclinical and Phase I trials. Phase II studies involve roughly
15 to 50 patients and are designed to allow early study termination
if a reagent is proving to have minimal efficacy. A response rate of
20% is usually considered worthy of further evaluation, although
this depends on the tumor type in question. Phase II studies tra-
ditionally have used a single arm design with all patients receiving
the investigational drug but in some illnesses; for example, those
in which patient selection may result in wide variations of outcome,
trials now involve randomization to the new agent versus a known
active agent, or the new agent may be added to a standard therapy.
If the new agent in question satisfies these steps, it is finally com-
pared to existing standard therapy in a Phase III trial, ideally a pro-
spective randomized controlled trial. Suitable end-points for a Phase
III study include progression-free survival and overall survival. Data
on quality of life and comparative toxicities are also collected, in order
to determine the overall clinical benefit of a treatment. Phase III trials
are generally large, consisting of hundreds of patients, because the
difference between treatments may be small and the numbers
required for adequate statistical power are therefore increased.
CLASSIFICATION AND TOXICITIES OF CYTOTOXIC
DRUGS (TABLES 4.4 AND 4.5 AND FIG. 4.4)
Alkylating Agents and Nitrosoureas
The alkylating agents were the first chemotherapy agents devel-
oped for use in malignant diseases. They work by covalently link-
ing an alkyl group (R-CH2) to other molecules, particularly nucleic
acids and proteins. The most lethal interaction is thought to be
the alkylation of two separate bases on antiparallel strands of
Table 4.5 Toxicities of Chemotherapy
Toxicity Drug
Pulmonary fibrosis Busulphan
BCNU, CCNU
Bleomycin
Gemcitabine (infiltrates)
Hepatic Methotrexate (fibrosis)
6-MP
Asparaginase
Neurological Vinca alkaloids
Ifosfamide
Gastrointestinal Vinca alkaloids (paralytic ileus)
Abbreviations: BCNU,1,3-bis(2-chloroethyl)-1-nitrosourea; CCNU,1-(2-chloroethyl)-
3-cyclohexyl-1-nitrosourea; 6-MP, mercaptopurine.
DNA, binding them together and preventing their separation at
the time of DNA replication, which ultimately leads to cell death.
Alkylating agents are active against a broad range of malignan-
cies. The main toxicities are myelosuppression, gastro-intestinal
toxicity, and alopecia. Long-term use leads to infertility and
secondary cancers, particularly leukemias (9). Cyclophosphamide
and ifosfamide administration is complicated by a chemical cystitis
which can vary in severity from mild cystitis to massive hemorrhage.
This can be prevented by administration of sodium-2-mercaptoethane
(mesna), which inactivates acrolein, the toxic metabolite in the
urine. Peculiar to ifosfamide is a neurological syndrome that can be
severe, characterized by confusion, somnolence, fits, cranial neu-
ropathies and, rarely, fatal coma, the mechanism of which is as yet
unknown. Prolonged treatment with busulphan can also lead to
a form of interstitial pulmonary fibrosis. To prevent this, chest

32
 multidisciplinary treatment of cancer: chemotherapy

Plant-derived
agents G0

Vinblastine Destroys mitotic spindle Mitosis

Vincristine
M
Docetaxel Prevents spindle disassembly
Paclitaxel G2 G1

Etoposide DNA synthesis

Inhibit topoisomerase
Topotecan
prevent DNA uncoiling
Irinotecan
Anti metabolites
Inhibits dihydrofolate reductase Methotrexate
Purine and
Inactivates 5 fluorouracil
Pyrimidine bases
Newer agents thymidylate synthase Gemcitabine
e.g., Inhibits DNA polymerase Cytarabine
DNA
Monoclonal
polymerase
antibodies
CH3 Alkylating agents
Tyrosine kinase Covalently link DNA
inhibitors N Mustine
CH3 by alkylation
CH3 Cyclophosphamine
Ifosfamide
Chlorambucil
Downstream signalling Melphalan
altering gene expression, Busulphan
cell growth and apoptosis NH3 Cross link DNA
Pl Platinum analogues
Act on NH3
cell membrane Cisplatin
targets Carboplatin
Oxaliplatin

Steroid hormones Antitumor

Intercalates between antibiotics
Glucocorticoids base pairs leading to
Estrogens Bind receptor and Doxorubicin
double strand breaks
Anti-oestrogens alter gene expression Epirubicin
Androgens Daunorubicin
Actinomycin D
Bleomycin
Mitoxantrone

RNA

Alter protein production

Proteins
e.g., hormones, enzymes
Figure 4.4 Chemotherapy drugs and their mechanism of action.

radiographs should be taken regularly, and if any fibrosis is noted
the drug should be stopped and steroids instituted.
Platinum Analogues
Cisplatin and its derivatives cause cell death by reacting with DNA
bases causing linkages with bases on the same strands of DNA
(intrastrand linkages) as well as cross-linking paired DNA strands,
ultimately causing cell death. Cisplatin has a wide spectrum of
activity against solid tumors and is an integral component of
curative regimens for testicular and ovarian cancer. It is excreted
renally and is highly nephrotoxic, requiring prolonged hydration
after a dose to ensure adequate clearance. Cumulative doses of
cisplatin also lead to neurotoxicity, usually manifested as a sensory
peripheral neuropathy or hearing loss. Carboplatin is a cisplatin
analogue which is much less nephrotoxic and neurotoxic and is a
valuable palliative treatment for both small cell and NSCL cancer.
Oxaliplatin is a third-generation platinum analogue that dem-
onstrates a degree of non-cross-resistance with other platinum
compounds and differences in its cellular mechanism of action.
Ovarian and colorectal tumors show sensitivity to oxaliplatin and,
in the latter, there is evidence for synergy with 5-FU (10). Hema-
tological toxicity is mild, but there is a neurotoxicity characterized
by reversible paresthesiae and, less commonly, with only partially
reversible peripheral neuropathy.
Antimetabolites
Antimetabolites are compounds with very similar structure to
essential RNA and DNA precursors, which either block a vital

33
 general principles
enzyme or get incorporated into the nuclear material and interfere
with its function. Methotrexate inhibits dihydrofolate reductase,
which is required for the production of purines and pyrimidines. It
accumulates in third spaces and should therefore be avoided in
patients with effusions because of the risk of severe toxicity. After
high doses, pancytopenia develops rapidly followed by oral ulcer-
ation and diarrhea. The small bowel is also susceptible and, occa-
sionally, severe hemorrhage and perforation occur. Renal failure can
also occur with high-dose methotrexate. Folinic acid (leukovorin) is
able to inhibit the action of methotrexate and can be given to pre-
vent systemic toxicity. Methotrexate also acts partly through inhibi-
tion of the enzyme thymidylate synthase (TS). More specific
inhibitors of TS have been developed such as ralitrexed (Tomudex)
and palitrexed (11).
5-Fluorouracil acts as an analogue of uracil, interfering with RNA
and DNA synthesis. The main toxic effects are nausea, mucositis,
diarrhea, myelosuppression and, when infused continuously, plan-
tar-palmar erythrodysesthesia. Capecitabine is a new, orally avail-
able tumor-selective fluoropyrimidine. Side-effects are similar to
those seen with 5-FU and severe toxicities are infrequent.
Cytarabine (cytosine arabinoside) is a pyrimidine analogue used
in lymphoma and leukemia. It is strongly myelosuppressive and
rarely causes syndromes of pulmonary, hepatic, and neurotoxicity.
Gemcitabine, a new pyrimidine analogue, is structurally similar to
cytarabine. A rare pulmonary toxicity has been implicated (12).
Antitumor Antibiotics
The anthracyclines are the most important group of antitumor
antibiotics and act by intercalating between base pairs in DNA,
causing strand breaks. The major long-term complication of
these agents is a cumulative dose-limiting cardiotoxicity, thought
to be due to free radical formation, which is irreversible and may
be fatal. They are also very myelosuppressive. Bleomycin is of
value in the treatment of testicular teratomas, lymphomas and
some squamous cell carcinomas and can be given into body
cavities to control malignant pleural or pericardial effusions.
However, bleomycin can cause significant pulmonary damage,
initially manifesting as a pneumonitis and progressing to a fatal
pulmonary fibrosis. This effect is dose-related but increasing age,
underlying emphysema, and previous radiotherapy all increase
the risk of pulmonary toxicity. Patients who have received bleo-
mycin are also at higher risk of respiratory complications following
a general anesthetic. The lung damage is only partially reversible
after stopping the drug. Actinomycin D works by a similar mecha-
nism to bleomycin, but may provoke radiation recall phenomena
causing inflammatory reactions in previously irradiated areas. The
mechanism of this is unknown.
Plant-Derived Agents
Vinca alkaloids were isolated from the periwinkle plant and act as
mitotic spindle poisons. Vincristine and vinblastine are widely
used, both as single agents and in combination therapy. The most
important side-effect is neurotoxicity, usually a mild peripheral
neuropathy which can progress to an irreversible neuropathy with
wrist drop, foot drop, and other paralyses. Constipation, which
can occasionally cause paralytic ileus, is a further complication.
Paclitaxel (taxol), isolated from the bark of the Pacific Yew tree, inter-
feres with cell division by promoting the assembly of microtubules and
34
preventing their disassembly. Administration is associated with
allergic hypersensitivity reactions, which can be limited by pre-
medicating with corticosteroids and antihistamines. Neutropenia
is the dose-limiting toxicity. Neurotoxicity occurs with higher
cumulative doses of paclitaxel and is manifested as a “glove and
stocking” sensory neuropathy. Docetaxel is a semi-synthetic taxoid
which may be more potent than paclitaxel and also has incomplete
cross-resistance, although toxicities are similar (13).
Topoisomerase inhibitors block the actions of DNA topoi-
somerase I and II, nuclear enzymes that unwind supercoiled DNA
to allow essential DNA reactions to occur, including those involved
in replication and repair. An example is etoposide, which has good
oral bioavailability and clearance which is decreased in renal dis-
ease. Side-effects include myelosuppression, alopecia, nausea, vom-
iting, and diarrhea. Topetecan, an inhibitor of topoisomerase I, has
significant activity in refractory ovarian cancer. Irinotecan is now
licensed in the United Kingdom for the treatment of 5-FU-relapsed
colorectal cancer. The main toxicities are myelosuppression, alope-
cia, and diarrhea. Early diarrhea (within 24 hours) appears to be
due to cholinergic release and can be limited by subcutaneous
atropine administration, but late diarrhea occurs by a different
mechanism. This can be prolonged and severe, and requires prompt
administration of loperamide to prevent dehydration.
Key Points: Classification and Toxicities of Cytotoxics
■ Alkylating agents are active against a broad range of malig-
nancies and can result in myelosuppression, gastro-intestinal
toxicity, and alopecia. Cyclophosphamide and ifosfamide can
cause cystitis
■ Bleomycin and busulphan can cause severe pulmonary
fibrosis
■ Platinum analogues (such as cisplatin) are an integral part of
regimens for testicular and ovarian cancer; neurotoxicity can
result
■ Antimetabolites (methotrexate, 5-FU, cytosine arabinoside)
interfere with RNA and/or DNA synthesis and can cause
myelosuppression and gastro-intestinal disturbance
■ The major long-term complication of anthracyclines (e.g.,
doxorubicin) is cardiotoxicity
■ Plant-derived agents include vinca alkaloids (vincristine and
vinblastine) and paclitaxel (taxol)
ENDOCRINE THERAPIES
The proliferation of certain tissues is influenced by specific
hormones. Glucocorticoid hormones interact with receptors pre-
dominantly in the cell nucleus and interfere with DNA synthesis.
They are widely used in the treatment of leukemias and lympho-
mas. The growth of some tumors, particularly carcinomas of the
breast or prostate, is partly dependent on hormones, and altera-
tion in the endocrine environment of these tumors may bring
about regression. This can be achieved by surgically removing the
gland producing the hormone (e.g., orchidectomy in prostate
cancer), or medically by preventing the production of the
hormone (e.g., aromatase inhibitors decrease estrogen production).
Alternatively, hormones with the opposite action or an antagonist
can be administered. Tamoxifen, an estrogen antagonist, has been
 multidisciplinary treatment of cancer: chemotherapy
a major advance in the treatment of postmenopausal metastatic
breast cancer and as adjuvant treatment of primary breast tumors
(14). The presence of estrogen receptors (ER) on the primary tumor
is correlated with response to endocrine therapy. In prostatic cancer,
gonadotropin-releasing hormone analogues paradoxically inhibit
luteinizing hormone release and suppress testosterone release. Unfor-
tunately, the effects of hormones are usually temporary, because cells
that acquire hormone resistance eventually predominate.
BIOLOGICAL RESPONSE MODIFIERS
Various biological agents have been developed in the hope of
stimulating the body to recognize malignant tissue as foreign. This
can take the form of passive immunotherapy using the infusion of
antibodies, active immunotherapy with tumor-related vaccines
and immunomodulation with substances that stimulate the
immune system. These agents work in a completely different man-
ner to conventional cytotoxic chemotherapy and may require
alternative modalities of imaging to assess their response. Delayed
responses can also be seen many months after treatment.
Positron emission tomography may be more helpful than conven-
tional imaging due to its ability to measure decreased metabolism in a
tumor prior to any morphological change on conventional scans (15).
Cytokines
Cytokines are a group of proteins released from various cell types,
some of which stimulate the growth of cells and some modulate
the immune response. Interferon α (IFN-α) is used in hairy cell
leukemia and chronic myeloid leukemia with good response.
Lower response rates are seen in melanoma and renal cell cancer
Transmembrane
receptor, e.g.,
transtuzumab
Receptor
tyrosine kinase,
e.g., erlotinib
mRNA, e.g.,
oblimersen
DNA
transcription,
e.g., vorinostat
Figure 4.5 Novel pathways which are targeted in cancer therapeutics.
(16). Side-effects include an influenza type illness and leucopenia
may occur. Interleukin-2 produces responses in 15% to 30% of
patients with metastatic renal carcinoma and melanoma, some of
these responses being very durable.
Differentiation Agents
Vitamin A and its active derivatives regulate the growth of a variety
of cell types by binding receptors that are members of the steroid
receptor superfamily, and thereby altering gene expression. At the
cellular level, activation of retinoid receptors can inhibit cell prolif-
eration, induce proliferation, and induce apoptosis in normal and
transformed cells in tissue culture. ATRA (all-transretinoic acid)
induces complete remission in the majority of patients with acute
promyelocytic leukemia (APL), with rapid resolution of the char-
acteristic life-threatening coagulopathy. The duration of remission
with ATRA alone is usually brief and post-remission chemotherapy
is required to diminish the likelihood of relapse. ATRA improves
disease-free and overall survival as compared with chemotherapy
alone in the treatment of APL (17).
TARGETED THERAPIES
Although historically cytotoxic chemotherapy has always exploited
differences between malignant and non-malignant cells, predom-
inantly in their ability to respond to DNA damage, a new generation
of reagents is now being used in cancer therapy based upon the
emergent understanding of cancer genetics, cell biology, and
immunology. These agents have been rationally designed to target
cancer cells, either specific biochemical pathways critical to their
survival, markers of cellular differentiation, or both, to allow
destruction of malignant tissues (Fig. 4.5).
Circulating growth
factors, e.g.,
bevacizumab
P
P Non-receptor
tyrosine kinases,
e.g., imatinib
Proteosome, e.g.,
bortezomib
35
 general principles
Monoclonal Antibodies
Antibodies are glycoprotein molecules that form a major constit-
uent of the response to infection. They are found on the surface of
B-lymphocytes as part of the B cell receptor complex, as well as
being secreted in soluble form by plasma cells. A vast array of anti-
body molecules is produced by an individual organism, each
corresponding to a specific antigen. Antibodies are able to bind to
foreign antigen and target this for destruction by a variety of
means, including complement-mediated cytotoxicity (CMC), and
antibody dependent cellular cytotoxicity (ADCC). Both this spec-
ificity of antibodies to individual target antigens, and their ability
to activate destruction of the target have been exploited to develop
therapeutics in human diseases, particularly cancer therapy.
Monoclonal antibodies are specific antibody molecules, targeting
a single antigen. They are generated from animal models, and are
therefore specific to the species from which they were originally gen-
erated. If such antibodies are used for therapeutic purposes in
humans, the antibody itself is recognized as foreign. This results in
rapid destruction as well an allergic or even anaphylactic response.
To prevent this, various degrees of modification may be undertaken
in order to reduce the immunogenicity of the immunoglobulin mol-
ecule. Chimeric antibodies are formed, through recombinant tech-
nology, by the fusion of the variable region of the immunized species
to a human constant domain. This reduces the immunogenicity of
the antibody, while improving the effector function of the constant
domain. This process may be taken a step further with the formation
of humanized antibodies. In this case only the complementarity
determining regions of the immunized species are used, with the rest
of the antibody molecule being human. Fully human antibodies may
also be produced in one of two ways. Either transgenic mice, in
which human antibody genes have been inserted, may be immu-
nized to obtain human antibodies, or phage display libraries may be
used to generate a spectrum of human variable regions, which may
subsequently be converted to complete antibodies (Fig. 4.6).
Antibodies Used in Hematological Malignancies
Hematological malignancies were the first to be successfully treated
with this new generation of agents. Rituximab, a chimeric mouse/
human antibody against the CD20 B lymphocyte marker, is now a
standard component of the first line treatment of diffuse large B cell
lymphoma (DLBCL), and of follicular lymphoma (FL), together
accounting for about 50% of all non-Hodgkin Lymphoma. By a
combination of CMC, ADCC, and induction of apoptosis, Ritux-
imab causes destruction of all mature B cells, but spares hemopoietic
stem cells and plasma cells, allowing regeneration of normal B cell
clones. Addition of Rituximab to standard CHOP combination
Mouse antibody Chimeric antibody Humanised antibody
Figure 4.6 Modifications to monoclonal antibodies to reduce toxicity and improve function.
36
chemotherapy improves both response rate and survival in DLBCL
(18). It is used together with combination chemotherapy in patients
with symptomatic stage III or IV FL where it has shown benefit in
both response and disease free survival. A benefit in overall survival
has been shown in patients treated on relapse and is awaited in use as
initial therapy (19,20). It also has single agent activity and may be
used alone in patients with disease refractory to other modalities
(21). A role is being developed in using Rituximab as maintenance
therapy following completion of chemotherapy with further advan-
tages seen in prolonging remission and survival (22). It is likely that
increasingly patients will be maintained on long-term treatment.
Alemtuzumab (Campath-1H) is a humanized monoclonal
antibody against CD52, a cell surface marker on both B and T lym-
phocytes, but again not expressed on hemopoietic stem cells. It has
shown benefit in patients with chronic lymphocytic lymphoma
(CLL) refractory to standard alkylating agent and fludarabine ther-
apy (23), and benefit over standard first line therapy with chloram-
bucil (24). Due to its effects on both B and T cells, Alemtuzumab is
highly immunosuppressive. As such, both opportunistic infections
and viral reactivation are common in patients receiving therapy.
Early trials of this agent revealed serious infections in a large
proportion of the study population (25) and, as such, routine
prophylaxis with both antiviral and antifungal agents is recom-
mended. Such patients are likely to require imaging for suspected
infections including cross-sectional studies, and a broad differential
should be maintained. Particular consideration should be given to
atypical pneumonias, including fungal infections, pneumocystis
pneumonia, and activation of latent tuberculosis.
Conjugated Antibodies in Hematological Malignancies
In addition to their inherent cytotoxic effect through CMC,
ADCC, and signaling, monoclonal antibodies may be conjugated
to other compounds to deliver cytotoxic drugs or radioisotopes
selectively to malignant tissues.
Gemtuzumab ozogamicin (Mylotarg) is an anti-CD33 antibody
conjugated to a chemotherapeutic agent calicheamicin. On bind-
ing to the CD33 cell surface marker in acute myeloid leukemia, the
antibody is internalized, and the chemotherapeutic released where
it causes cell death by DNA double-strand breaks (26). It has been
shown to induce complete remission in first relapse with a favor-
able safety and toxicity profile, although an increase in incidence
of hepatic veno-occlusive disease has been reported (27).
Two anti-CD20 antibody conjugates to radioisotopes have been
developed, 131I-tositumomab (Bexxar), and 90Y-ibritumomab
(Zevalin). As with Rituximab, these antibodies target B-lymphocytes,
and have been used successfully in relapsed and refractory follicular
Variable
domain
Constant
domain
Human antibody
 multidisciplinary treatment of cancer: chemotherapy

lymphoma. By targeting the radioisotope to B lymphocytes, the fully humanized anti-EGFR antibody, panitumumab, has been
cytotoxic effects are limited to these cells and those nearby, known developed which has demonstrated activity in colorectal cancer
as bystander effect. Trials to date have shown benefit from both without the risk of infusion reactions (45), and is currently under
agents alone (28,29), with data showing an increase in progres- further investigation. The skin rash associated with both cetuximab
sion-free survival in follicular lymphoma when Zevalin was given and panitumumab is generally responsive to topical treatment and
in first remission after initial chemotherapy (30). Further trials are its presence has been correlated with tumor response.
ongoing in combination with chemotherapy. In contrast to the above antibodies which target tumor cell bound
antigen, the humanized antivascular endothelial growth factor
Antibodies in Solid Tumors (VEGF) antibody bevacizumab (Avastin) binds circulating VEGF,
Whereas antibody use in hematological malignancy has largely a regulator of neovascularization in both normal and malignant
focused on marking the target cells for immune destruction or tissues (46). Preclinical studies suggest that bevacizumab inhibits
active signaling, in solid tumors a different approach has been the ability of tumors to form new vessels essential for growth. It also
taken. Most of the currently used antibodies have been developed has a role in the regression of existing microvessels (47), as well as
to target and inhibit specific molecular signaling pathways by stabilizing the tumor vasculature, improving the penetration of
binding to transmembrane receptors. Examples of this include chemotherapy agents (48). Bevacizumab has an established role in
trastuzumab (Herceptin), which targets the Her-2/neu receptor, a several tumor types, with the most extensive experience in colorec-
transmembrane growth stimulatory molecule. When over expressed tal cancer. It has demonstrated a benefit in disease free and overall
in breast cancer the HER-2/neu receptor forms dimers, activating survival in combination with chemotherapy in the metastatic set-
an intracellular tyrosine kinase and a chain of signaling molecules ting (49,50), and assessment in the adjuvant and neo-adjuvant set-
to stimulate cell growth and division. Around 25% or breast can- ting is ongoing. Evidence also exists for its use in metastatic
cers show overexpression which is associated with more aggressive non-small cell lung cancer, although problems with hemoptysis
disease (31). Trastuzumab binds to the extracellular domain of the have led to some restrictions in its use, predominantly in avoiding
receptor, preventing dimerization, causing down regulation and central tumors of squamous histology (51). Other toxicities of bev-
cell cycle arrest (32), in addition to inducing ADCC (33). Clinical acizumab include impaired wound healing and gastrointestinal
trials have shown benefit in HER2 overexpressing metastatic perforation, as well as an increase in hypertension and thromboem-
breast cancer both in combination with chemotherapy (34–36), bolic events (49). Particular care is therefore required in the use of
and as a single agent (37). Following on from the benefits seen in this agent in patients who have recently undergone surgery, or in
the metastatic setting, trastuzumab has been investigated as an whom surgery is being considered, with a drug-free interval of at
adjuvant therapy following standard chemotherapy. It has been least four weeks before or after surgery recommended. Renal carci-
found to be highly effective with a significant reduction in the noma, ovarian carcinoma, and breast cancer have all seen benefit
risk of relapse (38), and an improvement in survival (39). from the addition of bevacizumab to standard therapies and early
An initially unexpected side-effect of treatment, particularly phase trials are ongoing in many other disease sites.
when combined with anthracycline-based chemotherapy was Vast arrays of antibodies are now in various stages of preclini-
cardiac toxicity, with 27% of patients developing New York Heart cal and clinical development, and as such monoclonal antibodies
Association grade III or IV cardiac failure in the initial chemotherapy are likely play an increasing role in cancer therapy ( Table 4.6).
combination trial (40). The HER-2/neu receptor has been found to
be expressed in cardiac muscle although the exact mechanism of
cardiac failure is not clear. Trastuzumab is therefore now used only
with non-anthracycline containing chemotherapy, and regular Table 4.6 Monoclonal Antibodies in Clinical Development
cardiac monitoring is required during a course of treatment. Agent Target Tumor type
Another member of the Her family of transmembrane receptors, Abagovomab CA 125 Ovarian
EGFR (Her-1) has been successfully targeted with the chimeric Edrecolomab EpCAM Colorectal
antibody cetuximab (Erbitux) in squamous cancers of the head and Oregovomab CA125 Ovarian
neck. The addition of cetuximab to radiotherapy for loco-regional Galiximab CD80 NHL
disease improved duration of disease control and survival (41). Lumiliximab CD23 CLL
Labetuzumab CEA Colorectal
Responses have also been seen in colorectal cancer. Initial trials Vitaxin VNRintegrin Sarcoma
in heavily pre-treated patients with metastatic disease showed an Adecatumumab EpCAM Prostate, breast
apparent ability to reverse chemotherapy resistance and therefore AGS-PSCA PSCA Prostate, bladder
improve response rates when given in combination with the che- Ipilimumab CTLA-4 Melanoma
motherapy drug irinotecan (42). Modest response rates have also Mapatumumab TRAIL-R1 NHL, colorectal, lung
Zanolimumab CD4 T cell lymphoma
been seen in refractory tumors treated with antibody alone (43), Aflibercept VEGFR 1 and 2 Ovarian
and further trials are ongoing to establish the role of this antibody MDX-220 TAG-72 AML
earlier in the disease course. Unlike Her-2, the expression of EGFR HCD122 CD40 CLL, myeloma
as measured by immunohistochemistry does not appear to cor- AMG479 IGF1 Phase 1
relate with response to the antibody and therefore should not be Abbreviations: AML, acute myeloid leukemia; CAM, cell adhesion molecule;
used as a marker to select patients for therapy (44). CLL, chronic lymphocytic lymphoma; IGF, insulin-like growth factor; NHL,
The main toxicities of cetuximab include infusion reactions, and Non-Hodgkin’s lymphoma; PSCA, prostate stem cell antigen; VEGFR, vascular
an acneiform rash, predominantly affecting the face and trunk. A endothelial growth factor receptor.

37
 general principles
Key Points: Monoclonal Antibodies
■ Antibodies allow specific targeting of cancer cells, or signal-
ing pathways critical to cancer cell growth and survival
■ Cancer cell death may be induced by recruitment of immune
effectors, modulation of cell signaling, or both
■ Radioisotopes or chemotherapeutics may be ligated to anti-
bodies to localize their cell killing effects
■ Antibodies may induce an array of novel toxicities depen-
dent on their target
SMALL MOLECULE KINASE INHIBITORS
Many transmembrane receptors belong to the family of mole-
cules known as the receptor tyrosine kinases. These molecules
induce a conformational change on activation, usually by bind-
ing an extracellular ligand, and undergo phosphorylation of a
tyrosine residue on the intracellular domain of the receptor
molecule. This initiates a cascade of intracellular molecular sig-
nals, which may include further tyrosine kinases, often leading
to an increase in cell growth or division. Many of these mole-
cules are the products of oncogenes, and when overexpressed
may contribute to tumor formation. Examples of this include
the HER2/neu and EGFR receptors as described above.
As an alternative to targeting the extracellular domain of such
a molecule with monoclonal antibodies, a variety of small mol-
ecules have been developed which are able to bind the intracel-
lular ATP binding site, and thus inhibit activation of the
downstream signaling pathway. The first of these to achieve
widespread clinical use was imatinib (Gleevec), an inhibitor of
the protein product of the BCR-ABL fusion gene found in over
90% of patients with chronic myeloid leukemia. Imatinib inhib-
its the tyrosine kinase associated with Abl, a non-receptor
tyrosine kinase, as well as that of other gene products, C-KIT,
platelet-derived growth factor (PDGF), and ARG. A trial com-
paring imatinib to standard therapy of CML with interferon and
low dose cytarabine chemotherapy showed an improvement in
response rate, and a reduction in progression to accelerated
phase disease or blast crisis (52).
Gastrointestinal stromal tumors (GISTs) have been found to
have mutations in the KIT proto-oncogene, leading to constitu-
tive activation of the KIT transmembrane receptor tyrosine
kinase, and thus uncontrolled cell growth. Having been found
resistant to conventional chemotherapy, GISTs were found to be
sensitive to imatinib with over half of patients in an early trial
having a partial response, and a further quarter disease stabiliza-
tion (53). Further trials confirmed high response rates, with a
dose escalation study showing prolonged disease-free survival by
doubling the standard dose (54). Increasing experience with ima-
tinib and other targeted therapies has revealed that RECIST may
no longer be the most appropriate method of radiological assess-
ment for response. Tumors responding to imatinib may in fact
grow in size initially, and it is rather their appearance, and in
particularly density on CT imaging, in addition to size which
provides a better prediction of outcome (55). Indeed the best pre-
dictor of outcome in GIST is with positron emission tomography
38
(PET), and functional imaging is increasingly being used for early
assessment of response to novel, targeted agents.
Two drugs have been developed to target the tyrosine kinase
associated with EGFR, gefitinib (Iressa), and erlotinib (Tarceva).
An early phase II trial of gefitinib in previously-treated, advanced
non-small cell lung cancer (NSCLC) showed promising response
rates in a disease often refractory to standard chemotherapy.
This led to approval in the United States; however, subsequent
phase III trials comparing gefitinib to best supportive care failed
to show a survival advantage (56), and the approval was with-
drawn. A similar trial, however, comparing erlotinib to best sup-
portive care in patients with recurrent disease after initially
successful chemotherapy showed an improvement in both
response rate and survival with manageable toxicity (57). Erlotinib
is now widely used in the second and third line treatment of
advanced NSCLC.
Recently several drugs have emerged which inhibit multiple
intracellular signaling pathways, known as multi-targeted kinase
inhibitors. Two of these have shown promising activity in clear-
cell renal carcinoma, another disease previously resistant to
standard chemotherapy (Fig. 4.7). Sunitinib (Sutent) is active
against both VEGF receptor and PDGFR tyrosine kinases, which
are activated in many renal cell carcinomas due to inactivation
of the von Hippel–Lindau (VHL) tumor suppressor gene. A
phase III comparison of sunitinib against standard therapy with
interferon in the first line setting, showed an improvement in
both response and disease-free survival (58). Interestingly, in
this trial the significant increase in disease-free survival (5.5 ver-
sus 2.8 months) was seen despite a modest number of respond-
ers by RECIST criteria (10% partial response <1% complete
response), with the majority of patients achieving stable disease
(74% in the sunitinib arm). This data again suggests that
response by RECIST may not be the most appropriate endpoint
in trials of targeted therapies, and that disease stabilization can
lead to improvements in survival.
Sorafenib (Nexavar) also targets the VEGF and PDGF receptor
tyrosine kinases, in addition to Flt-3, C-KIT, and RET. It has
been studied in renal cell carcinoma following failure of first line
therapy with cytokines, and showed an improvement in response
rate and disease-free survival (59). Sorafenib has also been stud-
ied in hepatocellular carcinoma, another disease with poor
response to conventional cytotoxic chemotherapy. Early data
suggest a doubling in time to disease progression compared to
placebo, and an improvement in overall survival in patients with
advanced disease (60).
The HER2/neu receptor, successfully targeted with the mono-
clonal antibody trastuzumab, has now been targeted by a tyrosine
kinase inhibitor that jointly targets both the HER1 (EGFR) and
HER2 receptors. Lapatinib (Tykerb) has shown activity in breast
cancer which has progressed despite therapy with trastuzumab,
with benefit in time to disease progression in combination with
capecitabine when compared to capecitabine alone (61).
OTHER MOLECULAR TARGETED THERAPIES
A variety of other intracellular pathways have been targeted in
cancer therapy with several agents now reaching the clinic
( Table 4.7).
 multidisciplinary treatment of cancer: chemotherapy

VEGF PDGF

EGFR VEGFR PDGFR

PI3K

Sunitinib
AKT Sorafenib

Temsirolimus mTOR

HIF
HIF
HIF
HIF
HIF

HIF HIF

HIF

X
VHL

Figure 4.7 Mode of action of mTOR inhibitors, and the multi-targeted tyrosine kinase inhibitors in renal cancer. Abbreviations: EGFR, epidermal growth factor receptor; HIF,
hypoxia inducible factor; mTOR, mammalian target of rapamicin; PDGF, platelet-derived growth factor; PDGFR, PDGF receptor; PI3K, phosphoinositide-3 kinase; VEGF,
vascular endothelial growth factor; VEGFR, VEGF receptor ; VHL, von Hippel–Lindau protein (inactivated due to somatic mutation in 50–70% renal cell carcinomas).

Table 4.7 Other Molecular Targeted Therapies in Clinical Use

Class of agent Example Mechanism Disease site
mTOR inhibitor Temsirolimus Inhibition of intracellular signaling via mammalian target of rapamicin Renal cancer (66)
HDAC inhibitor Vorinostat Chromatin modulation Lymphoma (64)
Proteosome inhibitor Bortezomib Inhibition of protein degradation Lymphoma (62,63)
IMIDs Thalidomide Immune modulation Myeloma (67)
Anti-sense oligonucleotides Oblimersen mRNA degradation Melanoma (65)
HSP90 inhibitors Tanespimycin Inhibition of protein folding Breast cancer (68)

Abbreviations: HDAC, histone deacetylase; HSP, heat shock protein; IMID, immuno-modulatory drug; mTOR, mammalian target of rapamicin.

Key Points: Small Molecule Kinase Inhibitors
■ A variety of drugs rationally designed to target specific
abnormal signaling pathways has revolutionized the treat-
ment of several previously resistant tumor types such as
GIST and renal cell carcinoma
■ Many of these agents are orally active with modest toxicity
profiles
■ Size criteria alone may not be the best way of assessing
response to these agents, and novel imaging techniques are
being developed in parallel with their use
THE PLACE OF CHEMOTHERAPY IN CANCER
MANAGEMENT
Whilst in the past chemotherapy has largely been given for
advanced metastatic disease, the challenge now is to elucidate the
optimal way of combining systemic therapy with other modalities
of treatment, at diagnosis, after primary treatment and in meta-
static disease. Treatment of the individual patient is best served by
multidisciplinary teams consisting of surgeon, radiologist, radia-
tion oncologist, and medical oncologist, in order to choose the
optimal treatment in any situation, and to organize these treatments

39
 general principles
in such a way as to minimize the potential for progression of dis-
ease. Chemotherapy is likely to be used increasingly as a primary
treatment both to aid surgery and reduce the likelihood of relapse
from occult metastases. The rapidly expanding knowledge of the
molecular processes involved in carcinogenesis will likely yield
many new potential therapies in the coming decades. Some of
these new agents are now appearing in practice.
Summary
■ Chemotherapeutic agents are developed for their potential to
cause a greater proportion of cell death among tumor cells
than in normal cells
■ Cell destruction by anticancer agents follows logkill kinetics
by killing a proportion of cells and not a given number; hence
tumors are best treated when small
■ Chemotherapy is given in three clinical settings: adjuvant
(for presumed microscopic disease), primary or neo-
adjuvant (prior to surgery) and for metastatic disease
■ Chemotherapy schedules are designed to achieve an ade-
quate dose intensity, usually in combination to overcome
resistant populations of cells, intermittently to allow normal
tissue time to repair, and usually intravenously
■ Cytotoxic drugs are subdivided into alkylating agents, plati-
num analogues, antimetabolites, antitumor antibiotics, and
plant-derived agents
■ Endocrine therapies alter the endocrine environment of cer-
tain tumors and can cause regression, e.g., orchidectomy in
prostate cancer or tamoxifen in breast tumors
■ Targeted therapies have an increasing role in cancer manage-
ment and are leading to significant changes in the way out-
comes in treatment are assessed. They also carry a range of
novel toxicities requiring different approaches to patient
assessment
ACKNOWLEDGMENTS
Peter Johnson, Sarah Lowndes and Matthew Wheater acknowledge
the support of Cancer Research UK.
REFERENCES
1. Skipper HE, Schabel FM Jr, Wilcox WS, et al. Experimental
evaluation of potential anticancer agents. XIII. On the criteria
and kinetics associated with “curability” of experimental leu-
kemia. Cancer Chemother Rep 1964; 35: 1–111.
2. Early Breast, Cancer Trialists’, Collaborative Group. Polychemo-
therapy for early breast cancer: an overview of the randomised
trials. Lancet 1998; 352: 930–42.
3. International Multicentre Pooled Analysis of Colon Cancer
Trials (IMPACT) investigators. Efficacy of adjuvant fluorouracil
and folinic acid in colon cancer. Lancet 19; 345: 939–44.
4. Medical Research, Council Oesophageal, Cancer Working.
Surgical resection with or without preoperative chemotherapy
in oesophageal cancer: a randomised controlled trial. Lancet
2002; 359: 1727–33.
40
5. Goldie JH, Colman AJ. A mathematical model for relating the
drug sensitivity of tumors to their spontaneous mutation rate.
Cancer Treat Rep 1979; 63: 1727–33.
6. Lokich JJ, Ahlgren JD, Gullo SJ, Phillips JA, Fryer JG. A
prospective randomized comparison of continuous infusion
fluorouracil with a conventional bolus schedule in metastatic
colorectal carcinoma: a Mid-Atlantic Oncology Program
Study. J Clin Oncol 1989; 7: 425–32.
7. Mcleod HL, Evans WE. Oral cancer chemotherapy: the promise
and the pitfalls. Clin Cancer Res 1999; 5: 2669–71.
8. Lorenz M, Muller H. Randomised multicenter trial of fluorouracil
plus leukovorin administered either via hepatic arterial or intrave-
nous infusion versus fluorodeoxyuridine administered via hepatic
arterial infusion in patients with non-resectable liver metastases
from colorectal carcinoma. J Clin Oncol 2000; 18: 243–54.
9. Armitage JO, Carbone PP, Connors JM, et al. Treatment-
related myelodysplasia and acute leukemia in non-Hodgkin’s
lymphoma patients. J Clin Oncol 2003; 21: 897–906.
10. Schmoll HJ. The role of oxaliplatin in the treatment of
advanced metastatic colorectal cancer: prospects and future
directions. Semin Oncol 2002; 29(Suppl 15): 34–9.
11. Rose MG, Farrell MP, Schmitz JC. Thymidylate synthase: a crit-
ical target for cancer chemotherapy. Clin Colorectal Cancer
2002; 1: 220–9.
12. Gupta N, Ahmed I, Steinberg H, et al. Gemcitabine-induced
pulmonary toxicity: case report and review of the literature.
Am J Clin Oncol 2002; 25: 96–100.
13. Vassey PA. Paclitaxel and Docetaxel in breast and ovarian cancer.
Drug Ther Bull 1997; 35: 43–6.
14. Early Breast, Cancer Trialists’, Collaborative Group. Tamoxifen
for early breast cancer: an overview of the randomised trials.
Lancet 1998; 351: 1451–67.
15. van den Abbeele AD, Badawi RD. Use of positron emission
tomography in oncology and its potential role to assess the
response to imatinib mesylate therapy in gastrointestinal stromal
tumours (GISTs). Eur J Cancer 2002; 38(Suppl 5): S60–S65.
16. Medical Research, Council Renal, Cancer Collaborators.
Interferon-alpha and survival in metastatic renal carcinoma:
early results of a randomised controlled trial. Lancet 1999;
353: 14–17.
17. Tallman MS, Andersen JW, Schiffer CA, et al. All-transretinoic
acid in acute promyelocytic leukaemia: long-term outcome and
prognostic factor analysis from the North American Intergroup
protocol. Blood 2002; 100: 4298–302.
18. Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus
rituximab compared with CHOP alone in elderly patients with
diffuse large-B-cell lymphoma. N Engl J Med 2002; 346: 235–42.
19. Marcus R, Imrie K, Belch A, et al. CVP chemotherapy plus
rituximab compared with CVP as first-line treatment for
advanced follicular lymphoma. Blood 2005; 105: 1417–23.
20. Forstpointner R, Dreyling M, Repp R, et al. The addition of
rituximab to a combination of fludarabine, cyclophosph-
amide, mitoxantrone (FCM) significantly increases the
response rate and prolongs survival as compared with FCM
alone in patients with relapsed and refractory follicular and
mantle cell lymphomas: results of a prospective randomized
study of the German Low-Grade Lymphoma Study Group.
Blood 2004; 104: 3064–71.
 multidisciplinary treatment of cancer: chemotherapy
21. McLaughlin P, Grillo-Lopez AJ, Link BK, et al. Rituximab
chimeric anti-CD20 monoclonal antibody therapy for relapsed
indolent lymphoma: half of patients respond to a four-dose
treatment program. J Clin Oncol 1998; 16: 2825–33.
22. Forstpointner R, Unterhalt M, Dreyling M, et al. Maintenance
therapy with rituximab leads to a significant prolongation of
response duration after salvage therapy with a combination of
rituximab, fludarabine, cyclophosphamide, and mitoxantrone
(R-FCM) in patients with recurring and refractory follicular
and mantle cell lymphomas: results of a prospective random-
ized study of the German Low Grade Lymphoma Study Group
(GLSG). Blood 2006; 108: 4003–8.
23. Keating MJ, Flinn I, Jain V, et al. Therapeutic role of alemtu-
zumab (Campath-1H) in patients who have failed fludarabine:
results of a large international study. Blood 2002; 99:
3554–61.
24. Hillmen P, Skotnicki AB, Robak T, et al. Alemtuzumab
compared with chlorambucil as first-line therapy for chronic
lymphocytic leukemia. J Clin Oncol 2007; 25: 5616–23.
25. Rai KR, Freter CE, Mercier RJ, et al. Alemtuzumab in previ-
ously treated chronic lymphocytic leukemia patients who also
had received fludarabine. J Clin Oncol 2002; 20: 3891–7.
26. Walker S, Landovitz R, Ding WD, Ellestad GA, Kahne D. Cleavage
behavior of calicheamicin gamma 1 and calicheamicin T. Proc
Natl Acad Sci USA 1992; 89: 4608–12.
27. Sievers EL, Larson RA, Stadtmauer EA, et al. Efficacy and
safety of gemtuzumab ozogamicin in patients with CD33-
positive acute myeloid leukemia in first relapse. J Clin Oncol
2001; 19: 3244–54.
28. Witzig TE, Gordon LI, Cabanillas F, et al. Randomized
controlled trial of yttrium-90-labeled ibritumomab tiuxetan
radioimmunotherapy versus rituximab immunotherapy for
patients with relapsed or refractory low-grade, follicular, or
transformed B-cell non-Hodgkin’s lymphoma. J Clin Oncol
2002; 20: 2453–63.
29. Kaminski MS, Zelenetz AD, Press OW, et al. Pivotal study of
iodine I 131 tositumomab for chemotherapy-refractory
low-grade or transformed low-grade B-cell non-Hodgkin’s
lymphomas. J Clin Oncol 2001; 19: 3918–28.
30. Hagenbeek A, Bischof-Delaloye A, Radford JA, et al. 90Y-
ibritumomab tiuxetan (Zevalin(R)) consolidation of first
remission in advanced stage follicular non-Hodgkin’s
lymphoma: first results of the International Randomized
Phase 3 First-Line Indolent Trial (FIT) in 414 patients. Blood
(ASH Annual Meeting Abstracts) 2007; 110: 643.
31. Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer:
correlation of relapse and survival with amplification of the
HER-2/neu oncogene. Science 1987; 235: 177–82.
32. Kute T, Lack CM, Willingham M, et al. Development of
Herceptin resistance in breast cancer cells. Cytometry A
2004; 57: 86–93.
33. Menard S, Pupa SM, Campiglio M, Tagliabue E. Biologic and
therapeutic role of HER2 in cancer. Oncogene 2003; 22:
6570–8.
34. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemother-
apy plus a monoclonal antibody against HER2 for metastatic
breast cancer that overexpresses HER2. N Engl J Med 2001;
344: 783–92.
35. Marty M, Cognetti F, Maraninchi D, et al. Randomized phase
II trial of the efficacy and safety of trastuzumab combined
with docetaxel in patients with human epidermal growth fac-
tor receptor 2-positive metastatic breast cancer administered
as first-line treatment: the M77001 study group. J Clin Oncol
2005; 23: 4265–74.
36. Chan A, Martin M, Untch M, et al. Vinorelbine plus trastu-
zumab combination as first-line therapy for HER 2-positive
metastatic breast cancer patients: an international phase II
trial. Br J Cancer 2006; 95: 788–93.
37. Baselga J, Tripathy D, Mendelsohn J, et al. Phase II study of
weekly intravenous trastuzumab (Herceptin) in patients with
HER2/neu-overexpressing metastatic breast cancer. Semin
Oncol 1999; 26(4 Suppl 12): 78–83.
38. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastu-
zumab after adjuvant chemotherapy in HER2-positive breast
cancer. N Engl J Med 2005; 353: 1659–72.
39. Smith I, Procter M, Gelber RD, et al. 2-year follow-up of trastu-
zumab after adjuvant chemotherapy in HER2-positive breast
cancer: a randomised controlled trial. Lancet 2007; 369: 29–36.
40. Seidman A, Hudis C, Pierri MK, et al. Cardiac dysfunction in
the trastuzumab clinical trials experience. J Clin Oncol 2002;
20: 1215–21.
41. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetux-
imab for squamous-cell carcinoma of the head and neck. N
Engl J Med 2006; 354: 567–78.
42. Cunningham D, Humblet Y, Siena S, et al. Cetuximab mono-
therapy and cetuximab plus irinotecan in irinotecan-refractory
metastatic colorectal cancer. N Engl J Med 2004; 351: 337–45.
43. Jonker DJ, O’Callaghan CJ, Karapetis CS, et al. Cetuximab for
the treatment of colorectal cancer. N Engl J Med 2007; 357:
2040–8.
44. Chung KY, Shia J, Kemeny NE, et al. Cetuximab shows activity
in colorectal cancer patients with tumors that do not express
the epidermal growth factor receptor by immunohistochemistry.
J Clin Oncol 2005; 23: 1803–10.
45. Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III
trial of panitumumab plus best supportive care compared
with best supportive care alone in patients with chemotherapy-
refractory metastatic colorectal cancer. J Clin Oncol 2007; 25:
1658–64.
46. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and
its receptors. Nat Med 2003; 9: 669–76.
47. Lee CG, Heijn M, di Tomaso, et al. Anti-vascular endothelial
growth factor treatment augments tumor radiation response
under normoxic or hypoxic conditions. Cancer Res 2000; 60:
5565–70.
48. Jain RK. Normalization of tumor vasculature: an emerging
concept in antiangiogenic therapy. Science 2005; 307:
58–62.
49. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab
plus irinotecan, fluorouracil, and leucovorin for metastatic
colorectal cancer. N Engl J Med 2004; 350: 2335–42.
50. Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in
combination with oxaliplatin, fluorouracil, and leucovorin
(FOLFOX4) for previously treated metastatic colorectal
cancer: results from the Eastern Cooperative Oncology Group
Study E3200. J Clin Oncol 2007; 25: 1539–44.
41
 general principles
51. Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized
phase II trial comparing bevacizumab plus carboplatin and
paclitaxel with carboplatin and paclitaxel alone in previously
untreated locally advanced or metastatic non-small-cell lung
cancer. J Clin Oncol 2004; 22: 2184–91.
52. O’Brien SG, Guilhot F, Larson RA, et al. Imatinib compared
with interferon and low-dose cytarabine for newly diagnosed
chronic-phase chronic myeloid leukemia. N Engl J Med 2003;
348: 994–1004.
53. Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and
safety of imatinib mesylate in advanced gastrointestinal
stromal tumors. N Engl J Med 2002; 347: 472–80.
54. Verweij J, Casali PG, Zalcberg J, et al. Progression-free survival
in gastrointestinal stromal tumours with high-dose imatinib:
randomised trial. Lancet 2004; 364: 1127–34.
55. Choi H, Charnsangavej C, Faria SC, et al. Correlation of
computed tomography and positron emission tomography in
patients with metastatic gastrointestinal stromal tumor treated
at a single institution with imatinib mesylate: proposal of new
computed tomography response criteria. J Clin Oncol 2007;
25: 1753–9.
56. Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best
supportive care in previously treated patients with refrac-
tory advanced non-small-cell lung cancer: results from a
randomised, placebo-controlled, multicentre study (Iressa
Survival Evaluation in Lung Cancer). Lancet 2005; 366:
1527–37.
57. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib
in previously treated non-small-cell lung cancer. N Engl J Med
2005; 353: 123–32.
58. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus inter-
feron alfa in metastatic renal-cell carcinoma. N Engl J Med
2007; 356: 115–24.
42
59. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced
clear-cell renal-cell carcinoma. N Engl J Med 2007; 356:
125–34.
60. Llovet J, Ricci S, Mazzaferro V, et al. Sorafenib improves
survival in advanced hepatocellular carcinoma (HCC): results
of a phase III randomised placebo-controlled trial (SHARP
trial). J Clin Oncol 2007; 25(18S).
61. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecit-
abine for HER2-positive advanced breast cancer. N Engl J Med
2006; 355: 2733–43.
62. Ludwig H, Khayat D, Giaccone G, Facon T. Proteasome inhibi-
tion and its clinical prospects in the treatment of hematologic
and solid malignancies. Cancer 2005; 104: 1794–807.
63. Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib
or high-dose dexamethasone for relapsed multiple myeloma.
N Engl J Med 2005; 352: 2487–98.
64. Duvic M, Talpur R, Ni X, et al. Phase 2 trial of oral vorinostat
(suberoylanilide hydroxamic acid, SAHA) for refractory cuta-
neous T-cell lymphoma (CTCL). Blood 2007; 109: 31–9.
65. Bedikian AY, Millward M, Pehamberger H, et al. Bcl-2
antisense (oblimersen sodium) plus dacarbazine in patients
with advanced melanoma: the Oblimersen Melanoma Study
Group. J Clin Oncol 2006; 24: 4738–45.
66. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, inter-
feron alfa, or both for advanced renal-cell carcinoma. N Engl J
Med 2007; 356: 2271–81.
67. Melchert M, List A. The thalidomide saga. Int J Biochem Cell
Biol 2007; 39: 1489–99.
68. Modi S, Stopeck AT, Gordon MS, et al. Combination of trastu-
zumab and tanespimycin (17-AAG, KOS-953) is safe and
active in trastuzumab-refractory HER-2 overexpressing breast
cancer: a phase I dose-escalation study. J Clin Oncol 2007; 25:
5410–7.
 5 Multidisciplinary Treatment of Cancer: Radiotherapy
Robert Huddart, Alan Horwich, and Stephen Morris
INTRODUCTION
Radiation has been used in the management of cancer for the last
100 years. It is estimated to be used in about half of patients who
develop cancer in the United Kingdom each year, with a curative
role in approximately two-thirds of these and a palliative role in
the remainder (Table 5.1).
Radiotherapy may be given with radical, adjuvant, or palliative
intent. It is given with radical intent when there is a realistic
prospect of cure with radiotherapy. In these circumstances, radio-
therapy is used as an alternative modality of local control to
surgery. This may be desirable for a number of reasons: the
patient may be inoperable, or not fit enough for surgery, or similar
results to surgery are obtained with less or a more acceptable
(defined by patient) range of morbidity. In this situation, both
the physician and patient should be willing to accept the short-
term morbidity of treatment and the risk, of the order of less than
5%, of significant long-term damage to tissues such as bowel,
especially when weighed against the prospect of cure and the
preservation of the structure and function of treated organs.
Examples of radiotherapy used as the sole modality of curative
treatment in early cancers include:
• Head and neck cancer
• Gynecological tumors (especially carcinoma of the cervix)
• Early Hodgkin & non-Hodgkin’s lymphomas
• Seminoma of the testis (even when associated with overt
retroperitoneal metastasis)
• Early carcinoma of the prostate
• Locally invasive cancers of the bladder
• Skin cancers
• Localized lung carcinoma
• Medulloblastoma and ependymomas
• Thyroid cancer
Radiotherapy is given with adjuvant intent after surgery when there
is risk of microscopic residual tumor. If residual microscopic tumor
cells are present, postoperative radiotherapy can improve the local
results of surgery, allow for more conservative surgery (e.g., in breast
cancer and sarcoma) and improve survival. Radiotherapy can be given
in the neoadjuvant setting before surgery to downstage the tumor,
improve resectability, and reduce recurrence risk, e.g., in rectal cancer.
Increasingly radiotherapy is being given with concomitant
chemotherapy in order to improve outcomes. Such treatment has
become routine in several tumor sites, e.g., several head and neck
sites, cervical cancer, anal cancer.
When there is no prospect of cure, as in metastatic or very
advanced local disease, radiotherapy can be given for local control
or palliation of symptoms such as spinal cord compression,
superior vena caval obstruction, brain and bone metastases.
The aim of radiotherapy is to deliver a lethal dose of radiation
to the tumor. The aim of the clinical oncologist is the holistic
management of the patient to ensure both control of the tumor
and quality of life. The balance between the likelihood of tumor
control and the risk of normal tissue damage is a measure of the
therapeutic ratio of the treatment. This is demonstrated in
Figure 5.1 where the therapeutic ratio is defined as the percentage
of tumor cures achieved at a given risk of normal tissue damage.
The decision and justification for treatment with radical, adjuvant
or palliative intent is made by the clinical oncologist/radiation
oncologist. The stage of the cancer, its sensitivity to radiotherapy,
the availability of any other options, the risks of toxicity and the
patient’s informed choice guide this decision.
RADIATION BIOLOGY
The effects of radiation on human tissues involve a succession of
processes extending from microseconds after exposure, to months
and years thereafter. DNA is the most important target for radiation.
A therapeutic dose of radiation produces in every exposed cell fast
electrons and a large number of ionizations. Some of these directly
damage DNA, others indirectly damage DNA by generating free
radicals (in an oxygen dependant reaction) that react with DNA.
Chemical lesions in DNA are very effectively repaired, but some of
them fail to repair and oxygen acts to fix free radical damage. On
average, for every cell killed by radiation, there may be more than
1000 damaged bases, 1000 single-strand breaks, and 40 double-
strand DNA breaks. This DNA damage, if not repaired, leads to cell
death rapidly or after several cell divisions. Therefore, cells with a
short mitotic cycle will show signs of radiation damage more quickly.
Clinical radiotherapy has been found to be most effective if admin-
istered in multiple fractions. This is thought to be due to a number
of processes. The five Rs of radiobiology underlying this are:
• Radiosensitivity (cellular)
• Repair (of DNA damage)
• Reassortment (of cell cycle distribution)
• Repopulation (of surviving cells)
• Reoxygenation (of hypoxic tissue)
An intriguing range of radiation sensitivity is seen in different types
of tumor. For example, with conventionally fractionated radiother-
apy a dose of about 25 gray (Gy) is needed to control a 2 cm semi-
noma, a dose of 35–40 Gy to control a 2 cm lymphoma, and upwards
of 60 Gy to control a similar size of epithelial tumor, such as
squamous carcinoma of the head and neck. Doses over 70 Gy will
not control a small high-grade astrocytoma. A similar range of
radiosensitivity is seen in the laboratory in cell lines derived from
these human tumors. The biological basis of this intrinsic cellular
radiosensitivity remains imperfectly understood (1). Overlaid on
these differences, evidence has developed that variations or poly-
morphisms in key DNA repair pathways can affect both host and
tumor radiosensitivity. This is most clearly shown in a number of rare
radiotherapy sensitivity syndromes with recognized major defects
43
 general principles

Table 5.1 Radiotherapy Results be killed. It has been hypothesized that after a period of a few
weeks some tumors may exhibit increased proliferation rates,
Site Stage Approximate Five-Year Survival (%)
termed accelerated repopulation. This process has been suggested
Larynx T1/2 90 to be a significant factor in treatment failure when therapy is given
T3/4 50
Oral cavity T1/2 80
over an extended period. Accelerated radiation schedules, such as
Tongue T3/4 25 those involving more than one fraction per day, have been used to
Cervix I 85 mitigate this phenomenon.
II 65 Normal tissues are rarely hypoxic, whereas tumors with
III 25 necrotic centers often contain hypoxic cells. Hypoxia can induce
Prostate T1/2 85
radio-resistance both by reducing the number of oxygen depen-
T3 70
Bladder T2 45 dant free radicals which damage DNA and also by inducing sur-
T3 25 vival signals such as HIF-1. Hence, hypoxic tumor cells are more
Hodgkin’s disease I/II 80 likely to survive the first dose of radiation. However, the selective
Seminoma II 90 loss of oxic cells may thereafter allow hypoxic cells to become
High-grade gliomas Any 0–5
reoxygenated, leading to an increase in their radiosensitivity.
Attempts to improve oxygenation have included the use of oxy-
gen itself, carbogen (a mixture of carbon dioxide and oxygen),
C and oxygen mimetic chemicals such as misonidazole. Smoking,
B
which reduces oxygen carriage in the blood, has been associated
Irradiation with poorer outcomes. Anaemia has also been associated with
volume
poorer outcomes, but whether this is related to hypoxia or other
A factors and whether correction of anaemia improves outcomes
remains controversial.
Tumor control or

All of these aspects of radiobiology determine the direction of

complications

Tumor clinically applied research. Current directions include the search

control Complications
Tumor
volume
Dose (Gy)
Figure 5.1 Dose-response curves for tumor control and complications. Small
changes in dose have major effects on steep part of sigmoid curves. Optimal dose
(B) gives high tumor control with low complication rate—further increases in
dose (C) produce little improvement in control at expense of high complication
rate. Suboptimal dose (A) significantly reduces tumor control.
in DNA repair e.g., Ataxia Telengectasia, Xeroderma Pigmentosa.
More recently, subtle polymorphisms in repair enzymes have been
associated with poorer outcomes from radiotherapy treatment (2).
This may refer to the second “R,” repair of sublethal damage to DNA
which is an important consideration both for reducing normal
tissue toxicity and ensuring tumor cell-kill.
The sensitivity of a cell to radiation depends on its position in
the cell cycle. It is most sensitive in M and G2, and most resistant
in late S and G1 phases. This position sensitivity in the cell cycle
causes cell cycle progression effects otherwise known as reassort-
ment. Cells that survive a first dose of radiation will tend to be in
a resistant phase of the cell cycle and within a few hours they may
progress into a more sensitive phase. This has important relevance
when considering timing and fractionation of radiotherapy. It
has also been capitalized on by synchronized chemotherapy and
concomitant chemotherapy with radiotherapy.
Repopulation occurs where cells that survive irradiation may
proliferate and thus increase the number of tumor cells that must
for ways to predict cellular radiosensitivity, analysis of the rate of
tumor repopulation, and prediction of the normal tissues’ sensi-
tivity to radiation in individual patients. The aim is that radiation
dose, delivery, and scheduling can be adjusted to improve the
therapeutic ratio in the patient’s favor.
Key Points: General Considerations
■ Treatment with radiotherapy may be radical, adjuvant, or
given with palliative intent
■ The therapeutic ratio is the balance between the likelihood of
tumor control and the risk of normal tissue damage
■ When considering radical radiotherapy, the risk of significant
late damage to normal tissue should be <5%
■ DNA is the most important target for radiation therapy
■ Clinical radiotherapy is more effective in multiple fractions
because cellular sensitivity depends on position in the cell
cycle, the phenomenon of repopulation, and reoxygenation
of hypoxic tissue
FRACTIONATION SCHEDULES AND DAMAGE
TO NORMAL TISSUES
The biological effects of ionizing radiation upon any given tissue
depend on the total absorbed dose of radiation administered
(expressed in grays).
Radical radiotherapy is given conventionally in multiple frac-
tions over a number of weeks. This allows a high total dose to be
given, obtaining better tumor control without a high incidence of
normal tissue damage. Normal tissue reactions to radiotherapy are
divided into acute and late. Acute reacting tissue reactions occur

44
 multidisciplinary treatment of cancer: radiotherapy
Table 5.2 Late Side-Effects of Radiotherapy
Organ Effects Threshold dose* (Gy)
Lens Cataract 5 killing have been devised. The most commonly used linear qua-
Kidney Nephritis/atrophy 15
Lung Fibrosis 20
Spinal cord Paraplegia 45
Bowel Stricture 50–60
Bladder Contracture 60
Skin Atrophy/telangiectasia 50+
Limb Oedema 50+
*Assumes 2 Gy daily fractions.
within three months of radiotherapy and occur in rapidly dividing
tissues, such as stem cells in the skin, gut, and marrow. Late reacting
tissue reactions occur months to years after radiotherapy and occur
in tissues that proliferate slowly such as lung, kidney, and liver
(Table 5.2). The total dose, volume irradiated, number of fractions,
and overall time of the radiotherapy have important effects on
these acute and late reactions. Protracted radiation schedules allow
more time for the processes of repair, repopulation, and re-
oxygenation, influencing the cytotoxicity of the treatment in both
normal tissues and tumor. As well as dose and time, the volume of
tissue irradiated is important. In acute reacting tissues, such as
gastrointestinal mucosa, a small volume irradiated may heal with-
out loss of function. Similarly, a small area of bone marrow irradi-
ated will not have a significant effect on peripheral blood counts.
However, modest doses of total body irradiation can cause pro-
found myelosuppression. In late reacting tissues, the concept of
parallel and serial organs are important in determining outcome.
In parallel organs, destruction of a small volume of liver or lung is
unlikely to have significant consequences, but if a large volume is
irradiated, damage can lead to organ failure and death. Thus small
volumes (but not large volumes) of parallel organs can be treated
safely to high doses. Conversely, in serial organs such as the spinal
cord, the whole organ has to remain in tact to avoid serious dam-
age. As shown by the example of spinal cord, the dose to any part
of the organ has to be kept below tolerance as overdosage to only a
small volume can have catastrophic consequences. Volume is less
important though larger volumes are associated with lower tolerance
doses. Dose-limiting late reacting tissues include:
• Spinal cord
• Brain
• Liver
• Kidney
Tolerance doses for acute and late tissue reactions are “dissoci-
ated.” A severe acute reaction is not necessarily followed by a severe
late tissue reaction, and late damage can occur even when there
has been no acute reaction. A severe acute reaction can cause con-
sequential late damage, such as a chronic ulcer in the skin, if toler-
ance is exceeded and there are no stem cells left after radiotherapy
to repopulate the area.
Smaller fraction sizes spare normal tissues rather than tumor.
This is because of repair and repopulation of normal tissues between
fractions, and the reoxygenation and reassortment of tumor cells
during the increased treatment time. This, coupled with the fact
that late tissue damage is more sensitive to increases in fraction size
than acutely reacting tissues in radiobiological models, has led to
the adoption of conventional 2 Gy/fraction treatments. To compare
radiotherapy schedules and fractionation, models of radiation cell-
dratic (LQ) model is a mathematical description of the relationship
between cell survival and radiation dose in cell survival curves. It
best fits in the low-dose region, <3 Gy/fraction. Based on the model,
the “alpha:beta ratio” (the ratio between quadratic and linear com-
ponents of the model) for normal and tumor tissue can describe the
fractionation response. A low ratio is characteristic of late respond-
ing tissues, e.g., spinal cord, where the alpha:beta = 2. A high ratio is
characteristic of acute responding tissues and tumors. Using a
smaller fraction size means an increase in the total dose applied is
needed to achieve an equivalent reduction in cell survival in late
reacting tissues than seen in acute responding tissues. This effect is
greater in tissues with a low alpha:beta ratio (late reacting tissues)
than for tissues with high alpha:beta ratio (tumors, acute reacting
tissues). Hence, smaller fraction sizes relatively spares late reacting
tissues, and means a higher dose can be applied for equivalent late
toxicity and achieve a higher tumor control probability. Using the
LQ model, the formulae can calculate iso-effective radiotherapy
schedules in terms of dose to acute and late reacting tissues. It is
important to stress that the calculations are only a guide as they are
not universally correct. The basic LQ model is appropriate if the
overall time of two regimens is the same. The effect of overall time
is complex and should be considered separately. There is no math-
ematical model to unify dose, dose per fraction, and overall time
parameters. The alpha:beta ratio is not a constant and should be
chosen to match the specific tissue. Recent evidence suggests that
the ratio in some cancers such as prostate and breast may be lower
than thought previously, and trials investigating larger fraction sizes
have been undertaken (3). Deviation from predictions of the LQ
model have been seen in extreme conditions such as reduced spinal
cord tolerance in the CHART regimen discussed below.
New fractionation schedules have been developed to overcome
radio-resistance and improve the therapeutic ratio. Accelerated
radiotherapy is the use of a reduced overall treatment time with a
conventional dose per fraction, achieved using multiple fractions
per day or by extending the working week. The aim is to reduce
the protective effect of tumor cell repopulation during radiother-
apy. Hyperfractionation is the use of a reduced dose per fraction
over a conventional overall treatment time, employing multiple
fractions per day. The therapeutic advantage is thought to derive
from a greater increase in tolerance with decreasing dose per frac-
tion for late responding normal tissues than for tumors. To allow
for sublethal damage repair, multiple fractions should not be given
more often than six hours apart. Hypofractionation is the use of
fraction sizes larger than the conventional 2 Gy.
These new schedules have been evaluated in a number of trials
particularly in head and neck cancer. Accelerated radiotherapy
was, for instance, investigated in a randomized controlled trial
(RCT) by the EORTC of conventional radiotherapy over 7–8 weeks
versus accelerated radiotherapy over five weeks (4). The acceler-
ated arm showed a 12% increase in local tumor control (p = 0.017),
but no increase in survival. However, a problem with accelerated
fractionation is that both acute and late reactions can be significantly
increased. A schedule known as CHART (continuous hyperfrac-
tionated accelerated radiotherapy) combines these approaches.
45
 general principles
CHART uses a total dose of 54 Gy in 36 fractions over 12 days,
with three 1.5 Gy fractions per day six hours apart and treatment
on weekends. The total dose is reduced to remain within toler-
ance of the acute responding tissues. A U.K. Phase III RCT of
CHART versus conventional radiotherapy for non small cell
lung cancer (NSCLC) has shown a significant improvement in
survival from 24% to 37% at two years and from 12% to 18% at
four years for NSCLC (5,6) with a trend for greater gain in more
advanced tumors. However, in head and neck cancers CHART
showed a small non-significant improvement in disease-free
interval and a trend for improved benefit for patients with more
advanced disease. Early mucosal reactions appeared sooner and
were more troublesome with CHART, but they settled quickly,
and long-term morbidity with CHART was less than or equal to
that of conventional therapy. CHART is resource- and labor-
intensive. Modified schedules such as CHARTWELL (weekend
less) are currently under investigation (7). The future may lie
with the use of newer fractionation and dose schedules in sub-
groups of patients, selected by predictions of their tumor cell
repopulation rate or radiosensitivity.
Key Points: Fractionation
■ The biological effects of ionizing radiation depend on the
total absorbed dose (expressed in Gy)
■ Radical radiotherapy is given in multiple fractions over a
number of weeks to obtain better tumor control without
excessive damage to normal tissue
■ Acute reacting tissue reactions occur within three months in
rapidly dividing tissues such as skin, gut, and marrow
■ Late reacting tissue reactions occur in slowly proliferating tissue
such as lung, kidney, and liver
■ Small fractions spare normal tissues rather than tumor
IMAGING FOR RADIOTHERAPY
Accurate imaging is the principal pillar of radiotherapy. It can be
argued that the development of computed tomography (CT)
scanning has had a more profound effect on radiotherapy practice
than on any other specialty. It has increased the accuracy of tumor
staging, not only of the primary tumor, but also of local nodal
disease and small volume distant metastases. This enables a more
appropriate choice of patients for radical local treatments. Addi-
tionally, CT enables precise localization of the tumor or organ
within a two-dimensional (2D) axial slice, the same slice on which
radiation treatment plans are designed (Fig. 5.2) and calculated (8).
This allows rapid and accurate display of alternative radiotherapy
isodose plans, with intrinsic compensation for differential beam
attenuation in heterogeneous tissues or by irregular body surface
contours. The ability to reproduce imaging in 3D has allowed fur-
ther developments in radiotherapy with improved conformation
of the high-dose region to the shape of the tumor, a technique
called conformal radiotherapy. This has been shown to greatly
reduce the volume of normal tissues in the high-dose region (9).
As potential damage to adjacent normal tissue limits the radia-
tion dose and as conformal techniques reduce the risk of normal
tissue damage, they have the potential for allowing an increase in
46
ISO at tat
Pct POI. ‘Norm’ = 36.002 Gy
103.0%
95.0%
90.0%
80.0%
70.0% Norm
60.0%
50.0%
20.0%
Figure 5.2 Radiation isodose distribution for a conformal three-field plan to treat
bladder cancer.
radiation dose (10). Trials, particularly in prostate cancer, have
quantified the reduction in toxicity associated with conformal
radiotherapy (11) and this has led to investigating dose escalation
with improved outcomes (12). A further development of confor-
mal radiotherapy is the implementation of intensity modulated
radiotherapy. This uses complex computer algorithms to vary the
intensity across standard radiotherapy treatments (standard fields
have a uniform radiation intensity across a field). These treat-
ments allow even more precise radiotherapy dose delivery includ-
ing the ability to treat concave shapes and to treat different parts
of the target volume to different doses (“dose painting”). Clinical
evaluation of these techniques is underway but holds significant
promise for the future.
The precision of radiotherapy deriving from axial imaging is
now being complemented by increased sophistication of tissue
characterization based on functional imaging techniques such as
magnetic resonance (MR) and 18F-fluoro-deoxyglucose positron
emission tomography (18FDG PET). There are challenges to co-
register images because 3D radiation planning software is still
based on CT images. However, there is considerable promise to
better definition of the tumor volume, for example, in lung can-
cers associated with adjacent normal tissue collapse, or to demon-
strate sub-targets of more resistant tumor, such as areas of hypoxia
or of rapid cellular proliferation which may prove possible using
new contrast agents.
The final challenge to imaging for radiotherapy is to translate
the accuracy of planning techniques to the regular daily treatment
fraction. Patients and their internal organs can move daily. If these
excursions are large, then this can lead to the tumor being missed
and hence receiving less than the intended dose. Initial progress
was made to ensure the patient’s overall position was accurate.
Approaches to this include attempts to image directly using the
linear accelerator beam associated with a real-time portal imager
to locate, compare and match bony anatomy. However, image
quality is not good and a recent development has been the incor-
poration of a kilovoltage CT facility (“Cone Beam CT”) on the
gantry of the linear accelerator. Alternatively, tumors can be
imaged prior to each radiation fraction using ultrasound techniques
or kilovoltage detectors associated with metal seeds implanted
within the tumor. This approach has even been adapted to cope
with tumor movement during the radiation fraction linking
real-time imaging with a tracking robotic linear accelerator (13).
 multidisciplinary treatment of cancer: radiotherapy

of intensity modulation together with sophisticated planning

Key Points: Imaging for Radiotherapy
■ CT has had a profound effect on radiotherapy planning by
increasing the accuracy of tumor staging, allowing more
appropriate choice for radical local therapy, and designing
treatment plans
■ Conformal radiotherapy and intensity modulated radiotherapy
based on 3D imaging allows a reduction of normal tissues in
the high-dose region
■ As planning software is based on CT images, MR and 18FDG
PET images have to be co-registered
RADIOTHERAPY TECHNIQUES
External Beam
Most radiotherapy is based on photons delivered from linear accel-
erators or other forms of external beam apparatus, such as those
containing radioactive cobalt. However, in some settings, the rela-
tively slow reduction in dose with depth in the tissue is undesirable.
Thus, in view of the rapid dose fall-off, an electron beam may be
particularly useful to treat a relatively superficial lesion situated
above a sensitive critical structure (Fig. 5.3). An example is the
treatment of cervical lymph nodes overlying the spinal cord.
Nowadays, high-dose curative radiotherapy techniques are
based on 3D planning and usually on conformal shaped beams. It
is important to realize that safe and effective practice depends on
a technology chain, which includes: initial definition of the tumor;
knowledge of the biological margin for microscopic extension of
tumor stem cells; knowledge of the additional planning radiother-
apy margin required because of uncertainties of treatment set up
due to patient or tumor movements or difficulties with accurate
alignment; careful patient positioning; and target verification.
There has been extensive and valuable research in each of the
fields, and new technologies have had a considerable impact on
standards of practice. Examples include real-time portal imaging
devices to verify beam alignment, the use of multileaf collimators
for automated beam shaping and, more recently, the development
110
100
90
80
70
% Dose
allows the shaping of a high dose radiation isodose around a sen-
sitive normal tissue. This approach has permitted the high-dose
treatment of tumors close to the spinal cord in various head and
neck cancer sites, and intensity modulated radiotherapy is now
being investigated to treat pelvic tumors with associated pelvic
lymph nodes, attempting to spare irradiation of bowel (14).
Key Points: External Beam Radiotherapy
■ Radiotherapy is usually delivered using photons
■ Electron beam therapy is used to treat relatively superficial
lesions
■ High dose curative radiotherapy techniques are based on 3D
planning with conformal shaped beams
■ Intensity modulation therapy allows high dose techniques to
be delivered, sparing sensitive surrounding normal tissue
Brachytherapy
A second technique to localize radiation is the use of brachytherapy,
which encompasses the use of radioactive sources placed within
or adjacent to tumors. The rapid fall-off of radiation intensity at a
short distance from the source, based on the inverse square law
(dose reduces in relation to the square of distance—doubling the
distance reduces dose by a factor of four), greatly restricts side-
effects in adjacent organs. The three main subdivisions of
brachytherapy are: interstitial implantation, intracavitary treat-
ment, and radiation moulds. Interstitial treatment uses radioac-
tive sources in the form of grains, needles, or wires inserted into
the tumor itself. An even distribution of sources is planned to
avoid areas of under dosage and most treatments involve tempo-
rary implantations over several days. A range of isotopes is used as
shown in Table 5.3. The commonest sites for considering inter-
stitial implant therapy are small tumors of the tongue, prostate
cancer, penile cancer, early breast cancer, and malignant cervical
lymphadenopathy. Intracavitary treatment involves the placement
of radioactive sources within the body of the uterus and adjacent
to the cervix in the vault of the vagina to treat carcinomas of the
cervix or of the corpus uteri. Increasingly, it is being used in other
cavities such as bronchus, oesophagus, and the biliary tree. In
Table 5.3 Radioisotopes in Common Clinical Use
Element Isotope T½ Radiation Energy (MV)

60 1
50
2 Phosphorous 32P 14 days β 1.71
Cobalt 60Co 5 yr γ 1.17, 1.33
40 3 Iodine 125I 60 days γ 0.027, 0.035
30 131I 8 days β 0.61
γ 0.36
20 4
5
Caesium 37Cs 30 yr β 0.51
10 γ 0.66
0 Iridium 92Ir 74 days γ 0.30, 0.61
0 2 4 6 8 10 12 14 16 18 20 Gold 98Au 3 days β 0.96
γ 0.412
Depth (cm)
Strontium 89Sr 50 days β 0.58
Figure 5.3 Dose distributions for photon and electron beams: 1, 10 MV photon beam;
Abbreviations: β, electron emission; γ, γ-ray emission; T½, half-life.
2, 6 MV photon beam; 3, 60 Co; 4, 160 KV photon beam; 5, 10 MeV electron beam.

47
 general principles
these situations, cooperation with diagnostic radiology is
extremely important. In the past, radium was used; however, this
caused a considerable hazard to staff and has largely been replaced
by caesium. Treatments usually last from one to three days,
although a recent development has been high-dose intracavitary
brachytherapy, which has the advantage of efficiency in terms of
patient numbers. The final brachytherapy technique of a surface
mould is rarely used today due to difficulties in radiation protection,
inconvenience for the patient and availability of alternative external
beam modalities.
Key Points: Brachytherapy
■ Brachytherapy involves the use of radiotherapy sources
within or adjacent to tumors
■ In interstitial treatment, radioactive sources are inserted into
the tumor
■ Intracavitary treatment involves the placement of sources
within the cavity of an organ such as uterus, cervix, or
oesophagus
Palliative Irradiation
Radiotherapy is widely employed to relieve the symptoms of
metastatic malignant disease and is especially effective at relieving
pain from bone metastases. Approximately three-quarters of
patients experience some degree of pain relief and often this is
complete. The theoretical basis of palliative treatment is different
from radical treatment in that there is no requirement to take
doses to tissue tolerance in order to destroy all malignant cells
within the site. Relief of symptoms requires only a modest degree
of tumor cell-kill and the patient’s relatively short prognosis
requires simple, non-toxic and rapid treatment. In the setting of
palliative radiotherapy for painful bone metastasis, it has been
demonstrated that a single fraction of 8 Gy provides equivalent
pain relief to the use of 10 fractions each of 3 Gy (15). Similarly,
rapid, low-dose schedules can be used in the relief of bleeding, as
for example with uncontrolled bladder tumors or lung tumors.
However, other symptoms such as frequency of micturition due to
a bladder tumor are much more difficult to control.
Key Points: Palliative Radiation
■ With palliative radiotherapy there is no requirement to take
doses to tissue tolerance as relief of symptoms requires only
a modest cell-kill
■ Typically, palliative radiotherapy is used for pain relief (as in
bone metastases) or cessation of bleeding
Chemoradiation
There is considerable potential for improving radiotherapy results
either by radiosensitization or by the combination of chemotherapy
and radiation. Conceptually these are distinct. Combining
chemotherapy and radiotherapy has the potential to combat
micrometastatic disease at the same time as enhancing primary
tumor control by radiation. Similar concepts would apply to com-
bining hormonal therapies for radiation in tumors which are sen-
sitive to hormone manipulation such as prostate cancer and breast
48
cancer. However, the history of combining chemotherapy and
radiotherapy is a cautionary tale. There are many examples show-
ing that initial response to chemotherapy has not contributed to
the control achieved by a subsequent course of radiotherapy. At the
same time, there is added risk of toxicity. Thus, even where modest
gains have been achieved by using neoadjuvant chemotherapy
prior to radiation, the question remains about overall therapeutic
benefit. For instance, the use of cisplatin 5-FU chemotherapy prior
to local treatment in head and neck cancers has failed to produce
clear evidence of a survival advantage, but has allowed an increased
rate of organ conservation. It appears that response to chemother-
apy indicates a better prognostic group of patients who are likely to
remain disease-free if treated with conservative management based
on radiotherapy and who therefore do not require organ removal.
Disappointing results of neoadjuvant chemotherapy have led to
more intensive investigation of synchronous chemo-irradiation
despite concerns that this would increase acute toxicity. This
approach is in widespread use for locally advanced cervical cancer
(16). It has shown some benefit in bladder cancer and has improved
organ conservation in cancers of the anal canal.
There is research interest in specific biological targeting of
agents to improve the effectiveness of radiotherapy. In the past,
this has been based on seeking to redress hypoxic radioresistance
by the use of oxygen or oxygen mimetic chemicals such as mis-
onidazole. Many anticancer drugs under development are targeted
at combating cellular proliferation or DNA repair and may also
offer the opportunity for radiosensitization. This is a complex
field of clinical research since the principles of administering
chemotherapy and radiotherapy independently must be modified
for their concomitant use.
DIRECTION OF RESEARCH
A number of important areas for applied radiation research
can be identified. These include investigation of molecular
aspects of radiation sensitivity; investigation of radiosensitiza-
tion; evaluation of altered fractionation schedules; the develop-
ment of predictive tests of radiation efficacy in order to allow
appropriate dose or modality modifications; investigation of
combined chemoradiation; applications of radiation physics
and functional imaging; and modulation of dose-limiting nor-
mal tissue effects. The potential for considerable patient benefit
from each of these areas, combined with the existing level of
success in radiation treatment of cancer, emphasises the impor-
tance of an investigative approach in our cancer management
protocols, and of multidisciplinary considerations in clinical
management decisions.
Summary
■ Radiotherapy is estimated to be used in 50% of patients who
present with cancer in the United Kingdom, with a curative
role in two-thirds and palliative role in one-third
■ Radiotherapy is given with radical intent when there is a
prospect of cure, with adjuvant intent after surgery where
there is a risk of microscopic residual tumor, with neoadjuvant
intent to downstage tumors prior to surgery, or as palliation
 multidisciplinary treatment of cancer: radiotherapy
■ Normal tissue reaction to radiotherapy is divided into acute
(within three months) and late (months to years). Acute
tissue reactions typically occur in skin, gut, and marrow; late
in lung, kidney, and liver
■ Radical radiotherapy is given in multiple fractions over a
number of weeks to obtain better tumor control without
excessive damage to normal tissue
■ Palliative irradiation requires only a modest degree of tumor
cell-kill and requires simple, non-toxic and rapid treatment
■ Brachytherapy can be interstitial (in the tumor itself),
intracavitary, or given using a radiation mould
■ Chemotherapy can be administered with radiotherapy either
for radiosensitization or by the combination of chemotherapy
and radiotherapy for spatial cooperation
ACKNOWLEDGMENTS
This work was undertaken in The Royal Marsden NHS Foundation
Trust who received a proportion of its funding from the NHS
Executive; the views expressed in this publication are those of the
authors and not necessarily those of the NHS Executive. This work
was supported by the Institute of Cancer Research, the Bob Champion
Cancer Trust and Cancer Research UK Section of Radiotherapy
[CUK] grant number C46/A2131.
REFERENCES
1. Steel GG, Peacock JH. Why are some human tumours more
radiosensitive than others? Radiother Oncol 1989; 15: 63–72.
2. Alsner J, Andreassen CN, Overgaard J. Genetic markers for
prediction of normal tissue toxicity after radiotherapy. Semin
Radiat Oncol 2008; 18: 126–35.
3. Bentzen SM, Agrawal RK, Aird EG, et al. The UK Standardisa-
tion of Breast Radiotherapy (START) Trial A of radiotherapy
hypofractionation for treatment of early breast cancer: a
randomised trial. Lancet Oncol 2008; 9: 331–41.
4. Horiot JC, Bontemps P, van den Bogaert W, et al. Accelerated
fractionation (AF) compared to conventional fractionation
(CF) improves loco-regional control in the radiotherapy of
advanced head and neck cancers: results of the EORTC 22851
randomized trial. Radiother Oncol 1997; 44: 111–21.
5. Saunders MI, Dische S, Barrett A, et al. Randomised multi-
centre trials of CHART vs conventional radiotherapy in head
and neck and non-small-cell lung cancer: an interim report.
CHART Steering Committee. Br J Cancer 1996; 73: 1455–62.
6. Rowell NP. Updated data for chart in NSCLC: a missed oppor-
tunity. Radiother Oncol 2000; 55: 85–7.
7. Saunders MI, Rojas A, Lyn BE, et al. Dose-escalation with
CHARTWEL (continuous hyperfractionated accelerated
radiotherapy week-end less) combined with neo-adjuvant
chemotherapy in the treatment of locally advanced non-small
cell lung cancer. Clin Oncol (R Coll Radiol) 2002; 14: 352–60.
8. Dobbs HJ, Husband JE. Computed tomography for radiotherapy
planning. Appl Radiol 1984; 13: 51–61.
9. Horwich A, Wynne C, Nahum A, et al. Conformal radiotherapy
at the Royal Marsden Hospital (UK). Int J Radiat Biol 1994; 65:
117–22.
10. Tait D. Conformal therapy. Br J Cancer 1990; 62: 702–4.
11. Dearnaley DP, Khoo VS, Norman A, et al. Comparison of radi-
ation side-effects of conformal and conventional radiotherapy
in prostate cancer: a randomised trial. Lancet 1999; 353:
267–72.
12. Dearnaley DP, Sydes MR, Graham JD, et al. Escalated-dose
versus standard-dose conformal radiotherapy in prostate
cancer: first results from the MRC RT01 randomised controlled
trial. Lancet Oncol 2007; 8: 475–87.
13. Mangar SA, Huddart RA, Parker CC, et al. Technological
advances in radiotherapy for the treatment of localised prostate
cancer. Eur J Cancer 2005; 41: 908–21.
14. Nutting C, Dearnaley D, Webb S. Intensity modulated radiation
therapy: a clinical review. BJR 2000; 73: 459–69.
15. Price P, Hoskin PJ, Easton D, et al. Prospective randomised
trial of single and multi-fraction radiotherapy schedules in the
treatment of painful bone metastases. Radiother Oncol 1986;
6: 247–55.
16. Thomas GM. Improved treatment for cervical cancer–concurrent
chemotherapy and radiotherapy. N Engl J Med 1999; 340:
1198–200.
49
 6 Assessment of Response to Treatment
Lawrence H Schwartz and Binsheng Zhao
INTRODUCTION
For decades, advanced cancer imaging focused on detection of
cancers, characterization of lesions which were detected either by
physical examination, or at imaging and appropriate staging of
cancers, and it is only recently that great attention has focused on
the role of imaging in assessing response to therapy. Indeed, the
precise role of imaging, the modalities used, frequency of imaging,
and types of assessments of these imaging studies is under intense
scrutiny by numerous investigators throughout the world.
A general principle to follow in imaging of response assessment
is that the subsequent, follow-up examinations should be per-
formed with the same modality and same imaging protocol. This
enables comparison of the size and number of lesions. The intro-
duction of new modalities or imaging of new body parts should
be performed if there are questions based upon initial imaging, or
if new clinical symptoms are present. Increasingly, radiologists
participate in clinical investigations or clinical trials involving
novel imaging or therapeutic agents to assess their efficacy. Gen-
eral guidelines regarding good clinical practice are appropriate in
these research investigations as well as for those undertaken in
routine clinical practice and, at present, the greatest difference lies
in the degree of quantification of imaging findings between
research and clinical studies, as well as the documentation of the
findings. Ultimately, the individual patient care and overall accu-
rate interpretation of the imaging findings is paramount whether
a routine case or one involving a clinical research investigation.
While cure, prolongation of survival and/or pain palliation
relief are the ultimate goals for cancer treatment, these cannot eas-
ily be judged for a given patient and the results of treatment for
groups of patients may take a long time to accrue. Because of this,
over the past 30 years, objective response rate obtained from
radiographic images has been used to assess tumor response to
both routine clinical care and in investigative drugs tested in clin-
ical trials. While a variety of chemotherapeutic options exist for
treatment of certain types of cancers, rarely one single drug can
work 100% of the time and oncologists cannot predict in advance
which tumors will respond to which treatments. Thus assessment
of response to a given therapy is the key to gauging the success of
a therapy. It is the goal of imaging to determine if a therapy is
effective or ineffective with high accuracy at the earliest possible
time so that a second- or third-line treatment can be prescribed
and the toxicity of unsuccessful therapies are minimized.
One of the latest advances in the field of medicine is personal-
ized medicine, popularized in the late 1990s by the completion of
the Human Genome Project. Personalized medicine allows selec-
tion of a medicine/therapy for a patient based on specific tumor
biology and other clinical information relevant for the patient
enabling more effective and safe treatment to individual patients.
Once a patient is diagnosed with cancer, the physician and the
radiologist need to work out an appropriate treatment and an
50
optimal imaging technique (e.g., single modality or multiple
modalities; imaging parameters) to monitor the treatment at
suitable timing. These are by no means easy tasks due to heteroge-
neity of a specific cancer and cancer subtypes, multiple possible
choices of treatments and different modes of biological interac-
tions between cancers and drugs. All these factors in combination
can affect patterns of metastatic spread and response to therapy.
The selection of an appropriate treatment regimen and imaging
modalities to monitor this treatment response may be limited by
national, regional, or an institution’s availability of specific imag-
ing, as well as cost. As these treatment options continually evolve,
imaging modalities continually improve and the response assess-
ment metrics change, strong collaboration between radiologists
and clinicians will remain the key to meeting these challenges.
Radiographic changes of tumors treated with newer generations
of cytostatic agents do not necessarily occur at the same magnitude
or speed as observed in those treated with classic cytotoxic drugs
(1–4). As a result, investigators have, to a certain extent, become
dissatisfied with the use of traditional imaging response assess-
ment criteria since they do not always adequately capture the effects
of novel therapies on primary tumors and metastases (5–8). Fur-
thermore, tumor response to such targeted therapies may not be
detected by changes in size but rather by analysis of cystic change,
central necrosis, and/or metabolic changes. As greater numbers of
anti-cancer therapies are introduced into clinical practice and
even greater numbers of experimental anti-cancer drugs enter
clinical trials, there is an urgent need for the development and val-
idation of accurate and early imaging surrogate endpoints to assess
both the efficacy and safety of these novel target drugs. Improving
imaging biomarkers will not only help the individual patient but
may also shorten the time for developing a successful anti-cancer
therapy by improving statistical power, decreasing the clinical trial
duration, and reducing the funding spent in the costly drug devel-
opment process. Among the promising imaging biomarkers, func-
tional imaging techniques such as 18F-fluoro-2-deoxy-D-glucose
positron emission tomography (FDG PET) and fluoro-L-thymidine
positron emission tomography (FLT PET) show tremendous poten-
tial. In some instances, FDG PET can help stratify certain types of
cancer patients who are most likely respond to a specific treatment
and also predict early patient survival.
CONVENTIONAL RESPONSE ASSESSMENT
Anatomic imaging has played an important role in the assessment
of response to therapy in solid tumors (9). Computed tomogra-
phy (CT) remains the most common modality of choice for mon-
itoring tumor change after a therapy is initiated. This is likely to
continue for some time since CT is so widely available and pro-
vides accurate and reliable anatomical information not only about
tumor shrinkage but also concerning progression of disease, either
by identifying growth in existing lesions or the development of
 assessment of response to treatment
new lesions. With the recent advances in multiple-row detector
technology, CT can now scan patients in an “ultra” fast speed and
generate isotropic images at sub-millimeter spatial resolution
without adding extra radiation dose to the patient.
Magnetic resonance (MR) imaging, though providing high
quality anatomical information, is less frequently used clinically,
in part because of its complexity, cost, and limitation in the chest
which is a frequent site of metastatic spread. However, in some
body regions, for instance the head, MR imaging is more appro-
priate than CT with better contrast-to-noise ratio and improved
detection of metastases. With dynamic MR imaging and CT tech-
nologies, functional information may be obtained by utilizing
blood pool imaging contrast agents.
As greater numbers of therapeutic options become available for
certain types of cancers and as a better understanding is acquired of
the underlying mechanisms of drug and cancer interactions, it is now
becoming possible to optimize the choice of imaging modality, pro-
tocol and follow-up interval to visualize and quantify tumor changes
with therapy either directly or indirectly. For instance, the use of
dynamic contrast-enhanced MR imaging is the optimum choice for
assessing response to treatment of antiangiogenic agents. In order to
compare tumor measurements on serial scans meaningfully, the
imaging technique and imaging protocol should be standardized and
strictly followed throughout the treatment (vide infra).
Objective response rate, defined as percentage change in the
tumor greatest diameter (or product of the two greatest perpen-
dicular diameters) between two serial scans (e.g., baseline and fol-
low-up scans), has been used to assess response in day-to-day
treatments and, in recent years, adopted as an endpoint for evalu-
ating effectiveness of new anti-cancer agents on clinical trials. With
improved anatomic imaging technologies, for example, from the
two-dimensional (2D) projection technique (e.g., chest x-ray) to
the three-dimensional (3D) volumetric technique (e.g., multiple-
row detector CT), the accuracy and reproducibility of size mea-
surements obtained from imaging studies has greatly improved.
Figure 6.1 A partial response by RECIST or WHO criteria, with a decrease in size of multiple liver metastases.
Despite these remarkable advances in technology including the
introduction of new imaging modalities, the standard response
evaluation criteria for assessing changes in tumor size have
remained relatively stable over the past three decades.
The WHO and RECIST Criteria
The two widely accepted response assessment guidelines are the
World Health Organization (WHO) criteria and the Response
Evaluation Criteria in Solid Tumors (RECIST) (10–12).
The basis and methodology for measuring tumors and response
to therapy were first codified by the WHO in 1979 (10). The WHO
recommendations were based upon two meetings on the Stan-
dardization of Reporting of Results of Cancer Treatment. These
results became the basis for assessing cancer treatment, drug devel-
opment, and clinical trial outcomes and decisions for over 20 years
(11). The WHO suggested using the cross product (bidimensional
measurement) of the greatest diameter of the tumor and the
greatest diameter perpendicular to it on a transverse image, to
approximate tumor size. Based upon the change in tumor size,
the WHO recommended reporting results of cancer treatment
responses in four categories:
• Complete response (CR)
• Partial response (PR) (Fig. 6.1)
• Stable disease (SD) (Fig. 6.2)
• Disease progression (PD)
Any new disease would be considered progressive disease and
any “substantial” enlargement in tumors not easily measured
would also be considered progression. Details of these criteria
are presented in Table 6.1.
In 1994, the European Organization for Research and Treatment
of Cancer (EORTC), the National Cancer Institute (NCI) of the
United States and the NCI of Canada trials group set up a task
force with the main objective of reviewing the existing sets of
criteria used to evaluate response to treatment in solid tumors.
51
 general principles
Figure 6.2 A patient with stable disease by RECIST criteria with a decrease in tumor size of 15%, not meeting the RECIST cut-off value of 30% decrease for a partial response.
Table 6.1 Comparison of the WHO and the RECIST Criteria
Response Category WHO Definition
Complete response (CR) Disappearance of all disease, as confirmed at 4 wk follow-up
Partial response (PR) 50% decrease in the sum of the cross products of measurable
disease, as confirmed at 4 wk
Stable disease (SD) Neither PR nor PD
Disease progression (PD) 25% increase in the sum of the cross products or in a single
lesion, or presence of new disease
After three years of meetings, they published a series of new guidelines
for response assessment based upon retrospective review of
collaborative studies in 4000 patients (12). Their recommenda-
tions included the adoption of a simplified approach to measuring
tumors utilizing only the greatest diameter (unidimensional mea-
surement) and the sum of the greatest diameters instead of the
sum of the cross products. These new criteria became known as
RECIST (Response Evaluation Criteria in Solid Tumors) and were
guided by several important principles:
1. The need to maintain the standard four categories of
response assessment (CR, PR, SD, PD)
2. The goal of maintaining constancy of results such that
no major discrepancy in the meaning of partial response
would exist between the older WHO criteria and the new
criteria
3. The recognition of both the arbitrary nature of the cut-
off for PR and the need to maintain this cut-off until
other potentially more reliable or powerful surrogates
could be developed
4. Concern about categorizing patients as PD too easily
5. Recognition that cytostatic agents may not have the same
measurement “activity” and that other serum markers
and specific tumors may present unique challenges
Key Points: The WHO and RECIST Criteria
■ The WHO and RECIST criteria are the two widely accepted
response assessment guidelines
■ The WHO uses the cross product of the two greatest diameters
of tumor on a transverse image to approximate tumor volume
52
RECIST Definition
Disappearance of all disease, as confirmed at 4 wk follow-up
30% decrease in the sum of the maximal diameters of
measurable disease, as confirmed at 4 wk
Neither PR nor PD
20% increase in the sum of the maximal diameters of
measurable disease, presence of new disease
■ The simplified RECIST uses the greatest diameter of tumor
to approximate tumor volume
■ For consistency between the two criteria, both criteria report
treatment response using four categories, i.e., CR, PR, SD,
and PD
■ The cut-off values defined in the WHO criteria for categorizing
response were determined in part by experiments using
the standard imaging and measurement techniques used
30 years ago
■ The cut-off values in the RECIST criteria were derived from
those of the WHO criteria so that old and new clinical trial
results are comparable
Potential Variations in Tumor Size Measurement
While response is mainly judged by serial tumor measurements
on CT scans or other imaging studies, inaccurate estimations of
efficacy of a therapy may result from errors or misjudgments in
any of the following steps in assessment:
• Determination of modality/modalities and frequency/
timing of follow-up studies
• Use of imaging protocols
• Selection and measuring of target lesions on baseline
study
• Identification and measurement of the target lesions and
new lesions (if any) on follow-up studies (13–19).
Standardization of an appropriate imaging procedure, including
modality, imaging protocol, and follow-up timing, for monitoring
treatment of an individual cancer type is critically important and
 assessment of response to treatment
should be strictly followed throughout the treatment. This is due
to the differential appearance of tumors, with variable signal-
to-noise and contrast-to-noise ratios on images with various
modalities or imaging techniques within a modality. While CT is
relatively well standardized, imaging parameters such as slice
thickness, reconstruction kernel, radiation dose, and use and
timing of intravenous contrast material can impact on tumor
visualization and measurement. MR imaging parameters are
much more variable than CT and differences in such parameters
on follow-up can have a major impact on the interpretation of
the results both with regard to conventional and newer response
assessment criteria.
Advanced cancers often present with multiple lesions. Although
measuring larger numbers of lesions will decrease variation in the
size measurement and thus in response classification, it will
increase workload for the radiologist and the probability for mea-
surement errors. The RECIST criteria suggest that for each patient,
five lesions per organ and 10 lesions in total should be selected as
the target lesions in baseline studies (12). Mathematical modeling
and retrospective clinical studies showed that by reducing the
number of the target lesions from ten to four or six, permitted
sufficiently stable response categorization could be observed using
either RECIST or WHO criteria (20,21).
Monitoring tumor change on serial scans can be tedious, time-
consuming, and sometimes lacks reproducibility, especially if the
radiologist measures too few lesions or different radiologists mea-
sure different lesions at baseline and follow-up. Even the same
radiologist can pick up different lesions and measure differently if
he/she is asked to repeat this process. This is illustrated in one
reported study, in which three independent radiologists were
asked to evaluate 15 patients with pulmonary metastases by select-
ing the five largest pulmonary metastases for each patient. The
result showed that all three radiologists reported the identical
five metastases as “largest” in only five (33%) of the cases. They
identified the same metastases in 54/75 (72%) and at least two
radiologists identified the same metastases in 66/75 (88%) (18).
Inter-observer and intra-observer measurement variabilities
are another major cause for possible misclassification of response.
For the same lesion, different radiologists may choose different
Serial reading mode
First scan Repeat scan
Figure 6.3 Radiologist’s manual measurements on repeat CT scans with two different reading modes.
Serial reading mode
First scan (mm) Second scan (mm2)
Uni 23.2 19.8
Bi 335.3 269.5
Unidimensional and bidimensional variations were –15.8% and –21.8% when the lesion was measured in the serial mode; Unidimensional and bidimensional variation
were –5.5% and –7.5% when the lesion was measured in the side-by-side mode.
image planes and different sites of the lesion to measure tumor
diameter/diameters, generating different measurement values
(17). This can also be a source of error when the same radiologist
is asked to measure the same lesion on separate occasions. Such
variations in measurement can be amplified if the lesion has a
complex shape, contains areas of low attenuation on CT, and/or is
attached to surrounding structures which are difficult to distin-
guish from the lesion. The study reported by Erasmus et al. (17)
on the effects of inter-observer and intra-observer variability in
measurement of non-small cell lung cancer (NSCLC) showed that
the probability of misclassifying a tumor with the WHO or
RECIST criteria was greatest for progression (43% bidimensional,
30% unidimensional) when classified by inter-observer measure-
ments and lowest for response (2.5% bidimensional, 3.0% unidi-
mensional) when classified by intra-observer measurements. The
authors thus recommended that the same radiologist should
perform all serial measurements of an individual patient in order
to improve the consistency of the response assessment. Tumor
measurements can also be affected by the measurement tools
used, e.g., hand-held caliper on film, electronic caliper on diag-
nostic workstation, and semi-automated/automated technique
(16). Window/level setting on the workstation monitor is another
factor which can affect apparent diameter of the tumor.
Follow-up studies, even if the same imaging technique, imaging
parameters and same scanner are used, can result in differences in
tumor measurement (22–24). Possible reasons include alteration
of patient’s position in the scanner, depth of breath-hold and
movement of organs surrounding the tumor. Figure 6.3 shows a
tumor imaged with CT twice on the same day at a major cancer
center in the United States (24). The tumor had not changed in
size in the two repeat scans performed within 15 minutes of
each other; however, the measured size values of the tumor were
different between the first and the second scans, even when the
size was measured side-by-side. Serial reading (i.e., radiologist
blindly reads each scan) was found less consistent than side-by-side
reading (Fig. 6.3).
The variability in response assessment can be profound if a clin-
ical trial is conducted in multiple centers. An example was the renal
cytokine multicenter trial conducted in the 1990s, which showed
Side-by-side reading mode
First scan Repeat scan
Side-by-side reading mode
First scan (mm) Second scan (mm2)
22.9 24.2
318.5 295.4
53
 general principles
40% major disagreements and 10.5% minor disagreements between
the objective responses reported by the large multicenter trial and
by an independent evaluation committee (15).
The timing to follow-up tumor changes after the onset of therapy
can also affect outcomes of the response assessment. Different
mechanisms of tumor and drug interactions and different imag-
ing techniques can make the optimal timing for assessment of
tumor progression and regression variable. For traditional
chemotherapies, at least a two-month interval has been suggested
to permit observation of a 50% reduction of the tumor initial size
(25). This interval was recommended based on a study analyzing
the volume doubling time of some tumors. The study found that
tumor volume doubling times, from as short as a week to over a
year, had a median value of approximately 60 days (26). However,
for the new generation cytostatic agents which have a biological
antiproliferative effect that induces a delay in tumor growth, a
two-month interval may no longer be appropriate.
Key Points: Potential Variations in Tumor Size
Measurement
■ A number of factors other than real change in tumor size can
affect measurement of tumor size and this may affect response
classification
■ Optimal imaging technique and imaging protocols for a
specific cancer type and treatment should be standardized
and strictly observed throughout the patient’s treatment
■ Differences in the time interval to follow-up can affect
response assessment
■ If there are multiple lesions in a patient, different target
lesions may be selected by different radiologists. Target
lesions on serial scans may also be mismatched
■ Inter-observer variation is usually larger than intra-observer
variation in tumor size measurement and thus in response
assessment
■ Measurement variation has a greater impact on misclassification
of progression than on that of regression
■ Measurement variation can be reduced if a patient’s follow-up
examinations are read by the same radiologist treatment
■ Measurement variation can be reduced if serial images are
read side-by-side
■ Window/level setting can affect apparent diameter of the
tumor on a workstation monitor
Limitations of Conventional Methodology
For tumors that show size reduction with appropriate therapy,
responses may not be accurately assessed because of intrinsic lim-
itations associated with the criteria established in the conventional
response assessment. These limitations include:
• Use of unidimensional or bidimensional measurements
to quantify tumor volume change approximately
• Use of non-biologically determined cut-off values for
categorizing response
• Lack of information regarding change of tumor attenua-
tion or density
The basis and methodology of the WHO criteria for measuring
tumors and evaluating response to therapy were established
54
almost 30 years ago. At that time, both cancer imaging technolo-
gies and radiologists’ reading/measurement tools were relatively
primitive compared to those available today. Furthermore, since
the standard “modalities” to measure tumors were simply physical
palpation and plain X-ray films, only one-dimensional (1D) and/
or two-dimensional (2D) measurements were possible. Twenty
years later, despite the remarkable advances made in imaging
technology, as well as in computer hardware and software, the
RECIST guidelines adopted the major components from the
WHO criteria partly because of the need to compare new trial
results with those reported in the past.
The unidimensional RECIST criteria have met with a mixed
response in the oncology community. Several studies have shown
that the correlation between the RECIST and WHO criteria is not
as high as in the original RECIST paper, especially for certain
tumor types and sites of metastatic disease (27–31). This may be
because the RECIST paper looked at concordance with the WHO
criteria for the surrogate of Best Overall Response but did not
look in depth at concordance with other imaging surrogates, such
as time to progression and disease-free survival.
Unidimensional (1D) or bidimensional (2D) tumor change can
serve as an adequate proxy for volume change only when the
tumor is spherical or approximately spherical prior to therapy and
when changes in tumor size in response to therapy are also sym-
metric and conform to the overall spherical shape. Thus, assump-
tions with regard to the relationship between unidimensional and
bidimensional measurements and volume change cannot be
assumed to be true as tumors may grow or shrink in irregular pat-
terns. The RECIST guideline does mention the volumetric tech-
nique and suggests the use of the same four categories as WHO to
report responses. However, the suggested cut-off values for clas-
sifying the volumetric responses are converted directly from those
used in the WHO and RECIST criteria using the spherical rela-
tionship (Table 6.2). The measurement of lymph node metastases
deserves special mention as published data has revealed that
lymph node involvement measured in the short axis diameter best
predicts the presence of metastatic disease (32–34).
The use of a 50% cut-off used in the WHO criteria for response
was derived in large part from a study by Moertel et al. (25) who
evaluated the effect of measurement error on response assessment
by placing solid spheres on a mattress and covering them with
foam and asking 16 oncologists, blinded to the size of the spheres,
to palpate these simulated lesions. By comparing 50% and 25%
Table 6.2 Relationship Between Change in Diameter, Product,
and Volume
Diameter, 2r Product, (2r)2 Volume, 4/3πr3
Response Decrease Decrease Decrease
30% 50% 65%
50% 75% 87%
Disease progression Increase Increase Increase
12% 25% 40%
20% 44% 73%
25% 56% 95%
30% 69% 120%
Note: Values in bold represent the RECIST (diameter) and WHO (product) criteria
for change in tumor size to meet response and disease progression definitions.
 assessment of response to treatment
reduction cut-offs, they found that intra- and inter-observer’s
misclassification rates for response due to measurement error was
acceptable when the 50% cut-off was used (13,25). Warr and col-
leagues (35) performed similar experiments with regard to disease
progression and determined that using a 25% cut-off for disease
progression, the false categorization of disease progression was
unacceptably high (33%); they recommended that the PD category
be increased to either 50% or 100%. Although the cut-off values
used in the WHO criteria were determined crudely and “validated”
based upon physical palpation and plain radiograph analysis, simi-
lar studies were never repeated for the modern imaging techniques
and measurement tools. Furthermore, response and progression
assessed upon these arbitrarily determined cut-off values have not
been shown to be correlated with any other parameters indicating
a known potential benefit for cancer patients (36,37).
Neither the WHO nor the RECIST criteria provide guidelines
on how to use information about change in tumor attenuation to
assess response to therapy, particularly to the new targeted drugs
that may alter tumor composition through the development of
cystic change and central necrosis without change in tumor size
(Fig. 6.4). In view of these advances, there is clearly a need to
re-evaluate the current response assessment criteria and develop
new imaging methodologies that can better assess response to
both cytotoxic and cytostatic drugs.
Key Points: Limitations of Conventional Methodology
■ The use of unidimensional or bidimensional change to
approximate volumetric change in the assessment of response
to therapy can be inaccurate and insensitive
■ Neither the WHO nor the RECIST can capture tumor
changes accurately if tumors have an irregular shape and
change in size is asymmetrical
■ The cut-off value of 50% reduction in the WHO criteria for
categorizing tumor response was crudely determined almost
30 years ago using the standard imaging equipment and mea-
surement tools of that era
■ Response and progression assessed using these cut-off values
have not shown correlation with any other biomarkers which
indicate known potential clinical benefit for patient
Figure 6.4 Cystic change within a lung cancer without overall change in size of the lesion. Conventional response criteria do not capture this “benefit.”
■ The current response criteria do not include tumor volume
and attenuation changes which can be accurately calculated
and characterized using modern high resolution imaging
techniques. Such information may better indicate tumor
response or progression in response to therapy, particularly in
the assessment of response to new anticancer drugs
NOVEL RESPONSE ASSESSMENTS
More than a decade ago, chemotherapeutic agents were predomi-
nately developed to destroy cells, particularly rapidly dividing
malignant cells. If a tumor responds to cytotoxic drugs, reduction
of tumor size can be observed on anatomical images such as CT
and MR imaging. The new generation of anti-cancer agents are
not designed to eradicate cells, but to prevent cells from dividing.
This may result in “responded” tumors with stabilized size or size
change to a lesser degree than is seen with cytotoxic therapies.
How a tumor changes after initiation of a specific therapy depends
on the tumor type, the drug, and the mode with which they inter-
act. Therefore, different imaging modalities and techniques should
be chosen to characterize tumor change with therapy optimally,
for example taking into account potential changes in size, central
necrosis, metabolic activity and angiogenic status.
Continuous development of more accurate and early response
imaging methodologies, such as PET to quantify tumor metabolic
activity and dynamic contrast-enhanced MR imaging (DCE-MRI)
to image angiogenesis, have re-ignited interest in further evalua-
tion and improvement of the existing anatomic response assess-
ment criteria. The remaining portion of this chapter will highlight
some of the recent efforts and achievements in the development
of more accurate, reliable, and early response assessment methods
using different imaging modalities and techniques.
Modified RECIST Criteria
For tumors that have complex growth patterns or change size with
therapies at lower magnitudes than those treated with traditional
cytotoxic drugs, both the RECIST and the WHO criteria are
unlikely to be entirely appropriate. Some research groups have begun
55
 general principles

to modify the RECIST criteria based on tumor characteristics and
typical patterns of change, aiming to establish more sensitive
criteria to quantify response.
Trends in changes of response assessment in malignant pleural
mesothelioma (MPM) are one example of modifications of
RECIST. MPM can arise anywhere along the pleural surface of the
thorax or less commonly in the upper abdomen and thus usu-
ally manifests a very irregular tumor growth pattern. Measuring
the tumor’s longest extent (diameter) on the axial plane, while
following RECIST or WHO guidelines, does not truthfully
“capture” the growth of the tumor. Furthermore, there is no
standardized site at which to measure the tumor extent. Mea-
surement reproducibility can be very poor on serial images.
Several studies have reported the inadequacy of using the
RECIST criteria for assessing therapeutic response in MPM
(38–40). Byrne et al. thus suggested a modified RECIST guide-
line. Instead of measuring the longest extent of tumor on the
axial plane, tumor thickness perpendicular to the chest wall or
mediastinum is recommended to be measured in two positions
at three separate levels. The total tumor measurement is the
sum of all measurements. Their study showed that the modified
RECIST criteria for tumor response correlated with survival
and lung function (38).
In monitoring gastrointestinal stromal tumors (GISTs)
treated with imatinib mesylate, several research groups reported
that the RECIST criteria significantly underestimated tumor
response (7,8,41,42). After initiation of imatinib, GISTs usually
decrease in size, but the 30% change needed to categorize a
patient as “a response” is not usually reached. Additionally,
responding GIST tumors generally become more homogenous
and hypoattenuated on contrast-enhanced CT images (Fig.
6.5). Based on such typical change patterns, Choi’s group sug-
gested modifying the RECIST criteria by lowering the current
cut-off value of the partial response from 30% reduction to
10% reduction and considering tumor attenuation decrease of
15% as an additional response criterion. Their preliminary
results showed that using the modified RECIST criteria,
responders correlated at least as well as those classified by the
18
F-FDG PET criteria. In addition, significantly longer time to
progression was found in responders than in non-responders.
This same phenomena may be seen with other tumor types and
with various therapies.

Figure 6.5 Baseline CT demonstrates a large liver metastasis from gastric cancer which decreases slightly in size but undergoes cystic change. At the third follow up
(lower right) there is progression with increasing nodular enhancement of tumor along the periphery.

56
 assessment of response to treatment

calculated with a high degree of accuracy. If change in tumor vol-

Key Points: Modified RECIST Criteria
■ Different types of tumors treated with different therapeutic agents
may manifest diverse change patterns on anatomical images
■ Tumor changes in attenuation and size seen in newer
anti-cancer drugs cannot be assessed accurately by the current
RECIST and WHO criteria
■ Modified RECIST criteria for MPM, by measuring tumor
thickness rather than the longest extent, and for GISTs, by
lowering the cut-off value for response and incorporating
attenuation change, show promising clinical results
■ Multiple center trials are needed to validate modified
response criteria
Volumetric Response
With the advent of the multi-row detector CT technology, high
spatial resolution images can be obtained at no additional cost of
radiation dose and acquisition time. Tumor volumes can now be
ume can identify tumor response earlier and more accurately than
the conventional techniques, at least for some types of cancers and
treatments, there is no need to request additional imaging
procedure(s) to better assess response.
Using the thin-sectional CT images, a pilot study on compari-
son of tumor volume, unidimensional and bidimensional mea-
surements showed that changes in NSCLC tumors could be
determined by the volumetric technique as early as three weeks
after initiation of a novel chemotherapy, whereas changes detected
by the unidimensional and bidimensional techniques were con-
siderably less sensitive during this same time period (6). Figure 6.6
shows an example taken from this study, demonstrating different
objective rates obtained by the unidimensional, bidimensional
and volumetric techniques. In this patient, tumor growth was only
detected with the volumetric technique. Comparison studies on
conventional and volumetric response assessment techniques as
well as clinical benefits of the volumetric response need to be
further investigated with large patient datasets.

(A) (B)
Baseline

(C) (D)
24 days follow-up
Figure 6.6 Unidimensional, bidimensional, and volumetric measurements of a NSCLC. (A) Tumor contour (white outline), the greatest, and greatest perpendicular
diameters (black lines). (B) 3D visualization of the segmented tumor. (C) and (D) The same tumor measured on the follow-up CT scan obtained 24 days later. (B) and
(D) are viewed under the same angle along the z-axial direction and tumor growth can only be identified in 3D space. Measurements on baseline scan: uni = 25.0 mm;
bi = 510.0 mm2; vol = 3419.8 mm3. Measurements on follow-up scan: uni = 25.9 mm; bi = 512.8 mm2; vol = 4607.8 mm3. The size changes are 3.6%, 0.5%, and 34.7% for
unidimensional, bidimensional, and volumetric measurements, respectively. Source: Reprinted with permission of Ref. 6.

57
 general principles
Measuring tumor volume requires the tumor boundary or edge
to be traced on each sequential image containing the tumor mass.
The area of the tumor on one image is obtained by counting the
numbers of the pixels enclosed by the tumor contour (contour
pixels included) and then multiplied by the square of the in-plane
resolution [i.e., resolution in x (= y) axis]. Tumor volume is calcu-
lated by summing up all tumor areas and then multiplied by the
scan axial resolution (i.e., resolution in z axis). Contouring tumor
by hand is subjective, not easily reproducible and can be very
tedious and time-consuming particularly when tumors are large
and images are thin sections. The radiologist would face an over-
whelming workload, not only in generating accurate and repro-
ducible volume measurements on serial images, but also in
measuring a large number of tumors and carrying out efficient
follow-up for assessing response to therapy.
Historical film-based interpretation of images can no longer
satisfy oncologists’ demands. Contemporary, powerful image
display, manipulation, and measurement tools provided by PACS
workstations (or other stand-alone applications installed on
computer) are assisting radiologists with efficient and accurate
image interpretation. In addition to measuring tumor size,
other metrics such as tumor attenuation distribution on CT, and
glucose uptake value (SUV) on FDG PET can be readily quantified
with the help of diversified application software. More reliable
and automated/semi-automated 3D image processing methods
are anticipated to be developed and validated for different medical
applications including early detection of cancer or/and cancer
recurrence, efficient follow-up of tumors on serial scans, and
accurate quantification of tumor changes during the course of
therapy. Such software packages can be used in either stand-alone
mode or as an additional module to be integrated into existing
imaging workstations.
Key Points: Volumetric Response
■ Asymmetric tumor change, particularly along the z-axial
direction, cannot be detected by conventional response criteria
■ Volume change is the true measure of change in tumor size
■ Volume measurement may detect change in tumor size
earlier than the conventional measurement techniques
■ Thin-sectional images generated by multiple-row detector CT
have made accurate volume measurement feasible
■ Computer methods will play an important role in assisting the
radiologist with automatic calculation of tumor volumes
■ Usefulness of the volumetric techniques in the assessment of
response to therapy needs to be investigated with large-sized
clinical trials
Functional Imaging
The ability to visualize viable tumor cells and thus indicate
tumor change at the cellular level places functional imaging at the
cutting-edge of technology for early assessment of response to
therapy. Studies have found that uptake of 18F-fluorodeoxyglucose
(18F-FDG) on positron emission tomography is associated with
growth rate and proliferation capacity (43–45). While accumula-
tion of 18F-FDG occurs largely in viable tumor cells rather than in
healthy tissues, a decrease in 18F-FDG uptake indicates decay of
tumor activity and death of viable tumor cells.
58
Uptake of 18F-FDG by tumor on PET is assessed by visual inter-
pretation, semi-quantitative measures [e.g., standard uptake value
(SUV)] and more complex analytical kinetic techniques (e.g., met-
abolic rate of glucose) (46,47). Among these methods, SUV is the
most commonly used method to assess tumor response because it
is quantitative, is simple, enables patients to be stratified for clinical
trials, and can be used to predict patient survival. The SUV is
defined as the attenuation-corrected 18F-FDG accumulation in a
lesion normalized to the injected dose and the patient’s body
weight (body surface area or lean body mass). Since SUV is obtained
at a single snapshot of a dynamic process, one major shortcoming
of this method is considerable measurement variation. Thus it has
been observed that there is a continuous increase of SUV up to
90 minutes after injection of FDG as well as an approximate 16%
increase of SUV between 40 and 60 minutes (48,49). In contrast to
the SUV, the full kinetic quantitative analysis provides an absolute
rate for 18F-FDG and is independent of imaging time. However,
dynamic data acquisition and required arterial blood sampling
make the dynamic technique less practical in clinical settings and
to date there is no evidence to show that quantitative dynamic
imaging is superior to the SUV method (49,50).
Measurements of 18F-FDG uptake on PET can vary radically
due to a number of factors, including chemo-sensitivity of tumor
to the drug, the patient’s blood glucose level, fasting time before
the scan, dose of 18F-FDG injected, time to start scanning after
injection of tracer, image reconstruction algorithm used for PET
and selection of tumor region-of-interest to estimate SUV. Fur-
thermore, a change in the patient’s weight during therapy and the
timing of the follow-up scan can also affect SUV measurement
irrespective of actual changes in the tumor. Precisely how these
factors influence the response assessment negatively is not yet
completely understood. To qualify 18F-FDG uptake as a biomarker/
surrogate endpoint of clinical trials, imaging techniques and pro-
tocols need to be standardized so that results from smaller clinical
trials and large-scale multicenter trials can be compared (51,52).
In 1999, while realizing the need to standardize imaging tech-
niques and protocols and to define functional response criteria,
the European Organization for Research and Treatment of Cancer
(EORTC) PET community proposed an initial guidance of utiliz-
ing 18F-FDG PET to assess response to anticancer therapies (49).
Based on limited clinical studies available at the time, consensus
was reached to standardize patient preparation, image acquisition,
common measurement criteria, and reporting of alterations in
18
F-FDG uptake with therapy. Seven years later, the NCI and the
Cancer Imaging Program of the NCI organized a workshop to
review recent status of 18F-FDG PET technology and clinical
experience both in diagnosis and response assessment. They
then published an updated guidance covering more aspects of
standardization of PET studies particularly related to quality
assurance (53). These recommendations will be used to prepare
the increasing number of NCI-sponsored multi-center clinical
trials utilizing PET imaging to evaluate anticancer drugs.
Molecular imaging probes for cancer intermediary metabolism,
endocrine status, hypoxia, oncofetal and differentiation antigens,
gene expression imaging, and pharmacology are being developed in
the laboratory and are slowly finding their way into clinical research
(54,55). Among the numerous metabolic probes that may be useful
in the future as highly selective biomarkers, the thymidine analogue
 assessment of response to treatment
3′-deoxy-3′-18fluorothymidine (18F-FLT) is likely to be the next met-
abolic radiotracer that becomes widely available for clinical PET
imaging (56,57). In the laboratory it has been shown that FLT is a
better biomarker than FDG for some cancer treatments in which
proliferation of cancer cells is stopped, but the cancer cells remain
viable (58). By incorporating selective molecular imaging probes
into clinical trials of anticancer agents, it will be possible to improve
treatment selection and to better monitor treatment response.
Key Points: Functional Imaging
■ Functional/molecular imaging can detect tumor change at
cellular level and thus earlier than anatomical imaging
■ New generation, targeted cancer agents are not designed to
kill tumor cells and thus are not assessed accurately by ana-
tomical imaging. New molecular imaging techniques are
required to assess these novel approaches
■ Several methods have been developed to assess tumor 18F-FDG
uptake on PET, including visual interpretation, semi-quantitative
measures (e.g., SUV) and quantitative analytical kinetic techniques
(e.g., metabolic rate of glucose)
■ SUV is widely used as a functional biomarker to stratify
patients for clinical trials and allow early prediction of clinical
outcomes including survival
■ A variety of non-tumoral factors considerably influence SUV
measurement and thus the response classification
■ Standardization of PET imaging technique and protocols is
the key to meaningfully comparing results from multi-center
clinical trials and to develop PET imaging as a biomarker/
surrogate endpoint of clinical trials
■ An initiate consensus proposed in 1999 and an updated guid-
ance published in 2006 are standardizing current 18F-FDG
PET practice in the evaluation of anticancer drugs
■ New and more effective tumor-specific radiotracers and
appropriate imaging techniques to better visualize different
types of tumors are under intensive investigation
Key Points: Novel Response Assessments
■ New generation, targeted cancer agents require more accurate
and early response assessment methods
■ Tumor volume change and attenuation-based changes that
can be derived readily from anatomical images provide addi-
tional information and may add value to conventional response
assessment methods
■ Functional imaging techniques, particularly 18F-FDG PET,
have shown great promise in early prediction of patient survival
and stratifying patients for clinical trials
■ Guidelines are established to standardize the current 18F-FDG
PET clinical studies in the evaluation of anti-cancer therapies
■ Molecular imaging probes for capturing various characteris-
tics of cancers, gene expression imaging, and pharmacology
are being developed and are being introduced into clinical
research
■ By incorporating selective molecular imaging probes into clinical
trials testing anti-cancer agents, it will be possible to improve
treatment selection and better monitor treatment response
Summary
■ The 2D WHO and 1D RECIST criteria to assess response in
solid tumors have been widely accepted
■ For consistency between the two criteria, both criteria report
treatment response using four categories, i.e., CR, PR, SD,
and PD
■ Neither the WHO nor the RECIST can capture tumor
changes accurately if tumors have an irregular shape and
change in size is asymmetrical
■ The appropriate imaging modality, imaging technique and
protocol need to be determined by the radiologist so that a
specific type of cancer treated with a specific treatment can
be visualized, quantified and followed up optimally
■ Volume measurement may detect change in tumor size
earlier than the conventional measurement techniques. Thin-
sectional images generated by multiple-row detector CT have
made accurate volume measurement feasible
■ There is an important need to improve conventional meth-
odologies by developing more accurate and sensitive response
assessment methods, including tumor volume and attenua-
tion changes, that can be readily and accurately obtained
from high resolution imaging modalities such as multi-row
detector CT
■ Tumor changes in attenuation and size seen in newer anti-
cancer drugs cannot be assessed accurately by the current
RECIST and WHO criteria
■ Several methods have been developed to assess tumor
18
F-FDG uptake on PET, including visual interpretation,
semi-quantitative measures (e.g., SUV) and quantitative
analytical kinetic techniques (e.g., metabolic rate of glucose)
■ Standardization of PET imaging technique and protocols is
key to comparing results from multi-center clinical trials
meaningfully and to qualifying PET imaging as a biomarker/
surrogate endpoint of clinical trials
REFERENCES
1. Padhani AR, Husband JE. Are current tumour response
criteria relevant for the 21st century? Br J Radiol 2000; 73:
1031–3.
2. Ratain MJ, Eckhardt SG. Phase II studies of modern drugs
directed against new targets: if you are fazed, too, then resist
RECIST. J Clin Oncol 2004; 22: 4442–5.
3. Choi H. Critical issues in response evaluation on computed
tomography: lessions from the Gastrointestinal stromal
tumour model. Cur Oncol Rep 2005; 7: 307–11.
4. Gwyther SJ, Schwartz LH. How to assess anti-tumor efficacy
by imaging techniques. Eur J Cancer 2008; 44: 39–45.
5. Scher HI, Morris MJ, Kelly WK, et al. Prostate cancer clinical
trial end point: “RECIST”ing a step backwards. Clin Cancer
Res 2005; 11: 5223–32.
6. Zhao B, Schwartz LH, Moskowitz C, et al. Computerized
quantification of tumor response in lung cancer – initial
results. Radiology 2006; 241: 892–8.
7. Choi HA, Charnsangavej C, Faria SC, et al. Correlation of
computed tomography and positron emission tomography in
59
 general principles
patients with metastatic gastrointestinal stomal tumors treated
at a single institution with imatinib mesylate: proposal of new
computed tomography response criteria. J Clin Oncol 2007;
25: 1753–9.
8. Benjamin RS, Choi H, Macapinlac HA. We should desist using
RECIST, at least in GIST. J Clin Oncol 2007; 25: 1760–4.
9. Ollivier L, Husband JE, Leclere J. Assessment of response to
treatment. In: Husband JE, Reznek RH, eds. Imaging in Oncol-
ogy, 2nd edn. London: Taylor and Francis, 2004: 67–84.
10. WHO handbook for reporting results of cancer treatment.
Geneva (Switzerland): World Health Organization Offset
Publication No. 48; 1979.
11. Miller AB, Hogestraeten B, Staquet M, et al. Reporting results
of cancer treatment. Cancer 1981; 47: 207–14.
12. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to
evaluate response to treatment in solid tumors. J Natl Cancer
Inst 2000; 92: 205–16.
13. Lavin PT, Flowerdew G. Studies in variation associated
with the measurement of solid tumors. Cancer 1980; 46:
1286–90.
14. Hopper KD, Kasales CJ, Van Slyke MA, et al. Analysis of
interobserver and intraobserver variability in CT tumor
measurements. AJR Am J Roentgenol 1996; 167: 851–4.
15. Thiesse P, Ollivier L, Di Stefano-Louineau D, et al. Response
rate accuracy in oncology trial: reasons for interobserver
variability. J Clin Oncol 1997; 15: 3507–14.
16. Schwartz LH, Ginsberg MS, DeCorato D, et al. Evaluation
of tumor measurements in oncology: use of film-based and
electronic techniques. J Clin Oncol 18: 2179–84.
17. Erasmus JJ, Gladish GW, Broemeling L, et al. Interobserver
and intraobserver variability in measurement of non-small-
call carcinoma lung lesions: implications for assessment of
tumor response. J Clin Oncol 2003; 21: 2574–82.
18. Zhao B, Schwartz LH, Lefkowitz RA, Wang L. Measuring
tumor burden – comparison of automatic and manual tech-
niques. Image Processing, Proc. SPIE 2004; 5370: 1695–700.
19. Zhao B, Schwartz LH, Moskowitz CS, et al. Effect of CT slice
thickness on measurements of pulmonary metastases – initial
experience. Radiology 2005; 234: 934–9.
20. Schwartz LH, Mazumdar M, Brown W, et al. Variability in
response assessment in solid tumors: effect of number of
lesions chosen for measurement. Clin Cancer Res 2003; 9:
4318–23.
21. Mazumdar M, Smith A, Debroy PP, et al. A theoretical
approach to choosing the minimum number of multiple
tumors required for assessing treatment response. J Clin
Epidemiol 2005; 58: 150–3.
22. Wormanns D, Kohl G, Klotz E, et al. Volumetric measurements
of pulmonary nodules at multi-row detector CT: in vivo
reproducibility. Eur Radiol 2004; 14: 86–92.
23. Goodman LR, Gulsun M, Washington L, et al. Inherent vari-
ability of CT lung nodule measurements in vivo using semiau-
tomated volumetric measurements. AJR Am J Roentgenol
2006; 186: 989–94.
24. Zhao B, James LP, Moskowitz C, et al. Evaluating variability
in tumor measurements from same-day repeat CT scans
in patients with non-small cell lung cancer. Radiology 2009;
252: 263–72.
60
25. Moertel CG, Hanley JA. The effect of measuring error on the
results of therapeutic trials in advanced cancer. Cancer 1976;
38: 388–94.
26. Steel GG. Cytokinetics of neoplasia. In: Holland JF, Frei E, eds.
Cancer Medicine. Philadephia: Lea and Febiger, 1973;
125–40.
27. Sohaib SA, Turner B, Hanson JA, et al. CT assessment of
tumour response to treatment: comparison of linear, cross-
sectional and volumetric measures of tumours size. Br J Radiol
2000; 73: 1178–84.
28. Warren KE, et al. Comparison of one-, two-, and three-
dimensional measurements of childhood brain tumors. J Natl
Cancer Inst 2001; 93: 1401–5.
29. Trillet-Lenoir V, Freyer G, Kaemmerlenet P, et al. Assessment
of tumour response to chemotherapy for metastatic colorectal
cancer: accuracy of the RECIST criteria. Br J Radiol 2002; 75:
903–8.
30. Schwartz LH, Mazumdar M, Wang L, et al. Response assessment
classification in patients with advanced renal cell carcinoma
treated on clinical trials. Cancer 2003; 98: 1611–19.
31. McHugh K, Kao S. Can paediatric radiologists resist RECIST
(response evaluation criteria in solid tumours)? Pediatr Radiol
2003; 33: 739–43.
32. Kamiyoshihara M, Kawashima O, Ishikawa S, et al. Mediastinal
lymph node evaluation by computed tomographic scan in
lung cancer. J Cardiovasc Surg (Torino) 2001; 42: 119–24.
33. Konishi J, Yamazaki K, Tsukamoto E, et al. Mediastinal lymph
node staging by FDG-PET in patients with non-small cell lung
cancer: analysis of false-positive FDG-PET findings. Respira-
tion 2003; 70: 500–6.
34. Schwartz LH, Colville JAC, Ginsberg MS, et al. Measuring
tumor response and shape change on CT: esophageal cancer as
a paradigm. Annal Oncol 2006; 17: 1018–23.
35. Warr D, Mckinney S, Tannock I. Influence of measurement
error on assessment of response to anticancer chemotherapy:
proposal for new criteria of tumor response. J Clin Oncol
1984; 2: 1040–6.
36. Gelmon KA. The fine points of end-points: phase II trials in
lung cancer. Ann Oncol 1998; 9: 1045–6.
37. Sekine I, Kubota K, Nishiwaki Y, et al. Response rate as an
end-point for evaluating new cytotoxic agents in phase II trials
of non-small cell lung cancer. Ann Oncol 1998; 9: 1079–84.
38. Byrne MJ, Nowak AK. Modified RECIST criteria for assessment
of response in malignant pleural mesothelioma. Ann Oncol
2004; 15: 257–60.
39. Monetti F, Casanova S, Grasso A, et al. Inadequacy of the new
Response Evaluation Criteria in Solid Tumors (RECIST) in
patients with malignant pleural mesothelioma: report of four
cases. Lung Cancer 2004; 43: 71–4.
40. Ceresoli GL, Chiti A, Zucali PA, et al. Assessment of tumor
response in malignant pleural mesothelioma. Cancer Treatment
Reviews 2007; 33: 533–41.
41. Stroobants S, Goeminne J, Seeger M, et al. 18FDG-positron
emission tomography for the early prediction of response in
advanced soft tissue sarcoma treated with imatinib mesylate.
Eur J Cancer 2003; 39: 2012–20.
42. Antoch G, Kanja J, Bauer S, et al. Comparison of PET, CT, and
dua-modality PET/CT imaging for monitoring of imatinib
 assessment of response to treatment
(STI-571) therapy inpatients with gastrointestinal stromal
tumors. J Nucl Med 2004; 45: 357–65.
43. Minn H, Joensuu H, Ahonen A, et al. Fluorodeoxyglucose
imaging: a method to assess the proliferative activity of human
cancer in vivo. Cancer 1988; 61: 1776–81.
44. Herhole K, Rudolf J, Heiss WD. FDG transport and phospho-
rylation in human gliomas measured with dynamic PET.
J Neuro Oncol 1992; 12: 159–65.
45. Duhaylongsod FG, Lowe VJ, Patz EF, et al. Lung tumor growth
with glucose metabolism measured by fluoride-18 fluoro-
deoxyglucose positron emission tomography. Ann Thorac
Surg 1995; 60: 1348–52.
46. Larson SM, Erdi Y, Akhurst T, et al. Tumor treatment response
based on visual and quantitative changes in global tumor
glycolysis using PET-FDG imaging. The visual response score
and the change in total lesion glycolysis. Clin Positron Imaging
1999; 2: 159–71.
47. Hoekstra CJ, Paglianiti I, Hoekstra OS, et al. Monitoring
response to therapy in cancer using [18F]-2-fluoro-2-deoxy-
D-glucose and positron emission tomography: an overview
of different analytical methods. Eur J Nucl Med 2000; 27:
731–43.
48. Weber WA, Ziegler SI, Thodtmann R, et al. Reproducibility of
metabolic measurements in malignant tumors using FDG
PET. J Nucl Med 1999; 40: 1771–7.
49. Young H, Baum R, Cremerius U, et al. Measurement of clinical
and subclinical tumour response using [18F]-fluorodeoxyglucose
and positron emission tomography: review and 1999 EORTC
recommendations. Eur J Cancer 1999; 35: 1773–82.
50. de Geus-Oei LF, van der Heijden HFM, Visser EP, et al.
Chemotherapy response evaluation with 18F-FDG PET in patients
with non-small cell lung cancer. J Nucl Med 2007; 48: 1592–8.
51. Smith JJ, Sorensen AG, Thrall JH. Biomarkers in imaging:
realizing radiology’s future. Radiology 2003; 227: 633–9.
52. Larson SM, Schwartz L. 18F-FDG PET as a candidate for
“Qualified Biomarker”: functional assessment of treatment
response in oncology. J Nucl Med 2006; 47: 901–3.
53. Shankar LK, Hoffman JM, Bacharach S, et al. Guidelines for
the use of 18FDG-PET as an indicator of therapeutic response
in patients in National Cancer Institute trials. J Nucl Med
2006; 47: 1059–66.
54. Divgi CR, Pandit-Taskar N, Jungbluth AA, et al. Preoperative
characterisation of clear-cell renal carcinoma using iodine-
124-labelled antibody chimeric G250 (124I-cG250) and PET
in patients with renal masses: a phase I trial. Lancet Oncol
2007; 8: 304–10.
55. Gambhir SS, Herschman HR, Cherry SR, et al. Imaging trans-
gene expression with radionuclide imaging technologies.
Neoplasia 2000; 2: 118–38.
56. Shields AF. PET imaging with 18F-FLT and thymidine analogs:
promise and pitfalls. J Nucl Med 2003; 44: 1432–4.
57. Shields AF, Grierson JR, Dohmen BM, et al. Imaging prolifera-
tion in vivo with [F-18]FLT and positron emission tomography.
Nat Med 1998; 4: 1334–6.
58. Solit DB, Santos E, Pratilas CA, et al. 3’-deoxy-3’-[18F]fluoro-
thymidine positron emission tomography is a sensitive method
for imaging the response of BRAF-dependent tumors to MEK
inhibition. Cancer Res 2007; 67: 11463–9.
61
 7 Secondary Malignancies
Rod Skinner and ADJ Pearson
INTRODUCTION
As the treatment of childhood malignancy has improved over the
last 50 years, the overall five-year survival rate has risen steadily
and is now at least 75% (1). However, approximately 60% of long-
term survivors of childhood malignancy suffer from at least one
late side effect of treatment, whilst 30% experience a potentially
serious complication (2,3). Although most can expect to be cured,
five-year survivors still experience an increased risk of morbidity
and mortality compared to their healthy peers (2–4). Analysis of
data from the Childhood Cancer Survivor Study performed in the
United States, with follow-up of 16 to 32 years from initial diag-
nosis, revealed that five-year survivors had a standardized mortal-
ity ratio (SMR) (an age and gender standardized measure of
mortality expressed as a ratio to the mortality rate of the general
population) of 8.4 (Table 7.1). Amongst these five-year survivors,
57.5% of subsequent deaths were due to recurrence of the pri-
mary malignancy itself, whilst most of the remainder resulted
from late treatment-related toxicity, with 18.6% being due to sec-
ond or subsequent malignant neoplasms (SMR 15.2), followed by
cardiac (6.9%; SMR 7.0) and pulmonary (2.6%; SMR 8.8) com-
plications (4). Twenty-five years after diagnosis of childhood
malignancy, the death rate due to a subsequent malignancy
exceeded that due to all other causes (4).
Secondary malignant neoplasms (SMNs) may be regarded as
occurring secondary to previous treatment (although other genetic
and environmental factors may also be relevant), and may be the
second, third, or even subsequent malignancy experienced by the
patient. Indeed, some patients receiving chemotherapy and/or
radiotherapy for non-malignant conditions [e.g., some patients
undergoing hematopoietic stem cell transplantation (HSCT)] may
develop a first malignancy that is secondary to their previous treatment.
SMNs are one of the most devastating of late adverse effects of
treatment for cancer or leukemia, causing considerable morbidity
and mortality in individuals who might otherwise have been cured
of their primary malignancy.
Although the relative risk (RR) of developing a SMN (i.e., the
increased risk of developing a malignancy expressed as a ratio to
the risk in a healthy age-matched population) in survivors of
childhood cancer is relatively high, the absolute risk remains low
since malignancy is rare in childhood. Conversely, even though
the RR is higher in children than in adults, the absolute frequency
of SMNs is higher in the adult population because primary malig-
nancies are much commoner in adulthood.
Some groups of survivors are at higher risk of developing a
SMN by virtue of the specific treatment that they have received
or as a result of factors related to their initial malignancy, or to
genetic or environmental influences (Table 7.2). Identification of
these risk factors and reduction of their potential impact are vital
components of strategies to reduce the burden of SMNs faced by
survivors of malignancy or HSCT, whilst still maintaining the
62
cytotoxic efficacy and success rates of contemporary treatment
strategies. Improved understanding of the nature of malignancy
in general is an integral part of efforts to meet the challenge of
preventing second malignancies.
Most (but not all) SMNs fall into two broad categories with
important aetiological and clinical characteristics (“Typical Clinical
Presentations” section and Table 7.4). Depending on their previous
treatment, some groups of patients may be at particularly high
risk of one or both of these categories. Secondary myelodysplasia
(MDS)/acute myeloid leukemia (AML) tends to occur relatively
early (classically 3–5 years) after treatment with chemotherapy
(typically alkylating agents or topoisomerase II inhibitors), whilst
a variety of solid tumors may arise later (typically 10–15 years)
after treatment with radiotherapy, sometimes in association with
cytotoxic drugs such as alkylating agents or anthracyclines.
Some SMNs arise in the context of a wide variety of cancer pre-
disposition syndromes. The prototype for these conditions is the
Li–Fraumeni syndrome, in which family members seem to be at
increased risk of a range of malignancies and individual patients
display a high incidence of second and indeed multiple subsequent
malignancies (5).
Key Points: Introduction
■ Five year survivors have a standardized mortality ratio
(a measure of mortality expressed as a ratio to the mortality
rate of the general population) of 8.4; although nearly 60%
of deaths occurring later than five years from initial diagnosis
are due to recurrence of the primary malignancy, almost 20%
are caused by secondary malignancy
■ Twenty-five years after diagnosis of a childhood malignancy,
the mortality rate due to a subsequent malignancy exceeds
that due to all other causes
■ Although the relative risk of developing a secondary malig-
nant neoplasm (SMN) in survivors of childhood cancer is
relatively high, the absolute risk remains low since malig-
nancy is rare in childhood
EPIDEMIOLOGY (TABLE 7.3)
Although the occurrence of SMNs in survivors of malignancy has
been recognized since the late 1970s (6), appreciation of their
true frequency has evolved more gradually. Nearly all the early
reports were in survivors of childhood malignancies (6–9), at
least in part due to the higher survival rates in this age group
(allowing more opportunity to develop late adverse effects in
general, including SMNs), but there is growing recognition of
their occurrence in survivors of adult cancer and leukemia
(10–12). The epidemiological characteristics of SMNs in survi-
vors of malignancy have been categorized by a variety of publica-
tions varying in study design (e.g., cohort or case control studies),
 secondary maligncies
Table 7.1 Second Malignant Neoplasms are a Major Cause of Late
Mortality in Survivors of Childhood Cancer [Mertens et al. (4)]
20,483 5-yr survivors of childhood/adolescent malignancy
(diagnosed between 1970–1986) enrolled retrospectively
into CCSS
2,821 Deaths during follow-up period (1979–2002)
2,534 Cause of death ascertained
82% Estimated probability of survival 30 yr from initial
diagnosis
18% All-cause cumulative 30-yr mortality in 5-yr survivors.
These deaths were due to:
57.5% Recurrence of primary malignancy
18.6% Second or subsequent malignant neoplasm
7.3% External causes (accidents, suicide, homicide, etc.)
6.9% Cardiac disease
2.6% Pulmonary disease
1.9% Infections
25 years after initial diagnosis, the death rate due to a second or subsequent
malignancy exceeded that due to all other causes
Abbreviations: CCSS, Childhood Cancer Survivor Study (centers from North
America).
Table 7.2 Risk Factors for the Development
of Secondary Malignancies
• Chemotherapy, especially
° Alkylkating agents
° Epipodophyllotoxins
• Radiotherapy
• Genetic factors (e.g., cancer predisposition syndromes—see Table 7.5)
• Environmental factors (e.g., tobacco smoking)
• Combinations of above factors, especially related to complex interactions.
e.g., between
° Diagnosis of initial primary malignancy (e.g., Hodgkin disease)
° Treatment received (especially combination treatments, e.g., hematopoietic
stem cell transplants involving both radiotherapy and high-dose chemo-
therapy)
° Use of certain treatments in susceptible patients (e.g., radiotherapy in
patients with hereditary retinoblastoma)
statistical measures employed (e.g., RR, SMR, standardized inci-
dence ratio, SIR (an age and gender standardized measure of
incidence expressed as a ratio to the incidence rate in the general
population), study population (e.g., treatment center, regional or
national registry-based), initial diagnosis (e.g., all at risk patients
or only those with certain diseases such as Hodgkin disease, HD),
or treatment (e.g., radiotherapy, HSCT).
The first large studies of secondary malignancy reported that
about 1% of five-year survivors of childhood malignancy devel-
oped a SMN (6,7). Subsequent longer-term studies, including
both single-center and larger population-based cohort studies
from Europe and the United States, have reported the occurrence
of SMNs in 4–13% of individuals during follow-up of up to
30 years after treatment in childhood, representing RRs of approx-
imately 4–15 (7–9,13–15). A consistent finding is that some pri-
mary malignancies, especially retinoblastoma, HD, and soft tissue
sarcoma, are much more likely to be associated with the later
development of a SMN (7,9,15). Likewise, numerous studies have
shown that the commonest SMNs are bone tumors, followed by
thyroid cancer, soft tissue sarcomas, and skin tumors (7,9,14,15).
In contrast, studies in survivors of adult malignancy have shown
either no (16) or only a relatively small increased risk (RR ≤ 2) of
developing SMN compared to the healthy general population (11,17).
Selected examples of studies that have provided important
information about the epidemiological characteristics of SMNs in
certain patient populations are shown in Table 7.3.
Survivors at Particularly High Risk of Developing
Secondary Malignancy
Although the absolute risk of developing a SMN in most studies
has been reassuringly low over long-term follow-up of up to
25 years, it is well recognized that some survivors have much
higher risks of developing a SMN as a result of genetic predisposi-
tion (e.g., hereditary retinoblastoma), their initial diagnosis (e.g.,
HD), or certain treatment modalities (e.g., HSCT). It is likely that
these risk factors may interact adversely, e.g., leading to a higher
risk of SMN in survivors of HSCT when the conditioning regimen
included radiotherapy (18).
Hereditary Retinoblastoma
It has been recognized for over 30 years that patients with retinoblas-
toma have a high likelihood of developing secondary malignancy.
This risk is largely confined to individuals with hereditary retinoblas-
toma (approximately 40% of all patients with retinoblastoma) and is
related to the presence of germline mutations in RB1, the retinoblas-
toma tumor suppressor gene. By 50 years after diagnosis, the cumula-
tive incidence of a SMN was 51% in hereditary cases (with a RR of
30), but only 5% in non-hereditary cases of retinoblastoma (19).
Although increasing doses of radiotherapy have been associated with
stepwise increments in the RR of developing a secondary soft tissue
sarcoma, the increased risk is not related exclusively to radiotherapy
exposure since it is well documented that SMNs may occur outside
radiotherapy fields (20,21). The commonest SMNs observed in sur-
vivors of retinoblastoma are osteosarcoma (with an extremely high
RR of up to 500) (21), soft tissue sarcomas, and melanomas. Pinealo-
blastomas are also reported, constituting the entity of trilateral retin-
oblastoma. Third and even subsequent malignancies (similar in
distribution to the second malignancies described above) are also
well described in survivors of retinoblastoma, predominantly in those
treated with radiotherapy, occurring within 10 years of development
of a SMN in 22% of individuals (22).
Hodgkin Disease
Several long-term follow-up studies have been reported since
1993 describing the incidence and characteristics of SMNs in well
defined cohorts of survivors of HD treated during various time
periods from 1935 onwards (but all inclusive of the 1970s and
1980s) (12,23–31). These studies have all shown a high preva-
lence of SMNs in HD survivors, increasing with time after treat-
ment to reach a cumulative incidence of up to 26% by 30 years
from initial diagnosis (25). The overall RR of developing a SMN
has varied according to the type of SMN (7 for solid but 27.4 for
hematological malignancies) (28), the length of time since diag-
nosis (2%, 7–11%, and 18–26% at 10, 20, and 30 years, respec-
tively) (25,26), and gender (10.6 for males, 15.4 for females) (27).
The commonest SMNs observed have included breast, thyroid,
gastrointestinal tract, and lung cancers, basal cell carcinoma and
soft tissue sarcomas (25,26). Although numerically less common
63
 general principles

Table 7.3 Epidemiology of Secondary Malignant Neoplasms—Selected Illustrative Examples

Reference Study characteristics Results Risk factors Comments

Neglia et al. (15) CCSS 314 SMNs (in 298 patients) Female sex Despite increased SIR,
All childhood and Cumulative incidence 3.2% at HD or soft tissue sarcoma as only 1.88 excess
adolescent malignancies 20 years primary malignancy malignancies occurred
(cancer and leukemia) Overall SIR 6.4 (5.7–7.1) per 1000 patient years
diagnosed 1970–1986 Commonest SMNs of follow-up
13,581 5-yr survivors • Breast: 60 SMNs, SIR 16.2
(12.4–20.8)
• Thyroid: 43 SMNs, SIR 11.3
(8.2–15.3)
• CNS: 36 SMNs, SIR 9.9
(6.9–13.6)
• Bone: 28 SMNs, SIR 19.1
(12.7–27.7)
• Leukemia: 24 SMNs, SIR 6.9
(4.4–10.2)
Marees et al. (20) Dutch RBL Registry 74 second malignancies Most (89%) SMNs in hereditary Third and subsequent
RBL diagnosed 1945–2005 • Hereditary RBL: 62 SMNs, SIR RBL occurred in patients treated malignancies not
668 survivors 20.4 (15.6–26.1); commonest with radiotherapy included in this
Median follow-up 21.9 SMNs (± chemotherapy), but analysis
(hereditary) and 24.9 yr ° Soft tissue sarcomas: 20 only 40% occurred within
(non-hereditary RBL) SMNs, SIR 243 (148–375) radiotherapy field
° Bone: 16 SMNs, SIR 314
(180–511)
• Non-hereditary RBL: 12 SMNs,
SIR 1.86 (0.96–3.2)
Cumulative incidence 28.0% at
40 yr in hereditary RBL
Bhatia et al. (25) LESG 212 SMNs (in 173 patients) Recurrence of HD 32 patients developed
HD diagnosed 1955–1986 at ≤16 yr Cumulative incidence 10.6% at Combination treatment third neoplasms
age 20 yr, 26.3% at 30 yr (chemo- and radiotherapy) (cumulative incidence
1380 survivors Overall SIR 18.5 (15.6–21.7) Chemotherapy (leukemia as SMN) 21% at 10 yr after second)
Median follow-up 17.0 yr Commonest SMNs Radiotherapy (solid SMNs) Increased lung and colon
• Breast: 40 SMNs, SIR 56.7 cancers at earlier age
(40.5–77.3) than usual
• Thyroid: 19 SMNs, SIR 36.4
(21.9–56.8)
• Leukemia: 27 SMNs, SIR 174.8
(115.1–254.3)
Baker et al. (36) Single center (Minneapolis, USA) 147 PTMs (in 137 patients) PTLD: allogeneic HSCT After exclusion of PTLD,
3372 HSCTs performed 1974–2001 Cumulative incidence 6.9% at (especially if performed for overall SIR still raised at
• Allogeneic 2179 20 years primary immuno-deficiency), 5.4 (4.3–6.6)
• Autologous 1193 Overall SIR 8.1 (6.7–9.6) use of ATG Cumulative incidence of
Commonest PTMs AML/MDS: autologous HSCT, PTLD
• PTLD: 44 PTMs, SIR 54.3 use of PBSC and of AML/MDS
(39.5–71.6) Solid PTMs: older age (≥20 yr) plateaued
• AML/MDS: 36 PTMs, SIR 300 at HSCT at 1.4% each by 10 yr
(210–406) Cumulative incidence of solid
• Melanoma: 8 PTMs, SIR 8.3 tumors did not plateau –
(3.6–15.1) 3.8% at 20 yr
• Oral: 5 PTMs, SIR 10.2
(3.2–21.1)

Abbreviations: AML, acute myeloid leukemia; ATG, anti-thymocyte globulin; CCSS, Childhood Cancer Survivor Study (centers from North America); HSCT,
hematopoietic stem cell transplant; HD, Hodgkin disease; LESG, Late Effects Study Group (centers from USA, England, France, Italy); MDS, myelodysplasia; PBSC,
peripheral blood stem cells; PTLD, post-transplant lymphoproliferative disorder; PTM, post-transplant malignancy; RBL, retinoblastoma; SIR, standardized incidence
ratio (95% confidence limits in brackets); SMN, secondary malignant neoplasm.

in absolute terms, hematological SMNs [acute leukemias,
non-Hodgkin lymphoma (NHL)] had similarly increased RRs
(26). Viewed collectively, the findings of these cohort studies
suggest that the incidence of radiotherapy-related solid SMNs
(e.g., breast and thyroid cancer) has continued to rise with
increasing duration of follow-up to 30 years from diagnosis,
whilst hematological SMNs (which are more likely to be related to
chemotherapy) occur at a much earlier median of four years and
have probably all occurred by 15 years post-diagnosis (25). Further-
more, a worrying trend has emerged with the earlier development of
several cancers that are traditionally commoner in middle and older
age, exemplified by the occurrence of lung, gastric, and colorectal

64
 secondary maligncies
cancers at unusually young ages in survivors of HD treated in
childhood (25).
Hematopoietic Stem Cell Transplantation
Several studies since the 1990s have demonstrated a particularly
high risk of SMNs in survivors of HSCT. This has been observed in
a multicenter study including survivors of all HSCTs performed at
participating centers (32), in survivors of HSCT performed for acute
leukemia (until recent years, the commonest indication for HSCT)
(33,34), and in both autologous and allogeneic HSCTs (32,34–36).
The increased risks of certain SMNs after HSCT have been described,
including solid tumors in general (34), oral and skin (37), and thy-
roid (38) cancer in particular. These studies have highlighted some
of the potential factors that may generate a high incidence of SMNs
following HSCT, including the initial diagnosis, previous chemo-
therapy and radiotherapy (both that given as part of first and
second-line treatment before HSCT is performed and that given as
part of conditioning treatment), graft-versus-host disease (GvHD),
and its treatment. Some of these reports have also highlighted the
risk of post-transplant lymphoproliferative disorder (PTLD),
usually manifesting as an EBV-related B cell NHL (33,35,36).
A study of over 1000 five-year survivors of autologous (n = 79)
or allogeneic HSCT survivors transplanted consecutively in 45
European centers before 1986 reported actuarial incidences of all
SMNs of 3.5% at 10 years and 12.8% at 15 years, with a RR of 3.8.
The commonest SMNs included skin (n = 14), oral (n = 7),
uterine (n = 5), thyroid (n = 5), and breast (n = 4) cancer, and
glioblastomas (n = 3). The most important risk factors for the
development of a SMN after HSCT in this analysis were older
patient age at transplant and the treatment of GvHD with
cyclosporine A, whilst transplant type (allogeneic versus autologous/
syngeneic) and conditioning treatment were not significant
factors, leading to the suggestion that immunosuppression is a
central factor in the development of SMNs following HSCT (32).
A very large cohort study of 3182 survivors of allogeneic HSCT
for childhood acute leukemia performed in 235 centers between
1964 and 1992 also found a high and increasing cumulative inci-
dence of SMNs reaching 11% at 15 years, with brain (n = 9) and
thyroid (n = 5) tumors accounting for 56% of these. In contrast to
the previous report, this study demonstrated clearly the impor-
tance of total body irradiation (TBI) as a risk factor for SMNs
overall following HSCT and speculated on the contributory role
of previous cranial radiotherapy (i.e., given during earlier antileu-
kaemic treatment) in nine of the 14 patients who later developed
brain and thyroid SMNs (33). A large single center study of
2129 survivors of HSCT performed predominantly for hemato-
logical malignancies demonstrated that the incidence of solid
SMNs continued to rise to 15% at 15 years post-HSCT, with the
expectation of additional increases with further follow-up, and
confirmed that most thyroid, liver, and oral cancers occurred in
recipients of TBI, whilst chronic hepatitis C infection appeared to be
an additional risk factor for the development of liver cancer (34).
A greatly increased risk of MDS/AML has been described in survi-
vors of autologous HSCT, especially in adults with lymphoma with
an incidence of up to 14% at five years post-transplant, and has been
attributed to prior and conditioning chemotherapy and radiother-
apy, with possible additional factors including the pronounced
myeloproliferation that occurs during stem cell engraftment and
possibly genetic polymorphisms relevant to drug metabolism and
DNA repair (39). However, an analysis of 605 patients undergoing
autologous bone marrow transplantation for NHL after condition-
ing treatment with cyclophosphamide and TBI demonstrated sig-
nificant risks both of MDS/AML and of solid SMNs. The overall
incidence of SMNs (including MD/AML) was 21% by 10 years, split
approximately equally between MDS/AML and other SMNs (includ-
ing solid tumors and non-MDS hematological malignancies) (40).
As in the other reports of post-HSCT SMNs, the incidence of solid
tumors continued to rise with longer follow-up leading to a
projected incidence of all SMNs of 29% by 15 years (40).
Although some reports have specifically excluded patients with
PTLD, others have shown that it is one of the most frequent or
indeed the most common malignancy occurring after HSCT, par-
ticularly in patients transplanted for primary immunodeficiency,
and/or in the setting of mismatched allogeneic transplants
performed using in vitro or in vivo T-cell depletion (33,35,36).
Other studies have demonstrated significantly increased risks of
thyroid cancer (with a standardized incidence ratio of 3.3 compared
to the general population) (38), oral, and skin cancers (37,41)
after HSCT.
Key Points: Epidemiology
■ Although early reports of SMNs were in survivors of
childhood malignancy, there is a growing recognition of
their occurrence in survivors of adult cancer and leukemia
■ Some primary malignancies such as retinoblastoma, Hodgkin
disease, and soft tissue sarcoma are much more likely to be
associated with a later development of a SMN
■ The commonest SMNs in survivors of retinoblastoma are
osteosarcoma, soft tissue sarcomas, and melanomas
■ In survivors of Hodgkin disease, the commonest SMNs
observed include breast, thyroid, gastrointestinal tract, and
lung cancers, basal cell carcinoma and soft tissue sarcomas
■ In survivors of hematopoietic stem cell transplantation, the
increased risk of SMNs includes solid tumors in general
(especially oral, skin, and thyroid cancer) and hematological
malignancies (especially acute myeloid leukemia and
myelodysplasia)
ETIOLOGY
Radiotherapy
The cumulative incidence of SMN is significantly related to the
exposure to radiation with thyroid and breast cancer and brain
tumors being the commonest SMNs reported. Studies have
reported substantially increased risks of breast cancer among
survivors of HD at 10–20 years post-treatment. On univariate
analysis, an increased risk was associated with female gender,
increasing radiation dose, and age at treatment (12–16 years).
Mantle radiation dose increased risk, and this was 2.5-fold for
female patients treated with more than 35 Gy (42). However, the
substantially increased RRs of breast cancer observed at
10–20 years post-diagnosis are not sustained into ages at which
the risk of breast cancer in the general population becomes sub-
stantial (43). The incidence of SMNs varies with the tissue and
organs irradiated, patient age, genetic factors, but predominantly
65
 general principles
with dose distribution, size of the irradiated volume, absolute dose,
and dose-rate. Data suggests that SMNs are mainly observed in
tissues that have absorbed doses above 2 Gy (fractionated irradia-
tion) and that their incidence increases with dose. However, in
children, thyroid and breast cancers are observed following doses
as low as 100 mGy, and in adults lung cancers have been reported
for doses of 500 mGy, possibly due to interaction with tobacco (44).
Chemotherapy
Chemotherapy can cause malignancies, predominantly acute leu-
kemia, and MDS. The two main classes of leukemogenic agents
are the alkylating agents and topoisomerase II inhibitors. Amongst
alkylating agents, chlorambucil and melphalan are probably the
most potent leukemogenic agents, and cyclophosphamide the
least. The topoisomerase II inhibitor etoposide (VP-16) has been
associated with higher incidences of SMNs, especially AML.
Etoposide kills cells by stabilizing a covalent enzyme-cleaved
DNA complex (known as the cleavage complex) that is a tran-
sient intermediate in the catalytic cycle of topoisomerase II. The
accumulation of cleavage complexes in treated cells leads to the
generation of permanent DNA strand breaks, which trigger
recombination/repair pathways, mutagenesis, and chromosomal
translocations. If these breaks overwhelm the cell, they can initi-
ate death pathways. Rearrangements involving the MLL gene on
chromosome band 11q23 are a hallmark of therapy-related AML
following treatment with topoisomerase II poisons, including
etoposide (45).
There are two genetically distinct topoisomerase II isoforms,
both of which are the target of topoisomerase II inhibitors. Topoi-
somerase II alpha is essential for cell proliferation and is highly
expressed in vigorously growing cells, whereas topoisomerase II
beta is not essential for growth and has recently been implicated in
treatment-associated secondary malignancies. Recently it has been
shown that etoposide-induced carcinogenesis involves mainly the
beta rather than the alpha isozyme of topoisomerase II (46). This
suggests that topoisomerase II alpha-specific anticancer drugs
will offer the potential of effective chemotherapy without the
development of treatment-related SMNs.
The cytotoxicity of anthracyclines is at least partly mediated by
topoisomerase II inhibition and they too appear to be associated
with an increased risk of AML (47). However, antimetabolites,
such as methotrexate or mercaptopurine, and the vinca alkaloids,
are probably associated with a low risk of SMNs. Cytotoxic
chemotherapy may predispose to the development of renal cell
carcinoma, involving Xp11.2/TFE3 translocation (48,49). In the
future, a genome-wide approach may allow the identification of
risk factors for therapy-related AML (50).
Hereditary Retinoblastoma
After 20 years, the risk of SMNs in survivors of hereditary retino-
blastoma (SIR = 20.4) is much higher than that in survivors of
nonhereditary retinoblastoma (SIR = 1.86) (20). Among patients
with hereditary disease, treatment with radiotherapy is associated
with a further increase in the risk of a subsequent cancer (hazard
ratio = 2.81) (20). After 30 years of follow-up, elevated risks of
epithelial cancers (lung, bladder, and breast) were observed among
survivors of hereditary retinoblastoma (20).
66
Key Points: Etiology
■ Following radiotherapy the incidence of SMNs is significantly
related to the radiation dose with thyroid and breast cancer
and brain tumors being the commonest malignancies
■ The two main classes of leukemogenic chemotherapeutic
agents are the alkylating agents and topoisomerases II
inhibitors, which cause predominantly acute leukemia and
myelodysplasia
TYPICAL CLINICAL PRESENTATIONS (TABLE 7.4)
Chemotherapy
MDS and AML are much the commonest hematological SMNs
reported, with a peak incidence occurring 4–6 years from diagno-
sis of the initial malignancy, and reaching a plateau by 15 years.
Although treatment with alkylating agents or with topoisomerase
II inhibitors is associated with an increased risk of developing
subsequent hematological malignancies, the clinical and cytoge-
netic characteristics of the SMNs differ between the two classes of
drugs. In general, alkylator-induced MDS/AML tends to present
initially with MDS, 1–20 years (median 4–6 years) after initial
treatment, and is characterized by losses or deletions of material
from chromosomes five or seven (e.g., 7q or monosomy 7). The
overall incidence is usually <5% of exposed patients, whilst older
age at exposure to and higher doses of alkylating agents appear to
be important risk factors. In contrast, epipodophyllotoxin-induced
leukemia usually occurs earlier, within the first five years (median
2–3 years) post-treatment, and presents more acutely in younger
patients, most often as M4 or M5 AML, typically characterized by
balanced translocations leading to MLL gene rearrangements. The
incidence is usually <4%, and does not appear to be dose-related.
Instead, patients treated with epipodophyllotoxins weekly or more
frequently have been found to have a much higher risk than those
treated less often (51).
Alkylating agents have also been associated with the development
of bone SMNs, although the absolute risk was <1% except for
patients whose primary malignancy was hereditary retinoblastoma,
Ewing’s sarcoma, or another bone malignancy (52).
Radiotherapy
Radiotherapy-associated SMNs embrace a variety of solid tumors.
The latency period between radiation exposure and development
of the SMN is typically at least 10 years, whilst the incidence con-
tinues to increase with time after treatment. Most radiotherapy-
associated SMNs occur within or on the edge of the radiation
treatment field, whilst young age at radiotherapy treatment and
higher radiotherapy doses are important risk factors (53).
Numerous reports have shown that breast cancer is particularly
common in survivors of childhood HD previously treated with
mantle radiotherapy, typically presenting in young women
(median age 32 years) with a mean latent period of 15–18 years
(25). About one-third of women with a breast SMN subsequently
developed cancer in the contralateral breast (25). It is also clear
that there is an increased risk of other solid tumors arising within
the radiotherapy fields, including thyroid, lung, oesophageal, gastric,
and colorectal cancers (15,25).
 secondary maligncies

Table 7.4 Clinical Categories/Presentations of Secondary Malignant Neoplasms

Chemotherapy-related Radiotherapy-related After hematopoietic stem cell
transplantation
Alkylating agents Epipodophyllo-toxins
Nature of SMN AML/MDS (typically AML (typically M4 or M5) Solid tumors AML/MDS (mainly in recipients
presenting as MDS) (usually within radiation field) of autologous transplants)
Solid tumors (mainly in
recipients of radiotherapy)
PTLD (mainly in recipients of
allogeneic transplants for
primary immunodeficiency)
Incidence Up to 5% of exposed Up to 4% of exposed Up to ∼20% in high risk 15% by 15 yr (up to 30% in one
patients patients groups (e.g., Hodgkin disease) report)
Latency 1–20 (median 4–6) yr <5 (median 2–3) yr Up to at least 30 yr and possibly longer Bimodal–within 1st 10 yr for
AML/MDS, up to 30 yr or later
for solid tumors
Age of presentation Typically older adults Younger patients including Any Any
children
Associated features Chromosomal losses or MLL gene rearrangements Risk higher in some cancer Note potential importance of
deletions predisposition syndromes earlier treatment, i.e., that given
(e.g., hereditary retinoblastoma) prior to transplant
Risk factors Higher doses of alkylating Increased dose frequency Higher radiation dose Chemotherapy
agents (weekly or more often) Other dose characteristics are probably Radiotherapy
Older patient age at Not related to cumulative also important (e.g., dose rate) In some patients
exposure dose Age at treatment (e.g., risk of breast • GvHD
cancer higher in Hodgkin disease if • Hepatitis C infection
irradiated during puberty)

Abbreviations: AML, acute myeloid leukemia; MDS, myelodysplasia; GvHD, graft-versus-host disease; SMN, secondary malignant neoplasm.

Other well described associations include secondary thyroid
cancer following craniospinal radiotherapy for acute lymphoblas-
tic leukemia (ALL) and brain tumors, and secondary brain tumors
after cranial radiotherapy for ALL or primary brain tumors (54).
The risk factors for thyroid cancer include increasing radiation
dose and young age at treatment (55), whilst amongst survivors of
ALL, females, recipients of craniospinal radiotherapy, and those
treated for relapse are more likely to develop SMNs including
brain tumors, AML, NHL, parotid tumors, thyroid cancer, and
soft tissue sarcomas (54). A variety of aggressively behaving sarco-
mas, particularly osteosarcoma, may arise within previous radio-
therapy treatment fields, especially in patients with retinoblastoma,
Ewing’s sarcoma, or primary soft tissue sarcomas, with a typical
latent period of about a decade. Apart from the presence of the
primary tumors listed above, the most important risk factors are
the radiation dose (with a steep dose-risk relationship) and the
cumulative dose of alkylating agent chemotherapy (52,56).
Hematopoietic Stem Cell Transplantation
Solid SMNs, hematological SMNs, and PTLD are all seen in survi-
vors of HSCT. Although a wide variety of SMNs are reported,
solid tumors typically occur in survivors who received TBI during
conditioning treatment, whilst hematological SMNs, especially
AML/MDS, are usually seen in survivors of autologous HSCT and
have been attributed to extensive prior chemotherapy, especially
with alkylating agents. PTLD usually occurs in recipients of allo-
geneic HSCT performed for primary immune disorders, particu-
larly when using mismatched donors. Whereas the risk of solid
radiotherapy-associated SMNs continues to rise with longer
follow-up after HSCT, with latency periods of 15 years or longer,
PTLD usually occurs very early post-HSCT (within 2 years) and
chemotherapy-associated hematological SMNs tend to develop
within 10 years of treatment. Since survival rates and durations
have improved enormously after HSCT in the last two decades, it
is likely that the full extent of the occurrence of post-HSCT SMNs
is yet to be revealed (57).
Cancer Predisposition Syndromes
Numerous hereditary cancer predisposition syndromes are known
in which patients have increased risk for both primary malig-
nancies and SMNs. They may be categorized by their mode of
inheritance (Table 7.5). Autosomal dominant conditions include
the Li–Fraumeni syndrome (LFS), hereditary retinoblastoma, here-
ditary Wilms’ tumor, multiple endocrine neoplasia (MEN) syn-
dromes, and familial breast/ovarian cancer syndromes. There is an
increased risk of primary solid or hematological malignancies in
several autosomal recessive conditions, such as Fanconi anaemia,
Bloom syndrome, ataxia telangiectasia and xeroderma pigmentosa,
and SMNs may occur in these patients.
Proband patients with LFS and other affected family members
typically develop a range of primary malignancies including
sarcomas, breast cancers, acute leukemias, brain tumors, and
adrenocortical carcinoma, whilst the more frequently described
SMNs are sarcomas (including osteosarcoma), brain tumors,
lymphomas, ovarian, thyroid, and lung cancers (58). A study of
24 LFS kindreds in whom a primary malignancy had already
occurred between 1968 and 1986 showed that 15% of individuals
developed a second, 4% a third, and 2% a fourth malignancy. The
RR of developing a second malignancy was 5.3, with a cumulative
probability of 57% by 30 years after the first cancer (58).
The epidemiology of hereditary retinoblastoma has been
described above (“Epidemiology” section). Wilms’ tumor may
arise as a primary malignancy in several dominantly inherited
conditions including WAGR (Wilms’ tumor, aniridia, genitourinary

67
 general principles
Table 7.5 Cancer Predisposition Syndromes
Secondary malignant neoplasms may occur in a variety of cancer predisposition
syndromes, including:
Autosomal dominant
• Li–Fraumeni syndrome
• Hereditary retinoblastoma
• Hereditary Wilms’ tumor
• Neurofibromatosis-1
• Multiple endocrine neoplasia
• Familial breast/ovarian cancer syndromes
• Hereditary colon cancer syndromes
Autosomal recessive
• Fanconi anaemia
• Bloom syndrome
• Ataxia telangiectasia
• Xeroderma pigmentosa
abnormalities, and mental retardation), Beckwith–Wiedemann
syndrome and Denys–Drash syndrome, with increased risk for
several SMNs including contralateral Wilms’ tumor, hepatocellu-
lar carcinoma and HD (59). The MEN syndromes were first
described over 50 years ago and are well characterized. Primary
and second tumors in MEN1 include parathyroid, pancreatic, and
pituitary tumors, whilst MEN2a and MEN2b are both character-
ized by medullary thyroid carcinomas, parathyroid adenomas and
pheochromocytomas (60). Gene carriers are also at increased
risk of developing both primary and secondary tumors (60).
Familial breast/ovarian cancer syndromes due to germline BRCA1
and BRCA2 abnormalities are associated with increased risks of
several SMNs, particularly including contralateral breast and
ovarian cancers, but also gastrointestinal and prostate cancers and
melanoma (61,62).
Fanconi anemia is associated with an increased risk of primary
MDS or AML, usually occurring during the first three decades of
life, whilst solid tumors are reported increasingly as primary or
second malignancies during longer follow-up, usually but not
exclusively in survivors of HSCT. Squamous cell carcinomas of
the head, neck, and anogenital regions are the commonest solid
tumors reported, but hepatic, brain, renal, skin, and breast malig-
nancies are also described (63–65). Although radiotherapy (dur-
ing HSCT conditioning) has long been regarded as a major risk
factor for secondary solid tumors in FA, more recent evidence
suggests that the occurrence of acute or chronic GvHD may be the
most important factor (66).
Key Points: Clinical Presentation
■ Following chemotherapy, hematological SMNs occur with a
peak incidence 4–6 years from the diagnosis of the original
malignancy
■ The latency period between radiation exposure and the
development of a SMN is typically at least 10 years with a
mean latent period of 15–18 years
■ Following hematopoietic stem cell transplantation, solid
tumors typically occur in survivors who received total body
irradiation during conditioning treatment, while hemato-
logical SMNs are usually seen in survivors of autologous
transplants
68
TREATMENT
The therapy for a SMN should generally be the same as that which
would have been employed if a primary malignancy. Radiotherapy
should be avoided if this will not reduce the probability of
long-term cure.
OUTCOME
As for primary malignancies, the long-term outcome of SMNs
varies considerably depending on several patient (e.g., age, under-
lying cancer predisposition syndrome) and malignancy-associated
aspects. In general, the prognosis is poor for most hematological
SMNs with reported median survival durations of 7–13 months
and one-year survival rates of <10% for chemotherapy-associated
leukemia (67–69), and some solid SMNs, but the outlook may be
considerably better for other solid SMNs (e.g., 70–80% survival
reported in breast cancer) (28,70). The prognosis should be
guarded in patients with cancer predisposition syndromes, princi-
pally due to the risk of acquiring yet another malignancy. For
example, retinoblastoma survivors who develop a SMN have a
22% risk of acquiring a third or subsequent malignancy within
10 years (22), whilst patients with bilateral retinoblastoma have
been reported to have a 26% risk of death from a SMN within
40 years of presentation with their primary tumor (71). Histori-
cally, PTLD has had a poor prognosis, with reported survival rates
of 0–25% (33,35,36), although contemporary treatment strategies
(including the use of rituximab, an anti-CD20 monoclonal
antibody) may improve this gloomy outlook.
PREVENTION
SMNs may be genuinely secondary to treatment for a primary
malignancy; a consequence of lifestyle factors such as excessive
exposure to tobacco, alcohol, or sunlight, or related to the presence
of a cancer predisposition syndrome.
Primary prevention may be feasible for therapy-associated or
lifestyle-related SMNs. In particular, paediatric oncologists are
seeking to reduce the use of radiotherapy, particularly in pri-
mary childhood malignancies which often have excellent out-
comes with chemotherapy-based treatment strategies. It is
anticipated that this should decrease the risk of later solid
SMNs, especially in children who have a much longer future “at
risk” period, but such major changes in management approaches
should ideally be informed by well designed prospective con-
trolled clinical trials. Likewise, attempts are being made to
reduce judiciously the use of and/or the cumulative doses of
alkylating agents, and to limit the use of epipodophyllotoxins or
avoid the use of higher risk schedules (weekly or more frequent)
(51). Improved health education strategies to increase the
knowledge of survivors of malignancy about the potential
health risks of tobacco smoking, excess alcohol ingestion, and
sunlight exposure should benefit both children and adults,
although there is no published evidence yet to prove the efficacy
of this approach in large survivor cohorts.
Chemoprevention is an area of increased interest (72).
Although there is evidence to suggest that tamoxifen may reduce
 secondary maligncies
the subsequent risk of primary or secondary breast cancer in high-
risk women, this success is tempered by the increased incidence of
endometrial cancer in these individuals. Nutritional supplements
are also under investigation, e.g., the possible role of vitamin E in
the prevention of prostate cancer in smokers.
Knowledge of specific germline mutations (e.g., the presence of a
BRCA1 or BRCA2 mutation) may guide the selection or avoidance
of particular systemic agents for therapy to reduce the probability of
SMNs (73).
Finally, formal surveillance strategies may allow increased early
detection of certain SMNs in high risk populations (74). Such
approaches are likely to be particularly useful in cancer predispo-
sition syndromes (e.g., familial breast/ovarian cancer, Fanconi
anemia especially but not exclusively after HSCT) and in some
high-risk diagnosis/treatment scenarios (e.g., breast screening in
female survivors of HD treated with radiotherapy fields including
breast tissue) (75).
Summary
■ The majority of treatment-related deaths occurring after five
years from diagnosis are due to SMNs
■ Two broad groups of SMNs are:
■ Secondary myelodysplasia/acute myeloid leukemia occur-
ring three to five years after treatment with chemotherapy
(typically alkylating agents or topoisomerase II inhibitors)
■ Solid tumors arising 10–15 years after treatment with
radiotherapy
■ Some SMNs arise in the context of cancer predisposition
syndromes, including Li–Fraumeni syndrome, hereditary
retinoblastoma, hereditary Wilms’ tumor, multiple endocrine
neoplasia syndromes, and familial breast/ovarian cancer
syndromes
■ Individuals with hereditary retinoblastoma have a cumulative
incidence of 51% of SMN by 50 years after initial diagnosis;
the commonest SMN is osteosarcoma. Most but not all of
these SMNs occur inside the radiotherapy field
■ Breast cancer is particularly common in survivors of
childhood Hodgkin disease previously treated with mantle
radiotherapy
■ Secondary thyroid cancer following craniospinal radiotherapy
for acute lymphoblastic leukemia, and secondary brain tumors
after cranial radiotherapy for ALL are well recognized
■ MLL gene rearrangements are a hallmark of therapy-related
acute myeloid leukemia occurring after treatment with
topoisomerase II inhibitors
REFERENCES
1. Ablett S, ed. Quest for Cure. UK Children’s Cancer Study Group:
The First 25 Years. London: Trident Communications Ltd., 2002.
2. Curry HL, Parkes SE, Powell JE, Mann JR. Caring for survivors
of childhood cancers: the size of the problem. Eur J Cancer
2006; 42: 501–8.
3. Oeffinger KC, Mertens AC, Sklar CA, et al. Chronic health
conditions in adult survivors of childhood cancer. N Engl J
Med 2006; 355: 1572–82.
4. Mertens AC, Liu Q, Neglia JP, et al. Cause-specific late mor-
tality among 5-year survivors of childhood cancer: The Child-
hood Cancer Survivor Study. J Natl Cancer Inst 2008; 100:
1368–79.
5. Garber JE, Goldstein AM, Kantor AF, et al. Follow-up study of
twenty-four families with Li-Fraumeni syndrome. Cancer Res
1991; 51: 6094–7.
6. Li FP, Myers MH, Heise HW, Jaffe N. The course of five-year
survivors of cancer in childhood. J Pediatr 1978; 93: 185–7.
7. Meadows AT, Baum E, Fossati-Bellani F, et al. Second malig-
nant neoplasms in children: an update from the Late Effects
Study Group. J Clin Oncol 1985; 3: 532–8.
8. Olsen JH, Garwicz S, Hertz H, et al. Second malignant
neoplasms after cancer in childhood or adolescence. Nordic
Society of Paediatric Haematology and Oncology Associa-
tion of the Nordic Cancer Registries. Br Med J 1993; 307:
1030–6.
9. Hawkins MM, Draper GJ, Kingston JE. Incidence of second
primary tumours among childhood cancer survivors. Br J
Cancer 1987; 56: 339–47.
10. Holland JM, Arsanjani A, Liem BJ, et al. Second malignancies
in early stage laryngeal carcinoma patients treated with radio-
therapy. J Laryngol Otol 2002; 116: 190–3.
11. Dong C, Hemminki K. Second primary neoplasms among
53,159 haematolymphoproliferative malignancy patients in
Sweden 1958–1996: a search for common mechanisms. Br J
Cancer 2001; 85: 997–1005.
12. Swerdlow AJ, Barber JA, Hudson GV, et al. Risk of second malig-
nancy after Hodgkin’s disease in a collaborative British cohort:
the relation to age at treatment. J Clin Oncol 2000; 18: 498–509.
13. Green DM, Zevon MA, Reese PA, et al. Second malignant
tumors following treatment during childhood and adoles-
cence for cancer. Med Pediatr Oncol 1994; 22: 1–10.
14. de Vathaire F, Schweisguth O, Rodary C, et al. Long-term risk
of second malignant neoplasm after a cancer in childhood. Br
J Cancer 1989; 59: 448–52.
15. Neglia JP, Friedman DL, Yasui Y, et al. Second malignant neo-
plasms in five-year survivors of childhood cancer: Childhood
Cancer Survivor Study. J Natl Cancer Inst 2001; 93: 618–29.
16. Sankila R, Pukkala E, Teppo L. Risk of subsequent malignant
neoplasms among 470,000 cancer patients in Finland, 1953–
1991. Int J Cancer 1995; 60: 464–70.
17. Curtis RE, Boice JDJ, Kleinerman RA, Flannery JT, Fraumeni
JFJ. Summary: multiple primary cancers in Connecticut,
1935–1982. Natl Cancer Inst Monogr 1985; 68: 219–42.
18. Faraci M, Békássy AN, De Fazio V, Tichelli A, Dini G. Non-
endocrine late complications in children after allogeneic
haematopoietic SCT. Bone Marrow Transpl 2008; 41(Suppl 2):
S49–S57.
19. Wong FL, Boice JDJ, Abramson DH, et al. Cancer incidence
after retinoblastoma. Radiation dose and sarcoma risk. JAMA
1997; 278: 1262–7.
20. Marees T, Moll AC, Imhof SM, et al. Risk of second malignan-
cies in survivors of retinoblastoma: more than 40 years of
follow-up. J Natl Cancer Inst 2008; 100: 1771–9.
21. Roarty JD, McLean IW, Zimmerman LE. Incidence of second
neoplasms in patients with bilateral retinoblastoma. Ophthal-
mology 1988; 95: 1583–7.
69
 general principles
22. Abramson DH, Melson DR, Dunkel IJ, Frank CM. Third (fourth
and fifth) nonocular tumors in survivors of retinoblastoma.
Ophthalmology 2001; 108: 1868–76.
23. Tarbell NJ, Gelber RD, Weinstein HJ, Mauch P. Sex differences
in risk of second malignant tumours after Hodgkin’s disease
in childhood. Lancet 1993; 341: 1428–32.
24. Beaty OR, Hudson MM, Greenwald C, et al. Subsequent malig-
nancies in children and adolescents after treatment for Hodgkin’s
disease. J Clin Oncol 1995; 13: 603–9.
25. Bhatia S, Yasui Y, Robison LL, et al. High risk of subsequent
neoplasms continues with extended follow-up of childhood
Hodgkin’s disease: report from the Late Effects Study Group. J
Clin Oncol 2003; 21: 4386–94.
26. Sankila R, Garwicz S, Olsen JH, et al. Risk of subsequent
malignant neoplasms among 1,641 Hodgkin’s disease patients
diagnosed in childhood and adolescence: a population-based
cohort study in the five Nordic countries. Association of the
Nordic Cancer Registries and the Nordic Society of Pediatric
Hematology and Oncology. J Clin Oncol 1996; 14: 1442–6.
27. Wolden SL, Lamborn KR, Cleary SF, Tate DJ, Donaldson SS.
Second cancers following pediatric Hodgkin’s disease. J Clin
Oncol 1998; 16: 536–44.
28. Metayer C, Lynch CF, Clarke EA, et al. Second cancers among
long-term survivors of Hodgkin’s disease diagnosed in child-
hood and adolescence. J Clin Oncol 2000; 18: 2435–43.
29. Green DM, Hyland A, Barcos MP, et al. Second malignant neo-
plasms after treatment for Hodgkin’s disease in childhood or
adolescence. J Clin Oncol 2000; 18: 1492–9.
30. Dores GM, Metayer C, Curtis RE, et al. Second malignant neo-
plasms among long-term survivors of Hodgkin’s disease: a
population-based evaluation over 25 years. J Clin Oncol 2002;
20: 3484–94.
31. Franklin J, Pluetschow A, Paus M, et al. Second malignancy
risk associated with treatment of Hodgkin’s lymphoma: meta-
analysis of the randomised trials. Ann Oncol 2006; 17:
1749–60.
32. Kolb HJ, Socie G, Duell T, et al. Malignant neoplasms in long-
term survivors of bone marrow transplantation. Ann Intern
Med 1999; 131: 738–44.
33. Socie G, Curtis RE, Deeg HJ, et al. New malignant diseases
after allogeneic marrow transplantation for childhood acute
leukemia. J Clin Oncol 2000; 18: 348–57.
34. Bhatia S, Louie AD, Bhatia R, et al. Solid cancers after bone
marrow transplantation. J Clin Oncol 2001; 19: 464–71.
35. Bhatia S, Ramsay NKC, Steinbuch M, et al. Malignant neoplasms
following bone marrow transplantation. Blood 1996; 87: 3633–9.
36. Baker KS, DeFor TE, Burns LJ, et al. New malignancies after blood
or marrow stem-cell transplantation in children and adults:
incidence and risk factors. J Clin Oncol 2003; 21: 1352–8.
37. Lishner M, Patterson B, Kandel R, et al. Cutaneous and mucosal
neoplasms in bone marrow transplant recipients. Cancer 1990;
65: 473–6.
38. Cohen A, Rovelli A, van Lint MT, et al. Secondary thyroid
carcinoma after allogeneic bone marrow transplantation
during childhood. Bone Marrow Transpl 2001; 28: 1125–8.
39. Hake CR, Graubert TA, Fenske TS. Does autologous trans-
plantation directly increase the risk of secondary leukemia in
lymphoma pateints? Bone Marrow Transpl 2007; 39: 59–70.
70
40. Brown JR, Yeckes H, Friedberg JW, et al. Increasing incidence
of late second malignancies after conditioning with cyclo-
phosphamide and total-body irradiation and autlogous bone
marrow transplantation for non-Hodgkin’s lymphoma. J Clin
Oncol 2005; 23: 2208–14.
41. Hasegawa W, Pond GR, Rifkind JT, et al. Long-term follow-up
of secondary malignancies in adults after allogeneic bone marrow
transplantation. Bone Marrow Transpl 2005; 35: 51–5.
42. Constine LS, Tarbell N, Hudson MM, et al. Subsequent malig-
nancies in children treated for Hodgkin’s disease: associations
with gender and radiation dose. Int J Radiat Oncol Biol Phys
2008; 72: 24–33.
43. Reulen RC, Taylor AJ, Winter DL, et al. Long-term population-
based risks of breast cancer after childhood cancer. Int J
Cancer 2008; 123: 2156–63.
44. Tubiana M. Can we reduce the incidence of second primary
malignancies occurring after radiotherapy? A critical review.
Radiother Oncol 2009; Epub ahead of print.
45. Super HJ, McCabe NR, Thirman, et al. Rearrangements of the
MLL gene in therapy-related acute myeloid leukemia in patients
previously treated with agents targeting DNA-topoisomerase
II. Blood 1993; 82: 3705–11.
46. Azarova AM, Lyu YL, Lin CP, et al. Roles of DNA topoisomerase
II isozymes in chemotherapy and secondary malignancies.
Proc Natl Acad Sci USA 2007; 104: 11014–19.
47. Le Deley M-C, Leblanc T, Shamsaldin A, et al. Risk of secondary
leukemia after a solid tumor in childhood according to the
dose of epipodophyllotoxins and anthracyclines: a case-control
study by the Societe Francaise d’Oncologie Paediatrique.
J Clin Oncol 2003; 21: 1074–81.
48. Altinok G, Kattar MM, Mohamed A, et al. Pediatric renal
carcinoma associated with Xp11.2 translocations/TFE3 gene
fusions and clinicopathologic associations. Pediatr Dev Pathol
2005; 8: 168–80.
49. Argani P, Laé M, Ballard ET, et al. Translocation carcinomas of
the kidney after chemotherapy in childhood. J Clin Oncol
2006; 24: 529–34.
50. Bogni A, Cheng C, Liu W, et al. Genome-wide approach to
identify risk factors for therapy-related myeloid leukemia.
Leukemia 2006; 20: 239–46.
51. Pui C, Ribeiro RC, Hancock ML, et al. Acute myeloid leuke-
mia in children treated with epipodophyllotoxins for
acute lymphoblastic leukemia. N Engl J Med 1991; 325:
1682–7.
52. Hawkins MM, Wilson LM, Burton HS, et al. Radiotherapy,
alkylating agents, and risk of bone cancer after childhood can-
cer. J Natl Cancer Inst 1996; 88: 270–8.
53. Garwicz S, Anderson H, Olsen JH, et al. Second malignant
neoplasms after cancerin childhood and adolescence: a
population-based case-control study in the 5 Nordic countries.
Int J Cancer 2000; 88: 672–8.
54. Bhatia S, Sather HN, Pabustan OB, et al. Low incidence of
second neoplasms among children diagnosed with acute
lymphoblastic leukemia after 1983. Blood 2002; 99:
4257–64.
55. Tucker MA, Morris Jones PH, Boice JD, et al. Therapeutic
radiation at a young age is linked to secondary thyroid cancer.
The Late Effects Study Group. Cancer Res 1991; 51: 2885–8.
 secondary maligncies
56. Le Vu B, de Vathaire F, Shamsaldin A, et al. Radiation dose,
chemotherapy and risk of osteosarcoma after solid tumours
during childhood. Int J Cancer 1998; 77: 370–7.
57. Deeg HJ, Socie G. Malignancies after hematopoietic stem cell
transplantation: many questions, some answers. Blood 1998;
91: 1833–44.
58. Hisida M, Garber JE, Fung CY. Multiple primary cancers in
families with Li-Fraumeni syndrome. J Natl Cancer Inst 1998;
90: 606–11.
59. Hartley AL, Birch JM, Blair V, et al. Second primary neo-
plasms in a population-based series of patients diagnosed
with renal tumours in childhood. Med Pediatr Oncol 1994;
22: 318–24.
60. Hemminki K, Jiang Y. Second primary neoplasms after 19281
endocrine gland tumours: aetiological links? Eur J Cancer
2001; 37: 1886–94.
61. The Breast Cancer Linkage Consortium. Cancer risk in
BRCA2 mutation carriers. J Natl Cancer Inst 1999; 91: 1310–6.
62. Arver B, Du Q, Chen J, Luo L, Lindblom A. Hereditary breast
cancer: a review. Semin Cancer Biol 2000; 10: 271–88.
63. Rosenberg PS, Greene MH, Alter BP. Cancer incidence in
persons with Fanconi anemia. Blood 2003; 101: 822–6.
64. Kutler DI, Singh B, Satagopan J, et al. A 20-year perspective on
the International Fanconi Anemia Registry (IFAR). Blood
2003; 101: 1249–56.
65. Kutler DI, Auerbach AD, Satagopan J, et al. High incidence
of head and neck squamous cell carcinoma in patients with
Fanconi anemia. Arch Otolaryngol Head Neck Surg 2003; 129:
106–12.
66. Socie G, Devergie A, Girinski T, et al. Transplantation for Fanconi’s
anaemia: long-term follow-up of fifty patients transplanted from
a sibling donor after low-dose cyclophosphamide and thoraco-
abdominal irradiation for conditioning. Br J Haem 1998; 103:
249–55.
67. Neugut AI, Robinson E, Nieves J, Murray T, Tsai WY. Poor
survival of treatment-related acute nonlymphocytic leukemia.
JAMA 1990; 264: 1006–8.
68. Consuelo del Canizo M, Luz Amigo M, Hernandez JM, et al.
Incidence and characterization of secondary myelodysplastic
syndromes following autologous transplantation. Haemato-
logica 2000; 85: 403–9.
69. Pagano L, Pulsoni A, Tosti ME, et al. Clinical and biological
features of acute myeloid leukaemia occurring as a second
malignancy: GIMEMA archive of adult acute leukaemia. Br J
Haem 2001; 112: 109–7.
70. Bhatia S, Robison LL, Oberlin O, et al. Breast cancer and other
second neoplasms after childhood Hodgkin’s disease. N Engl J
Med 1996; 334: 745–51.
71. Eng C, Li FP, Abramson DH, et al. Mortality from second
tumors among long-term survivors of retinoblastoma. J Natl
Cancer Inst 1993; 85: 1121–8.
72. Mayne ST, Cartmel B. Chemoprevention of second cancers.
Cancer Epidemiol Biomarkers Prev 2006; 15: 2033–7.
73. Tutt A, Ashworth A. Can genetic testing guide treatment in
breast cancer? Eur J Cancer 2008; 44: 2774–80.
74. Vogel VG. Identifying and screening patients at risk of second
cancers. Cancer Epidemiol Biomarkers Prev 2006; 15:
2027–32.
75. Oeffinger KC, Ford JS, Moskowitz CS, et al. Breast cancer sur-
veillance practices among women previously treated with
chest radiation for a childhood cancer. JAMA 2009; 301:
404–14.
71
 8 Lung Cancer
Stephen M Ellis and Zelena Aziz
INTRODUCTION
Lung cancer is responsible for more cancer deaths than any other
cancer worldwide, both in men and women, with 1.2 million new
cases diagnosed per year. The number of estimated new cases in
the United States for 2008 is 215,020 with an estimated 161,840
deaths. Complete resection gives the highest probability of long-
term remission and even cure, but only approximately 25% of
patients are candidates for surgical treatment at the time of diag-
nosis. The primary aim of staging is to determine whether a tumor
can be completely removed by surgery; clear surgical margins in
resected specimens, and the absence of tumor cells in resected
lymph nodes being the prime determinants of local recurrence
and survival. Imaging has an important role in the detection,
diagnosis, and staging of the disease. Disease stage not only dictates
treatment but also provides information on prognosis. The current
(sixth) edition of the TNM classification of lung cancer has been in
use since 1997, but in 1999, a new staging project was initiated by
the International Association for the Study of Lung Cancer
(IASLC). Recently, a proposal for the revision of the T, N, and M
descriptors in the forthcoming seventh edition has been published
by the IASLC’s Lung Cancer Staging Project, and it is anticipated
that these new recommendations will be accepted in full.
This chapter outlines the new staging of non-small cell lung
cancer and emphasizes the appropriate use of CT, MRI, and PET
imaging in patient management.
CELLULAR CLASSIFICATION
Lung carcinoma is most conveniently divided into two types, small
cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC),
reflecting a marked difference in natural history and response to
therapy between these basic groups. Each of the cancer subtypes
defined in the most widely accepted classification of lung tumors,
updated by the World Health Organization (WHO) (Table 8.1) in
1999 (1), can be divided into one of SCLC or NSCLC. Small cell lung
cancer is thought to be of neuroendocrine cell origin; it originates
submucosally and spreads rapidly both to lymph nodes and hematog-
enously. Non-small cell lung cancer comprises mostly squamous cell,
adenocarcinoma, and large cell carcinoma. Squamous cell lung can-
cers arise from dysplastic epithelium predominantly in segmental
and more proximal bronchi; they comprise approximately 30% of all
cases of lung carcinoma, although relative incidence is falling. Ade-
nocarcinoma is the predominant histological subtype of lung carci-
noma in many countries. In Europe, the incidence has increased by
10% in the last 25 years. Adenocarcinomas arise form bronchial
glands and have a propensity to from acinar structures and secrete
mucin. They usually arise within lung parenchyma. Adenocarcino-
mas are highly heterogeneous histologically, and mixed pattern ade-
nocarcinomas are more common than tumors showing a single
pattern. Bronchioloalveolar carcinomas are classified as a subtype of
72
adenocarcinoma but under the current classification, the definition
of bronchioloalveolar cell carcinoma is restricted to only noninva-
sive tumors. Tumors showing stromal, vascular, or pleural invasion
are classified as adenocarcinoma mixed type with predominant
bronchioloalveolar pattern. Large cell carcinoma consists of a mixed
group of undifferentiated relatively aggressive tumors. The large cell
carcinoma class includes several variants including the large cell neu-
roendocrine carcinoma and basaloid carcinoma, both of which have
a dismal prognosis. The remaining types of NSCLC are unusual.
They include the various adenosquamous carcinomas and a number
a lower grade invasive tumors that arise in the lung, notably carcinoids
and carcinomas of salivary-gland type.
CLINICAL FEATURES
Approximately 15–25% of patients with bronchial carcinoma are
asymptomatic at the time of diagnosis (2,3). The symptoms vary
with extent of disease (4). They can be divided into those due to
the primary tumor, those related to metastatic disease, and those
reflecting the systemic effects of malignancy. There is a fairly even
distribution of patients between these three groups.
Typical symptoms due to a central primary tumor are cough,
wheeze, hemoptysis, and recurrent pneumonia. Extension within
the mediastinum may lead to dysphagia, hoarseness, superior vena
caval compression or diaphragmatic paralysis. Large effusions
from pleural spread may cause breathlessness. Chest wall invasion
leads to local pain and, in the case of an apical Pancoast’s tumor,
the characteristic signs of brachial plexus infiltration.
Non-specific manifestations of lung cancer include anorexia,
weight loss, and a range of paraneoplastic phenomena, such as the
Eaton–Lambert syndrome, inappropriate secretion of antidiuretic
hormone, and hypertrophic osteoarthropathy.
STAGING SMALL CELL LUNG CANCER
Small cell lung cancer behaves as a systemic disease and because
occult or overt metastatic disease is present at diagnosis in most
patients, survival is usually not affected by small differences in the
amount of loco regional tumor involvement. A simple two-stage
system (limited or extensive disease) developed by the Veterans
Administration Lung Cancer Study Group is commonly used for
staging SCLC patients (5). The purpose of this relatively simple
division is to separately classify those patients with disease that is
limited to a set of standard radiotherapy fields from patients
whose disease is more extensive.
Patients with disease confined to one hemithorax, with or without
mediastinal, contralateral hilar, or ipsilateral supraclavicular or sca-
lene lymph nodes are considered to have limited-stage disease, while
those with disease involvement at any other location (including the
presence of a cytologically positive pleural effusion) are considered
to have extensive-stage disease (Table 8.2). Patients with distant
 lung cancer

Table 8.1 The 1999 World Health Organization/International metastases are always considered to have extensive-stage disease.
Association for the Study of Lung Cancer Histological Therapeutic strategies are markedly different for SCLC than for
Classification of Malignant Lung Tumors NSCLC because of the frequent finding of disseminated disease. Sys-
temic chemotherapy forms the mainstay of treatment but although
Squamous cell carcinoma response rates of 70–80% can be achieved, long-term cure rates are
Variants
Papillary
dismal at less than 5% (6). Several studies have shown that the addi-
Clear cell tional use of thoracic radiotherapy in those patients whose disease
Small cell can be encompassed within a suitable radiation port (limited disease)
Basaloid results in a survival dividend (7). These patients may also benefit
Small cell carcinoma from prophylactic cranial irradiation and although some contro-
Variant versy exists regarding routine pre-treatment CT scanning of the brain
Combined small cell carcinoma
in asymptomatic patients, most authors consider it prudent to obtain
Adenocarcinoma
Acinar
a baseline scan of the brain in all patients. For patients entering clini-
Papillary cal trials, accurate delineation of the extent of extrathoracic disease is
Bronchioloalveolar cell carcinoma important to allow stratification and response evaluation, and in
Non-mucinous practice this is the most frequent indication for imaging.
Mucinous
Mixed mucinous and non-mucinous or intermediate cell type
Solid adenocarcinoma with mucin
Adenocarcinoma with mixed subtypes BACKGROUND TO THE NEW LUNG CANCER
Variants STAGING PROJECT
Well-differentiated fetal adenocarcinoma
Mucinous (colloid) adenocarcinoma The previous (sixth) edition TNM Classification of Malignant
Mucinous cystadenocarcinoma
Tumors introduced in 2002 was based on the international staging
Signet-ring adenocarcinoma
Clear cell adenocarcinoma system published by Mountain in 1997 (8). As in previous lung
Large cell carcinoma cancer staging publications, the tumor stage (T1–T4) was based
Variants on tumor size and proximity and involvement of vital intratho-
Large cell neuroendocrine carcinoma racic structures as well as including non-size based descriptors.
Combined large cell neuroendocrine carcinoma Nodal status was divided into N0 (no local node involvement), N1
Basaloid carcinoma
(ipsilateral hilar node), N2 (ipsilateral mediastinal node), or N3
Lymphoepithelioma-like carcinoma
Clear cell carcinoma (contralateral mediastinal/hilar node or supraclavicular node)
Large cell carcinoma with rhabdoid phenotype involvement. Using the T and N descriptors, in the absence of
Adenosquamous carcinoma metastatic disease, lung cancer has been staged as 1A, 1B, 2A, 2B,
Carcinomas with pleiomorphic, sarcomatoid or sarcomatous elements 3A, and 3B. This staging system has proved useful in categorizing
Carcinomas with spindle and/or giant cells patients both in terms of treatment recruitment in studies, and in
Pleomorphic carcinoma
terms of prognosis, but several problems and shortcomings have
Spindle cell carcinoma
Giant cell carcinoma been highlighted: (i) the proposals made in the sixth edition were
Carcinosarcomas based on a relatively small database of 5319 cases collected between
Pulmonary balstoma 1975 and 1988 from a single institution; (ii) previous changes to
Others the recommendations for lung cancer staging have been made
Carcinoid with little internal, and no external validation; and (iii) results of
Typical carcinoid numerous studies have demonstrated overlapping prognoses for
Atypical carcinoid
patients with different stages particularly between 1B and 2A and
Carinomas of salivary gland-type
Mucoepidermoid carcinoma
it has been suggested that T1 and T2 descriptors should be sub-
Adenoid cystic carcinoma categorized. These problems, coupled with the significant refine-
Others ments to the techniques available for staging led to the establishment
Unclassified carcinoma of the Lung Cancer Staging Project in 1998. The aim of the Lung
Cancer Staging Project was to bring together the large databases
available worldwide and to form recommendations for the seventh
edition of the TNM staging.
A total of 67,725 non-small cell lung cases from more than 19
Table 8.2 Staging of Small Cell Lung Cancer countries were included in the analyses of the T, N, and M descrip-
Stage Description tors and the subsequent analysis for TNM subsets and stage
Limited stage Disease confined to one hemithorax; includes involvement groupings. Cases were those diagnosed between 1990 and 2000
of mediastinal, contralateral hilar, and/or supraclavicular and cases treated by all modalities of care, including multimodal-
and scalene lymph nodes. Malignant pleural effusion is ity treatment were included. The current proposals for T, (9) N
excluded (10), and M (11) descriptors and for TNM stage groupings were
Extensive stage Disease has spread beyond the definition of limited stage,
based on survival analysis (12) (Figs. 8.1 and 8.2) and have been
or malignant pleural effusion is present
subject to intense internal and external validation.

73
 primary tumor evaluation and staging

100% Deaths/N MST 5-Yr

IA 443/831 60 50%
80% IB 1133/1842 37 40%
IIA 19/25 38 24%
60% IIB 1571/2151 18 25%
IIIA 2397/3005 14 18%
IIIB 1088/1224 10 8%
40% IV 2343/2458 6 2%

20%

0%
0 2 4 6 8 10
(A) Survival. Yr

100% Deaths/N MST 5-Yr

IA 443/831 60 50%
80% IB 750/1284 43 43%
IIA 318/483 34 46%
IIB 1652/2248 18 25%
60%
IIIA 2528/3175 14 19%
IIIB 676/758 10 7%
40% IV 2627/2757 6 2%

20%

0%
0 2 4 6 8 10
(B) Survival. Yr
Figure 8.1 Overall survival, expressed as median survival time (MST) and five-year survival, by clinical stage using the sixth edition of TNM (A), and proposed International
Association of the Study of Lung Cancer recommendations (B) (116).

100% Deaths/N MST 5-Yr

IA 1168/3666 119 73%
80% IB 2231/4426 70 54%
IIA 306/562 54 48%
60% IIB 1951/2982 33 38%
IIIA 2348/3091 23 25%
40% IIIB 838/1042 16 19%
IV 146/183 18 21%
20%

0%
0 2 4 6 8 10
(A) Survival. Yr

100% Deaths/N MST 5-Yr

IA 1168/3666 119 73%
80% IB 1450/3100 81 58%
IIA 1485/2579 49 46%
60% IIB 1502/2252 31 36%
IIIA 2896/3792 22 24%
40% IIIB 263/297 13 9%
IV 224/266 17 13%
20%

0%
0 2 4 6 8 10
(B) Survival. Yr
Figure 8.2 Overall survival, expressed as median survival time (MST) and five-year survival, by pathologic stage using sixth edition of TNM (A), and proposed Interna-
tional Association of the Study of Lung Cancer recommendations (B).

74
 lung cancer

surgery. Similarly, it was found that cases with additional nodules

STAGING NON-SMALL CELL LUNG CANCER
in a different lobe of the ipsilateral lung had a better prognosis
than the current classification (M1) would indicate, and these
TNM Grading (Table 8.3) cases have now been reclassified as T4.
Primary Tumor (T Status) (Fig. 8.3) (13)
The IASLC staging project has not incorporated recommenda-
The IASLC lung cancer staging project committee recognized the
tions for the size independent T2 and T3 descriptors atelectasis or
crucial importance of tumor size and the new sub-classification of
obstructive pneumonitis that extends to the hilar region (T2)
T1 and T2 into T1a (≤2 cm) and T1b (>2 but ≤3 cm), and T2a (>3
(Fig. 8.5A and B) or whole lung (T3) and main bronchus involve-
but ≤5 cm) and T2b (>5 but ≤7 cm) was based on distinct differ-
ment >2 cm (T2) or <2 cm (T3) from the carina because of the
ences in survival between these groups. In addition, T2 tumors
small number of patients and inconsistent clinical and pathologic
larger than 7 cm have been reclassified as T3. Primary tumors
results. However, an interesting study has evaluated the prognostic
associated with satellite nodules in the same lobe (Fig. 8.4) have
significance of the size independent descriptors for T2 based on
been reclassified as T3 (from T4) because the survival of these
the analysis of >10,000 patients with stage 1B NSCLC (14). The
patients is better than those with other T4 descriptors. This T3
authors clearly demonstrate that patients who have T2 tumors ≤3 cm,
designation actually reflects current clinical practice in which
i.e., the tumor is graded T2 on criteria other than size, have a
many patients with satellite nodules in the primary lobe undergo
better prognosis than patients with tumors >3 cm (Figs. 8.6 and 8.7).
definitive surgery, providing there are no contraindications to

Table 8.3 Proposed Definitions for T, N, and M Descriptors

T (Primary tumor)
TX Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in sputum or bronchial washings but not visualized by
imaging or bronchoscopy
T0 No evidence of primary tumor
Tis Carcinoma in situ
T1 Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the
lobar bronchus (i.e., not in the main bronchus)a
T1a Tumor ≥2 cm in greatest dimension
T1b Tumor >2 cm but ≤3 cm in greatest dimension
T2 Tumor >3 cm but ≤7 cm OR tumor with any of the following features:
(T2 tumors with these features are classified as T2a if ≤5 cm)
Involves main bronchus ≥2 cm distal to the carina
Invades visceral pleural
Associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not always involve the entire lung
T2a Tumor >3 cm but ≤5 cm in greatest dimension
T2b Tumor >5 cm but ≤7 cm in greatest dimension
T3 Tumor >7 cm OR one that directly invades the following: chest wall (including superior sulcus tumors), diaphragm, phrenic nerve, mediastinal
pleura, parietal pericardium OR
Tumor in the main bronchus <2 cm distal to the carina but without involvement of the carina OR
Atelectasis or obstructive penumonitis of the entire lung OR
Separate tumor nodule(s) in the same lobe
T4 Tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, oesophagus, vertebral
body, carina OR
Separate tumor nodule(s) in a different ipsilateral lobe
N (Regional lymph nodes)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in ipsilateral peribronchial and or ipsilaterla hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension
N2 Metastasis in ipsilateral mediastinal and or subcarinal lymph node(s)
N3 Metastasis in contralateral mediatinal, contralateral hilar ipsilateral or contralateral scalene, or supraclavicular lymph node(s)
M (Distant metastasis)
MX Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis
M1a Separate tumor nodules in a contralateral lobe
Tumor with pleural nodules or malignant pleural (or pericardial) effusionb
M1b Distant metastasis
a
The uncommon superficial spreading tumor of any size with its invasive component limited to the bronchial wall, which may extend proximally to the main bronchus
is also classified as T1.
b
Most pleural and pericardial effusions with lung cancer are due to tumor. In a few patients, multiple cytopathologic examinations of pleural (pericardial) fluid are
negative for tumor, and the fluid is not bloody and not an exudate. Where these elements and clinical judgement dictate that the effusion is not related to the tumor,
the effusion should be excluded as a staging element.

75
 primary tumor evaluation and staging

T1 T2

≤3 cm
≥2 cm Invades visceral
but not
parietal
≤3 cm
pleura

>3 cm <7 cm

Atelectasis or
pneumonitis of lobe

T3

< 2 cm

Atelectasis or
obstructive pneumonitis
of the entire lung

Invades parietal but not

visceral pericardium

T4 T4

Malignant pleural effusion now M1a

Satellite nodule different lobe same lung T4
(same lobe T3)
Note tumor >7 cm is T3 and malignant pleural effusion now affects M staging not T stage

Figure 8.3 Staging lung cancer—primary tumor (T).

Twenty-one percent of patients staged as 1B despite a tumor size
≤3 cm had 5-year and median survival rates that were similar to a
group of almost 10,000 Stage 1A patients used as a comparator.
Thus, in patients staged as IB by virtue of a T2 tumor, those that have
a tumor size ≤3 cm have an independent favorable prognosis when
compared to those with T2 tumors >3 cm. It is suggested that crite-
ria other than size used to distinguish T1 from T2 tumors should be
linked to and not independent of size; these findings may influence
future changes in the T2 descriptor.
In the previous classification, tumors associated with a malig-
nant pleural effusion were classified as T4, but it has been found
that their prognosis is much worse than that of other T4 tumors.
The Lung Cancer Staging Project study found that the five-year
survival rate for patients with a clinical malignant pleural effusion
was 2% compared with 30% for other T4 tumors; hence, malig-
nant pleural or pericardial effusions and pleural nodules have
been reclassified as MI (Fig. 8.8). It is important to be aware that
pleural metastases are common at presentation and that the diag-
nosis of pleural metastases or malignant effusion can be difficult
to confirm (Fig. 8.9); cytologic evaluation is positive in only
approximately 66% of patients with a malignant pleural effusion
at presentation.

76
 lung cancer
Figure 8.4 This is an axial CT image of a primary NSCLC (black open arrow) with
a satellite nodule in the same lobe (white arrow) therefore making this a T3 tumor.
(A)
(B)
Figure 8.5 (A) This is the CXR of a patient with NSCLC (squamous cell carcinoma)
demonstrating right lower lobe collapse (white arrow) indicating at least a T2 tumor.
(B) A CT scan of the same patient demonstrating the cavitating proximal tumor
(white arrow) causing bronchial obstruction and subsequent lobar collapse.
Figure 8.6 The outer edge of the collapsed lower lobe is marked (white arrow),
note the fluid-filled bronchi (black arrows) with adjacent enhancing vessels indi-
cating the tissue represented is collapsed lung rather than tumor infiltration.
Figure 8.7 By way of comparison to “collapsed lung” in this case of NSCLC the
heterogeneously enhancing tumor infiltrating the lung (white arrow) is compared
to the collapsed but non-infiltrated lung demonstrating normal vascular architec-
ture (black arrows). This distinction identifies the tumor as T2b conferring a worse
prognosis than a sub 3 cm T2 tumor.
Figure 8.8 This is an axial CT image of a patient with a primary NSCLC in the
right lower lobe and a malignant pericardial effusion (white arrows) and therefore
staged M1 disease.
77
 primary tumor evaluation and staging

Figure 8.9 CT and PET-CT fusion images of a patient with NSCLC. The primary tumor is seen in the left lower lobe (open white arrows) but previously unsuspected
pleural metastases were identified on PET-CT scanning, one of these is demonstrated on these images (white arrows).

Imaging Considerations
Mediastinal Invasion
The extent of the primary tumor determines therapeutic manage-
ment and imaging is often used in an attempt to assess chest wall
(T3) or mediastinal (T4) invasion. Despite advances in CT technol-
ogy and the excellent soft-tissue contrast resolution of MRI, differ-
entiating between anatomic contiguity and subtle invasion remains
difficult. Both CT and MRI can demonstrate the presence of exten-
sive tumor within the mediastinum. Clear-cut encasement of vital
mediastinal structures such as the oesophagus, trachea, or major ves-
sels, or deep penetration of tissue planes is conclusive evidence of a
T4 tumor (Fig. 8.10A and B). Unfortunately, where lesser degrees of
“invasion” are present, criteria for irresectable (T4) disease are more
difficult to define. Tumors that merely abut the mediastinum either
alone, or in the presence of obliteration of, or interdigitation with
mediastinal fat planes, cannot be conclusively considered invasive;
loss of fat planes may reflect inflammatory change, fibrosis, or blur-
ring from motion artefact rather than malignant invasion (Fig. 8.11).
CT features that suggest a tumor in contact with the mediastinum
may be resectable include: (i) less than 3 cm contact with the medi-
astinum; (ii) the presence of a fat plane between tumor and adjacent
mediastinal structures; and (iii) less than 90 degrees circumferential
contact with the aorta (15). Despite the use of these and similar
criteria, the overall utility of CT for assessing mediastinal invasion
has been disappointingly low.
The introduction of multidetector CT (MDCT) into clinical
practice has enabled better assessment of mediastinal invasion.
Advantages include the ability to acquire thin-sections in less time,
more reliable contrast opacification of vascular structures, less arte-
fact from cardiac and respiratory motion, and limitation of partial
volume averaging. Thin-section multiplanar reformats (MPRs)
allow detailed assessment of important regions such as the carina,
aortapulmonary window, and the aortic arch. Early studies show
that thin-section coronal reformats can improve the diagnostic accu-
racy of mediastinal invasion; the use of MDCT acquired volumetric
thin-section images (1.25 mm section thickness) has been shown to
have a sensitivity, specificity, positive predictive value and negative
predictive value of 86%, 93%, 60%, and 98%, respectively (16).

78
 lung cancer
(A)
Figures 8.10 These are an (A) axial image and (B) coronal reconstruction demonstrating the invasion of tumor (black arrow) into the SVC (white arrow) via the azygos
vein. Note on the axial image the clear demarcation between tumor and enhanced blood as opposed to the ill-defined margin seen during mixing of unenhanced blood
from the azygos with enhanced blood in the SVC.
Figure 8.11 The magnified area highlights the close apposition of a primary
NSCLC to the oesophagus. To date imaging has failed to determine whether such
tumors are resectable and this decision is often made at surgery.
Tumor invasion of the pericardium or heart may be better
delineated on cardiac-gated MR imaging than on CT; the nor-
mal pericardium is of low signal intensity and disruption of the
pericardium can therefore be recognized (17). Direct invasion of
the cardiac chambers is readily demonstrated on T1-weighted
images because flowing blood in the cardiac chambers is depicted
as signal void, and the tumor is conspicuous because of its higher
signal intensity (18). Cine MR images to demonstrate the pres-
ence or absence of a sliding motion between the primary tumor
and adjacent structures may be useful to demonstrate invasion
of the pericardium, cardiac chambers, main pulmonary artery,
and ascending aorta (19). However, false-positive diagnoses may
arise for cardiovascular structures that show minimal motion
such as the distal aortic arch, descending thoracic aorta, SVC,
and pulmonary veins.
(B)
Overall, there is no objective evidence to suggest a significant
difference in overall diagnostic accuracy between CT and MR for
distinguishing T3 and T4 tumors from less extensive disease and
the routine use of MRI for the diagnosis of mediastinal invasion is
not recommended.
Key Points: Mediastinal Invasion
■ MDCT with multiplanar reconstructions may improve accuracy
of mediastinal invasion
■ In general, MR has no significant advantage over CT in the
detection of mediastinal invasion
■ On CT, <3 cm of mediastinal contact, a preserved fat plane, or
<90% of aortic contact are good indicators of resectability
■ Both CT and MR are inaccurate at predicting unresectability
Chest Wall Invasion
A peripheral lung tumor may cross the parietal pleura and invade
ribs and intercostal muscles. Such localized invasion of the chest
wall (T3) by NSCLC does not necessarily preclude surgery (Fig.
8.12A–C). However, the mortality rate associated with en bloc
resection of the tumor and contiguous structures remains substan-
tial and therefore information about chest wall invasion is still an
important factor in the clinical decision to perform surgery. With
CT, the only findings with a high positive predictive value are rib
destruction adjacent to a tumor mass or extension of tumor beyond
ribs into the chest wall. Contact with the chest wall parietal pleura
does not imply invasion even when associated with pleural thicken-
ing, although the more extensive the abnormality, the more likely it
is that invasion has occurred. As with the mediastinal pleura,
parietal pleural thickening is a non-specific finding that may be sec-
ondary to reactive fibrosis or inflammation. The angle of contact
between tumor and chest wall, obliteration of the extrapleural fat
plane and the presence of extrapleural soft tissue are also unreliable
signs of invasion (19–21). Preservation of the extrapleural fat line is
79
 primary tumor evaluation and staging

(A) (B) (C)

Figure 8.12 (A) This is a section of a chest X-ray demonstrating an isolated pulmonary mass in the left upper zone (black arrow) causing erosion of the underlying rib.
(B) An axial CT image demonstrating the rib erosion (black arrow) seen on the chest X-ray. (C) A technetium bone scan demonstrates the skeletal involvement (open
black arrow) of this primary NSCLC. The rib involvement in itself (black arrows) does not preclude treatment with intent to cure but the patient’s performance status
was too poor to consider anything but palliative treatment.

(A) (B)
Figure 8.13 T1-weighted coronal MR image of a patient with known NSCLC demonstrating tumor in the right supraclavicular fossa (white arrows) infiltrating (A) the
right sternocleidomastoid muscle (block arrows) and (B) the C6, 7, and 8 nerve roots (white arrows).

reassuring, but this sign does not invariably exclude invasive disease
(20). Thin-section sagittal MPR from multidetector-row CT
(MDCT) data sets have been shown to significantly improve the
accuracy of chest wall invasion compared to routine CT (21).
MR does not confer any advantages for the assessment of chest
wall invasion again because of the overlap in appearances between
tumor extension and associated inflammatory change.
Both CT (22) and MR (23,24) have been used to apply dynamic
imaging to assess the respiratory shift, defined as a change in the
relative location between the peripheral lung tumor and the chest
wall, during the respiratory cycle. Free tumor movement along the
chest wall (proving lack of attachment between the parietal and
visceral pleura) has been found to have a sensitivity of 100% in a
recent study (25). A significant limitation of this technique (appli-
cable to both CT and MR) is the fact that only absence of tumor
invasion can be diagnosed. Benign fibrous adhesions may cause
false-positive results by simulating tumor infiltration and the
specificity of this technique is only 83% (23). There have been
promising reports concerning the use of ultrasound in diagnosing
chest wall invasion. The pleura can be seen as an echogenic interface,
and disruption of the pleural line is a useful sign of chest wall
invasion. Lack of movement of the tumor with respiration, implying
adherence, can also be observed. A recent study has demonstrated
a sensitivity of 89% and specificity of 95% in assessing chest wall
involvement (24). In practical terms, these techniques are not
widely practised, and currently, unless definite chest wall invasion
is demonstrated on CT most patients will be referred for consid-
eration of surgery if there are no other precluding factors.
Superior Sulcus Tumors
Superior sulcus tumors are usually classified as T3 or higher
because invasion of extrathoracic tissue is invariably present. MRI
is regarded as the optimal modality for demonstrating involvement
of the brachial plexus (Fig. 8.13), subclavian vessels and vertebral
bodies. Involvement of the brachial plexus or subclavian vessels is
not defined by the standard AJCC staging system, but limited
involvement of the lower trunk or roots (C8, T1) of the brachial
plexus is generally regarded as T3 disease, whereas more extensive
invasion into the brachial plexus trunks or roots (C5–C7), subcla-
vian vessels, vertebral bodies or spinal cord constitutes T4 disease.

80
 lung cancer

It is important to be aware that a T4 classification in the context of
superior sulcus tumors does not always imply irresectability and
decisions are often made on a case by case basis. Invasion of subcla-
vian, common carotid and vertebral arteries are considered relative
contraindications to surgery, but tumors that invade less than 50%
of the vertebral body may be resectable.
Key Points: Chest Wall Invasion
■ Both CT and MR can predict resectable tumors, but may fail
to distinguish inflammatory chest wall adherence from early
invasion
■ More extensive chest wall disease is readily identified by
either modality, but need not imply inoperability
■ MRI is the optimal technique for demonstrating the extent
of superior sulcus tumors
Lymph Node Descriptor (N Status) (26)
Accurate staging of lymph node involvement is a critical aspect of
the initial management of patients with NSCLC that influences deci-
sions about the appropriateness and timing of surgery, radiation,
and systemic therapy. Several studies have suggested that the N
descriptors could be refined to provide more accurate prognostic
stratification by subdividing them either according to specific ana-
tomical locations or stations (e.g., N1 peribronchial versus N1 per-
hilar) or the number of nodes involved (e.g., single versus multiple
N2 nodes). The IASLC did investigate whether survival was influ-
enced by anatomical location, the presence of “skip metastases” (N2
disease in the absence of N1) or by the number of involved lymph
node stations. Data showed that there were no significant differences
in analysis by station. However, grouping the lymph node stations
into six anatomic “zones” produced interesting results. Lymph nodes
at levels 1 through 4 were grouped together into the upper zone, lev-
els 5 and 6 into the aortopulmonary zone, level 7 into the subcarinal
zone, levels 8 and 9 into the lower zone, levels 10 and 11 into the hilar
zone, and levels 12–14 into the peripheral zone. The most salient
finding with respect to N staging was that patients fall into three
prognostically distinct categories, depending on the extent of nodal
metastases: single-zone N1, either multiple-zone N1 or single-zone
N2, and multiple-zone N2 nodes. These results suggest that the over-
all disease burden, rather than just the anatomic location of lymph
node involvement, may have the most important influence on out-
come. These prognostically distinct groups suggested that it might
be appropriate to subdivide the current N staging descriptors into
N1a (single N1 zone), N1b (multiple N1 zones), N2a (single N2
zone), and N2b (multiple N2 zones). However, only 1992 cases had
sufficient data for analysis and further exploration of these prognos-
tic nodal groups in conjunction with T stage could not be performed.
Subsequently, a change in the N descriptor was not made. Prospec-
tive studies are needed to validate the amalgamation of lymph node
stations into zones and subdividing N descriptors.
Classification of Regional Lymph Nodes
The position of hilar and mediastinal nodes should be described
according to the recently unified American Thoracic Society (ATS)
and American Joint Committee on Cancer classification (27,28)
which uses fixed anatomical landmarks to localize individual
nodal stations (Fig. 8.14A–E and Table 8.4). It is worth noting
that there is no division into right and left subcarinal stations, so
subcarinal nodal disease is always designated N2.

3A
2
1 3P

(A) (B)

6 6
4 5 7 5
10
8
10 9
4R 4L
8 9
(C) (D) (E)
Figure 8.14 Axial CT images demonstrating nodal stations: (A) station 1, (B) stations 2–3, (C) stations 4–6 and 8, (D) stations 5–8 and 10, and (E) station 9.

81
 primary tumor evaluation and staging

Table 8.4 American Joint Committee on Cancer-Union Internationale Contre Le Cancer (AJCC-UICC) Classification of Regional
Lymph Nodes (28)

N2 (ipsilateral) and N3 (contralateral) nodes are in stations 1–8 and lie within the mediastinal pleural envelope
Highest mediastinal nodes (station 1) lie above a horizontal line at the upper rim of the brachiocephalic (left innominate) vein where it crosses the midline of the trachea.
Upper paratracheal nodes (station 2 nodes) are divided into right and left. They lie above a horizontal line drawn tangential to the upper margin of the aortic arch
and below the inferior boundary of station 1 nodes.
Prevascular nodes (station 3A) lie in the midline anterior to the ascending aorta and retrotracheal nodes (station 3P) lie in the midline posterior to the trachea.
Midline station 3 nodes are considered to be ipsilateral.
Lower paratracheal nodes (station 4) are divided into right and left. Those on the right lie to the right of the midline of the trachea between a horizontal line drawn
tangential to the upper margin of the aortic arch and a line extending across the right main bronchus at the
upper margin of the upper lobe bronchus. Those on the left lie to the left of the midline of the trachea
between a horizontal line drawn tangential to the upper margin of the aortic arch and a line extending across
1R 1L
the left main bronchus at the level of the upper margin of the left upper lobe bronchus, medial to the
ligamentum arteriosum.
2R
Subaortic (aortopulmonary) nodes (station 5) lie lateral to the ligamentum arteriosum or the aorta or left pulmonary
2L
artery and proximal to the first branch of the left pulmonary artery, within the mediastinal pleural envelope.
Para-aortic nodes (station 6) lie anterior and lateral to the ascending aorta and the aortic arch or the innominate
artery, beneath a line tangential to the upper margin of the aortic arch.
4R 4L
Subcarinal nodes (station 7) lie caudal to the carina of the trachea, but not associated with the lower lobe 5
bronchi or arteries within the lung. 11
Para-oesophageal nodes (station 8) lie adjacent to the wall of the oesophagus and to the right or left of the 10 12
midline, excluding subcarinal nodes. 7
10 11
N1 nodes (ipsilateral stations 9–14 nodes) lie outside the mediastinal pleural envelope and within the visceral 12

pleura 12
11
Pulmonary ligament nodes (station 9) lie within the pulmonary ligament, including those in the posterior wall 11
8
and lower part of the inferior pulmonary vein.
9 9
12
Hilar nodes (station 10), the proximal lobar nodes, lie distal to the mediastinal pleural reflection and adjacent to
12
the bronchus intermedius on the right; radiographically, the hilar shadow may be created by enlargement of
both hilar and interlobar nodes.
Interlobar nodes (station 11) lie between the lobar bronchi.
Lobar nodes (station 12) lie adjacent to the distal lobar bronchi. AJCC–UICC lymph node classification
Segmental nodes (station 13) lie adjacent to the segmental bronchi. illustrating the mediastinal nodal stations
(station 3 and station 6 nodes are not illustrated).
Subsegmental nodes (station 14) lie around the subsegmental bronchi.

Figure 8.15 Axial CT image of a patient with NSCLC. Note in the magnified region
a lymph node (white arrow) that straddles the margin between station 10 (N1) and Figure 8.16 This is an axial CT image of the same patient as in Figure 8.4 demonstrat-
station 4 (N2), the distinction cannot be made via imaging and can only truly be ing N2 station 4 lymphadenopathy (black arrow) but also N3 station 4 and 5 lymph-
determined at surgery. adenopathy (white arrows), but there was no hilar nodal involvement on CT criteria.

Distinction between nodal stations may be difficult and subject to
interobserver variation (27). The differentiation between hilar nodes
(station 10), which lie outside the mediastinal pleural reflection, and
adjacent tracheobronchial nodes (station 4), which are contained
within the mediastinal pleura, can be problematic, particularly on
the right (Fig. 8.15). The location is, however, of crucial importance
because tracheobronchial node involvement converts N1 to N2
disease (28). Spread is usually sequential, first to the ipsilateral seg-
mental, interlobar, or lobar intrapulmonary nodes (N1 nodes), then
to ipsilateral hilar nodes (N1 nodes) and thereafter to ipsilateral
mediastinal nodes (N2). However, skip metastases to mediastinal
nodes, without hilar node involvement (Fig. 8.16), are recognized

82
 lung cancer
in up to 33% of cases (29) and skip involvement of contralateral
mediastinal nodes (N3) is not infrequent.
Imaging Considerations
On CT scanning, lymph node size is the only criteria available
to assess tumor involvement; a short axis diameter of greater
than 1 cm is considered abnormal (30). However, in the context
of NSCLC, lymph node size is not a reliable indicator of tumor
involvement (31–33). A study by Prenzel and colleagues of
256 patients with NSCLC who had hilar and mediastinal nodal
clearance at the time of tumor resection identified 77% of
139 patients with no histological evidence of nodal metastasis
had nodes greater than 1 cm in short axis diameter. Of the
127 patients with no nodes greater than 1 cm in short axis diameter,
12% had histological evidence of metastases in nodes removed
at surgery (34). A meta-analysis of 20 studies (n = 3438) evalu-
ating CT scanning for the staging of mediastinal metastases
found a sensitivity of 58%, a specificity of 82%, a positive pre-
dictive value (PPV) of 56%, and a negative predictive value
(NPV) of 83% (35). The distinction between N1 and N2 disease
is a crucial determinant of whether treatment given is with
intent to cure, any improvement in the preoperative assessment
of nodal involvement will therefore have a profound affect on
patient management. Positron emission tomography (PET)
scanning uses 18F-fluoro-2-deoxy-D-glucose (FDG), a glucose
analog, as a tracer that detects increased metabolic activity. The
major pitfall of FDG-PET is the false positive uptake in inflam-
matory tissues; potentially more specific tracers have been studied
but as yet have shown no clear advantage over FDG (31). Further-
more, the studies and recommendations regarding PET scanning
in cancer staging are based upon dedicated PET scanners and it
is doubtful the same is true of dual headed coincidence gamma
camera PET.
In the investigation of nodal staging FDG-PET has proved to be
of greatest use in complementing CT by detecting increased meta-
bolic activity in tumor-involved nodes yet to reach significance by
CT size criteria and relatively low metabolic activity in enlarged
uninvolved reactive lymphadenopathy (36–39). A recent meta-
analysis based on 17 studies (n = 833) compared the relative per-
formance of FDG PET and CT in the nodal staging for NSCLC.
The sensitivity of FDG PET for detecting lymph node positivity
ranged from 66% to 100% (overall 83%), and for CT the range
was 20% to 81% (overall 59%). Specificity data for FDG PET had
a range of 81–100% (overall 92%) compared to a range of
44–100% (overall 78%) for CT (32). Furthermore, there appears
to be an improvement in accuracy when reporting combine
PET-CT scan rather than separate PET and CT scans. The per-
ceived utility of FDG PET has lead to the inclusion of PET
imaging in the National Institute for Clinical Excellence (NICE)
guidelines for the management of NSCLC with intent to cure (40).
Nevertheless, FDG PET should only be considered an adjunct in
terms of nodal staging as the false positive rate is too high; (41,42)
PET positive nodes should be sampled if the confirmation of
nodal metastasis would affect patient management. The authors
of a meta-analysis of the relationship between size, PET positivity,
and probability of malignancy proposed that PET negative nodes
less than 15 mm should proceed directly to surgery and those
with nodes greater than 16 mm should have histological proof of
malignant involvement before being denied surgical resection.
They found a 5% post-test probability of malignancy for nodes
sized 10–15 mm and negative on PET and a 21% post-test proba-
bility of malignant involvement in PET negative nodes greater
than 16 mm. Until recently, magnetic resonance imaging (MRI)
has had little to contribute to nodal staging. The initially promis-
ing use of iron containing agents taken up by functioning reticu-
loendothelial cells thereby causing a signal drop off in nodes not
replaced by tumor was hampered by high false positive rates (33).
However, short inversion time inversion recovery (STIR) turbo
spin-echo MRI and diffusion-weighted MRI have recently been
proposed as alternatives to PET for identifying tumor infiltration
of lymph nodes (43,44).
Determining Whether There Are Nodal Metastases
Lymphadenopathy identified on imaging that would decide
whether treatment with curative intent is considered to be an
option should be sampled to confirm tumor involvement
(36,45,46). The main techniques available for obtaining tissue
from mediastinal nodes for staging are mediastinotomy, medi-
astinoscopy, transbronchial fine needle aspiration (FNA), tran-
sthoracic FNA, and transoesophageal FNA. Mediastinotomy is
the most invasive and preserved for nodes that are not accessi-
ble by alternative means, i.e., those in station 5, 6, and 10. Medi-
astinoscopy involves an incision superior to the sternal notch
and explores the plane anterior to the trachea (nodal stations 1,
2, and 4). As the majority of equivocal N2 lymph nodes lie in
this area, mediastinoscopy has been the mainstay of nodal sampling
in the staging of lung cancer but is invasive and requires a gen-
eral anaeshetic. Transbronchial FNA involves the deployment of
a fine needle through the biopsy port of the bronchoscope. The
needle punctures the bronchus enabling aspiration of adjacent
lymph nodes but is limited by the orientation of the broncho-
scope, which must be pointed in the direction of the puncture
site. This technique is ideally suited to subcarinal (station 7)
nodes and possibly lower station 4 nodes not readily accessible
to mediastinoscopy. An extension of this technique is endo-
bronchial ultrasound-guided transbronchial needle aspiration
(EBUS-TBNA); the technique requires a flexible bronchoscope
containing an ultrasound probe and a port through which an
FNA can be performed under real-time ultrasound imaging.
The adoption of EBUS-TBNA will enable the sampling of para-
tracheal nodes previously only accessible at mediastinoscopy
(37). Transoesophageal FNA is the equivalent of EBUS-TBNA
only using an endoscope rather than a bronchoscope (38). Only
lymph nodes adjacent to the oesophagus (station 3P, 7, 8, and 9)
can be sampled in this way.
Finally, some lymphadenopathy may be amenable to percu-
taneous transthoracic needle aspiration or biopsy. The main
indication for a transthoracic approach would be to sample
station 5 or 6 nodes as these are not accessible via the other
minimally invasive techniques. However, the sternum makes
much of the station 6 region inaccessible via a percutaneous
route, and there will be a significant distance between the skin
entry site and the target node limiting the minimum size of
lymph node that can be sampled in this way.
The decision as to which technique to employ will frequently
be determined by local availability but the minimally invasive
83
 primary tumor evaluation and staging
techniques, when available, should enable sampling of all but
station 3A, 5, and 6 nodes and mediastinoscopy should be
reserved for cases where EBUS-TBNA has failed.
Key Points: Nodal Detection
■ CT and FDG-PET are synergistic in the staging of lung cancer
■ When there is intent to cure patients should undergo an
FDG-PET scan
■ New MR sequences may turn out to be at least comparable to
PET in the identification of significant mediastinal adenopathy
■ N2 adenopathy identified on imaging that would determine
whether there is an intent to cure should be sampled
■ Transoesophageal and transbronchial FNA, if available, are the
preferred techniques for mediastinal nodal sampling
Metastatic Disease (M Status)
The IASLC Lung Cancer Staging Project has proposed that the M1
descriptor should be subclassified into M1a (additional nodules
in the contralateral lung) and M1b (distant metastases outside
the lung and pleura) (39). Additionally, on the basis of survival
analysis, the current M descriptor should be modified to reclassify
pleural metastases (malignant pleural effusions, pleural nodules)
from T4 to M1a. Malignant pericardial effusions are also included
in the M1a descriptor.
Extrathoracic Disease Spread
The identification of disease spread outside the thorax precludes
the option to treat with curative intent. Most SCLCs and around
40% of NSCLC have metastasized at presentation; (41) of the
NSCLC with metastases 90% have symptoms indicative of the site
(41) and specific imaging may be employed to confirm this. Rou-
tine staging advocates the inclusion of the liver and adrenal glands
on initial staging CT scanning, as these are common sites for
metastases, anatomically conveniently placed to be included in a
CT scan of the thorax and, in the case of the adrenal glands, do not
tend to present with any clinical indication of involvement. If after
an initial CT staging scan the NSCLC is considered curable, cur-
rent NICE recommendations are to perform a whole body FDG-
PET scan to exclude extra-thoracic metastases as well as to identify
potential intra thoracic metastases (40). The American College of
surgeons Oncology Trial reports a sensitivity of 83%, specificity of
90%, PPV of 36%, and a NPP of 99% for FDG-PET in the detec-
tion of metastases (42). The poor PPV results from the non-spe-
cific nature of imaging based on metabolic activity and tissue
sampling of possible metastases should be performed if the con-
firmation of metastatic involvement would alter patient manage-
ment (47). Whole-body MRI has been proposed as an alternative
to FDG-PET. One study by Ohno and colleagues compared whole
body MRI and FDG-PET in the staging of 90 lung cancer patients;
they found significantly higher specificity and sensitivity (95%
and 94.8%, respectively) for the detection of head and neck and
bone metastases compared to (89.1% and 88.2%, respectively) for
FDG-PET (p < 0.05). They also found a significantly superior
accuracy for whole body MRI for the detection of metastases
(80.0%) on a per patient basis compared to FDG-PET (73.3%,
p < 0.05) and concluded that, as a diagnostic technique for the
detection of lung cancer metastases, whole body MRI is at least as
84
effective as FDG-PET (43). Patients with limited disease SCLC
would be considered for radical chemo-radiotherapy and those
with extensive disease would just have palliative chemotherapy,
FDG-PET scanning may detect occult metastases or more accu-
rately define disease extent for calculating a radiotherapy field.
However, there is little evidence in the literature for the utility of
FDG-PET in SCLC staging probably as a result of the large pro-
portion of patients that have CT diagnosed metastases at presen-
tation and the relatively small incidence of SCLC compared to
NSCLC. In a study by Brink et al., 120 patients with SCLC had
FDG-PET scanning as part of their primary staging with 91 also
having brain MRI or CT (44). All the tumors demonstrated
increased FDG uptake. FDG-PET upstaged 10 patients to exten-
sive disease and downstaged three patients to limited disease by
excluding adrenal metastases. Therefore, in this study, FDG-
PET altered the management in 9% of patients suggesting that it
may be prudent to consider FDG-PET imaging when radical
chemo-radiotherapy is being considered based on conventional
staging or being denied based on adrenal involvement alone as
diagnosed on CT scanning.
Liver Metastases
The incidence of liver metastases is relatively low in the region of
2% (41), but due to its anatomical site the liver is readily imaged on
initial CT staging enabling rapid exclusion of patients with hepatic
metastases early in the staging process, biopsy confirmation is not
usually required. The overall sensitivity and specificity of CT scanning
for the detection of liver metastases are 97% and 94%, respectively
(40), and small hepatic cysts that may mimic metastases due to
partial volume artifact can be characterized on ultrasound scan-
ning. In the presence of a negative CT and potential curative ther-
apy, an FDG-PET should be performed routinely and that has a
reported sensitivity and specificity of 100% for liver metastases
(Fig. 8.17) (48). MR is of no additional value to CT for routine
staging but may be used to solve specific problems with lesion
characterization.
Brain Metastases
A review of 17 papers compared the performance of clinical eval-
uation against brain CT (Fig. 8.18) there was pooled sensitivity of
76% (95% CI 64–84), a specificity of 87% (95% CI 74–94), a pos-
itive predictive value (PPV) of 54% (range 21–100%), and a nega-
tive predictive value (NPV) of 94% (CI 91–96) (45). MRI is the
imaging modality of choice for the investigation of brain metasta-
ses (49,50) and the figures would be expected to be marginally
worse if clinical symptoms were compared to MR brain findings.
Taking into account the cost of routinely including CT brain in
the staging of NSCLC and the low pick up rate in the absence of
clinical signs or symptoms, the NICE recommendations are that
routine imaging of the brain is not thought to be clinically or
financially worthwhile (51). However, the data considered is
skewed in favor of early stage NSCLC where there is a lower risk of
brain metastases. There is some evidence based on post resection
recurrence of NSCLC in the brain, that higher stage tumors con-
sidered for resection particularly those that are not squamous cell
histologically may warrant pre-operative imaging of the brain,
preferably MRI (52–54). This apparent risk of brain metastases is
borne out by the ASCO 2003 recommendations stating that MRI
 lung cancer

T:127 Ant

R R
i i
g g
h h
t t

C:81 Top

T:127 Ant

R R
i i
g g
h h
t t

Figure 8.17 This is a collage of images from a PET-CT scan of a patient with NSCLC (open arrow). There is a MIP image on the left, CT images on the top right and
PET-CT fusion images on the bottom right all demonstrating the presence of a liver metastasis (black arrows).

or CT of the brain should be performed on patients with stage III

NSCLC being considered for aggressive local therapy (55).

Figure 8.18 This is a contrast-enhanced axial CT image through the brain of a
patient with SCLC. Two enhancing metastatic deposits are seen (black arrows).
Note that metastases do not always have adjacent vasogenic edema.
Adrenal Metastases
Adrenal metastases do not present with clinical signs and, in the
context of lung cancer, are identified on CT staging. Although the
adrenal glands are a common site of metastases in NSCLC (56,57),
a significant proportion of isolated adrenal masses identified in
potentially operable NSCLC may be due to benign disease, par-
ticularly adenomas with a 1% incidence in the adult population
(58,59). Indicators of metastatic disease on CT are a size of 3 cm
or greater, irregular enhancing rim, poorly defined margins, and
invasion of adjacent structures. The finding of a hounsfield unit
(HU) number of 10 or less in the adrenal lesion on non-contrast
CT is a viable identifier of benign disease (60) and in cases where
an adrenal adenoma contains insufficient fat to have such a low
HU number the fat content may be identified using chemical shift
analysis on MRI scanning (61). Such CT and MRI characteriza-
tion becomes unnecessary when FDG-PET is included in the work
up for surgical resection. Reported sensitivity and specificity for
FDG-PET diagnosis of adrenal metastases are 100% and 80–90%
respectively (62,63). Therefore, an adrenal lesion negative on
FDG-PET (Fig. 8.19) can be considered benign but an adrenal
lesion that is positive on FDG-PET should be sampled either by
FNA or core biopsy to confirm malignancy before denying a
patient curative therapy (64).
It has been suggested that ipsilateral adrenal metastases should
be considered as local rather than disseminated disease spread

85
 primary tumor evaluation and staging

and therefore potentially surgically resectable (65) but the

patients likely to benefit from such an approach cannot be readily
identified (66,67).

Figure 8.19 This is a PET-CT fusion image through the upper abdomen of a
patient with primary adenocarcinoma of the lung and an adrenal nodule (white
arrow). The absence of FDG uptake in the adrenal lesion indicated that there was
no metastasis and the primary tumor, which demonstrated avid FDG uptake was
resected.
Bone Metastases
The presence of bone metastases in NSCLC is usually evident clin-
ically either through symptoms or abnormal laboratory results
(68). Occult skeletal metastases are rare; therefore, routine techne-
tium 99m-methylene diphosphonate (99mTc-MDP) bone scintig-
raphy is not advocated and reserved for those patients with clinical
evidence of metastatic disease. In the context of a patient with
potentially curable disease FDG-PET should be performed routinely
and appears to be as good as if not better than 99mTc-MDP bone scin-
tigraphy in the identification of skeletal metastases (Fig. 8.20);
accuracy of FDG-PET 93.5–96%; and accuracy of 99mTc-MDP
bone scintigraphy 66–72.5% (69,70). NSCLC bone metastases are
usually in the central skeleton and osteolytic, therefore the supe-
rior coverage of 99mTc-MDP bone scintigraphy and greater sensi-
tivity than FDG-PET in detecting osteoblastic metastases are less
relevant than they would be in the management of other tumors.

Figure 8.20 These images are from a PET-CT scan of a patient with primary NSCLC (white arrows) and numerous small mediastinal lymph nodes. The PET scan not
only showed significant uptake in the mediastinal nodes (open arrow) but also highlighted a sclerotic metastasis in the thoracic spine (black arrows).

86
 lung cancer

Key Points: Metastatic Disease
■ FDG-PET should be performed to exclude metastatic disease
if curative therapy is being contemplated
■ The negative predictive value of FDG-PET makes it a viable
excluder of metastases
■ Solitary apparent metastases identified on FDG-PET should
be investigated before curative therapy is withheld
■ FDG-PET cannot identify brain metastases but in the absence
of symptoms routine staging scanning of the brain is not
advocated
The Staging System (Fig. 8.21)
The International Staging System for NSCLC stratifies disease
extent in terms of prognosis and the current edition includes
changes that incorporate the modifications to the T, N, and M
grading (Table 8.5).
Stage I tumors are confined to the lung and visceral pleura,
without nodal or distant spread, and when a tumor involves the
main bronchus, the tumor is >2 cm beyond the carina. Stage I
tumors are divided into A and B according to whether the tumor
is T1b or T2a.
Stage II tumors are divided into A and B. Stage IIA tumors
are the same as Stage IA but with ipsilateral nodal metastases.
Stage IIA also includes T2b tumors (>5 but ≤7 cm), but with N0
disease. T2b tumors with ipsilateral nodal metastases are Stage IIB
IA
T1, N0
IB
T2a, N0
IIA
T2a N1 or T2b N0
IIB
T2b N1 or T3 N0
IIIA
N2 or T3 N1 or T4±N1
and all T3 tumors with no nodal or distant spread are also within
the Stage IIB category. Additions to Stage IIB are tumors with
separate nodules within the same lobe (T3 in the current system)
but no distant spread.
Stage IIIA includes tumors of any size with N2 adenopathy, T3
tumors based on size criteria (>7 cm) or local invasion with N1
adenopathy. Tumors with satellite nodules in the same lobe with
either N1 or N2 adenopathy are also Stage IIIA. New additions to
the Stage IIIA category are T4 tumors (invasion or satellite nodule
in a different ipsilateral lobe) with either N0 or N1 disease.
Stage IIIB includes tumors with N3 disease and T4 tumors with
N2 or N3 disease.
Stage IV disease now includes tumors with malignant pleural/
pericardial effusions, satellite nodules in a contralateral lobe or
distant metastasis.
TREATMENT OPTIONS
As is the case with most cancers, the treatment options and prog-
nosis of lung cancer are heavily dependent on the cell type and
stage. Treatment with curative intent involves surgical resection or
radical radiotherapy and is only considered an option in non-small
cell lung cancer (NSCLC); small cell lung cancer (SCLC) behaves as
a systemic disease and is not therefore suitable for therapies with
curative intent.
The treatment of choice for Stage I to IIIA NSCLC is surgical
resection. The limited data available (71–74) suggests better sur-
vival and reduced recurrence rates if a lobectomy is performed as
opposed to a wedge resection. For central tumors involving proxi-
mal airways surgical clearance may require a pneumonectomy; if
the patient is unable to tolerate a pneumonectomy, a sleeve resection
lobectomy offers an alternative lung preserving option (75). The
case for neoadjuvent chemotherapy remains to be proven with
evidence to date suggesting no improvement in survival (76).
Stage IIb and IIIa NSCLC include T3 tumors that may be locally
invasive potentially affecting their surgical resectability. In patients
for whom treatment with intent to cure is viable based on tumor
type and staging but surgery is not considered possible for other
reasons, radical radiotherapy may be a suitable alternative. The
Table 8.5 Descriptors, Proposed T and M Categories, and
Proposed Stage Groupings (12)
Sixth edition T/M Proposed N0 N1 N2 N3
descriptor T/M

IIIA T1 (≤2 cm) T1a 1A 2A 3A 3B

N3 or T4 N2 T1 (>2–3 cm) T1b 1A 2A 3A 3B
T2 (≤5 cm) T2a 1B 2A 3A 3B
T2 (>5–7 cm) T2b 2A 2B 3A 3B
IV T2 (>7 cm) T3 2B 3A 3A 3B
Metastases T3 invasion T3 2B 3A 3A 3B
T4 (same lobe nodules) T3 2B 3A 3A 3B
T4 (invasion) T4 3A 3A 3B 3B
M1 (ipsilateral lung) T4 3A 3A 3B 3B
T4 (pleural effusion) M1a 4 4 4 4
M1 (contralateral lung) M1a 4 4 4 4
M1 (distant) M1b 4 4 4 4
Figure 8.21 Summary of progression through the staging based on TNM
characterization. Cells in bold indicate a change from the sixth edition for a particular category.

87
 primary tumor evaluation and staging
survival data for radical radiotherapy compared to surgery is poor,
but such a comparison is hampered by surgical upstaging. Whereby
poorer survival may be offset by the discovery of a more advanced
stage at surgery, the data for radical radiotherapy relies upon the
pre-treatment staging. In addition, the patients receiving radical
radiotherapy rather than surgical resection have by definition
some co-morbidity that precludes surgical resection (77).
When radical therapy is not possible due to N2 nodal disease
and/or concerns over surgical resectability of a T3 tumor, down-
staging with chemotherapy or radiotherapy may be considered.
This should be assessed on an individual patient basis at a multi-
disciplinary meeting; the difficulties in ascertaining the success or
failure of such induction therapy are dealt with later. Although
surgical resection of NSCLC with N2 adenopathy is not advo-
cated, those patients found to have previously unsuspected N2
disease—therefore presumably of undetectable volume—during
surgical resection have a better five year survival than those not
undergoing surgical resection (41). This could represent a lead-
time bias whereby the time that it would have taken to develop
detectable N2 adenopathy is added to the survival time.
There is as yet insufficient data to recommend routine adjuvant
chemotherapy for resected Stage I to III tumors (78), but some
data exists to suggest a small survival benefit from cisplatin con-
taining adjuvant chemotherapy, particularly in Stage II disease
(79,80). The NICE 2005 recommendation is to discuss postopera-
tive chemotherapy to patients explaining the pros and cons of
such therapy (81).
For irresectable tumors, the treatment decisions are based upon
symptom control and increasing survival time. Active supportive
care with chemotherapy gives a 1.8–4.5 month survival benefit
over active supportive care alone (82) and localized radiotherapy
may be used to assist in the control of symptoms such as hemop-
tysis and chest wall pain. There is no evidence to suggest endo-
bronchial therapies such as photodynamic therapy, cryotherapy,
electrocautery and Nd-YAG laser therapy have a curative role but
where available they may be employed for symptom control
offsetting airway obstruction.
Percutaneous radiofrequency ablation (RFA) is being proposed
as an alternative to surgical resection in patients for whom sur-
gery is not considered appropriate. This procedure is relatively
safe, the most common complication being a pneumothorax, and
provides an alternative to radiotherapy. The case series to date
indicated tumor response rates from 38% to 98% but included
both primary and metastatic disease and were often unclear as to
whether treatment was given with curative intent. In large lesions,
a combination of RFA and radical radiotherapy should have an
improved response rate compared to radiotherapy alone as the
RFA targets the area of the mass least well treated by radiotherapy,
evidence for this is not at present available.
Chemotherapy is the mainstay of treatment for SCLC and pro-
longs survival (83). Recommended regimes involve multiple che-
motherapeutic agents including a platinum-containing agent. SCLC
is radiosensitive and the simplified staging of SCLC to limited and
extensive is based on the apparent disease extent being within a
radiotherapy field. Radiotherapy may be used as an adjunct to che-
motherapy in limited stage disease with a small but significant
increase survival (84,85) and considered in extensive disease when
complete response to chemotherapy is seen in any associated
88
extrathoracic sites. Prophylactic cranial irradiation is recommended
for limited stage disease if a good or partial CT response to primary
therapy is seen; many centers offer this routinely at the onset of
therapy. Surgical resection of SCLC is not recommended and there
is no supportive evidence for such an approach.
Key Points: Treatment Options
■ The treatment of choice with intent to cure is surgical resection
by lobectomy or pneumonectomy
■ Chemotherapy plus active supportive care has a significant
survival benefit over supportive care alone
■ Radiotherapy and RFA offer potentially curative options
when surgery is not feasible due to factors other than staging
■ Chemotherapy is the treatment of choice for SCLC
RESTAGING FOLLOWING ATTEMPTED DOWNSTAGING
A proportion of patients will have induction therapy in the hope
of down-staging their tumor to make treatment with intent to
cure an option. This is most likely to involve nodal downstaging
from N2 disease or tumor downstaging from T4 disease. For the
latter, tumor size or resectability are readily determined by CT
scanning with MRI of possible benefit in determining degree of
mediastinal invasion or brachial plexus involvement in the case of
a Pancoast tumor. Determining nodal response is challenging as a
reduction in size although indicating a response to treatment does
not infer eradication of tumor from that node and a failure to
reduce in size does not necessarily indicate that the node remains
infiltrated with viable tumor. As FDG-PET is considered a more
sensitive determinant of nodal metastases than CT scanning and
the majority, if not all, patients undergoing nodal down-staging
will have had their nodal disease investigated with FDG-PET, it is
reasonable to consider FDG-PET as the ideal determinant of nodal
down-staging. Unfortunately, the studies to date have found FDG-
PET less sensitive at detecting nodal metastases following induction
therapy than at initial staging (86–88), the limited resolution of
FDG-PET will always make the determination of eradication of
tumor from previously involved nodes an inexact science. However,
re-mediastinoscopy is not without its problems due to adhesions
from initial mediastinoscopy (89) and FDG-PET is probably the
best tool for the assessment of the success of induction treatment.
IMAGING OF RECURRENT DISEASE
Loco-regional recurrence of lung cancer may involve the lung
resection margin, ipsilateral lymph nodes (including supraclavic-
ular nodes), the pleura, and/or the chest wall. Nodules in the lung
distant to the resection margin and disease in the contra-lateral
hemithorax or elsewhere in the body are considered metastatic
deposits (90). Metastatic recurrence, presumably occult at the
time of surgery, is more common than loco-regional recurrence
(91). As is to be expected, the likelihood of recurrence increases as
the T and N stage of the resected tumor increases; around 20–30%
of patients with Stage I disease at resection have recurrent
tumor within five years. The figure for resected stage II disease is
approximately 50% and for Stage III disease is up to 80% (92).
 lung cancer
In addition, it is estimated that the rate of new lung cancer devel-
oping following treatment of NSCLC with intent to cure is in the
region of 1−2% per patient per year. Follow up of these patients
should consider the likelihood of recurrence, take into account
the greater likelihood of metastatic recurrence compared to loco-
regional recurrence and at the same time consider the available
treatment options. Loco-regional recurrence may be amenable to
repeat surgical resection or radical radiotherapy but the likelihood
of a treatment with curative intent is small and there is no appar-
ent survival benefit from intensive imaging surveillance (93). Fur-
thermore, the treatment of metastatic recurrence is palliative and
therefore the identification of metastases is clinically irrelevant
unless they are symptomatic. For this reason CT scanning tends to
be reserved for patients that develop abnormalities on follow-up
CXR or symptoms suggestive of metastatic disease (94), an
approach that falls within The American College of Chest Physi-
cians recommendations which advise six-monthly surveillance,
including CXR or CT, for the first two years and yearly from then
on (95). One of the main difficulties in diagnosing loco-regional
tumor recurrence is distinguishing benign post-surgical changes
from recurrent tumor growth. Following lobectomy there will be
extra soft tissue at the bronchial resection margin representing
local inflammation and healing which to some extent will persist
and therefore be present on follow up imaging and post operative
radiotherapy would also generate areas of inflammation. It would
seem prudent to perform routine baseline imaging following
resection to facilitate subsequent identification of tumor recur-
rence but given the poor outcome for patients with tumor recur-
rence and the greater likelihood of metastatic recurrence, baseline
CT is not usually performed and most centers will follow up with
plain CXR and reserve CT scanning for patients with abnormal
CXR or significant symptoms. Once tumor recurrence is sus-
pected on CT imaging, FDG-PET imaging may help distinguish
post surgical fibrotic tissue from tumor recurrence by highlight-
ing soft tissue with significant metabolic activity and potentially
identify metastatic disease (96). The efficacy of FDG-PET imaging
is reduced by false positive findings secondary to inflammation
and post radiotherapy fibrosis and should therefore not be con-
sidered within 4–5 months of therapy (97). The specificity of
FDG-PET is improved by the use of hybrid PET/CT which is
superior to PET alone (98) in determining tumor extent and bur-
den (99). Data on the negative predictive value of FDG-PET is not
surprisingly unavailable but common practice would be to take
metabolic inactivity to indicate the absence of recurrence assum-
ing the original primary tumor was FDG-PET positive.
Key Points: Imaging of Recurrent Disease
■ Metastatic recurrence is more common than loco-regional
recurrence
■ FDG-PET is the most useful imaging modality for the detection
of loco-regional and metastatic recurrence
POPULATION SCREENING FOR LUNG CANCER
Despite the high number of annual deaths associated with lung
cancer, and evidence to support the effectiveness of treatment for
early disease, screening has been the subject of debate for the last
three decades. Previous systematic reviews of screening for lung
cancer using chest X-ray alone or in combination with sputum
cytology, concluded that there was insufficient evidence of benefit
in terms of reduction in disease-specific mortality (100,101).
Although these historical randomized controlled trials using chest
radiography demonstrated that the median survival in the
screened group was at least three times better in the study group,
the lung cancer deaths were virtually identical in the two groups
after a median of 20 years (102). The apparent disparity between
the greatly improved survival and the lack of improvement in
mortality from lung cancer has been attributed to overdiagnosis
in the screened population.
Recent interest in screening has focused on the potential of
low-dose computed tomography. A recent systematic literature
review of lung cancer screening studies (103) performed between
1994 and 2005 identified 12 studies of computed tomography
screening for lung cancer which included two randomized
controlled trials and 10 studies of screening without compara-
tor groups. Two main issues of study quality have been high-
lighted which have implications for the interpretation of the
results. Firstly, the duration of follow-up was limited in most
studies, with few presenting data beyond two years. Consequently,
none of the studies reported total or disease-specific mortality
rates for the screened population (or comparator populations
where present). Secondly, the lack of comparator groups in
most of the studies meant that it was not possible to determine
the effects of screening on lung cancer and total mortality rates in
comparison with no screening. The results of the twelve studies
are summarized:
The proportion of positive screenings at baseline CT examina-
tions varied widely between studies from 5.1% (104) and 51%
(105). Some of this variation can be explained by the differences
between studies in the definition of a positive CT result.
Between 1.8% (106) and 32% (107) of subjects with positive
screenings went on to receive a diagnosis of lung cancer. The
prevalence of lung cancer detected was between 0.4% and 3.2%
(the number needed to be screened to detect one lung cancer was
between 31 and 249).
Between 53% and 100% of tumors were identified as Stage I
disease at baseline screening. Resectability of tumors found by
screening was high, >78% in most studies.
Only one study (108) reported five-year survival; 76.2% of the
people with cancer detected at baseline (n = 14) survived five
years. In the ELCAP (Early Lung Cancer Action Project) study,
none of the subjects (n = 27) with tumors diagnosed at baseline
screening had died after two years of follow-up (109).
After 2005, two further studies were published with conflict-
ing conclusions (110,111). The results of the largest single
arm observational report of CT screening was published in
2006 (112) and represents a combination of results of ELCAP
with that of the International Early Lung Cancer Action Program
(IELCAP). In this study, of the 31,567 participants who received a
baseline scan, a total of 484 cancers were found. Four hundred
and twelve (85%) of these were clinical Stage I non-small-cell
carcinomas and 302 underwent surgical resection. The compar-
ator cohort comprised only eight patients with Stage I disease
who received no treatment and died of their disease within five
89
 primary tumor evaluation and staging
years. The results of this study have proven to be controversial.
Despite the lack of total, or disease-specific mortality rates for
the screened population, the authors concluded that low-dose
CT screening could lead to a therapeutic strategy that resulted
in an actuarial predicted 10-year survival of 88% for patients
with Stage I disease. Median follow-up in this study was only
40 months.
Though the calculated survival results are impressive, in the
absence of a control arm, screening could simply be identifying
more cancers at an early stage while not changing the numbers of
advanced cancers or the number of deaths from lung cancer. A sub-
sequent study supports this premise. Investigators applied a vali-
dated lung cancer prediction model to three prospective, single-arm
observational studies of CT screening, combining 3246 participants
(111). CT screening found three times the number of expected can-
cers, resulted in ten times the expected number of resections (109 of
144 cancers were resectable), and identified more than the expected
number of advanced stage cancers. Despite having a 94% four-year
survival for participants with clinical Stage I cancers who under-
went surgery, CT screening did not result in a reduction in the
expected number of deaths from lung cancer. These results empha-
size the importance of using long-term mortality, and not survival
as the critical outcome measure for screening.
Certainly, radiological screening can detect early stage, slow
growing or indolent disease, but as yet has not demonstrated
prevention of more aggressive and early metastatic lung cancer.
A significant conclusion from all these screening studies is that
the natural history of lung cancers detected by CT scanning is
unknown and it cannot be assumed that screening-detected lung
cancer is the same as lung cancer that presents clinically and, as
such, is a universally aggressive and fairly rapidly progressive
condition. There is evidence from screening studies that sup-
ports this premise. The histopathology of tumors among smok-
ers detected by screening was not typical of that recognized in
clinical practice with a higher than usual prevalence of adeno-
carcinoma. In addition, the Japanese studies that included non-
smokers (113,114) identified a similar rate of cancers among
smokers and non-smokers. This is not in keeping with experience
from tumors presenting clinically where >80% occur in smokers.
In the non-smokers, the tumors identified were well-differentiated
adenocarcinomas or bronchioloalveolar carcinoma. The natural
history of these well-differentiated, small, screening-detected
adenocarcinomas is not yet well understood but raises the pos-
sibility that screening is detecting tumors that are different from
those seen presenting clinically and that some screening-detected
tumors may never have caused symptoms or death, and would
therefore have gone undetected in the absence of screening. CT
data of tumor-doubling times lend further evidence that over-
diagnosis is a factor in the apparent improvement in survival
with CT screening. Aoki et al. found that those with bronchi-
oloalveolar cell cancer had tumor doubling times ranging from
662 to 1486 days with a mean of 880 days (113). A mean dou-
bling time of 880 days would take a 1 cm bronchoalveolar cell
cancer 19 years to grow to 2 cm. In the Mayo CT screening study,
27% were found to be slow growing cancers with doubling times
of over 400 days (114).
Other problems with CT screening include the high numbers
of false positive screens, the as yet unmeasured impact to an
90
individual of knowing one has an abnormality and the risks of
unnecessary surgery. Two studies have demonstrated up to 18%
(115) and 20% (116) of resections for benign disease. PET and
needle biopsy may reduce the number of resections for benign
nodules but the nature of subcentimeter nodules will always
prove difficult, and unnecessary surgery will undoubtedly
occur.
To show a reduction in mortality, randomized-controlled
trial evidence—or at least a population-based study with a
comparative population–based control group—will be neces-
sary. The cost/benefit of CT screening is now the subject of a
prospective randomized trial by the National Cancer Institute
and the American College of Radiology Imaging Network; the
results of which are anticipated in two years. What are required
to inform a decision about the clinical effectiveness of CT
screening for lung are (115):
• Randomized controlled trial evidence that CT screening
reduces mortality either with whole population screening,
or for particular subgroups
• A better understanding of the natural history and epide-
miology of screening-detected lung cancers, particularly
small well-differentiated adenocarcinomas
• An assessment of morbidity improvements arising from
early detection and the quality of life effects of a positive
screen while waiting for a diagnosis (whether eventually
malignant or benign)
In conclusion, the current evidence base for CT screening for
lung cancer is insufficient to show clinical effectiveness in terms
of a reduction in mortality and it is unlikely at present that CT
screening will move from the realms of personal choice to a
matter of public policy.
Summary
■ For T1 and T2 tumors an increase in nodal staging results in
an increase in overall staging
■ If there is N2 disease, the step from T3 to T4 increases overall
stage from IIIA to IIIB
■ For N0 disease there is an increase in overall staging for each
increase in T staging, except from T1a to T1b
■ All N3 disease is at least Stage IIIB
■ For N1 disease, <T2b gives a stage IIA, >T2b gives a stage
of IIIA
REFERENCES
1. Travis WD, Colby TV, Corrin B. World health organization
pathology panel: world health organization. Histological
typing of lung and pleural tumours: International Histological
Classification of Tumours. 3rd edn. New York: Springer
Verlag, 1999.
2. Filderman AE, Shaw C, Matthay RA. Lung cancer. Part I:
etiology, pathology, natural history, manifestations, and
diagnostic techniques. Invest Radiol 1986; 21: 80–90.
3. Ferguson MK. Diagnosing and staging of non-small cell lung
cancer. Hematol Oncol Clin North Am 1990; 4: 1053–68.
 lung cancer
4. Beckles MA, Spiro SG, Colice GL, Rudd RM. Initial evaluation
of the patient with lung cancer: symptoms, signs, laboratory
tests, and paraneoplastic syndromes. Chest 2003;
123(Suppl 1): 97S–104S.
5. Ihde D, Souhami B, Comis R, et al. Small cell lung cancer.
Lung Cancer 1997; 17(Suppl 1): S19–S21.
6. Lassen U, Osterlind K, Hansen M, et al. Long-term survival
in small-cell lung cancer: posttreatment characteristics in
patients surviving 5 to 18+ years—an analysis of 1,714 con-
secutive patients. J Clin Oncol 1995; 13: 1215–20.
7. Perry MC, Eaton WL, Propert KJ, et al. Chemotherapy with
or without radiation therapy in limited small-cell carcinoma
of the lung. N Engl J Med 1987; 316: 912–8.
8. Mountain CF. Revisions in the international system for staging
lung cancer. Chest 1997; 111: 1710–7.
9. Rami-Porta R, Ball D, Crowley J, et al. The IASLC lung cancer
staging project: proposals for the revision of the T descriptors
in the forthcoming (seventh) edition of the TNM classifica-
tion for lung cancer. J Thorac Oncol 2007; 2: 593–602.
10. Rusch VW, Crowley J, Giroux DJ, et al. The IASLC lung cancer
staging project: proposals for the revision of the N descriptors
in the forthcoming seventh edition of the TNM classification
for lung cancer. J Thorac Oncol 2007; 2: 603–12.
11. Postmus PE, Brambilla E, Chansky K, et al. The IASLC lung
cancer staging project: proposals for revision of the M
descriptors in the forthcoming (seventh) edition of the
TNM classification of lung cancer. J Thorac Oncol 2007; 2:
686–93.
12. Goldstraw P, Crowley J, Chansky K, et al. The IASLC Lung
Cancer Staging Project: proposals for the revision of the
TNM stage groupings in the forthcoming (seventh) edition
of the TNM Classification of Malignant Tumours. J Thorac
Oncol 2007; 2: 706–14.
13. Ou SH, Zell JA, Ziogas A, Anton-Culver H. Prognostic sig-
nificance of the non-size-based AJCC T2 descriptors: visceral
pleura invasion, hilar atelectasis, or obstructive pneumonitis
in stage IB non-small cell lung cancer is dependent on tumor
size. Chest 2008; 133: 662–9.
14. Glazer HS, Kaiser LR, Anderson DJ, et al. Indeterminate medi-
astinal invasion in bronchogenic carcinoma: CT evaluation.
Radiology 1989; 173: 37–42.
15. Higashino T, Ohno Y, Takenaka D, et al. Thin-section multi-
planar reformats from multidetector-row CT data: utility for
assessment of regional tumor extent in non-small cell lung
cancer. Eur J Radiol 2005; 56: 48–55.
16. Ohno Y, Sugimura K, Hatabu H. MR imaging of lung cancer.
Eur J Radiol 2002; 44: 172–81.
17. White CS. MR evaluation of the pericardium and cardiac
malignancies. Magn Reson Imaging Clin N Am 1996; 4:
237–51.
18. Seo JS, Kim YJ, Choi BW, Choe KO. Usefulness of magnetic
resonance imaging for evaluation of cardiovascular invasion:
evaluation of sliding motion between thoracic mass and
adjacent structures on cine MR images. J Magn Reson Imaging
2005; 22: 234–41.
19. Ratto GB, Piacenza G, Frola C, et al. Chest wall involvement
by lung cancer: computed tomographic detection and results
of operation. Ann Thorac Surg 1991; 51: 182–8.
20. Pennes DR, Glazer GM, Wimbish KJ, et al. Chest wall invasion
by lung cancer: limitations of CT evaluation. AJR Am J
Roentgenol 1985; 144: 507–11.
21. Glazer HS, Duncan-Meyer J, Aronberg DJ, et al. Pleural and
chest wall invasion in bronchogenic carcinoma: CT evaluation.
Radiology 1985; 157: 191–4.
22. Scott IR, Muller NL, Miller RR, Evans KG, Nelems B. Resectable
stage III lung cancer: CT, surgical, and pathologic correlation.
Radiology 1988; 166(1 Pt 1): 75–9.
23. Sakai S, Murayama S, Murakami J, Hashiguchi N, Masuda K.
Bronchogenic carcinoma invasion of the chest wall: evaluation
with dynamic cine MRI during breathing. J Comput Assist
Tomogr 1997; 21: 595–600.
24. Akata S, Kajiwara N, Park J, et al. Evaluation of chest wall
invasion by lung cancer using respiratory dynamic MRI.
J Med Imaging Radiat Oncol 2008; 52: 36–9.
25. Murata K, Takahashi M, Mori M, et al. Chest wall and
mediastinal invasion by lung cancer: evaluation with multi-
section expiratory dynamic CT. Radiology 1994; 191: 251–5.
26. Bandi V, Lunn W, Ernst A, et al. Ultrasound vs. CT in detecting
chest wall invasion by tumor: a prospective study. Chest 2008;
133: 881–6.
27. Ko JP, Drucker EA, Shepard JA, et al. CT depiction of regional
nodal stations for lung cancer staging. AJR Am J Roentgenol
2000; 174: 775–82.
28. Mountain CF, Dresler CM. Regional lymph node classification
for lung cancer staging. Chest 1997; 111: 1718–23.
29. Watanabe S, Ladas G, Goldstraw P. Inter-observer variability
in systematic nodal dissection: comparison of European and
Japanese nodal designation. Ann Thorac Surg 2002; 73: 245–8.
30. Asamura H, Suzuki K, Kondo H, Tsuchiya R. Where is the
boundary between N1 and N2 stations in lung cancer? Ann
Thorac Surg 2000; 70: 1839–45.
31. Prenzel KL, Monig SP, Sinning JM, et al. Lymph node size
and metastatic infiltration in non-small cell lung cancer.
Chest 2003; 123: 463–7.
32. De Leyn P, Vansteenkiste J, Cuypers P, et al. Role of cervical
mediastinoscopy in staging of non-small cell lung cancer
without enlarged mediastinal lymph nodes on CT scan. Eur J
Cardiothorac Surg 1997; 12: 706–12.
33. Choi YS, Shim YM, Kim J, Kim K. Mediastinoscopy in patients
with clinical stage I non-small cell lung cancer. Ann Thorac
Surg 2003; 75: 364–6.
34. Tateishi M, Fukuyama Y, Hamatake M, et al. Skip mediastinal
lymph node metastasis in non-small cell lung cancer. J Surg
Oncol 1994; 57: 139–42.
35. Glazer GM, Gross BH, Aisen AM, et al. Imaging of the pul-
monary hilum: a prospective comparative study in patients
with lung cancer. AJR Am J Roentgenol 1985; 145: 245–8.
36. Reed CE, Harpole DH, Posther KE, et al. Results of the
American College of Surgeons Oncology Group Z0050 trial:
the utility of positron emission tomography in staging
potentially operable non-small cell lung cancer. J Thorac
Cardiovasc Surg 2003; 126: 1943–51.
37. Vansteenkiste JF, Stroobants SG, De Leyn PR, et al. Lymph
node staging in non-small-cell lung cancer with FDG-PET
scan: a prospective study on 690 lymph node stations from
68 patients. J Clin Oncol 1998; 16: 2142–9.
91
 primary tumor evaluation and staging
38. Birim O, Kappetein AP, Stijnen T, Bogers AJ. Meta-analysis of
positron emission tomographic and computed tomographic
imaging in detecting mediastinal lymph node metastases in
nonsmall cell lung cancer. Ann Thorac Surg 2005; 79:
375–82.
39. Gould MK, Kuschner WG, Rydzak CE, et al. Test performance
of positron emission tomography and computed tomography
for mediastinal staging in patients with non-small-cell lung
cancer: a meta-analysis. Ann Intern Med 2003; 139: 879–92.
40. Lung cancer: diagnosis and treatment. National Institute for
Health and Clinical Excellence [CG24], 2005.
41. Dietlein M, Weber K, Gandjour A, et al. Cost-effectiveness
of FDG-PET for the management of potentially operable
non-small cell lung cancer: priority for a PET-based strategy
after nodal-negative CT results. Eur J Nucl Med 2000; 27:
1598–609.
42. Scott WJ, Shepherd J, Gambhir SS. Cost-effectiveness of
FDG-PET for staging non-small cell lung cancer: a decision
analysis. Ann Thorac Surg 1998; 66: 1876–83.
43. Ohno Y, Koyama H, Nogami M, et al. STIR turbo SE MR
imaging vs. coregistered FDG-PET/CT: quantitative and
qualitative assessment of N-stage in non-small-cell lung can-
cer patients. J Magn Reson Imaging 2007; 26: 1071–80.
44. Nomori H, Mori T, Ikeda K, et al. Diffusion-weighted
magnetic resonance imaging can be used in place of positron
emission tomography for N staging of non-small cell lung
cancer with fewer false-positive results. J Thorac Cardiovasc
Surg 2008; 135: 816–22.
45. Toloza EM, Harpole L, McCrory DC. Noninvasive staging of
non-small cell lung cancer: a review of the current evidence.
Chest 2003; 123(Suppl 1): 137S–46S.
46. Wynants J, Stroobants S, Dooms C, Vansteenkiste J. Staging
of lung cancer. Radiol Clin North Am 2007; 45: 609–25.
47. Verboom P, van Tinteren H, Hoekstra OS, et al. Cost-
effectiveness of FDG-PET in staging non-small cell lung
cancer: the PLUS study. Eur J Nucl Med Mol Imaging
2003; 30: 1444–9.
48. Vincent BD, El Bayoumi E, Hoffman B, et al. Real-time endo-
bronchial ultrasound-guided transbronchial lymph node
aspiration. Ann Thorac Surg 2008; 85: 224–30.
49. Eloubeidi MA. Endoscopic ultrasound-guided fine-needle
aspiration in the staging and diagnosis of patients withlung
cancer. Semin Thorac Cardiovasc Surg 2007; 19: 206–11.
50. Detterbeck FC, Jones DR, Molina PL. Extrathoracic staging.
In: Detterbeck FC, Rivera MP, Socinski MA, Rosenman JG,
eds. Diagnosis and Treatment of Lung Cancer: An Evidence-
Based Guide for the Practicing Clinician. Philadelphia:
W.B.Saunders Company, 2001: 94–110.
51. Viney RC, Boyer MJ, King MT, et al. Randomized controlled
trial of the role of positron emission tomography in the
management of stage I and II non-small-cell lung cancer.
J Clin Oncol 2004; 22: 2357–62.
52. Brink I, Schumacher T, Mix M, et al. Impact of [18F]FDG-PET
on the primary staging of small-cell lung cancer. Eur J Nucl
Med Mol Imaging 2004; 31: 1614–20.
53. Marom EM, McAdams HP, Erasmus JJ, et al. Staging non-
small cell lung cancer with whole-body PET. Radiology 1999;
212: 803–9.
92
54. Sze G, Shin J, Krol G, et al. Intraparenchymal brain metastases:
MR imaging versus contrast-enhanced CT. Radiology 1988;
168: 187–94.
55. Yokoi K, Kamiya N, Matsuguma H, et al. Detection of
brain metastasis in potentially operable non-small cell
lung cancer: a comparison of CT and MRI. Chest 1999; 115:
714–19.
56. Kormas P, Bradshaw JR, Jeyasingham K. Preoperative
computed tomography of the brain in non-small cell bron-
chogenic carcinoma. Thorax 1992; 47: 106–8.
57. Figlin RA, Piantadosi S, Feld R. Intracranial recurrence of
carcinoma after complete surgical resection of stage I, II, and
III non-small-cell lung cancer. N Engl J Med 1988; 318:
1300–5.
58. Robnett TJ, Machtay M, Stevenson JP, Algazy KM, Hahn SM.
Factors affecting the risk of brain metastases after definitive
chemoradiation for locally advanced non-small-cell lung
carcinoma. J Clin Oncol 2001; 19: 1344–9.
59. Earnest F, Ryu JH, Miller GM, et al. Suspected non-small cell
lung cancer: incidence of occult brain and skeletal metastases
and effectiveness of imaging for detection–pilot study.
Radiology 1999; 211: 137–45.
60. Pfister DG, Johnson DH, Azzoli CG, et al. American Society
of Clinical Oncology treatment of unresectable non-small-
cell lung cancer guideline: update 2003. J Clin Oncol 2004;
22: 330–53.
61. Salvatierra A, Baamonde C, Llamas JM, Cruz F, Lopez-Pujol
J. Extrathoracic staging of bronchogenic carcinoma. Chest
1990; 97: 1052–8.
62. Oliver TW, Jr., Bernardino ME, Miller JI, et al. Isolated
adrenal masses in nonsmall-cell bronchogenic carcinoma.
Radiology 1984; 153: 217–18.
63. Ettinghausen SE, Burt ME. Prospective evaluation of unilat-
eral adrenal masses in patients with operable non-small-cell
lung cancer. J Clin Oncol 1991; 9: 1462–6.
64. Erasmus JJ, Patz EFJ, McAdams HP, et al. Evaluation of adre-
nal masses in patients with bronchogenic carcinoma using
18F-fluorodeoxyglucose positron emission tomography. AJR
Am J Roentgenol 1997; 168: 1357–60.
65. Boland GW, Lee MJ, Gazelle GS, et al. Characterization of
adrenal masses using unenhanced CT: an analysis of the CT
literature. AJR Am J Roentgenol 1998; 171: 201–4.
66. Outwater EK, Siegelman ES, Huang AB, Birnbaum BA. Adre-
nal masses: correlation between CT attenuation value and
chemical shift ratio at MR imaging with in-phase and
opposed-phase sequences. Radiology 1996; 200: 749–52.
67. Yun M, Kim W, Alnafisi N, et al. 18F-FDG PET in character-
izing adrenal lesions detected on CT or MRI. J Nucl Med
2001; 42: 1795–9.
68. Erasmus JJ, Sabloff BS. CT, positron emission tomography,
and MRI in staging lung cancer. Clin Chest Med 2008; 29:
39–57.
69. Kocijancic I, Vidmar K, Zwitter M, Snoj M. The significance
of adrenal metastases from lung carcinoma. Eur J Surg Oncol
2003; 29: 87–8.
70. Porte H, Siat J, Guibert B, et al. Resection of adrenal metasta-
ses from non-small cell lung cancer: a multicenter study. Ann
Thorac Surg 2001; 71: 981–5.
 lung cancer
71. Tanvetyanon T, Robinson LA, Schell MJ, et al. Outcomes of
adrenalectomy for isolated synchronous versus metachro-
nous adrenal metastases in non-small-cell lung cancer: a sys-
tematic review and pooled analysis. J Clin Oncol 2008; 26:
1142–7.
72. Bury T, Barreto A, Daenen F, et al. Fluorine-18 deoxyglucose
positron emission tomography for the detection of bone
metastases in patients with non-small cell lung cancer. Eur J
Nucl Med 1998; 25: 1244–7.
73. Hsia TC, Shen YY, Yen RF, Kao CH, ChangLai SP. Comparing
whole body 18F-2-deoxyglucose positron emission tomogra-
phy and technetium-99m methylene diophosphate bone
scan to detect bone metastases in patients with non-small
cell lung cancer. Neoplasma 2002; 49: 267–71.
74. Kiser AC, Detterbeck FC. General aspects of surgical treatment.
In: Detterbeck FC, Rivera MP, Socinski MA, Rosenman JG,
eds. Diagnosis and Treatment of Lung Cancer: An Evidence-
Based Guide for the Practicing Clinician. Philadelphia:
W.B.Saunders, 2001: 133–47.
75. Bernard A, Ferrand L, Hagry O, et al. Identification of
prognostic factors determining risk groups for lung resection.
Ann Thorac Surg 2000; 70: 1161–7.
76. van Meerbeeck JP, Damhuis RA, Vos de Wael ML. High post-
operative risk after pneumonectomy in elderly patients with
right-sided lung cancer. Eur Respir J 2002; 19: 141–5.
77. Deneffe G, Lacquet LM, Verbeken E, Vermaut G. Surgical
treatment of bronchogenic carcinoma: a retrospective study
of 720 thoracotomies. Ann Thorac Surg 1988; 45: 380–3.
78. Martin-Ucar AE, Chaudhuri N, Edwards JG, Waller DA.
Can pneumonectomy for non-small cell lung cancer be
avoided? An audit of parenchymal sparing lung surgery.
Eur J Cardiothorac Surg 2002; 21: 601–5.
79. Pre-operative chemotherapy in patients with resectable non-
small cell lung cancer (NSCLC): First results of the MRC
LU22/NVALT/EORTC 08012 multi-centre randomised trial:
2007.
80. Rowell NP, Williams CJ. Radical radiotherapy for stage I/II
non-small cell lung cancer in patients not sufficiently fit for
or declining surgery (medically inoperable): a systemic
review. Thorax 2001; 56: 628–38.
81. Alam N, Darling G, Evans WK, Mackay JA, Shepherd FA.
Adjuvant chemotherapy for completely resected non-small
cell lung cancer: a systematic review. Crit Rev Oncol Hematol
2006; 58: 146–55.
82. Tsuboi M, Ohira T, Saji H, et al. The present status of postop-
erative adjuvant chemotherapy for completely resected
non-small cell lung cancer. Ann Thorac Cardiovasc Surg
2007; 13: 73–7.
83. Chemotherapy in stage IV (metastatic) non-small cell lung
cancer. Lung Cancer Disease Site Group and Cancer Care
Ontario Practice Guidelines Initiative. 2002.
84. Agra Y, Pelayo M, Sacristan M, et al. Chemotherapy versus best
supportive care for extensive small cell lung cancer. Cochrane
Database of SystematicReviews CD001990[4]. 2003.
85. Marsiglia H, Baldeyrou P, Lartigau E, et al. High-
dose-rate brachytherapy as sole modality for early-stage
endobronchial carcinoma. Int J Radiat Oncol Biol Phys
2000; 47: 665–72.
86. Pignon JP, Arriagada R, Ihde DC, et al. A meta-analysis of
thoracic radiotherapy for small-cell lung cancer. N Engl J
Med 1992; 327: 1618–24.
87. Akhurst T, Downey RJ, Ginsberg MS, et al. An initial experi-
ence with FDG-PET in the imaging of residual disease after
induction therapy for lung cancer. Ann Thorac Surg 2002;
73: 259–64.
88. Ryu JS, Choi NC, Fischman AJ, Lynch TJ, Mathisen DJ. FDG-
PET in staging and restaging non-small cell lung cancer
after neoadjuvant chemoradiotherapy: correlation with
histopathology. Lung Cancer 2002; 35: 179–87.
89. Port JL, Kent MS, Korst RJ, et al. Positron emission tomography
scanning poorly predicts response to preoperative chemo-
therapy in non-small cell lung cancer. Ann Thorac Surg 2004;
77: 254–9.
90. De Leyn P, Stroobants S, De Wever W, et al. Prospective
comparative study of integrated positron emission tomogra-
phy-computed tomography scan compared with remediasti-
noscopy in the assessment of residual mediastinal lymph
node disease after induction chemotherapy for mediastinos-
copy-proven stage IIIA-N2 Non-small-cell lung cancer: a
Leuven Lung Cancer Group Study. J Clin Oncol 2006; 24:
3333–9.
91. Yano T, Yokoyama H, Inoue T, et al. The first site of recur-
rence after complete resection in non-small-cell carcinoma
of the lung. Comparison between pN0 disease and pN2 dis-
ease. J Thorac Cardiovasc Surg 1994; 108: 680–3.
92. Jang KM, Lee KS, Shim YM, et al. The rates and CT patterns
of locoregional recurrence after resection surgery of lung
cancer: correlation with histopathology and tumor staging.
J Thorac Imaging 2003; 18: 225–30.
93. Downey RJ. Follow-up of patients with completely resected
lung cancer. Chest 1999; 115: 1487–8.
94. Benamore R, Shepherd FA, Leighl N, et al. Does intensive
follow-up alter outcome in patients with advanced lung can-
cer? J Thorac Oncol 2007; 2: 273–81.
95. Colice GL, Rubins J, Unger M. Follow-up and surveillance of
the lung cancer patient following curative-intent therapy.
Chest 2003; 123(Suppl 1): 272S–83S.
96. Rubins J, Unger M, Colice GL. Follow-up and surveillance of
the lung cancer patient following curative intent therapy:
ACCP evidence-based clinical practice guideline (2nd
edition). Chest 2007; 132(Suppl 3): 355S–367S.
97. Israel O, Kuten A. Early detection of cancer recurrence:
18F-FDG PET/CT can make a difference in diagnosis and
patient care. J Nucl Med 2007; 48(Suppl 1): 28S–35S.
98. Erasmus JJ, McAdams HP, Patz EF, Jr. Non-small cell lung
cancer: FDG-PET imaging. J Thorac Imaging 1999; 14:
247–56.
99. Keidar Z, Haim N, Guralnik L, et al. PET/CT using 18F-FDG
in suspected lung cancer recurrence: diagnostic value and
impact on patient management. J Nucl Med 2004; 45:
1640–6.
100. Fontana RS, Sanderson DR, Woolner LB, et al. Lung cancer
screening: the Mayo program. J Occ Med 1986; 28: 746–50.
101. Melamed MR, Flehinger BJ, Zaman MB, et al. Screening for
early lung cancer. Results of the Memorial Sloan-Kettering
study in New York. Chest 1984; 86: 44–53.
93
 primary tumor evaluation and staging
102. Marcus PM, Bergstralh EJ, Fagerstrom RM, et al. Lung cancer
mortality in the Mayo Lung Project: impact of extended
follow-up. J Natl Cancer Inst 2000; 92: 1308–16.
103. Black C, de Verteuil R, Walker S, et al. Population screening
for lung cancer using computed tomography, is there
evidence of clinical effectiveness? A systematic review of the
literature. Thorax 2007; 62: 131–8.
104. Sone S, Li F, Yang ZG, et al. Results of three-year mass screen-
ing programme for lung cancer using mobile low-dose spiral
computed tomography scanner. Br J Cancer 2001; 84: 25–32.
105. Swensen SJ, Jett JR, Hartman TE, et al. Lung cancer screening
with CT: Mayo Clinic experience. Radiology 2003; 226: 756–61.
106. MacRedmond R, Logan PM, Lee M, et al. Screening for lung
cancer using low dose CT scanning. Thorax 2004; 59: 237–41.
107. Pastorino U, Bellomi M, Landoni C, et al. Early lung-cancer
detection with spiral CT and positron emission tomography
in heavy smokers: 2-year results. Lancet 2003; 362: 593–7.
108. Sobue T, Moriyama N, Kaneko M, et al. Screening for lung
cancer with low-dose helical computed tomography: anti-lung
cancer association project. J Clin Oncol 2002; 20: 911–20.
109. Henschke CI, Naidich DP, Yankelevitz DF, et al. Early lung
cancer action project: initial findings on repeat screenings.
Cancer 2001; 92: 153–9.
94
110. Henschke CI, Yankelevitz DF, Libby DM, et al. Survival of
patients with stage I lung cancer detected on CT screening.
N Engl J Med 2006; 355: 1763–71.
111. Bach PB, Jett JR, Pastorino U, et al. Computed tomography
screening and lung cancer outcomes. JAMA 2007; 297:
953–61.
112. Nawa T, Nakagawa T, Kusano S, et al. Lung cancer screening
using low-dose spiral CT: results of baseline and 1-year
follow-up studies. Chest 2002; 122: 15–20.
113. Aoki T, Nakata H, Watanabe H, et al. Evolution of peripheral
lung adenocarcinomas: CT findings correlated with histology
tumour doubling time. AJR Am J Roentgenol 2000; 174:
763–8.
114. Lindell RM, Hartman TE, Swensen SJ, et al. Five-year lung
cancer screening experience: CT appearance, growth rate,
location and histologic features of 61 lung cancers. Radiology
2007; 242: 555–62.
115. Crestanello JA, Allen MS, Jett JR, et al. Thoracic surgical
operations in patients enrolled in a conputed tomographic
screening trial. J Thoac Cardiovasc Surg 2004; 128: 254–9.
116. Diederich S, Wormanns D, Semik M, et al. Screening for early
lung cancer with low-dose spiral CT: prevalence in 817
asymptomatic smokers. Radiology 2002; 222: 773–81.
 9 Mediastinal Tumors
Jonathan Goldin
INTRODUCTION
Mediastinal tumors include a wide spectrum of pathologies. By
clearly depicting the location and composition of such masses
imaging is critical to narrowing the differential diagnosis (Table 9.1).
Mediastinal masses are often asymptomatic or may be present with
non-specific symptoms including shortness of breath, chest pain or
discomfort, and cough. This chapter will review the common medi-
astinal tumors in each anatomic compartment and the imaging
features associated with their diagnostic and prognostic features.
The structural and histological anatomy of the mediastinum is
well characterized and closely related to the tumors that arise in
this location. The margins of the mediastinum are superiorly the
thoracic inlet, inferiorly the diaphragm, laterally the pleural sur-
faces of the two lungs, anteriorly the anterior rib elements together
with sternum, and posteriorly the thoracic vertebrae and poste-
rior rib elements. Traditionally, it is further subdivided based on
structural landmarks into:
• Anterior (by a line along the posterior aspect of heart)
• Middle (between the anterior margin and a line drawn
along the anterior vertebral bodies)
• Posterior divisions (bounded by the anterior body line
to the costo-vertebral recess)
The histological contents of each of these compartments have
important implications for correctly diagnosing the pathology of
the masses (Table 9.2) (1).
The anterior mediastinum contains the thymus, fat, and lymph
nodes. Anterior mediastinal masses most commonly include:
• Thymoma
• Teratoma
• Thyroid disease
• Lymphoma and other anterior mediastinal metastatic
lymph node masses
The middle mediastinum contains the heart, pericardium, ascend-
ing and transverse aorta, brachiocephalic veins, trachea, bronchi,
and lymph nodes. Middle mediastinal masses are typically benign
(including congenital, foregut, and pericardial cysts). The most
common masses in this location are nodal metastases and lym-
phoma. The vast majority of metastases arise from intrathoracic
primary lung tumors (>90%). Extrathoracic neoplasms that have
been described to spread to mediastinal nodes include breast cancer,
renal cell cancer, melanoma, and head and neck tumors (2).
The posterior mediastinum consists of the descending thoracic
aorta, esophagus, azygous vein, autonomic ganglia and nerves,
thoracic lymph nodes, and fat. Posterior mediastinal masses are
often:
• Neurogenic tumors
• Primary and secondary tumors of the spine
• Esophageal tumors
Lymph node masses due to either lymphoma or metastatic nodes
are the most common cause of soft tissue mass in any location.
More than two-thirds of primary mediastinal tumors in adults
occur in the anterior mediastinum and are of benign pathology,
whereas in children mediastinal tumors are more often malignant
and seen in the posterior mediastinum (3). The factors most
frequently associated with malignant mediastinal tumors are
• Location
• Patient age
• The presence or absence of symptoms
• The presence or absence of known malignant disease
elsewhere
Malignant masses are most commonly situated in the anterior
compartment accounting for 60% of such lesions compared with
29% and 16% in the middle and posterior compartments, respec-
tively (Table 9.2) (4,5). Lymphoma and neuroblastoma are most
frequent in the first and second decades, and lymphomas and
germ cell tumors present most frequently in the second to fourth
decades of life. Malignant lesions are more likely to be symptomatic
(85%) than benign neoplasms (46%) (5).
Key Points: Diagnosis
■ Patient age is an important predictor of malignancy and
tumor type; for example, most tumors detected in adults are
benign
■ Lymphoma and neuroblastoma are most frequent in the
second to fourth decade
■ Malignant masses are most commonly located in the anterior
mediastinum
■ Symptoms related to a mediastinal mass are more commonly
seen with large malignant masses than benign disease
■ MR imaging tissue and/or CT attenuation characteristics may
be helpful for determining the nature of a mediastinal mass
DIAGNOSTIC WORK-UP
The imaging work-up of mediastinal masses should start with a pos-
teroanterior and lateral chest radiograph. Indeed, not uncommonly,
mediastinal masses are detected incidentally on chest radiographs.
Key information regarding the size, anatomical location, density, and
composition of the mass is provided by the chest radiograph. The
next step should include pre- and post-contrast computed tomogra-
phy (CT) or magnetic resonance (MR) imaging to further character-
ize mediastinal masses and their relationship to surrounding
structures as well as to identify cystic, vascular, and soft-tissue struc-
tures. Significant post-contrast enhancement of the mass may also
be a helpful feature. MR imaging is particularly useful for evaluating
neurogenic tumors, by helping to determine the presence of intraspi-
nal extension or invasion, as well as the extent of vascular invasion
95
 primary tumor evaluation and staging

Table 9.1 Primary Malignant Tumors of the Mediastinum • Lymph nodes

(10% of all Mediastinal Masses) • Silicosis

Thymic tumors
• Sarcoidosis
Thyroid and parathyroid carcinomas
• Tuberculosis
Lymphoma • Histoplasmosis
Malignant germ cell tumors • Pneumocystis
Mesenchymal tumors
Neurogenic Tumors
Contrast Enhancement
Lesions showing significant contrast enhancement include:
Table 9.2 Differential Diagnosis of a Mediastinal Mass
by Anatomic Location
• Vascular lesions (aneurysms or pseudoaneurysms)
• Vascular neoplasms, typically thymic carcinoids,
Anterior (60%) Middle (29%) Posterior (11%) parathyroid adenomas, and Castleman’s disease (7)
Thymoma Lymphoma Neurogenic tumor Positron emission tomography (PET) studies and combined PET-CT
Teratoma, seminoma Pericardial cyst Bronchogenic cyst
evaluations have become increasingly useful in the evaluation of
Lymphoma Bronchogenic cyst Enteric cyst
Carcinoma Metastatic cyst Xanthogranuloma
mediastinal masses. Malignant primary mediastinal tumors are
Parathyroid adenoma Systemic granuloma Diaphragmatic more likely to be hypermetabolic than benign lesions. However, in
hernia the setting of a patient with a known extramediastinal primary
Intrathoracic goiter Meningocele tumor, a metabolically active mass on PET is more likely to be
Lipoma Paravertebral abscess due to metastatic disease than to another primary lesion or an
Lymphangioma
Aortic aneurysm
incidental benign mediastinal mass or lymph node.
Although other nuclear scans and biochemical studies can be
used to further characterize a lesion, tissue diagnosis is almost
or cardiac involvement. Both MR imaging and CT data provides for always required. If a mass is likely to be benign after initial
the potential for 3D visualization which may facilitate the depiction work-up, it can be removed surgically without biopsy. Otherwise,
of anatomical relations and assist with surgical planning. a diagnostic biopsy specimen can be obtained by transthoracic or
The CT attenuation or MR imaging tissue signal characteristics transbronchial needle aspiration, mediastinoscopy, anterior
of the mass, suggesting fat, water, or calcium, are particularly helpful mediastinotomy, or video-assisted thoracic surgery, depending
in narrowing down the differential diagnosis. on the anatomical location and radiographic appearance of the
lesion.
Fat
In the anterior mediastinum there are only three major disease Key Points: Diagnosis of Mediastinal Tumors
entities that contain fat (fat attenuation/signal intensity on CT ■ Chest radiography is often performed for an unrelated
and MR imaging respectively). These are: cause—most common way in which an asymptomatic mass
• Teratoma is identified
• Thymolipoma ■ Chest radiography should be the first study performed in an

• Morgagni hernia individual with chest symptoms

■ Lateral radiograph findings are helpful in the determination of

Fluid the involved compartment of the mediastinum

Several different types of mediastinal masses are composed of ■ CT is a routine part of the diagnostic evaluation of mediastinal

fluid and reflect water attenuation/signal intensity on CT and MR lesions

imaging, respectively. Many of these lesions are neoplastic in ■ CT can depict the exact location of the mediastinal tumor

nature (6). These include: and its relationship to adjacent structures

■ CT can differentiate primary mediastinal masses from those
• Cysts arising from thymus or pericardium that encroach on the mediastinum from the lung
• Foregut duplication cysts ■ CT can differentiate tissue densities (particularly cyst from
• Neurogenic tumors solid and calcified versus non calcified)
• Abscesses ■ CT can reveal evidence of local invasion of adjacent structures
• Lymphangiomas (particularly in children) by a mass or the presence of intrathoracic metastases
■ MR imaging is the routine first cross-sectional study in some
Calcification centers for the diagnostic evaluation of mediastinal lesions
There are many calcified anterior mediastinal masses that include and in follow-up evaluation after treatment (particularly in
lesions: lymphoma)
■ MR imaging provides superior images of vascular structures and
• Arising from thyroid, thymus, or parathyroid glands
can better delineate the relationship of an identified mediastinal
• Germ cell tumors
mass to nearby intrathoracic vessels
• Treated lymphoma

96
 mediastinal tumors
■ MR imaging can differentiate between a possible mediastinal
mass and a vascular abnormality, such as an aortic aneurysm,
better than CT
■ MR imaging provides increased anatomical detail compared
with CT in the thoracic inlet, subcarinal and aortopulmonary
window areas, at the thoraco-abdominal level, and in the infe-
rior aspects of the mediastinum at the level of the diaphragm
■ Positron emission tomography is rapidly evolving as an
important technique for assessing mediastinal lymph node
metastases in patients with lung, colorectal, and breast
cancer, and also in lymphoma and malignant melanoma
TRANSTHORACIC NEEDLE BIOPSY
Increasingly, imaging-guided percutaneous core-needle biopsy
has become the modality of choice for diagnosing mediastinal
masses (Figs. 9.1 and 9.2) (8–19). Differentiation between thymo-
mas, lymphomas, and germ cell tumors can be made when tissue
obtained from a core needle biopsy is subjected to special histo-
logical staining methods, including immunohistochemical tech-
niques. Fine needle aspiration has been described for neurogenic
(A) (B)
(E)
Figure 9.1 Series of CT images showing placement of a biopsy needle (arrowhead) into a soft tissue mass (m) in the superior aspect of the anterior mediastinum with
sagittal reconstructions confirming good placement. Histology confirmed Hodgkin’s lymphoma. Source: Courtesy Dr. Robert Suh.
tumors, but since surgical resection is the treatment of choice for
these tumors, needle biopsy may be deemed an unnecessary step.
TUMORS OF THE ANTERIOR MEDIASTINUM
Thymic Masses
Thymoma
Thymomas are the most anterior of all mediastinal masses and are
uncommon tumors with an incidence 0.15 per 100,000 population.
They account for approximately 20% of anterior mediastinal neo-
plasms in adults, usually occur in patients between the ages of 45
and 60 years, and rarely below the age of 20 years (20–25).
Thymoma is most commonly detected as an incidental finding
on a chest radiograph (23,26,27). Symptoms occur late, are due to
mass effect or local invasion, and include chest pain, cough, or dys-
pnoea (28). In addition, patients may present with parathymic syn-
dromes (29). Approximately 30–50% of patients with this tumor
either have or will develop myasthenia gravis compared to only
10–15% of patients with myasthenia gravis who develop a thymoma
(30,31). Hypogammaglobulinemia and pure red blood cell aplasia
are present in 10% and 5% of patients with a thymoma respectively
(21). Good’s syndrome is diagnosed in patients with a thymoma
(C) (D)
97
 primary tumor evaluation and staging

LN LN

(A) (B)
Figure 9.2 CT-guided biopsy (A) and (B). A long transthoracic approach has been used to biopsy a contralateral lymph node (LN) in a patient with suspected primary
lung cancer in the left lower lobe. Biopsy was positive for squamous carcinoma indicating N3 disease and obviating the need for invasive mediastinoscopy.

and combined B-cell/T-cell immunodeficiency (32). Thymoma is Table 9.3 Masaoka Staging System of Thymoma
also associated with various other autoimmune disorders, such as
Stage Degree of invasion Five-year
systemic lupus erythematosus, polymyositis, and myocarditis
survival
(5,21,33,34). Up to 20% of patients with thymoma have a malignant rate (%)
neoplasm such as lymphoma, lung cancer, or thyroid cancer.
I No capsular invasion by tumor or complete 96–100
encapsulation macroscopically
Pathology II Invasion of adjacent fat or mediastinal pleura 86–95
Thymomas are classified as benign or invasive, with 15–37% being macroscopically or microscopic invasion of tumor
invasive (35). Thymomas typically spread along pleural and peri- III Gross invasion of surrounding mediastinal structures 56–69
cardial surfaces, leaving behind discrete tumor droplets that are or lung
IVA Intrathoracic spread to pleura or pericardium Up to 50
visible on CT as small nodules, masses, or plaque-like lesions.
IVB Distant metastases
Tumor may cross into the abdomen (32%) either directly across a
hemidiaphragm or via the retrocrural space (21,22,33). Thymomas
may spread to mediastinal, supraclavicular, and cervical lymph
nodes, leading to lymph node enlargement in these regions.
Lymphogenous and hematogenous spread is rare (28,29).
Thymomas have a wide spectrum of histological diversity and
Table 9.4 World Health Organization Classification
are classified based on cell type predominance as lymphocytic,
of Thymomas
epithelial, or spindle cell variants. Invasive thymomas are indistin-
guishable from benign lesions histologically. There is however Class of thymoma Cytologic features
strong association between histological subtype and invasiveness
Type A Spindle cell, medullary
as well as prognosis (36–38). The Masaoka staging system is still Type AB Mixed
currently used to stratify five-year survival rates (Table 9.3). More Type B1 Lymphocyte rich, lymphocytic, predominantly
recently, the World Health Organization (WHO) (39) devised a cortical organoid
new classification system to group thymomas based on cytological Type B2 Cortical
differences, which may be helpful in determining treatment Type B3 Epithelial, atypical squamous, well-differentiated
thymic carcinoma
regimens and predicting prognosis (Table 9.4).

98
 mediastinal tumors

Imaging Findings
Typically thymomas appear on a chest radiograph as a well-defined
lobulated mass in the anterosuperior mediastinum (21,33). These
lesions are usually asymmetric, commonly draping along one side
of the heart. Differentiation between normal thymic tissue and a
true thymic mass can be very challenging. In the adult the shape
of the normal thymus is either:
• Arrowhead (62%)
• Two ovoid limbs (32%)
• Single asymmetric ovoid lobe (6%) (40)
The maximum diameter or thickness of each limb should be
≤13 mm (40). Further evaluation with contrast-enhanced tho-
racic CT or MR imaging usually reveals an encapsulated, well-
defined soft-tissue mass (Fig. 9.3). On contrast-enhanced
imaging a thymoma either shows mild uniform contrast
enhancement or conversely relatively low attenuation compared
to other mediastinal soft tissues (2). Both CT and MR examina-
tion should include evaluation of the chest and abdomen in
order to identify distant metastases which if present, would
denote Stage IVB disease.
In the majority of thymomas the pattern of contrast enhance-
ment is mild and uniform. Further differentiation between benign
and invasive thymomas may be impossible (2). Typically, benign
thymomas are round or oval masses found in the prevascular
anterior mediastinum, with well-defined margins and a clear fat
plane between the thymoma and adjacent mediastinal structures
(2). Calcifications may be seen in 12% to 25% (40). Up to one-
third of thymomas have components that are hemorrhagic,
necrotic, or cystic (21,28). Thirty-four percent of thymomas
invade through their own capsules, extending into surrounding
structures and by drop metastases into the pleural cavity (Figs. 9.4
and 9.5) (29,33,41–44). Elevation of a hemi-diaphragm on
imaging is highly suggestive of phrenic nerve invasion. Thrombosis
of the superior vena cava or innominate veins may be seen in
invasive thymoma. MR imaging can be particularly helpful for
detecting major vein thrombosis and in the detection of early
pleural drop metastases that characteristically show high signal
intensity on T1-weighted sequences.
Thymic Carcinoma
Thymic carcinomas are very rare, occurring predominantly in
men between 40 and 60 years of age. Unlike thymomas, most
patients present with non-specific thoracic symptoms including
cough, shortness of breath, and chest pain (45). In addition, many
patients complain of systemic features including fatigue, weight
loss, and anorexia. Patients may also present with late locally
extensive disease including superior vena cava syndrome and
cardiac tamponade (46).
Pathologically thymic carcinomas are a heterogeneous group
of aggressive, invasive epithelial malignancies (5). Histologically,
thymic carcinomas are large, firm, infiltrating masses with areas

(A) (B)

(C) (D)
Figure 9.3 Benign thymoma. (A) and (B) Contrast-enhanced T1-weighted MR images of a young adult demonstrating a well-defined anterior mediastinal mass with
moderate contrast enhancement and a clear fat plane between the mediastinal mass and the mediastinal structures. (C) and (D) CT images in another patient with a
well-defined mass, showing preserved fat planes and homogeneous soft tissue density within the tumor.

99
 primary tumor evaluation and staging

(A) (B)
Figure 9.4 Malignant thymoma. (A) and (B) Contrast-enhanced CT demonstrates a heterogeneous enhancing mass with ill-defined margins and loss of definition of the
adjacent fat planes.

(A) (B) (C) (D)

Figure 9.5 Spread of invasive thymoma. (A) and (C) Axial CT images with (B) and (D) corresponding PET scans. (A) and (B) drop metastasis in the costophrenic angle;
(C) and (D) drop metastases in the cardiophrenic recess.

of cystic change and necrosis. The Masaoka staging system used
for thymomas is not useful as a prognostic tool in thymic carci-
noma. They are classified as low grade or high grade, with
squamous cell-like and lymphoepithelioma-like variants being
the most common cell types (47). In contrast to thymomas,
thymic carcinomas are cytologically malignant, with typical fea-
tures of cellular necrosis, atypia, and mitoses (46).
The CT and MR imaging appearances of thymic carcinomas are
most often indistinguishable from thymomas. However, these
lesions tend to be very aggressive, with a strong tendency to metas-
tasise to distant locations such as lungs, liver, brain, and bone in
contrast to thymomas which rarely metastasise. Thus, the detection
of distant metastases is an important clue to making the correct
diagnosis. Furthermore, the observation of irregular margins,
calcifications, cyst formation, heterogeneous enhancement,
lymphadenopathy, and great vessel invasion are all more common
in thymic carcinomas compared to thymomas (48). PET-CT is
also helpful in distinguishing thymomas from thymic carcinomas
because the latter are more likely to be hypermetabolic (49).
Thymic Carcinoid
Thymic carcinoid tumors arise from amine precursor uptake and
decarboxylation (APUD) cells of neural crest origin. Approximately
50% of thymic carcinoid tumors are hormonally active, usually
secreting adrenocorticotropic hormone (ACTH) which may result
in Cushing’s syndrome (50). Occasionally patients may present
with the syndrome of inappropriate antidiuretic hormone secre-
tion (SIADH). Underlying Multiple Endocrine Neoplasia (MEN I

100
 mediastinal tumors
or MEN II) is discovered in 20% of patients with a thymic carci-
noid tumor. In patients with suspected MEN I, imaging of the
chest, abdomen, and brain should be performed for full staging.
On either CT or MR imaging thymic carcinoid tumors are
generally indistinguishable from thymomas and thymic carcino-
mas (Fig. 9.6). If a thymic carcinoid tumor is clinically suspected,
somatostatin receptor scintigraphy, for example with 111Indiethylene
triamine pentaacetic acid (DTPA) (Octreotide) or 99mTcEDDA/
HYNIC-octreotate, may be performed to confirm the diagnosis
(51). Thymic carcinoid tumors are usually malignant, and patients
tend to have locally invasive disease, distant metastases, and a poor
prognosis (52). The tumors often recur locally after surgical resec-
tion. Sclerotic bone metastases are seen occasionally in mediastinal
carcinoid and the lesion itself may calcify (53).
Thymic Cyst
Thymic cysts may be congenital or acquired. Acquired thymic
cysts are considerably more common than congenital cysts and
may arise in association with neoplasms such as thymomas, lym-
phomas, or germ cell tumors (Fig. 9.7). Although teratomas are
the most common type of germ cell tumor to develop cystic areas,
other cell types may contain cysts. Thymic cysts may also be seen
in the anterior mediastinum after radiation therapy for Hodgkin’s
disease, and occasionally multilocular thymic cysts are seen in
(A)
(C)
Figure 9.6 Primary neuroendocrine thymic cancer. (A) and (B) Pre- and post-contrast-enhanced axial CT images. (C) Contrast-enhanced coronal CT image. (D) Axial
fat suppressed MR image. There is an irregular anterior mediastinal mass. The axial fat sat MR image demonstrates the soft tissue intensity of the solid mass within the
anterior medastinum.
patients with AIDS, particularly in children (54). Sometimes
acquired cysts are unassociated with neoplasms and are thought
to be related to an inflammatory process (55). Such lesions may
contain cellular debris, cholesterol crystals, and/or hemorrhage,
leading to a complicated appearance on CT and MR imaging.
Furthermore, the cystic material may leak into the surrounding
mediastinal tissues, inciting an inflammatory response.
Congenital thymic cysts are remnants of the thymopharyngeal
duct (56). Inflammatory cysts probably arise from a focus of
inflamed thymic parenchyma. Radiographically, they appear as
simple homogeneous cysts. Microscopically, thymic cysts may be
identical to cystic thymic neoplasms. Thus thorough sampling
and careful histological examination are essential (57). Surgical
excision is curative.
Thymolipoma
Thymolipoma is a rare, benign, slowly growing tumor of the thy-
mus gland that occurs in young adults of both sexes (4). Despite
their usually large size, they are generally asymptomatic; occasionally
however, they may compress or displace adjacent structures, leading
to symptoms. On CT these tumors may be shown clearly to lie
within the thymus. They are frequently pedunculated, filling a
large portion of one hemithorax; in such cases, it may be difficult
to discern the thymic origin of the mass. In general thymomas are
(B)
(D)
101
 primary tumor evaluation and staging

(A) (B)

(C)

Figure 9.7 A large anterior mass is identified on the plain chest radiograph (A) PA, and (B) lateral projection in a patient with known lymphoma. PET-CT (C) demonstrates
both the fluid and lack of metabolic activity in the incidental pericardial cyst. There is no evidence of recurrent disease.

(A) (B)

Figure 9.8 Thymic hyperplasia in a 46 year old female patient with rebound thymic hyperplasia following chemotherapy for breast cancer (right mastectomy and axillary
node dissection). (A) Axial and (B) coronal contrast-enhanced CT images show the mediastinal mass with a well-maintained thymic contour and clear fat planes between
the thymus and adjacent mediastinal structures.

predominantly fatty in attenuation / signal on CT or MR imaging,
with a variable amount of soft tissue elements.
Rebound Thymic Hyperplasia
Rebound hyperplasia of the thymus reflects rebound enlargement
of the thymus after temporary atrophy of the gland, which occurs
during a period of illness or physical stress. It occurs mainly in chil-
dren and adolescents. Although uncommon in adults, it has been
increasingly described following chemotherapy and immunotherapy
(Fig. 9.8) (58,59).
In one series, enlargement of the thymus appeared 1–11 months
(mean five months) after cessation of chemotherapy and persisted
for up to 4.5 years, even after cure of the malignancy being treated
(60). A history of chemotherapy even several years earlier must be
considered when an enlarged thymus is identified. The possible
mechanisms could be rebound enlargement after initial atrophy

102
 mediastinal tumors
caused by chemotherapy drugs or, in the case of immunotherapy,
stimulation of T-cell production (59,61–64).
It can be difficult to distinguish benign hyperplasia from tumor
infiltration on the basis of imaging information alone (58). In the
setting of Hodgkin’s disease, thymic involvement by recurrence
of lymphoma is usually accompanied by lymph node disease in
the mediastinum. In patients with solid tumors, infiltration of
the thymus by these tumors is rare, and thus benign thymic
hyperplasia after chemotherapy is the most likely diagnosis. Lack
of clinical or imaging evidence of recurrence at any other site
may serve as further support for the diagnosis of thymic rebound
hyperplasia.
Imaging
Thymic enlargement appears on CT and MR imaging as an ante-
rior mediastinal mass which may be confused with a neoplastic
process (65). This may be a source of concern, particularly in the
setting of a known malignancy. Awareness of the possibility of
benign thymic enlargement in these patients may prevent invasive
diagnostic procedures. On the initial studies prior to treatment,
there is usually no evidence of an anterior mediastinal mass in the
adult patient. The development of a new anterior mediastinal
mass in the normal site of the thymus is the first finding and
should alert the radiologist to the likelihood of thymic rebound.
Typically the enlarged thymus has an arrowhead-triangular shape,
a bilobed configuration, convex borders, and is of homogeneous
soft tissue density.
The signal intensities on conventional MR imaging of the
normal thymus can overlap those of an abnormal thymus (66,67).
Initial results with chemical-shift MR imaging suggest that this
sequence may be a useful diagnostic test in the diagnosis of thymic
hyperplasia, but there is currently only limited experience with
the use of this technique (68,69). FDG PET physiological thymic
uptake is seen in about one-third of young healthy adults and thus
its role in differentiating benign hyperplasia from neoplasm
requires further clarification (70).
Key Points: Thymic Masses
■ Thymomas account for 20% of anterior mediastinal masses
■ Thymomas show mild contrast enhancement on CT and MR
imaging
■ MR imaging is useful for detecting pleural drop metastases
■ Thymic carcinoma is rare and predominately occurs in males
over 60 years of age
■ CT and MR imaging appearances may be identical to thymoma
but they tend to be more aggressive. Distant metastases are
common
■ In general, thymic carcinoid tumors are indistinguishable
from thymomas on imaging
■ Acquired thymic cysts develop in thymomas, germ cell
tumors, and lymphoma
■ Thymolipoma is a large, predominantly fatty, benign neoplasm
occurring in young adults
■ Rebound thymic hyperplasia may occur many years after
chemotherapy and may be difficult to distinguish from
tumor infiltration
Mediastinal Germ Cell Tumors
Mediastinal germ cell tumors (GCTs) are derived from primitive
germ cells that fail to migrate completely during early embryonic
development (71–73). The majority are benign. GCTs are found
in young adults (males more common than females) in the second
to fourth decades, and represent 2% to 6% of mediastinal masses
and 5% to 15% of malignant mediastinal tumors (4). Malignant
GCTs are more common (>90%) in men. A mediastinal GCT
should prompt a search for a primary gonadal malignancy.
GCTs are classified into three groups based on cell type:
• Benign teratomas
• Seminomas
• Embryonal tumors
The embryonal tumors, also called malignant teratomas or non-
seminomatous GCTs, are diverse and include choriocarcinomas,
yolk sac carcinomas, embryonal carcinomas, and teratocarcino-
mas (74). These tumors often produce serum markers such as
alpha fetoprotein (AFP) and human chorionic gonadotropin
(HCG), which can be useful in the diagnostic evaluation (4).
Mediastinal Teratomas (benign)
Approximately 80% of mediastinal germ cell tumors are benign,
and most of the benign lesions represent teratomas. Consisting of
tissue from at least two of the three primitive germ layers, benign
teratomas are the most common mediastinal GCT (75). Ectoder-
mal tissues, which usually predominate, include skin, hair, sweat
glands, and tooth-like structures. Mesodermal tissues, such as fat,
cartilage, bone, and smooth muscle are less common, as are endo-
dermal structures like respiratory and intestinal epithelium (76).
The majority of mediastinal teratomas are mature teratomas
that are histologically well-defined and benign (75). If a teratoma
contains fetal tissue or neuroendocrine tissue, it is defined as
immature and malignant. In children, the prognosis is favorable,
but it can often recur or metastasise. Mature teratomas do have
the potential in rare circumstances to undergo malignant trans-
formation into a variety of malignancies (77). Reports of rhab-
domyosarcoma, adenocarcinoma, leukemia, and anaplastic small
cell tumors have all been identified as arising from mature or
immature teratomas.
Most patients are completely asymptomatic. Like other medi-
astinal masses, presenting symptoms include cough, dyspnea, and
chest pain. Digestive enzymes secreted by intestinal mucosa or
pancreatic tissue found in the teratoma can lead to the rupture of
the bronchi, pleura, pericardium, or lung (4). A rare result of a
ruptured mediastinal teratoma is the expectoration of hair or
sebum (78,79).
CT and MR imaging are used to assess resectability, and may
identify sebaceous elements and fat, supporting the diagnosis.
Benign teratomas are well-defined, round, or lobulated masses
when seen on a chest radiograph. Up to 26% are calcified, as they
often contain elements of bone or teeth (80).
Teratomas are usually predominantly cystic in nature, although
they frequently have a soft tissue component, often showing a thin
outer capsule. Fat and calcium are also common elements. Fat/
fluid levels are said to be a specific finding for teratomas; however,
they are rarely seen. Entirely solid teratomas are occasionally
encountered; these lesions are usually malignant. Typically, benign
103
 primary tumor evaluation and staging

teratomas are encapsulated and well defined on CT. However, they
may show areas of hemorrhage, leading to a complex CT appear-
ance. Malignant teratomas are most often large, multinodular in
appearance, and poorly defined at CT (Fig. 9.9). Both benign and
malignant teratomas may grow and may rupture or form fistulae
with adjacent structures in the mediastinum or with lung, pleura,
or pericardium (81).
Mediastinal Seminoma
Primary mediastinal seminomas, although uncommon, com-
prise 25% to 50% of malignant mediastinal GCTs occurring
most frequently in men aged 20–40 years. Patients present with
dyspnea, substernal pain, weakness, cough, fever, gynecomastia,
or weight loss. Because of the tumor location, about 10% of
patients present with superior vena cava syndrome (82). However,
tumors can grow up to 20–30 cm in diameter before symptoms
develop (83).
Radiographically, seminomas are bulky, lobulated, homogeneous
masses. Local invasion is rare, but metastasis to lymph nodes and
bone does occur (4). CT and gallium scanning are used to evaluate
the extent of disease (84).
Non-seminomatous Germ Cell Tumors
Malignant non-seminomatous germ cell tumors (NSGCTs) com-
prise a heterogeneous group of masses that includes embryonal
cell carcinomas, endodermal thymus tumors, choriocarcinomas,
yolk sac tumors, and mixed GCTs with multiple cellular components.
These tumors are often symptomatic and predominantly affect
young men (4). They can be associated with hematological malig-
nancies, and 20% of patients have Kleinfelter syndrome (85,86).
At diagnosis, 85% of patients are symptomatic. Symptoms include
chest pain, hemoptysis, cough, fever, or weight loss. Gynecomastia
can develop as a result of beta-HCG secretion from certain tumor
types (74,87).
In contrast to pure seminomas, NSGCTs carry a poorer progno-
sis; patients with these tumors have a five-year overall survival rate
of 48%, compared to 86% in patients with seminomas (88).
These tumors are large, irregularly shaped, with areas of central
necrosis, hemorrhage, or cyst formation (Fig. 9.10) (89). Measure-
ment of AFP and beta-HCG levels is important in making the
diagnosis. An elevated AFP level is suggestive of an endodermal
sinus tumor or embryonal carcinoma and is sufficient, in the
presence of a mediastinal mass, to establish the diagnosis.

(A) (B)
Figure 9.9 Large malignant teratoma. (A) Coronal reformatted CT image, and (B) resected macroscopic specimen.

(A) (B)

Figure 9.10 Yolk sac tumor of the anterior mediastinum. (A) Axial CT, (B) PET and (C) PET-CT images. The large anterior mediastinal mass shows areas of high
metabolic activity on PET-CT which is characteristic of this aggressive tumor.

104
 mediastinal tumors
Key Points: Germ Cell Tumors (GCTs)
■ Germ cell tumors represent 5% to 15% of malignant mediastinal
tumors
■ Approximately 80% of GCTs are benign teratomas
■ CT and MR imaging are useful for determining resectability
of benign teratomas
■ Primary mediastinal seminomas appear as large homogeneous
soft tissue masses on CT
■ Mediastinal NSGCT is more aggressive than seminoma with
an overall five-year survival rate of 48%
■ On imaging NSGCTs are inhomogeneous masses containing foci
of hemorrhage, necrosis and cyst formations
Thyroid Cancer
A very common cause of a superior mediastinal mass is substernal
extension of an enlarged thyroid gland (Fig. 9.11). In patients
undergoing thyroidectomy, the incidence of mediastinal multi-
nodular goiter is 1% to 15% (90). Most goiters are euthyroid and
are found incidentally during a physical examination. Up to 10%
of substernal goiters contain foci of carcinoma and direct extension
of thyroid cancer does occur (91–93). They are rarely symptomatic
but substernal goiters and more frequently thyroid carcinomas, if
they become large enough, can cause compression of mediastinal
structures resulting in symptoms including stridor, dysphagia,
pain, and superior venal caval syndrome (94).
Radiographically, mediastinal goiters are encapsulated, lobulated,
heterogeneous tumors (4). The key to diagnosing an anterior medi-
astinal mass as a thyroid lesion is to follow the lesion up into the neck
and look for evidence of thyroid lobe involvement (Fig. 9.11).
Because of their high iodine content these masses may demonstrate
higher CT attenuation on unenhanced imaging than normal soft
tissue structures and persistent enhancement above baseline on
contrast-enhanced imaging (95,96). Most commonly, goiters are
bilateral and cancers are unilateral, but this rule is not absolute. Both
benign and malignant thyroid masses, including goiters, thyroiditis,
(A)
Figure 9.11 Retrosternal thyroid causing a mass effect on the trachea. Contrast-enhanced CT images, (A) axial, (B) coronal.
and thyroid neoplasms, may calcify and contain areas of heteroge-
neity due to hemorrhage, fibrosis, or cysts. Goiters tend to be well-
marginated. A lesion with ill-defined margins and nearby lymph
node enlargement suggests the diagnosis of thyroid cancer; invasion
of an adjacent structure, such as the trachea, is diagnostic for a neo-
plasm. The finding of multiple concomitant small lung nodules is
suspicious for metastatic disease from thyroid cancer. Further-
more, thyroid cancer can metastasise to mediastinal lymph nodes.
Anaplastic thyroid cancer has a strong propensity to extend into the
upper mediastinum; this is seen in 26% to 50% of cases (91).
If the goiter contains functional thyroid tissue, then scintigra-
phy with a radioactive isotope of iodine can be diagnostic (4).
Almost all substernal goiters will show uptake of iodine. This is
not true for all thyroid tumors or metastases, which may not have
enough functioning thyroid tissue resulting in false positives. If
scanning with radioactive iodine is scheduled the procedure
should be done prior to administration of iodine for CT studies as
the iodine content of the contrast medium will interfere with the
radioactive tracer uptake. PET or PET-CT is also usually positive
in patients with both new and recurrent thyroid cancer and is
helpful in detecting small foci of tumor.
Key Points: Thyroid Cancer
■ Ten percent of substernal goiters may contain foci of
carcinoma
■ Direct extension of thyroid cancer into the upper mediastinum
is common
■ Thyroid cancer (in particular anaplastic cancer) can metastasise
to mediastinal nodes
■ Radioactive iodine is used to identify functioning thyroid
tissue in the mediastinum, but false negative scans occur
■ Radionuclide scans must be performed before contrast-
enhanced CT studies
■ PET-CT is often positive in the setting of both new and
recurrent thyroid cancer
(B)
105
 primary tumor evaluation and staging
Mediastinal Parathyroid Adenoma
The mediastinum is the most common location in which an
ectopic parathyroid tumor may develop. Overall, 20% of para-
thyroid adenomas develop in the mediastinum, with 80%
occurring in the anterior mediastinum (97). These tumors are
encapsulated, round, and usually <3 cm in size so that they may
not be identified on CT. Thus, MR imaging or nuclear scans
with 99mTc and 201Ti are more effective for the diagnosis of para-
thyroid adenomas (98).
Parathyroid adenomas usually occur immediately lateral to the
thyroid gland. Occasionally, however, they may be seen in ectopic
locations such as within the thymus, the tracheo-esophageal
groove, retro-esophageal region, or posterosuperior mediastinum.
They tend to be small, oval, well-defined soft tissue attenuation
structures that enhance strongly with intravenous contrast mate-
rial and may contain calcifications on CT (99). Sestamibi scan-
ning or ultrasonography of the neck are often the first imaging
modalities used to search for a parathyroid adenoma in a patient
with primary hyperparathyroidism (100). If these studies are
inconclusive, then CT or MR imaging may be performed to look
for an ectopic focus in the mediastinum.
Mediastinal Lymphoma
Lymphoma is one of the most common mediastinal neoplasms. The
two major classifications—Hodgkin’s disease (HD) and non-Hodgkin’s
lymphoma (NHL)—may both affect the mediastinum. Typically, HD
involves the mediastinum, whereas NHL involves the lungs; but with
extensive or disseminated disease, there may be an overlap between
both regions. Primary mediastinal lymphoma is a rare entity com-
prising only 10% of lymphomas in the mediastinum. Lymphoma
usually occurs in the anterior mediastinum and is part of more wide-
spread disease. HD represents approximately 50–70% of mediastinal
lymphomas, while non-Hodgkin’s lymphoma comprises 15–25%
(101,102). The three most common types of mediastinal lymphoma
include nodular sclerosing HD, large B-cell lymphoma, and lympho-
blastic lymphoma (4).
(A)
Figure 9.12 Lymph node mass in the middle mediastinum due to renal cell carcinoma. (A) Lateral chest radiograph demonstrating the presence of a middle mediastinal
mass. (B) Contrast-enhanced CT confirming the presence of the mass.
106
Most patients experience constitutional symptoms (B symp-
toms), including fevers, night sweats, and weight loss. For patients
with mediastinal involvement, cough, dyspnea, chest pain, pleural
effusions, and superior vena cava syndrome may occur (103).
The chest radiograph finding is abnormal in up to 76% of
patients with HD, often showing enlargement of the prevascular
and paratracheal nodes (104–106). A CT examination is usually
sufficient to identify lymphoma; however, in certain circum-
stances, such as after radiation treatment, MR imaging may be
better in distinguishing scars from residual disease (104). Imaging
with positron emission tomography may also be useful in staging
and following disease progression (107). A detailed account of the
lymphomas is presented in chapter 33.
TUMORS OF THE MIDDLE MEDIASTINUM
Middle mediastinal masses are most often benign and include
congenital cysts. The most common malignant masses in this
location are metastases to lymph nodes and lymphoma, but both
lymphoma and metastatic disease may be found in any of the
mediastinal compartments. The vast majority of metastases arise
from intrathoracic primary lung tumors (>90%). Extrathoracic
neoplasms that spread to mediastinal nodes include breast cancer,
renal cell cancer, melanoma, and head and neck tumors (Fig. 9.12)
(2). Primary esophageal cancer and associated nodal disease can
also present as masses in the middle mediastinum (Fig. 9.13).
Metastases
Lymph node size on chest CT is the most common criterion for
the identification of abnormal lymph nodes, with a short-axis
nodal diameter of 10 mm, which is generally considered the upper
limit of normal (108,109). CT may overestimate or underestimate
disease extent within the mediastinum. Imaging with FDG PET
has been shown to be useful in the detection of nodal disease. In a
meta-analysis of nodal staging comparing PET and CT in non-
small cell lung cancer, the mean sensitivity and specificity of PET
(B)
 mediastinal tumors
(A) (B)
Figure 9.13 A metastasis from malignant melanoma within the esophagus. Contrast-enhanced CT images, (A) axial, (B) reformatted sagittal image, (C) coronal
reformatted image.
was 79% and 91% respectively, compared with 60% and 77% for
CT respectively (110).
Similar usefulness of PET has been shown for nodal staging in
patients with breast cancer. Metastatic spread to the mediastinal
lymph nodes commonly occurs in patients with breast cancer
(111). The failure to recognize mediastinal disease may lead to
treatment failure and/or the development of distant metastatic
disease in patients diagnosed with only locoregional disease by
conventional imaging modalities. In a study of 33 patients with
advanced breast cancer who underwent both FDG PET and CT as
part of their diagnostic evaluation as well as confirmation by
biopsy or follow-up imaging, the sensitivity, specificity, and accu-
racy for identification of nodal disease by FDG PET was 85%,
90%, and 88% respectively, compared with 54%, 85%, and 73%
respectively, by prospective interpretation with CT (111).
Integrated PET-CT has been shown to be more accurate than
either PET or CT alone in tumor staging in NSCLC (112,113). In
one recent study comparing PET, CT, and fused PET-CT, the
reported accuracy for detecting metastatic mediastinal lymph nodes
in NSCLC was 63% for CT alone, 89% for PET alone, and 93% for
PET-CT. Sensitivity and specificity for PET-CT was 89% and 94%,
for PET 89% and 89%, and CT 70% and 59% (112). Similar results
have been reported for the use of PET-CT in the staging and restag-
ing of lymphoma. A recent study by Schaefer et al. (114) was per-
formed comparing fused PET-CT with contrast-enhanced CT in
60 patients with HD or NHL. The sensitivity of PET-CT and con-
trast-enhanced CT was 94% and 88%, and the specificity was 100%
and 88% respectively. The promising technology of fused PET-CT
in lung carcinoma, esophageal carcinoma, and lymphoma will lead
to further utilization in other mediastinal diseases.
Esophageal Carcinoma
Esophageal carcinomas most commonly involve the distal esoph-
agus and are of adenocarcinoma histology, usually in the setting
of pre-existing Barrett’s esophagus. These aggressive malignancies
are often associated with a dismal prognosis, with surgery alone
resulting in a survival rate of only 6–40% at 9–24 months (115).
Therefore, accurate staging is essential to guide treatment planning
(C)
and identify patients who may benefit from multimodality
therapy. Traditional non-invasive staging modalities include CT,
endoscopic ultrasonography (EUS), and FDG PET. Endoscopic
ultrasonography is useful for the evaluation of the depth of
primary tumor penetration within the wall and invasion of
periesophageal tissues. Endoscopic ultrasonography has a reported
accuracy for determining T and N staging of 85% and 75%
respectively, and a sensitivity ranging from 85–95% and 70 –80%,
respectively (116). CT has the benefit of evaluating mediastinal
invasion, spread to lymph nodes, and distant metastases. A full
discussion of imaging esophageal cancer is given in chapter 11.
Mesenchymal Tumors
Mesenchymal tumors of the thorax are uncommon and may
originate from the muscle, bone, cartilage, vessel, nerves, fat, and
fibrous tissue. These tumors can occur at any site in the thorax
including the lung, pleura, mediastinum, or chest wall. Mesen-
chymal tumors may also be observed in any mediastinal com-
partment and represent less than 5–10% of all mediastinal tumors
(117). Nevertheless, they are particularly frequent in the middle
mediastinum. These tumors occur with equal frequency in men
and women. They are usually asymptomatic and identified inci-
dentally. Others may cause symptoms by mass effect or local
invasion. Histological types of mediastinal mesenchymal tumors
are shown in Table 9.5 (118).
Mesenchymal soft tissue neoplasms show a wide range of gener-
ally non-specific imaging features. Occasionally, the radiological
pattern of a mesenchymal tumor is characteristic allowing the
radiologist to make a confident diagnosis. The typical CT finding
of a lipoma is a well-defined mass that has homogeneous fat
attenuation (119). The presence of any soft tissue strands should
suggest the possibility of liposarcoma (117). Liposarcomas are not
homogeneously fatty like lipomas, but contain islands of soft tissue
(120). Poorly differentiated liposarcomas may not demonstrate
any visible fatty component on imaging studies (120). The prog-
nosis of these tumors depends on the grade and extent of local
invasion. The most common CT finding of lymphangioma is that
of a smoothly-marginated cystic mass with homogeneous water
107
 primary tumor evaluation and staging
Table 9.5 Histological Types of Mediastinal Mesenchymal
Tumors (118)
Neoplasms of adipose tissue
Lipoma
Liposarcoma
Neoplasms of muscle
Leiomyoma and leiomyosarcoma
Rhabdomyosarcoma
Neoplasms of vascular tissue
Lymphangioma
Hemangioma
Lymphangiomatosis
Hemangiopericytoma
Epithelioid hemangioendothelioma
Neoplasms of fibrous tissue
Fibromatosis
Fibrosarcoma
Malignant fibrous histiocytoma
Fibrous tumor of the pleura
Malignant mesothelioma
Miscellaneous soft tissue tumors
Hamartoma
Chondrosarcoma
density (121–123). Multiple loculations may be seen within the
mass in approximately one-third of patients (122). Hemorrhage
into a lesion may lead to an increase in size and attenuation values
on CT. The findings on MR imaging are variable and non-specific.
Hemangiomas on CT are often heterogeneous in attenuation on
unenhanced images, and fat may occasionally be seen within
them. Heterogeneous enhancement is typical after contrast
medium injection, but is not always present (124). Enhancement
may be dense, multifocal or diffuse, and central or peripheral.
Hemangiopericytomas are inhomogeneous in appearance with
central areas of low attenuation and peripheral rim enhancement
after administration of intravenous contrast medium (125). On
MR imaging they are heterogeneous in signal intensity on T1- and
T2-weighted spin-echo images (125). Although some hemangio-
pericytomas are truly benign, many invade locally at the time of
diagnosis and may recur after surgical excision (118).
Key Points: Malignant Middle Mediastinal Masses
■ The most common malignant masses are metastases to
lymph nodes and lymphoma
■ PET-CT is useful for identifying occult nodal disease in
patients with lung cancer, esophageal cancer, breast cancer,
and lymphoma
■ Mesenchymal tumors are uncommon, representing less than
5–10% of all mediastinal tumors
■ Mesenchymal tumors originate from muscle, cartilage, bone,
vessels, nerves, fat, and fibrous tissue
NON-MALIGNANT MIDDLE MEDIASTINAL MASSES
Mediastinal Cysts
Mediastinal cysts comprise 12% to 20% of mediastinal masses
and are found in the middle compartment of the mediastinum
108
(126–128). Despite a similar incidence in children and adults,
children are more often symptomatic at presentation due to com-
pression on the surrounding structures (129). It is important that
the radiologist reporting cases of suspected malignany is able to
distinguish benign cystic lesions of the mediastinum from other
malignant masses and therefore a brief summary of their imaging
findings is presented below. The most common type of mediasti-
nal cysts are foregut cysts, which are derived from an embryonic
abnormality, with enterogenous cysts (50–70%) and bronchogenic
cysts (7–15%) being the most common subtypes (4).
Enterogenous Cysts
Enterogenous cysts arise from the dorsal foregut and are lined by
squamous or enteric (alimentary) epithelium and may contain
gastric or pancreatic tissue. Esophageal duplication cysts are
located in or are attached to the esophageal wall. Twelve percent
of patients with esophageal duplication cysts have associated
malformations, mostly of the GI tract (130).
Symptoms of enterogenous cysts are similar to those of other
mediastinal cysts. They are often asymptomatic, but if they con-
tain gastric or pancreatic mucosa, there is the added risk of
hemorrhage or rupture of the cyst from mucosal secretions.
Radiographically, it can be difficult to distinguish these from
bronchogenic cysts, although they are more often calcified. The
presence of cartilage suggests the presence of a bronchogenic
cyst (131). Most cysts should be surgically excised, and video-
assisted thoracic surgery is the treatment of choice (132).
Bronchogenic Cysts
Bronchogenic cysts are formed during embryonic development as
an anomalous budding of the laryngotracheal groove (131).
Approximately 40% of bronchogenic cysts are symptomatic
resulting in cough, dyspnea, or chest pain (131).
Radiographically, bronchogenic cysts can be identified on
plain radiographs but are best defined by CT. They are well-
defined round masses with a homogeneous density similar to
water; however, some bronchogenic cysts are mucoid and can
give the impression of being a solid mass (129). Bronchogenic
cysts are non-enhancing, and when there is a direct communi-
cation with the tracheobronchial tree, air-fluid levels may be
seen (133). MR imaging can differentiate the lesion from other
masses.
Tissue is often required to make a definitive diagnosis of a bron-
chogenic cyst. This can be accomplished by tracheobronchial,
endoscopic, or thoracoscopic needle aspiration. Most bronchogenic
cysts are removed surgically or are drained by needle aspiration.
The treatment of asymptomatic cysts is controversial as surgery is
not without risk, yet bronchogenic cysts can grow thus causing
symptoms in due course.
Pericardial Cysts
Pericardial cysts are part of a larger group of mesothelial cysts.
They are benign and form as a result of a persistent parietal recess
during embryogenesis (131). They are estimated to occur in 1 of
100,000 people. Although most are congenital, a few cases of
acquired pericardial cysts do exist. They are often asymptomatic
and are identified in the fourth to fifth decade of life. Rarely, car-
diac compression may occur, causing hemodynamic compromise
 mediastinal tumors
(134). Radiographically, pericardial cysts are well-marginated
spherical or tear drop-shaped masses that characteristically abut
the heart, anterior chest wall, and diaphragm (4). The most com-
mon location of pericardial cysts is at the right cardiophrenic
angle (70%), followed by the left cardiophrenic angle (22%) (135).
On CT these masses appear as unilocular and non-enhancing
lesions. As with most mediastinal cysts, surgical removal is the
treatment of choice, although clinically asymptomatic patients
may be observed without intervention.
Pericardial cysts may mimic thymic cysts occasionally. However,
the former are usually simple in appearance at CT, unlike thymic
cysts which often contain soft tissue components. Moreover, peri-
cardial cysts are generally located more inferiorly in the anterior
mediastinum compared with thymic cysts; approximately 90%
are tucked down between the heart and the hemidiaphragm, usu-
ally on the right side (136). Pericardial cysts may change in shape
on follow-up imaging studies.
Lymphangiomas
Lymphangiomas are rare congenital abnormalities of the lym-
phatic vessels. Typically, they are isolated solitary masses, but
they can be more widespread or associated with chromosomal
abnormalities (137). These lesions are benign in nature and 75%
are found in the cervical region. In 10% of cases, the cysts extend
into the mediastinum and are associated with chylothorax and
hemangiomas (137). Although these tumors are commonly
identified in children before the age of two years, when the mass
is isolated to the mediastinum it is often not identified until it
has become large enough to cause compressive symptoms (138).
Such symptoms include chest pain, cough, and dyspnea. Radio-
graphically, these lesions appear cystic and can be confused with
pericardial cysts, although lymphangiomas are more likely to
have a loculated appearance (138). The use of lymphangio-
graphic contrast media combined with CT can help to differen-
tiate these entities (137). Total resection is optimal; however, in
cases complicated by chylothorax, there is some evidence sug-
gesting that additional radiotherapy may be of some benefit
(139). Lymphangiomatosis seen in young women is typically a
more progressive form of disease in which multiple tumors are
found and invade multiple organ structures, including the lung,
heart, and bone (140).
Key Points: Benign Middle Mediastinal Tumors
■ Mediastinal cysts comprise 10% to 20% of all mediastinal
masses and occur in the middle mediastinum
■ The most common type of mediastinal cyst is foregut cysts of
which the most frequent subtypes are enterogenous cysts and
bronchogenic cysts
■ Other benign cystic lesions in the mediastinum include
pericardial cysts and lymphangiomas
TUMORS OF THE POSTERIOR MEDIASTINUM
Neurogenic Tumors
Neurogenic tumors are derived from tissue of the neural crest,
including cells of the peripheral, autonomic, and paraganglionic
nervous systems. Ninety-five percent of posterior mediastinal
masses arise in the intercostal nerve rami or the sympathetic chain
region (141). They are classified on the basis of cell type and
comprise approximately 12% to 21% of all mediastinal masses,
although 95% occur in the posterior compartment where they
account for 30% of the masses (142). Seventy to eighty percent of
neurogenic tumors are benign, and nearly half are asymptomatic;
however, they can occasionally cause compressive or neurologic
symptoms (141,143,144).
Benign Nerve Sheath Tumors
Nerve sheath tumors are slow growing and comprise 40% to 65%
of neurogenic mediastinal masses. Neurilemomas or schwanno-
mas constitute 75% of this group of masses. These tumors are
firm, encapsulated masses consisting of Schwann cells. Neurofi-
bromas are non-encapsulated, soft and friable, and are associated
with Von Recklinghausen neurofibromatosis (145,146). In gen-
eral these benign lesions are asymptomatic and are discovered
incidentally.
Radiographically, nerve sheath tumors are sharply marginated
spherical masses. Being adjacent to the spine, they can cause ero-
sion and deformity of the ribs and ventral bodies as they increase
in size. Low attenuation on CT may indicate hypocellularity, cystic
change, hemorrhage, or the presence of lipid within myelin (4).
Ten percent of these tumors grow through the intervertebral
foramina and create a dumbbell appearance on radiographs (147).
MR imaging is used to rule out intraspinal extension.
Malignant Tumors of Nerve Sheath Origin
Malignant nerve sheath tumors are spindle cell sarcomas of the
posterior mediastinum, and include malignant neurofibromas,
malignant schwannomas, and neurogenic fibrosarcomas (Fig. 9.14).
They affect men and women equally in the third to fifth decade of
life and are closely associated with neurofibromatosis, with a 5%
risk of sarcomatous degeneration (148). Pain and nerve deficits
are common. Complete surgical resection is the optimal treatment,
but in patients with unresectable tumors, adjuvant chemotherapy
and radiation are options.
Autonomic Ganglionic Tumors
Tumors of the autonomic nervous system arise from neuronal
cells rather than from the nerve sheath. They form a continuum
ranging from benign encapsulated ganglioneuroma to aggressive
malignant non-encapsulated neuroblastoma. Derived from
embryologic origins, these tumors arise in the adrenal glands or in
the sympathetic ganglia. However, ganglioneuromas and gangli-
oneuroblastomas arise mostly in the sympathetic ganglia of the
posterior mediastinum (149). Fifty percent of neuroblastomas
arise in the adrenal glands and up to 30% in the mediastinum
(149,150).
Ganglioneuroma
Ganglioneuromas are benign tumors composed of one or more
mature ganglionic cells. Arising from the nerve ganglion cells,
they are the most benign and differentiated of the autonomic
ganglionic tumors (151). Most patients are asymptomatic and
receive diagnoses in the second or third decade of life (152).
Radiographically, the tumors are oblong and well-marginated,
109
 primary tumor evaluation and staging

(A) (B)
Figure 9.14 Synovial sarcoma. Contrast-enhanced CT images, (A) axial, (B) coronal, demonstrating the large complex mass arising in the posterior mediastinum.

occurring along the anterolateral aspect of the spine and spanning

three to five vertebrae (152). CT is not particularly helpful as the
mass can be homogeneous or heterogeneous. Complete surgical
resection is ideal.
Ganglioneuroblastoma
Ganglioneuroblastomas have histological features of both ganglio-
neuromas and neuroblastomas. They are the least common type of
neurogenic tumor. Prognosis depends on histological appearance
(4). Both sexes are equally affected in the first decade of life (153).
Symptoms may arise due to large tumor size, intraspinal extension,
and metastasis. Staging is similar to that for neuroblastoma, as
described in the following section.
Key Points: Posterior Mediastinal Tumors
■ Seventy to eighty percent of neural tumors are benign and
nearly half of them are asymptomatic
■ Malignant tumors of nerve sheath origin include malignant
neurofibromas, malignant schwannomas, and neurogenic
fibrosarcomas
■ Neuroblastoma arises in the sympathetic ganglia in the
adrenal glands (50%) or mediastinum (30%)
■ Ganglioneuroblastoma are uncommon tumors and arise
almost entirely in the posterior mediastinum

Neuroblastoma Summary
Neuroblastoma is a disease of young children, with approxi-
■ Symptoms related to a mediastinal mass are more commonly
mately 90% occurring in patients under five years of age
seen with large malignant masses than benign disease
(150,154). Neuroblastomas are highly aggressive and readily
■ Clear depiction by imaging of the location and composition of
metastasizing tumors that are composed of small round cells
such masses is critical to narrowing the differential diagnosis
arranged in sheets or pseudorosettes (155). They are non-
■ In a patient with a known primary tumor, an FDG PET
encapsulated lesions, often exhibiting hemorrhage, necrosis, or
positive mediastinal mass is more likely to be metastatic than
cystic degeneration. Symptoms include pain, neurologic defi-
due to benign disease
cits, Horner syndrome, respiratory distress, and ataxia (154,155).
■ MR imaging provides increased anatomical detail compared
Neuroblastoma has the highest propensity of any tumor in its
with CT in the thoracic inlet, subcarinal and aortopulmo-
class to produce vasoactive substances that can cause hyperten-
nary window areas, at the thoraco-abdominal level, and in
sion, flushing, and diarrhea (149). Grossly, these tumors appear
the inferior aspects of the mediastinum at the level of the
as an elongated paraspinous mass, sometimes impinging on
diaphragm
adjacent structures and causing skeletal damage (156,157). On
■ Fifteen to seventeen percent of thymomas are invasive. These
CT, 80% of these tumors have calcification (157). As with all
tumors spread across the diaphragm in 32% of cases
neurogenic tumors, MR imaging is useful to determine the
■ Positron emission tomography is rapidly evolving as an impor-
extent of intraspinal involvement (158). Radionuclide imaging
tant technique for assessing mediastinal lymph node metastases
with I-metaiodobenzylguanidine can also be used to detect primary
in patients with lung, colorectal, and breast cancer and also in
and metastatic disease (159). A detailed account of neuroblastoma
lymphoma and malignant melanoma
is presented in chapter 38.

110
 mediastinal tumors
■ Thymolipoma is a large, predominately fatty benign neoplasm
occurring in young adults
■ Germ cell tumors represent 5% to 15% of malignant medi-
astinal tumors and approximately 80% of GCTs are benign
teratomas
■ On imaging NSGCTs are inhomogeneous masses containing
foci of hemorrhage, necrosis, and cyst formations
■ PET-CT is often positive in the setting of both new and
recurrent thyroid cancer
■ Mesenchymal tumors originate from muscle, cartilage, bone,
vessels, nerves, fat, and fibrous tissue, and represent 5% to
10% of all mediastinal masses
■ Seventy to eighty percent of neural tumors are benign and
nearly half of them are asymptomatic
REFERENCES
1. Fraser RS, Müller NL, Colman N, Pare PD. Diagnosis of
Diseases of the Chest (4th edn), Philadelphia: Saunders,
1999.
2. Tecce PM Fishman EK Kuhlman JE. CT evaluation of the
anterior mediastinum. Spectrum of disease. Radiographics
1994; 14: 973–90.
3. Hoffman OA, Gillespie DJ, Aughenbaugh GL, Brown LR.
Primary mediastinal neoplasms (other than thymoma).
Mayo Clinic Proc 1993; 68: 880–91.
4. Strollo DC, Rosado-de-Christenson ML, Jett JR, et al.
Primary mediastinal tumors. Part 1. Tumors of the anterior
mediastinum. Chest 1997; 112: 511.
5. Davis RD Jr, Newland Oldham H Jr, Sabiston DC Jr. Primary
cysts and neoplasms of the mediastinum: recent changes in
clinical presentation, methods of diagnosis, management
and results. Ann Thorac Surg 1987; 44: 229–37.
6. Kim JH, Goo JM, Lee HJ, et al. Cystic tumors in the anterior
mediastinum. Radiologic-pathological correlation. J Com-
put Assist Tomogr 2003; 27: 714–23.
7. McAdams HP, Rosado-de-Christenson M, Fishback NF,
Templeton PA. Castleman disease of the thorax: radiologic
features with clinical and histopathologic correlation.
Radiology 1998; 209: 221–8.
8. Adler OB, Rosenberger A, Peleg H. Fineneedle aspiration
biopsy of mediastinal masses: evaluation of 136 experiences.
AJR Am J Roentgenol 1983; 140: 893–6.
9. Belfiore G, Camera L, Moggio G, et al. Middle mediastinal
lesions: preliminary experience with CT-guided fine-needle
aspiration biopsy with suprasternal approach. Radiology
1997; 202: 870–3.
10. Bressler EL, Kirkham JA. Mediastinal masses: alternative
approaches to CT-guided needle biopsy. Radiology 1994;
191: 391–6.
11. De Gregorio Ariza MA, Alfonso Aguiran ER, Villavieja Atance
JL, et al. Transthoracic aspiration biopsy of pulmonary and
mediastinal lesions. Eur J Radiol 1991; 12: 98–103.
12. Gupta S, Gulati M, Rajwanshi A, Gupta D, Suri S. Sono-
graphically guided fine-needle aspiration biopsy of superior
mediastinal lesions by the suprasternal route. AJR Am J
Roentgenol 1998; 171: 1303–6.
13. Herman SJ, Holub RV, Weisbrod GL, Chamberlain DW.
Anterior mediastinal masses: utility of transthoracic needle
biopsy. Radiology 1991; 180: 167–70.
14. Rubens DJ, Strang JG, Fultz PJ, Gottleib RH. Sonographic
guidance of mediastinal biopsy: an effective alternative to
CTguidance. AJR Am J Roentgenol 1997; 169: 1605–10.
15. Saito T, Kobayashi H, Sugama Y, et al. Ultrasonically guided
needle biopsy in the diagnosis of mediastinal masses. Ann
Rev Respir Dis 1988; 138: 679–84.
16. Weisbrod GL. Percutaneous fine-needle aspiration biopsy of
the mediastinum. Clin Chest Med 1987; 8: 27–41.
17. Wernecke K, Vassallo P, Peters PE, von Bassewitz DB. Medi-
astinal tumors: biopsy under US guidance. Radiology 1989;
172: 473–6.
18. Westcott JL. Percutaneous transthoracic needle biopsy.
Radiology 1988; 169: 593–601.
19. Yang PC, Chang DB, Lee YC, et al. Mediastinal malignancy:
ultrasound guided biopsy through the supraclavicular
approach Thorax 1992; 47: 377–80.
20. Wychulis AR, Payne WS, Clagett OT, et al. Surgical treatment
of mediastinal tumors. J Thorac Cardiovasc Surg 1972; 62:
379–91.
21. Rosai J, Levine GD. Tumors of the thymus. In: Firminger HI,
ed. Atlas of Tumor Pathology. Washington, DC: Armed
Forces Institute of Pathology, 1976: 34–212.
22. Engels EA, Pfeiffer RM. Malignant thymoma in the United
States: demographic patterns in incidence and associations
with subsequent malignancies. Int J Cancer 2003; 105:
546–51.
23. Mullen B, Richardson JD. Primary anterior mediastinal
tumors in children and adults. Ann Thorac Surg 1986; 42:
338–45.
24. Gerein AN, Srivastava SP, Burgess J. Thymoma: a ten-year
review. Am J Surg 1978; 136: 49–53.
25. Strollo DC, Rosado-de-Christenson ML. Tumors of the
thymus. J Thorac Imaging 1999; 14: 152–71.
26. Cohen DJ, Ronnigan LD, Graeber GM, et al. Management of
patients with malignant thymoma. J Thorac Cardiovasc Surg
1984; 87: 301–7.
27. Laurent E, Latrabe V, Lecesne R, et al. Mediastinal masses:
diagnostic approach. Eur Radiol 1998; 8: 1148–59.
28. Lewis JE, Wick MR, Scheithauer BW, et al. Thymoma: a
clinicopathologic review. Cancer 1987; 60: 2727–43.
29. Verstandig AG, Epstein DM, Miller WT, et al. Thymoma
report of 71 cases and a review. Crit Rev Diagn Imaging 1992;
33: 201–30.
30. Osserman KE, Genkins G. Studies in myasthenia gravis:
review of a 20 year-experience I nover 1200 patients. Mt Sinai
J Med 1971; 38: 497–537.
31. Marx A, Muller-Hermelink HK, Strobel P. The role of
thymomas in the development of myasthenia gravis. Ann
N Y Acad Sci 2003; 998: 223–6.
32. Souadjian JV, Enriquez P, Silverstein MN, et al. The spectrum
of diseases associated with thymoma. Arch Intern Med 1974;
134: 374–9.
33. Zerhouni EA, Scott WW, Baker RR, et al. Invasive thymomas:
diagnosis and evaluation by CT. J Comput Assist Tomogr
1982; 6: 92–100.
111
 primary tumor evaluation and staging
34. Kelleher P, Misbah SA. What is Good’s syndrome? Immuno-
logical abnormalities in patients with thymoma. J Clin Pathol
2003; 56: 12–16.
35. Ellis K Austin JHM, Jaretzki A. radiographic detection of thy-
moma in patient with myasthenia gravis. Am J Roentgenol
1988; 151: 873–81.
36. Okumura M, Ohta M, Tateyama H, et al. The world health
organization histologic classification system reflects the
oncologic behavior of thymoma: a clinical study of
273 patients. Cancer 2002; 94: 624–32.
37. Nakagawa K, Asamura H, Matsuno Y, et al. Thymoma: a clini-
copathologic study based on the new world health organization
classification. J Thorac Cardiovasc Surg 2003; 126: 1134–40.
38. Lardinois D, Rechsteiner R, Lang RH, et al. Prognostic
relevance of Masaoka and Muller-Hermelink classification
in patients with thymic tumors. Ann Thorac Surg 2000; 69:
1550–5.
39. Rosai J. In: Histological typing of tumours of the thymus.
World Health Organisation International Histological
Classification of Tumours, 2nd edn. Berlin: Springer,
1999.
40. Baron R, Lee j, Sagel S, et al. Computed tomography of the
normal thymus. Radiology 1982; 142: 127–34.
41. Lattes R. Thymoma and other tumors of the thymus: an
analysis of 107 cases. Cancer 1962; 15: 1224–60.
42. Rosado de Christenson ML, Galobardes J, Moran CA.
Thymoma: radiologic-pathologic correlation. Radiographics
1992; 12: 151–68.
43. Yokoi K, Miyazawa N, Mori K, et al. Invasive thymoma with
intracaval growth into right atrium. Ann Thorac Surg 1992;
53: 507–9.
44. Masaoka A, Monden Y, Nakahara K, et al. Follow-up study of
thymomas with special reference to their clinical stages. Cancer
1981; 48: 2485–92.
45. Hernandez-Ilizaliturri FJ, Tan D, Cipolla D, et al. Multimo-
dality therapy for thymic carcinoma (TCA): results of a
30-year single-institution experience. Am J Clin Oncol 2004;
27: 68–72.
46. Truong LD, Mody DR, Cagle PT, et al. Thymic carcinoma: a
clinicopathologic study of 13 cases. Am J Surg Pathol 1990;
14: 151–66.
47. Suster S, Rosai J. Thymic carcinoma: a clinicopathologic
study of 60 cases. Cancer 1991; 67: 1025–32.
48. Sadohara J, Fujimoto K, Muller NL, et al. Thymic epithelial
tumors: comparison of CT and MR imaging findings of low-
risk thymomas, high-risk thymomas, and thymic carcinomas.
Eur J Radiol 2006; 60: 70–9.
49. Sung YM, Lee KS, Kim B-T, et al. F-FDG PET/CT of thymic
epithelial tumors: usefulness for distinguishing and staging
tumor subgroups. J Nucl Med 2006; 47: 1628–34.
50. Wang WQ, Ye L, Bi YF, et al. Six cases of ectopic ACTH
syndrome causedby thymic carcinoid. J Endocrinol Invest
2006; 29: 293–7.
51. Hubalewska-Dydejczyk A, Fross-Baron K, Mikolajczak R,
et al. 99mTc-EDDA/HYNIC-octreotate scintigraphy, an effi-
cient method for the detection and staging of carcinoid
tumours: results of 3 years experience. Eur J Nucl Med Mol
Imaging 2006; 33: 1123–33.
112
52. Moran CA, Suster S. Neuroendocrine carcinomas (carcinoid
tumor) of the thymus. A clinicopathologic analysis of 80
cases. Am J Clin Pathol 2000; 114: 100–10.
53. Brown LR, Aughenbaugh GL, Wick MR, Baker BA, Salassa
RM. Roentgenologic diagnosis of primary corticotrophin-
producing carcinoid tumors of the mediastinum. Radiology
1982; 142; 143–8.
54. Leonidas JC, Berdon WE, Valderrama E, et al. Human immu-
nodeficiency virus infection and multilocular thymic cysts.
Radiology 1996; 198: 377–9.
55. Choi YW, McAdams HP, Jeon SC, et al. Idiopathic multilocu-
lar thymic cyst: CT features with clinical and histopathologic
correlation. Am J Roentgenol 2001; 177: 881–5.
56. Indeglia RA, Shea MA, Grage TB. Congenital cysts of the
thymus gland. Arch Surg 1967; 94: 149–52.
57. Suster S, Rosai J. Multilocular thymic cyst: an acquired reactive
process. Am J Surg Pathol 1991; 15: 388–98.
58. Heron CW, Husband JE, Williams MP. Hodgkin disease: CT
of the thymus. Radiology 1988; 167: 647–51.
59. Kissin CM, Husband JE, Nicholas D, Eversman W. Benign
thymic enlargement in adults after chemotherapy: CT
demonstration. Radiology 1987; 163: 67–70.
60. Yarom N, Zissin R, Apter S, et al. Rebound thymic enlarge-
ment on CT in adults. International Jounral of Clinical
Practice 2007; 61; 4: 562–8.
61. Mishra SK, Melinkeri SR, Dabadghao S. Benign thymic
hyperplasia after chemotherapy for acute myeloid leukemia.
Eur J Haematol 2001; 67: 252–4.
62. Hendrick P, Dohring W. Thymic atrophy and rebound
enlargement following chemotherapy for testicular cancer.
Acta Radiol 1989; 30: 263–7
63. Choyke PL, Zeman RK, Gootenberg JE, et al. Thymic atrophy
and regrowth in response to chemotherapy: CT evaluation.
AJR Am J Roentgenol 1987; 149: 269–72.
64. Hara M, McAdams HP, Vredenburgh JJ, Herndon JE, Patz EF
Jr. Thymic hyperplasia after high-dose chemotherapy and
autologous stem cell transplantation: incidence and signifi-
cance in patients with breast cancer. AJR Am J Roentgenol
1999; 173: 1341–4.
65. Jung KJ, Lee KS, Han J, et al. Malignant thymic epithelial
tumors: CT – pathologic correlation. AJR Am J Roentgenol
2001; 176: 433–9.
66. Mendelson DS. Imaging of the thymus. Chest Surg Clin N
Am 2001; 11: 269–93, x; Siegel MJ, Glazer HS, Wiener JI,
Molina PL. Normal and abnormal thymus in childhood: MR
imaging. Radiology 1989; 172: 367–71.
67. Camera L, Brunetti A, Romano M, et al. Morphological
imaging of thymic disorders. Ann Med 1999; 31: 57–62.
68. Takahashi K, Inaoka T, Murakami N, et al. Characterization
of the normal and hyperplastic thymus on chemical-shift
MR imaging. AJR Am J Roentgenol 2003; 180: 1265–9.
69. Brink I, Reinhardt MJ, Hoegerle S, et al. Increased metabolic
activity in the thymus gland studied with 18-FDG PET: age
dependency and frequency after chemotherapy. J Nucl Med
2001; 42: 591–5.
70. Nakahara T, Fujii H, Ide M, et al. FDG uptake in the morpho-
logically normal thymus: comparison of FDG positron emission
tomography and CT. Br J Radiol 2001; 74: 821–4.
 mediastinal tumors
71. Parker D, Holford CP, Begent RH. Effective treatment
for malignant mediastinal teratoma. Thorax 1983; 38:
897–902.
72. Bohle A, Studor UK, Sonntag RW, et al. Primary or secondary
extragonadal germ cell tumor? J Urol 1986; 135: 939–43.
73. Recondo J, Libshitz HI. Mediastinal extragonadal germ cell
tumors. Urology 1978; 11: 369–75.
74. Javadpour N. Significance of elevated serum alpha fetoprotein
(AFP) in seminoma. Cancer 1980; 45: 2166–8.
75. Nichols CR. Mediastinal germ cell tumors: clinical features
and biologic correlates. Chest 1991; 99: 472–9.
76. Crussi-Gonzalez F. Extragonadal teratomas. In: Hartmann
WH, ed. Atlas of Tumor Pathology. Washington, DC: Armed
Forces Institute of Pathology, 1982; 77–94.
77. Donadio AC, Motzer RJ, Bajorin DF, et al. Chemotherapy for
teratoma with malignant transformation. J Clin Oncol 2003;
21: 4285–91.
78. Adebonojo SA, Nicola ML. Teratoid tumors of the mediastinum.
Am Surg 1976; 42: 361–5.
79. Thompson DP, Moore TC. Acute thoracic distress in child-
hood due to spontaneous rupture of large mediastinal tera-
toma. J Pediatr Surg 1969; 4: 416–23.
80. Lewis BD, Hurt RD, Payne WS, et al. Benign teratoma of the
mediastinum. J Thorac Cardiovasc Surg 1983; 86: 727–31.
81. Sasaka K, Kurihara Y, Nakajima Y, et al. Spontaneous rupture:
a complication of benign mature teratomas of the mediasti-
num. Am J Roentgenol 1998; 170: 323–8.
82. Polansky SM, Barwick KW, Revie CE. Primary mediastinal
seminoma. AJR Am J Roentgenol 1979; 132: 17–21.
83. Hainsworth J. Diagnosis, staging, and clinical characteristic-
sof the patient with mediastinal germ cell carcinoma. Chest
Surg Clin N Am 2002; 12: 665–72.
84. Hosono M, Machida K, Honda N, et al. Intense Ga-67 accu-
mulation in pure primary mediastinal seminomas. Clin Nucl
Med 2003; 28: 25–8.
85. Dexeus FH, Logothetis CJ, Chong C, et al. Genetic abnormalities
in men with germ cell tumors. J Urol 1988; 140: 80–4.
86. Nichols CR, Hoffman R, Einhorn LH, et al. Hematologic
malignancies associated with primary mediastinal germ cell
tumors. Ann Intern Med 1985; 102: 603–9.
87. Hori K, Uematsu K, Yasoshima H, et al. Testicular seminoma
with human chorionic gonadotropin production. Pathol Int
1997; 47: 592–9.
88. International germ cell consensus classification. A prognostic
factor-based staging system for metastatic germ cell cancers:
international germ cell cancer collaborative group. J Clin
Oncol 1997; 15: 594–603.
89. Lee KS, Im JG, Han CH, et al. Malignant primary germ cell
tumors of the mediastinum: CT features. AJR Am J Roentgenol
1989; 153: 947–51.
90. Kathic M, Wang C, Grillo H. Substernal goiter. Ann Thorac
Surg 1985; 39: 391–9.
91. Takashima S, Morimoto S, Ikezo G, Beute G. Computed
tomographic evaluation of intrathoracic thyroid malignancy.
Am J Neuroradiol 1990: 11: 361–7
92. Cakir M, Arici C, Alakus H, et al. Incidental thyroid carci-
noma in thyrotoxic patients treated by surgery. Horm Res
2007; 67: 96–9.
93. Miccoli P, Minuto MN, Galleri D, et al. Incidental thyroid
carcinoma in a large series of consecutive patients operated
on for benign thyroid disease. ANZ J Surg 2006; 76: 123–6.
94. Katlic MR, Wang CA, Grillo HC. Substernal goiter. Ann
Thorac Surg 1985; 39: 391–9.
95. Glazer GM, Axel L, Moss AA. CT diagnosis of mediastinal
thyroid. AJR Am J Roentengol 1982; 138: 495–8.
96. Bashist B, Ellis K, Gold RP. Computed tomography of
intrathoracic goiters. AJR Am J Roentgenol 1983; 40:
455–60.
97. Clark O. Mediastinal parathyroid tumors. Arch Surg 1988;
123: 1096–100.
98. Oates E. Improved parathyroid scintigraphy with Tc 99m
MIBI, a superior radio tracer. Appl Radiol 1994; 23: 37–40.
99. Rodger SE, Hunter GJ, Hamberg LM, et al. Improved pre-
operative planning for directed parathyroidectomy with
4-dimensional computed tomography. Surgery 2006; 140:
932–40, discussion 940–1.
100. Lo C-Y, Lang BH, Chan WF, Kung AWC, Lam KSL. A pro-
spective evaluation of preoperative localization by techne-
tium-99m sestamibi scintigraphy and ultrasonography
in primary hyperparathyroidism. Am J Surg 2007; 193:
155–9.
101. Strickler JG, Kurtin PJ. Mediastinal lymphoma. Semin Diagn
Pathol 1991; 8: 2–13.
102. Lichtenstein AK, Levine A, Taylor CR, et al. Primary mediastinal
lymphoma in adults. Am J Med 1980; 68: 509– 14.
103. Vaeth JM, Moskowitz SA, Green JP. Mediastinal Hodgkin’s
disease. AJR Am J Roentgenol 1976; 126: 123–6.
104. Costello P, Jochelson M. Lymphoma of the mediastinum and
lung. In: Taveras JM, Ferrucci JT, eds. Radiology: Diagnosis,
Imaging, Intervention (vol 1). Philadelphia, PA: Lippincott-
Raven 1996: 1–13.
105. Keller AR, Kaplan HS, Lukes RJ, et al. Correlation of histopa-
thology with other prognostic indicators in Hodgkin’s disease.
Cancer 1968; 22: 487–99.
106. Castellino RA, Blank N, Hoppe RT, et al. Hodgkin disease:
contributions of chest CT in the initial staging evaluation.
Radiology 1986; 160: 603–5.
107. Schiepers C. Filmont JE. Czernin J. PET for staging of
Hodgkin’s disease and non-Hodgkin’s lymphoma. Eur J Nucl
Med Mol Imaging 2003; 30(suppl): S82–S88.
108. Glazer GM Gross BH, Quint LE, et al. Normal mediastinal
lymph nodes: number and size according to American
Thoracic Society mapping. Am J Roentgenol 1985; 144: 261–5.
109. Glazer GM, Orringer MB, Chenevert TL, et al. Mediastinal
lymph nodes: relaxation time/pathologic correlation and
implications in staging of lung cancer with MR imaging.
Radiology 1988; 168: 429–31; comment in: Radiology 1990;
174: 284–5.
110. Dwamena BA, Sonnad SS, Angobaldo JO, Wahl RL. Metastases
from non-small cell lung cancer: mediastinal staging in the
1990s––Meta-analytic comparison of PET and CT. Radiology
1999; 213: 530–6.
111. Eubank WB, Mankoff DA, Takasugi J, et al. 18fluorodeoxyg-
lucose positron emission tomography to detect mediastinal
or internal mammary metastases in breast cancer. J Clin
Oncol 2001; 19: 3516–23.
113
 primary tumor evaluation and staging
112. Antoch G, Stattaus J, Nemat AT, et al. Non-small cell lung
cancer: dual-modality PET/CT in preoperative staging.
Radiology 2003; 229: 526–33.
113. Lardinois D, Weder W, Hany TF, et al. Staging of non-small-cell
lung cancer with integrated positron-emission tomography and
computed tomography. N Engl J Med 2003; 348: 2500–7;
comments in: N Engl J Med 2003; 348: 2487–8; N Engl J Med
2003; 349: 1188–90; author reply 1188–90; N Engl J Med
2004; 350: 86–87; author reply 86–87.
114. Schaefer NG, Hany TF, Taverna C, et al. Non-Hodgkin
lymphoma and Hodgkin disease: coregistered FDG PET and
CT at staging and restaging—Do we need contrast-enhanced
CT? Radiology 2004; 232: 823–9.
115. Swisher SG, Maish M, Erasmus JJ, et al. Utility of PET, CT,
and EUS to identify pathologic responders in esophageal
cancer. Ann Thorac Surg 2004; 78: 1152–60, discussion
1152–60.
116. Dehdashti F, Siegel BA. Neoplasms of the esophagus and
stomach. Semin Nucl Med 2004; 34: 198–208.
117. Kuhlman JE, Bouchardy L, Fishman EK, et al. CT and MR
imaging evaluation of chest wall disorders. RadioGraphics
1994; 14: 571–95.
118. Fraser RS, Pare´ JAP, Fraser RG, et al. The normal chest. In:
Fraser RS, Pare JAP, Fraser RG, et al, eds. Synopsis of Diseases
of the Chest, 2nd edn. Philadelphia, PA: WB Saunders, 1994:
1–116
119. Baris YI, Kalyoncu AF, Aydiner A, et al. Intrathoracic lipomas
demonstrated by computed tomography. Respiration 1990;
57: 77–80.
120. Stark P, Eber CD, Jacobson F. Primary intrathoracic malignant
mesenchymal tumours: pictorial essay. J Thorac Imaging
1994; 9: 148–55.
121. Pilla TJ, Wolverson MK, Sundaram M, et al. CT evaluation of
cystic lymphangiomas of the mediastinum. Radiology 1982;
144: 841–42.
122. Shaffer K, Rosado-de-Christenson ML, Patz EF, Jr, et al. Tho-
racic lymphangioma in adults: CT and MR imaging features.
AJR Am J Roentgenol 1994; 162: 283–9.
123. Miyake H, Shiga M, Takaki H, et al. Mediastinal lymphangiomas
in adults: CT findings. J Thorac Imaging 1996; 11: 83–5.
124. McAdams HP, Rosado-de-Christenson ML, Moran CA.
Mediastinal hemangioma: radiographic and CT features in
14 patients. Radiology 1994; 193 : 399–402.
125. Halle M, Blum U, Dinkel E, Brugger W. CT and MR features
of primary pulmonary hemangiopericytomas. J Comput
Assist Tomogr 1993; 17: 51–5.
126. Pun YW, Moreno BR, Prieto VJ, Fernández FL. Multicenter
experience of video-assisted thoracic surgery to treat
mediastinal cysts and tumors. Archivos de Bronconeumologia
2002; 38: 410–14.
127. Wychulis AR, Payne WS, Clagett OT, et al. Surgical treatment
of mediastinal tumors: a 40 year experience. J Thorac
Cardiovasc Surg 1971; 62: 379–92.
128. Whooley BP, Urschel JD, Antkowiak JG, et al. Primary tumors
of the mediastinum. J Surg Oncol 1999; 70: 95–9.
129. Ahrens B, Wit J, Schmitt M, et al. Symptomatic bronchogenic
cyst in a six month old infant: case report and review of the
literature. J Thorac Cardiovasc Surg 2001; 122: 1021–3.
114
130. O’Neill JA. Foregut duplications. In: Fallis JC, Filler RM,
Lemoine G, eds. Current Topics in General Thoracic Surgery:
An International Series. New York, NY: Elsevier, 1991: 121–3.
131. Takeda S, Miyoshi S, Minami M, et al. Clinical spectrum of
mediastinal cysts. Chest 2003; 124: 125–32.
132. Cioffi U, Bonavina L, De Simone M. Presentation and surgical
management of bronchogenic and esophageal duplication
cysts in adults. Chest 1998; 113: 1492–6.
133. Crapo JD, Glassroth J, Karlinsky J, et al. Obstructive lung disease.
In: Baum’s Textbook of Pulmonary Diseases. Philadelphia,
PA: Lippincott Williams & Wilkins, 2004: 883–912.
134. Kornstein MJ, De Blois. Pathology of the Thymus and
Mediastinum, 1st edn. Philadelphia, PA: WB Saunders, 1995.
135. Feigin D, Fenoglio JJ, McAllister HA, et al. Pericardial cysts: a
radiologic-pathologic correlation and review. Radiology
1977; 125: 15–20.
136. Wang ZJ, Reddy GP, Gotway MB, et al. CT and MR imaging
of pericardial disase. Radiographics 2003; 23: S167–80.
137. Shahriari A, Odell JA. Cervical and thoracic components of
multiorgan lymphangiomatosis managed surgically. Ann
Thorac Surg 2001; 71: 694–6.
138. Nakazato Y, Ohno Y, Nakata Y, et al. Cystic lymphangioma of
the mediastinum. Am Heart J 1995; 129: 406–9.
139. Johnson DW, Klazynski PT, Gordon WH, et al. Mediastinal
lymphangioma and chylothorax: the role of radiotherapy.
Ann Thorac Surg 1986; 41: 325–38.
140. Rostom AY. Treatment of thoracic lymphangiomatosis. Arch
Dis Child 2000; 83: 138–9.
141. Kumar A, Kumar S, Aggarwal S, et al. Thoracoscopy: the
preferred approach for the resection of selected posterior
mediastinal tumors. J Laparoendosc Adv Surg Tech A 2002;
12: 345–53.
142. Reeder LB. Neurogenic tumors of the mediastinum. Semin
Thorac Cardiovasc Surg 2000; 12: 261–7.
143. Shapiro B, Orringer MB, Gross MD. Mediastinal paragan-
gliomas and pheochromocytomas. In: Shields TW, LoCicero
J III, Ponn RB, eds. General Thoracic Surgery (vol 2), 5th
edn. Philadelphia, PA: Williams & Wilkins, 2000; 2333–55.
144. Saenz NC. Posterior mediastinal neurogenic tumors in
infants and children. Semin Pediatr Surg 1999; 8: 78–84.
145. Wain JC. Neurogenic tumors of the mediastinum. Chest Surg
Clin N Am 1992; 2: 121–36.
146. Shields TW, Reynolds M. Neurogenic tumors of the thorax.
Surg Clin North Am 1988; 68: 645–68.
147. Aughenbaugh GL. Thoracic manifestations of neurocutaneous
diseases. Radiol Clin N Am 1984; 22: 741–56.
148. Ducatman BS, Scheithauer BW, Piepgras DG, et al. Malignant
peripheral nerve sheath tumors: a clinicopathologic study of
120 cases. Cancer 1986; 57: 2006–21.
149. Gale AW, Jelihovsy T, Grant AF, et al. Neurogenic tumors of
the mediastinum. Ann Thorac Surg 1974; 17: 434–43.
150. Davis S, Rogers MAM, Pendergrass TW. The incidence and
epidemiologic characteristics of neuroblastoma in the United
States. Am J Epidemiol 1987; 126: 1063–74.
151. Forsythe A, Volpe J, Muller R. Posterior mediastinal gangli-
oneuroma. Radiographics 2004; 24: 594–7.
152. Benjamin SP, McCormack LJ, Effler DB, et al. Primary tumors
of the mediastinum. Chest 1972; 62: 297–303.
 mediastinal tumors
153. Adams A, Hochholzer L. Ganglioneuroblastoma of the
posterior mediastinum: a clinicopathologic review of 80
cases. Cancer 1981; 47: 373–81.
154. Grosfeld JL, Baehner RL. Neuroblastoma: an analysis of 160
cases. World J Surg 1980; 4: 29–38.
155. Page DL, DeLellis RA, Hough AJ. Atlas of tumor pathology:
tumors of the adrenal. Washington, DC: Armed Forces Institute
of Pathology, 1986; 219–60.
156. Bar-Ziv J, Nogrady MB. Mediastinal neuroblastoma and
ganglioneuroma: the differentiation between primary and
secondary involvement on the chest roentgenogram. AJR
Am J Roentgenol 1975; 125: 380–90.
157. Stark DD, Moss AA, Brasch RC, et al. Neuroblastoma:
diagnostic imaging and staging. Radiology 1983; 148:
101–5.
158. Wang YM, Li YM, Sheih CP, et al. Magnetic resonance
imaging of neuroblastoma, ganglioneuroblastoma, and
ganglioneuroma. Acta Pediatr Surg 1995; 36: 420–4.
159. Hoefnagel CA. Radionuclide therapy in children with
neuroblastoma. Hell J Nucl Med 2002; 2: 107–10.
115
 10 Pleural Tumors
Sujal R Desai and David M Hansell
INTRODUCTION
Malignant pleural mesothelioma (MPM) is a relentlessly aggressive
thoracic tumor whose history is very closely (although not exclu-
sively) linked to the industrial use of asbestos. Malignant pleural
mesothelioma accounts for less than 1% of all intrathoracic malig-
nancies. However, it must be remembered that because of the long
latency following exposure, the incidence of MPM rises unabated;
indeed, it has been projected that, in the United Kingdom, the
incidence of MPM is unlikely to peak before the year 2020 (1,2).
This is compounded by the fact that advances in treatment have, at
best, been modest. Thus, the outlook of patients with MPM remains
bleak with a median survival of between 6 and 18 months (3).
Radiology has a role in the management of patients with MPM
and the following chapter reviews the epidemiology, histopathology,
imaging (including chest radiography and computed tomography,
but also magnetic resonance imaging and 18fluorodeoxyglucose-
positron emission tomography), and staging of MPM.
MALIGNANT PLEURAL MESOTHELIOMA
The Link with Asbestos
The causal relationship with asbestos exposure was established in the
1960s in a landmark study which convincingly identified
a definite or probable exposure to crocidolite (the important sub-
type of asbestos at the time) in 32 out of 33 of the patients with
MPM (4). Although other aetiological factors such as the Simian
virus (SV40) and various genetic predispositions (e.g., the Wilm’s
tumor gene, p53 and p16) have subsequently been proposed, the
strongest link by far is that with asbestos (3,5). MPM occurs more
commonly in men (with the peak incidence occurring in the sixth
and seventh decades) and there is a characteristically long latent
interval, generally no less than 20–40 years following first exposure.
The physical characteristics of asbestos fibers are of relevance in
the pathophysiology of MPM. Two broad groups, comprised of six
different asbestos fiber types, are recognized: the larger group is com-
prised of the amphiboles and includes amosite, crocidolite,
anthophylite, actinolite, and tremolite. The smaller group are the ser-
pentine fibers of which chrysolite (also known as “white” asbestos) is
perhaps the most important example. The relative hazards of the
various fiber types have been researched and, overall, it would appear
that the amphibolic fibers (crocidolite and amosite) are more strongly
linked with the development of MPM (6–8). The relative magnitude
and pattern of exposure before MPM develops has also been the sub-
ject of debate, but there are animal data which suggest that the
increased predisposition is dose-dependent and that MPM does not
develop below a threshold level of exposure (9). Furthermore, the
earlier notion that background (environmental) levels of asbestos in
non-occupationally exposed subjects (9), do not increase the risk of
developing MPM, has now been convincingly repudiated (10,11).
116
Histopathological Considerations
Before considering the imaging features it is worth revising some
of the salient histological features of MPM (4,9,12). Three subtypes
of MPM [epithelial, sarcomatous, and mixed (or biphasic)] are
recognized. In the majority of patients, MPM is of the epithelial
type accounting for some 50% to 60% of cases. The mixed or
biphasic type of MPM is seen in around one-third of patients and
the remainder are of the sarcomatoid variety. In rare patients with
a mixed tumor type, there are osteoblastic stromal elements within
the tumor leading to the finding of dense sheets of calcification on
histopathological and radiological examination (Fig. 10.1) (13–15).
The histological classification of MPM is important since there is a
bearing on prognosis and treatment. In general, sarcomatous MPM
tends to be more resistant to therapy than other cell types and is
associated with a median survival of less than one year from diag-
nosis (16–20). In contrast, epithelial MPM (in particular, some of
the well-differentiated variants) may have a more prolonged survival.
Although the radiological diagnosis of MPM can be difficult,
it is worth noting that the exercise of pathological diagnosis and
histological classification of MPM is not necessarily a straight-
forward undertaking. The evaluation of MPM is subject to not-
insignificant observer variability (21–23). An additional difficulty
has been the differentiation of MPM from metastatic adenocar-
cinoma. However, on this last note, there have been promising
advances with the development of sophisticated immunohis-
tochemical and antibody tests (24–27) including, more recently,
the identification of a possible marker in the blood (serum
mesothelin-related protein) for MPM (28,29).
The macroscopic appearances of MPM are reflected in the find-
ings at imaging. In the very early stages of disease, there are plaques
of tumor or nodules along the parietal pleura (18,24,30). However,
with time, the tumor generally spreads locally, giving rise in the
later stages to a diffuse pleural mass which can completely encase
the lung. In patients with such advanced disease, the pleura is
generally covered by a hard, ivory-white tumor and the pleural
layers are generally inseparable. Extension of tumor into fissures
and large cystic spaces (secondary to localized areas of necrosis) is
relatively common. Very occasionally (and presumably because of
a serendipitous diagnosis) MPM may also be entirely localized
(31). In patients fortunate enough to have such a localized tumor,
there is the hope of curative resection (Fig. 10.2).
As MPM progresses, the tumor can extend contiguously into
the chest wall, lung parenchyma, mediastinum, and diaphragm.
There is also a propensity for MPM to seed along biopsy tracts and
drain insertion sites. Visceral metastases are not infrequent at post
mortem but clinically significant metastases are uncommon
(32,33). Metastases to bronchopulmonary, hilar, and mediastinal
lymph nodes is well documented—there was metastatic nodal
disease in nearly 50% of patients with MPM in one series (34).
In contrast, spread to the axillary, cervical, supraclavicular, and
abdominal nodal stations is a less frequent finding (35).
 pleural tumors

Key Points: Epidemiology and Pathology
■ Malignant pleural mesothelioma (MPM) accounts for less
than 1% of all intrathoracic neoplasms; the tumor is inextri-
cably linked with asbestos exposure, is relentlessly aggressive,
and associated with an almost universally dismal prognosis
■ Because of the long latency following exposure (typically
20–40 years), there is a rising incidence of MPM which, in
the United Kingdom, is unlikely to peak before 2020
■ On macroscopic examination in advanced disease there is a
contiguous, ivory-white pleural mass which encases the lung.
Three microscopic subtypes (which are linked to outcome)
are recognized: epithelial, saromatous, and mixed or biphasic
■ Histological differentiation from adenocarcinoma of the
pleura is not straightforward but is aided by recent develop-
ment of sophisticated immunohistochemical and antibody
tests; in the future a serum marker (mesothelin-related protein)
may also be brought to bear

THE STAGING OF MPM

Until relatively recently, progress in the management of MPM

10.00 mm/div
10.00 mm/div
Figure 10.1 Coronal CT image in a 69-yr-old patient with malignant pleural
mesothelioma. There is extensive irregular pleural thickening in the left hemitho-
rax associated with amorphous stromal calcification.
had been hindered by the absence of a universally accepted and
validated system for staging the disease. However, recognition of
this issue and the publication of some promising results from
multimodality treatment trials in MPM led to the proposal of a
new staging system in 1995 under the auspices of the Interna-
tional Mesothelioma Interest Group (IMIG) ( Tables 10.1 and
10.2) (36–41). In essence, the new IMIG staging classification,
based on the TNM descriptors of locoregional tumor extent,
nodal involvement, and detection of metastases, brought the
staging of MPM into line with that of other solid tumors. Fur-
thermore, as with the staging of other malignancies, one of the
principal aims of the new staging classification––in addition to
prognostic evaluation––was to separate patients with potentially
resectable (i.e., T3 and lower stage) from those with essentially
non-surgical (i.e., T4) disease.
In the IMIG staging system there are key differences between and
within the TNM stages. For instance, based on the findings at tho-
racoscopy, it is known that there are significant differences in out-
come between patients with stage T1a (in which there is no

(A) (B)
Figure 10.2 Localized malignant pleural mesothelioma diagnosed incidentally. (A) Chest radiograph demonstrates a localized mass in the left upper zone. There is no
associated rib destruction. (B) CT through the upper lobes shows a lobulated pleurally based mass with no obvious CT evidence of chest wall or rib invasion. Biopsy
confirmed the diagnosis of an epithelioid mesothelioma and the patient was referred for surgical excision.

117
 primary tumor evaluation and staging

Table 10.1 TNM Descriptors of Disease Extent Based on the Recommendations of the International Mesothelioma Interest Group
TNM status Description
T
T1
∼T1a Tumor limited to ipsilateral parietal pleura, including mediastinal and diaphragmatic pleura. No involvement of the visceral pleura
∼T1b Tumor involving the ipsilateral parietal pleura, including mediastinal and diaphragmatic pleura. Scattered foci of tumor also involving the visceral pleura
T2 Tumor involving each of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following
features:
• Involvement of diaphragmatic muscles
• Confluent visceral pleural tumor (including the fissures) or extension of tumor from the visceral pleura into underlying pulmonary parenchyma
T3 Describes locally advanced but potentially resectable tumor.
Tumor involving all of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic & visceral pleura) with at least one of the following
features:
• Involvement of the endothoracic fascia
• Extension into the mediastinal fat
• Solitary, completely resectable focus of tumor extending into the soft tissues of the chest wall
• Nontransmural involvement of the pericardium
Describes locally advanced technically unresectable tumor.
T4 Tumor involving all of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic & visceral) with at least one of the following features:
• Diffuse extension or multifocal masses of tumor in the chest wall, with or without associated rib destruction
• Direct transdiaphragmatic extension of tumor to the peritoneum
• Direct extension of tumor to the contralateral pleura
• Direct extension of tumor to one or more mediastinal organs
• Direct extension of tumor into the spine
• Tumor extending through to the internal surface of the pericardium with or without a pericardial effusion or tumor involving the myocardium
N
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastases
N1 Metastases in the ipsilateral bronchopulmonary or hilar lymph nodes
N2 Metastases in the subcarinal or the ipsilateral mediastinal lymph nodes, including the ipsilateral internal mammary nodes
N3 Metastases in the contralateral mediastinal, contralateral internal mammary, ipsilateral, or contralateral supraclavicular lymph nodes
M
MX Presence of distant metastases cannot be assessed
M0 No distant metastases
M1 Distant metastases present

Table 10.2 New Staging of Malignant Pleural Mesothelioma classification, based on morphological descriptors, represents a
Based on Strict TNM Descriptors of Disease Extent significant and important advance in the management of MPM.

Stage Description
I THE RADIOLOGY OF MPM
∼Ia T1aN0M0
∼Ib T1bN0M0 Diagnosis and Staging
II T2N0M0 Because the symptoms (typically, non-pleuritic chest pain, dyspnoea,
III Any T3M0
Any N1M0
cough, and weight loss) are non-specific and characteristically
Any N2M0 appear late in the course of disease, patients with MPM usually
IV Any T4 have advanced disease at presentation (3,44). The plain chest
Any N3 radiograph and computed tomography (CT) are among the first
Any M1 (and frequently the only) imaging tests requested in patients with
suspected MPM. In specific instances, magnetic resonance imag-
ing (MRI) and, more recently, 18fluorodeoxyglucose-positron
involvement of the visceral pleura) and stage T1b (where there is emission tomography (18FDG-PET) and PET-CT are brought to
tumor involving the parietal pleura or there are scattered foci of bear in the investigation of patients with MPM. These various
MPM within the viscera pleura) (16). There are also significant tests are considered in the following sections.
differences in outlook when all four T categories are considered (34).
It is generally accepted that there are flaws in the preoperative stag-
ing of MPM. For instance, no account is taken of the prognostic Chest Radiography
influence of cell type. Moreover, the acknowledged limitations of all The appearances of MPM on plain chest radiography are fairly
imaging techniques have led to the development of protocols which characteristic and mirror the macroscopic histopathology (45). In
include “extended” surgical staging at some institutions (42,43). This the typical patient, extensive nodular or lobulated pleural thicken-
notwithstanding, there can be little argument that the new staging ing with encasement of one hemithorax is the rule (Fig. 10.3) (46).

118
 pleural tumors
A pleural effusion is evident in the early stages in the majority of
patients. Indeed, when the effusion is sizeable, an important clue
to the possible diagnosis of MPM is the relative absence of con-
tralateral mediastinal shift (Fig. 10.4). This is a characteristic fea-
ture of MPM which is likely to be due to relative fixation of the
Figure 10.3 Characteristic lobulated pleural thickening due to malignant pleural
mesothelioma virtually encases the left lung. There is marked volume loss in the
left hemithorax. In this patient, there is also evidence of diaphragmatic pleural
calcification secondary to prior asbestos exposure. Note that the right paratracheal
mass is due to thyroid enlargement.
Figure 10.4 Large right pleural effusion with no detectable shift of the mediasti-
num to the contralateral side. The relative absence of mediastinal shift in the pres-
ence of a large effusion can be a valuable radiographic clue to the diagnosis of
malignant pleural mesothelioma.
mediastinum and contraction of the lung by the encasing pleural
tumor. Progressive obliteration of the pleural space is the rule in
the majority of patients and because of this a diminution in the
volume of fluid is often seen over time (Fig. 10.5). In the absence
of pleural fluid, loss of volume of the affected side in the presence
of apparently limited disease is also a relatively common finding
in MPM. Despite the known link with asbestos exposure, calcified
pleural plaques and interstitial fibrosis are often conspicuous by
their absence on chest radiographs (47,48); indeed, in one study
(A)
(B)
Figure 10.5 Progressive disease in a patient with malignant pleural mesothelioma.
(A) There is extensive lobulated pleural thickening of the pleura and an apical
pneumothorax (following intervention) which renders the visceral and parietal
pleural thickening visible. (B) Chest radiograph performed almost exactly one
month later demonstrates rapidly progressive disease with complete obliteration
of the space.
119
 primary tumor evaluation and staging

of 247 patients, there was plain radiographic evidence of calcified
plaques in only up to 12% and a similar number had evidence of
pulmonary fibrosis (49). However, this is almost certainly a reflec-
tion of the lower sensitivity of plain chest radiography in com-
parison to CT (Fig. 10.6).
Whilst the plain chest radiograph undoubtedly remains an
important investigation, there are major questions concerning
sensitivity and specificity for the assessment of the local extent
and spread of MPM. For instance, hilar lymph node enlargement
or mediastinal widening may conceivably be due to direct tumor
extension or metastatic spread. Indeed, in most series which have
addressed the issue, plain chest radiography has underestimated
the extent of disease in comparison to CT (50,51). Thus, not
surprisingly, plain chest radiography is generally regarded as
having a limited role in the staging of MPM.
Computed Tomography
Because there is no anatomical superimposition and contrast reso-
lution is greater, CT is a far superior technique for the non-invasive
investigation of patients with MPM. The CT features of MPM have
been widely reported and are reasonably easily recognized (Fig.
10.7). However, it must be emphasized at the outset that CT will
generally not differentiate between MPM and other causes of
malignant pleural involvement. Indeed, a common conundrum
facing the radiologist is deciding whether malignant pleural dis-
ease is due to MPM or metastatic adenocarcinoma of the pleura.
Diagnosis of MPM
The ability of CT to distinguish between malignant and benign
pleural disease was first tested by Leung and colleagues (52). In their

(A) (B)
Figure 10.6 (A) Chest radiography and (B) CT in a patient with malignant pleural mesothelioma in the right hemithorax. Whilst there are no pleural plaques visible on the
plain chest radiograph, because of the greater contrast resolution and absence of superimposition, even a small calcified plaque (arrow) is readily demonstrated at CT.

(A) (B)
Figure 10.7 Characteristic CT appearances of malignant pleural mesothelioma. (A) Image at the level of the aortic arch shows circumferential pleural thickening which
varies in thickness. There is some contraction in the volume of the left lung. (B) CT at the level of the carina shows irregular nodular pleural thickening; there is clear
involvement of the mediastinal pleura.

120
 pleural tumors
study of 74 consecutive patients with pleural disease, features which
were indicative of a malignant aetiology were circumferential thick-
ening (sensitivity and specificity = 41% and 100%, respectively),
nodularity of the pleura (sensitivity and specificity = 51% and
94%), parietal pleural thickening exceeding 1 cm (sensitivity and
specificity = 36% and 94%), and mediastinal pleural involvement
(sensitivity and specificity = 56% and 88%). The presence of one or
more of these criteria was able to correctly identify 28 out of 39
cases of malignant pleural disease. However, the authors made the
important point that patients with malignant mesothelioma could
not be differentiated from those with other causes of malignant
pleural infiltration. Thus, in clinical practice, a confident diagnosis
of MPM will generally require histopathological confirmation.
Staging of Disease Extent
CT is undoubtedly superior to plain chest radiography for the
staging of MPM. However, the data regarding the true value of
CT in staging should not be viewed uncritically. In early CT stud-
ies (admittedly undertaken long before the advent of multislice
CT technology), the rate of false negative assessments for chest
wall invasion and mediastinal lymph node involvement were
unacceptably high (51). The evaluation of transdiaphragmatic
spread by CT was also disappointing. In another study, performed
over a decade later, similar reservations were expressed about the
role of CT (and, for that matter, MRI) in staging MPM (53). A
study, which compared the findings at CT with those at thoracos-
copy, thoracotomy, or post mortem, also highlighted the limita-
tions in defining the morphological extent and spread of disease
when using CT (54).
The CT signs thought to indicate invasion of adjacent structures
(and, by implication, possible irresectable disease) were evaluated
by Patz and colleagues and include encasement of the hemidia-
phragm, infiltration of the extrapleural soft tissues, rib displace-
ment, and infiltration of mediastinal soft tissues (Fig. 10.8) (55).
In contrast, the demonstration of preserved fat planes, at any site,
(A)
Figure 10.8 CT signs of irresectable disease in two patients. (A) Image through the upper zones with a left-sided malignant pleural mesothelioma. There are features
which strongly suggest chest wall invasion with asymmetry in the appearance of the soft tissues (arrows) between the ribs. (B) CT through the lower zones showing
infiltration (asterisk) of the pericardial mediastinal fat by tumor.
was regarded as a reasonable predictor of resectability. The sensi-
tivity of CT for predicting resectability at the diaphragm, chest
wall, and mediastinum exceeded 90%, and was comparable to that
seen with MRI (55). However, importantly, the specificity was low
(presumably related to the small numbers of patients with unre-
sectable disease in that study). In another study which used ROC
analysis, the authors concluded that CT and MRI were of roughly
equal accuracy in staging MPM and that there were issues regarding
accuracy for both techniques (53). Whether the advent of multi-
detector row CT (MDCT) machines, which have the capacity to
generate images of exquisite resolution (and, like MRI, in any
desired plane), will add to the role of CT in staging of MPM has
not yet been rigorously tested.
Surgical data indicate that involvement of hilar and mediastinal
nodes occurs not uncommonly in patients with MPM (Fig. 10.9)
(34). This is clearly important because, in keeping with other
malignancies, involvement of nodes by tumor is of prognostic
importance. Historically, the evaluation of nodal involvement on
imaging studies has been based, somewhat crudely, on the evalua-
tion of nodal size: a cut-off size of 1 cm in short-axis diameter has
traditionally been regarded as the dividing-line between normal
and malignant nodes. However, clinical experience has taught that
just as large nodes may simply reflect “reactive” pathology, so nodes
which are less than 1 cm in diameter may be infiltrated by tumor.
In the study by Heelan and colleagues, both CT and MRI had low
accuracy for the detection of N2 nodal disease (53). In addition to
the well known problem of reliance on nodal size, the authors sug-
gested that the presence of mediastinal pleural thickening in MPM
may, by obscuration, hamper the evaluation of lymph nodes.
It will be abundantly clear from the discussion above that CT is
an imperfect tool for the staging of MPM. Indeed, data in
118 patients with potentially resectable MPM have been presented
in which the initial radiological staging was based largely on CT
but supplemented with MRI and PET-CT in select cases (43). In
patients deemed suitable for extrapleural pneumonectomy,
(B)
121
 primary tumor evaluation and staging
Figure 10.9 Enlarged subcarinal lymph nodes (arrows) in malignant pleural
mesothelioma denoting “N2” disease.
extended surgical staging (comprising laparoscopy, peritoneal
lavage and, where these were negative, cervical mediastinoscopy)
was also undertaken. The study showed that surgery would have
been inappropriate in 15 out of 118 patients based on of the results
of extended staging procedures (43). Despite the obvious limita-
tions discussed above and because of its relatively wider availabil-
ity in comparison to MRI and PET machines, CT remains the
mainstay for the imaging diagnosis, staging and, where appropri-
ate, follow-up of patients with MPM.
Key Points: Chest Radiography and CT in Diagnosis
and Staging
■ The characteristic plain radiographic appearance of MPM is
that of extensive unilateral nodular or lobulated pleural
thickening with encasement. These appearances are indistin-
guishable from metastatic pleural adenocarcinoma (or
indeed, other causes of malignant pleural involvement, e.g.,
thyroid carcinoma). Pleural plaques are often absent on chest
radiography (cf CT)
■ Chest radiographs are of doubtful value in staging of MPM
■ CT signs of pleural malignancy (not confined to MPM) are
circumferential pleural thickening, nodularity, mediastinal
pleural thickening, and parietal pleural thickening greater
than 1 cm. Pleural plaques are not uncommon
■ CT is superior to chest radiography in staging extent of MPM
but there are concerns over evaluation of transdiaphragmatic
spread; sensitivity for predicting resectability (>90%) are
comparable to MRI. Rigorous data on value of MDCT in
staging MPM are awaited
Magnetic Resonance Imaging (MRI)
Because of its superb soft tissue contrast resolution, the absence of
ionizing radiation, and the capacity for multiplanar display, the
hope was always that MRI would replace CT in the diagnostic
122
evaluation and staging of MPM. However, the ever-important
issues of resource (more specifically, the lack thereof), coupled
with some of the well-known drawbacks (including longer exam-
ination times compared to CT, the tendency to claustrophobia in
some patients, image degradation due to breathing, magnetic
susceptibility artifacts, and a low spatial resolution) have meant
that thoracic MRI has never quite fulfilled its early promise.
Diagnosis of MPM
The morphological and signal characteristics of MPM on MRI
have been documented previously. In brief, there is intermediate
signal on T1-weighted images (with enhancement following intra-
venous contrast) and a moderate signal increase on T2-weighted
sequences (Fig. 10.10) (50,55–57). The morphological features of
MPM are identical to those seen on chest radiography or CT and
reflect the macroscopic pathological appearances. Not surprisingly,
as with CT, the differentiation of MPM and malignant pleural
invasion due to other tumors cannot be made with any confidence
with MRI.Figure 10.12
Staging of Disease Extent
The published series to date have all, admittedly, comprised small
patient numbers. Nevertheless, it is perhaps fair to state that none
conclusively favors MRI over CT for the staging of MPM (55,56).
For the purposes of staging, Patz and colleagues have shown that
CT and MRI have roughly equal accuracies in the detection of
transdiaphragmatic spread (55). However, it is suggested that MRI
may have advantages over CT in two specific areas. Firstly, in the
assessment of invasion of endothoracic fascia or the detection of a
solitary respectable focus of tumor (both denoting T3 disease),
where the comparative accuracies of MRI and CT are 69% and
46%, respectively (58). Secondly, MRI may be superior to CT in
the evaluation of diaphragmatic invasion, indicating a T4 tumor
(accuracy of MRI versus CT = 82% versus 55%, respectively).
More recently, Knuuttila et al., in their study of 34 patients with
MPM, concluded that enhancement of the interlobar fissures,
tumor invasion of the diaphragm, mediastinal soft tissue, or chest
wall involvement was better depicted by MRI (59). Interestingly,
the authors found that the contrast-enhanced T1-weighted
sequence in three planes was the most valuable. With the greater
availability of higher field strength MRI machines capable of rapid
image acquisition, MRI might become a more central test in the
staging of MPM. However, until that time, CT remains the princi-
pal imaging test in patients with MPM.
Key Points: MR in Diagnosis and Staging
■ The morphological features of MPM on MRI are identical to
those at CT. Intermediate signal is seen on T1-weighted and a
moderate signal increase is present on T2-weighted images;
there is enhancement with intravenous gadolinium
■ Earlier studies suggested equal accuracy with CT in staging
transdiaphragmatic invasion but MRI may be superior to CT
in identification of T3 or T4 disease
Positron Emission Tomography
There is little doubt that “functional” tumor imaging with 18fluoro-
deoxyglucose-positron emission tomography (18FDG-PET) has
 pleural tumors

(A) (B)
Figure 10.10 Coronal T1-weighted images in two patients with malignant mesothelioma. (A) Extensive and predominantly lower zone malignant mesothelioma. There
is invasion of the chest wall (arrows) and probable transdiaphragmatic spread as judged by irregularity and loss of subdiaphragmatic fat planes. (B) Left malignant
mesothelioma. Moderate enhancement of tumor is seen post-gadolinium. Loculated pleural fluid is noted at the base (arrow). Source: Images courtesy of Dr. David
MacVicar, Royal Marsden Hospital, and Dr. Pauline Kane, King’s College Hospital.

(A) (B)
Figure 10.11 A 62-year-old male with malignant pleural mesothelioma. (A) CT at the level of the aortic arch shows tumor that is apparently limited to the mediastional
pleura. An enlarged precarinal lymph node can be seen. (B) 18FDG-PET image at the same anatomical level demonstrating uptake along almost the entire pleural surface.
There is also intense 18FDG uptake in the precarinal lymph node. Source: Images courtesy of Professor David Lynch, University of Colorado.

contributed significantly to the clinical evaluation of patients with
malignancy. More recently, the development of “hybrid” PET-CT
scanners, in which the functional information from PET and the
morphological data from CT are coupled, has been greeted with
justifiable enthusiasm (60). Data on the value of 18FDG-PET
imaging and the newer integrated PET-CT scanning in the diag-
nosis, staging, prognostic evaluation, and follow-up of MPM have
been accruing steadily (61–68).
Diagnosis of MPM
It is clear from the published literature that metabolically active cells
in MPM will take up 18FDG (Fig. 10.11). In the late 1990s, Bénard
and colleagues showed that the standardized uptake values (SUVs)
were significantly greater for malignant pleural disease (the major-
ity of which, incidentally, were due to MPM) than benign (61).
Using a threshold value for SUV of 2.0, 18FDG-PET had a sensitivity
just over 90% and a specificity of 100% for malignant pleural dis-
ease. The authors also noted that 18FDG-PET imaging detected
malignant nodal disease in 12 patients, in 9 of whom the staging CT
had been considered “negative” for nodal involvement (61). In a
later, but again small study, there was significant uptake of 18FDG in
12 out of 13 patients with malignant disease and evidence of distant
metastatic spread in 2 (63). Interestingly, the one false negative
result occurred in a patient with an epithelial mesothelioma.

123
 primary tumor evaluation and staging

There is relatively recent evidence which suggests that differ- whom these were previously unsuspected by clinical and conven-
ences in the manner in which 18FDG is taken up by MPM may tional radiological assessment (69). Indeed, it is the reasonable
reflect differences in biological behavior and, by implication, presumption of some authors that metastatic disease, which man-
prognosis (66). In a pilot study of 12 patients, Gerbaudo and col- ifests soon after radical extrapleural pneumonectomy, may already
leagues identified four different patterns of 18FDG activity: focal, have been present but clinically silent at the time of surgery (42).
linear, diffuse, and heterogeneous. These patterns mirrored the This perhaps emphasises the potentially critical role of PET
overall extent of tumor as judged by radiological tests and surgical imaging in the evaluation of “M” status in patients with MPM.
observations (66). Interestingly, foci of extrathoracic disease had
more intense uptake (quantified by the “18F-FDG uptake index”) Key Points: 18FDG-PET in Diagnosis and Staging
than the primary tumor or areas of tumor within lymph nodes,
and there was an association between the 18F-FDG uptake index ■ Metabolically active MPM cells are known to take up 18FDG;
and surgical stage. However, a potentially more important finding different patterns of 18FDG uptake may reflect differences in
of this study was that the incremental uptake of 18FDG over time biological behavior
(termed the “malignant metabolic potential index”) seemed to ■ 18FDG-PET is thought to be of value in staging T0–T3
predict disease behavior better than the histological grade (66). disease but there are some questions over (irresectable) T4
Whilst these are early data in small cohorts, it is tempting to spec- MPM
ulate that 18FDG-PET imaging will have a significant role in the ■ Despite disappointing initial data, 18FDG-PET imaging,
prognostic evaluation of the patients with MPM. particularly with hybrid PET-CT machines, holds promise for
the more accurate staging of nodal disease
Staging of MPM ■ 18FDG-PET is likely to be of value in the detection of distant
The staging potential of 18FDG-PET has been explored, given the metastases and in follow-up evaluation
known constraints of axial imaging techniques in making the crit-
ical distinction between surgical and non-surgical disease. In 2003,
Flores and colleagues compared staging based on 18FDG-PET FOLLOW-UP RADIOLOGICAL EVALUATION OF MPM
images with the final surgical/pathological findings in 53 patients
It is clear that with advances in therapy, however modest, there
with MPM (67). Twenty-nine out of 32 patients with surgical/
will be a requirement for more accurate morphological follow-up
pathological grade T0–T3 stage disease were correctly identified
of patients with MPM. Whilst the standards for serial imaging are
by 18FDG-PET. However, the authors showed that 18FDG-PET
not yet defined, it is likely that plain chest radiography and CT
correctly staged only four out of 21 patients with irresectable T4
will be the mainstays of imaging follow-up. Furthermore, whilst
disease. Thus, the sensitivity, specificity, positive, and negative
further studies are clearly warranted, it is also probable that
predictive values of 18FDG-PET for the identification of T4 disease 18
FDG-PET imaging will have a role in the follow-up evaluation.
were, somewhat disappointingly, 19%, 91%, 57%, and 63%,
There are preliminary data that integrated PET-CT imaging may
respectively. Accordingly, the authors concluded that 18FDG-PET
be of value in the categorization of patients into those who do
did not reliably stage the local extent of tumor; the hypothesis was
and those who do not respond to treatment (68). Such a finding
that the poor spatial resolution of the then available PET scanners
has obvious attractions for future therapeutic trials in which
was a contributory factor. The advent of PET-CT machines has, in
accurate stratification is clearly desirable.
many ways, redressed the balance. In support of this, in a more
recent study, the respective sensitivity, specificity, positive and
negative predictive values of PET-CT for detecting T4 disease were Summary
67%, 93%, 86%, and 82%, respectively (69).
■ The plain chest radiograph and CT are the standard imaging
The problem of evaluating lymph node involvement on axial
techniques which should be used for initial diagnostic work-
imaging, with the undue (but ultimately necessary) reliance on size
up in patients with suspected MPM
criteria, applies equally to MPM as it does to other tumors. For rea-
■ The CT signs of pleural malignancy are associated with a
sons which have been discussed above, this approach is problem-
high positive predictive value but it must be emphasized that
atic. However, it should be remembered that surgical staging with
CT cannot differentiate between MPM and other causes of
cervical mediastinoscopy is also imperfect since certain node groups
malignant pleural infiltration
remain inaccessible (70). Although there are obvious attractions of
18 ■ MR may serve a useful “problem-solving” role in specific
FDG-PET imaging because of the information such images pro-
circumstances but, on the whole, offers no objective diagnostic
vide about metabolically active tissue, here too there are issues. In
or staging advantage over CT. Moreover, with the greater avail-
the study performed by Flores and colleagues, the sensitivity and
ability of the latter and the advent of multislice technology, CT
specificity of PET for nodal metastasis were a disappointingly 11%
remains the dominant imaging choice
and 86%, respectively (67). Whether integrated PET-CT imaging
■ Encouraging data about the potential role of 18FDG-PET
will significantly improve the non-invasive staging of nodal disease
imaging in the diagnosis, staging, and follow-up of patients
in patients with MPM remains to be seen (69).
with MPM are emerging but must not be viewed uncritically
The above notwithstanding, it seems likely that PET imaging
■ Because all imaging modalities have limitations, the need for a
will be of value in the identification of previously undetected
multidisciplinary approach, involving physicians, oncologists,
metastases from MPM (63,64,69,71). Erasmus and colleagues
surgeons, pathologists, and radiologists remains paramount
found metastases precluding surgery in 7 out of 29 patients, in

124
 pleural tumors
REFERENCES
1. Peto J, Hodgson JT, Matthews FE, Jones JR. Continuing increase
in mesothelioma mortality in Britain. Lancet 1995; 345: 535–9.
2. Peto J, Decarli A, La Vecchia C, Negri E. The European meso-
thelioma epidemic. Br J Cancer 2002; 79: 666–72.
3. Sterman DH, Albelda SM. Advances in the diagnosis, evalua-
tion, and management of malignant pleural mesothelioma.
Respirology 2005; 10: 266–83.
4. Wagner JC, Sleggs CA, Marchand P. Diffuse pleural mesothe-
lioma and asbestos exposure in the North Western Cape
Province. Br J Industr Med 1960; 17: 260–71.
5. Robinson BWS, Musk AW, Lake RA. Malignant mesothelioma.
The Lancet 2005; 366: 397–408.
6. Craighead JE. The epidemiology and pathogenesis of malignant
mesothelioma. Chest 1989; 96: 92S–3S.
7. McDonald AD, Fry JS, Woolley AJ, McDonald JC. Dust exposure
and mortality in an American chrysotile asbestos friction
products plant. Br J Industr Med 1984; 41: 151–7.
8. Gardner MJ, Winter PD, Pannett B, Powell CA. Follow up
study of workers manufacturing chrysotile asbestos cement
products. Br J Industr Med 1986; 43: 726–32.
9. Kannerstein M, Churg J, McCaughey WTE. Asbestos and
mesothelioma: a review. Pathol Annu 1978; 13: 81–129.
10. Hansen J, de Klerk N, Musk AW, Hobbs MST. Environmental
exposure to crocidolite and mesothelioma: exposure-response
relationships. Am J Respir Crit Care Med 1998; 157: 69–75.
11. Pan X, Day HW, Wang W, Beckett LA, Schenker MB. Residential
proximity to naturally occurring asbestos and mesothelioma risk
in California. Am J Respir Crit Care Med 2005; 172: 1019–25.
12. Parkes WR. Asbestos-related disorders. Br J Dis Chest 1973;
67: 261–300.
13. Salgado RA, Corthouts R, Parizel PM, et al. Malignant pleural
mesothelioma with heterologous osteoblastic elements:
computed tomography, magnetic resonance, and positron
emission tomography imaging characteristics of a rare tumor.
J Comput Assist Tomogr 2005; 29: 653–6.
14. Raizon A, Schwartz A, Hix W, Rockoff DS. Calcification as a
sign of sarcomatous degeneration of malignant pleural meso-
theliomas: a new CT finding. J Comput Assist Tomogr 1996;
20: 42–4.
15. Andrion A, Mazzucco G, Bernardi P, Mollo F. Sarcomatous
differentiation of the chest wall with osteochondroid differen-
tiation: evidence of mesothelial origin. Am J Surg Pathol 1989;
13: 707–12.
16. Boutin C, Rey F, Gouvernet J, et al. Thoracoscopy in pleural
malignant mesothelioma: a prospective study of 188 consecutive
patients. Part 2: prognosis and staging. Cancer 1993; 72:
394–404.
17. Hillerdal G. Malignant mesothelioma 1982: review of 4710
published cases. Br J Dis Chest 1983; 77: 321–43.
18. Boutin C, Rey F. Thoracoscopy in pleural malignant meso-
thelioma: a prospective study of 188 consecutive patients.
Part 1: diagnosis. Cancer 1993; 72: 389–93.
19. Law MR, Hodson ME, Heard BE. Malignant mesothelioma of
the pleura: relation between histological type and clinical
behaviour. Thorax 1982; 37: 810–15.
20. Ruffie P, Feld R, Minkin S, et al. Diffuse malignant mesothe-
lioma of the pleura in Ontario and Quebec: a retrospective
study of 332 patients. J Clin Oncol 1989; 7: 1157–68.
21. McDonald AD, Magner D, Eyssen G. Primary malignant
mesothelial tumors in Canada, 1960–1968: a pathologic review
by the mesothelioma panel of the Canadian tumor reference
centre. Cancer 1973; 31: 869–76.
22. McCaughey WT, Oldham PD. Diffuse mesothelioma: observer
variation in histological diagnosis. In: Bogovski P, ed. Biological
Effects of Asbestos. Lyon: International Agency for Research
on Cancer, 1973; 58–61.
23. Andrion A, Magnani C, Betta PG, et al. Malignant mesothe-
lioma of the pleura: interobserver variability. J Clin Pathol 1995;
48: 856–60.
24. Corson JM. Pathology of malignant mesothelioma. In:
Antman KH, Aisner J, eds. Asbestos-Related Malignancy.
Orlando: Grune & Stratton, 1987: 179–99.
25. Szpak CA, Johnston WW, Roggli V, et al. The diagnostic distinc-
tion between malignant mesothelioma of the pleura and
adenocarcinoma of the lung as defined by a monoclonal
antibody (B72.3). Am J Pathol 1986; 122: 252–60.
26. Wang N-S, Huang S-N, Gold P. Absence of carcinoembryonic
antigen-like material in mesothelioma: an immunohistochem-
ical differentiation from other lung cancers. Cancer 1979; 44:
937–43.
27. Friedman MT, Gentile P, Tarectecan A, Fuchs A. Malignant meso-
thelioma: immunohistochemistry and DNA ploidy analysis as
methods to differentiate mesothelioma from benign reactive
mesothelial cell proliferation abd adenocarcinoma in pleural and
peritoneall effusions. Arch Pathol Lab Med 1996; 120: 959–66.
28. Robinson BW, Creaney J, Lake R, et al. Mesothelin-family
proteins and diagnosis of mesothelioma. The Lancet 2003;
362: 1612–6.
29. Robinson BWS, Creaney J, Lake R, et al. Soluble mesothelin-
related protein − A blood test for mesothelioma. Lung Cancer
2005; 49(Suppl 1): S109–S111.
30. Churg A. Diseases of the pleura. In: Thurlbeck WM, Churg
AM, eds. Pathology of the Lung, 2nd edn. New York: Thieme
Medical Publishers, 1995: 1067–109.
31. Crotty TB, Myers JL, Katzenstein AA, et al. Localised malignant
mesothelioma: a clinicopathologic and flow cytometric study.
Am J Surg Pathol 1994; 18: 357–63.
32. Antman KH. Natural history and staging of malignant meso-
thelioma. Chest 1989; 96: 93S–5S.
33. Edge JR, Choudhury SL. Malignant mesothelioma of the
pleura in Barrow-in-Furness. Thorax 1978; 33: 26–30.
34. Rusch VW, Venkatraman E. The importance of surgical
staging in the treatment of malignant pleural mesothelioma.
J Thorac Cardiovasc Surg 1996; 111: 815–26.
35. Whitwell F, Rawcliffe RM. Diffuse malignant pleural mesothe-
lioma and asbestos exposure. Thorax 1971; 26: 6–22.
36. International Mesothelioma Interest Group. A proposed new
international TNM staging system for malignant pleural
mesothelioma. Chest 1995; 108: 1122–8.
37. Antman KH, Blum RH, Greenberger JS, et al. Multimodality
therapy for malignant mesothelioma based on a study of
natural history. Am J Med 1980; 68: 356–7.
125
 primary tumor evaluation and staging
38. Sugarbaker DJ, Heher EC, Lee TH, et al. Extrapleural pneumo-
nectomy, chemotherapy, and radiotherapy in the treatment of
diffuse malignant pleural mesothelioma. J Thorac Cardiovasc
Surg 1991; 102: 10–15.
39. Byrne MJ, Davidson JA, Musk AW, et al. Cisplatin and gem-
citabine treatment for malignant mesothelioma: a phase II
study. J Clin Oncol 1999; 17: 25–30.
40. Steele JPC, Shamash J, Evans MT, et al. Phase II study of
vinorelbine in patients with malignant pleural mesothelioma.
J Clin Oncol 2000; 18: 3912–17.
41. Maggi G, Casadio C, Cianci R, Rena O, Ruffini E. Trimodality
management of malignant pleural mesothelioma. Eur Cardio-
Thoracic Surg 2001; 19: 346–50.
42. Truong MT, Marom EM, Erasmus JJ. Preoperative evaluation
of patients with malignant pleural mesothelioma: role of
integrated CT-PET imaging. J Thorac Imaging 2006; 21:
146–53.
43. Rice DC, Erasmus JJ, Stevens CW, et al. Extended surgical stag-
ing for potentially resectable malignant pleural mesothelioma.
Ann Thorac Surg 2005; 80: 1988–93.
44. Yates DH, Corrin B, Stidolph PN, Browne K. Malignant
mesothelioma in south east England: clinicopathological
experience of 272 cases. Thorax 1997; 52: 507–12.
45. Brenner J, Sordillo PP, Magill GB, Golbey RB. Malignant
mesothelioma of the pleura: review of 123 patients. Cancer
1982; 49: 2431–5.
46. Legha SS, Muggia FM. Pleural mesothelioma: clinical features
and therapeutic implications. Ann Intern Med 1977; 87: 613–21.
47. Müller NL. Imaging of the pleura. Radiology 1993; 186:
297–309.
48. Gefter WB, Epstein DM, Miller WT. Radiographic evaluation
of asbestos-related chest disorders. Crit Rev Diagn Imag 1984;
21: 133–81.
49. Elmes PC, Simpson MJC. The clinical aspects of mesothelioma.
Q J Med 1976; 45: 427–49.
50. Strankinga WFM, Sperber M, Kaiser MC, Stam J. Accuracy of
diagnostic procedures in the initial evaluation and follow-up
of mesothelioma patients. Respiration 1987; 51: 179–87.
51. Rusch VW, Godwin JD, Shuman WP. The role of computed
tomography scanning in the initial assessment and follow-up
of malignant pleural mesothelioma. J Thorac Cardiovasc Surg
1988; 96: 171–7.
52. Leung AN, Müller NL, Miller RR. CT in differential diagno-
sis of diffuse pleural disease. Am J Roentgenol 1990; 154:
487–92.
53. Heelan RT, Rusch VW, Begg CB, et al. Staging of malignant
pleural mesothelioma: comparison of CT and MR imaging.
Am J Roentgenol 1999; 172: 1039–47.
54. Maasilta P, Vehmas T, Kivisaari L, Tammilehto L, Mattson K.
Correlations between findings at computed tomography (CT)
and at thoracoscopy/thoracotomy/autopsy in pleural mesothe-
lioma. Eur Respir J 1991; 4: 952–4.
55. Patz EF Jr, Shaffer K, Piwnica-Worms DR, et al. Malignant
pleural mesothelioma: value of CT and MRI imaging in pre-
dicting resectability. Am J Roentgenol 1992; 159: 961–6.
56. Lorigan JG, Libshitz HI. MR imaging of malignant pleural
mesothelioma. J Comput Assist Tomogr 1989; 13: 617–20.
126
57. Minami M, Kawauchi N, Yoshikawa K, et al. Malignancy
associated with chronic empyema: radiologic assessment.
Radiology 1991; 178: 417–23.
58. Knuuttila A, Kivisaari L, Kivisaari A, et al. Evaluation of pleural
disease using MR and CT with special reference to malignant
pleural mesothelioma. Acta Radiologica 2001; 42: 502–7.
59. Knuuttila A, Halme M, Kivisaari L, et al. The clinical impor-
tance of magnetic resonance imaging versus computed
tomography in malignant pleural mesothelioma. Lung Cancer
1998; 22: 215–25.
60. von Schulthess GK, Steinert HC, Hany TF. Integrated PET/CT:
current applications and future directions. Radiology 2006;
238: 405–22.
61. Bénard F, Sterman D, Smith RJ, et al. Metabolic imaging of
malignant pleural mesothelioma with fluorodeoxyglucose
positron emission tomography. Chest 1998; 114: 713–22.
62. Bénard F, Sterman D, Smith RJ, et al. Prognostic value of FDG
PET imaging in malignant pleural mesothelioma. J Nucl Med
1999; 40: 1241–5.
63. Carretta A, Landoni C, Melloni G, et al. 18-FDG positron
emission tomography in the evaluation of malignant pleural
diseases: a pilot study. Eur J Cardio-Thoracic Surg 2000; 17:
377–83.
64. Schneider DB, Clary-Macy C, Challa S, et al. Positron emission
tomography with F18-fluorodeoxyglucose in the staging and
preoperative evaluation of malignant pleural mesothelioma.
J Thorac Cardiovasc Surg 2000; 120: 128–33.
65. Gerbaudo VH, Sugarbaker DJ, Britz-Cunningham S, et al.
Assessment of malignant pleural mesothelioma with 18F-FDG
dual-head gamma-camera coincidence imaging: compariosn
with histopathology. J Nucl Med 2002; 43: 1144–9.
66. Gerbaudo VH, Britz-Cunningham S, Sugarbaker DJ, Treves
ST. Metabolic significance of the pattern, intensity and kinetics
of 18F-FDG uptake in malignant pleural mesothelioma.
Thorax 2003; 58: 1077–82.
67. Flores RM, Akhurst T, Gonen M, Larson SM, Rusch VW.
Positron emission tomography defines metastatic disease
but not locoregional disease in patients with malignant
pleural mesothelioma. J Thorac Cardiovasc Surg 2003; 126:
11–16.
68. Steinert HC, Dellea MMS, Burger C, Stahel R. Therapy
response evaluation in malignant pleural mesothelioma with
integrated PET-CT imaging. Lung Cancer 2005; 49(Suppl 1):
S33–S35.
69. Erasmus JJ, Truong MT, Smythe WR, et al. Integrated com-
puted tomography-positron emission tomography in patients
with potentially resectable malignant pleural mesothelioma:
staging implications. J Thorac Cardiovasc Surg 2005; 129:
1363–9.
70. Sugarbaker DJ, Flores RM, Jaklitsch MT, et al. Resection
margins, extrapleural nodal status, and cell type determine
postoperative long-term survival in trimodality therapy of
malignant pleural mesothelioma: results in 183 patients.
J Thorac Cardiovasc Surg 1999; 117: 54–65.
71. Nanni C, Castellucci P, Farsad M, et al. Role of 18F-FDG PET
for evaluating malignant pleural mesothelioma. Cancer Biother
Radio 2004; 19: 149–54.
 11 Esophageal Cancer
Richard M Gore, Jonathan W Berlin, Frank H Miller, Uday K Mehta,
Kiran H Thakrar, and Geraldine M Newmark
INTRODUCTION
Esophageal cancer is the eighth most common cancer (4% of total)
and sixth leading cause of cancer death (5.5% of total) worldwide
with approximately 400,000 new cases developing each year (1–4).
In the United States, this neoplasm afflicts more than 14,750 people
annually and is responsible for 7% of gastrointestinal tract malig-
nancies and 1% of all cancers (5). Despite newer diagnostic and
treatment modalities, esophageal cancer remains lethal, with a
dismal five-year survival rate of approximately 12% (6).
In the past, esophageal cancer was synonymous with squamous
cell carcinoma. Over the past three decades, however, the inci-
dence of adenocarcinoma of the esophagus and gastro-esophageal
junction (GEJ) has experienced the most rapid rate of increase of
any solid tumor malignancy in the West (7,8). In the United States,
the absolute incidence of adenocarcinoma has increased sixfold
from 0.38 per 100,000 in 1975 to 2.63 per 100,000 in 2005. For the
same period (1975–2005), the incidence of squamous cell carci-
noma of the esophagus declined from 3.1 to 1.9 per 100,000.
Indeed, in the United States, the incidence of adenocarcinoma has
now surpassed that of squamous cell carcinoma of the esophagus.
Worldwide, however, squamous cell carcinoma still accounts for
approximately 70% of esophageal tumors (1).
Because squamous cell carcinoma and adenocarcinoma of the
esophagus have different demographic, pathologic, therapeutic, and
prognostic features, they are discussed separately in this chapter.
EPIDEMIOLOGY AND ETIOLOGY
Squamous Cell Carcinoma
Squamous cell carcinoma of the esophagus has the widest varia-
tion in incidence by geographic location of any malignancy. In
most parts of the world the incidence rates range from 2.5 to 5.0
for men and 1.5 to 2.5 for women per 100,000 population (7).
In endemic areas such as the northern provinces of China, the
Transkei region of South Africa, the Gonbad region of northern
Iran, and the Normandy and Brittany regions of France, the inci-
dence rates often exceed 100 to 500 per 100,000 population (4,7,8).
A number of carcinogens have been identified in endemic areas.
In China, the soil and consequently the food contain high concen-
trations of nitrosamines. In India and Pakistan, the chewing of betel
nuts, betel leaf, and tobacco use are associated with an increased
incidence of squamous cell carcinoma. In Iran, the ingestion of
pyrolysate-rich beverages and hot tea are important risk factors.
In non-endemic parts of the world, habitual smoking and
alcohol consumption make a deadly and synergistic combination
in the development of squamous cell carcinoma. Individuals
who smoke more than 25 cigarettes per day have a 6.2-fold
increased risk of developing this neoplasm, while heavy alcohol
consumption increases the risk 3.5-fold (9). Consumption of
more than 30 g of tobacco and 120 g of alcohol daily increases
the risk of developing esophageal cancer 44-fold (1). Squamous cell
carcinoma virtually does not occur in non-smoking, non-drinking
white men in Europe and North America (1).
Other risk factors for the development of squamous cell carci-
noma of the esophagus include achalasia, caustic injury, human
papillomavirus, head and neck tumors, Plummer–Vinson syn-
drome, sprue, tylosis, and prior radiation (9). The prevalence of
squamous cell carcinoma is approximately 5% in patients with
achalasia, lye ingestion, and head and neck neoplasms (1,9). Tylosis
is a rare, hereditary, autosomal dominant disorder characterized
by hyperkeratosis of the palms of the hands and soles of the feet,
with a risk of developing esophageal cancer approaching 95% by
age 65 (1,9). Some 7.4% of patients with previous head and neck
tumors will have esophageal squamous cell carcinoma (1,9). Most
(63.6%) invasive tumors develop metachronously (9).
Oncogene activation (cyclin D1 and epidermal growth factor
receptors) and tumor suppressor gene inactivation (p53, p16) are
important in esphageal squamous cell carcinogenesis (10). It is
likely that environmental factors lead to injury of the esophageal
mucosa and thereby promote a hyperproliferative state, which
makes the epithelial cell susceptible to genetic alterations and
genomic instability (10).
Squamous cell carcinoma of the esophagus is rare under the age
of 40 years, but increases in incidence with each decade of life there-
after (7). Men have a two- to three-fold increased risk of developing
the neoplasm and also have increased mortality rates. Squamous
cell carcinoma occurs five times more frequently in the black popu-
lation and is among the five leading causes of cancer-related death
in African-American men. Blacks also present with later stage
disease and have poorer survival for similar stages of disease (8).
Adenocarcinoma
Esophageal adenocarcinoma is primarily a disease of developed
nations. The United States, Europe, and Canada have higher rates
of these neoplasms than developing countries in Asia and Africa.
Over the past quarter century, adenocarcinoma has overtaken
squamous cell carcinoma as the most common esophageal tumor
in white men, with an age-adjusted incidence of 2.63 per 100,000
population, a white-to-black ratio of 4:1 and a male-to-female
ratio of 7:1 in whites (7). In developed countries, the incidence of
adenocarcinoma of the esophagus and GEJ is increasing by 5% to
10% per year (7).
Esophageal adenocarcinoma may have one of three origins:
• Malignant degeneration of metaplastic columnar
epithelium (Barrett’s mucosa)
• Heterotopic islands of columnar epithelium
• Esophageal submucosal glands (11,12)
127
 primary tumor evaluation and staging
Barrett’s esophagus describes progressive columnar metaplasia of
the distal esophagus due to longstanding gastro-esophageal (GE)
reflux and reflux esophagitis. It is a premalignant condition and is
the single most important risk factor for adenocarcinoma of the
esophagus. Barrett’s epithelium is a disorder of white men and it
is identified at an average age of 55 years (13,14). Dysplasia is
recognized as the most important feature that predicts malignant
transformation of this metaplastic tissue. Dysplastic or early
carcinomatous changes can be identified histologically with endo-
scopic biopsy and brushing. The spectrum of change progresses
from no dysplasia, to low-grade dysplasia, then high-grade dysplasia
and, finally, adenocarcinoma. Patients with low-grade dysplasia
have variable progression or regression to normal histology at
follow-up. The presence of high-grade dysplasia is probably an
indication for endoscopic mucosal resection or esophagectomy
because 33% of these patients will have unsuspected foci of
adenocarcinoma (13,14). DNA ploidy studied by flow cytometry
appears to be a less reliable indicator of malignant potential than
the presence of high-grade dysplasia (13,14).
The prevalence of adenocarcinoma in Barrett’s esophagus is
difficult to quantify, with reports ranging from 2.4% to 46.5%,
with a mean of approximately 15%. Incidence rates vary between
1 in 55 to 1 in 441 patient-years (7,14). Prevalence data tend to
exaggerate the risk of cancer because most patients with Barrett’s
mucosa do not seek medical attention until complications such as
strictures, ulcers, or cancers have developed. In a study of asymp-
tomatic male veterans, 25% demonstrated Barrett’s esophagus
(13,14). Prospective studies indicate that the annual incidence of
malignant transformation in Barrett’s esophagus is 1% to 2% and
that the overall risk of developing adenocarcinoma of the esopha-
gus is 125 times greater than in the general population (7,14).
GE reflux is ubiquitous in patients with scleroderma due to a
patulous, incompetent, lower esophageal sphincter. There is poor
clearance of refluxed acid from the esophagus because of absent
peristalsis. Some 33% to 50% of patients with scleroderma who
undergo endoscopy for GE reflux symptoms have proven Barrett’s
esophagus. Because Barrett’s esophagus is the major precursor to
esophageal carcinoma, patients with scleroderma are at increased
risk for developing esophageal cancer (13,14).
Oncogene activation (cyclin D1, p16, pRb) and epidermal
growth factor receptors and tumor suppressor gene inactivation
(p53) are important in the stepwise progression from Barrett’s
metaplasia to low-grade dysplasia to high-grade dysplasia to
adenocarcinoma (10).
Medications that relax the lower esophageal sphincter have
been linked with an increased incidence of adenocarcinoma of
the esophagus. Long term (>5 years), daily use of nitroglycerine,
aminophylline, beta-blockers, anticholinergics, and benzodiaz-
epines is associated with an adjusted incidence risk ratio of 3.8
for adenocarcinoma but not squamous cell carcinoma of the
esophagus (1,15).
Obesity is the second greatest risk factor for the development of
esophageal adenocarcinoma. Obese persons with a body mass
index of greater than 30 kg/m2 have an odds ratio of 16.2 compared
to an aesthenic individual (16).
Several protective factors against the development of adenocarci-
noma have been identified. Colonization with Helicobacter pylori is
associated with a decreased risk of GE reflux and may be protective
128
against adenocarcinoma. There is an inverse relationship between
the use of aspirin or other nonsteroidal anti-inflammatory agents
and the risk of developing adenocarinoma or squamous cell
carcinoma of the esophagus (6).
Key Points: Epidemiology
■ The incidence of adenocarcinoma of the esophagus and GEJ
is the most rapidly rising of all solid tumors in the West
■ Squamous cell carcinoma of the esophagus in non-smoking,
non-drinking, white males is exceedingly rare
■ Heavy alcohol and tobacco users have a 44-fold risk of
developing squamous cell carcinoma of the esophagus
■ Patients with Barrett’s esophagus have a 125-fold risk
of developing adenocarcinoma of the esophagus
■ Obesity with a BMI > 30 kg/m 2 increases the risk of
adencarcinoma by 16.2
PATHOLOGY
Squamous Cell Carcinoma
In the United States the distribution of squamous cell carcinoma
is as follows: upper third (20%), middle third of esophagus (50%),
distal esophagus, and GEJ (30%). Squamous cell carcinoma of the
esophagus rarely invades the stomach, unlike adenocarcinomas
arising in Barrett’s mucosa. In fact, there is usually a discrete seg-
ment of normal esophagus between the squamous cell carcinoma
and the gastric cardia (17–19).
Squamous cell carcinomas of the esophagus (Fig. 11.1) are usually
advanced when diagnosed and this is reflected grossly. Although
there is overlap in appearance of these tumors, three gross des-
criptors are commonly used: fungating-polypoic (60%), ulcerative
(25%), and infiltrative (15%) (17–19).
Fungating tumors project into the lumen from either a broad or
narrow base and usually cause obstruction. Ulcerating tumors
typically have a large ulcer, are less bulky, and may undermine the
adjacent intact mucosa, imparting a multinodular appearance.
The ulcer may penetrate into the mediastinum. These tumors
often cause hemorrhage rather than obstruction. Infiltrative
tumors exhibit non-cohesive growth in the horizontal and vertical
planes of the esophagus. Circumferential involvement is common,
causing thickening and rigidity of the esophageal wall and luminal
stenosis (17–19).
Early cancers of the esophagus can be classified according to
the depth of invasion or the morphologic appearance of the
lesion. Esophageal cancer confined to the epithelium is called
ep-cancer. Cancer remaining within the muscularis mucosae is
referred to as mm-cancer. Tumors involving the submucosa are
called sm-cancer (17–19).
The Japanese Society of Esophageal Disease has developed a
macroscopic classification system based on the one developed for
early gastric cancer. A Type 0–I superficial esophageal cancer has
an elevation over 2 to 3 mm. A lesion with an elevation of 1 mm is
diagnosed as Type 0–IIa. A Type 0–IIc lesion consists of a very shallow
erosion with a depression of less than 0.5 mm. Type 0–III tumors
have a deeper and more distinct depression (17–19).
Early esophageal carcinoma is being recognized with increasing
frequency due to the use of endoscopy and mass screening
 esophageal cancer

(A) (B) (C)

(D) (E) (F)

Figure 11.1 Carcinoma of the esophagus: pathological findings. (A) Well differentiated squamous cell carcinoma showing well-formed cell nests, squamous pearls with
keratinization, and intercellular bridges. (B) Poorly differentiated adenocarcinoma composed of sheets of cells without gland formation. (C) Reddish, ulcerated polypoid
mid-esophageal squamous cell carcinoma. (D) Infiltrative-ulcerated squamous cell carcinoma of the mid esophagus. (E) Diffuse infiltrative squamous cell carcinoma of
the esophagus shows narrowing of the lumen and a tumor spread to a local lymph node (arrow). (F) Fungating-ulcerated adenocarcinoma of the distal esophagus.

techniques in endemic countries and at-risk populations in devel-

oped countries. When these tumors are found confined to the
mucosa and submucosa without lymph node involvement, five-
year survival rates approach 90% (17–19). Superficial esophageal
cancer is confined to mucosa and submucosa but patients may
have lymph node metastases. Small esophageal cancer describes all
tumors less than 3.5 cm in size regardless of the depth of mural
invasion or the presence or absence of lymph node metastases
(17–19).
Adenocarcinoma
Nearly 90% of adenocarcinomas develop in the distal esophagus
and many extend into the stomach if located near the GEJ. Fewer
cases develop in the middle third, and the smallest number in the
proximal esophagus. Adenocarcinomas arising in Barrett’s esoph-
agus comprise as many as 20% to 50% of all adenocarcinomas
involving the GEJ (20–22).
Grossly, adenocarcinomas of the esophagus (Fig. 11.1) range from
flat, infiltrative lesions to fungating polypoid masses. Ulceration is
often present and may be sufficiently deep to cause perforation.
Superficial cancers may be depressed, flat, or slightly elevated
lesions that can be easily overlooked at the time of endoscopy.
Adenocarcinomas range in size from 1 to 10 cm or more and may
occasionally be multiple (17,18,22,23).
Microscopically, adenocarcinomas of the esophagus resemble
those in the gastric cardia. Most are well or moderately differenti-
ated and advanced at the time of diagnosis. In most cases, special-
ized columnar epithelium is present in areas adjacent to the cancer;
however, if the neoplasm is large, there may be no residual Barrett’s
mucosa. High-grade dysplasia is seen in most cases and is most
abundant in areas closest to the tumor (17,18,22).
Key Points: Pathology
■ Twenty percent of squamous cell carcinomas involve the
upper third of the esophagus, pharyngo-esophagus,
cricopharyngeal segment, the cervical esophagus, and the
thoracic esophagus to the level of the aortic arch
■ Fifty percent involve the middle third of the esophagus, from
the aortic arch down to the inferior pulmonary vein
■ Thirty percent involve the distal esophagus
■ Ninety percent of adenocarcinomas develop in the distal
esophagus
■ Adenocarcinomas arising in Barrett’s esophagus comprise
20% to 50% of all tumors involving the GEJ
PATTERNS OF TUMOR SPREAD
Cancers of the esophagus are usually diagnosed at an advanced stage.
This is due to the anatomic configuration of the esophagus, its relation
to adjacent structures, and its lymphatic drainage (24–26).
Direct Extension
The esophagus takes a long course through the neck and chest,
and is adjacent to a large number of structures: aorta, heart,
lungs, bronchi, thyroid, larynx, trachea, thoracic duct, and
diaphragm. Lacking a serosal shield, the tumor is separated
from these structures by only a loose connective tissue adventi-
tia that provides little barrier to the local spread of tumor. As a
consequence, tracheo-esophageal and bronchio-esophageal fis-
tulas develop in 5% to 10% of patients with squamous cell carci-
noma of the esophagus. Aortic invasion by tumor may rarely
cause an aorto-esophageal fistula, a terminal complication of this

129
 primary tumor evaluation and staging
tumor (17–19,22). Adenocarcinoma of the Barrett’s esophagus
quite commonly (35–60%) directly invades the gastric cardia or
fundus (21,22).
Lymphatic Spread
In the esophagus, mucosal lymphatics merge with a submucosal
plexus, which in turn communicates with five lymphatic channels
in the muscularis. These channels then communicate with a network
of cooperating lymphatics that extend throughout the esophagus.
Lymph can flow through different routes before draining into a
node with “jump” metastases to lymph nodes in the neck or medi-
astinum often occurring in the absence of regional segmental
lymph node involvement (17–19).
Lymphatics draining the esophagus tend to follow arteries and
mainly course longitudinally, eventually draining into internal
jugular, cervical, supraclavicular, paratracheal, hilar, subcardinal,
para-esophageal, para-aortic, pericardial, left gastric, and celiac
lymph node chains. Although the nodes involved by tumor are
usually at the same level as the primary neoplasm, squamous cell
carcinoma not uncommonly skips sets of lymph nodes at one
level and invades more distal nodes. For example, lymph nodes in
the gastrohepatic and hepatoduodenal ligaments drain the lower
one-third of the esophagus, yet may be involved in 44% of middle
third lesions and up to 10% of upper third tumors (17–19).
Some 2% to 15% of patients dying of squamous cell carci-
noma of the esophagus will have gastric metastases at autopsy
(17–19). These metastases are probably a result of tumor emboli
that seed the gastric fundus via submucosal esophageal lym-
phatics extending subdiaphragmatically to the stomach. The
esophageal tumor may be located distant from the GEJ, with
normal esophagus interposed between the primary tumor and
the stomach (21,22).
New insights into the lymphatic drainage of the esophagus have
important implications for surgical resection. For cervical and
upper thoracic esophageal carcinomas, extended lymph node dis-
section is useful for staging the disease but does not seem to
increase long-term survival. For mid and distal esophageal tumors,
dissemination to cervical, upper thoracic, and abdominal lymph
nodes is common, and three-field lymphadenectomy may add to
survival. Distal esophageal cancers are best treated with transtho-
racic esophagectomy with extended lymphadenectomy while
tumors at the esophagogastric junction can be operated transhi-
atally with either partial or subtotal esophageal resection. Tumors
confined to the mucosa seldom metastasize and are good candidates
for endoscopic mucosal resection (EMR) (23).
Half of the sentinel nodes for lower esophageal tumors are located
in the mediastinum, nearly 75% of the sentinel lymph nodes for
gastric cardia cancers are within the abdomen. There is no statistical
difference in survival in randomized trials comparing an extensive
lymph node dissection with limited lymphadenectomy (2).
Hematogenous Metastases
Because of esophageal cancer’s rapid mural invasion and ready
access to both lymphatics and blood vessels, hematogenous meta-
stases are quite common in patients with advanced disease. The
lungs and liver are the most common sites of metastases. Other
regions include the adrenal glands, kidneys, pancreas, peritoneum,
and bone (21,22,24).
130
Key Points: Patterns of Tumor Spread
■ The esophagus lacks a serosal cover and local direct spread
occurs readily
■ Although nodal involvement is usually at the same level as
the tumor, squamous cell carcinoma may skip local nodes and
invade more distal ones—44% of middle third and 10% of
upper third lesions result in juxtohepatic and hepatoduodenal
nodal involvement
CLINICAL FEATURES
Squamous Cell Carcinoma
Dysphagia is the classic presenting symptom of esophageal carci-
noma. It indicates that the esophageal lumen has been reduced by
at least 50% to 75% of its normal caliber and that about two-
thirds of the circumference of the esophageal wall is involved.
Unfortunately, the presence of dysphagia also indicates that the
disease is incurable, with extensive involvement of the esophagus
and surrounding structures seen in at least 90% of cases (25,26).
Most patients are symptomatic for 2 to 4 months before seeking
medical attention. While some patients can accurately point to the
level of obstruction, others with middle or distal third esophageal
lesions sense the blockage at the level of the pharynx (25,26). Thus
the entire esophagus must be evaluated in all patients with unex-
plained pharyngeal dysphagia to exclude an esophageal cancer
below the subjective site of obstruction. The dysphagia accelerates
along with progression of disease. First, there is dysphagia to pills
and solid foods, then an inability to swallow any solids and increas-
ing dysphagia to liquids. Ultimately, liquids and even saliva cannot
be swallowed. Patients compensate for their swallowing difficulty
by several manoeuvres: increasing fluids taken with meals, eating
food of a more fluid consistency, and eating more slowly (25,26).
Weight loss is an almost uniform finding in esophageal cancer,
with a mean loss of weight from the onset of symptoms to the time
of presentation of 10.5 kg (22). Odynophagia is another common
symptom, and it typically is dull and steady, with radiation to the
back. Persistent substernal chest pain unrelated to swallowing and
the sudden onset of hiccoughs are ominous signs indicating trans-
mural disease involving the mediastinum or diaphragm (25,26).
Pneumonia and chronic cough due to aspiration or tracheo-
esophageal fistulae are other findings in advanced esophageal car-
cinoma. Hoarseness may develop due to tumor involvement of
the recurrent laryngeal nerve or to chronic aspiration. Bleeding
may result from tumor friability, producing iron-deficiency ane-
mia. When the tumor invades major vessels, the hemorrhage is
often brisk and life-threatening (25,26).
Physical examination usually contributes little: supraclavicular
lymph nodes may be palpable, the vocal cords may show unilateral
adductor paralysis, and there may be evidence of weight loss (23,26).
Adenocarcinoma
The clinical manifestations of adenocarcinoma of the esophagus
are similar to those of squamous cell carcinoma, with dysphagia,
odynophagia, weight loss, and debility being the most common
symptoms. Non-specific symptoms such as anorexia, early satiety,
nausea, vomiting, and bloating may occur because of encroachment
 esophageal cancer
into the stomach (25,26). Suggestive evidence of cancer includes
a history of chronic reflux esophagitis or previously diagnosed
Barrett’s esophagus. The patient typically is an obese 60-year-old
white male who smokes cigarettes and drinks alcohol. Complica-
tions include obstruction, hemorrhage, perforation, and fistula
formation. As in patients with squamous carcinoma of the esoph-
agus, by the time cases of esophageal adenocarcinoma become
symptomatic, the disease is generally far advanced and the prognosis
is poor (25,26).
Key Points: Clinical Features
■ In squamous cell carcinoma, dysphagia is the commonest
presenting symptom and indicates that the lumen has been
reduced by 50% to 70%; two-thirds of its circumference is
involved; the disease is incurable
■ In adenocarcinoma, symptoms usually indicate that the disease
is far advanced and the prognosis poor
SURVEILLANCE AND SCREENING FOR
ESOPHAGEAL CANCER
The purpose of screening in asymptomatic individuals and/or sur-
veillance in persons at risk is the early detection and diagnosis of
esophageal cancer. This hopes to improve outcome on the assump-
tion that treatment of early disease has a better patient outcome
than that of symptomatic disease. Screening techniques used in
endemic regions include an abrasive balloon covered with a fine
mesh that is swallowed. The balloon is then inflated and pulled up
the esophagus. Other screening methods include a standard endo-
scopic brush via a nasogastric tube, or an expandable brush in a
dissolvable capsule that is retrieved by a string, and a suction abra-
sive tube. The cytologic material retrieved is then evaluated. These
techniques have an accuracy of 80% in mass screening projects (9).
In the United States and Europe, the overall incidence of esopha-
geal carcinoma is too low to justify mass screening (1,9). Although
there are a large number of risk factors and predisposing condi-
tions to the development of both squamous cell and adenocarci-
noma of the esophagus, the strength of evidence and predictive
value of surveillance techniques only justify selective surveillance
in a small subset of patients (13).
In patients with Barrett’s esophagus, any surveillance pro-
gramme must include intensive antiacid and antireflux measures,
and possible ablation therapy (6,14). While medical therapy does
not appear to modify the course of dysplasia or interrupt its
progression to cancer, it can suppress inflammation so that true
dysplasia can be more readily interpreted (22).
Patients with achalasia should have a surveillance programme
that also provides symptomatic relief by including effective dila-
tion to promote complete esophageal emptying and periodic
monitoring for signs and symptoms of esophageal retention. This
should be combined with endoscopy every two years (9).
In view of the predisposition to esophageal cancer and the need for
periodic monitoring and treatment of lye strictures, some form of
surveillance is indicated (21,22). The strategies and goals of this sur-
veillance programme are comparable to those for achalasia: upper
gastrointestinal endoscopy every two years to monitor the stricture
and treatment for any recurrence of obstructive symptoms (9,25,26).
Since patients with tylosis almost always develop squamous cell
carcinoma of the esophagus, periodic intensive surveillance is
indicated. Some advocate prophylactic esophagectomy as well.
This is an inherited disease so that asymptomatic family members
should also be screened.
Patients with head and neck cancer should also undergo radio-
logic or endoscopic surveillance for the development of metachro-
nous esophageal carcinomas (15). The esophagus must also be
evaluated at the time of initial diagnosis. The association is due to
the fact that both esophageal and oropharyngeal-laryngeal
cancers are related to alcohol and tobacco abuse.
Key Points: Surveillance and Screening
■ Mass screening techniques in endemic areas have an 80%
accuracy
■ Surveillance is conducted in high-risk individuals: patients
with Barrett’s esophagus, achalasia, scleroderma, lye strictures,
tylosis, and head and neck cancers
RADIOLOGIC DIAGNOSIS: BARIUM STUDIES
The esophagogram has a high sensitivity in the diagnosis of esoph-
ageal cancer and accurately predicts lesion length in 59% of patients
(27–30). Polypoid and stenotic tumors are more easily seen than
flat lesions. Squamous cell carcinoma and adenocarcinoma of the
esophagus cannot be reliably differentiated on barium studies.
Squamous cell carcinomas involve the upper and middle esopha-
gus whereas adenocarcinomas predominate in the distal esopha-
gus. Unlike squamous cell carcinoma, adenocarcinoma has a
marked tendency to invade the gastric cardia or fundus (27–30).
Squamous Cell Carcinoma
On double-contrast barium studies, early squamous cell carcino-
mas of the esophagus appear as: small sessile polypoid lesions
(Fig. 11.2A) with smooth or slightly lobulated contours; plaque-like
lesions (Fig. 11.2B) that often have flat, central ulcers (Fig. 11.2C)
that are best visualized in profile; or as superficial spreading lesions
with a nodular appearance of the mucosa without a discrete mass.
When early esophageal cancer or superficial spreading cancer is
suspected on double-contrast barium examinations, endoscopic
biopsy should be performed (27,31). Unfortunately, these early
esophageal cancers are often subtle lesions that can be missed due
to interpretive or perceptive error (27–30).
Features that favor submucosal spread of tumor include a pro-
truded or elevated component, a lobulated or irregular margin of
this elevated component and a rigid esophageal wall (27–30).
Advanced squamous cell carcinoma of the esophagus can
manifest on plain chest films by widening of the mediastinum,
thickened retrotracheal stripe, anterior tracheal bowing, or by an
air-fluid level within a dilated, obstructed esophagus (26).
On double-contrast barium studies advanced squamous cell carci-
nomas may appear: infiltrative (Fig. 11.3), ulcerative (Fig. 11.4),
polypoid (Fig. 11.5) or, less commonly, varicoid (Fig. 11.6). Many
lesions have mixed morphologic features resulting in considerable
overlap in the radiologic classification of these lesions. Advanced
carcinomas most commonly have an infiltrative appearance because
they tend to grow circumferentially in the esophageal wall. There is
131
 primary tumor evaluation and staging

(A) (B) (C)

Figure 11.2 Early squamous cell carcinoma of the esophagus—double contrast barium features: (A) polypoid, (B) plaque-like, (C) plaque-like and ulcerated.

(A) (B)
Figure 11.3 Infiltrating squamous cell carcinoma of the proximal third of the esophagus. (A) Esophagram shows lumen narrowing, abrupt shelf-like borders, ulceration,
and circumferential tumor growth. (B) Endoscopic evaluation shows abrupt margins of this constricting neoplasm.

luminal narrowing associated with mucosal nodularity, ulceration,
abrupt shelf-like proximal and distal borders, and varying degrees of
obstruction. By the time the neoplasms compromise the lumen suf-
ficiently to cause dysphagia, they are almost always advanced, unre-
sectable lesions. Some infiltrative lesions have more gradual, tapered
borders that may simulate the appearance of a benign stricture.
Thus, if an esophageal stricture has any irregular contours or suspi-
cious features, endoscopic biopsy should be performed to exclude a
malignant tumor (27–30).
These advanced infiltrative squamous cell carcinomas are
most commonly found in the upper or mid thoracic esophagus
and, less commonly, in the cervical or distal thoracic esophagus.
Cervical esophageal cancers are more likely to be missed on bar-
ium studies because the barium passes so rapidly through the
cervical esophagus that it is often difficult to obtain adequate
images of this region (27–30).
Squamous cell carcinomas can also present as polypoid intra-
luminal masses often containing areas of ulceration due to tumor

132
 esophageal cancer
Figure 11.4 Ulcerative advanced squamous cell carcinoma of the esophagus with a
fistula (arrow) to the tracheobronchial tree.
Figure 11.5 Polypoid advanced squamous cell carcinoma of the esophagus located
at the thoracic inlet. Double contrast esophagram shows a polypoid mass along the
right lateral aspect of the cervico-thoracic junction (arrow).
Figure 11.6 Double contrast esophagram demonstrates an advanced varicoid
carcinoma of the esophagus with serpiginous, non-changing filling defects
resulting from submucosal spread of tumor.
Figure 11.7 Meniscoid squamous cell carcinoma of the esophagus with a rind of
tumor surrounding a central ulcer (arrow).
necrosis. As these lesions enlarge, they tend to have a circumferen-
tial pattern of growth that narrows and obstructs the lumen.
Accordingly, if a bulky, polypoid esophageal mass expands or dilates
the esophagus, then less common lesions such as carcinosarcoma or
fibrovascular polyp should be suspected (29).
Other squamous cell carcinomas can manifest as primarily ulcer-
ative lesions with a giant meniscoid ulcer, surrounded by a thin,
radiolucent rind of tumor (Fig. 11.7). They can simulate benign
133
 primary tumor evaluation and staging

ulcers caused by cytomegalovirus, human immunodeficiency virus,
and oral medications (e.g., quinidine potassium chloride or non-
steroidal anti-inflammatory agents). The rind of tumor that sur-
rounds a malignant ulcer tends to be thicker and more irregular than
the pencil-thin rim of edema surrounding a benign ulcer (27–30).
Least commonly, squamous cell carcinomas of the esophagus
appear as varicoid defects manifested by multiple submucosal
lesions that may simulate varices in a single image. This lesion
results from the submucosal spread of tumor. These serpiginous
defects have a fixed, unchanging appearance at fluoroscopy
whereas true varices change in size and shape with changes in
esophageal distension, peristalsis, and distension. Patients with
varicoid carcinoma often present with dysphagia, a rare symptom
in patients with varices that are soft, compressible structures (27).
Some 5% to 10% of patients with esophageal cancer develop
esophageal-airway fistulas involving the trachea or left main
bronchus. These complications often develop following radiation
therapy (27–30).
Adenocarcinoma
On double-contrast barium studies, early adenocarcinoma
(Fig. 11.8) arising from Barrett’s mucosa can manifest as small
sessile polyps, plaque-like lesions, or superficial spreading lesions
that cause focal nodularity of the mucosa without a discrete mass.
These early cancers can also cause focal irregularity, flattening, or
nodularity in a pre-existing peptic stricture. Accordingly, early
endoscopy and biopsy are necessary to exclude adenocarcinoma
whenever any of these suspicious features develop in the region of
a peptic stricture (27–30).
Advanced adenocarcinoma of the esophagus can appear infil-
trating, polypoid, ulcerative, or less commonly, varicoid on bar-
ium studies (27,29). Many neoplasms have mixed morphologic
features so that considerable overlap exists in the radiologic clas-
sification of these lesions. Squamous cell carcinomas tend to be
located in the upper or midthoracic esophagus and only rarely
invade the adjacent stomach by contiguous spread. Adenocarci-
nomas develop predominantly in the distal thoracic esophagus
and have a marked tendency to invade the gastric cardia and
fundus, differentiating features from squamous cell carcinoma
(27,29). Gastric involvement by esophageal adenocarcinoma
may manifest on barium studies as an obvious polypoid or
ulcerative mass that is contiguous with the primary tumor in the
distal esophagus. In other cases, tumor invasion of the fundus
may be recognized only by obliteration or distortion of the

(C)

(A)

(B) (D)
Figure 11.8 Barrett’s esophagus and early adenocarcinoma. (A) Magnification endoscopic view demonstrates the salmon pink dysplastic intestinal type gastric mucosa
highlighted by the pearly white colored normal squamous cell mucosa of the esophagus. (B) Lugol’s iodine chromoendoscopy shows normal esophageal mucosa staining
dark with large patches of unstained mucosa due to high-grade intestinal dysplasia. (C) Photomicrograph shows dysplasia with cytologic atypia. (D) Double contrast
esophagram reveals surface nodularity (arrow) in this patient with Barrett’s esophagus and early adenocarcinoma.

134
 esophageal cancer

normal cardia landmarks associated with nodularity and ulceration spread, lymph node and distant metastases, multidetector CT,
in this region (27–30). and endoscopic ultrasound (EUS) have become the primary
It may not always be possible to differentiate esophageal ade- means of pretherapeutic tumor staging. PET and PET-CT are
nocarcinoma of the gastric cardia invading the distal esopha- now commonly employed for both staging and monitoring
gus from a Barrett’s cancer arising from the distal esophagus. A tumor response to therapy. MR imaging has a limited role in
primary gastric carcinoma should be suspected when the bulk staging of esophageal cancer.
of the tumor involves the gastric cardia and fundus and a pri- Esophageal cancer is staged by using the tumor, nodal, and metas-
mary esophageal adenocarcinoma should be suspected when tasis (T,N,M) system of categorization according to the American
the bulk of tumor involves the distal esophagus (27). Neverthe- Joint Committee on Cancer (AJCC). The stage groupings for the
less, these neoplasms have similar pathologic, clinical, and TNM classification also predict prognosis and survival statistics
prognostic features (5). (Tables 11.1 and 11.2).
On barium studies, advanced infiltrative adenocarcinomas There are a number of inadequacies in the current staging
present with ulceration, mucosal nodularity, and shelf-like or system (7,21). First, it does not specifically consider adenocarci-
tapered borders that may be indistinguishable from advanced nomas that arise at the GEJ. According to current definitions, a
squamous cell carcinomas (27). The correct diagnosis should be tumor arising in the region of the GEJ that involves less than 2 cm
made when the lesion is located in the distal esophagus or is of the esophagus is classified as a proximal gastric cancer without
associated with a hiatal hernia, GE reflux, or other signs of reflux consideration of the presence or absence of associated Barrett’s
disease (27). epithelium, which is a clear indication of the esophageal origin of
Polypoid adenocarcinomas can appear as lobulated or fungating these tumors. Second, it classifies “non regional” lymph nodes in
masses, often containing areas of ulceration. Varicoid carcinomas quite general terms while assigning tumors with metastases to
that spread submucosally can present as multiple submucosal
defects that simulate esophageal varices. Varicoid carcinomas have a
fixed, unvarying configuration at fluoroscopy, unlike varices. Some
adenocarcinomas may have a giant meniscoid ulcer surrounded Table 11.1 Esophageal Carcinoma: the TNM Staging System
by a thin rind of tumor (27–30). Primary tumor (T)
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
Key Points: Barium Studies Tis Carcinoma in situ
T1 Tumor invades lamina propria or submucosa
■ Squamous cell carcinoma and adenocarcinoma cannot T2 Tumor invades muscularis propria
reliably be differentiated on barium studies T3 Tumor invades adventitia
■ Early squamous cell carcinomas present as small sessile polypoid T4 Tumor invades adjacent structures
lesions, plaque-like lesions, or as superficial spreading lesions Regional lymph nodes (N)
with a nodular appearance of the mucosa N0 No regional lymph node metastasis
■ Advanced squamous cell carcinomas may appear infiltrative, N1 Regional lymph node metastases
ulcerative, polypoid, or less commonly, varicoid. Distant metastases (M)
■ Early adenocarcinoma arising from Barrett’s mucosa can Mx Distant metastases cannot be assessed
manifest as small sessile polyps, plaque-like lesions, or M0 No distant metastases
superficial spreading lesions that cause focal nodularity of M1 Distant metastases
the mucosa. Tumors of the lower thoracic esophagus:
■ Advanced infiltrative adenocarcinomas present with M1a Metastasis in celiac lymph nodes
ulceration, mucosal nodularity, and shelf-like or tapered M1b Other distant metastasis
borders that may be indistinguishable from advanced Tumors of the midthoracic esophagus:
squamous cell carcinomas M1a Not applicable
M1b Non-regional lymph nodes and/or other distant
metastasis
Tumors of the upper thoracic esophagus:
STAGING
M1a Metastasis in cervical nodes
Since a multimodality approach is presently used to treat esoph- M1b Other distant metastasis
ageal cancer, a precise histologic diagnosis and highly accurate Stage grouping
tumor staging is a prerequisite for selecting the most suitable Stage 0 Tis N0 M0
treatment option (31–34). This requires histologic classification Stage I T1 N0 M0
Stage IIA T2 N0 M0
of the tumor type, the exclusion of distant solid organ metasta-
T3 N0 M0
ses, localization of the primary tumor in relation to the tracheo- Stage IIB T1 N1 M0
bronchial tree, and determination of the penetration of the T2 N1 M0
primary tumor through the esophageal wall into the surrounding Stage III T3 N1 M0
structures. T4 Any N M0
Stage IVA Any T Any N M1a
By virtue of their cross-sectional imaging format and ability to
Stage IVB Any T Any N M1b
demonstrate the extent of mural invasion, extraluminal tumor

135
 primary tumor evaluation and staging

Table 11.2 Gastro-Esophageal Carcinoma: The TNM according to the depth of invasion into and beyond the wall of
Staging System the esophagus. An N0 tumor has no associated regional lymph
node involvement; these nodes contain tumor in N1 lesions. In
Primary tumor (T)
T0 No evidence of primary tumor
esophageal carcinomas, the following are the most relevant
Tis Carcinoma in situ regional lymph nodes:
T1 Tumor invades lamina propria or submucosa
T2 Tumor invades muscularis propria • Cervical esophagus—cervical and supraclavicular nodes
T3 Tumor penetrates the serosa (visceral perito- • Upper and middle intrathoracic esophagus—mediastinal
neum) without invasion of adjacent structure nodes including peri-esophageal, paratracheal, and
T4 Tumor invades adjacent structures subcarinal nodes
Regional lymph nodes (N) • Lower intrathoracic esophagus—lower mediastinal nodes
N0 No regional lymph node metastasis and perigastric lymph nodes excluding the celiac nodes
N1 Metastasis in perigastric lymph nodes within
3 cm of the edge of the primary tumor The important regional lymph nodes for carcinomas of the GEJ
N2 Metastasis in perigastric lymph nodes along the are divided into two groups:
left gastric, common hepatic, splenic, or celiac
arteries • Metastases in perigastric lymph nodes within 3 cm from
Distant metastases (M) the edge of the primary tumor are considered N1
M0 No distant metastasis • Metastases further than 3 cm from the edge of the primary
M1 Distant metastasis tumor or in lymph nodes along the left gastric, common
Stage grouping hepatic, splenic, or celiac arteries are considered N2
Stage 0 Tis N0 M0 Accurate non-invasive evaluation of individual lymph node groups
Stage IA T1 N0 M0 for the presence of metastases is essential for therapeutic planning.
Stage IB T1 N1 M0
T2 N0 M0
Involvement of more distant lymph nodes and metastases to other
Stage II T1 N2 M0 distant sites (e.g., liver, lung, adrenal glands) are classified as M1;
T2 N1 M0 the absence of distant metastases is classified as M0 (32).
T3 N0 M0
Stage IIIA T2 N1 M0
T3 N1 M0 Key Points: Staging
T4 N0 M0
Stage IIIB T3 N2 M0 ■ Accurate T, N, and M staging is essential in choosing the
T4 N1 M0 appropriate treatment regimen
Stage IV T4 N2 M0
■ MDCT, endoscopic ultrasound, PET scanning, and PET/CT
Any T Any N M1
are the primary means of staging esophageal cancer
■ MR has a more limited role in evaluating these patients
■ PET/CT and MDCT are useful for monitoring tumor
response to therapy
these lymph nodes as Stage IV disease, which is considered unre-
sectable. Third, the staging system does not consider the number
of metastatic lymph nodes, a factor of prognostic importance.
IMAGING IN STAGING
Finally, analysis of the performance of the current staging system
in patients undergoing resection has shown that survival estimates
do not differ significantly between several stage groups and that
Barium Esophagram
The double-contrast barium esophagram easily delineates the
TNM combinations in the same stage grouping are dissimilar (i.e.,
height, length, and extent of the tumor. The finding of a long
the survival probabilities are not homogeneous) (7,21).
(7–8 cm) stricture, or a stricture that changes in the axis of the
The process of preoperative staging of esophageal carcinoma
esophagus usually indicates T4 disease (27). Since only the mucosa
begins with the initial clinical assessment and proceeds through
is depicted, the esophagram is a diagnostic and not a staging tool.
investigations of increasing complexity (32,33). As with most
gastrointestinal malignancies, the clinical presence of signs and
symptoms almost invariably indicates advanced disease (26). Upper Gastrointestinal Endoscopy
For the purpose of TNM staging, the esophagus is divided into Esophageal cancers are divided into either superficial lesions
the cervical esophagus (cricopharyngeus muscle to thoracic confined to the submucosa or advanced tumors invading the
inlet); upper thoracic esophagus (thoracic inlet to carina); mid- muscularis propria and beyond. These endoscopic biopsy results
dle thoracic esophagus (carina to a point one half way between are a reasonably reliable source of staging information or early
the carina and the GEJ); and lower thoracic esophagus (from that cancers because of the very strong association of tumor depth and
point one half way between the carina and GEJ to the GEJ or any the incidence of lymph node metastases (20,21).
intra-abdominal esophagus). Because different sites are related to
different regional lymph node groups, it is important to deter- CT Evaluation
mine the exact site of the primary tumor. In the TNM staging Recent developments in MDCT allow the production of high
system (Fig. 11.9), the primary tumor is classified from Tis to T4 quality multiplanar reformatted images as well as the performance

136
 esophageal cancer

T1

T2

Mucosa
Lamina propria
Muscularis mucosa
Submucosa
Muscularis propria
Esophageal wall
(adventitia)

T3

T4

N1
Adjacent Involved
Cervical
mediastinal lymph nodes
esophagus
structures

Intra-thoracic
esophagus

N1

N1

N2

Figure 11.9 Staging esophageal cancer—primary tumor (T) and lymph nodes (N).

of CT esophagography (CTE). These improvements have lead
to increased diagnostic and staging accuracy for esophageal
carcinoma (35–39).
Determining T Status
The normal esophagus has a mural thickness of approximately
3 mm; any wall thickening greater than 5 mm is abnormal. The
presence of intraluminal air, contrast, or fluid facilitates the
measurement of wall thickness. Mural thickening (Fig. 11.10) is
the major CT finding of esophageal cancer. This is a nonspecific
finding that can also result from infection, inflammation, trauma,
and radiation injury (40).
Recent advances in MDCT have allowed visualization of the
primary neoplasm without mural thickening. Esophageal cancer
manifests as a hyper-enhancing mass seen best during the later
arterial phase, 35 seconds post-contrast medium injection (37).
Portal venous phase imaging will only depict the cancer in 80%
of cases (37). Since CT does not define the mural layers of the
esophageal wall, it cannot reliably differentiate Tis, T1, and T2
tumors. If the para-esophageal fat is obliterated or made ill-
defined by an abnormal soft tissue mass, T3 disease is sug-
gested. Endoscopic ultrasound is clearly superior to CT in T
staging of early esophageal neoplasms. CT is more successful in
the depiction of T4 tumors than earlier stage disease. CT has a
reported sensitivity of 25% to 54%, specificity of 58% to 84%,
and accuracy of 54% to 57% depending upon whether early
T1/T2, or more advanced T3/T4 tumors predominate in the
series (35).

137
 primary tumor evaluation and staging

(A) (B)

(C) (D)
Figure 11.10 MDCT staging of esophageal cancer: value of multiplanar reformatted images. (A) Axial, (B) coronal, and (C) sagittal images of a long segment adenocar-
cinoma of the esophagus invading the stomach. The axial images demonstrate marked mural thickening of the esophagus with hyperenhancement of the mucosa. (D)
The long segment of involved esophagus lies between the two arrows in B and C. Coronal reformatted image in a different patient with adenocarcinoma shows a mass
(black arrow) at the gastro-esophageal junction with subcarinal adenopathy (white arrow).

CT esophagography (Fig. 11.11) is a technique that employs the
same principles as CT colonography and CT gastrography. The
esophagus is distended with air by placing a nasogastric or orogastric
tube into the proximal esophagus for insufflation. A data set is
then acquired and images are viewed with two-dimensional,
three-dimensional, multiplanar reformations, and endoluminal
views. In one study, this technique proved to be more accurate
than conventional axial image assessment in estimating tumor
length and the degree of tumor extension into the stomach (36).
Tracheobronchial Invasion
The preoperative identification of tracheobronchial invasion is
important because it may make tumor resection, particularly
by the transhiatal route, more difficult or even impossible.
The demonstration of a tracheobronchial fistula or the exten-
sion of tumor into the airway lumen is a specific sign of
invasion (36).
The posterior wall of the normal cervical trachea often has a
concave (inward bowing) appearance; however, the intrathoracic
trachea should have a convex (outward bowing) or linear appear-
ance. Tracheobronchial invasion should be suspected if an esoph-
ageal tumor either causes inward bowing of the posterior tracheal
or bronchial wall or displaces the trachea and/or bronchi away
from the spine (Fig. 11.12A) (27).
Invasion may also be present if the fat planes between the
esophagus and airway are lost at the level of the tumor but are

138
 esophageal cancer

(A) (B)

(C) (D)
Figure 11.11 MDCT esophagography. Adenocarcinoma of the distal esophagus (arrows) depicted on (A) coronal, (B) sagittal reformatted images obtained following insuf-
flation of air into the proximal esophagus via a nasogastric tube. (C) The luminal narrowing can also appreciated on the endoluminal 3-D view and (D) the shaded surface
display image.

preserved above and below the tumor. This criterion should be
used with caution because there are often no fat planes between
the esophagus and trachea. The likelihood of airway invasion
increases with the presence of respiratory symptoms, tumor
length, and T stage on EUS. CT has an accuracy of 85.1% when
compared to bronchoscopy in regard to impingement, displacement,
and invasion of the trachea and bronchi (27,29).
Pericardial Invasion
Pericardial invasion by esophageal cancer is rare, found in only
1% of patients at autopsy (23). Invasion should be suspected on
CT if a tumor extends directly into the pericardium, obliterating
the fat planes at this level, provided that normal fat planes exist
immediately above and below the tumor mass. If peri-esophageal
fat planes are absent at all levels, often seen in cachectic patients,
CT cannot accurately assess tumor invasion. Other signs sug-
gestive of invasion include pericardial thickening adjacent to
tumor, pericardial effusion, and inward deformity of the heart
(Fig. 11.12B) (35).
Aortic Invasion
The middle and lower intrathoracic esophagus lies in close prox-
imity to the aorta, particularly at the level of the carina and main-
stem bronchi. Invasion of the aorta by esophageal carcinoma is
found in only 3% of patients at autopsy (22). Because fat planes are
often absent between the esophagus and aorta, the criterion of fat

139
 primary tumor evaluation and staging

(A) (B)

(C) (D)
Figure 11.12 MDCT: T-staging. (A) Tracheal invasion is indicated by the posterior bowing (arrow) of the trachea by the esophageal tumor. (B) Invasion of the pericar-
dium and left atrium is suggested by bowing of the cardiac border. Invasion was confirmed by echocardiography. (C) Aortic invasion is signified by loss of the triangle
of fat between the aorta, spine, and esophagus. The angle subtended by the tumor and aorta is 180° (arrows). (D) By comparison, the fat (long thin arrow) is preserved
in this patient with an ulcerating, enhancing cancer (short thick arrow) along the anterior aspect of the distal esophagus.

plane obliteration cannot be used to predict tumor invasion of the
aorta. Tumor invasion of the aorta (Fig. 11.12C) is unlikely if the
mass involves the aortic circumference by ≤90°, and contact of ≥90°
is highly suggestive of invasion and contact in the range of 45° to 90°
is indeterminate. Aortic invasion is also predicted when the small
triangle of fat between the esophagus, aorta, and spine (Fig. 11.12D)
is obliterated. Scanning the patient in the prone as well as supine
position may improve diagnostic accuracy by helping to downstage
patients with suspected aortic invasion (31,32,36).
Diaphragmatic Invasion
Distal esophageal tumors may invade the diaphragmatic crura
and manifest as a soft tissue mass obliterating the fat planes that
normally surround the crura. Crural invasion is more commonly
seen with adenocarcinoma than squamous cell carcinoma. Because
of the oblique course of the GEJ, it can be difficult to accurately
assess tumor invasion of the diaphragm by means of axial images.
This is of minor clinical importance since crural invasion does not
necessarily preclude tumor resection (34,35).
Determining N Status
The rich, interconnecting network of lymphatics along the entire
esophagus and lack of serosa contribute to the high prevalence
(60–80%) of mediastinal and lymph node metastases (Fig. 11.9)
at the time of diagnosis. Lymph node metastases should be sus-
pected if they are enlarged: ≥5 mm supraclavicular (Fig. 11.13);
≥6 mm retrocrural; ≥8 mm gastro-hepatic ligament; ≥1 cm most
lymph node groups in the peri-esophageal chain, other mediasti-
nal regions and the upper abdomen. Groups of multiple small
nodes are suspicious as well.
CT accuracy in assessing tumor involvement of nodes is limited
by a number of factors. False positives may occur in patients with
inflammatory or infectious lymphadenopathy. False negatives
occur because normal sized nodes may harbor tumor and small
peri-esophageal lymph nodes are frequently indistinguishable from
the primary tumor mass. Reported N staging sensitivity is 40%,
specificity 90%, and accuracy 70% (34,35,37). Subdiaphragmatic
lymph nodes are detected at a slightly higher rate (sensitivity 61%,
specificity 94%, accuracy 82%) (31,32). These findings suggest

140
 esophageal cancer
(A)
(C)
Figure 11.13 MDCT: N-staging. (A) CT scan obtained at the level of the thoracic inlet reveals an enlarged left supraclavicular lymph node (arrow) in this patient with
squamous cell carcinoma of the middle third of the esophagus. (B) This node was positive on the PET-CT scan. (C) This lymph node was biopsied under sonographic
guidance and pathologic evaluation confirmed the presence of metastases.
that when a lymph node is enlarged, there is a better than 90%
chance that it contains tumor, but that normal sized lymph nodes
often harbor tumor as well (25).
Determining M Status
In patients with newly diagnosed esophageal cancer, metastases
(Fig. 11.14) are seen in the liver in 35%, lung 20%, bone 9%, kidney
2%, brain 2%, and 1% each pericardium, pleura, soft tissues,
stomach, pancreas, and spleen (17).
MDCT scan has a reported sensitivity of 89% and a positive
predictive value of 95% in the detection of hepatic metastases. In a
cohort of patients with squamous cell carcinoma, the detection of
solitary lung metastases was rare at the time of the diagnosis of the
primary cancer. Most nodules were either benign or a synchronous
primary lung cancer (40,41).
The presence of ascites, pleural effusion, or nodules in the omen-
tum or pleura are suspicious for metastases to these mesothelial-
lined surfaces. Minimally invasive laparoscopy and thoracoscopy
can confirm these findings.
CT Monitoring Tumor Response to Therapy
The results of MDCT in assessing tumor response to neoadjuvant
chemotherapy and radiation therapy have been mixed (38–50).
Beer reported volumetric tumor measurements performed two
(B)
weeks after initiation of neoadjuvant chemotherapy predicted
histopathologic tumor response with 100% sensitivity and 53%
specificity (42). In one study, post-chemotherapy CT predicted
pathological T stage with an accuracy of 88% and N stage with
accuracy of 84%. Six of fourteen tumors considered unresectable
on CT pre-chemotherapy were considered resectable post-
chemotherapy. Post-chemotherapy CT predicted surgical resectabil-
ity with an accuracy of 88%, the main pitfall being underestimation
and overestimation of tracheobronchial invasion (43).
Key Points: Computed Tomography
■ CT is poor for early T stage tumors
■ CT is inaccurate in demonstrating subtle nodal disease
■ CT is accurate in demonstrating tracheobronchial, aortic,
pericardial, and diaphragmatic invasion
■ CT is accurate in detecting metastases to the adrenal glands,
omentum, and para-aortic lymph nodes
Endoscopic Ultrasound
By virtue of its ability to visualize the various layers of the esopha-
geal wall and peri-esophageal tissues, endoscopic ultrasound has
proven very useful in the staging of esophageal carcinoma
141
 primary tumor evaluation and staging

(A) (B)

(C)
Figure 11.14 MDCT: M-staging. (A) Scan obtained beneath the level of the carina shows invasion (arrow) of the mediastinal fat by this squamous cell carcinoma. (B) A
scan obtained at a more superior level shows a pulmonary metastasis (arrow). (C) Bilateral adrenal metastases are also present (arrows).

(Table 11.3) (44,45). Normally, five ultrasonic layers of alternating
echogenicities are identified:
• An inner hyperechoic layer (superficial mucosa),
surrounded by a
• Hyperechoic layer (superficial mucosa), surrounded by a
• Hyperechoic layer (muscularis mucosae), surrounded by a
• Hyperechoic layer (submucosa), surrounded by a
• Hypoechoic layer (muscularis propria), which in turn is
surrounded by a
• Hyperechoic ring (adventitia)
On EUS, esophageal carcinomas manifest as hypoechoic masses
that disrupt the normal five-layer mural stratification of the
esophagus (Fig. 11.15). Endoscopic ultrasound nicely depicts the
depth of mural penetration and invasion of tumor into the peri-
esophageal tissues. Endoscopic ultrasound also shows tumor inva-
sion into most surrounding structures, which is important for
planning therapy (46–49).
Tumor stenosis that prevents the passage of the endoscope is a
major limitation of EUS and occurs in 19% to 63% of examinations.
These are usually T3 or T4 lesions and, although only the prox-
imal portion of the tumor is seen on EUS, fairly accurate T stag-
ing is still possible. Smaller caliber, endoluminal high frequency
probes may improve tumor visualization in these cases. These
20 MHz probes are passed through the biopsy channel of the
endoscope and can accurately determine T stage in 85% to 90%
of patients (50–55).
The reported accuracy of EUS in assessing depth of tumor
penetration (T stage) ranges from 85% to 90%. Tumor overstaging
usually results from peritumoral inflammation and understaging
relates to microscopic invasion beneath the spatial resolution of
EUS (56,57).
Determining N Status
By evaluating nodal morphology and echo architecture, EUS
can demonstrate tumor involvement in lymph nodes that are as
small as 4 to 5 mm in size (57). Well marginated, spherical,
hypoechoic lymph nodes that are less sharply demarcated are
usually malignant (Fig. 11.15). Lymph nodes that have a bean
or elongated shape, and a more hypoechoic pattern are more
likely benign. False positive results occur in patients with

142
 esophageal cancer

inflammatory nodes, usually due to granulomatous infection Determining M Status

that mimics the appearance of malignant nodes. Micrometastases
in normal-sized malignant nodes beneath the spatial resolution
of EUS are responsible for false negative results. Some authors
use a 5 mm or larger size criterion to indicate malignancy. Endo-
scopic ultrasound-guided lymph node biopsy should help over-
come the limitations of N staging on EUS and improve staging
accuracy (54,55,58).
Although EUS can image portions of the liver and celiac lymph
nodes, this technique is not useful for the evaluation of distant
metastases (M stage) due to limited depth of the transducer field.
Computed tomography and FDG PET scans are superior in this
regard (59–63).
Key Points: Endoscopic Ultrasound

Table 11.3 Gastro-Esophageal Carcinoma: Endoluminal ■ EUS is very accurate in assessing depth of tumor penetration
Ultrasound Staging (T stage)
■ EUS is accurate in a depicting local peri-esophageal and gastric
ES–T1 Hypoechoic tumor localized in the mucosa or submucosa
adenopathy
ES–T2 Hypoechoic tumor with penetration into muscularis
propria ■ EUS is inadequate for assessing distant metastases
ES–T3 Hypoechoic tumor with penetration in adventitia ■ Tumor stenosis prevents adequate assessment in 30% of
ES–T4 Hypoechoic tumor with penetration into adjacent patients
structures
N0 Hyperechoic indistinctly demarcated lymph nodes
N1 Hypoechoic clearly demarcated lymph nodes or direct
invasion of tumor into nodes Magnetic Resonance Imaging
M0 No distant spread Magnetic resonance is useful in staging advanced malignancies,
M1 Distant spread providing information for determining regional resectability
Staging and for planning subsequent therapy in patients treated by com-
0 Tis N0 M0 bined radiation and chemotherapy (64–69). MDCT and MR are
I T1 N0 M0 relatively equal in their ability to detect invasion of the aorta,
IIA T2 N0 M0 tracheobronchial tree, and heart.
T3 N0 M0
Standard MR, like CT, cannot reveal the depth of mural inva-
IIB T1 N0 M0
T2 N1 M0
sion because it cannot distinguish the layers of the wall. Magnetic
III T3 N1 M0 resonance cannot distinguish lesions limited to the submucosa
T4 N1 M0 (T1) from those affecting the muscularis (T2), but usually can
IV Any T Any N M1 identify tumors invading the adventitia.
IVA Any T Any N M1a Surface-coil MRI can provide detailed imaging of the esopha-
IVB Any T Any N M1b
geal wall (66,67). Recent advances in high resolution MR shows

Ao

LN

(A) (B)
Figure 11.15 Endoscopic ultrasound staging of esophageal carcinoma. (A) Stage T3N0 tumor (T) is depicted on this endosonogram. The arrow points to the tumor
invading the muscularis propria into the surrounding adventitia. (B) Stage T3N1 tumor (T) with a large, spherical, hypoechoic lymph node (LN) in the adventitial fat.
Abbreviation: Ao, aorta.

143
 primary tumor evaluation and staging

(A) (B) (C)

(D) (E)
Figure 11.16 Squamous cell carcinoma of the esophagus: MR features. Sagittal images of the esophagus were obtained (A) before and (B) following the intravenous
administration of gadolinium. Note the enhancing tumor (arrows) of the mid and distal esophagus. (C) Axial pre-contrast, (D) axial post-contrast, and (E) coronal
images in a different patient show an enhancing adenocarcinoma (arrows) of the distal esophagus.

MR useful in differentiating T2 from T3 lesions with a high
level of accuracy (66,67). Mural thickening and an alteration in
the cross-sectional appearance of the esophagus from the nor-
mal elliptical shape to circular helps to identify the location of
the tumor. Periesophageal nodular densities greater than 2 mm
in diameter separate from the esophageal wall are suspicious for
N1 disease. Uniformly high signal intensity fat on T1-weighted
images is indicative of N0 disease (66). The MR endoscope may
offer the potential advantage of high-resolution 3D tumor
reconstruction (68).
Esophageal carcinoma (Fig. 11.16) appears isointense relative to
the normal wall on T1-weighted images, with low-to-intermediate
signal intensity on proton-density images that slightly increases
on T2-weighted sequences. Esophageal neoplasms typically
enhance following IV administration of gadolinium–DTPA.
In patients with adequate mediastinal fat, extra-esophageal
spread of tumor is suggested on T1-weighted images when there is
hypointense signal extending from the primary mass into the
adjacent mediastinal fat coupled with irregularity in the external
margins of the lesion and interruption of the peri-esophageal fat.
Tumor masses larger than 4 cm are also always associated with
extra-esophageal tumor spread (69).
The MR criteria used to determine the presence of tracheo-
bronchial, pericardial, and aortic invasion are the same as are
utilized for CT. Involvement of the prevertebral fascial should be
suspected when the angle of contact with the vertebral body is
>180° and the interposed fat layer is lost. The size criteria for
mediastinal lymphadenopathy is identical for CT and MR (69).
Magnetic resonance is more accurate in the depiction of metastases
to the liver than CT, EUS, or conventional sonography (64).
Key Points: Magnetic Resonance
■ MR is superior to CT and non-intraoperative sonography in
the detection of liver metastases
■ The MR endoscope offers the potential of high resolution
T-staging
■ MR and CT are equivalent in their ability to detect invasion of
the aorta, tracheobronchial tree, and heart

144
 esophageal cancer
Figure 11.17 PET-CT of esophageal cancer: N staging. An isolated left cervical lymph node metastasis is present in this patient with cancer of the distal esophagus.
PET and PET-CT
Positron emission tomography scanning in esophageal cancer is
based on the fact that malignant tumors have increased glycolytic
activity and that FDG significantly accumulates in cells with active
glucose metabolism. FDG accumulates in 92% to 100% of esoph-
ageal cancers, with squamous cell carcinoma being slightly more
avid than adenocarcinoma. PET can map functional activity
before structural changes have occurred. Patients with high FDG
uptake [standard uptake values (SUV) > 3] have a shorter survival
than those with an SUV < 3 (70,71).
Recent technical advances have led to the development of com-
bined FDG PET and CT scanners. This fusion of morphologic
(CT) and functional (FDG PET) data dramatically improves the
diagnostic potential of either scanner alone. Having both imaging
technologies in a single scanner allows for more precise local-
ization of metabolic abnormalities (Fig. 11.17). Indeed, FDG
PET–CT may become the initial staging procedure for esophageal
neoplasms (72–79).
Determination of T Status
Because PET cannot differentiate between the layers of the esoph-
ageal wall or para-esophageal tissue, it has little role in the deter-
mination of the T status of esophageal tumors. Imaging can detect
primary esophageal neoplasms with a depth of invasion of T1b or
greater, but Tis and T1a tumors are undetectable. PET identifies
tumor in 80% of patients with esophageal cancer with 43% of T1
and 100% of T4 neoplasms being positive (75).
Determination of N Status
PET is superior to CT in assessing nonregional lymph nodes
(Fig. 11.17) as it identifies tumor in normal sized nodes where
uptake is not obscured by uptake in adjacent tissues. Because the
physiologic evaluation of esophageal cancers afforded by PET
relies both on the size of the metastatic nodes as well as the inten-
sity of FDG uptake and decay, it is possible to detect tumor in
normal sized lymph nodes.
PET cannot differentiate primary tumor from adjacent N1 disease.
PET is more accurate in detecting lymph node metastases in lung
cancer than in detecting esophageal cancer metastases. The reported
accuracy in detecting N disease in esophageal cancer is between
82.1% and 92.2% (80–82). PET has a greater accuracy in detecting
lymph nodes in the neck, upper thorax, and abdomen with a lower
sensitivity in the mid and lower thoracic regions (80).
Determination of M Status
PET-CT is superior to CT in screening for distant metastases (Fig.
11.18). In a meta-analysis of the various imaging modalities for
diagnosing hepatic metastases from colorectal, gastric, and esoph-
ageal cancer, PET had a sensitivity of 90%, MR 76%, CT 72%, and
transabdominal ultrasound 55% (75).
145
 primary tumor evaluation and staging
(A)
Figure 11.18 PET-CT of esophageal cancer: M staging. (A) Increased uptake is identified in this distal squamous cell carcinoma (arrow). Metastases to ribs, liver, and
lymph nodes are also evident. (B) Left hip metastases are evident as well.
Monitoring Tumor Response
PET-CT is currently the best imaging modality for assessing
tumor response to neoadjuvant therapy for esophageal carci-
noma. It can discriminate viable tumor from necrotic scar tissue,
not only after but also during chemotherapy. PET-CT is also use-
ful in distinguishing responders from non-responders early dur-
ing the course of chemoradiotherapy and has shown encouraging
results with high negative predictive values for early response to
neoadjuvant treatment in esophageal cancer. PET has been found
useful for following the response to induction chemotherapy and
radiation therapy for locally advanced esophageal cancer (83–85).
Low FDG uptake after therapy and reduction in the extent of
FDG uptake can provide a reliable assessment of tumor response
to therapy (83–85).
Some studies have shown little difference between CT and PET
in the initial staging (80–85). Others state that the relatively low
sensitivity for identifying local regional lesions precludes its
replacement by conventional CT. The primary advantage of PET
is its superior sensitivity for tumor detection and improved diag-
nostic value for distant metastatic sites, features that substantially
affect patient management decisions (83–87).
Therapy-induced changes in tumor glucose metabolism
detected by PET allow the selection of patients most likely to ben-
efit from neoadjuvant chemotherapy (88–91). Patients scanned
before and 14 days after initiation of chemotherapy in one series
could be divided into two categories: metabolic responders (>35%
decreased metabolic activity at the time of the second scan) and
non-responders (<35% activity at the time of the second scan).
Metabolic responders showed a high histopathologic response
rate (44%) with a three-year survival rate of 70%. Prognosis was
poor for metabolic nonresponders with a histopathologic response
rate of 3% and a three-year survival rate of 35%. This study sug-
gests PET should be performed early after the initiation of neoad-
juvant therapy at which stage it predicts response, prognosis, and
recurrence (92). These data provide the basis for clinical trials in
which preoperative treatment is stopped or changed to an alterna-
tive regimen for patients without a metabolic response early in
therapy (92).
146
(B)
Key Points: PET and PET–CT
■ PET cannot differentiate primary tumor from N1 disease
■ PET is superior to CT for detecting malignant lymph node
infiltration and hepatic metastases
■ PET–CT provides molecular imaging and anatomic data
improving the diagnostic potential of either modality
■ PET–CT has the potential to become the initial staging
procedure for esophageal neoplasms
Comparison of EUS, CT, MR, and PET
(Table 11.4 and Fig. 11.19)
Endoscopic ultrasound is more accurate than CT in local staging
of esophageal carcinoma and CT is more valuable in the detection
of distant metastases. Combining EUS and CT achieves the high-
est accuracy rate in TNM staging (86%) than either modality
alone. Accordingly, CT scan should be employed first to find dis-
tant metastases, and if none are present, EUS should be used for
local staging (72,74,76).
Computed tomography is readily available and is relatively
inexpensive. It provides exquisite anatomic detail of the chest and
abdomen in patients with esophageal cancer. The only reliable use
of CT in the determination of T stage is the exclusion of T4
tumors, which is suggested by the preservation of fat planes.
Enlarged lymph nodes are suspicious for metastatic disease but
require further study or tissue sampling if nodal metastases will
determine treatment. Its major use is in the detection of distant
metastatic disease; however, 30% to 60% of distant metastases
may be radiographically occult (72).
There is a significant learning curve for EUS staging of esopha-
geal cancer. This study should be performed at institutions where
there is a dedicated, experienced endoscopic ultrasonographer
with adequate instrumentation that allows specialty imaging and
EUS–FNA. Endoscopic ultrasound is the best means of clinically
determining T stage. The addition of EUS–FNA to routine EUS
evaluation of lymph nodes allows accuracy similar to the EUS
determination of T stage (72).
 esophageal cancer

Table 11.4 Gastro-Esophageal Carcinoma: Comparison local disease or evidence of nodal spread, neoadjuvant therapy
of Staging Techniques may be considered. The patient may be considered a candidate for
primary potentially curative surgery if no distant or advanced
Technique Advantages Disadvantages local disease is seen.
CT Advanced mediastinal disease Differentiating T stage Laparoscopy can be used to select patients in whom conven-
Tracheobronchial invasion Identifying involved lymph nodes tional non-invasive imaging has suggested resectable disease and
Distant metastases Tumors of gastro-esophageal identify those with “occult” liver or peritoneal metastases to
Liver junction
Lung
avoid unnecessary laparotomy. This technique is best suited for
Para-aortic nodes patients with tumors of the lower third of the esophagus or
EUS Early-stage disease Distant metastases tumors straddling the cardia that appear to be advanced on other
Differentiating T stage Tracheobronchial invasion imaging studies. In one series, staging laparoscopy avoided
Identifying involved nodes Tumor stenosis limits use in unnecessary laparotomy in 20% of patients and was most useful
advanced disease
in adenocarcinomas of the esophagus and GEJ (33).
MRI Advanced mediastinal disease Differentiating T stage
Tracheobronchial invasion Identifying involved nodes
Liver metastases Lung metastases THERAPY
18
FDG PET Distant metastases Local invasion
Response to treatment Expensive
18
FDG Fusion of functional and Local invasion
Depending on tumor stage and patient co-morbidities, there are a
PET–CT anatomic information Expensive number of therapeutic approaches to patients with esophageal
cancer: endoscopic mucosal resection (EMR), primary esophagec-
tomy, neoadjuvant or palliative chemotherapy/radiotherapy fol-
MDCT lowed by surgery, and palliative resection. Most of the therapeutic
modalities are associated with substantial morbidity and mortal-
ity. Accurate pretherapeutic staging is crucial to distinguish
Invasion or mets No invasion or mets patients with locoregional and systemic disease. Patients with dis-
tant metastases have no therapeutic curative approach, and are
STOP EUS with Bx only candidates for palliative treatment regimens (93–96).
The majority of patients with esophageal carcinoma will require
palliation and fall into two groups. First, those who for reasons of
Unresectable Resectable metastatic disease, age, co-morbid condition, or choice are unsuit-
able for radical surgery or chemotherapy and radiation therapy.
STOP PET/CT Second, those who have undergone treatment with curative intent
but the disease recurs. The goals of treatment are first to relieve
specific symptoms of dysphagia, mediastinal pain, and bleeding,
XRT + Chemo Surgery + XRT + Chemo
and second to delay death as a result of metastatic disease with
Figure 11.19 Staging of esophageal cancer—suggested algorithm. Abbreviations: minimal co-morbidity.
Bx, biopsy; Chemo, chemotherapy; CT, computed tomography; EUS, endoscopic Selection of palliative treatment must be individualized for each
ultrasound; MDCT, multi-detector computed tomography; PET, positron emission
patient and based on the physical characteristics and location of
tomography; XRT, radiation therapy.
the tumor, the performance status and age of the patient, tumor
burden, and expected survival.
The primary limitations of PET-CT for staging of esophageal
cancer are failure to detect metastatic deposits less than 1 cm in Key Points: Therapy of Esophageal Carcinoma
diameter and inability to determine T stage. Otherwise, PET-CT
has shown its superiority in the staging of esophageal cancers. ■ Endoscopic mucosal resection has a role in patients with disease
limited to the mucosa
■ Surgical resection is recommended for patients with localized
Key Point: EUS, CT, MR, and 18FDG PET
disease
■ At present, CT and EUS are the mainstays in the initial clini- ■ Advanced disease is treated with chemotherapy and

cal staging of esophageal cancer radiation; long-term cure is rare

■ PET-CT is rapidly becoming an indispensable tool in the ■ Radiation and chemotherapy may provide effective palliation

staging and follow-up of patients with cancer of the  There are multiple methods for endoscopic palliation

esophagus
Laparoscopic and Thoracoscopic Staging
Having obtained the non-invasive preoperative staging informa-
tion various treatment decisions will be made (71). If there is evi-
dence of advanced incurable disease with widespread metastases,
the patient will be considered for palliation alone. If there is bulky
Treating Stage 0–1 Neoplasms
The goal of therapy for Barrett’s esophagus with high-grade
dysplasia (carcinoma in situ) and Stage 1 esophageal cancer is
surgical resection with intent to cure. High-grade dysplasia is
rarely diagnosed outside of surveillance programs, but outcomes
are excellent when cancer is detected at this stage (93–96).

147
 primary tumor evaluation and staging
Conventional teaching suggests that all esophageal cancer requires
complete esophagectomy. Concern for the morbidity and mortality
of this operation has lead to the development of endoscopic mucosal
resection (EMR) for the excision of lesions limited to the mucosa.
Since lesions confined by the lamina propria have only a minimal
risk of lymph node or distant metastases, EMR obviates the risks
of surgery for patients with mucosal disease. The mucosa of the
esophagus is attached to the muscular layer by the loose connec-
tive tissue of the submucosa. Saline is injected into the submucosa
to lift the mucosa and minimize the risk of esophageal perfora-
tion. The musocal lesion can then be snared with electrocautery
using a cap-fitted endoscope. Trials using EMR to resect early
esophageal cancer have demonstrated five-year survival rates of
up to 95% (94–96).
Chemotherapy
Combined chemoradiotherapy is the standard of care in the non-
surgical management of esophageal cancer (97). Trials of pre-
operative chemotherapy followed by surgery have not shown a
consistent benefit. Preoperative chemoradiotherapy followed by
surgery continues to be actively studied in the surgical manage-
ment of locally advanced esophageal cancer. Pathologic complete
responses are seen in 20% to 40% of patients, with five-year survival
achieved in 30% to 35% (98). Newer agents, such as the taxanes
and irinotecan, have been evaluated in combined chemoradio-
therapy and appear promising. Increasing the dose of radiother-
apy, or adding a brachytherapy boost to chemoradiotherapy, has
not improved outcome of treatment in clinical trials. The advent
(A)
Figure 11.20 Efficacy of radiation and chemotherapy. (A) Squamous cell carcinoma of the esophagus before radiation and chemotherapy. (B) Note the dramatic response
to treatment.
148
of newer targeted therapies, including agents directed against
growth factor receptor pathways, tumor angiogenesis, and tumor
invasion and metastasis, is leading to a new generation of clini-
cal trials combining these agents with conventional cytotoxic
chemotherapy and radiation (97,98).
Radiation Therapy
Radiation therapy plays a key role in the management of unresec-
table esophageal cancer, both as a means of palliating dysphagia
and as an attempt to maintain long-term disease control. It is
uncommon, however, to achieve sustained remission with radiation
therapy alone (99,100).
Radiation therapy may be given following surgical resection,
concurrent with chemotherapy, or as neoadjuvant therapy with
chemotherapy prior to surgery (99,100).
External beam radiation therapy, using a dosage of 20 Gy in 5
fractions to 50.4 Gy in 28 fractions, can be used for either pallia-
tive or definitive treatment of esophageal cancer. This radiation is
delivered with cytotoxic systemic chemotherapy, generally using
multiple field techniques in an attempt to enhance the response
with an acceptable rate of morbidity (99,100). Squamous cell car-
cinomas are somewhat sensitive to external beam radiation therapy.
The effect is local shrinkage of tumor resulting in variable degrees
of palliation and an occasional cure (Fig. 11.20).
Neoplasms of the cervical and proximal thoracic esophagus
tend to be more radiosensitive than those located in the middle
and distal thoracic esophagus. Concurrent therapy with cisplati-
num and 5-fluorouracil and radiation is superior to radiation
(B)
 esophageal cancer

therapy alone in patients with localized carcinoma of the esopha-
gus as measured by control of local tumors, distant metastases and
survival (99,100).
Radiation therapy may transiently worsen dysphagia and this
usually peaks about five days into the course of treatment. Patients
may notice palliation as early as one week into a course of therapy
but may require an entire course of treatment to see a response.
Dysphagia may recur or slowly worsen at any time after radiation
therapy, even in the absence of tumor recurrence, and over 50% of
these patients will require peroral dilation (99,100).
The newest approach for radiation therapy is an intraluminal
after-loading delivery system using cobalt-60, iridium-192, or
cesium-137. Brachytherapy delivers a constant dose of localized
radiation and may be effective for the relief of dysphagia. It is
associated with a 10% complication rate if used concurrently with
chemotherapy.
Although it may be possible to further reduce postoperative
complications and mortality, the chances of improving long-
term prognosis seems small unless major breakthroughs occur
in radiation or chemotherapy.
Dilation, Stenting, and Photocoagulation (101–105)
Because few patients are cured of their tumor, palliation for dys-
phagia often is the only therapeutic goal in patients with esophageal
cancer (101). Peroral dilation can restore sufficient esophageal
lumen patency in more than 90% of patients. When dilation is not
successful, a peroral polyvinyl prosthesis, nitinol stent, Gianturco
stent, or Wallstent (Fig. 11.21) may be inserted by pulsion technique
through the stenosis, either radiologically or endoscopically
(102–104). This has proven to be a safe and highly effective method
for long lasting improvement of dysphagia. Metallic stents tend to
confer a slight quality of life and length of survival advantage when
compared to plastic endoprostheses. In patients with esophagopul-
monary or bronchial fistula, a perorally placed prosthesis blocks
leakage and stops pulmonary soilage (102–104).
Transendoscopic ablation by laser photocoagulation of obstruct-
ing intraluminal tumors is a promising, safe technique for palliation
of dysphagia. Indeed, patients with unresectable esophageal can-
cer are best palliated by either peroral prosthesis or by com-
bined therapy by laser ablation followed by external beam
radiation (106).

(A) (B) (C)

(D) (E) (F)

Figure 11.21 Palliative stent types for carcinoma of the esophagus. Photographs show FDA-approved covered esophageal stents: (A) the Z-stent; (B) the Ultraflex stent;
(C) the Wallstent II. (D) Coronal reformatted, (E) axial images, and (F) endoscopic views show a metallic Z-stent deployed in this patient with severe dysphagia and
inoperable cancer.

149
 primary tumor evaluation and staging

Surgery There are several techniques for re-establishing digestive conti-

When considering surgical resection for advanced esophageal
cancers, it is important to realize that survival remains at 25% at
one year and 10% at five years after surgery (105). Only about
20% of lesions are resectable. Survival rates increase dramatically
if no lymph nodes are involved, but this is rarely the case.
Esophagectomy combined with neoadjuvant chemotherapy and
radiation therapy does offer a survival advantage (107).
The choice of the surgical procedure is dependent on several
factors: the preoperative condition of the patient, preoperative
staging and findings at operation and the surgeon’s philosophy
about en bloc resection versus palliative procedures.
An en bloc resection includes the entire tumor mass, a margin
of normal esophagus and stomach to incorporate involved sub-
mucosal lymphatics, and all potential nodes. The surgical approach
to an en bloc resection can be a right thoracotomy with laparo-
tomy (Fig. 11.22), a left thoracotomy with a thoracoabdominal
incision (Fig. 11.23), or separate abdominal and cervical incisions
without thoracotomy (105).
A non-thoracotomy approach uses blunt dissection through a
cervical incision, and a transhiatal dissection (107). It is best
suited for distal lesions. This approach avoids a thoracotomy;
however, blind dissection precludes the possibility of wide
resection margins. Transhiatal esophagectomy (Fig. 11.24) is
associated with lower morbidity than transthoracic esophagec-
tomy with extended en bloc lymphadenectomy. However, disease-
free and long-term survival at five years is somewhat better with
the extended transthoracic approach (106).
nuity following esophagectomy. These methods use the stomach
or less commonly small bowel or colon via substernal, subcutane-
ous, or transpleural routes. Because of its proximity, rich vascular
supply, sufficient length to reach the anastomotic site, and need
for only one anastomosis, the stomach is the preferred reconstruc-
tive organ. A pyloroplasty or pyloromyotomy is performed to ensure
gastric emptying because of the effect of vagotomy, performed as
part of the esophagectomy (108–111).
Esophageal resection is an operation attended by one of the
highest surgical morbidities and mortalities. Complication rates
are considerably higher for resection of tumors of the middle and
proximal esophagus. Complications include:
• Anastomotic leak
• Torsion or gangrene of the gastric, colonic, or jejunal
“pull up”
• Subphrenic abscess
• Hemorrhage
• Wound infection and dehiscence
• Sepsis
• Anastomotic stricture
• Dumping syndrome
• Reflux esophagitis
The most frequent sources of morbidity include pneumothorax,
pleural effusion, pneumonia, and respiratory failure. Mediastinitis
and sepsis due to disruption at the anastomotic site cause serious
postoperative morbidity and mortality. GE anastomotic leak after

(A) (B) (C) (D)

Figure 11.22 Drawings illustrate transthoracic esophagectomy with a laparotomy and a right thoracotomy (Ivor Lewis procedure). In (A), an upper abdominal incision
(arrowhead) and a posterolateral thoracotomy (arrow) are made. In (B), the esophagus and its adjacent structures are dissected en bloc. Lymph node dissection is also
performed. Arrows indicate resection lines. In (C) and (D), an anastomosis is created between the remaining esophagus and the gastric tube. Straight arrow indicates the
pyloromyotomy, curved arrow indicates the intrathoracic (C) and cervical (D) anastomosis sites, arrowhead indicates the original cardioesophageal junction. Source:
From Ref. 91 (Fig. 11.1).

150
 esophageal cancer

(A) (B) (C)

Figure 11.23 Drawings illustrate transthoracic esophagectomy with a left thoracoabdominal approach. In (A), the posterior mediastinum and superior abdominal
compartment are approached with a single incision through the left sixth intercostal space (arrow). In (B), the esophagus and its adjacent structures are dissected en
bloc. Lymph node dissection is also performed. Arrows indicate resection lines. In (C), an anastomosis is created between the remaining esophagus and the gastric
tube. Arrow indicates the original cardioesophageal junction. Source: From Ref. 91 (Fig. 11.5).

(A) (B) (C) (D)

Figure 11.24 Drawings illustrate transhiatal esophagectomy without a thoracotomy. In (A), a cervical incision parallel to the anterior border of the left sternocleidomas-
toid muscle (arrowhead) and an upper abdominal incision (arrow) are made. In (B), the esophagus is dissected transhiatally by the surgeon passing his or her hand
through the widened hiatus. Combined circumferential dissection of the esophagus through both the cervical and abdominal wounds allows the esophagus to be com-
pletely mobilized. In (C), the esophagus and its adjacent structures are dissected. Lymph node dissection is also performed. Arrows indicate resection lines. In (D),
anastomoses are created between the remaining esophagus and the gastric tube. Straight arrow indicates the pyloromyotomy, curved arrow indicates the intrathoracic
anastomosis site, arrowhead indicates the original cardio-esophageal junction. Source: From Ref. 91 (Fig. 11.7).

151
 primary tumor evaluation and staging

cancer resection has a mortality rate of up to 60%. Covered esopha-
geal stenting can reduce mortality and morbidity of symptomatic
anastomotic leakage after surgery (108–111).
An esophagectomy can be performed with thoracoscopic and
laparoscopic techniques when feasible (Fig. 11.25). Endoscopic
instruments are capable of mobilizing the esophagus and stomach
as well as performing the gastric pull-up and esophagogastric
anastomosis.
DETECTION OF POSTOPERATIVE TUMOR RECURRENCE
In patients who have undergone surgical resection for esophageal
cancer, the recurrence rate is high, ranging from 34% to 79%
(112–114). The majority of patients present within one year of
operation and nearly all within two years of the primary surgery.
In approximately 30% of patients, the recurrence occurs in the
operative field with lymph node involvement or mediastinal
masses (35). Postoperative elevation of serum carcinoembryonic
antigen (CEA) has a sensitivity of 55%, specificity of 90%, and
In one autopsy series lymphatic and hematogenous spread of
tumor was seen in nearly equal proportions (42% and 40% of
patients, respectively). Thoracic adenopathy was more common
than abdominal nodal spread which in turn was more common
than cervical adenopathy (114).
Computed Tomography
Because of the high prevalence of extra-esophageal tumor spread at
the time of diagnosis, a significant number of patients present with
local or distal tumor recurrence after surgery. When evaluating
these patients, sufficient luminal distension is essential, as underdis-
tension of interposed stomach may result in a false diagnosis of
recurrent tumor. A baseline study several months following surgery
should be obtained to allow postoperative fluid, edema, or hemor-
rhage to resolve. CT findings of tumor recurrence include:
• Soft tissue masses in the mediastinum (Fig. 11.26) and
upper abdomen
• An intramural nodular mass in the interposed gastric wall

positive predictive value of 91% in detecting patients with recur-

rent esophageal cancer (20). Unlike colon cancer, there is no cor-
relation between preoperative CEA elevation and stage of tumor
or patient survival (21).
Recurrent esophageal carcinoma is usually both locoregional
and distant regardless of the type of therapy. Locoregional recur-
rences are usually extragastric in the mediastinum or in upper
abdominal lymph nodes. Tumors may recur in the intrathoracic
stomach or at the esophagogastric anastomosis (22).
Distant metastases adenocarcinoma most often occur due to
hematogenous spread of tumor to the liver (27%), bone (18%),
brain (11%), and lung (1%). Celiac and porta hepatis adenopathy
was observed in 25% of patients. Distant metastases can occur in
up to 40% of patients without locoregional lymph node spread.
• Peritoneal carcinomatosis; pulmonary, hepatic, or
adrenal metastases.
Without other CT signs of malignancy, the presence of isolated
pericardial or pleural fluid may only be a manifestation of
therapy (35).
Computed tomography is often more useful than barium stud-
ies or endoscopy in detecting recurrent tumor because these
lesions most often develop outside the lumen of the interposed
stomach. In one prospective study of a group of patients with
transhiatal esophagectomy and gastric interposition, 63% of
patients developed recurrent disease on CT although many of
these patients were asymptomatic. Only local recurrent disease
was found in 50% of patients and the other half had distant meta-
stases with or without local disease (112).

10 mm
10 mm

5 mm 5 mm
10 mm
5 mm
10 mm
5 mm
5 mm

(A) (B) (C) (D)

Figure 11.25 Drawings illustrate thoracoscopic port placement for minimally invasive esophagectomy. In (A), four thoracoscopic ports are introduced. The camera port
(10 mm) is placed at the seventh intercostal space on the midaxillary line. A 10 mm port is placed at the eighth or ninth intercostal space 2 cm posterior to the posterior
axillary line for the ultrasonic coagulating shears. Two additional ports are placed, one (5 mm) posterior to the tip of the scapula and one (10 mm) at the fourth inter-
costal space at the anterior axillary line for retraction of the lung and esophageal countertraction during dissection. Dotted line indicates the diaphragm. In (B), five
abdominal ports are placed on the anterior abdominal wall: one cut-down 10 mm port in the right side of the epigastrium and four 5 mm ports in the bilateral subcostal,
left epigastric, and right flank locations. Long dotted line indicates the diaphragm, short dotted line indicates the position of the neck incision. In (C), a pyloroplasty
(arrowhead) is performed using ultrasonic shears, and the incision is closed transversely. Then, a gastric tube (arrow) is constructed by dividing the stomach starting at
the distal lesser curve while preserving the right gastric vessels. In (D), an anastomosis (arrow) is created between the esophagus and the gastric tube. The gastric tube is
sutured using an end-to-end anastomosis stapler. Source: From ref. 91 (Fig. 11.12).

152
 esophageal cancer

(A) (B)

(C)
Figure 11.26 CT and PET-CT in recurrent diseases. (A) CT scan at the level of the thoracic inlet shows a large metastasis causing impression upon the trachea and
proximal esophagus (arrow). (B) Coronal reformatted image shows no definite recurrence at the level of the anastomosis (solid arrow). Broken arrow shows the gastric
pull up. (C) PET-CT shows marked FDG uptake by these nodes which contain recurrent tumor.

In another study, recurrence was found in 69% of symptomatic
patients and, in the majority of cases, local lesions were combined
with distant metastases. In these two series, recurrent tumors
developed 6 to 16 months after surgery. In a retrospective study of
patients with recurrent tumor, 61% had blood-borne metastases,
33% had lymph node metastases, and 33% had locoregional
recurrence (113).
In another study, PET-CT was significantly more sensitive,
specific, and accurate than CT alone (97.7%, 100%, 85.7% versus
77.3%, 61.7%, and 78.6%, respectively) for recurrent disease.
In a study comparing PET with CT and EUS in a group of
patients with suspected recurrent disease, the accuracy of PET for
peri-esophageal recurrence was 100% with a specificity of 57%
and accuracy of 74% (113).

PET-CT
PET-CT (Fig. 11.27) is less influenced by postsurgical and postra- Key Points: Detection of Postoperative Tumor
diation anatomic distortion than other imaging tests. In one Recurrence
group of postsurgical patients, only 8% were symptomatic but
■ Recurrent tumor is very common in esophageal carcinoma
35% had recurrent disease (112). PET was 100% sensitive but
with most patients presenting within one year of operation
only 75% specific for local recurrence compared to CT which was
■ On CT, the most common findings indicating recurrence are:
84% sensitive and 86% specific. PET is more sensitive than CT
soft tissue masses in the mediastinum and upper abdomen; an
for local recurrence since CT often has difficulty differentiating
intramural nodule in the interposed gastric wall; peritoneal,
postoperative change from recurrent tumor. PET is also more
lung, liver, or adrenal metastases
sensitive in the detection of bone and soft tissue metastases since
■ PET-CT is less influenced by postsurgical and postradiation
the entire body is imaged and recurrent tumor may be outside
anatomic distortion than other imaging tests
the scanning plane of CT.

153
 primary tumor evaluation and staging

L R L

L R L

Figure 11.27 PET-CT showing recurrent peritoneal tumor (arrow).

In a study of 222 patients with resectable carcinoma of the esoph- chemopreventive agents have shown promise in reducing the risk
agus (65% adenocarcinomas; 78% lower third of esophagus or car- of developing esophageal cancer in some populations.
dia), the following features were associated with a poorer prognosis:
black race, history of weight loss, poor or moderate differentiation,
full thickness invasion, positive lymph nodes, Ivor–Lewis esophagec- Summary
tomy, intraoperative blood transfusion, tumor location in the upper
■ Adenocarcinoma of the esophagus and GEJ has experienced
or middle third in node positive patients (81).
the most rapid rate of increase of any solid malignancy in the
Western world. Barrett’s esophagus metaplasia is the most
common precursor
CONCLUSION ■ Squamous cell carcinoma of the esophagus has the widest
variation in incidence of any neoplasm. Risk factors include:
Despite recent advances in the detection, staging, and therapy of
alcohol and tobacco use, environment and diet, increasing
esophageal carcinoma, it remains a lethal disease (115,116). In the
age, black race, alchalasia, head and neck cancers, lye strictures,
future, improvements in overall patient survival can only be
tylosis, and sprue
achieved by tailored therapeutic strategies, which are based on
■ A multimodality approach is used to treat esophageal cancer
individual histologic tumor type, tumor location, tumor stage at
so that highly accurate tumor staging is a prerequisite to
the time of presentation, consideration of established prognostic
selecting the most suitable treatment options
factors, and the physiologic status of the patient. Elucidation of
■ EUS is superior to CT and MR in assessing T stage and
the biochemical and genetic events that regulate and correlate
detecting tumor in normal sized local lymph nodes
with different stages of carcinogenesis will lead to development of
■ MR and CT are equal in their ability to detect local invasion, but
markers than can be employed diagnostically, prognostically, and
MR is slightly more accurate in the depiction of liver metastases
therapeutically. Innovations in novel molecular-based and bio-
■ Curative treatment in resectable cancers employs a combined
logic therapeutic agents, such as an epidermal growth factor
modality approach using preoperative chemoradiation
antagonist, will be required to improve therapy-related outcomes
and surgery, and for unresectable cancers, radiotherapy, and
and minimize treatment-related side effects.
sensitizing chemotherapy
Because prognosis is so closely related to stage at the time
■ FDG PET–CT is superior to CT, MR, and EUS in excluding
of diagnosis, high-risk populations need to be identified and
distant solid organ and lymph node metastases, and allows early
cost-effective strategies for screening and early detection need to
assessment of response of the primary tumor to neo-adjuvant
be developed. Early diagnostic biomarkers of esophageal cancer
treatment
could be useful for low-risk groups. Finally, prevention trials
■ Most patients will ultimately require palliation
should be pursued as dietary changes and NSAIDs and other

154
 esophageal cancer
REFERENCES
1. Mudan SS, Kang J-Y. Epidemiology and clinical presentation
in oesophageal cancer. In: Rankin SC, ed. Carcinoma of the
Esophagus. Cambridge: Cambridge University Press, 2008:
1–13.
2. Bashash M, Shah A, Hislop G, et al. Incidence and survival for
gastric and esophageal cancer diagnosed in British Columbia,
1990 to 1999. Can J Gastroenterol 2008; 22: 143–8.
3. Lepage C, Remontet L, Launoy G, et al. French network of cancer
registries (FRANCIM). Trends in incidence of digestive
cancers in France. Eur J Cancer Prev 2008; 17: 13–17.
4. He YT, Hou J, Chen ZF, et al. Trends in incidence of esopha-
geal and gastric cardia cancer in high-risk areas in China. Eur
J Cancer Prev 2008; 17: 71–6.
5. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA
Cancer J Clin. 2008; 58: 71–96.
6. Mortensen MB. Esophageal cancer: biology, natural history,
staging and therapeutic options. Minerva Med 2007; 98:
299–303.
7. Vallbohmer D, Brabender J, Schneider PM, et al. Epidemiology,
risk factors, and clinical manifestations of esophageal carci-
noma. In: Yeo CJ, ed. Surgery of the Alimentary Tract, 6th
edn. Philadelphia: WB Saunders, 2007: 441–7.
8. Gibbs JF, Rajput A, Chadha KS, et al. The changing profile of
esophageal cancer presentation and its implication for diagnosis.
J Natl Med Assoc 2007; 99: 620–6.
9. Siersam PD. Pathogenesis, diagnosis and therapeutic possi-
bilities of esophageal cancer. Curr Opin Gastroenterol 2007;
23: 456–61.
10. Esteller M. Epigenetics in cancer. N Engl J Med 2008; 358:
1148–59.
11. Deere HMR. Pathology of esophageal cancer. In: Rankin SC,
ed. Carcinoma of the Esophagus. Cambridge: Cambridge
University Press, 2008: 14–27.
12. Vieth M, Stolte M. Pathology of early upper GI cancer. Best
Practice Reseach Clin Gastroenterol 2005; 19: 857–69.
13. Wang KK, Sampliner RE. Update guidelines 2008 for the
diagnosis, surveillance, and therapy of Barrett’s esophagus.
Am J Gastroenterology 2008; 103: 788–97.
14. Musana AK, Resnick JM, Torbey CF, Mukesh BN, Greenlee
RT. Barrett’s esophagus: incidence and prevalence estimates
in a rural Mid–Western population. Am J Gastroenterol
2008; 103: 516–24.
15. Fortuny J, Johnson CC, Bohlke K, et al. Use of anti-
inflammatory drugs and lower esophageal sphincter-relaxing
drugs and risk of esophageal and gastric cancers. Clin Gastro-
enterol Hepatol 2007; 5: 1154–9.
16. Thompson CL, Khiani V, Chak A, Berger NA, Li L. Carbohy-
drate consumption and esophageal carcinoma. Am J Gastro-
enterol 2008; 103: 555–61.
17. Odze R, Antonioli DA. Pathology of gastric cancer. In: Rustgi
AK, ed. Gastrointestinal Cancers. Edinburgh: W B Saunders,
2003: 253–70.
18. Glickman JN, Odze RD. Pathology and natural history of
esophageal cancer. In: Abbruzzese JL, Evans DB, Willett CG,
Fenoglio-Preiser C, eds. Gastrointestinal Oncology. Oxford:
Oxford University Press, 2004: 167–81.
19. Glickman JN, Odze RD. Epithelial neoplasms of the esopha-
gus. In: Odze RD, Goldblum JR, Crawford JM, eds. Surgical
Pathology of the GI Tract, Liver, Biliary Tract and Pancreas.
Philadelphia: W B Saunders, 2004: 381–408.
20. Sabik JF, Rice TW, Goldblum JR, et al. Superficial esophageal
carcinoma. Ann Thorac Surg 1995; 60: 896–902.
21. Hagen JA, Louie BE. Carcinoma of the esophagus and gas-
troesophageal junction. In: Yeo CJ, ed. Surgery of the Alimen-
tary Tract, 6th edn. Philadelphia: W B Saunders , 2007: 441–7.
22. Bronner MP, Geisinger KR. The esophagus. In: Silverberg SG,
ed. Surgical Pathology and Cytopathology. Philadelphia:
Churchill Livingstone, 2006: 1281–321.
23. Prasad GA, Buttar NS, Wongkeesong LM, et al. Significance
of neoplastic involvement of margins obtained by endoscopic
mucosal resection in Barrett’s esophagus. Am J Gastroenterol
2007; 102: 2380–6.
24. Gore RM, Meyers MA. Pathways of abdominal and pelvic
disease spread. In: Gore RM, Levine MD, eds. Textbook of Gas-
trointestinal Radiology, 3rd edn. Philadelphia: W B Saunders,
2008: 2099–118.
25. Ginsberg GG, Fleischer DE. Esophageal tumors. In: Feldman
M, Friedman LS, Brandt LJ, eds. Gastrointestinal and Liver
Disease, 8th edn. Philadelphia: W B Saunders, 2006: 647–74.
26. Carey EJ, Fleischer DE. Esophageal cancer. In: Weinstein
WM, Hawkey CJ, Bosch J, eds. Clinical Gastroenterology and
Hepatology. Philadelphia: Elsevier, Mosby, 2005: 179–88.
27. Levine MS, Halvorsen RA. Carcinoma of the esophagus. In:
Gore RM, Levine MD, eds. Textbook of Gastrointestinal
Radiology, 3rd edn. Philadelphia: W B Saunders, 2008:
417–46.
28. Lee SS, Ha HK, Byun JH, et al. Superficial esophageal cancers:
esophagographic findings correlated with histopathologic
findings. Radiology 2005; 236: 535–44.
29. Levine MS, Rubesin SW. Diseases of the esophagus: diagnosis
with esophagography. Radiology 2005; 237: 414–27.
30. Kato H, Momma K, Yoshida M. Early esophageal cancer:
radiologic estimation of invasion into the muscularis mucosae.
Abdom Imaging 2003; 28: 464–9.
31. Caputo FM, Buquicchio GL. Esophageal cancer staging: the
role of radiology. Rays 2005; 30: 309–14.
32. Patel AN, Buenaventura PO. Current staging of esophageal
carcinomas. Surg Clin N Am 2005; 85: 555–67.
33. de Graaf GW, Ayantunde AA, Parsons SL, Duffy JP, Welch NJ.
The role of staging laparoscopy in oesogastric cancers. Eur J
Surg Oncol 2007; 33: 988–92.
34. Fiore D, Baggio V, Ruol A, et al. Multimodality imaging of
esophagus and cardia cancer before and after treatment.
Radiol Med 2006; 111: 804–17.
35. Bogot NR, Quint LE. CT in esophageal cancer. In: Rankin SC,
ed. Carcinoma of the Esophagus. Cambridge: Cambridge
University Press, 2008: 62–84.
36. Kim SH, Lee JM, Han JK, et al. Three-dimensional MDCT
imaging and CT esophagography for evaluation of esopha-
geal tumors: preliminary study. Eur Radiol 2006; 16:
2418–26.
37. Umeoka S, Koyama T, Togashi K, et al. Esophageal cancer:
evaluation with triple-phase dynamic CT—Initial experience.
Radiology 2006; 239: 777–83.
155
 primary tumor evaluation and staging
38. Sandha GS, Severin D, Postema E, McEwan A Stewart K. Is
positron emission tomography useful in locoregional staging
of esophageal cancer? Results of a multidisciplinary initiative
comparing CT, positron emission tomography, and EUS.
Gastrointest Endosc 2008; 67: 402–9.
39. Gollub MJ, Hong R, Sarasohn DM, Akhurst T. Limitations of
CT during PET/CT. J Nucl Med 2007; 48: 1583–91.
40. Onishi H, Murakami T, Kim T, et al. Hepatic metastases:
detection with multi-detector row CT, SPIO-enhanced MR
imaging, and both techniques combined. Radiology 2006;
239: 131–8.
41. Rappaport ED, Loft A. Liver metastases from colorectal cancer:
imaging with superparamagnetic iron oxide (SPIO)-enhanced
MR imaging, computed tomography and positron emission
tomography. Abdom Imaging 2007; 32: 624–34.
42. Walker SJ, Allen SM, Steel A, Cullen MH, Matthews HR.
Assessment of the response to chemotherapy of oesophageal
cancer. Eur J Cardiothorac Surg 1991; 5: 519–22.
43. Griffith JF, Chan AC, Chow LT, et al. Assessing chemotherapy
response of squamous cell oesophageal carcinoma with
spiral CT. Br J Radiol 1999; 72: 678–84.
44. Law S. Esophageal cancer: current staging classifications and
techniques, endoscopic ultrasound, nand laparoscopic and
thoracoscopic staging. In: Yeo CJ, ed. Surgery of the Alimentary
Tract, 6th edn. Philadelphia: W B Saunders, 2007: 465–86.
45. Pfau PR, Perlman SB, Stanko P, et al. The role and clinical
value of EUS in a multimodality esophageal carcinoma staging
program with CT and positron emission tomography.
Gastrointest Endosc 2007; 65: 377–84.
46. Erasmus JJ, Munden RF. The role of integrated computed
tomography positron-emission tomography in esophageal
cancer: staging and assessment of therapeutic response.
Semin Radiat Oncol 2007; 17: 29–37.
47. Onba O, Eroglu A, Kantarci M, et al. Preoperative staging of
esophageal carcinoma with multidetector CT and virtual
endoscopy. Eur J Radiol 2006; 57: 90–5.
48. Panebianco V, Grazhdani H, Iafrate F, et al. 3D CT protocol
in the assessment of the esophageal neoplastic lesions: can it
improve TNM staging? Eur Radiol 2006; 16: 414–21.
49. Gollub MJ, Lefkowitz R, Moskowitz CS, et al. Pelvic CT in
patients with esophageal cancer. AJR Am J Roentgenol 2005;
184: 487–90.
50. Law S. Esophageal cancer: current staging classifications and
techniques, endoscopic ultrasound, and laparoscopic and
thoracoscopic staging. In: Yeo CJ, ed. Surgery of the Alimen-
tary Tract, 6th edn. Philadelphia: W B Saunders, 2007:
465–86.
51. Lennon AM, Penman ID. Recent advances in the endoscopic
diagnosis of esophageal cancer. In Rankin SC, ed. Carcinoma
of the Esophagus. Cambridge: Cambridge University Press,
2008: 28–43.
52. Lennon AM, Penman ID. Endoscopic ultrasound in esopha-
geal cancer. In: Rankin SC, ed. Carcinoma of the Esophagus.
Cambridge: Cambridge University Press, 2008: 44–61.
53. Puli SR, Reddy JB, Bechtold ML, et al. Staging accuracy of
esophageal cancer by endoscopic ultrasound: a meta-analysis
and systematic review. World J Gastroenterol 2008; 14:
1479–90.
156
54. Lok KH, Lee CK, Yiu HL, et al. Current utilization and
performance status of endoscopic ultrasound in a community
hospital. J Dig Dis 2008; 9: 41–7.
55. van Vliet EP, Heijenbrok-Kal MH, Hunink MG, Kuipers EJ,
Siersema PD. Staging investigations for oesophageal cancer: a
meta-analysis. Br J Cancer 2008; 98: 547–57.
56. Cen P, Hofstetter WL, Lee JH, et al. Value of endoscopic
ultrasound staging in conjunction with the evaluation of
lymphovascular invasion in identifying low-risk esophageal
carcinoma. Cancer 2008; 112: 503–10.
57. Vazquez-Sequeiros E, Foruny-Olcina JR. Linear EUS: the
clinical impact of N staging in esophageal carcinoma. Minerva
Med 2007; 98: 313–19.
58. Shimpi RA, George J, Jowell P, Gress PG. Staging of esophageal
cancer by EUS: staging accuracy revisited. Gastrointest
Endosc 2007; 66: 475–82.
59. Moorjani N, Junemann-Ramirez M, Judd O, Fox B, Rahamim
JS. Endoscopic ultrasound in esophageal carcinoma: com-
parison with multislice computed tomography and impor-
tance in the clinical decision making process. Minerva Chir
2007; 62: 217–23.
60. Kaushik N, Khalid A, Brody D, Luketich J, McGrath K.
Endoscopic ultrasound compared with laparoscopy for
staging esophageal cancer. Ann Thorac Surg 2007; 83: 2000–2.
61. Mortensen MB, Edwin B, Hünerbein M, et al. Impact
of endoscopic ultrasonography (EUS) on surgical decision-
making in upper gastrointestinal tract cancer: an international
multicenter study. Surg Endosc 2007; 21: 431–8.
62. Jones DB. Role of endoscopic ultrasound in staging
upper gastrointestinal cancers. ANZ J Surg 2007; 77:
166–72.
63. Marsman WA, Fockens P. EUS for esophageal tumors.
Endoscopy 2006; 38: S17–S21.
64. Riddell AM, Richardson C, Scurr E, Brown G. The develop-
ment and optimization of high spatial resolution MRI for
imaging the oesophagus using an external surface coil. Br J
Radiol 2006; 79: 873–9.
65. Dave UR, Williams AD, Wilson JA, et al. Esophageal cancer
staging with endoscopic MR imaging: pilot study. Radiology
2004; 230: 281–6.
66. Riddell AM, Allum WH, Thompson JN, et al. The appear-
ances of oesophageal carcinoma demonstrated on high-
resolution, T2-weighted MRI, with histopathological
correlation. Eur Radiol 2007; 17: 391–9.
67. Riddell AM, Richardson C, Scurr E, et al. The development
and optimization of high spatial resolution MRI for imaging
the oesophagus using an external surface coil. Br J Radiol
2006; 79: 873–9.
68. Riddell AM, Hillier J, Brown G, et al. Potential of surface-coil
MRI for staging of esophageal cancer. AJR Am J Roentgenol
2006; 187: 1280–7.
69. Giovagnoni A, Valeri G, Ferrara C. MRI of esophageal cancer.
Abdom Imaging 2002; 27: 361–6.
70. Rankin SC. FDG-PET and PET/CT in esophageal cancer. In:
Rankin SC, ed. Carcinoma of the Esophagus. Cambridge:
Cambridge University Press, 2008: 85–106.
71. Mamede M, El Fakhri G, Abreu-e-Lima P, et al. Pre-operative
estimation of esophageal tumor metabolic length in
 esophageal cancer
FDG-PET images with surgical pathology confirmation.
Ann Nucl Med 2007; 21: 553–62.
72. Vinjamuri S, Ray S. Added value of PET and PET-CT in
oesophageal cancer: a review of current practice. Nucl Med
Commun 2008; 29: 4–10.
73. Bruzzi JF, Munden RF, Truong MT, et al. PET/CT of esophageal
cancer: its role in clinical management. Radiographics 2007;
27: 1635–52.
74. Chung HW, Lee KH, Lee EJ, et al. Comparison of uptake
characteristics and prognostic value of 201Tl and 18F-FDG
in esophageal cancer. World J Surg 2008; 32: 69–75.
75. Guo H, Zhu H, Xi Y, et al. Diagnostic and prognostic value of
18F–FDG PET/CT for patients with suspected recurrence
from squamous cell carcinoma of the esophagus. J Nucl Med
2007; 48: 1251–8.
76. Bruzzi JF, Truong MT, Macapinlac H, Munden RF, Erasmus J.
Integrated CT-PET imaging of esophageal cancer: unexpected
and unusual distribution of distant organ metastases. Curr
Probl Diagn Radiol 2007; 36: 21–9.
77. Erasmus JJ, Munden RF. The role of integrated computed
tomography positron-emission tomography in esophageal
cancer: staging and assessment of therapeutic response.
Semin Radiat Oncol 2007; 17: 29–37.
78. Katsoulis IE, Wong WL, Mattheou AK, et al. Fluorine-18
fluorodeoxyglucose positron emission tomography in the
preoperative staging of thoracic oesophageal and gastro-
oesophageal junction cancer: a prospective study. Int J Surg
2007; 5: 399–403.
79. Meyers BF, Downey RJ, Decker PA, et al: The utility of posi-
tron emission tomography in staging of potentially operable
carcinoma of the thoracic esophagus: results of the American
College of Surgeons Oncology Group Z0060 trial. J Thorac
Cardiovasc Surg 2007; 133: 738–45.
80. van Vliet EP, Heijenbrok-Kal MH, Hunink MG, Kuipers EJ,
Siersema PD. Staging investigations for oesophageal cancer: a
meta-analysis. Br J Cancer 2008; 12: 98: 547–57.
81. Sandha GS, Severin D, Postema E, McEwan A, Stewart K. Is
positron emission tomography useful in locoregional staging
of esophageal cancer? Results of a multidisciplinary initiative
comparing CT, positron emission tomography, and EUS.
Gastrointest Endosc 2008; 67: 402–9.
82. Mamede M, Abreu-E-Lima P, Oliva MR, et al. FDG-PET/
CT tumor segmentation-derived indices of metabolic
activity to assess response to neoadjuvant therapy and
progression-free survival in esophageal cancer: correlation
with histopathology results. Am J Clin Oncol 2007; 30:
377–88.
83. Ott K, Weber W, Siewert JR. The importance of PET in the
diagnosis and response evaluation of esophageal cancer. Dis
Esophagus 2006; 19: 433–42.
84. Rosenbaum SJ, Stergar H, Antoch G, et al. Staging and
follow-up of gastrointestinal tumors with PET/CT. Abdom
Imaging 2006; 31: 25–36.
85. van Westreenen HL, Plukker JT, Cobben DC, et al. Prognostic
value of the standardized uptake value in esophageal cancer.
AJR Am J Roentgenol 2005; 185: 436–40.
86. Munden RF, Macapinlac HA, Erasmus JJ. Esophageal cancer:
the role of integrated CT-PET in initial staging and response
assessment after preoperative therapy. J Thorac Imaging
2006; 21: 137–45.
87. Upponi S, Ganeshan A, Slater A, et al. Imaging following sur-
gery for oesophageal cancer. Clin Radiol 2007; 62: 724–31.
88. Westerterp M, van Westreenen HL, Sloof GW, Plukker JT,
Van Lanschott JJ. Role of positron emission tomography in
the (re-)staging of oesophageal cancer. Scand J Gastroenterol
2006; 243: 116–22.
89. Westerterp M, van Westreenen, Reitsma JB, et al. Esophageal
cancer: CT, endoscopic ultrasound, and FDG PET for assessment
of response to neoadjuvant therapy-systematic review. Radi-
ology 2005; 236: 841–51.
90. Fiore D, Baggio V, Ruol A, et al. Multimodal imaging of
esophagus and cardia cancer before and after treatment.
Radiol Med 2006; 111: 804–17.
91. Kim TJ, Lee KH, Kim YH, et al. Postoperative imaging of
esophageal cancer: what chest radiologists need to know.
Radiographics 2007; 27: 409–29.
92. Sloof GW. Response monitoring of neoadjuvant therapy using
CT, EUS, and FDG-PET. Best Pract Res Clin Gastroenterol
2006; 20: 941–57.
93. Ilson DH. Cancer of the gastroesophageal junction: com-
bined modality therapy. Surg Oncol Clin N Am 2006; 15:
803–24.
94. Kouzu T, Hishikavwa E, Miyazaki S. What are the findings of
esophageal cancer to be treated endoscopically. Abdom Imag
2003; 28: 470–6.
95. Ng EK. Endoscopic therapy for oesophageal cancer. Dig Dis
2005; 23: 102–5.
96. Theisen J, Feith M, Stein HJ. Management of early esopha-
geal cancer. Adv Surg 2007; 41: 229–39.
97. Harper P, Landau D. Chemotherapy and radiotherapy in
esophageal cancer. In: Rankin SC, ed. Carcinoma of the Esoph-
agus. Cambridge: Cambridge University Press, 2008: 122–33.
98. Liao Z, Cox JD, Komaki R. Radiochemotherapy of esopha-
geal cancer. J Thoracic Oncol 2007; 2: 553–68.
99. Hung AY, Canning CA, Patel KM, Holland JM, Kachnic LA.
Radiation therapy for gastrointestinal cancer. Hemat Oncol
Clin N Am 2006; 20: 287–320.
100. Al-Refaie WB, Hofstetter WL. Multimodality treatment
of esophageal cancer. In: Yeo CJ, ed. Surgery of the
Alimentary Tract, 6th edn. Philadelphia: W B Saunders,
2007: 499–512.
101. Adler DG, Merwat SN. Endoscopic approaches for palliation
of luminal gastrointestinal obstruction. Gastroenterol Clin N
Am 2006; 35: 65–82.
102. Siersema PD. Treatment options for esophageal strictures.
Nat Clin Pract Gastroenterol Hepatol 2008; 5: 142–52.
103. Lovat LB. Lasers in esophageal cancer. In: Rankin SC, ed.
Carcinoma of the Esophagus. Cambridge: Cambridge
University Press, 2008: 145–50.
104. Sabharwal T, Adam A. Role of stents in the management of
esophageal cancer. In: Rankin SC, ed. Carcinoma of the
Esophagus. Cambridge: Cambridge University Press, 2008:
134–44.
105. Dehn TC, Mee AS, Jephcott C, et al. In: Yeo CJ, ed. Surgery of
the Alimentary Tract, 6th edn. Philadelphia: W B Saunders,
2007: 487–98.
157
 primary tumor evaluation and staging
106. Chang AC, Ji H, Birkmeyer NJ, Orringer MB, Birkmeyer JD.
Outcomes after transhiatal and transthoracic esophagec-
tomy for cancer. Ann Thorac Surg 2008; 85: 424–9.
107. Liu JF, Wang QZ, Ping YM, Zhang YD. Complications after
esophagectomy for cancer: 53-year experience with 20,796
patients. World J Surg 2008; 32: 395–400.
108. Pennathur A, Luketich JD. Resection for esophageal cancer:
strategies for optimal management. Ann Thorac Surg 2008;
85: S751–6.
109. Kitagawa Y, Kitajima M. Gastroesophageal carcinoma:
individual surgical therapy. Surg Clin North Am 2006; 15:
793–802.
110. Kato H, Fukuchi M, Miyazaki T, et al. Surgical treatment for
esophageal cancer. Dig Surg 2007; 24: 88–95.
111. Mason R. The role of surgery in the management of esopha-
geal cancer and palliation of inoperable disease. In: Rankin
158
SC, ed. Carcinoma of the Esophagus. Cambridge: Cambridge
University Press, 2008: 107–21.
112. Kato H, Miyazaki T, Nakajima M, et al. Value of positron emis-
sion tomography in the diagnosis of recurrent oesophageal
carcinoma. Br J Surg 2004; 91: 1004–5.
113. Flamen P, Lerut A, Van Cutsem E, et al. The utility of positron
emission tomography for the diagnosis and staging of recurrent
esophageal cancer. J Thorac Cardiovasc Surg 2000; 120: 1085–92.
114. Katayama A, Mafune K, Tanaka Y, et al. Autopsy findings
in patients after curative esophagectomy for esophageal
carcinoma. J Am Coll Surg 2003; 196: 866–73.
115. Pennathur A, Luketich JD. Resection for esophageal cancer:
strategies for optimal management. Ann Thorac Surg 2008;
85: S751–6.
116. Wieder HA, Stahl A, Lordick F, Ott K. Esophageal cancer.
Recent Results Cancer Res 2008; 170: 71–9.
 12 Gastric Cancer
Alison M McLean
INTRODUCTION
Gastric adenocarcinoma is by far the most common neoplasm of
the stomach accounting for 90% to 95% of malignant tumors.
Discussion of the diagnosis, staging, and treatment of this tumor
forms the major part of this chapter.
EPIDEMIOLOGY AND ETIOLOGY
Despite a declining incidence, particularly in the West, gastric
adenocarcinoma remains the second leading cause of cancer death
worldwide. It is the fourth most common cancer with nearly a
million new cases diagnosed every year (1).
Demographic trends differ by tumor location and histology.
While there has been a marked decline in distal intestinal type
tumors in the West, the incidence of proximal diffuse type adeno-
carcinomas of the gastric cardia has been increasing (2).
The incidence of tumor by sub-site within the stomach varies
widely based on geographic location, race, and socio-economic
status.
Distal gastric cancer predominates in developing countries, in
blacks, and in lower socio-economic groups whereas proximal
tumors are more common in developed countries in whites and
in those of higher socio-economic status (3).
These diverging trends in incidence suggest that they may rep-
resent two different diseases with different etiological factors.
The main risk factors for distal gastric cancer include Helicobacter
pylori and dietary factors whereas gastro-esophageal reflux
and obesity are probably important in the development of
proximal gastric cancer (4–8). Risk factors for gastric cancer
include:
• Male gender
• Genetic factors
• Infectious agents—H. pylori
• Exogenous chemicals—including smoking
• Dietary nitrates
• High salt and pickled foods intake
• Polyposis syndromes/gastric adenomas
• Previous partial gastrectomy
Hereditary gastric cancer represents approximately 10% of gastric
cancers and there are associations with hereditary non-polyposis
colorectal cancer (HNPCC), familial adenomatous polyposis
(FAP), and with the BRCA2 gene mutation (9).
The relation between H. pylori and the development of gastric
cancer is complex, although there appears to be a definite but
variable risk with studies suggesting that eradication of H. pylori
will affect the incidence of gastric cancer as a result of regression
of precancerous conditions of intestinal metaplasia and gastric
atrophy (5).
CLINICAL FEATURES
The initial diagnosis of gastric cancer is often delayed because
80% of patients are asymptomatic during the early stages of disease
and the disease is only detected when it has become advanced and
symptomatic because of local invasion (10). Approximately 50%
of patients have advanced unresectable cancer at the time of diag-
nosis and in most parts of the world the five-year survival is low at
around 20% (11). The typical patient is male (male:female ratio
1.7:1) and between 40 and 70 years of age (mean age 65). Patients
may present with weight loss, abdominal pain and dyspepsia, nausea
and vomiting, and early satiety. Gastric cancer is a recognized but
uncommon cause of upper gastrointestinal bleeding (12).
Proximal tumors at the gastro-esophageal junction may present
with dysphagia and distal tumors with gastric outlet obstruction.
Patients over the age of 40 presenting with new symptoms of
dyspepsia or with any of the above sinister features require inves-
tigation (13). In Japan, rigorous screening procedures based on
barium studies and endoscopy have resulted in an increased
proportion of cases detected at an early stage and the overall
reported five-year survival rate in Japan is closer to 60% (14).
PATHOLOGY
Previous histological classification systems for gastric cancer have
been based on patterns of gross and morphological features.
Tumors have been categorized as superficial spreading, polypoid,
fungating, ulcerative, and scirrhous infiltrating. The WHO histo-
logic classification identifies nine sub-types: papillary, tubular
and mucinous adenocarcinoma, signet-ring cell carcinoma, squa-
mous cell carcinoma, adenocanthoma, undifferentiated carci-
noma, unclassified carcinoma, and carcinoid tumor (15). However,
the simplest and now most universally accepted system was
described by Lauren who separated gastric tumors into two major
categories based on their gland-forming potential, intestinal
(gland-forming) and diffuse (non-gland-forming), which includes
signet-ring cell types and anaplastic tumors (Table 12.1) (16). Of
the two major categories, intestinal type tumors demonstrate a
classic progression of carcinomatosis similar to that identified in
colon cancer. Environmental and other factors result in progressive
changes to the gastric mucosa from chronic gastritis, atrophy, and
hypoacidity to metaplasia, progressing to dysplasia and ultimately
cancer.
It is this subtype which has decreased in incidence worldwide.
In a recent series, intestinal type tumors account for 30% of cases
as compared to diffuse type tumors which accounted for 70% of
new cases. The incidence of diffuse tumors has remained relatively
static. They are more common in young and female patients, and
familial and genetic factors have been identified. They demon-
strate early transmural and lymphatic spread with a poor overall
prognosis (13).
159
 primary tumor evaluation and staging
Table 12.1 Gastric Cancer—Lauren Classification (16)
Intestinal (epidemic) Diffuse (endemic)
Cells similar to intestinal Poorly differentiated solitary
epithelium cells
Arranged in “Indian file”
Signet ring cells
Marked stromal reaction
Forms glands No glands
Associated with chronic gastritis Hereditary
Common in areas of high incidence Younger age—Blood group A
M:F = 2:1 M:F = 1:1
Better prognosis Worse prognosis
Classification of gastro-esophageal junction tumors can be
difficult. A tumor arising at the gastric cardia is classified as gastric
if greater than 50% of the tumor is below the gastro-esophageal
junction and esophageal if more than 50% involves the esophagus.
Tumors which equally cross the gastro-esophageal junction are
differentiated by their histology. Squamous cell, small cell, and
undifferentiated carcinomas are considered esophageal, and
adenocarcinoma and signet-ring cell tumors are classified as gastric.
If Barrett’s metaplasia is present in the esophagus, adenocarcinoma
is likely to be esophageal in origin.
Key Points: Pathology and Epidemiology
■ There has been an overall decline in the incidence of
gastric cancer
■ The decrease has been predominantly in distal intestinal type
tumors, which are related to H. pylori infection
■ There has been a relative rise in proximal gastric cancers,
which are probably related to obesity and reflux
PATTERNS OF TUMOR SPREAD
Gastric adenocarcinoma can be divided into early gastric cancer
and advanced gastric cancer.
Early Gastric Cancer
The incidence of early gastric cancer (EGC) has increased with
improved detection due to advances in diagnostic techniques. In
the West, EGC accounts for 4% to 16% of all gastric cancers, while
in Japan the proportion of EGC is between 30% and 50% (17).
Early gastric cancer is confined to mucosa or submucosa. Most
EGCs are located in the distal 50% of the stomach along the
lesser curvature (18). Despite being limited to the mucosa or
submucosa, there is an incidence of lymph node involvement of
between 8% and 15%, which increases with submucosal involve-
ment and with increasing size of the tumor, being uncommon in
tumors less than 1 cm (17). Between 9% and 29% of EGCs are
multicentric.
Three basic types of tumor are described based on their
morphological pattern: protruded, superficial, or excavated.
Tumor size is also prognostically important as small tumors
tend to be less invasive than large tumors and, therefore, usually
160
carry better overall prognosis. Tumors may remain confined to
the mucosa for months or years, with the median interval for
progress from early to advanced cancer having been estimated
to be 37 months (19).
Key Points: Early Gastric Cancer
■ Lymph node involvement occurs in 8% to 15% of EGCs,
increasing with submucosal involvement and size greater
than 1 cm
■ Most tumors are located in the distal 50% of the stomach
■ Nine to twenty-nine percent of EGCs are multicentric
■ Diagnosis of EGC is increasing with earlier investigation of
symptomatic patients
■ Progression from early to advanced disease may be very slow
(median = 37 months)
Advanced Disease
Direct Extension
With advancing disease, tumor spreads beyond the submucosa
and extends both longitudinally and vertically through the layers
of the gastric wall. Having penetrated the muscularis propria and
subserosa, tumor may spread by local extension via the subperi-
toneal spaces of various supporting peritoneal ligaments into
adjacent structures.
Tumors arising at the cardia and lesser curvature may extend
into the hepato-gastric ligament and directly into the liver.
Cancers on the proximal greater curvature tend to invade the
gastro-splenic ligament and splenic hilum. Tumors arising
more distally on the greater curvature may extend directly into
the gastro-colic ligament and superior aspect of the transverse
colon. Posteriorly, tumors may extend into the lesser sac and
pancreas (15).
Lymphatic Spread
Invasion of the lymphatics results in regional lymph node
involvement. Lymph node metastases occur in 90% of patients
with advanced gastric cancer. Initially, nodes immediately adja-
cent to the tumor are involved (first tier—perigastric) with
progression to involvement of higher echelons of nodes in the
extraperigastic nodal groups (second tier). The progression of
nodal involvement is determined by the anatomic position of
the primary tumor and this pattern forms the basis for the
detailed Japanese system of nodal staging classification of
regional lymph nodes. The presence of extensive intramural
lymphatic communications results in adenopathy at sites distant
from the primary tumor (20).
Hematogenous and Peritoneal Spread
Transcoelomic spread carries tumor through the peritoneum and
peritoneal metastases are seen in approximately 40% of patients
with advanced disease. Hematogenous spread to the liver and
lungs occurs in approximately 35% of patients (10,21).
“Diffuse type” carcinomas tend to disseminate more widely
than tumors of the “intestinal” type and up to 10% may develop
bilateral drop metastases to the ovaries, resulting in Krukenberg
tumors (22).
 gastric cancer

include Tis and T1 lesions. Invasion into the lamina propria or

Key Points: Advanced Disease
■ Tumor spreads through subperitoneal and peritoneal spaces
■ Nodal metastases occur in 90% of patients with advanced
disease
■ The anatomic position of the tumor within the stomach
determines the pathway of lymphatic spread
■ Hematogenous spread to the liver or lungs occurs in
approximately 35% patients
STAGING AND HISTOLOGICAL CLASSIFICATION
submucosa, although still regarded as early, carries an increased
incidence of lymph node involvement of between 8% and 15%.
Tumors that have penetrated into or beyond the muscularis
propria (T2 or greater) are defined as advanced. However, a tumor
may penetrate the muscularis propria with extension into the
gastro-colic or gastro-hepatic ligaments, or the greater and lesser
omentum without perforation of the visceral peritoneum covering
the structures. In these cases, the tumor is still classified as T2.
When there is penetration of the visceral peritoneum covering the
gastric ligaments or omentum, the tumor is classified as T3. T4
tumors invade adjacent structures.

The two most important factors influencing survival in patients
with resectable gastric cancer are the depth of invasion through
the gastric wall and the extent of lymph node involvement.
There are two staging systems in use for gastric cancer—the
UICC/AJCC system and the Japanese classification. Both use a
similar system of assessment of depth of invasion of the primary
tumor based on the layers of penetration of the bowel wall, but
they differ in the system of nodal staging. The UICC system based
on TNM classification is almost universally used in Europe and
the United States (Table 12.2) (23).
Tumor (T) Staging
The stomach is divided into five anatomical areas: cardia, fundus,
body, antrum, and pylorus (Fig. 12.1). There are five layers of the
gastric wall: mucosa, submucosa, muscularis propria, subserosa,
and serosa; and T staging is defined by the depth of mural
penetration (Fig. 12.2).
Early gastric cancer includes lesions which are limited to the
gastric epithelium and, therefore, are regarded as “in situ” lesions,
together with tumors which have invaded into the submucosa and
Nodal (N) Staging
The pattern of lymphatic drainage into regional lymph nodes
is determined by the anatomic position of the primary tumor
(Fig. 12.3). The Japanese classification system is based on detailed
analysis of the anatomic patterns of lymphatic drainage and is
dependent on the site and distance of the involved nodes from the
primary tumor. It identifies 33 regional lymph node stations,
classified into three groups, which are based on the anatomic
position of the primary tumor (20).
The UICC/AJCC classification is simpler and is based on the
number of involved nodes, requiring a minimum of 15 nodes in
the resected specimen, and appears to provide easy and accurate
prognostic stratification. Metastatic involvement of less than six
regional nodes is designated N1, 7 to 15 nodes involved is desig-
nated N2, and over 15 nodes is N3. The prognostic impact of N
staging is partially dependant on the total number of nodes
resected and examined. The ratio of involved nodes to the total
number of nodes resected may be a more powerful prognostic
indicator (24). Regional nodes include the perigastric nodes
within 3 cm of the primary tumor (first compartment) and
extraperigastric (second compartment) nodes along the left

Table 12.2 Pathological Staging of Gastric Carcinoma Using

T (Tumor), N (Node), and M (Metastases) System (23)
TX Primary tumor cannot be assessed
Fundus
T0 No evidence of primary tumor
Carcinoma in situ: intraepithelial tumor without invasion of the lamina Cardia
Tis propria
T1 Tumor invades lamina propria or submucosa
T2a Tumor invades muscularis propria Body
T2b Tumor invades subserosa Pylorus
Tumor penetrates serosa (visceral peritoneum) without invasion of
T3 adjacent structures
T4 Tumor invades adjacent structures
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis Antrum
N1 Metastasis in 1–6 regional lymph nodes
N2 Metastasis in 7–15 regional lymph nodes
N3 Metastasis >15 regional lymph nodes
MX Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis
Involvement of other intra-abdominal nodes such as retropancreatic, mesenteric,
and para-aortic is classified as “distant metastasis.”
Figure 12.1 Anatomical divisions of the stomach.

161
 primary tumor evaluation and staging

T2

T1

Mucosa
Lamina propria
Muscularis mucosa
Submucosa

Muscularis propria
Subserosa
Serosa

T3

T4

N1
Involved
lymph nodes
Pancreas

N1 Metastases in
1–6 regional lymph nodes

N2 Metastases in
7–15 regional lymph nodes

N3 Metastases in more than

15 regional lymph nodes

Figure 12.2 Staging gastric cancer—primary tumor (T) and lymph nodes (N).

gastric, common hepatic, splenic and coeliac arteries, and the
hepato-duodenal nodes.
Involvement of other nodes outside the first and second com-
partment such as retropancreatic, mesenteric, and para-aortic
nodes is classified as distant metastases.
In early gastric cancer, lymph nodes are identified in between
9% and 15% of cases, whereas in advanced disease up to 90% of
patients have evidence of tumor in regional nodes at laparotomy.
Metastases (M Stage)
In advanced disease, approximately 25% to 35% of patients will
have liver or lung metastases (10,21). Direct infiltration into the
pancreas occurs in approximately 23% and into the colon in
around 5% of cases. Intraperitoneal seeding results in peritoneal
and omental deposits in around 40% with seeded metastases to
the rectosigmoid colon, cecum, or small bowel, and the develop-
ment of ascites.

162
 gastric cancer

2 in a change in stage distribution, with the proportion of patients

1 having Stage I and II disease increasing from 14% in 1970 to 31%
Perigastric nodes in 1989 (25,26).
3 4 1st compartment Overall, in the United States, data collected nationally and pub-
lished in 2000 indicates that five-year survival in advanced gastric
5 cancer following gastrectomy is poor. However, a recently pub-
3
lished, single institution study from Johns Hopkins University of
6 patients who underwent surgery for gastric cancer reported the
4
following distribution (27):
10
4 16
7 Patients at presentation (%) 5-Year survival (%)
9 11
12 Stage 1 20 63
Stage 2 19 28
13 14 Stage 3 34 18
8
Stage 4 27 10
Overall survival = 26%.

In Japan, due to intensive screening using barium meal supple-

Extraperigastric nodes
2nd compartment
15
Figure 12.3 Regional lymph nodes of the stomach. Group 1: Perigastric nodes
(first compartment)—1, right pericardial; 2, left pericardial; 3, lesser curvature; 4,
greater curvature; 5, suprapyloric; 6, infrapyloric. Group 2: Extraperigastric nodes
(second compartment)—7, left gastric artery; 8, common hepatic artery; 9, celiac
artery; 10, splenic hilus; 11, splenic artery; 12, hepatic pedicle. Group 3: Distant
metastases—13, retropancreatic; 14, mesenteric root; 15, middle colic artery; 16,
para-aortic.
mented by endoscopy, gastric cancer is usually diagnosed at a
much earlier stage when the tumor has not penetrated beyond the
submucosa. Arguments that the biology and histology of the
tumor are different have not been sustained by comparative study.
The proportion of cases with early as compared to advanced can-
cer has risen with screening in Japan from 1% before 1951 to over
40%, with an associated improvement in overall survival (28). The
overall lower incidence of gastric cancer in Europe and the United
States makes it difficult to justify similar population screening
programs. Nevertheless, following selected screening of high-risk
groups (patients over 40 complaining of dyspepsia) subjected to
early investigation over a two-year period, early gastric cancer
accounted for 15% of all cancers diagnosed (29). In EGC, where
tumor is confined to the mucosa or submucosa, five-year survival
post-surgery is as high as 90% to 95%.

Key Points: Staging

Table 12.3 Stage Grouping and Stage Survival in Gastric
■ Tumors which penetrate the muscularis propria into the Cancer (11)
lesser and greater omenta without penetration of the
Stage
visceral peritoneum are still classified as T2
■ There are two major tiers of lymph node involvement:
0 Tis N0 M0
IA T1 N0 M0
perigastric and extraperigastric IB T1 N1 M0
■ Involvement of retropancreatic, para-aortic, and mesenteric T2a/b N0 M0
nodes is classified as metastatic (M1) disease II T1 N2 M0
■ Seventy percent of patients going to surgery will have tumor T2a/b N1 M0
in regional nodes at laparotomy T3 N0 M0
IIIA T2a/b N2 M0
■ Twenty-five percent of patients have liver metastases and
T3 N1 M0
25% peritoneal metastases at presentation T4 N0 M0
IIIB T3 N2 M0
IV T4 N1, N2, N2 M0
Stage Grouping and Survival T1,T2,T3 N3 M0
Stage grouping effectively separates survival by stage (Table 12.3). Any T Any N M1
The majority of patients present with advanced disease with up to Stage Survival at 5 Yr (%)
80% of patients presenting with disease considered too extensive
Ia 78
for radical surgery. Ib 58
The early diagnosis of gastric cancer remains an elusive and II 34
challenging goal and the majority of patients present with IIIa 20
advanced disease. However, evidence over the last 15 years indi- IIIb 8
IV 7
cates that earlier investigation of symptomatic patients is resulting

163
 primary tumor evaluation and staging
Key Point: Stage Grouping and Survival
■ The proportion of patients with Stage I and II disease has
increased from 14% in 1970 to 31% in 1989 following earlier
investigation of symptomatic patients
TREATMENT
The treatment of gastric cancer is based on the stage of disease.
Surgery with complete resection of the tumor and adjacent lymph
nodes is the only proven effective treatment for cure and abdominal
exploration is offered to all patients in whom there is no evidence
of metastatic or disseminated disease.
Surgery alone is likely to be curative in early disease. Locally
advanced disease may respond to a more aggressive surgical
approach with en bloc resection of adjacent organs and possibly
combined with chemotherapy and radiotherapy. Where disease is
disseminated, surgery may still be offered for palliation.
Surgery
Early Gastric Cancer
T1 lesions which can be demonstrated on preoperative staging to
be small, less than 1.5 cm, limited to the mucosa, and well differ-
entiated may be treated with endoscopic mucosal resection or
limited wedge resection (30). Otherwise the standard treatment for
EGC is surgical resection with lymph node dissection. Lymphatic
mapping and sentinal node identification has proved a potentially
useful tool in early gastric cancer facilitating less extensive function
preserving gastrectomy in those in whom the sentinal node uptake
is negative (28,31).
Advanced Gastric Cancer
Depending on the anatomic position of the primary tumor, surgi-
cal treatment is subtotal or total gastrectomy with the aim of clear
margins, which usually means a 6 cm surgical margin for T2/3
tumors. Total gastrectomy with Roux-en-Y esophago-jejunal
anastomosis is favored for proximal gastric cancers. Distal antral
tumors may undergo subtotal or total gastrectomy (13). The
extent of en bloc resection of adjacent structures such as the spleen
and distal pancreas will vary.
The extent of lymphadenectomy is influenced by the nodal
drainage of the tumor and has been a subject of debate for many
years.
Traditional surgical resection (D1) removes only nodes in
compartment 1 (first tier) and within 3 cm of the primary
tumor. However, favorable outcomes of extended lymph-
adenectomy (D2 resection) from Japan have influenced the
surgical approach in the West. A D2 resection (extended lymph-
adenectomy) involves both the first and second tiers of nodes,
that is, perigastric and extra-perigastric including the celiac
axis, hepato-duodenal, splenic, and retroduodenal nodes
together with the omental bursa, and appears to confer
improved survival. This more extensive surgery appears to
confer better locoregional disease control and a lower recur-
rence rate (32,33). It has been estimated that approximately
30% of all patients suitable for potential curative surgery have
164
positive nodes around the celiac axis (level 2, stations 7–12),
which argues for the necessity for a D2 resection to achieve dis-
ease clearance (34). However, there has been an adverse effect
on morbidity and mortality of the extended D2 resection,
which in its classic form includes distal pancreatectomy and
splenectomy, which in two studies appeared to nullify any survival
benefit from the D2 procedure (Dutch and MRC trials). However,
the modern consensus view is that distal pancreatectomy is
unnecessary and the need for routine splenectomy is questionable
(32,33,35).
Recent data suggest that modified D2 resections are being
performed with much lower postoperative mortality (4%) with
improved outcomes (13).
There are several reports published on the feasibility and pre-
liminary results of minimally invasive surgery as compared to
conventional open surgery for gastric cancer, which indicate
reduced perioperative morbidity and reduced hospital stay. How-
ever, the longer-term benefits in relation to long-term survival are
not proven (36).
The absence or presence of residual tumor after surgical resection
is defined by the symbol R:
• RX presence of residual tumor cannot be assessed
• R0 no residual tumor
• R1 microscopic residual tumor
• R2 macroscopic residual tumor
In patients who do not have curable disease, surgery may offer the
best palliation. Even in the presence of liver metastases, resection
may contribute to improved survival and alleviate symptoms of
gastro-intestinal obstruction. Endoprotheses may be used in
patients with dysphagia due to tumors at the cardia or to relieve
outlet obstruction in distal tumors.
Chemotherapy
Although surgery offers the best chance of cure, the early lym-
phatic dissemination of disease has limited its effectiveness, except
in early tumors. Removal of all micro-metastases by surgery is
probably an unrealistic goal.
It is now recognized that the use of combined treatment strate-
gies can improve the prognosis of patients with more advanced
disease (37,38). In 2001, the results of a trial (Intergroup–0116)
(39) using a combination of chemotherapy and chemoradiation
given after potentially curative surgery demonstrated an improved
three-year survival from 41% to 50%. This study attracted some
criticism as it included patients who had undergone less than
radical surgery with extended resection of second tier nodes in
only 10% of patients. It was argued that the chemoradiotherapy
had compensated for inadequate surgery in these patients and
that as the increased mortality which had accompanied radical
node dissection decreased with more sophisticated surgical tech-
nique, the benefit of the nodal clearance alone would become
apparent.
Subsequently, the results of the MRC MAGIC trial of periopera-
tive infusional chemotherapy (epirubicin, cisplatin, and fluoruracil)
(2006) demonstrated an improved five-year survival from 23% to
36% in patients, the majority of whom had undergone D2 tumor
resections (40,41).
 gastric cancer

Further studies have introduced the option of administering

chemotherapy before surgery. This has the advantage of attack-
ing micrometastatic disease and allows more patients to receive
systemic treatment as the increased morbity following major
surgery may delay or prevent the use of postoperative chemo-
therapy (42–44).
Recent reports of a large randomized study from Japan (45)
using the cytotoxic agent S-1 given over an extended 12-month
period has demonstrated an improved overall survival from
70% to 80%, although the patient population included a much
higher proportion of T2 and fewer T4 tumors than the MAGIC
trial.
Angiogenesis has been evaluated as a possible predictor of prog-
nosis in gastric cancer with a higher microvessel count in poorly
differentiated, poor prognosis tumors, suggesting a possible
benefit of adjuvant therapy using antivascular endothelial growth
factor agents (46).
Trials exploring the use of combined treatment strategies con-
tinue, but it seems likely that whether treatment is given pre- or
postoperatively, surgery alone is no longer the standard treatment
for patients with resectable gastric cancer (47).
Figure 12.4 Early gastric cancer—small early gastric cancer in the mid body of the
stomach with shallow ulceration and surrounding distorted clubbed folds (arrowed).
Key Points: Treatment
■ Overall five-year survival is poor at 5% to 10% as a result of
late presentation
■ In EGC, five-year survival post-surgery is up to 90% to 95%
■ There is a trend towards more radical surgery with extended
lymphadenectomy, resulting in improvement in five-year
survival
■ Overall post-surgical five-year survival is as high as 26%
■ Combined treatment strategies with chemotherapy have
demonstrated improved five-year survival by approximately 10%

DIAGNOSIS

In the United States and United Kingdom, endoscopy has

largely replaced upper gastro-intestinal barium studies for the
primary diagnosis of gastric cancer. Nevertheless, several stud-
ies indicate that biphasic upper gastro-intestinal studies can be
as effective as endoscopy for the diagnosis of gastric carcinoma
(48,49).
Carefully conducted double barium studies using high-density
barium, variable gastric distension and compression, remain the
cornerstone of screening in Japan.
Early lesions may be identified as irregular mucosal nodularity,
ulceration, or contour irregularity. The most commonly over-
looked findings are shallow depressions with minimal barium
pooling and misinterpretation of radiating folds required for the
early detection of lesions (Fig. 12.4).
The barium appearances of advanced disease reflect the gross
pathology and may be polypoid, ulcerating, or infiltrating (Fig. 12.5)
(15). Classic barium features are described to differentiate benign
and malignant ulcers but, in practice, most patients who are diag-
nosed with a gastric ulcer on barium examination will undergo
endoscopy and biopsy.
Figure 12.5 Advanced gastric cancer with a large area of ulceration and surround-
ing nodular clubbed and amputated folds (arrowed).
RADIOLOGICAL STAGING
While diagnosis depends on excellent visualization of the mucosa
with endoscopy or barium examination, an assessment of the
depth of tumor invasion through the gastric wall and the presence
of nodal and metastatic disease requires cross-sectional imaging.
CT scanning and endoscopic ultrasound are the primary tools
for preoperative staging. Most patients who are considered eligi-
ble for surgery will also undergo diagnostic laparoscopy and
the majority of patients will proceed to surgery either for cure or
palliation.

165
 primary tumor evaluation and staging
The aims of imaging are:
• To determine whether surgery is likely to be curative or
palliative
• To identify those patients who may be suitable for
minimally invasive surgery and/or endoscopic resection
• To identify patients who might benefit from neoadjuvant
therapy to downstage disease and improve the chances
of subsequent R0 resection
• To identify serosal or peritoneal involvement
• To monitor the effects of chemotherapy in appropriate
patients
• To predict prognosis
Imaging Techniques
CT
Although CT has been widely used in gastric cancer staging since
the 1980s, initial studies of the impact of CT in staging suggested
that its use was mainly limited to the diagnosis of advanced dis-
ease due to the poor spatial resolution (50–56). Subsequent stud-
ies following the introduction of spiral scanning focused on the
refinement of technical factors, and demonstrated that distension
of the stomach using tap water as a negative intraluminal contrast
and biphasic contrast enhancement provided good visualization
of the gastric wall and the ability to accurately T-stage lesions.
Recent further technical advances, with the advent of multi-
detector CT (MDCT) have reinforced the value of preoperative
staging of gastric cancer with CT (57–59). Multidetector row scan-
ners allow thin collimation and fast scanning, which improve the
spatial resolution, and the near isotropic imaging allows high
quality multiplanar reformations (MPRs) which enhance both the
detection and staging of disease. These reformations have advan-
tages in assessing both the intra- and extraluminal components of
the disease (Fig. 12.6) (60).
Figure 12.6 Coronal reconstruction of gastro-esophageal junction cancer demon-
strating extension of tumor into the proximal stomach.
166
Virtual gastroscopy is an emerging examination tool, using air
distension of the stomach and volumetric imaging to create an
endoscopic mucosal view of the stomach, and one which shows
promise in the detection and staging of early gastric cancer
(Table 12.4) (61).
Tumor (T Staging) (Table 12.5)
With water distension, the normal gastric wall measures less
than 6 mm, except at the gastro-esophageal junction where the
transverse plane of scanning may result in apparent wall thicken-
ing. The gastric antral wall is slightly thicker than the gastric body.
Gastric folds may be prominent but their thickness is no more
than that of the adjacent gastric wall (58). With intravenous (IV)
contrast, the wall may be seen as a three-layered structure with
maximum enhancement in the inner mucosal layer, a low attenu-
ation stripe, probably due to fat deposition, representing the sub-
mucosal layer, and an outer layer of intermediate density, which
represents the muscularis propria and serosal layer. The serosal
margin is usually well defined against the perigastric fat.
Gastric carcinoma results in both increased enhancement and
thickening of the gastric wall (Fig. 12.7). Early gastric cancer may
demonstrate increased enhancement and thickening, which is
limited to the mucosal layer, with preservation of the submucosal
low-density stripe. Using this technique, CT was able to visualize
49% of EGCs where thickening was limited to the inner layer (59).
The early phase of enhancement—around 45 seconds—was most
accurate at determining the depth of tumor invasion through the
Table 12.4 Gastric Cancer Staging: CT Technique
• Fasting—6 hr at least—preferably overnight
• Approximately 800−1000 ml of tap water immediately prior to scan or
effervescent granules to produce gastric distension
• Position: supine—unless the tumor is known to be distal when the prone
position may be preferable
• Buscopan 20 mg IV (optional and less important with fast scanning
techniques)
• Late arterial phase: 100−120 ml non-ionic contrast 3−4 ml/sec. Scan at 40 sec
after start of injection
• Portal venous phase: 70 sec after start of injection—diaphragm to pelvis
Table 12.5 CT Criteria for T Staging and N Staging
in Gastric Cancer
T1 Focal thickening of inner mucosal layer with preservation of low-density
stripe at the base of the lesion. Clear fat plane around tumor
T2 Focal or diffuse thickening of gastric wall. Loss of layered structure.
Smooth outer border/clear fat plane around lesion
T3 Transmural tumor with irregular or nodular outer border of thickened
gastric wall and/or blurred fat plane around lesion
T4 Obliteration of the fat plane between the gastric tumor and adjacent organ
N0 No nodes
N1 1–6 regional nodes involved
N2 7–15 regional nodes involved
N3 >15 nodes involved
M1 Extraperigastric nodes NOT removable at surgery
Hepato-duodenal ligament/hilum of liver
Pancreatic
Mesenteric
Para-aortic
 gastric cancer
(A)
Figure 12.7 (A) Small ulcerated cancer: prepyloric region of the lesser curvature (arrowed) showing thickening with increased contrast medium enhancement of the
gastric wall. Tumor limited to gastric wall (T2). (B) Circumferential tumor: gastric antrum (arrowed). Patient scanned prone with gastric water load (T2). Enlarged
regional nodes (infrapyloric) (N1) (arrowhead).
Figure 12.8 Coronal MPR of obstructing distal gastric cancer demonstrating
extent of tumor of the gastric antrum up to the pylorus.
wall. Early advanced cancer was demonstrated as thickening of the
wall with loss of the middle and outer layers, and transmural
enhancement, with a positive predictive value of between 80%
and 100%. The changes in EGC may be very subtle, but using this
technique, Cho et al. detected 56% of EGCs and 95% of advanced
tumors, with an overall accuracy of T staging of 65% (57). When
optimal technique is employed, endoscopically proven lesions
which are not visualized at MDCT are almost all early gastric
cancer without lymph node metastases (62).
The utilization of multiplanar reconstructions (MPR) has been
shown to both increase the detection of early gastric cancers and pro-
vides superior evaluation of the Z-axis extent of the tumor (Fig. 12.8)
(63). In comparison with transverse CT imaging, its use improved the
(B)
T-staging accuracy of gastric cancer (60,61). Carcinoma of the cardia
may be difficult to demonstrate on CT because of the normal soft
tissue thickening which occurs at the gastro-esophageal junction.
Prolapsed hiatus hernias may give the erroneous impression of a
mass in this region. Adequate water distension, scanning in the prone
position, or reformatting in the coronal plane may enable better
delineation of the extent of tumor (Fig. 12.9) (64).
Diffusely infiltrating scirrhous tumors presenting a linitis
plastica appearance may also be difficult to assess as the fibrous
response elicited by the tumor results in nondistensibility and, there-
fore, some difficulty in evaluating the extent of tumor (Fig. 12.10).
Evaluation of the pattern of gastric wall thickening and enhance-
ment may suggest the underlying histology and may distinguish
mucinous poor prognosis tumors from nonmucinous carcino-
mas. A diffusely thickened, low attenuating, middle or outer layer
and preservation of the thin, high attenuating inner layer may
indicate a mucinous carcinoma (65).
Accuracy in assessing depth of tumor invasion is less in early
(T1 and T2) lesions than in advanced (T3 and T4) tumor where
the accuracy of T staging is 78%. Serosal invasion is suggested by
an irregular outer border of the thickened gastric wall or a blurred
fat plane around the lesion (Fig. 12.11). The accuracy of dynamic
CT in determining the degree of serosal invasion is high at 83%
(56). Takao et al. reported the accuracies of helical CT in the
detection and staging of advanced gastric cancer to be 98% and
82%, respectively (66).
A further study of 62 resected cases, which included 19 EGCs,
demonstrated an overall T stage accuracy of 69% and accuracy in
assessing the degree of serosal invasion of 80% (56). The demonstra-
tion of linear or nodular areas of soft tissue extending beyond the
wall into the perigastric fat is suggestive of trans-serosal invasion.
The positive and negative predictive values of helical CT to
foresee curative resection have been demonstrated to be 75% and
84%, respectively (67). Tumor spreads along recognized pathways
into the pancreas, liver, spleen, and transverse mesocolon. Loss of
the fat plane between the tumor and an adjacent organ suggests
167
 primary tumor evaluation and staging

(A) (B)

(C)
Figure 12.9 (A) Axial CT—There is thickening of the wall at the gastric cardia consistent with tumor (arrows) with small nodes in the left gastric territory (arrowhead).
(B) Coronal reconstruction identifies bulky tumor mass extending into the lower esophagus (arrows). (C) Endoscopic ultrasound demonstrates disruption of the layered
structure of the gastro-esophageal junction wall (small arrow) with an enlarged adjacent node (large arrow).

Figure 12.11 Tumor infiltrating along the lesser curvature. There is increased
Figure 12.10 Extensive diffuse thickening of the gastric wall in the proximal and contrast medium enhancement of the gastric wall and an irregular margin with
mid-stomach as a result of linitis plastica infiltration of the stomach. blurring of the fat plane indicating serosal involvement.

168
 gastric cancer

direct infiltration (Fig. 12.12A and B). In an emaciated patient this
may be difficult to evaluate because of generalized loss of retro-
peritoneal fat. In such patients, particular attention should be
paid to the smoothness or otherwise of the outer border of the
gastric wall. The partial volume effect of CT may pose problems,
particularly in assessment of direct invasion into the left lobe of
the liver as at this point the stomach contacts the left lobe oblique
to the scanning plane, which makes invasion difficult to evaluate
(Figs. 12.13 and 12.14) (56).
Loss of the fat plane between the stomach and pancreas does
not necessarily imply invasion, as false positives may result from
inflammatory changes with adhesions to the pancreas that are
impossible to differentiate using any form of imaging.
Nodes (N Staging)
The diagnosis of abnormal nodes on CT is based on size criteria
assessed on short-axis diameter. CT is relatively insensitive and
non-specific for detecting nodal metastases due to its inability to
detect microscopic nodal involvement which is common in gastric
cancer. Dorffman et al. demonstrated that the upper limit of normal
diameter for upper abdominal lymph nodes varies between 6 and
11 mm depending on their location (68). Gastro-hepatic ligament
nodes are considered abnormal if they exceed 8 mm in diameter
(69), which is therefore taken as the upper limit of normal in evalu-
ating nodes in the anticipated drainage pathways for gastric cancer.
Demonstration of involved perigastric nodes immediately adjacent
to the tumor may be more difficult than demonstration of nodes at
the next level in the gastro-hepatic ligament, celiac axis, and supe-
rior mesenteric artery region (Fig. 12.15). Optimum demonstration
of nodes is dependent on scanning technique and requires good
gastric distension and vascular enhancement. An understanding of
the expected sites of drainage is essential. The predicted first-order
nodes involved are dependent on the site of the primary lesion in
the upper, mid, or distal stomach. Although accurate evaluation of
perigastric nodes obviously contributes to the staging accuracy, in
practical terms it is more important to identify the extraperigastric
nodes as these would not be necessarily resected in a standard gast-
rectomy, but would only be surgically staged with an extended (D2)
type of lymphadenectomy.
Enlarged nodes in the para-aortic, retropancreatic, and retro-
crural regions are not removed at surgery and are classified as
metastases (M1) (Fig. 12.16). However, as in many other cancers,

(A) (B)
Figure 12.12 (A) Distal body/antral cancer. There is blurring along the greater curvature (vertical arrows), suggesting serosal infiltration with loss of the fat plane between
the stomach and the pancreas (horizontal arrows), suggesting direct infiltration. (B) Tumor extending beyond the serosal surface of the lesser curvature into the lesser
omentum with encasement of the left gastric artery.

(A) (B) (C)

Figure 12.13 (A) Extensive tumor infiltrating the entire stomach with trans-serosal extension into the lesser omentum (horizontal arrow) and gastro-colic ligament
(vertical arrow). (B) Loss of the fat plane between tumor and the pancreas, suggesting infiltration (arrows). (C) Endoscopic ultrasound from the same patient. There is
marked thickening of the gastric wall with loss of the normal layered structure. Note the loss of plane between the stomach and liver suggesting direct invasion (arrow).

169
 primary tumor evaluation and staging

(A) (B)
Figure 12.14 (A) Very extensive tumor thickening of proximal gastric wall with direct infiltration of the liver and pancreas (arrows). (B) Direct tumor infiltration into
the spleen with secondary splenic infarction.

(A) (B)
Figure 12.15 (A) Enlarged perigastric lymph nodes (arrowed). (B) Enlarged nodes adjacent to the greater curvature of the stomach in the gastro-colic ligament
(white arrows).

Figure 12.16 (A) Enlarged gastric cardia nodes (white arrow) and retrocrural nodes (black arrow) with ascites. (B) Enlarged para-aortic nodes with carcinoma of the
distal body of the stomach.

170
 gastric cancer

CT is relatively insensitive in the detection of nodal metastases administer neo-adjuvant therapy cannot be made on the basis of
due to the inability to identify microscopic nodal invasion, which imaging procedures alone (75).
is not uncommon in gastric cancer, and the presence of reactive
nodes that may be greater than 10 mm (53,57). The reported accu- Metastases (M Staging)
racy in nodal staging in gastric carcinoma varies from 48% to 70% Liver metastases due to blood-borne spread via the portal vein
(52–54,57,70) (Table 12.6). A study of 1082 resected nodes in are present in up to 25% of patients at presentation. The accu-
patients with gastric cancer studied preoperatively with spiral racy of CT in the detection of liver metastases is covered else-
(helical) CT (5 mm slice thickness) demonstrated positive nodes where in the book (see chap. 52). The presence of ascites
in 21% of nodes between 5 and 9 mm, 23% of those between 10 almost invariably reflects peritoneal seeding, although indi-
and 14 mm, and 82% over 14 mm (71). Metastases were more vidual peritoneal deposits may be extremely small and missed
common in nodes demonstrating increased attenuation post- by CT. It is evident that laparoscopy is more sensitive than CT
contrast and in those with a small short-to-long axis ratio. in the detection of early peritoneal disease (76,77). Neverthe-
A recent detailed study of nodes resected at surgery identified less, in a study of 105 patients, Davies et al. concluded that
55% of metastatic lymph nodes to be less than 5 mm in diameter. while CT remained relatively poor at identifying lymph node
Although this study demonstrated a significant difference in mean metastases, it correctly identified invasion into adjacent struc-
diameter of metastatic (6 mm) and non-metastatic (4 mm) nodes, tures, identifying 76% of patients with invasion of the colon or
it highlighted the difficulty of accurate preoperative evaluation of mesocolon and 71% of patients with peritoneal metastases
lymph node metastases and thus confirmed that the decision to (Fig. 12.17) (78).
In advanced disease, particularly if chemotherapy is contem-
plated, the pelvis should be included in the initial assessment of
disease extent in order to demonstrate Krukenberg tumors, which
Table 12.6 Staging Accuracy of Gastric Cancer: CT and
may be seen as uni- or bilateral, often partially cystic, adnexal
Endoscopic Ultrasound (52,56,57,70,72–74)
masses.
T Stage (%) Serosal N Stage (%) Attention to technical detail will greatly enhance the accuracy of
Invasion (%)
scanning for all stages, but the inherent limitations of CT must be
CT EUS MRI CT CT EUS MRI recognized (Table 12.7). The accuracy of CT staging is higher in
Tio, 1989 – 83 – – 66 – advanced T3 and T4 disease than in early T1 and T2 stages.
Botet, 1991 42 92 – 48 78 –
Rosch, 1992 – 71 – – 75 –
Miniami, 1992 69 – – 80 – – – Endoscopic Ultrasound
Ziegler, 1993 43 86 – 51 74 – Tumor (T Staging)
Cho, 1994 65 – – 83 70 – – Endoscopic ultrasound is the most accurate technique for the
Matsushita, – – 88 – – – local staging of the primary tumor because of its ability to resolve
1994
Oi, 1997 – – 81 93 – – –
individual layers of the gastric wall, which closely parallel its
Takao, 1998 82 – – – – – histopathological structure. EUS shows the gastric wall as a five-
Dux, 1999 51 – – 51 – – layered structure of alternating hyper- and hypoechoic bands
Sohn, 2000 67 – 73 55 – 58 (Fig. 12.18) (79).
Willis, 2000 – 78 – – 77 – T1 tumors are seen as a hypoechoic disruption of the first three
Abbreviations: CT, computed tomography; EUS, endoscopic ultrasound; MRI, layers, that is, the mucosa and submucosa. Differentiation within
magnetic resonance imaging. the T1 category between tumors limited to the mucosa, and thus

(A) (B)
Figure 12.17 (A) Extensive infiltration of the gastric wall by mucinous adenocarcinoma (arrows). (B) Small volume ascites with widespread nodular omental and
peritoneal metastases (arrowed).

171
 primary tumor evaluation and staging
suitable for endoscopic resection, and those where submucosal
infiltration has occurred with its attendant increase in lymph
node metastases may be difficult on EUS. Increasing use of high-
resolution 20-MHz mini-probes enhances visualization of the
muscularis mucosa, with an ability to distinguish mucosal versus
submucosal invasion of 73% (80).
Table 12.7 Recognized Pitfalls in the Staging of Gastric Cancer
with CT Scanning
Tumor
“Pseudo-mass”: gastro-esophageal junction—oblique scanning plane,
underdistension of stomach
Underdistension of stomach—inaccurate evaluation of extent of gastric wall
thickening
Difficulty in differentiating T2/T3 tumor
Stomach not entirely covered by serosa (lesser curvature/anterior antrum)
Lesions limited to muscularis propria
OR Both = T2
Extending deeply in subserosa
Loss of plane between gastric wall and left lobe of liver—oblique plane
scanning
Loss of plane between tumor and pancreas—inflammatory adhesions
Loss of fat planes simulating direct organ invasion in cachectic patient
Nodes
Recognized limitation of CT in demonstrating nodal micrometastases
Poor distension of stomach—failure to appreciate perigastric nodes
Metastases
Failure to appreciate tiny omental/peritoneal deposits
Failure to identify pelvic metastases (Krukenberg tumor)
Treatment response
Residual rigidity of gastric wall in linitis plastica—difficult to evaluate
response
to treatment in infiltrating tumors
Failure to recognize differential response of metastases in different sites
(e.g., liver metastases vs. Krukenberg tumor)
Figure 12.18 Endoscopic ultrasound of gastric wall demonstrating five-layered
structure: (i) inner bright layer, mucosal; (ii) dark layer, deep mucosa; (iii) bright
layer, submucosa; (iv) dark layer, muscularis propria; (v) outer bright layer, serosal
surface.
172
Ulceration in association with tumors leads to peritumoral
inflammatory changes, which are impossible to differentiate
from tumor on EUS. This can result in an overstaging of ulcerat-
ing T1 tumors of up to 40%. However, in non-ulcerated tumors,
the horizontal extent of the lesion demonstrated on EUS corre-
sponds with the spread of tumor, which is important when
partial resection is considered or where accurate assessment of
response to tumor with chemotherapy is required (80,81). A T2
tumor invades the fourth layer and/or shows hyperechoic
appearance of the surrounding fat measuring less than one-third
of the tumor extent. The T2 category includes tumors that are
limited to the muscularis propria (T2a) and those that are infil-
trating into the subserosa (T2b) but have not yet invaded the
serosa and become T3.
A T3 tumor penetrates the fifth layer—the serosa (Fig. 12.19).
Certain parts of the stomach (lesser curvature and anterior aspect
of the gastric antrum) are not covered by serosa. In these areas
lesions infiltrating deeply into the subserosa and those limited to
the muscularis propria are both defined as T2. However, in gen-
eral, the extension of hypoechoic strands of tumor beyond the
normally smooth gastric wall indicates a T3 tumor (Fig. 12.20).
Invasion into adjacent organs (T4) can usually be seen clearly with
hypoechoic tumor extending directly into adjacent structures (79).
Overall, T staging accuracy with EUS is superior to CT, with
various studies reporting a T staging accuracy with EUS of between
61% and 92% (52,70,72,73). The accuracy of T2 staging is lower
than other stages with a high rate of overstaging (74). EUS is proba-
bly most useful in dichotomizing T stage into intramural—(T0–T2)
and extramural (T3–T4) disease with an accuracy of staging of 85%,
sensitivity of 79%, and specificity 94% (82). A review by Kelly et al.
of the staging performance of EUS found the overall accuracy of T
staging to be 91% using a T1/2 or T3/4 divide (83).
Endoscopic ultrasound appears to be reliable in predicting
complete resectability (i.e., resection with no residual tumor),
Figure 12.19 Tumor destroying the layered structure of the gastric wall (arrowed)
and thickening of the muscularis propria with an irregular serosal margin, suggest-
ing a T3 tumor. Note the normal five-layer appearance of the normal gastric wall.
 gastric cancer
with a sensitivity of 94% and specificity of 83% (Table 12.6)
(74,84). Five to fifteen percent of gastric tumors diffusely infil-
trate the wall of the stomach, spreading predominantly in the sub-
mucosa and inciting a marked fibrotic response in the submucosa
and muscularis propria, eventually resulting in a typical linitis
plastica appearance. Such scirrhous tumors may be difficult to
diagnose at an early stage as the mucosa over the lesion may be
relatively unaffected, such that the endoscopic appearance and
superficial mucosal biopsies are normal. On EUS, such tumors
typically produce irregular hypoechoic thickening of both the
Figure 12.20 Diffuse thickening of the gastric wall with complete loss of the layered
structure, indicating extensive tumor infiltration. The serosal margin is breached
(black arrow) and there are enlarged perigastric nodes (arrows).
Figure 12.21 Endoscopic ultrasound—linitis plastica: preservation of the layered
structure of the bowel wall despite wall thickening in a patient with linitis plastica
infiltration.
third (submucosal) and fourth (muscularis propria) layers, but
with preservation of their normal layered structure, unlike in
other forms of advanced gastric cancer where the architectural
layers of the wall are destroyed (Fig. 12.21) (85).
Nodes (N Staging)
The accuracy of detection of lymph nodes in gastric cancer on EUS
has been variably reported to be between 66% and 83%
(52,70,72,86,87). The limitation of the field-of-view to approxi-
mately 6 cm from the probe restricts visualization to the perigastric
nodes, with reduced accuracy in detection of nodes distant from the
primary tumor. Nodes are identified as well-defined, round, or ellip-
tical structures adjacent to the gastric wall with a more hypoechoic
pattern than the surrounding tissue (Fig. 12.22). Various attempts
have been made to discriminate between benign and malignant
nodes on the basis of shape, internal echogenicity, and the sharpness
of the marginal echoes (88). However, in gastric cancer, lymph nodes
without metastastic infiltration cannot usually be seen at EUS with a
negative predictive value of 82.1% (89). An overall accuracy of lymph
node staging of 83% has been reported from analysis of a total of
1519 resected nodes in patients with gastric cancer (89).
The introduction of linear-array endoscopic probes has enabled
directed fine-needle aspiration (FNA) biopsies of lymph nodes
and other tissues within 5 cm of the intestinal wall, with an overall
diagnostic yield of between 77% and 89% depending on the type
of tissue sampled (90). Assessment of mediastinal node involve-
ment probably has a greater impact in lung cancer staging than in
gastro-esophageal cancers.
Magnetic Resonance Imaging
The use of MR imaging in gastric cancer has been fairly limited.
Technical improvements, including breathhold fast sequences,
use of antiperistaltic agents, and the development of high spatial
resolution imaging show promise for its future use in gastric
Figure 12.22 Extensive gastric tumor with destruction of the normal wall archi-
tecture. There is a trace of ascites outlining the serosa (arrowhead). Enlarged
perigastric lymph node (arrows).
173
 primary tumor evaluation and staging
cancer staging. Several recent studies have highlighted its poten-
tial. An in vitro study on resected specimens with EGC using high
spatial resolution MR clearly depicted the gastric wall as a four-
to six-layered structure, and depth of mural involvement on MR
correlated well with the histopathological staging (91).
A comparative study between breathhold (two-dimensional)
fast low-angle shot (FLASH) and T2-weighted turbo spin-echo
fast MR compared with helical CT in gastric cancer staging found
similar accuracies for T and N staging (92). Further studies in
patients with advanced gastric cancer have demonstrated sensi-
tivities for T staging and the detection of extraserosal invasion of
between 80% and 93% (93,94).
Recent studies using IV administration of ultra-small particles
of superparamagnetic iron oxide-ferumoxtran have shown excel-
lent sensitivity and specificity in the identification of nodes con-
taining metastatic deposits with an accuracy of nodal staging
much superior to CT and EUS (95).
Positron Emission Tomography
The position of 18F-fluorodeoxyglucose (FDG) PET scanning in
the workup of gastric cancer patients is evolving as the results of
several studies emerge.
The value of PET is the ability to image larger areas and, although
it is probably not a primary tumor staging modality, it may play a
valuable role in detection of distant metastases (96–99). PET is
probably not helpful in primary T staging as it is a functional imag-
ing modality. In primary tumor detection, variable levels of FDG
uptake have been found. Mucinous carcinoma, signet-ring cell car-
cinoma, and poorly differentiated adenocarcinomas tend to show
significantly lower FDG uptake than other histological types (100).
Larger and more advanced tumors with nodal involvement have
a higher detection rate by PET—76.7% for tumors >3 cm as com-
pared to 16.8% for tumors <3 cm (101). In early gastric cancer,
only intestinal type (Lauren classification) were detected with PET
with no FDG uptake in diffuse type tumors (101).
The relatively poor spatial resolution of PET limits its usefulness
in detection of lymph nodes immediately adjacent to the tumor
(level 1 and 2 perigastric) as these cannot be separated from the
main tumor. However, in patents undergoing surgery, this is less
important as these nodes will be removed with the tumor. Detection
of extraperigastric nodes in the higher tiers—level 3 and 4—is
more important as this may influence the aggressiveness of nodal
resection or preclude curative surgery.
The presence of peritoneal metastases implies incurable disease.
Two patterns of uptake have been described—diffuse uniform
uptake and localized discrete foci unrelated to solid organs or
known lymph node stations (102). However, the value of PET
remains questionable as small nodules may be below the limit of
resolution of PET and there is variable uptake depending on the
tumor type and cell differentiation.
Hematogenous metastases to the liver are likely to be identified
with PET as well as CT and it is possible that a small deposit may
be better seen at PET imaging where there is a high target to
background ratio.
Recent studies suggest that PET may be useful in evaluating the
early metabolic response of gastric cancer to chemotherapy and
may therefore be able to predict the clinical outcome (103). This
may also allow early changes in treatment for non-responders.
174
Key Points: PET in Staging
■ PET is not helpful in primary T and N staging but is
valuable in detection of peritoneal disease and distant
metastases
■ PET may predict outcome post-chemotherapy
Laparoscopy
Laparoscopy is widely used prior to surgery where the tumor has
been assessed as greater than T1 stage by other imaging and other-
wise considered potentially resectable. The aim is to detect disease
not seen on CT, particularly peritoneal metastases (104,105).
Several studies have looked at the prediction of serosal involve-
ment laparoscopically with accuracy of visually determined T stage
assessment varying between 55% and 88% (105). Laparoscopy also
allows a direct method of biopsy of possibly involved lymph nodes
and also may detect hepatic metastases not seen on other imaging
studies with a reported accuracy of up to 98% (106).
Intraoperative Ultrasound
Initial studies have demonstrated a high accuracy for this tech-
nique in evaluating the local extent of tumor invasion at the time
of surgery to determine the appropriate type of surgical procedure.
An accuracy of 81% is reported in determining the depth of tumor
invasion, with 100% accuracy in detection of extraserosal tumor.
A high accuracy in detection of lymph node metastases—up to
93%—is also reported with this technique (107).
Summary
Although most studies indicate superior T staging of EUS versus CT,
the use of thin section multidetector CT with negative intraluminal
contrast has narrowed the difference between the two techniques
and it may be that MDCT will replace EUS for staging, except in very
early stage tumors where endoscopic resection is considered (108).
The main factor determining management is the presence of
serosal invasion and identification of T3/4 disease. Computed
tomography and MR appear to be equally accurate and compa-
rable in this context.
Key Points: Radiological Staging
■ Accuracy of CT staging is higher in advanced T3 and T4 than
in T1 and T2 disease
■ CT staging of nodal involvement remains limited as size is a
relatively poor predictor of involvement
■ CT can accurately identify local spread to mesocolon/colon
(76%) and peritoneal deposits (71%). The presence of ascites
usually indicates peritoneal seeding
■ In advanced disease, the specificity of CT is high with few
false positives
■ EUS is superior to CT in T staging, especially in Stage I and
II disease
■ EUS can distinguish between T1/2 intramural, and T3/4
(extramural disease with an accuracy of 91%)
■ Although currently not widely used, the accuracy of MR
tumor staging is similar to CT
■ FDG PET is valuable in the identification of metastatic
disease and in assessing response of the tumor to treatment
 gastric cancer

Recommendations for Staging MONITORING THE EFFECTS OF TREATMENT

Once the primary diagnosis of gastric cancer has been made,
the patient should be assessed for possible surgery. Patients who
clinically present with advanced disease or cachexia, and who are
clinically deemed unsuitable for surgery, are initially most appro-
priately staged by ultrasound. If extensive metastatic disease is
demonstrated, then palliation may be all that is considered
appropriate. However, if active management with either surgery
or chemotherapy is contemplated, then CT scanning is appropri-
ate for initial tumor staging. In advanced disease, this provides a
baseline for chemotherapy. In some institutions, patients with
disease considered resectable on MDCT will proceed to EUS for
more refined presurgical staging. The use of thin-section MDCT
with negative intraluminal contrast has narrowed the difference
between the two techniques and it may be that MDCT will replace
EUS for staging, except in very early stage tumors where endo-
scopic resection is considered (108). In this way, the likely extent
of surgery can be planned preoperatively. Laparoscopy should
be included to identify small peritoneal deposits and additional
techniques of laparoscopic or intraoperative ultrasound, if avail-
able, may contribute further staging information. In the relatively
small group of patients presenting with EGC, evaluation of the
extent of the lesion with EUS may enable more limited surgery or
potentially, in a small group, excision by endoscopic strip biopsy
(Fig. 12.23).
Diagnosis
endoscopy/barium meal
Confirm histology
Computed Tomography
Objective assessment of tumor response and post-treatment pre-
diction of resectability requires technically meticulous and repro-
ducible imaging. Computed tomography has been used in this
context, although the difficulty in evaluating the significance of
gastric wall thickening and non-distensibility is recognized (109).
Certain anatomical areas of the stomach, especially the cardia, are
difficult to evaluate. Scirrhous tumors presenting a linitis plastica
appearance are difficult to assess because of non-distensibility as a
result of the fibrous response incited by the tumor. This non-
distensibility often persists unchanged after treatment such that it
is impossible to measure the effects of the treatment on the
primary tumor (Fig. 12.24).
Transmural tumor extension may mask the presence of contigu-
ous lymph nodes and, in cachectic patients, the absence of fat also
frequently limits the ability to separate involved adjacent nodes
from the primary tumor. Soft tissue stranding extending into the
mesenteric fat may be due to tumor infiltration or inflammatory
disease and is difficult to quantify (110).
Metastatic disease which manifests as liver deposits, or less
commonly as separate Kruckenberg tumors in the ovary, may
be more easily defined and thus constitute measurable disease,
which can be followed in patients with potentially resectable
disease who undergo neo-adjuvant chemotherapy prior to sur-
gery. The ability of CT to detect extramural disease, pancreatic
invasion as opposed to inflammatory adhesions, peritoneal seed-
ings, and lymph node involvement on post-treatment scans is
limited. However, follow-up scans remain valuable to exclude
disease progression prior to surgery (111).

Endoscopic Ultrasound
The usefulness of EUS in assessment of residual disease postchemo-
Staging Cachexic radiotherapy remains unclear as viable tumor, necrotic tumor,
patient fibrosis, and reactive inflammatory changes can all have a similar
appearance. Conventional EUS staging criteria are unreliable,
CT scan
± laparoscopy though comparison of the maximum cross-sectional area of the
Treatable tumor before and after chemotherapy may be of some value (112).
disease Ultrasound

PET
Recent studies suggest that FDG-PET may be useful in evaluating
No metastases Metastases the early metabolic response of gastric cancer to chemotherapy and
Metastases
potentially resectable unresectable may therefore be able to predict the clinical outcome (103). This
may also allow early changes in treatment for non-responders.

EUS Consider Consider

palliative palliative RECURRENT GASTRIC CANCER
T Stage chemotherapy chemotherapy
N Stage
Despite apparent complete tumor resection at surgery, up to 70% of
patients develop recurrent tumor, usually within two years. The fre-
quency of recurrence and survival are strongly dependent on stage
T1–3 T4 of disease at time of surgery and extent of surgical resection.
Surgery Chemotherapy New molecular techniques have identified circulating tumor
other treatments cells in the peripheral blood even in early tumor stages, which
Figure 12.23 Flow diagram for gastric cancer staging. Abbreviations: CT, computed strongly supports the theory that clinically occult tumor cells
tomography; EUS, endoscopic ultrasound. released from the original tumor enter the blood circulation

175
 primary tumor evaluation and staging
(A)
(C)
Figure 12.24 (A) Diffuse circumferential tumor in the upper body of the stomach (arrows). (B) Decrease in tumor after three months’ chemotherapy (arrows). (C)
Following six months’ chemotherapy there is slight residual thickening and loss of distensibilty but it is difficult to define whether there is residual tumor present.
during surgical manoeuvres, migrate, and form metastatic tumors
to distant target organs (113).
The most common sites of tumor recurrence are in the area
of the celiac axis or hepatic pedicle, and also at the anastomotic
site or gastric stump, within the pancreas, and abdominal wall
incision site (114).
Tumor may spread to adjacent organs via ligaments or perito-
neal reflections. The liver may be invaded via the gastro-hepatic
ligament, the transverse colon via the gastro-colic ligament, and
the pancreas via the lesser sac.
Lymph node metastases are common. Intraperitoneal seeding
may be manifest on CT as nodules, loculated fluid collections, or
irregular beaded thickening and stranding of the mesentery or
omentum. Drop metastases may seed into the pouch of Douglas.
The liver is a common site for blood-borne metastases via the portal
vein. Involvement of the lungs, adrenals, kidneys, and bones is less
common. Ureteral metastases have been described resulting in a
thickened enhancing ureteric wall with obstructive hydronephrosis.
Metastases to other segments of intestine commonly show segmen-
tal wall thickening with a thick inner enhancing layer (115).
A recent study has investigated the use of 18FDG PET for the
diagnosis of recurrent gastric cancer. In 20 patients with estab-
lished disease recurrence (116), the sensitivity and specificity
of 18FDG PET was 70% and 69%, respectively, with a negative
predictive value of 60%. Survival of the 18FDG PET-positive
176
(B)
group was significantly less than the 18FDG PET-negative group
(approximately 9 versus 21 months), suggesting that although
18
FDG PET is not suitable for screening purposes in the follow-up
of treated gastric cancer, it may provide prognostic information.
18
FDG PET has a low sensitivity for detection of intraperitoneal
spread of disease and differentiation between normal physio-
logical bowel 18FDG uptake and uptake related to peritoneal
carcinoma may be difficult (100,102). However, 18FDG PET
may identify sites of disease where other imaging studies are
apparently negative.
Key Points: Recurrent Disease
■ Despite complete resection, 70% of patients develop recurrent
disease within two years
■ Although the sensitivity of 18FDG PET scanning is relatively
low in recurrent disease (70%), it may identify patients in a
poor prognostic group
GASTRIC LYMPHOMA (see also chap. 34)
The stomach is the most common primary site of extranodal
lymphoma, with primary gastric lymphoma representing up to
5% of gastric malignancy. An important advance has been the
 gastric cancer
recognition of lymphomas arising in specific mucosa-associated
lymphoid tissue (MALT), which is normally present in bronchial
and intestinal mucosa. Lymphomas arising within these specific
areas exhibit a biological behavior which differs from that of
nodal lymphoma and are classified as low-grade or high-grade at
histology.
Normal gastric mucosa contains no lymphoid tissue and lym-
phoid infiltration only develops as a result of inflammation. The
development of gastric MALT lymphoma is linked to the follicular
gastritis caused by H. pylori infection. Low-grade gastric MALT
demonstrates a diffuse infiltrate of small centrocyte-like cells that
invade the epithelial lining of glands or crypts and form discrete
lymphoepithelial lesions. It is frequently multifocal. In high-grade
MALT, recently re-classified as diffuse large B cell lymphoma
(DLBCL), this transforms to form confluent clusters or sheets of
large lymphoid cells, and this may be associated with areas of a
low-grade component (117–119).
Up to 80% of patients with low-grade MALT lymphoma, where
the disease is limited to the submucosa, achieve complete remission
of the tumor following eradication of H. pylori infection with antibi-
otics and a proton pump inhibitor. H. pylori appears to act as an
antigenic stimulus creating genetic mutations, which result in the
development of lymphoma within acquired epithelial lymphoid tis-
sue. The elimination of the H. pylori abolishes the antigenic drive,
resulting in regression of the tumor. In contrast, the proliferative
process of high-grade lymphoma is probably autonomous and no
longer dependent on antigenic drive, and therefore unresponsive
to H. pylori eradication (119). Thus, it is important to differentiate
low-grade MALT from high-grade DLBCL before deciding therapy.
Recent studies have identified a specific chromosomal translo-
cation within lymphoma cells which shows a strong negative
prediction for responsiveness to H. pylori eradication. Histological
complete remission was demonstrated in 68% of 67 translocation-
negative cases, while in 44 translocation-positive cases, only two
(A)
Figure 12.25 MALT lymphoma—early disease. Endoscopic ultrasound demonstrates: (A) Focal area of wall thickening involving all layers of the bowel with thickening
predominantly in the mucosa and submucosa (arrowed). (B) Enlarged lymph node adjacent to thickened gastric wall (arrowed).
patients showed a transient histological remission (120). In
patients who fail to respond to eradication therapy, chemotherapy,
radiotherapy, or surgery may be considered.
Diagnosis
Diagnosis is usually based on the endoscopic findings, which may
mimic benign and other malignant gastric lesions. Multiple biop-
sies may be required as the disease is frequently multifocal and
foci of malignant large B cells (high-grade disease) may be seen in
10% to 15% of cases. A report of barium meal findings identified
most low-grade (MALT) lymphomas as superficial spreading
lesions, with mucosal nodularity, shallow ulceration, and minimal
fold thickening, whereas most high-grade lymphomas demon-
strated mass-forming lesions or marked fold thickening
(121,122).
Staging
Endoscopic ultrasound is beyond dispute the best technique for
locoregional staging, that is, assessment of the vertical extent of
tumor (117,118). Endoscopic ultrasound upstaged 80% of low-
grade MALT lymphomas and 36% of DLBCL compared with CT
staging (118). Endoscopic ultrasound also gives prognostic infor-
mation on the probability of a histological remission following
H. pylori eradication. Lesions confined to the mucosa and sub-
mucosa without nodal involvement are likely to remit in 80% of
cases. Endoscopic ultrasound is less sensitive in the diagnosis of
multifocality and assessment of the horizontal extent of tumor
(Figs. 12.25 and 12.26).
Computed tomography has also been used for staging, but is
unable to identify the depth of invasion. Kessar et al. (123) found
that minimal gastric wall thickening was the most common find-
ing in seven patients with low-grade gastric MALT lymphoma.
Choi et al. (124) showed an abnormality on CT in 69% of patients
with histologically proven gastric MALT; there was a higher
(B)
177
 primary tumor evaluation and staging

(A) (B)

(C)
Figure 12.26 MALT lymphoma. (A) Computed tomography demonstrates bulky homogeneous tumor in the antropyloric region (arrows) with transpyloric extension
into the duodenal cap and infiltration of the pancreas. There is also thickening of the greater curvature in the mid body of the stomach. (B) Endoscopic ultrasound
confirms a bulky antral mass (arrowed) with pancreatic involvement (P). (C) In the mid-stomach there is marked thickening of the mucosal layer (M) indicating mucosal
infiltration without transmural extension.

incidence of gastric wall thickening and lymphadenopathy in the Assessment of Response

high-grade groups where there is deep invasion to the muscularis
propria and beyond. In biopsy-positive cases, the absence of an
abnormality on CT is highly predictive of low-grade MALT
lymphoma (124).
Key Points: Gastric Lymphoma
■ The stomach is the most common primary site of extranodal
lymphoma
■ MALT lymphoma may be low-grade or high-grade (DLBCL)
■ Eighty percent of patients with low-grade lymphoma achieve
complete remission following eradication of H. pylori infection
■ EUS is the best technique for initial locoregional staging, but
is less useful in follow-up post-treatment
■ Only minimal gastric wall thickening is demonstrated on CT
in low-grade MALT
Endoscopic ultrasound has been used to evaluate response to treat-
ment, and studies have demonstrated a decrease in wall thickness
and increased echogenicity of the gastric wall, returning towards
normal with histological remission. However, a recent study sug-
gests that the endosonographic changes take place significantly
later than histological remission (117,118). As in adenocarcinoma
of the stomach, EUS is less specific in tumor re-staging after
treatment, tending to overstage residual disease as it is not pos-
sible to differentiate between residual tumor infiltration and the
inflammatory response to therapy.
GASTRO-INTESTINAL STROMAL CELL TUMORS
Gastro-intestinal stromal cell tumors (GIST) are rare, non-epithelial,
non-lymphoid tumors arising from the mesenchyme of the
gastro-intestinal tract. They are thought possibly to derive from

178
 gastric cancer

the intestinal cells of Cajal (ICCs)—cells that are part of a
complex system acting as pacemakers for the gastro-intestinal
tract. They are a heterogeneous group of tumors with a broad
spectrum of differentiation ranging from completely differen-
tiated tumors with myoid (leiomyoma or leiomyosarcoma
type), neural (schwannoma type), or ganglionic plexus pheno-
types (e.g., ganglioneuroma), to tumors completely lacking
differentiation (125).
The true incidence of GIST tumors is difficult to establish as
many smooth muscle tumors have been reclassified as GISTs.
The immunohistochemical defining feature of GISTs is the c-kit
protein (CD117 antigen), a tyrosine kinase transmembrane recep-
tor. Most GISTs also express CD34 protein. Gastro-intestinal
stromal cell tumors may present throughout the gastro-intestinal
tract and approximately 60% to 70% occur in the stomach.
Around 10% to 30% of GISTs are malignant with varying degrees
of differentiation, the risk of malignancy increasing with an extra-
gastric location and a size greater than 5 cm. In the esophagus
most lesions are benign. Tumors may be asymptomatic and
discovered accidentally but may present with pain or bleeding due
to ulceration. Barium studies classically show a smooth, discrete
submucosal mass with a tendency to ulceration as the tumor
increases in size. There is often a substantial extraluminal compo-
nent, only seen on cross-sectional imaging (126).
On CT, benign GISTs are usually homogeneous and of soft
tissue density. Malignancy is suspected where the tumor has a
heterogeneous density with central areas of low attenuation
reflecting cystic degeneration or necrosis. Calcification occurs
infrequently. Tumors may ulcerate into the gastric lumen, result-
ing in intratumoral gas and may metastasize, particularly to the
liver and peritoneal cavity. Liver metastases may be hypervascular
or partially cystic (Figs. 12.27 and 12.28).
Until fairly recently, the only therapy available for GISTs was
surgical resection. However, new treatment programs with a
tyrosine kinase inhibitor (Imatinib) have resulted in a dramatic
response of the tumor in many patients with a sustained objective

(A) (B)
Figure 12.27 (A, B) Large heterogeneous centrally necrotic GIST tumor arising from the wall of the gastric antrum (arrowed).

(A) (B)
Figure 12.28 (A, B) Large GIST projecting into the mid body of the stomach with a large heterogeneous extragastric component.

179
 primary tumor evaluation and staging

response in more than 50% of patients with advanced unresectable

or metastatic disease (127).
Conventional RECIST criteria are often insensitive in demon-
strating a response of the tumor to treatment as lesions often
become cystic without a significant reduction in size. In a small
study of patients with liver metastases undergoing treatment with
Imatinib, all lesions became almost cystic on treatment (20–25 HU),
retaining a clearly defined margin while only slightly decreasing in
overall size (128). Several recent studies have identified the predic-
tive value of changes in standardized uptake values with 18F-FDG
PET (SUVmax) in determining tumor response to treatment (129).
However, not all GIST tumors are PET positive. In these patients,
small changes in tumor density and size on CT can be used as
sensitive criteria for assessing response (130).

Key Points: GIST

■ Sixty to seventy percent of GISTs arise in the stomach
■ Ten to thirty percent of GISTs are malignant
■ A specific defining c-kit protein (CD117 antigen) has been
identified within the tumor
■ There is often excellent response of malignant tumors to
treatment with a tyrosine kinase inhibitor (Imatinib)
Figure 12.29 Small tumor (carcinoid) (arrows) localized to superficial mucosal
■ Following treatment, lesions may become entirely cystic
layer with preservation of the layered structure of the bowel wall (T1).
■ FDG PET is useful in evaluating treatment response

association with Zollinger–Ellison syndrome with superimposed

(see chap. 32 on
GASTRIC CARCINOID TUMORS
polypoid masses of carcinoid tumor (132).
“Neuroendocrine Tumors”) Type 3 gastric carcinoid tumors are sporadic and not associated
with hypergastrinemia. These are large solitary tumors which may
There has been an increased detection of gastric carcinoid tumors
show ulceration and are more likely to be invasive with distant
as a result of improvements in imaging and the widespread use of
metastases. They are more common in men and the incidence of
endoscopy. These tumors have a particular behavior which distin-
metastatic spread is directly related to tumor size, with metastases
guishes them from other gastro-intestinal carcinoid tumors. They
reported in two-thirds of tumors larger than 3 cm (Fig. 12.30).
are rare, accounting for less than 1% of gastric neoplasms. They
These tumors have a poor prognosis, with 20% of patients surviv-
have recently been categorized into three subtypes with different
ing five years, and are treated with total gastrectomy and regional
appearances, predisposing conditions, and clinical outcomes (131).
lymph node resection. Systemic chemotherapy is recommended
Type 1 carcinoids are generally benign and account for most of the
when liver metastases are present.
lesions described. These are usually small, mucosal, or sub-mucosal
tumors measuring 1 cm or less, and may be multicentric. They
occur predominantly in the body and fundus of the stomach on a Key Points: Gastric Carcinoids
background of chronic atrophic gastritis. In this condition, there
is loss of acid-secreting parietal cells in the body and fundus of the ■ The majority of carcinoids are small, benign mucosal/
stomach with reduction in gastric acid secretion. This results in submucosal tumors of <1 cm associated with hypergastrinemia
hyperstimulation of the antral G cells to produce gastrin, and the ■ A small proportion of tumors are associated with Zollinger–

hypergastrinemia acts as a trophic factor for enterochromaffin-like Ellison syndrome and MEN 1
cells, resulting in hyperplasia which may progress to dysplasia and ■ Larger solitary tumors may occur sporadically without

the development of carcinoid tumors. These lesions are almost hypergastrinemia and are more likely to be malignant and to
universally benign and are limited to the mucosa or submucosa. invade and metastasize
They are treated conservatively either via endoscopic or local
resection, or by antrectomy, thus removing the gastrin-producing
cells (Fig. 12.29). Summary
Type 2 gastric carcinoid tumors are the least common type and
■ The prognosis of gastric cancer remains poor because of late
are associated with the hypergastrinemic state of Zollinger–Ellison
presentation
syndrome in association with multiple endocrine neoplasia type I
■ Early diagnosis and treatment when the tumor is limited to
(MEN 1). These tumors are also frequently multicentric, but have
the mucosa or submucosa (EGC) results in dramatically better
a higher incidence of lymph node metastases. On CT, the most
survival rates
striking feature is often the diffuse gastric wall thickening in

180
 gastric cancer
(A)
Figure 12.30 (A) Enhancing polypoid mass arising from the greater curvature of the stomach (arrow). Enlarged enhancing node in the lesser omentum (arrowhead).
(B) Endoscopic ultrasound demonstrates the heterogeneous echotexture of the lesion with cystic degeneration. At surgery a malignant carcinoid tumor was excised with
an infiltrated lymph node.
■ More aggressive surgical treatments with extended lymph-
adenectomy appear to confer a survival benefit
■ Although gastric cancer is chemo-sensitive, the long-term
benefits of chemotherapy have been disappointing. However,
new combined treatment strategies are showing survival
benefit
■ Preoperative staging with CT is standard practice and will
identify advanced disease with high specificity
■ EUS is more accurate in staging early disease and predicting
resectability
■ The accuracy of CT and EUS in staging nodal disease is rela-
tively limited due to the insensitivity in identifying microscopic
nodal invasion
■ Despite complete resection, 70% of patients develop recurrent
disease within two years
■ In MALT lymphoma, 80% of patients achieve complete
remission following eradication of H. pylori infection
■ EUS is the best technique for locoregional staging of MALT
lymphoma
■ Gastric carcinoids present a spectrum of disease from small
benign mucosal nodules to large invasive metastasizing
tumors
REFERENCES
1. Ferlay J, Bray F, Pisani P, Parkin DM. GLOBOCAN 2002:
Cancer Incidence, Mortality and Prevalence Worldwide.
Lyon: IARC Press, 2004.
2. Pera M, Cameron AJ, Trastek VF, Carpenter HA, Zinsmeister AR.
Increasing incidence of adenocarcinoma of the esophagus and
esophagogastric junction. Gastroenterology 1993; 104: 510–13.
(B)
3. Crew KD, Neugut AI. Epidemiology of gastric cancer. World
J Gastroenterol 2006; 12: 354–62.
4. Karpeh MS, Kelsen DP, Tepper JE. Cancer of the stomach.
In: De Vita VT Jr, Hellman S, Rosenberg SA, eds. Cancer:
Principles and Practice of Oncology, 6th edn. Philadelphia:
Lippencott Williams & Wilkins, 2001: 1092–126.
5. Hansson LE, Engstrand L, Nyrén O, et al. Helicobacter pylori
infection: independent risk indicator of gastric adenocarci-
noma. Gastroenterology 1993; 105: 1098–103.
6. Lewandrowski KB, Compton CC. Pathology of gastric
cancer and conditions predisposing to gastric cancer. In:
Anil KR, ed. Gastrointestinal Cancers: Biology, Diagnosis
and Therapy. Philadelphia: Lippincott-Raven Publishers,
1995.
7. Dixon MF, Mapstone NP, Neville PM, Moayyedi P, Axon AT.
Bile reflux gastritis and intestinal metaplasia at the cardia.
Gut 2000; 51: 351–5.
8. Corella D, Guillén M. Dietary habits and epidemiology
of gastric carcinoma. Hepatogastroenterology 2001; 48:
1537–43.
9. Watson, P, Lynch HT. Extracolonic cancer in hereditary non-
polyposis colorectal cancer. Cancer 1993; 71: 677–85.
10. Gore RM. Gastric cancer. Clinical and pathologic features.
Radiol Clin North Am 1997; 35: 295–310.
11. Hundahl SA, Phillips JL, Menck HR. The National Cancer
Database Report on poor survival of U.S. gastric carci-
noma patients treated with gastrectomy: Fifth Edition
American Joint Committee on Cancer Staging, proximal
disease, and the “different disease” hypothesis. Cancer
2000; 88: 921−32.
12. Albert C. Clinical aspects of gastric cancer. In: Anil KR, ed.
Gastrointestinal Cancers: Biology, Diagnosis and Therapy.
Philadelphia: Lippincott-Raven Publishers, 1995.
181
 primary tumor evaluation and staging
13. Clark CJ, Thirlby RC, Picozzi V Jr, et al. Current problems in
surgery. Gastric Cancer 2006; 43: 566–670.
14. Tominaga S. Trends in cancer mortality, incidence and
survival in Japan. Gan To Kagako Ryoho 1992; 19(Suppl 8):
1113–20.
15. Gore R, Levine MS, Ghahremani GG, Miller FH. Gastric
cancer. Radiologic Diagnosis. Rad Clin North Am 1997; 35:
311–29.
16. Lauren P. The two histological main types of gastric carci-
noma: diffuse and so-called intestinal type carcinoma. Acta
Pathol Microbiol Scand 1995; 64: 31–49.
17. Okabayashi T, Kobayashi M, Nishimori I, et al. Clinicopatho-
logical features and medical management of early gastric
cancer. Am J Surg. 2008; 195: 229–32.
18. Green PH, O’Toole KM, Weinberg LM, Goldfarb JP. Early
gastric cancer. Gastroenterology 1981; 81: 247–56.
19. Tsukuma H, Mishima T, Oshima A. Prospective study of
“early” gastric cancer. Int J Cancer 1983; 31: 421–6.
20. Sayegh ME, Sano T, Dexter S, et al. TNM and Japanese stag-
ing systems for gastric cancer: how do they coexist? Gastric
Cancer 2004; 7: 140–8.
21. Lundh G, Bern JI, Kolig G, et al. A co-operative international
study of gastric cancer (under the auspices of the Interna-
tional federation of surgical colleges). Ann Roy Coll Surg
Engl 1974; 54: 219–28.
22. Holtz F, Hort WR. Krukenberg tumours of the ovary: a
clinico-pathological analysis of 27 cases. Cancer 1988; 50:
2438–47.
23. Greene FL et al., eds. AJCC Cancer Staging Handbook. TNM
Classification of Malignant Tumours, 6th edn. New York:
Springer-Verlag, 2002.
24. McKee M, Posner M. The staging of gastric cancer:
nothing novel but perhaps better. Ann Surg Oncol 2003; 10:
1005–6.
25. Allum WH, Powell DJ, McConkey CC, Fielding JW. Gastric
cancer. Br J Surg 1989; 76: 535–40.
26. Sue-Ling HM, Johnston D, Martin IG, et al. Gastric cancer: a
curable disease in Britain. Br Med J 1993; 307: 591–6.
27. Cunningham SC, Kamangar F, Kim MP, et al. Survival after
gastric adenocarcinoma resection: eighteen-year experience
at a single institution. J Gastrointestinal Surg 2005; 9:
718–25.
28. Fujii M, Sasaki J, Nakajima T. State of the art in the treatment
of gastric cancer: from the 71st Japanese Gastric Cancer
Congress. Gastric Cancer 1999; 2: 151–7.
29. Hallissey MT, Allum WH, Jewkes AJ, Ellis DJ, Fielding JW.
Early detection of gastric cancer. Br Med J 1990; 301:
513–15.
30. Salmon P. Endoscopic treatment of gastro-intestinal
tumours: can surgery be avoided? Endoscopy 1992; 24:
229–31.
31. Ichikura I, Chochi K, Sugasawa H, et al. Individualized sur-
gery for early gastric cancer guided by sentinal node biopsy.
Surgery 2006; 139: 501–7.
32. Cuschieri A, Weeden S, Fielding J, et al. Patient survival after
D1 and D2 resection for gastric cancer: long term results of
the MRC randomised surgical trial. Surgical Co-operative
Group. Br J Cancer 1999; 79: 1522–30.
182
33. Bonenkamp JJ, Hermans J, Sasako M, et al. Extended lymph
node dissection for gastric cancer. N Engl J Med 1999; 340:
908–14.
34. Siewert JR, Bötcher K, Roger JD, et al. Prognostic relevance
of systematic lymph node dissection in gastric carcinoma.
German Gastric Carcinoma Study Group. Br J Surg 1993; 80:
1015–18.
35. Meyer HJ, Jähne J, Wilke H, Pilchmayr R. Surgical treatment
of gastric cancer: retrospective survey of 1704 operated cases
with special reference to total gastrectomy as the operation of
choice. Semin Surg Oncol 1991; 7: 356–64.
36. Gemmill EH, McCulloch P. Systematic review of minimally
invasive resection for gastro-oesophageal cancer. Br J Surg
2007; 94: 1461–7.
37. Saini A, Waxman J. Chemotherapy for gastric cancer. Gut
1992; 33: 1153–4.
38. Cunningham D, Chua YJ. East meets West in the treatment
of gastric cancer. N Engl J Med 2007; 357: 1863–5.
39. Macdonald JS, Smalley SR, Benedetti J, et al. Chemoradio-
therapy after surgery compared with surgery alone for ade-
nocarcinoma of the stomach or gastroesophageal junction.
N Engl J Med 2001; 345: 725–30.
40. Cunningham D, Allum WH, Stenning SP, et al. Perioperative
chemotherapy versus surgery alone for resectable gastro-
esophageal cancer. N Engl J Med 2006; 355: 11–20.
41. Ross P, Nicolson M, Cunningham D, et al. Prospective ran-
domized trial comparing mitomycin, cisplatin and protracted
venous-infusion fluorouracil (PVI 5-FU) with epirubicin,
cisplatin and PVI 5-FU in advanced esophagogastric cancer.
J Clin Oncol 2002; 20: 1996–2004.
42. Herman SJ, Bonenkamp JJ, Boon MC, et al. Adjuvant therapy
after curative resection for gastric cancer: meta-analysis of
randomized trials. J Clin Oncol 1993; 11: 1441–7.
43. Fink U, Schuhmacher C, Stein HJ, et al. Preoperative chemo-
therapy for Stage III–IV gastric carcinoma: feasibility,
response and outcome after complete resection. Br J Surg
1995; 82: 1248–52.
44. Ota DM. A pilot study of preoperative chemoradiation for
gastric cancer. Ann Surg Oncol 2001; 8: 482–3.
45. Sakuramoto S, Sasako M, Yamaguchi T, et al. Adjuvant
chemotherapy for gastric cancer with S-1, an oral fluoropy-
rimidine. N Engl J Med 2007; 357: 1810–2.0
46. Erenoglu C, Akin L, Uluutku H, et al. Angiogenesis predicts
poor prognosis in gastric carcinoma. Digestive Surg 2000; 17:
581–6.
47. Roukos DH. Current status and future perspectives in gastric
cancer management. Cancer Treatment Rev 2000; 26:
243–55.
48. Low VH, Levine MS, Rubesin SE, Laufer I. Diagnosis of gas-
tric carcinoma. Sensitivity of double contrast barium studies.
Am J Roentgenol 1994; 162: 329–34.
49. Shindoh N, Nakagawa T, Ozaki Y, et al. Overlooked gastric
carcinoma. Pitfalls in upper gastrointestinal radiology.
Radiology 2000; 217: 409–14.
50. Moss AA, Schnyder P, Marks W, Margulis AR. Gastric adeno-
carcinoma: a comparison of the accuracy and economics of
staging by computed tomography and surgery. Gastroenter-
ology 1981; 80: 45–50.
 gastric cancer
51. Dehn TC, Reznek RH, Nockler IB, White FE. The preopera-
tive assessment of advanced gastric cancer by computed
tomography. Br J Surg 1984; 71: 413–17.
52. Botet JF, Lightdale CJ, Zalber AG, et al. Preoperative staging
of gastric cancer: comparison in endoscopic US and dynamic
CT. Radiology 1991; 181: 426–32.
53. Sussman SK, Halvorsen RA, Illescas FF, et al. Gastric adeno-
carcinoma: CT versus surgical staging. Radiology 1988; 167:
335–40.
54. Kleinhaus U, Militianu D. Computed tomography in the
preoperative evaluation of gastric carcinoma. Gastrointest
Radiol 1988; 13: 97–101.
55. Halvorsen RA, Thompson WM. Gastrointestinal cancer:
diagnosis, staging, and the follow-up role of imaging. Semin
Ultrasound CT MR 1989; 10: 467–80.
56. Minami M, Kawawuchi N, Itai Y, Niki S, Sasaki Y. Gastric
tumours: radiologic–pathologic correlation and accuracy of
T staging with dynamic CT. Radiology 1992; 185: 173–8.
57. Cho JS, Kim JK, Rho SM, et al. Preoperative assessment
of gastric carcinoma: value of two-phase dynamic CT
with mechanical iv. injection of contrast material. Am J
Roentgenol 1994; 163: 69–75.
58. Hori S, Tsuda K, Murayama S, et al. CT of gastric carcinoma:
preliminary results with a new scanning technique. Radio-
graphics 1992; 12: 257–68.
59. Tsuda K, Hori S, Murakami T, et al. Intramural invasion of
gastric cancer: evaluated by CT with water-filling method.
J Comput Assist Tomogr 1995;19: 941–7.
60. Chen CY, Hsu JS, Wu DC, et al. Gastric cancer: preoperative
local staging with 3D multidetector row CT – correlation
with surgical and histopathologicial results. Radiology 2007;
242: 472–82.
61. Kim HJ, Kim AY, Oh ST, et al. Gastric cancer staging at
multi-detector row CT gastrography: comparison of
transverse and volumetric CT scanning. Radiology 2005
236:879-85.
62. Yu JS, Choi SH, Choi WH, et al. Value of nonvisualised
primary lesions of gastric cancer on preoperative MDCT.
Am J Roentgenol 2007; 189: 315–19.
63. Shimizu K, Ito K, Matsunaga N, Shimizu A, Kawakami Y.
Diagnosis of gastric cancer with MDCT using water-filling
method and multiplanar reconstruction: CT-histologic
correlation. Am J Roentgenol 2005; 185: 1152–8.
64. Kumano S, Murakami T, Kim T, et al. T staging of gastric
cancer: role of multidetector row CT. Radiology 2005; 237:
961–6.
65. Park MS, Yu JS, Kim MJ, et al. Mucinous versus nonmucinous
gastric carcinoma: differentiation with helical CT. Radiology
2002; 223: 540–6.
66. Takao M, Fukuda T, Iwanaga S, et al. Gastric cancer: evaluation
of triaphasic spiral CT and radiologic/pathologic correlation.
J Comp Assist Tomogr 1998; 22: 288–94.
67. Dux M, Richter GM, Hansmann J, Kuntz C, Kauffmann GW.
Helical hydro-CT for diagnosis and staging of gastric carci-
noma. J Comput Assist Tomogr 1999; 23: 913–22.
68. Dorffman RE, Alpern MB, Gross DH, Chandler MA. Upper
abdominal lymph nodes: criteria for normal size determined
with CT. Radiology 1991; 180: 319–22.
69. Balfe DM, Mauro MA, Koehler RE, et al. Gastrohepatic liga-
ment: normal and pathologic CT anatomy. Radiology 1984;
150: 483–90.
70. Ziegler K, Sanft C, Zimmer T, et al. Comparison of computed
tomography, endosonography and intraoperative assessment
in TN staging of gastric carcinoma. Gut 1993; 34: 603–10.
71. Fukuya T, Honda H, Hayashi T, et al. Lymph node metastases:
efficacy of detection with helical CT in patients with gastric
cancer. Radiology 1995; 197: 705–11.
72. Rosch T. Endoscopic ultrasonography. Endoscopy 1994; 26:
148–68.
73. Tio TL, Coene PP, Schouwink MH, Tytgat GN. Esophogastric
carcinoma: preoperative TNM classification with endosonog-
raphy. Radiology 1989; 173: 411–17.
74. Willis S, Truong S, Gribnitz S, Fass J, Schumpelick V.
Endoscopic ultrasonography in the preoperative staging
of gastric cancer: accuracy and impact on surgical therapy.
Surg Endosc 2000; 14: 951–4.
75. Mönig SP, Zirbes TK, Schroder W, et al. Staging of gastric
cancer: correlation of lymph node size and metastatic infil-
tration. Am J Roentgenol 1999; 173: 365–7.
76. Kriplani AK, Kapur BM. Laparoscopy for preoperative
staging and assessment of operability in gastric carcinoma.
Gastrointest Endosc 1991; 37: 441–3.
77. Watt I, Stewart I, Anderson D, Bell G, Anderson JR. Laparoscopy,
ultrasound and computed tomography in cancer of the oesoph-
agus and gastric cardia: a prospective comparison for detecting
intra-abdominal metastases. Br J Surg 1989; 76: 1036–9.
78. Davies J, Chalmers AG, Sue-Ling HM, et al. Spiral computed
tomography and operative staging of gastric carcinoma: a
comparison with histopatholoical staging. Gut 1997; 41:
313–19.
79. McLean AM, Fairclough P. Endoscopic ultrasound: current
applications. Clin Radiol 1996; 51: 83–98.
80. Yanai H, Fujimura H, Suzumi M, et al. Delineation of the
gastric muscularis mucosae and assessment of depth of inva-
sion of early gastric cancer using a 20 megahertz endoscopic
ultrasound probe. Gastrointest Endosc 1993; 39: 505–12.
81. Maruta S, Tsukamoto Y, Niwa Y, et al. Endoscopic ultrasono-
graphy for assessing the horizontal extent of invasive gastric
carcinoma. Am J Gastroenterol 1993; 88: 555–9.
82. Barbour AP, Rizk N, Gerdes H, et al. Endoscopic ultrasound
predicts outcomes for patients with adenocarcinoma of
the gastro-oesophageal junction. J Am Coll Surg 2007; 205:
593–601.
83. Kelly S, Harris KM, Berry E, et al. A systematic review of
the staging performance of endoscopic ultrasound in gastro-
oesophageal carcinoma. GUT 2001; 49: 534–9.
84. [No authors listed]. Clinical applications of endoscopic
ultrasonography in gastroenterology: state of the art 1993.
Results of a consensus conference, Orlando, Florida, 18 January
1993. Endoscopy 1993; 25: 358–66.
85. Fujishima H, Misawa T, Chijiwa Y, et al. Scirrhous carcinoma
of the stomach versus hypertrophic gastritis: findings at
endoscopic US. Radiology 1991; 181: 197–200.
86. Grimm H, Binmoeller KF, Hamper K, et al. Endosonography
for preoperative locoregional staging of esophageal and
gastric cancer. Endoscopy 1993; 25: 224–30.
183
 primary tumor evaluation and staging
87. Rosch T, Classen M. Endoscopic ultrasonography. In: Cotton
PB, Tytgat GN, William CB, eds. Gastrointestinal Endoscopy.
London: Current Science, 1993: 66–82.
88. Catalano MF, Sivak MV Jr, Rice T, Gragg LA, Van Dam J.
Endosonographic features predictive of lymph node meta-
stasis. Gastrointest Endosc 1994; 40: 442–6.
89. Akahosi K, Misawa T, Fujishima H, et al. Preoperative evalu-
ation of gastric cancer by endoscopic ultrasound. Gut 1991;
32: 479–82.
90. Wiersema MJ, Vilman P, Giovannini M, Chang KJ,
Wiersema LM. Endosonography-guided fine-needle aspi-
ration biopsy: diagnostic accuracy and complication assess-
ment. Gastroenterology 1997; 112: 1087–96.
91. Yamada I, Saito N, Takeshita K, et al. Early gastric carcinoma:
evaluation with high-spatial-resolution MR imaging in vitro.
Radiology 2001; 220: 115–21.
92. Sohn KN, Lee JM, Lee S-Y, et al. Comparing MR imaging and
CT in the staging of gastric carcinoma. Am J Roentgenol
2000; 174: 1551–7.
93. Oi H, Matsushita M, Murakami T, Nakamura H. Dynamic
MR imaging for extraserosal invasion of advanced gastric
cancer: evaluation with MR imaging. Abdo Imaging 1997;
22: 35–40.
94. Matsushita M, Oi H, Murakami T, et al. Extraserosal invasion
in advanced gastric cancer: evaluation with MR imaging.
Radiology 1994; 192: 87–91.
95. Tatsumi Y, Tanigawa N, Nishimura H, et al. Preoperative
diagnosis of lymph node metastases in gastric cancer by
magnetic resonance imaging with ferumoxtran-10. Gastric
Cancer 2006; 9: 120–8.
96. Lim JS, Yun MJ, Kim MJ, et al. CT and PET in stomach
cancer: preoperative staging and monitoring of response to
therapy. Radiographics 2006; 26: 143–56.
97. Rowen EM, Turkington TG, Coleman RE. Clinical applications
of PET in oncology. Radiology 2004; 231: 305–32.
98. Chen J, Cheong JH, Yun MJ, et al. Improvement in preopera-
tive staging of gastric adenocarcinoma with positron
emission tomography. Cancer 2005; 103: 2383–90.
99. McAteer D, Wallis F, Couper G, et al. Evaluation of 18F-FDG
positron emission tomography in gastric and oesophageal
carcinoma. Br J Radiol 1999; 72: 525–9.
100. Yoshioka T, Yamaghuchi K, Kubota K, et al. Evaluation of
18F-FDG PET in patients with advanced, metastatic or recur-
rent gastric cancer. J Nucl Med 2003; 44: 690–9.
101. Mukai K, Ishida Y, Okajma K, et al. Usefulness of preopera-
tive FDG-PET for detection of gastric cancer. Gastric Cancer
2006; 9: 192–6.
102. Lin EC, Lear J, Quaife RA. Metastatic peritoneal seeding
patterns demonstrated by FDG positron emission tomo-
graphic imaging. Clin Nucl Med 2001; 26: 249–50.
103. Di Fabio F, Pinto C, Rojas Llimpe FL, et al. The predic-
tive value of 18F-FDG-PET early evaluation in patients
with metastatic gastric adenocarcinoma treated with
chemotherapy plus cetuximab. Gastric Cancer 2007; 10:
221–7.
104. Burke EC, Karpeh MS, Conlon KC, Brennan MF. Laparo-
scopy in the management of gastric adenocarcinoma. Ann
Surg 1997; 225: 262–7.
184
105. Mansfield PF. Laparoscopic staging for gastric cancer. Ann
Surg Oncol 2000; 8: 622–3.
106. Molloy RG, McCourtney JS, Anderson JR. Laparoscopy in
the management of patients with cancer of the gastric cardia
and oesophagus. Br J Surg 1995; 82: 352–4.
107. Kodama I, Machi J, Tanaka M, et al. The value of operative
ultrasonography in diagnosing tumour extension of carci-
noma of the stomach. Surg Gynecol Obstetr 1992; 174:
479–84.
108. Habermann C, Weiss F, Riecken R, et al. Preoperative staging
of gastric adenocarcinoma: comparison of helical CT and
endoscopic US. Radiology 2004; 230: 465–71.
109. Ng VW, Husband JE, Nicolson VM, Minty I, Bamias A. CT
evaluation of treatment response in advanced gastric cancer.
Clin Radiol 1996; 51: 214–20.
110. Gossios K, Tsianos EV, Nicolson V, et al. CT evaluation of
the resectability of gastric cancer postchemotherapy. Abdom
Imaging 1996; 21: 293–8.
111. Ng CS, Husband JE, MacVicar AD, Ross P, Cunningham DC.
Correlation of CT with histopathological findings in
patients with gastric and gastro-oesophageal carcinomas
following neo-adjuvant chemotherapy. Clin Radiol 1998;
53: 422–7.
112. Isenberg G, Chak A, Canto MI, et al. Endoscopic ultrasound
in restaging of oesophageal cancer after neoadjuvant chemo-
radiation. Gastrointest Endosc 1998; 48: 158–63.
113. Roukos DH, Kappas AM. Limitations in controlling risk for
recurrence after curative surgery for advanced gastric cancer
are now well explained by molecular based mechanisms. Ann
Surg Oncol 2001; 8: 620–1.
114. Ha HK, Kim HH, Kim HS, et al. Local recurrence after
surgery for gastric carcinoma: CT findings. Am J Roentgenol
1993; 161: 975–7.
115. Kim KA, Park CM, Park SW, et al. CT findings in the
abdomen and pelvis after gastric carcinoma resection. Am J
Roentgenol 2002; 179: 1037–41.
116. De Potter T, Flamen P, Van Cutsem E, et al. Whole-body PET
with FDG for the diagnosis of recurrent gastric cancer. Eur J
Nucl Med Mol Imaging 2002; 29: 525–9.
117. Boot H, de Jong D. Diagnosis, treatment decisions and
follow-up in primary gastric lymphoma. Gut 2002; 51:
621–2.
118. Püspök A, Raderer M, Chott A, et al. Endoscopic ultrasound
in the follow-up and response assessment of patients with
primary gastric lymphoma. Gut 2002; 51: 691–4.
119. de Jong D, Aleman BM, Taal BG, Boot H. Controversies and
consensus in the diagnosis, work-up and treatment of gastric
lymphoma: an international survey. Ann Oncol 1999; 10:
275–80.
120. Liu H, Ye A, Ruskone-Fourmestraux A, et al. T(11;18) is a
marker for all stage gastric MALT lymphomas that will not
response to H. pylori eradication. Gastroenterology 2002;
122: 1286–94.
121. Park MS, Kim KW, Yu JS, et al. Radiographic findings
of primary B cell lymphoma of the stomach: low-grade
versus high-grade malignancy in relation to the mucosa-
associated lymphoid tissue concept. Am J Roentgenol 2002;
179: 1297–304.
 gastric cancer
122. Kim YH, Lim HK, Han JK, et al. Low-grade gastric mucosa-
associated lymphoid tissue lymphoma: correlation of radio-
graphic and pathologic findings. Radiology 1999; 212:
241–8.
123. Kessar P, Norton A, Rohatiner AZ, Lister TA, Reznek RH. CT
appearances of mucosa-associated lymphoid tissue (MALT)
lymphoma. Eur Radiol 1999; 9: 693–6.
124. Choi D, Lim HK, Lee SJ, et al. Gastric mucosa-associated
lymphoid tissue lymphoma: helical CT findings and
pathologic correlation. Am J Roentgenol 2002; 178:
1117–22.
125. Miettinen M, Sarlomo-Rikala M, Lasota J. Gastrointestinal
stromal tumours: recent advances in understanding of their
biology. Hum Pathol 1999; 30: 1213–20.
126. Sharp RM, Ansel HJ, Keel SB. Best cases from the AFIP:
gastrointestinal stromal tumour. Radiographics 2001; 21:
1557–60.
127. Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and
safety of imatinib mesylate in advanced gastrointestinal
stromal tumours. N Engl J Med 2002; 15: 461–3.
128. Chen MY, Bechtold RE, Savage PD. Cystic changes in hepatic
metastases from gastrointestinal stromal tumours (GISTs)
treated with Gleevec (Imatinib Mesylate). Am J Roentgenol
2002; 179: 1059–62.
129. Choi H, Charnsangavej C, de Castro Faria S, et al. CT evalua-
tion of the response of gastrointestinal stromal tumours after
imatinib mesylate treatment: a quantitative analysis correlated
with FDG PET findings. Am J Roentgenol 2004; 183: 1619–28.
130. Choi H, Charnsangavej C, Faria SC, et al. Correlation of
computed tomography and positron emission tomography
in patients with metastatic gastrointestinal stromal cell tumor
treated at a single institution with imatinib mesylate: pro-
posal of new computed tomography response criteria. J Clin
Oncol 2007; 25: 1753–9.
131. Binstock AJ, Johnson CD, Stephens DH, Lloyd RV, Fletcher
JG. Carcinoid tumours of the stomach: a clinical and radio-
graphic study. Am J Roentgenol 2001; 176: 947–51.
132. Berger MW, Stephens DH. Gastric carcinoid tumours associ-
ated with chronic hypergastrinaemia in a patient with
Zollinger–Ellison syndrome. Radiology 1996; 201: 371–3.
185
 13 Colorectal Cancer
Gina Brown, Janet E Husband, and Gary Cook
INTRODUCTION
Colorectal cancer (CRC) is the third most common malignant
neoplasm worldwide (1) and the second leading cause of can-
cer deaths in the United States (2). It is estimated that there
will be 148,810 new cases diagnosed in the United States in
2008, and 49,960 deaths due to this disease (2). The disease is
particularly common in North America, northern Europe, and
Australasia, less common in Asia and rare in sub-Saharan
Africa. In the United Kingdom in 2005 there were 36,766 new
cases of bowel cancer detected; the disease accounts for approx-
imately 13% of all new malignancies diagnosed (3). Although
the incidence of colorectal cancer has increased steadily over
many decades, recent trends have shown a reduction in mortal-
ity which is believed to be due to screening, improved chemo-
therapy and surgery (2). In the United Kingdom the lifetime
risk of developing colorectal cancer is 1 in 18 in males and 1 in
20 in females; in 2006 there were 15,957 deaths from colorectal
cancer (3).
Colorectal cancer can occur at any age but is most frequent
after the age of 50 years, and the incidence increases as age
advances. It is slightly more common in males than in females in
those over 50 years of age (2). Risk factors for colorectal cancer
include genetic predisposition, previous history of polyps, chronic
inflammation, physical inactivity, obesity, a diet of red meat,
smoking, and excess alcohol consumption.
Overall five-year survival rates for colorectal cancer are in the
region of 60% (2) and remain disappointing; however, recent new
approaches to management using neo-adjuvant and adjuvant
chemotherapy, as well as preoperative radiotherapy, have demon-
strated encouraging results in those with locally advanced disease
at presentation, and may lead to improved outcomes in the longer
term. The combination of improved total mesorectal surgical
techniques and preoperative radiotherapy in rectal cancer—using
a dose ≥30 Gy and multifield techniques—has been shown to pro-
duce improvements in overall survival (4). Preoperative radio-
therapy is associated with improvements in local recurrences and
an increase in the proportion of patients undergoing curative sur-
gery, but is accompanied by an increase in acute and late compli-
cations related to rectal and sexual function, compared with
surgery alone. Combination chemoradiotherapy provides further
improvement in local recurrence (5–9). The current generation of
clinical trials in colorectal cancer are focusing on strategies that
incorporate novel systemic agents with surgical strategies and
refining preoperative radiotherapy techniques for rectal cancer.
Such approaches are aimed at reducing both local and distant
recurrences (10–12). The use of modern staging methods enables
better selection of patients and thereby reduces treatment related
morbidity.
186
Key Points: Epidemiology
■ Colorectal cancer is the third most frequent cancer, and also the
third most frequent cause of cancer death in the western world
■ Colorectal cancer is most common after the age of 50 years
■ Overall five-year survival is approximately 60%
■ For early cancers, the five-year survival is approximately 90%
■ Etiological factors include genetic predisposition, smoking,
and diet
SCREENING FOR COLORECTAL CANCER
Screening programs for colorectal cancer are now being conducted
and evaluated in the United States and Europe. Screening is based
on the premise that early cancers and precancerous polyps can be
detected by fecal occult blood testing (FOBT) (13,14). Currently
the role of radiology is limited to barium studies, but computed
tomography colonography (CT colonoscopy) can detect large and
medium sized polyps (15). The technique is therefore indicated
for the detection of such polyps, or for the detection of cancers in
symptomatic patients who are unable to undergo colonoscopy, or
in whom the procedure has failed.
The American Cancer Society Guidelines on screening and sur-
veillance for the early detection of colorectal cancer recommend
that screening should commence at the age of 50 years and should
be conducted according to one of five different options (16):
• A fecal occult blood test (FOBT) or fecal immunochemical
test (FIT) every year
• A flexible sigmoidoscopy (FSIG) every five years
• Annual FOBT or FIT and flexible sigmoidoscopy every
five years
• A double-contrast barium enema every five years
• A colonoscopy every 10 years
The combined testing by annual FOBT or FIT and flexible sigmoi-
doscopy every five years is the preferred recommendation. These
guidelines suggest that positive results from FOBT, sigmoidoscopy,
or barium enema should be followed by colonoscopy. Colonoscopy
is regarded as the “gold standard.” In individuals considered to be
at high risk of developing colorectal cancer, screening should begin
before the age of 50 years. High risk factors include:
• A strong family history of colorectal cancer or polyps
• Families with hereditary colorectal cancer syndromes
(e.g., familial adenomatous polyposis coli)
• History of polyps or colorectal cancer in the individual
• History of chronic inflammatory bowel disease in the
individual
 colorectal cancer

Despite these robust recommendations, screening for colorectal
cancer has a low compliance in the United States, and only about
39% of colorectal cancers currently diagnosed are early stage
tumors (2). Increased awareness of the potential benefits of screening
as well as its limitations are now the subject of an energetic cam-
paign but, as yet, it is too early to detect a reduction in mortality
from colorectal cancer as a result of screening.
Key Points: Screening
■ Screening is based primarily on fecal occult blood testing
■ Barium studies have a limited but useful role in screening
■ Only about 39% of colorectal cancers are early cancers
■ CT colonography is indicated for patients unable to complete
colonoscopy
STAGING COLORECTAL TUMORS
Tumors of the rectum and colon share similar precancerous
lesions and conditions, as well as histopathological appearances
and modes of spread (17,18). Nevertheless, rectal cancer should
be regarded as a separate entity because its location within the
bony pelvis limits the ability to obtain wide radial resection mar-
gins, increasing the risk of local recurrence (19). Good quality
anatomical surgery has become a focus of attention (20,21) and
trials utilizing preoperative radiotherapy have yielded improve-
ments in local recurrence rates (7,9). The availability of a range of
operative approaches and preoperative therapy options has
increased the importance of accurate preoperative staging. In the
light of these advances, imaging now has a central role in the pre-
operative local staging of colorectal cancer and in the assessment
of metastatic disease, both at presentation and during follow-up.
Goals for Local Staging
Colon Cancer
Knowledge of the extent of disease at initial diagnosis is critical for
the proper management of patients with colorectal cancer. Until
recently, the role of CT in staging colonic tumors has been limited to
the detection of metastatic disease, and routine CT staging has been
shown to alter clinical management in around 20% of patients with
colon cancer (22–24), and most often this relates to the detection
of liver metastases. There is very little published work comparing
CT-predicted tumor stage with clinical outcome. However, when the
accepted pathological TNM definitions of T-stage (Table 13.1) are
applied to CT staging, the overall accuracy of T-stage prediction by
observers was only 60% compared with histology, whereas identifi-
cation of T3/T4 tumors showed a sensitivity of 85.9% to 92.4%, with
a positive predictive value (PPV) of at least 90% to 92%. These results
differ from previous studies, which have reported sensitivities of
between 55% and 61% and specificities of 67% to 81%, and lacked
the accepted pathological definitions of depth of invasion, particu-
larly perforation of the peritonealized colon. Multidetector CT scan-
ners, which are able to obtain 1 mm thick slices within a single
breath-hold thus permitting 3D reconstruction, give improved reso-
lution and image quality. Two small series using CT colonography
(“virtual colonoscopy”) have produced good results, with correct
T-staging reported in 26 of 33 (78.7%) and 30 of 37 (81%) colorectal
Table 13.1 International TNM Staging Classification of Colorectal
Cancer (Fifth Edition)
TNM definitions
Primary tumor (T)
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
Tis Carcinoma in situ: intraepithelial or invasion of the lamina propriaa
T1 Tumor invades submucosa
T2 Tumor invades muscularis propria
T3 Tumor invades through the muscularis propria into the subserosa, or
into non-peritonealized pericolic or perirectal tissues
T4 Tumor directly invades other organs or structures, and/or perforates
visceral peritoneumb
Regional lymph nodes (N)
NX Regional nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in one to three regional lymph nodes
N2 Metastasis in four or more regional lymph nodes
Distant metastasis (M)
MX Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis
A tumor nodule 3 mm or less in diameter is classified in the T category as a non-
contiguous extension, which is T3.
a
Tis includes cancer cells confined within the glandular basement membrane
(intraepithelial) or lamina propria (intramucosal) with no extension through
the muscularis mucosae into the submucosa.
b
Direct invasion in T4 includes invasion of other segments of the colorectum by
way of the serosa; for example, invasion of the sigmoid colon by a carcinoma of
the cecum.
tumors (25,26). The reported sensitivities for lymph node detection
range between 19% and 97% (26–30).
For many patients the current treatment strategy of surgical
excision, followed by adjuvant chemotherapy, fails either to clear
locoregional spread, or to eradicate distant micrometastases,
leading to disease relapse. Preoperative therapy has the potential
to make an impact upon both of these causes of failure based on
the premise that optimum systemic therapy at the earliest possible
opportunity is likely to be more effective at eradicating distant
metastases than the same treatment given after the delay and
immunological stress of surgery. Added to this, shrinking the
primary tumor before surgery may reduce the risk of incomplete
surgical excision together with the associated risk of tumor cell
shedding during surgery.
Recent advances in radiology (31), and in chemotherapy, have
enabled the design of a randomized trial to investigate the role of
neoadjuvant therapy for patients with colon cancer. Occasionally
patients may present with a complication of the primary tumor,
or with disease that has infiltrated adjacent local structures; in
these cases, preoperative identification of extensive tumor spread
will influence the surgical approach and in some irresectable
cases preoperative chemotherapy or radiotherapy has also been
advocated (32).
Rectal Cancer
It is generally agreed that surgery should be offered to the vast
majority of patients with rectal cancer, as local symptoms, due to
growth within the pelvis, are associated with intractable pain,

187
 primary tumor evaluation and staging
which is difficult to palliate. Surgical technique, the physical con-
straints of the narrow tapering bony pelvis, as well as proximity of
the rectum to adjacent anatomical structures within the pelvis
hamper the ability to obtain a surgical specimen, clear of tumor, at
the lateral circumferential margins (33,34). These observations
have led to a focus of attention on high-quality anatomical
surgery as exemplified by total mesorectal excision (TME) and on
targeting preoperative therapy to reduce local recurrences.
In rectal cancer, the observation of morphological features
currently provides the best method of staging tumors into distinct
prognostic groups. The presence or absence of such features is
predictive of local recurrence, distant metastatic disease, or both.
Successful primary surgical removal of the tumor, with clear
resection margins, is dependent on accurate staging. It also results
in a reduction in local recurrence rates and improvement in
survival by reducing or eliminating the metastatic potential of
local recurrences (35,36).
Prognostic Factors in Rectal Cancer
Patterns of Local Spread
When colorectal tumors invade through the bowel wall into the
perirectal fat, they most commonly do so with a relatively well-
circumscribed margin. In 25% of cases however, the pattern of
spread is widely infiltrative with ill-defined borders; a pattern of
spread which has a poor prognosis (37–39).
Extent of Local Spread
Dukes’ 1932 paper (40) highlighted the importance of extent of
extramural spread in the prediction of local recurrence as well as
survival. Importantly, Dukes also observed that once spread
beyond the bowel wall occurs, the incidence of lymph node invasion
increases, rising from 14.2% in tumors confined to the bowel wall
to 43.2% in those tumors extending beyond the bowel wall.
Spread Beyond the Peritoneal Membrane
This is defined as perforation of the peritoneal membrane by
tumor, which results in both local recurrence and transcoelomic
dissemination and, in one study, peritoneal involvement was
detected in 25.8% (54/209) of cases (41). Peritoneal involvement
is an independent prognostic factor and predicts for local recur-
rence after surgery for upper and middle rectal cancers (41), as
well as for all colon cancers (42).
Venous Spread
Invasion of extramural veins by tumor is an important adverse prog-
nostic factor associated with low survival rates regardless of Dukes’
stage. Talbot and Ritchie (43) reported a five-year survival of only
33%. Venous invasion also predicts for significantly reduced actuar-
ial survival rates in patients with node-negative tumors (44,45).
Venous invasion is not only a poor predictor of survival, but is also
the third strongest independent predictor of metastasis, after lymph
node status and extent of local tumor infiltration (21,46,47).
Lymph Node Spread
In rectal cancer, nodal spread is from the level of the tumor
upwards within a discrete compartment comprising a fatty enve-
lope that encloses the rectum—the mesorectum. When there is
extensive lymph node spread with blockage of the lymphatic
188
channels, downward spread may occur, and in lower rectal tumors,
spread to the inguinal nodes may occur, though this is infrequent
(48). Spread to the pelvic sidewall is relatively unusual, occurring
in less than 10% of cases. The presence of lymph node metastases
in the resected specimen is an independent adverse prognostic
indicator, and this effect is most pronounced when four or more
nodes are involved. Dukes and Bussey (49) showed that for 1, 2 to
5, 6 to 10, and more than 10 affected nodes, the five-year survival
rates were 63.6%, 36.1%, 21.9%, and 2.1% respectively. This
observation has been reaffirmed by other studies (50,51).
Quality of Pathology as a Prognostic Factor
Histopathology is regarded as the gold standard for the prognostic
assessment of colorectal cancer specimens. However, the thor-
oughness of the histopathological assessment has a bearing on its
usefulness. In 1997, an audit of colorectal histopathology report-
ing showed substantial deficiencies in the completeness of the
reporting, including under-reporting of the circumferential resec-
tion margin (CRM) status and missing T and N status in the final
reports. Consequently, proforma reporting for histopathology
was introduced in the United Kingdom, and similar guidelines for
both histopathological specimen preparation and reporting were
suggested by the American College of Pathology. This has resulted
in some improvements in tumor assessment, but important
features, such as CRM status and the presence or absence of extra-
mural venous invasion (EMVI) are not universally reported. In an
audit of histopathology reporting from the Leeds Registry under-
reporting of CRM status and EMVI, as well as poor lymph node
harvesting, was associated with significantly worse outcomes for
patients staged as apparently T3N0 disease.
Key Points: Prognostic Factors in Rectal Cancer
■ Pattern of local spread—a primary tumor with an infiltrating
outer border has a poorer prognosis than a well-defined tumor
■ Extent of local spread—increasing extramural spread is a
poor prognostic factor
■ Peritoneal perforation by tumor—predicts for local recurrence
■ Venous spread—an independent adverse prognostic indicator
■ Lymph node spread—an important prognostic factor and
prognosis is dependent on the number of involved lymph
nodes
Circumferential Resection Margin
The circumferential margin of involvement by tumor has become
a major prognostic factor in assessing rectal cancer, and an impor-
tant concept in the oncological treatment of adenocarcinoma of
the rectum is the integrity of the rectum and its mesorectal tissue
(33). CRM-positive patients have a 15% five-year survival rate.
The draining lymphatic vessels and nodes are located throughout
the mesorectum. If the mesorectum is divided or disrupted dur-
ing surgical excision of rectal carcinoma, tumor spillage may
occur, or involved nodes may be left in situ, which predisposes to
local recurrence of tumor. Oncological excision of the rectum
involves mobilization of the rectum in the plane formed by the
mesorectal fascia posterolaterally around the mesorectum. This
plane allows the rectum and mesorectum to be removed en bloc,
 colorectal cancer
(A) (B)
Figure 13.1 (A) A total mesorectal specimen is shown following surgery. (B) After formalin fixation, the specimen is sectioned axially and laid out. This enables a visual
inspection of the circumferential resection margin [arrows in (B) and (C)] and an assessment of the relationship of tumor to these margins. (C) Slices are then selected
for glass-mounting and staining with hematoxylin and eosin prior to assessment by microscopy.
without disruption of the presacral fascia and its underlying
venous plexus. When the surgically excised specimen is sectioned
transversely, the lateral border of the specimen is termed the
circumferential resection margin (CRM) (Fig. 13.1).
Key Points: Circumferential Resection Margin
■ The circumferential margin of tumor is an important
prognostic indicator
■ The risk of local recurrence is significantly greater in
CRM-positive patients
■ CRM-positive patients have a 15% five-year survival rate
Staging Classifications
The purpose of a good histopathological staging technique is to
enable separation of patients into distinct prognostic groups so
that subgroups of patients who have different risks of recurrence
can be treated accordingly.
Dukes
In 1932, Cuthbert Dukes proposed a classification based on analysis
of 215 patients as follows:
• A—carcinoma limited to the wall of the rectum
• B—spread of the carcinoma into extrarectal tissues but
no nodal involvement
• C—lymph node involvement is present
Later observations on the spread of rectal cancer showed a striking
difference in survival after surgery among the three prognostic
groups (A, B, and C) and this classification has also been applied
to colonic tumors in general. Although the classification permit-
ted clear separation into prognostic groups, the patients within
group B represented a broad range with widely differing survival
rates dependent on the extent of extramural spread.
(C)
Table 13.2 Astler and Coller’s Modification of the Dukes’
Staging System
Stage Histopathology definition
Stage A Lesion limited to the mucosa
Stage B1 Lesion involving the submucosa or muscularis
propria but not beyond it
Stage B2 Lesion beyond the muscularis propria
Stage C1 B1 with nodal metastasis
Stage C2 B2 with nodal metastasis
Astler–Coller
In subsequent years, the pathological Dukes’ system was subject to
further modifications (52,53). Significant differences in survival were
observed when Dukes’ C cases were subdivided according to depth of
tumor penetration, as proposed by Astler and Coller, and designated
as C1 and C2. The prognostic advantage of Astler–Coller C1 over
Astler–Coller C2 status was also confirmed by Jass and Love (54). The
Astler–Coller modification was favored in the United States, but the
use of A, B, and C classes that had different definitions resulted in
considerable confusion with the Dukes’ system (Table 13.2).
TNM
The TNM system was introduced to overcome confusion between
existing staging classifications (namely Dukes’ and Astler–Coller).
The TNM classification allowed a clinical staging based on clinical
and radiological examination findings to be incorporated (denoted
by the prefix c, i.e., cTNM) and considered alongside the pathologi-
cal assessment of TNM stage (denoted by the prefix p, i.e., pTNM).
The TNM classification for colorectal cancer has since been modi-
fied further (Table 13.1 and Fig. 13.2); the most recent sixth edition
was published in 2002, but remains controversial (55). The fifth
edition will be used in this text (56). This international classification
is the most commonly used in staging colorectal cancer.
189
 primary tumor evaluation and staging

T1
T2

Adjacent
structures Mucosa

Submucosa
Muscularis propria
Subserosa

T3

T4

T4 T4

N1

N2

(A) (B)
Figure 13.2 Staging colorectal cancer in (A) primary tumor (T) and (B) lymph nodes (N).

Key Point: Staging Classification
■ TNM classification is the most widely used staging system in
colorectal cancer
Goals for Staging Metastatic Disease
Besides providing important prognostic information, the identifi-
cation of distant metastases has been shown to be beneficial both
at initial staging and during follow-up of patients with colorectal
cancer (57). Firstly, a proportion of patients with metastatic
disease may achieve long-term cure by metastatectomy (58).
Secondly, for those with irresectable metastatic disease, palliative
chemotherapy has been shown to be superior to supportive care
alone (59). Finally, for some patients who are asymptomatic and
there is no evidence of obstruction, the preoperative demonstration
of widespread metastatic disease may preclude the need for
surgery, thus avoiding operative morbidity.
STAGING THE PRIMARY TUMOR AND NODAL SPREAD
Computed Tomography
T Staging
The usefulness of CT in the local staging of both colon and rectal
cancer has previously been shown to be limited (29,60). The main
criterion for identification of tumor is focal thickening of the rectal
wall. Extension into perirectal tissues is indicated by irregularity of
the border of the rectal wall and strands of soft tissue extending
into perirectal fat (61,62). However, these findings were noted to be
non-specific, and may be due to fibrosis, inflammation, and des-
moplasia. Thus, sensitivity for local invasion was poor, and ranged
from 48% to 55% (63). A major limitation is insufficient spatial
resolution to detect focal tumor spread external to the muscularis
propria (34,64,65). Invasion into adjacent structures was also
difficult to assess, as loss of fat planes may occur due to vascular or
lymphatic congestion, inflammation, and absence of intrapelvic fat
as a result of cachexia (62). Lack of fat between the planes is a
particular problem for low rectal tumors because of lack of
contrast between tumor and adjacent muscle (66). Patients undergo
preoperative CT examination of the thorax, abdomen, and pelvis to
detect metastatic disease (67). Such patients are offered preoperative
chemotherapy for the primary tumor, and for resectable hepatic
metastatic and/or pulmonary metastatic disease.
In a recent study, using carefully defined criteria for image inter-
pretation, a much higher sensitivity (86–92%) and PPV (90–92%)
for the identification of T3 and T4 tumors by preoperative CT was
achieved (68). In this series, there was good correlation between
CT-predicted “poor prognosis” T-stage (i.e., T4 and T3c and d) and
poor histological group (PPV: 74–75%) and comparison of out-
comes showed that CT-predicted T-stage discriminated between
good and poor survival with similar accuracy to pathological crite-
ria (31), thus establishing an evidence base for the use of CT. In a
small minority of patients, the demonstration of locally advanced,
irresectable, tumor (T4) will enable more radical treatment to be
planned, including more radical surgery and the use of preoperative

190
 colorectal cancer
chemoradiotherapy in selected cases (Fig. 13.3). CT may also identify
complications related to the primary tumor. These include:
• Intestinal obstruction
• Local tumor perforation/fistula formation
• Pericolic abscess
• Intussusception
• Acute appendicitis
Intestinal obstruction is the most common complication of carci-
noma of the colon. It has an unfavorable effect upon prognosis as
it most often relates to advanced disease (69). Local tumor perfora-
tion (Fig. 13.4) through the peritoneal membrane is common and
also indicates an unfavorable prognosis; this is not only due to
Figure 13.3 Preoperative CT shows a fixed irresectable locally advanced transverse
colon tumor invading the anterior abdominal wall.
Figure 13.4 Local tumor perforation through the peritoneal membrane. Tumor
(arrow) demonstrated extending through the peritoneal membrane.
associated peritonitis, but also because of the risk of dissemination
of malignant cells within the abdomen resulting in transcoelomic
spread and peritoneal involvement (41). Tumor cells may be pres-
ent in peritoneal washings in up to 42% of patients (70). Trans-
coelomic metastases favor certain sites, such as the lower right
small bowel mesentery (superior and inferior ileocolic recesses),
the intersigmoid recess and the rectovesical or rectouterine pouch
(pouch of Douglas) (71,72). Penetration of the wall of the colon by
cancer cells is sometimes associated with the development of a
pericolic abscess. Other complications include intussusception of
the colon, which in adults is more often due to carcinoma than a
benign cause (73). On occasion, acute appendicitis may be the pre-
senting feature due to tumor growth in the right colon producing
back pressure and appendiceal obstruction (74).
Key Points: T Staging with Computed Tomography
■ Computed tomography in local staging of colorectal cancer
permits stratification into good and poor prognosis tumors
■ High sensitivity for detection of poor prognosis T3 and T4
tumors can be achieved using multidetector CT
■ Demonstration of T4 invasion in colon cancer may alter
the surgical approach
■ Preoperative assessment of T-stage can potentially influence the
preoperative treatment plan in colon cancer
■ CT is useful for detection of complications related to the
primary tumor, for example, obstruction, perforation, and
abscess formation
N Staging
The inaccuracy of CT in the detection of lymph node metastases
relates to the use of size as the only criterion. This results in both
overstaging of enlarged nodes and understaging of normal-sized
nodes. The large comparative study reported by the Radiology
Diagnostic Oncology Group found the sensitivity for detecting
lymph node metastases in 322 patients to be 38% for rectal cancer
and 56% for colon cancer; the overall accuracy in all patients
studied was only 62% (29,60).
Key Point: Nodal Staging
■ CT is inaccurate for detection of nodal metastases in
colorectal cancer
Magnetic Resonance Imaging
Magnetic resonance (MR) imaging of colonic tumors has proved
to be time-consuming and sometimes difficult. Motion and peri-
stalsis related artefacts need to be overcome and in contrast to the
constant position of the rectum and relative ease of obtaining true
axial images, the colon is much longer, tortuous, and the true axial
plane alters according to tumor location. Variability in the loca-
tion of colonic tumors is a particular problem when imaging
tumors of the transverse and sigmoid colon, as both these regions
of the colon are suspended on mobile mesenteries. To date there
have been few reports on the performance of MR imaging in stag-
ing colonic tumors. The majority of studies evaluating MR imag-
ing have focused on the detection of masses using MR
191
 primary tumor evaluation and staging
colonography. However, in one series, TNM MR staging agreed
with surgical and pathological staging in 41 of 48 (85%) patients,
including 27 colon cancers (75). With regard to depth of tumor
penetration, MR imaging agreed with pathologic results in 22 of
25 colon cancers (88%).
MR Staging of Rectal Cancer
MR imaging now has a central role for staging primary rectal
tumors. Initially, endorectal coil MR imaging was necessary to
visualize rectal tumors (76–78), but this was superseded by
high-resolution pelvic phased-array coil techniques. Criteria
for identifying the layers of the bowel wall and for T staging
rectal cancer were proposed but researchers often used different
imaging parameters, and many reported conflicting results
(78–82). The use of intravenous (IV) contrast medium for
delineating extension beyond the rectal wall was also the subject
of controversy (79,80,83). However, despite these inconsisten-
cies, accuracies of 80%, or greater, were achieved using the
endorectal coil, and most authors agreed that T2-weighted
images provided better contrast between the tumor and the rec-
tal wall than could be obtained with T1-weighted images. These
studies showed that the higher resolution achieved with
endorectal imaging produced images which demonstrated the
different anatomical layers of the bowel wall.
Unfortunately, the role of endorectal imaging in the routine
staging of rectal cancer is limited. In common with endoluminal
ultrasound, stenosis, pain and discomfort, bowel wall motion,
inability to assess lesions in the upper rectum, difficulties in coil
placement, and coil migration all hamper successful imaging of
rectal tumors by this means (Fig. 13.5).
Figure 13.5 Endorectal coil imaging of the normal rectum. Note small incidental
prostate lesion (arrow).
192
High Spatial Resolution Magnetic Resonance Imaging
Using the Pelvic Phased-Array Coil
The examination should be performed in those patients with
histologically proven rectal carcinoma who present for disease
staging. Ensuring that the patient is comfortable and pain-free
will help to ensure a good quality examination, free from unwanted
motion artefact. There is no role for purgative bowel preparation
or enemas. Although small bowel movement is not usually a sig-
nificant cause of artefact, anti-peristaltic agents can improve the
overall quality of images obtained. The patient is placed supine on
the table and the flexible multi-element phased array surface
body/pelvic coil is placed firmly around the pelvis to ensure good
compression and to minimize the possibility of motion. A full
bladder is unnecessary and may render the patient uncomfortable
due to compression from the surface coil.
The initial sequences performed are localization images in
the coronal and sagittal planes to image the tumor and plan the
high-resolution images that are performed axial to the rectum.
The first series is sagittal T2-weighted fast spin-echo (T2W
FSE), which enables identification of the primary tumor. The
second series is large field of view axial sections of the whole
pelvis from the iliac crest to the symphysis pubis. While the sec-
ond series is being acquired, the high-resolution images can be
planned. The sagittal T2-weighted images obtained are used to
plan T2-weighted thin-section axial images through the rectal
cancer and adjacent peri-rectal tissues. It is critical that these
images are performed perpendicular to the long-axis of the rec-
tum to prevent over or under-estimation of depth of spread.
The images are obtained by using a 16 cm field of view and
3 mm section thickness.
When staging tumors arising in the lower third of the rectum,
the rapid change in calibre of the rectal lumen at the level of the
anorectal junction limits the usefulness of oblique axial imag-
ing alone. At this level, axial images may not show the rectal wall
in its entirety, and clear delineation between the outer edge of
the rectal wall and the levator muscle may not be possible.
Potentially this can lead to overstaging. It is therefore useful to
utilize a high spatial resolution coronal imaging sequence which
will show the levator, the sphincter complex, the intersphinc-
teric plane and the relationship to the rectal wall optimally
(Fig. 13.6).
For staging low anterior wall rectal tumors, a small field of
view series in the sagittal plane is helpful in determining the
precise relationship of the invasive edge of tumor to critical
anterior structures, such as the prostate and posterior vaginal
wall.
T Staging
Using a high-resolution technique, thin-slice MR imaging can be
used to measure the depth of extramural spread accurately, and
the results show good correlation with corresponding pathologi-
cal measurements in resection specimens (84). Through careful
correlation of preoperative images with histopathology sections,
criteria for T staging have been derived (Table 13.3).
This high-resolution technique has the advantage of being non-
invasive, employing a short imaging time (30–40 minutes), and
can be performed using standard software on a 1.5 T field-strength
magnet. Moreover, the high spatial and contrast resolution of the

Figure 13.6 Coronal T2-weighted MR image showing relationship of outlined tumor
(*) and intersphincteric plane (open arrow) to anal sphincter complex (arrow).
Table 13.3 MR Imaging Criteria for T Staging
Low signal in the submucosal layer, replacement of
submucosal layer.
Lack of abnormal signal extending into circular
muscle layer.
Intermediate signal intensity within muscle. Outer muscle
coat replaced by intermediate signal intensity tumor but
this does not extend beyond the outer rectal muscle into
perirectal fat.
Broad based bulge or nodular projection (not fine spiculation)
of intermediate signal intensity (higher signal than muscle,
lower signal than submucosa) projecting beyond outer
muscle coat.
Extension of abnormal signal into adjacent organ, extension
of tumor signal through the peritoneal reflection.
technique provides detailed anatomic imaging (Figs. 13.7 and
13.8) which permits assessment of the relationship of the tumor
to the mesorectal fascia (84).
In a single-center prospective study, it was shown that MR
imaging predicted the histological status of the CRM, with a
positive predictive value 92% (85). The technique has since been
shown to be reproducible in the multi-center setting, and in a
large prospective multi-center study performed by the MERCURY
research group, which recruited 679 consecutive patients with
rectal cancer in 11 centers in Britain, Germany, Norway, and
Sweden. In this study it was shown that using a 1 mm cut-off for
prediction of CRM status, a high negative predictive value could
be obtained (94%) (86). MR imaging has now become manda-
tory in the United Kingdom for preoperative staging of rectal
colorectal cancer
(A)
MR imaging
T stage
T1
(B)
Figure 13.7 The bowel wall layers depicted using high spatial resolution MR imag-
ing. (A) Axial high-resolution T2-weighted MR image of the bowel wall demon-
T2 strating the bowel wall layers. The corresponding layers are shown on the histology
H&E section (B). The mucosa is of low signal (curved arrow), the submucosa is of
high signal (open arrow) and the muscularis propria comprising the circular
(inner layer of the muscularis propria) and the outer longitudinal layer are of low
T3 signal intensity (arrows).
T4
cancers, and enables selective use of preoperative therapy based
on CRM status and other prognostic features. Furthermore, the
discussion of preoperative MR imaging by the multidisciplinary
team (MDT) enables a preoperative treatment plan to be insti-
tuted that reduces the rate of subsequent CRM involvement by
tumor (87).
The largest study to date looking at the depth of extramural
spread using MR imaging staging of rectal cancer has been the
MERCURY study. Direct comparison of the extramural depth of
invasion measured by MR imaging and histology was made in 295
of 311 (94.9%) patients undergoing primary surgery. The mean
difference between MR imaging and histopathology was –0.046 mm
(SD = 3.85 mm, 95% confidence interval –0.487 to 0.395 mm).
Thus, MR imaging has been shown to be equivalent to within
0.5 mm for prediction of local tumor spread (88).
Even in patients undergoing careful radical excision of the rectum
and mesorectum, venous invasion remains an important indepen-
dent prognostic factor (47,89). Extramural venous invasion (EMVI)
193
 primary tumor evaluation and staging

(A) (B)
Figure 13.8 The mesorectal fascia depicted on (A) T2-weighted axial MR image with (B) histological correlation (arrows).

has been shown to be associated with higher risk of local recurrence

(52), distant metastases (45,90–93) and death (44,46,52,93–97).
The typical appearance on MR, which is the only imaging
modality that has been shown to demonstrate extramural venous Table 13.4 MRI-EMVI Grading Score to Evaluate the Presence
invasion in rectal cancer (85) is that of discrete serpiginous or or Absence of Radiological Features Indicative of EMVI
tubular projections of intermediate signal intensity into perirectal MRI-EMVI Predicted Typical imaging features Schematic
fat, following the course of a visible perirectal vessel (usually a score EMVI illustration
vein). We have previously reported that extramural vascular inva- The pattern of tumor
sion was correctly identified in 15 out of 18 patients with rectal extension through the
0 muscle coat is not nodular,
cancer (85). More recently, we have devised an MR imaging-EMVI
and there are no vessels
grading score to evaluate the presence or absence of radiological adjacent to areas
features indicative of EMVI (Table 13.4). In a recent study, carried of tumor penetration.
out in our own unit, we found that the proportion of patients Minimal extramural stranding/
Negative

with MRI-detected EMVI in 94 rectal and rectosigmoid cancers nodular extension seen, but
1
undergoing primary surgery was 26%, which was similar to the not in the vicinity of any
histologically-proven proportion (28%). The sensitivity and spec- vascular structures.
ificity of MR imaging for detecting EMVI in this series was 62%
and 88%, respectively. Some patients with microscopic vascular Stranding demonstrated in the
vicinity of extramural vessels,
invasion could not be resolved on MR imaging, while others with but these vessels are of normal
2
very obvious EMVI on the pre-operative images had false-negative calibre, and there is no definite
histopathology due to obliteration of normal venous architecture tumor signal seen within the
which makes it difficult for the pathologist to appreciate that a vessel.
tumor deposit lies within the course of a vessel (Fig. 13.9).
Intermediate signal intensity
In the same study, we were able to show that MR imaging- apparent within vessels,
detected EMVI is associated with poor clinical outcome. Despite 3
although the contour and
MDT-directed pre-operative and post-operative therapy, the pres- calibre of these vessels is
Positive

ence of EMVI on pre-operative MR imaging was associated with a only slightly expanded
four-fold higher risk of distant metastasis (52% versus 12%), and
Obvious irregular vessel contour
a reduction in relapse-free survival at three years to only 35% or nodular expansion of vessel
versus 74% for patients with no EMVI (98). 4 by definite tumor signal.
Locally-advanced upper rectal tumors may perforate through
the peritoneum. In one prospective study of 412 colon cancers,
local peritoneal involvement was found to be an independent risk Source: With permission from Ref. 98.

194
 colorectal cancer

(A) (B)
Figure 13.9 (A) Axial T2-weighted MR image and (B) corresponding histological section showing tumor nodule infiltrating and destroying extramural vein (arrow).

(A) (B)
Figure 13.10 (A) Axial T2-weighted MR image with (B) histological correlation of extramural venous invasion. There is nodular extension of tumor into perirectal fat
corresponding to extramural venous spread (arrows).

factor for intraperitoneal recurrence after surgery. Similarly, in
rectal cancer, peritoneal involvement predicts for local recurrence.
The typical appearance seen on rectal MR imaging is one of
nodular extension of intermediate signal intensity through the
fine low signal intensity peritoneal reflection at or above the level
of its attachment to the anterior surface of the rectum: This is best
demonstrated on axial high resolution images. The Cardiff series
included 11 patients with pT4 tumors, nine of whom had histo-
logical evidence of perforation with tumor cells seen on the peri-
toneal surface. This was correctly identified in seven out of nine
cases. In the two other cases, MR imaging suggested nodular
tumor infiltration through the peritoneum, and while histology
confirmed that the tumor was close to the peritoneal surface, there
was no actual perforation (85). Although cases of peritoneal
perforation were undoubtedly identified using preoperative MR
imaging, many cases will be missed by MR imaging due to failure
to resolve microscopic infiltration of peritoneal lined clefts. The
accuracy of MR imaging in correctly identifying peritoneal
involvement at this site is therefore less reliable than detection of
other prognostic factors (99). However, knowledge of the rela-
tionship of tumor to the peritoneal reflection anteriorly should
prompt a careful search for subtle peritoneal infiltration.
The ability to identify these important pathological prognostic
factors such as extramural venous invasion (Fig. 13.10), peritoneal
infiltration (Fig. 13.11), and depth of extramural spread (Fig. 13.12)
gives the possibility of a more tailored preoperative treatment
strategy based on the presence or absence of one or more of these
risk factors (85). Clinical studies are underway to determine

195
 primary tumor evaluation and staging

(A) (B)
Figure 13.11 (A) Axial T2-weighted MR image of the peritoneal infiltration. Tumor (open arrow) demonstrated on the surface of the peritoneal attachment (arrow)
corresponded histologically to T4 peritoneal infiltration (B).

(A) (B)
Figure 13.12 (A) Axial T2-weighted MR image with (B) histological correlation showing assessment of depth of extramural spread (arrow).

whether such an approach may prevent both local recurrence and
systemic failure (Fig. 13.13) (10).
Key Points: T Staging with Magnetic Resonance
■ Endorectal coil imaging is limited due to patient discomfort and
other practical problems
■ High spatial resolution thin section MR imaging provides
accurate preoperative assessment of the CRM and other
important pathological prognostic factors namely depth of
extramural spread, venous invasion, and peritoneal infiltration
■ The presence or absence of such features will influence
preoperative treatment strategies
N Staging
While the majority of published studies use size criteria to predict
nodal status, there has been no agreement regarding the discrimi-
nant threshold that should be used. Some authors regard any
visible node in the perirectal fat as positive for metastatic disease
(83), while others employ size criteria with cut-off values for nodal
positivity ranging from 3 to 10 mm (29,79). It is, however, univer-
sally accepted that using size criteria alone will result in false
positive diagnoses (78), and in rectal cancer, substantial overlap
between nodes that may be benign or malignant, render size a
poor predictor of nodal status.
By careful matching of nodes seen in vivo, with nodes harvested
from the surgical specimens, criteria have been defined based on
the morphological characteristics of the lymph nodes (85). These

196
 colorectal cancer

Biopsy proven adenocarcinoma rectum

CT thorax/abdomen/pelvis
no metastatic disease or
resectable metastatic disease

High spatial resolution MRI scan

Poor risk, distances of tumor

Moderate risk, CRM safe
Good risk mesorectal fascia (CRM) <1 mm
T3 > 5 mm or N2
T3 < 5 mm, CRM safe tumor below level of levators
risk of distant failure high
risk of +ve CRM and local failure high

Preoperative therapy
Neoadjuvant
TME surgery without +/– preoperative
chemoradiotherapy
preoperative therapy systemic therapy
plus TME
TME surgery

Figure 13.13 Preoperative treatment strategy based on assessment of local tumor stage and risk of margin positivity with MR imaging.

(A) (B)
Figure 13.14 (A) Axial T2-weighted MR image shows a lymph node (arrow) with an irregular border corresponding to a node fully replaced by tumor with extra-
capsular penetration on histological examination (B).

are defined as malignant if either an irregular border is demon-
strated or mixed signal intensity is present within the node (Figs.
13.14 and 13.15). Benign features are smooth contour and uni-
form signal intensity (Fig. 13.16). Using these criteria, Brown and
colleagues reported a sensitivity of 85% (51/60 patients, CI
74–91.9%) and a specificity of 97% (216/221 patients, CI
94.8–99%) (85). In this retrospective study, the results were sig-
nificantly better than using size criteria alone and, when these cri-
teria were applied in a prospective study, agreement with
histological N stage was 85% (kappa = 0.68) (85). The inability to
detect very small tumor foci (measuring less than 2 mm in diam-
eter) within lymph nodes, however, remains a limitation of any of
the current staging techniques. It is possible that this constraint
may be overcome in the future by a combination of new lymph
node specific contrast agents (100,101). Differentiation between
benign and malignant nodes rests on the identification of tumor
cells within the lymph node and the distinction between tumor
cells and normal lymphoid tissue. Although T2-weighted imaging
permits visualization of tumor foci of 3 mm or more in diameter,
smaller tumor foci may be very difficult to depict. For this reason,
lymph node specific contrast agents have been developed which
exploit the fact that normal lymphoid tissue takes up ultra-small
particles.
Ultra-small iron oxide particles show magnetic susceptibility
artefact on MR imaging and when taken up by normal lymph
nodes, the signal intensity darkens on T2*-weighted sequences. This
sequence exaggerates the susceptibility of iron oxide and produces a
very distinctive appearance. A disadvantage of the technique is the
necessity to delay imaging for 24 to 36 hours following contrast
administration. MR lymphography is highly accurate for identifying
normal lymph nodes, but the identification of small subcentimeter
metastases in normal sized nodes is more challenging.

197
 primary tumor evaluation and staging

(A) (B)
Figure 13.15 (A) Axial T2-weighted MR image shows mixed signal intensity present within a lymph node (arrow) which corresponds histologically (B) to necrosis and
tumor within a partially replaced lymph node (arrow).

(A) (B)
Figure 13.16 (A) Axial T2-weighted MR image of a benign lymph node. The node has uniform signal intensity. (B) Histological examination confirms a smooth contour.

Our early results in rectal cancer are promising and we have
been able to develop criteria to discriminate between malignant
and non-malignant lymph nodes based on the pattern of nodal
enhancement (101). This is independent of nodal size and mor-
phology on conventional T2-weighted sequences. Four different
patterns of contrast uptake in mesorectal lymph nodes are
described. Normal nodes show uniform low signal intensity on
MR lymphography (Fig. 13.17). Reactive nodal hyperplasia results
in central uptake of ultra-small iron oxide particles, which pro-
duces a central low signal intensity pattern. This appearance is
often associated with nodal enlargement and the clear demonstra-
tion of central uptake of iron oxide may enable confident distinc-
tion between benign and malignant disease.
Malignant lymph nodes show two types of pattern following
administration of ultra-small iron oxide particles, depending on
how much of the node has been replaced by tumor. Complete
replacement of the node by tumor results in uniform high signal
of the node because there is no uptake of contrast material. Partial
replacement of a node by tumor results in partial uptake of con-
trast medium into the normal portion of the node and the region
of the metastasis, which is usually eccentric, remains high signal
(Fig. 13.18).

198
 colorectal cancer

(A) (B)
Figure 13.17 Axial T2*-weighted MR images of a normal lymph node before and after administration of USPIO contrast medium. (A) Pre-contrast the node shows
uniform high signal. (B) Post-contrast the node shows uniform uptake of the ultra-small iron oxide particles.

(A) (B)
Figure 13.18 A malignant lymph node from rectal cancer. (A) Axial T2*-weighted MR image post USPIO demonstrating uniform high signal intensity in a 3 mm lymph
node indicating tumor replacement. (B) Corresponding surgical specimen confirming the presence of metastasis.

Key Points: Nodal Staging Intraluminal Endoscopic Ultrasound

T Staging
■ Size is a poor predictor of nodal status
Intraluminal endoscopic ultrasound (EUS) can be undertaken
■ Irregularity of contour and mixed signal intensity are features
with a flexible or rigid probe (102,103), which may be passed
of malignant nodes
through a short rectoscope to assess high rectal tumors. The tech-
■ Benign features include a smooth contour and uniform sig-
nique makes use of the interfaces between the tissue layers and at
nal intensity
boundaries between layers of different acoustic impedance. The
■ Ultra-small iron oxide particles have been evaluated
bowel wall is depicted as several layers that comprise reflections
in the staging of perirectal lymph nodes and can help
from both tissue and interfaces (Table 13.5). This gives a typical
to improve characterization of nodes detected on MR imaging
pattern of five layers when using a 7.0 MHz probe (Fig. 13.19).

199
 primary tumor evaluation and staging

Table 13.5 Rectal Wall Layers on Endosonography Table 13.6 Criteria for Sonographic T Staging
1. Bright interface reflection from the mucosal surface T1 Submucosal penetration with deepest part still intact
2. Low reflective layer of the deep mucosal T2 Muscularis propria penetrated but outer aspect intact
3. Bright reflective layer of submucosa T3 Disruption of outer border of the muscularis propria with tumor
4. Low reflective layer of muscularis mucosae budding or mass extension into perirectal fat
5. Bright interface reflection from the outer border of the muscle layer and T4 Invasion adjacent structure or peritoneum
adventitial fat

The perirectal tissues are moderately echogenic. Normal lymph

nodes are not seen, being isoechoic. Perirectal vessels are seen, but
the mesorectum is not fully visualized. Rectal cancers are generally
hypoechoic, so they can be clearly distinguished from more echo-
genic tissue layers such as the submucosa and perirectal fat. The
invading tumor border is irregular in outline, and causes blurring
or loss of definition of layer borders (Fig. 13.20). The sonographic
criteria for T staging are summarized in Table 13.6. Accuracies as
high as 90% have been documented in staging rectal cancer by
EUS (102,104–107). However, studies such as these excluded
patients with clinically fixed tumors, tumors of the upper rectum,
and patients with bulky or stenosing tumors. A major limitation
of reliance on the routine use of EUS for staging patients with
rectal cancer is that up to 20% of patients presenting with rectal
cancer cannot be evaluated by rigid probe endorectal ultrasound
(108). In these instances, endoscopic systems using a mini-probe
or dedicated ultrasound endoscope may be used and all systems
use the water-filled balloon systems to achieve acoustic contact.
Nonetheless, the technique has major limitations, including:

• Loss of contrast between the tumor and perirectal fat once

Figure 13.19 Normal rectal wall layers shown on endosonography. Source: Courtesy tumor has penetrated the rectal wall, making assessment
of Mr. Darren Gold, North Hampshire Hospital, Basingstoke, Hants. of the depth of tumor penetration inaccurate (108)
• Tumors with a bulky intraluminal projection can only
be examined by placing the probe tangential rather than
perpendicular to the tumor, resulting in difficulties in
interpretation of the depth of tumor invasion (109)
• Inability to distinguish peritumoral fibrosis from
tumor (110)
• The mesorectal fascia is not visualized, and therefore
there is no good correlation between the mesorectal
margin on EUS and histology (102)

With very high 20-MHz probes it may be possible to subdivide

Figure 13.20 Endoscopic ultrasound showing a uT3 tumor; only perirectal fat in
the immediate vicinity of the rectal wall is shown. The mesorectal fascia is not
demonstrated. Source: Courtesy of Mr. Darren Gold, North Hampshire Hospital,
Basingstoke, Hants.
the mucosa, lamina propria, and muscularis mucosae, but the
depth of acoustic penetration is small, which limits the use of the
20-MHz probe to an assessment of the mucosa and submucosal
layers only (111). However, this gives high-frequency ultrasound
the unique advantage of being able to depict the mucosal and sub-
mucosal layers in great detail and the technique is well suited to
staging early non-invasive cancers. It is therefore now possible
accurately to stage T1 tumors and subdivide these into minimal
(SM1), slight (SM2), or deep (SM3) (Fig. 13.21). This is of impor-
tance when considering patients for local excision as the risk of
nodal involvement also increases dramatically with the depth of
penetration (0% for T1 slight, 26% for T1 deep) (112). However,
it should also be borne in mind that non-sessile tumors such as
villous tumors and larger polyps cannot be accurately staged by
EUS (113).

200
 colorectal cancer
Figure 13.21 Endoscopic ultrasound 10 MHz image showing T1 (SM1) tumor,
suitable for local excision. Source: Courtesy of Mr. Darren Gold, North Hampshire
Hospital, Basingstoke, Hants.
Key Points: Endoscopic Ultrasound
■ Rectal tumors are hypoechoic on ultrasound
■ About 20% of patients presenting with rectal cancer cannot be
evaluated with EUS
■ Assessment of deep penetrating tumors is inaccurate
■ Peritumoral fibrosis cannot be distinguished from tumor
■ EUS is highly accurate for staging early T1 rectal cancers but
is less accurate for polypoidal non-sessile lesions
N Staging
The spatial resolution of high-resolution (7 MHz) sonographic
equipment is in the region of 0.5 mm; thus, small nodes of 5 mm
may be detected, but there is no reliable method for distinguishing
involved from reactive lymph nodes, as both may be hypoechoic
(Fig. 13.22). The field of view is often restricted compared to the
resected specimen, particularly with a rigid probe, and nodes
containing micrometastases will not be detected. Many papers
have reported nodal staging accuracies in excess of 70%; however,
in the majority of these studies, no analysis was performed on a
node by node basis. Given that EUS is unable to detect nodes
less than 5 mm in diameter, the accuracy of the technique may not
be as high as reported. A study assessing the node for node
accuracy showed that there was a significant decrease in diag-
nostic accuracy of EUS according to pathologic technique (114).
For example, in one study, when careful nodal harvesting was
employed, the overall accuracy decreased from 76% to 43% and
the study also showed that EUS sensitivity for metastatic lymph
nodes was significantly lower for nodes smaller than 5 mm in
diameter (p = 0.025). The accuracy of EUS may be increased
by performing needle aspiration biopsies of nodes within the
perirectal fat (115,116).
Figure 13.22 Endoscopic ultrasound depiction of a malignant hypoechoic lymph
node seen adjacent to tumor. Source: Courtesy of Mr. Darren Gold, North Hampshire
Hospital, Basingstoke, Hants.
Key Points: Endoscopic Ultrasound Nodal Staging
■ EUS is unreliable for distinguishing malignant from benign
nodes
■ EUS cannot detect lymph nodes smaller than 5 mm in diameter
DISTANT METASTASES
Liver Metastases: Goals for Liver Staging
In recent years, the benefits of surgical resection and systemic che-
motherapy in prolonging survival in patients with hepatic metasta-
ses have become established. Results of surgery in patients with
resectable liver disease show 40% five-year survival compared with
no survival at five years in untreated patients (58,117–119). Current
strategies now aim to increase the number of patients who are suit-
able for curative hepatic resection. Such strategies include the use of
preoperative systemic chemotherapy so that patients initially thought
to have non-resectable disease may undergo surgery with curative
intent (120–123). The key element in improving outcomes is patient
selection, which requires careful assessment of the precise location of
metastases and exclusion of patients with irresectable extrahepatic
disease. The size and number of lesions and length of disease-free
interval are of prognostic importance but involvement of one or
both lobes of the liver and the extent of liver resection are not prog-
nostic features. An algorithm for the use of imaging in the preoperative
assessment of liver metastases is shown in Figure 13.23.
Currently, ablative therapy techniques such as RFA are recom-
mended as non-curative treatment options and represent a
clinically useful method of controlling metastatic disease when
there is insufficient segmental sparing to permit radical resection
surgery.
201
 primary tumor evaluation and staging

investigation prior to hepatic resection (126–129). However, the

Key Points: Liver Staging
■ Preoperative systemic chemotherapy and ablative therapy
aim to increase the number of patients who are suitable for
curative hepatic resection
■ The size and number of liver metastases and length of
disease-free interval are of prognostic importance
Computed Tomography
Colorectal carcinomas metastasize to the liver via the portal
venous system, but metastases usually receive their blood supply
from the hepatic artery (124). Computed tomography performed
during peak level of hepatic parenchymal enhancement will iden-
tify the vast majority of colorectal metastases and, for many insti-
tutions, CT is the modality of choice for the surveillance of patients
at risk of developing liver metastases. The technique exploits the
relative hypovascularity of colorectal neoplasms compared with
normal parenchyma, and accuracy rates of up to 85% can be
achieved (sensitivity 70%, specificity 94%) (Fig. 13.24) (125).
However, CT arterioportography was shown to be superior to
conventional CT for the detection of focal liver lesions and, until
very recently, has been advocated as an important preoperative
Postoperative
surveillance
Transabdominal ultrasound
or
CT scan abdomen/pelvis
Confirmation
of
distribution of metastases
confirmation of resectability
CT using 2.5–5 mm collimation
or
MRI using liver specific contrast
technique is invasive, requiring the percutaneous placement of an
angiographic catheter in the superior mesenteric or splenic artery
and continuous sampling of CT data at each level following con-
trast infusion. Recently, comparisons of CT arterioportography
with spiral CT and MR suggest that CT arterioportography is not
significantly more sensitive or accurate (130). The introduction of
multidetector technology is likely to improve the results of CT still
further and the role of CT arterioportography in the preoperative
assessment of liver metastases is now challenged (131).
Magnetic Resonance
Magnetic resonance is the technique of choice for staging patients
with colorectal liver metastases, since it shows superior sensitivity
in identifying lesions compared with CT and PET-CT. The tech-
nique requires the use of liver-specific contrast agents which
results in higher sensitivities in the detection of metastatic disease.
Such agents include superparamagnetic iron oxide (SPIO)
Mangafodipir Trisodium (Mn-DPDP), and the gadolinium-related
gadoxetic acid disodium. Mangafodipir Trisodium, for example, is
taken up by the functioning hepatocytes and excreted by the bil-
iary system. Contrast uptake leads to persistent elevation of
T1-weighted signal intensity of normal liver parenchyma within
10 minutes of injection. Comparison of T1-weighted images
before and after administration of this agent shows a 100%
increase in the signal-to-noise ratio of the liver, and a 400%
increase in conspicuity between the hypointense liver metastases
and surrounding parenchyma (132). When compared with CT,
the use of liver-specific agents increases the sensitivity and accu-
racy of detection of metastases (Fig. 13.25). In a study comparing
the performance of Mn-DPDP MR imaging with CT and intra-
operative ultrasound (133), MR imaging influenced the operative
decision in 74%. However, intraoperative ultrasound still detected
further lesions not seen on preoperative imaging, all of which
were less than 1 cm in diameter. Compared with histopathology,
sensitivities for CT, MR imaging, and intraoperative ultrasound
were 61%, 83%, and 93% respectively (133).

Confirmation of absence
of inoperable
extrahepatic disease

FDG-positron emission tomography

or
CT thorax/abdomen/pelvis

Hepatic resection
peroperative
road-mapping to
ensure adequate margins

Intraoperative
ultrasound

Figure 13.23 Algorithm for the use of imaging in the preoperative assessment of
liver metastases. Figure 13.24 CT demonstration of a liver metastasis (arrow).

202
 colorectal cancer
(A)
Figure 13.25 (A) CT shows no convincing evidence of metastatic disease. (B) Axial T2-weighted MR image in same patient following injection of Mn-DPDP. Metastases
are visible as low signal intensity lesions measuring 5–10 mm in diameter (arrows).
Ultrasound
Transabdominal ultrasound has not been proven to be as accurate
as CT or MR imaging in the detection of liver metastases. This is
because assessment of such lesions is limited by the lack of inher-
ent contrast between tumor and surrounding liver. However, it
represents an inexpensive and widely available modality that still
has a role in characterizing lesions considered to be indeterminate
on CT. The ability to improve the conspicuity of metastases using
ultrasound contrast agents has been the subject of several small
studies. Ultrasound contrast agents comprise tiny microbubbles
of gas that interact with the ultrasound beam, producing an
enhancement of the Doppler signal from blood (133,134). Delayed
enhancement of the normal liver, a feature of some types of
microbubble contrast agents, allows detection of smaller malig-
nant lesions than on baseline images. The technique thus improves
detection of metastases by allowing clear distinction between liver
parenchyma and metastases. The technique is as accurate as CT in
the detection of small liver metastases (135), and although the
agent is not universally used in the preoperative assessment of
patients with suspected liver metastases, in skilled hands is an
effective method of delineating intrahepatic metastases. The use
of intraoperative ultrasound with or without contrast is widely
advocated as a mandatory procedure during planned resections
for metastatic disease within the liver. The technique remains an
important component of intraoperative management and has
been shown to alter the surgical approach in 20% to 44% of
patients (136,137). Real-time intraoperative depiction of the sur-
gical anatomic planes and of the precise extent of abnormality
provides valuable guidance during surgery which maximizes
hepatic conservation with adequate clearance (138,139).
Positron Emission Tomography
18
F-fluorodeoxyglucose positron emission tomography (18FDG
PET) or 18FDG PET-CT is recommended in the routine assessment
of patients prior to planned hepatic resection or metastatectomy for
colorectal cancer (140,141). The technique is primarily used to
identify unsuspected extrahepatic disease, which may influence
the operative approach. 18FDG PET has been shown to be a cost-
effective tool in the evaluation of extrahepatic disease in patients
(B)
being considered for hepatic resection (142) and the use of 18FDG
PET in the selection of patients for hepatic resection is associated
with an improved survival (143). Compared with contrast-enhanced
MR imaging techniques, 18FDG PET shows lower sensitivity for
sub-centimeter lesions, although some authors have found it to be
beneficial for determining the cause of equivocal lesions (141). Fur-
thermore, liver specific contrast-enhanced MR imaging is superior
to 18FDG PET-CT in the detection of small liver metastases and the
technique therefore remains a prerequisite for surgical planning in
patients with confined liver metastases (141).
Key Points: Liver Staging with Computed Tomography,
Magnetic Resonance, Ultrasound, or 18FDG PET
■ Colorectal liver metastases are hypovascular lesions
■ The liver should be imaged during the parenchymal phase of
contrast enhancement
■ The accuracy of CT in the detection of liver metastases is in
the order of 85%, with a sensitivity of 74% and a
specificity of 90%
■ MR imaging using liver-specific contrast agent has the high-
est sensitivity and specificity for detecting metastatic disease
■ The addition of diffusion-weighted MR imaging further
increases sensitivity and specificity
■ Transabdominal ultrasound is useful for characterizing inde-
terminate lesions detected on CT
■ Ultrasound contrast agents improve accuracy
■ Intraoperative ultrasound alters the surgical approach in
20% to 44% of patients
■ Intraoperative ultrasound identifies more lesions in the liver
than preoperative CT or MR imaging
■ 18FDG PET is less sensitive than contrast-enhanced MR imaging
in the detection of sub-centimeter liver metastases
■ 18FDG PET has an important role in the detection of occult
extrahepatic metastases
■ Liver-specific contrast-enhanced MR imaging is a prerequisite
for surgical planning prior to metastatectomy in the detection
of metastases
203
 primary tumor evaluation and staging

Computed Tomography
RECURRENT DISEASE
Treatment aimed at local control or palliation is more successful if
recurrence is detected early by recognizing both the likely sites and
Detection of Local Recurrence patterns of local recurrence. The key to early recognition of local
Local recurrence of colorectal cancer is a frequent problem and
pelvic recurrence lies in the ability to distinguish between the
an important cause of morbidity and mortality in patients with
post-surgical appearances following anterior resection (AR) or
rectal cancer. It is reported to occur in 15% to 35% of patients
abdominoperineal resection (APR) for rectal cancer and a recur-
following rectal cancer surgery (144–146). There is increased
rent mass due to tumor regrowth. This is much easier when post-
risk of recurrence in those with positive resection margins. There
surgical imaging baseline studies are available for comparison as a
is also strong evidence that adopting a technique that ensures
reference point since post-surgical changes can range from only
careful dissection along the mesorectal fascia reduces the rate of
minimal presacral soft tissue thickening to more extensive fibrosis
local recurrence (147,148).
and scar tissue formation. It is therefore recommended that imag-
As in rectal cancer, the incidence of recurrence in colon cancer
ing is performed at three months’ post-surgery in order to obtain
depends on the stage of disease at the time of primary surgery and is
baseline images of the expected anatomical changes. The key to
seen in up to 50% of patients. Most patients who relapse following
detection of local recurrence is the demonstration of an increase
rectal cancer surgery recur within two years, and 75% recur within
in soft tissue or definite growth of a mass on subsequent studies
five years (144). Abdominopelvic pain is the most frequent present-
(154). Such growth may be gradual and referral to the baseline
ing symptom. The outlook for patients with local disease relapse is
scan, even after several interval examinations, should always be
poor because only 8% will have resectable recurrent disease, and the
undertaken if there is doubt about the CT findings.
mean survival following the detection of recurrence is one year
It should be appreciated that follow-up with CT or MR imaging
(149,150). The American Society for Clinical Oncology evidence-
after APR is mandatory because imaging provides the only means
based guidelines for surveillance of colorectal cancer patients recom-
of assessing the primary surgical site and recurrence will only
mend postoperative serum carcinoembryonic antigen (CEA) testing
become clinically apparent if this is locally extensive and infiltrat-
every two to three months, regular monitoring of symptoms, and
ing through the perineum. The presence of an enlarging mass,
colonoscopy every three to five years. Colonoscopy serves the dual
however, is good evidence of recurrent tumor and biopsy may not
purpose of screening for metachronous polyps or malignancy, as
always be necessary (155). Currently, 18FDG PET is proving to be
well as identifying anastomotic suture line recurrences.
useful for providing confirmatory evidence of local recurrence
There is variability in the methods of follow-up of patients after
and can sometimes identify small volume disease which, in many
surgery for colorectal cancer. Most undergo regular clinical assess-
cases, is amenable to resection (151).
ment and measurement of CEA with interval colonoscopy. This is
Other patterns of recurrence are also common. Following sub-
supported by regular CT examinations to detect distant disease in
total mesorectal excision or incomplete primary surgery, a tumor
the liver and lungs, as well as to detect local recurrence. Demon-
deposit within the mesorectum may show regrowth. This is mani-
stration of a rising CEA should prompt a search for recurrence
fest as a growing nodule within the mesorectum on serial CT scans
and the presence of liver metastases is known to cause the highest
and may be confirmed by 18FDG PET imaging as tumor. If this is an
rise of CEA levels (151,152). The development of symptoms such
isolated recurrence, and confined within the mesorectum, curative
as pelvic pain may also be due to local recurrence. However, clin-
surgery may be performed by a complete total mesorectal excision.
ical assessment and measurement of CEA levels alone are not
Residual tumor left at the margins or at the pelvic sidewall is diffi-
adequate follow-up as identification of local recurrence before
cult to detect clinically and may not be obvious on routine imaging
symptomatology may allow earlier and more effective treatment.
until nodular thickening of the pelvic sidewall fascia or mesorectal
It is also well recognized that recurrence may occur in the absence
margins occurs (Fig. 13.26A). In advanced disease, recurrence
of a rise in the CEA level. Imaging is a vitally important part of
appears as a rind of nodular thickening growing along the mesorec-
follow-up but the frequency of CT examinations is subject to
tal margin and encircling the resection bed (Fig. 13.26B). Such
some variation. It is currently recommended that CT is performed
tumors have a propensity to grow into the pelvic sidewalls and
six-monthly for three years and yearly thereafter. The frequency
invade the sacrum and are the most difficult to palliate.
and timing of scans will be influenced by the stage, histology, and
A common manifestation of local recurrence is peritoneal seed-
site of the primary tumor, as well as other factors that predict for
ing. This frequently occurs in the pouch of Douglas or rectovesical
relapse such as positive circumferential resection margins (153). It
pouch and is manifest as a growing intraperitoneal mass. The
is important to identify local recurrence at the earliest opportu-
lesions are seldom amenable to curative surgery as they represent
nity because therapy is more effective if given earlier and salvage
widespread transcoelomic peritoneal spread. This pattern of recur-
surgery may be possible in a small number of patients.
rence is frequently associated with the development of hydroneph-
rosis, which may herald the development of a discrete recurrent
Key Points: Detection of Local Recurrence mass (Fig. 13.27) (156). Ovarian metastases occur in 6% to 8% of
patients with colorectal cancer, and appear to be more common in
■ Local recurrence often presents with pain and is difficult to
premenopausal women (157,158). Several studies have described
detect clinically
the CT appearances (159), namely, large, lobulated or oval, multi-
■ There is increased risk of local recurrence in patients with
cystic, or solid ovarian masses. As with primary ovarian cancers,
incomplete excision and margin-positive status in both rectal
there is a tendency for ovarian metastases to occur bilaterally (160).
and colon cancer
In colon cancer, local recurrence usually develops at the site of the

204
 colorectal cancer

(A) (B)
Figure 13.26 (A) A CT study of the pelvis six months post-surgery showing an area of soft tissue density in the presacral area (arrow) considered to represent baseline
postoperative changes. Note ureteric stent (arrowhead). (B) Follow-up CT showed definite recurrence with extension of tumor along the peritoneal reflection (arrow)
and tumor encasing the ureteric stent (arrowhead).

(A) (B)
Figure 13.27 Hydronephrosis frequently heralds the development of recurrent disease. (A) A follow-up CT after surgery shows hydronephrosis (arrow) but no obvious
underlying cause was demonstrated. (B) CT seven months later demonstrates obvious peritoneal recurrence (arrowheads).

anastomosis and recurrence may be intra- or extraperitoneal.

Intraperitoneal recurrence is often characterized by nodular thick- ■ Nodal disease along the pelvic sidewall is a well recognized
ening of the leaves of the mesentery, by streaky soft tissue stranding manifestation of recurrence
■ Peritoneal recurrence is common
and omental deposits. In advanced disease, soft tissue masses
■ The development of unilateral hydronephrosis, in the absence
develop and the bowel wall may be infiltrated but intestinal
obstruction is a late complication of recurrent disease. of a demonstrable mass, is most likely to be due to peritoneal
or nodal recurrence
■ Ovarian metastases occur in 6% to 8% of patients
Key Points: CT Detection of Local Recurrence
Magnetic Resonance Imaging
■ Post-surgery baseline CT should be performed at three months
The anatomical location of local recurrence in patients with colorec-
■ A growing mass in the sacral hollow following APR is good
tal cancer has profound implications for resectability and survival
evidence of recurrence
(161,162). Interpretation of MR imaging of sites of recurrence within
■ Mesorectal nodules may be the first sign of recurrence
the pelvis, in particular whether there is involvement of the pelvic

205
 primary tumor evaluation and staging

(A) (B)
Figure 13.28 Anastomotic recurrence. (A) and (B) Sagittal T2-weighted MR images after surgery showing the tumor recurrence.

sidewall or sacrum, will determine whether a curative procedure can

be attempted. The emergence of MR imaging as a staging tool affords
the opportunity to investigate sites/compartments where recurrence
occurs. Local recurrence can usually be confirmed by biopsy in
the majority of patients. In patients with recurrent disease which is
inaccessible or unsafe to biopsy (due, for example to co-morbidity),
the diagnosis can be made by the presence of at least two of the
following: an enlarging mass by MR imaging criteria, FDG PET or
PET-CT positivity and/or rising carcinoembryonic antigen (CEA).
Detailed documentation of the patterns of pelvic failure is important
because such information may lead to improvements in surgical
technique, may enable identification of patient subgroups that are
likely to benefit from preoperative therapy, may help to refine radio-
therapy fields and serve as a defined endpoint for colorectal cancer
trials. The classification of disease recurrence sites according to
anatomical compartments also permits better understanding of the Figure 13.29 MR image demonstrating recurrence following previous anterior
resection for rectal carcinoma. A crescentic nodular mass (arrow) is seen along the
etiology and prevention of pelvic recurrences. line of the mesorectal margin typical of so-called marginal recurrence.

Central Compartment Disease

Anastomotic recurrences: Disease relating to a colorectal anasto-
mosis or within the mesorectal space can be classified as central
compartment disease (Fig. 13.28) and is most likely to be amena-
ble to potentially curative resection. The surgical anastomosis can
be identified on MR imaging as a change in bowel calibre and
visualization of the suture line (Fig. 13.28). This pattern is shown
as a low/intermediate signal intensity abnormality on an MR
image centered on the anastomosis (Fig. 13.28). It may be difficult
to differentiate intra-mural versus extra-mural anastomotic recur-
rence, which may result from either distal margin involvement by
tumor or tumor spillage/seeding during formation of the anasto-
mosis (163–165). Clinical definitions of anastomotic recurrence
have varied between “involving or abutting the anastomosis” (166)
and “a suture line recurrence with histological verification, with no
clinically apparent contiguous extramural disease” (167). Cases of
mural or extramural recurrences centered on the anastomotic
suture line can be missed by colonoscopic surveillance and MR
imaging can be of value in early detection of this potentially resec-
table form of recurrent disease.
Mesorectal margin recurrence is characterized by abnormal low/
intermediate signal intensity on MR imaging arising along the
margins of the surgical excision, following the plane of the TME
(Fig. 13.29). This pattern characteristically develops in a crescen-
tic fashion and is most commonly due to positive margins after
excision, with tumor growing along the lateral extent of the TME
plane.
Presacral Compartment Disease
A presacral recurrence pattern is demonstrated on MR imaging as
abnormal signal arising from the anterior surface of the pelvic
parietal, or presacral, fascia (Fig. 13.30). This is characterized by
intermediate signal following the plane of the presacral fascia.

206
 colorectal cancer

Figure 13.31 Axial T2-weighted MR image showing the presacral fascia (black
arrow) and a nodular intermediate signal intensity mass (white arrow) pushing the
fascia forward in keeping with a retro presacral fascia recurrence.

Figure 13.30 Sagittal MR image showing presacral fascia (black arrow) and a
recurrent mass lying anterior to it (white arrows).

Disease can also recur behind the presacral fascia and will charac-
teristically bow the fascia forward and infiltrate towards the bony
cortex of the sacrum (Fig. 13.31).

Perineal Recurrence
This is characterized by abnormal low/intermediate signal inten-
sity arising below the pelvic floor formed by the levator muscle
(Fig. 13.32). Tumor involves one or all of the levator muscles, and
spreads directly into the ischio-anal fossa from the perineal scar.
This pattern is commonly due to positive surgical margins at the
“waist” of an abdomino-perineal excision (APE) (168). For a stan-
dard APE, the levators are divided as they insert into the rectum.
This is the narrowest point of the operative specimen, the “waist,”
which coincides with the end of the mesorectum. Therefore, at this
point there is the narrowest margin of excision for a low-lying rectal
tumor, and the most common site of positive CRM. This pattern
may be avoided by a more radical “cylindrical” excision (169,170).
Studies are underway to assess the efficacy of using this approach in
low lying tumors at risk of radial margin involvement.

Peritoneal Disease
Recurrent disease on MR imaging arising from, or growing along,
the residual peritoneal reflection is termed a peritoneal pattern of
recurrence. A nodular growth pattern is seen tracking the line of the
peritoneum and most commonly occurs as a pattern of relapse in Figure 13.32 Sagittal MR image of a patient with a mucinous levator muscle
patients with previously treated T4 tumors which had perforated recurrence following an abdominoperineal resection.

207
 primary tumor evaluation and staging
through the peritoneal membrane. It is likely that this results in
shedding of tumor cells into the peritoneal cavity with consequent
peritoneal based growth—often in the rectovesical pouch but also
along the line of the peritoneum lining the pelvic brim when the
earliest manifestation may be unexplained hydronephrosis (156).
Nodal (Pelvic Sidewall)
Pelvic sidewall recurrent nodal disease refers to tumor in draining
nodal regions lateral to the pelvic parietal fascia. Typically this
occurs in the obturator fossa along the course of the internal iliac
vascular branches in the posterior pelvis. Malignant pelvic side-
wall lymph nodes may be enlarged and show an irregular outline
and mixed signal intensity on MR imaging (Fig. 13.33). Treatment
with chemoradiation is the preferred option in the United States
and Europe and may be effective. In some centers pelvic sidewall
dissection is performed (171).
18
FDG PET and 18FDG PET-CT
18
FDG PET and 18FDG PET-CT are likely to become the comple-
mentary imaging methods of choice in the detection of recurrence.
PET demonstrates increased uptake of 18FDG in tumor but not in
Figure 13.33 MR image showing pelvic sidewall nodal disease (arrow).
(A)
Figure 13.34 (A) A patient with a residual presacral mass on CT following surgery and radiotherapy for rectal cancer. (B) Focal areas of intense 18FDG activity within the
mass on PET confirm the presence of active disease.
208
scar tissue (Fig. 13.34). Following radiotherapy or in the presence of
infected collections, 18FDG uptake within a mass may be due to the
presence of inflammatory cells. 18FDG PET is considered to be
reliable approximately six months after completion of radiotherapy.
Key Points: Magnetic Resonance and 18FDG PET
Detection of Local Recurrence
■ High resolution MR imaging is useful in the detection and
anatomical localization of recurrence
■ The superior depiction of the surgical anatomic planes and
depiction of the precise extent of recurrent disease on T2-weighted
imaging provides valuable treatment planning information
■ 18FDG PET and 18FDG PET-CT are likely to become the
complementary imaging methods of choice in the detection
of recurrence
■ PET demonstrates increased uptake of 18FDG in tumor but
not in scar tissue and has poor sensitivity in patients with
mucinous recurrences
■ Following radiotherapy or in the presence of infected collections,
18
FDG uptake within a mass may be due to the presence of
inflammatory cells
■ 18FDG PET is considered to be reliable approximately six
months after completion of radiotherapy
■ Transabdominal ultrasound is useful for characterizing
indeterminate lesions detected on CT
■ Ultrasound contrast agents are currently being evaluated
■ Intraoperative ultrasound alters the surgical approach in
20% to 44% of patients
■ Intraoperative ultrasound identifies more lesions in the liver
than preoperative CT or MR imaging
■ 18FDG PET has a well-defined and evolving role in the detection
of liver metastases and is more sensitive than CT in detecting
recurrent disease
■ 18FDG PET and MR imaging provide complementary
information in patients being considered for hepatic
resection
■ The greatest strength of 18FDG PET may be in the detection of
occult extrahepatic metastases
(B)
 colorectal cancer
Detection of Distant Recurrence
There is growing evidence that intensive follow-up that incorporates
CEA monitoring and CT scanning of chest, abdomen, and pelvis
contributes to the detection of asymptomatic disease recurrence in
patients with colorectal cancer who may subsequently proceed to
potentially curative resection of metastatic disease (172,173). The
importance of performing CT of the lungs as well as liver in patients
with rectal cancer is evidenced by good outcomes achieved in patients
undergoing subsequent pulmonary metastatectomy (174–179).
Outside the liver and pelvis, 18FDG PET detects occult distant
metastases in significant numbers of patients, often leading to
changes in management (Fig. 13.35). It is particularly efficient in
detecting small volume disease in areas which may be difficult to
visualize with CT, such as mesentery or peritoneum. It is possible
(A)
(C)
Figure 13.35 A patient with rising CEA. (A) to (D) 18FDG PET-CT shows that the residual presacral mass (C) and (D) is not active. There is unexpected increased activity
in a lumbar vertebra (B), and in the sacrum (D) indicating metastatic disease.
that combined 18FDG PET-CT will be particularly useful in this
scenario as small volume disease may not only be detected but can
be accurately located and so enable surgical excision. In patients
with a rising CEA level in whom recurrent disease has not been
detected by CT, 18FDG PET is able accurately to locate recurrence
in approximately two-thirds of cases (180,181).
A number of studies have demonstrated that 18FDG PET is a
cost-effective technique in evaluating recurrent colorectal cancer
(42,180), often by detecting distant disease that precludes expen-
sive and inappropriate surgery but also, in one-third of patients,
by enabling a more appropriate surgical approach (182). A meta-
analysis of the use of 18FDG PET in the evaluation of recurrent
disease has concluded that the addition of 18FDG PET resulted in
a change of management in 29% of patients (183).
(B)
(D)
209
 primary tumor evaluation and staging
Key Points: Detection of Distant Recurrence
■ CEA monitoring, with routine serial CT, has an important role
in the detection of asymptomatic distant recurrence
■ 18FDG PET has been shown to be a valuable technique in the
detection of distant recurrence
Summary
■ Colorectal cancer is the third most common cause of cancer
death in the western world
■ Five-year survival rates for early stage cancers are greater
than 90% but only 60% for all stages of disease
■ Screening for colorectal cancer is based on fecal occult blood
testing, flexible sigmoidoscopy and colonoscopy
■ Total mesorectal excision for rectal cancer results in reduc-
tion of local recurrence rate
■ The circumferential resection margin (CRM) involvement
by tumor is an important independent prognostic indicator
■ TNM staging is the most widely used staging system
■ Pelvic coil high resolution MR imaging has a positive predic-
tive value of 92% for prediction of positive CRM status
■ MR imaging has a high sensitivity and specificity for detec-
tion of mesorectal nodal deposits in rectal cancer
■ MR imaging using liver-specific contrast agents is the modal-
ity of choice for the detection of liver metastases
■ 18FDG PET is not the modality of choice for the detection of
liver metastases but is helpful in detecting unsuspected extra-
hepatic disease in some patients undergoing liver resection
■ Recurrent disease (local or distant) is seen in up to 50% of
patients with colorectal cancer
■ Hydronephrosis is an early sign of tumor recurrence
■ Ovarian metastases are seen in 6% to 8% of patients
■ Routine annual CT is the modality of choice in the
follow-up of colorectal cancer patients and will detect the
majority of unsuspected asymptomatic recurrences
■ 18FDG PET or PET-CT is helpful in suspected recurrence when
routine serial CT has failed to show a cause for CEA elevation
REFERENCES
1. Shike M, Winawer SJ, Greenwald PH, et al. Primary preven-
tion of colorectal cancer. The WHO collaborating centre for
the prevention of colorectal cancer. Bulletin of the World
Health Organization. 1990; 68: 377–85.
2. American Cancer Society: Cancer Facts and Figures 2008.
[Available from: http://www.cancer.org/downloads/STT/2008
CAFFfinalsecured.pdf].
3. Cancer Research UK CancerStats 2008. [Available from:
http://info.cancerresearchuk.org/cancerstats/types/bowel].
4. Birgisson H, Talback M, Gunnarsson U, Pahlman L,
Glimelius B. Improved survival in cancer of the colon and
rectum in Sweden. Eur J Surg Oncol 2005; 31: 845–53.
5. Wong RK, Tandan V, De Silva S, Figueredo A. Pre-operative
radiotherapy and curative surgery for the management of
localized rectal carcinoma. Cochrane database of systematic
reviews (Online). 2007: CD002102.
210
6. Sauer R, Becker H, Hohenberger W, et al. Preoperative versus
postoperative chemoradiotherapy for rectal cancer. New Engl
J Med 2004; 351: 1731–40.
7. Anonymous. Improved survival with preoperative radio-
therapy in resectable rectal cancer. Swedish rectal cancer trial.
New Engl J Med 1997; 336: 980–7.
8. Dahlberg M, Glimelius B, Pahlman L. Improved survival and
reduction in local failure rates after preoperative radio-
therapy: evidence for the generalizability of the results of
Swedish rectal cancer trial. Ann Surg 1999; 229: 493–7.
9. Kapiteijn E, Marijnen CA, Nagtegaal ID, et al. Preoperative
radiotherapy combined with total mesorectal excision for
resectable rectal cancer. New Engl J Med 2001; 345: 638–46.
10. Chau I, Allen M, Cunningham D, et al. Neoadjuvant systemic
fluorouracil and mitomycin C prior to synchronous chemo-
radiation is an effective strategy in locally advanced rectal
cancer. Brit J Cancer 2003; 88: 1017–24.
11. Chau I, Brown G, Cunningham D, et al. Neoadjuvant capecit-
abine and oxaliplatin followed by synchronous chemoradia-
tion and total mesorectal excision in magnetic resonance
imaging-defined poor-risk rectal cancer. J Clin Oncol 2006;
24: 668–74.
12. Esposito A, Mancini R, Ettorre G, et al. A combined approach
of neoadjuvant chemotherapy and surgery for colorectal liver
metastases. J Exp Clin Cancer Res 2003; 22(Suppl 4): 197–202.
13. Hardcastle JD, Armitage NC, Chamberlain J, Balfour TW,
Amar SS. A control trial of faecal occult blood screening for
colorectal cancer: 2-year results. Brit J Surg 1985; 72(Suppl):
S69–S71.
14. Bond JH. Colon polyps and cancer. Endoscopy 2001; 33:
46–54.
15. Halligan S, Altman DG, Taylor SA, et al. CT colonography in
the detection of colorectal polyps and cancer: systematic
review, meta-analysis, and proposed minimum data set for
study level reporting. Radiology 2005; 237: 893–904.
16. American Cancer Society. Cancer Facts and Figures 2003.
[Available from: www.cancer.org/].
17. Muto T, Bussey HJ, Morson BC. The evolution of cancer of
the colon and rectum. Cancer 1975; 36: 2251–70.
18. Fenoglio CM. Premalignant lesions of the colorectum. Prog
Clin Biol Res 1985; 186: 23–43.
19. Adam IJ, Mohamdee MO, Martin IG, et al. Role of circumfer-
ential margin involvement in the local recurrence of rectal
cancer. Lancet 1994; 344: 707–11.
20. Heald RJ. Total mesorectal excision is optimal surgery for
rectal cancer: a Scandinavian consensus. Brit J Surg 1995; 82:
1297–9.
21. Carlsen E, Schlichting E, Guldvog I, Johnson E, Heald RJ.
Effect of the introduction of total mesorectal excision for the
treatment of rectal cancer. Brit J Surg 1998; 85: 526–9.
22. Kerner BA, Oliver GC, Eisenstat TE, Rubin RJ, Salvati EP. Is
preoperative computerized tomography useful in assessing
patients with colorectal carcinoma? Diseases of the Colon
and Rectum 1993; 36: 1050–3.
23. Barton JB, Langdale LA, Cummins JS, et al. The utility of
routine preoperative computed tomography scanning in the
management of veterans with colon cancer. Am J Surg 2002;
183: 499–503.
 colorectal cancer
24. Mauchley DC, Lynge DC, Langdale LA, et al. Clinical utility
and cost-effectiveness of routine preoperative computed
tomography scanning in patients with colon cancer. Am J
Surg 2005; 189: 512–7; discussion 7.
25. Hundt W, Braunschweig R, Reiser M. Evaluation of spiral CT
in staging of colon and rectum carcinoma. Eur Radiol 1999;
9: 78–84.
26. Laghi A, Iannaccone R, Trenna S, et al. Multislice spiral CT
colonography in the evaluation of colorectal neoplasms. La
Radiologia Medica 2002; 104: 394–403.
27. Freeny PC, Marks WM, Ryan JA, Bolen JW. Colorectal carci-
noma evaluation with CT: preoperative staging and detection
of postoperative recurrence. Radiology 1986; 158: 347–53.
28. Acunas B, Rozanes I, Acunas G, et al. Preoperative CT staging
of colon carcinoma (excluding the recto-sigmoid region).
Eur J Radiol 1990; 11: 150–3.
29. Zerhouni EA, Rutter C, Hamilton SR, et al. CT and MR imaging
in the staging of colorectal carcinoma: report of the Radiology
Diagnostic Oncology Group II. Radiology 1996; 200:
443–51.
30. McAndrew MR, Saba AK. Efficacy of routine preoperative
computed tomography scans in colon cancer. Am Surgeon
1999; 65: 205–8.
31. Smith NJ, Bees N, Barbachano Y, et al. Preoperative computed
tomography staging of nonmetastatic colon cancer predicts
outcome: implications for clinical trials. BritJ Cancer 2007;
96: 1030–6.
32. Ashayeri E, Smyles J, Calhoun T, Carreno ET, Hagler N. The
application of preoperative radiation therapy for unresect-
able malignancies. JNatl Med Assoc 1988; 80: 883–8.
33. Quirke P, Durdey P, Dixon MF, Williams NS. Local recur-
rence of rectal adenocarcinoma due to inadequate surgical
resection. Histopathological study of lateral tumour spread
and surgical excision. Lancet 1986; 2: 996–9.
34. Holdsworth PJ, Johnston D, Chalmers AG, et al. Endolumi-
nal ultrasound and computed tomography in the staging of
rectal cancer. Brit J Surg 1988; 75: 1019–22.
35. Avradopoulos KA, Vezeridis MP, Wanebo HJ. Pelvic exenter-
ation for recurrent rectal cancer. Adv Surg 1996; 29: 215–33.
36. Maetani S, Nishikawa T, Iijima Y, et al. Extensive en bloc
resection of regionally recurrent carcinoma of the rectum.
Cancer 1992; 69: 2876–83.
37. Jass JR. Comment on: The grading of rectal cancer: historical
perspectives and a multivariate analysis of 447 cases. Jass JR,
Atkin WS, Cuzick J, et al. Histopathology 1986; 10; 437–59.
Histopathology 2002; 41: 56–7, discussion 57–8.
38. Grinnell RS. The grading and prognosis of carcinoma of the
colon and rectum. Ann Surg 1939; 109: 500–33.
39. Spratt JA SHJ. Prevalence and prognosis of carcinoma of the
colon and rectum. Cancer 1967; 20: 1976–85.
40. Dukes. The classification of cancer of the rectum. J Path Bact
1932; 35: 323.
41. Shepherd NA, Baxter KJ, Love SB. Influence of local peritoneal
involvement on pelvic recurrence and prognosis in rectal
cancer. J Clin Pathol 1995; 48: 849–55.
42. Gambhir SS, Valk P, Shepherd J. Cost-effective analysis mod-
elling of the role of FDG-PET in the management of patients
with recurrent colorectal cancer. J Nucl Med 1997; 38: 90.
43. Talbot IC, Ritchie S, Leighton MH, et al. The clinical signifi-
cance of invasion of veins by rectal cancer. Brit J Surg 1980;
67: 439–42.
44. Horn A, Dahl O, Morild I. The role of venous and neural
invasion on survival in rectal adenocarcinoma. Dis Colon
Rectum 1990; 33: 598–601.
45. Horn A, Dahl O, Morild I. Venous and neural invasion as
predictors of recurrence in rectal adenocarcinoma. Dis Colon
Rectum 1991; 34: 798–804.
46. Harrison JC, Dean PJ, el-Zeky F, Vander Zwaag R. From
Dukes through Jass: pathological prognostic indicators in
rectal cancer. Hum Pathol 1994; 25: 498–505.
47. Bokey EL, Ojerskog B, Chapuis PH, et al. Local recurrence
after curative excision of the rectum for cancer without adju-
vant therapy: role of total anatomical dissection. Brit J Surg
1999; 86: 1164–70.
48. Hojo K, Koyama Y, Moriya Y. Lymphatic spread and its prog-
nostic value in patients with rectal cancer. Am J Surg 1982;
144: 350–4.
49. Dukes CE, Bussey JH. The spread of cancer and its effect on
prognosis. Cancer 1958; 12: 309–20.
50. Wolmark N, Fisher B, Wieand HS. The prognostic value of
the modifications of the Dukes’ C class of colorectal cancer.
An analysis of the NSABP clinical trials. Ann Surg 1986; 203:
115–22.
51. Moran MR, James EC, Rothenberger DA, Goldberg SM.
Prognostic value of positive lymph nodes in rectal cancer.
Dis Colon Rectum 1992; 35: 579–81.
52. Rich T, Gunderson LL, Lew R, et al. Patterns of recurrence of
rectal cancer after potentially curative surgery. Cancer 1983;
52: 1317–29.
53. Fisher ER, Sass R, Palekar A, Fisher B, Wolmark N. Dukes’
classification revisited. Findings from the National Surgical
Adjuvant Breast and Bowel Projects (Protocol R-01). Cancer
1989; 64: 2354–60.
54. Jass JR, Love SB. Prognostic value of direct spread in Dukes’
C cases of rectal cancer. Dis Colon Rectum 1989; 32:
477–80.
55. Sobin LH, Wittekind Ch, eds. TNM Classification of Malig-
nant Tumours, 6th edn. New York: John Wiley and Sons,
2002.
56. Sobin LH, Wittekind Ch, eds. TNM Classification of Malig-
nant Tumours. 5th edn. New York: John Wiley and Sons,
1997.
57. Bleeker WA, Mulder NH, Hermans J, Otter R, Plukker JT.
Value and cost of follow-up after adjuvant treatment of
patients with Dukes’ C colonic cancer. Br J Surg 2001; 88:
101–6.
58. Fong Y, Cohen AM, Fortner JG, et al. Liver resection for
colorectal metastases. J Clin Oncol 1997; 15: 938–46.
59. Nordic NGTATG. Expectancy or primary chemotherapy in
patients with advanced asymptomatic colorectal cancer: a
randomized trial. J Clin Oncol 1992; 10: 904–11.
60. Kim NK, Kim MJ, Yun SH, Sohn SK, Min JS. Comparative
study of transrectal ultrasonography, pelvic computerized
tomography, and magnetic resonance imaging in preopera-
tive staging of rectal cancer. Dis Colon Rectum 1999; 42:
770–5.
211
 primary tumor evaluation and staging
61. Thoeni RF, Moss AA, Schnyder P, Margulis AR. Detection
and staging of primary rectal and rectosigmoid cancer by
computed tomography. Radiology 1981; 141: 135–8.
62. Thoeni RF. CT evaluation of carcinomas of the colon and
rectum. Radiol Clin N Am 1989; 27: 731–41.
63. Mehta S, Johnson RJ, Schofield PF. Staging of colorectal cancer.
Clin Radiol 1994; 49: 515–23.
64. Butch RJ, Stark DD, Wittenberg J, et al. Staging rectal cancer
by MR and CT. AJR 1986; 146: 1155–60.
65. Rifkin MD, Wechsler RJ. A comparison of computed tomog-
raphy and endorectal ultrasound in staging rectal cancer. Int
J Colorectal Dis 1986; 1: 219–23.
66. Beets-Tan RG, Beets GL, Borstlap AC, et al. Preoperative assess-
ment of local tumor extent in advanced rectal cancer: CT or
high-resolution MRI? Abdom Imaging 2000; 25: 533–41.
67. Mentha G, Majno P, Terraz S, et al. Treatment strategies for
the management of advanced colorectal liver metastases
detected synchronously with the primary tumour. Eur J Surg
Oncol 2007; 33(Suppl 2): S76–S83.
68. Burton S, Brown G, Bees N, et al. Accuracy of CT prediction
of poor prognostic features in colonic cancer. Brit J Radiol
2008; 81: 10–19.
69. Fielding LP, Phillips RK, Fry JS, Hittinger R. Prediction of
outcome after curative resection for large bowel cancer.
Lancet 1986; 2: 904–7.
70. Wong LS, Morris AG, Fraser IA. The exfoliation of free malig-
nant cells in the peritoneal cavity during resection of colorectal
cancer. Surg Oncol 1996; 5: 115–21.
71. Coakley FV, Hricak H. Imaging of peritoneal and mesenteric
disease: key concepts for the clinical radiologist. Clin Radiol
1999; 54: 563–74.
72. DeMeo JH, Fulcher AS, Austin RF Jr. Anatomic CT demon-
stration of the peritoneal spaces, ligaments, and mesenteries:
normal and pathologic processes. Radiographics 1995; 15:
755–70.
73. Aston SJ, Machlfeder HI. Intussusception in the adult. Am
Surgeon 1975; 41: 576–80.
74. Arnbjornsson E. Acute appendicitis as a sign of a colorectal
carcinoma. J Surg Oncol 1982; 20: 17–20.
75. Low RN, McCue M, Barone R, Saleh F, Song T. MR staging
of primary colorectal carcinoma: comparison with surgical
and histopathologic findings. Abdom Imaging 2003; 28:
784–93.
76. Chan TW, Kressel HY, Milestone B, et al. Rectal carcinoma:
staging at MR imaging with endorectal surface coil. Work in
progress. Radiology 1991; 181: 461–7.
77. Imai Y. MR imaging of rectal cancer using endorectal surface
coil: histopathological correlation. Nihon Igaku Hoshasen
Gakkai zasshi 1999; 59: 458–66.
78. Schnall MD, Furth EE, Rosato EF, Kressel HY. Rectal tumor
stage: correlation of endorectal MR imaging and pathologic
findings. Radiology 1994; 190: 709–14.
79. Vogl TJ, Pegios W, Mack MG, et al. Accuracy of staging rectal
tumors with contrast-enhanced transrectal MR imaging. AJR
1997; 168: 1427–34.
80. Pegios W, Vogl J, Mack MG, et al. MRI diagnosis and
staging of rectal carcinoma. Abdominal Imaging 1996; 21:
211–8.
212
81. Murano A, Sasaki F, Kido C, et al. Endoscopic MRI using
3D-spoiled GRASS (SPGR) sequence for local staging of
rectal carcinoma. J Comput Assist Tomogr 1995; 19: 586–91.
82. Joosten FB, Jansen JB, Joosten HJ, Rosenbusch G. Staging of
rectal carcinoma using MR double surface coil, MR endorectal
coil, and intrarectal ultrasound: correlation with histopathologic
findings. J Comput Assist Tomo 1995; 19: 752–8.
83. Okizuka H, Sugimura K, Ishida T. Preoperative local staging
of rectal carcinoma with MR imaging and a rectal balloon.
J Magn Reson Imaging 1993; 3: 329–35.
84. Brown G, Richards CJ, Newcombe RG, et al. Rectal carci-
noma: thin-section MR imaging for staging in 28 patients.
Radiology 1999; 211: 215–22.
85. Brown G, Radcliffe AG, Newcombe RG, et al. Preoperative
assessment of prognostic factors in rectal cancer using high-
resolution magnetic resonance imaging. Brit J Surg 2003; 90:
355–64.
86. MERCURY. Diagnostic accuracy of preoperative magnetic
resonance imaging in predicting curative resection of rectal
cancer: prospective observational study. BMJ (Clinical
Research ed.) 2006; 333: 779.
87. Burton S, Brown G, Daniels IR, et al. MRI directed multidis-
ciplinary team preoperative treatment strategy: the way to
eliminate positive circumferential margins? Brit J Cancer
2006; 94: 351–7.
88. MERCURY. Extramural depth of tumor invasion at thin-
section MR in patients with rectal cancer: results of the
MERCURY study. Radiology 2007; 243: 132–9.
89. Heald RJ, Ryall RD. Recurrence and survival after total
mesorectal excision for rectal cancer. Lancet 1986; 1:
1479–82.
90. Ouchi K, Sugawara T, Ono H, et al. Histologic features and
clinical significance of venous invasion in colorectal carci-
noma with hepatic metastasis. Cancer 1996; 78: 2313–7.
91. Gunther K, Dworak O, Remke S, et al. Prediction of distant
metastases after curative surgery for rectal cancer. J Surg Res
2002; 103: 68–78.
92. Shirouzu K, Isomoto H, Kakegawa T, Morimatsu M.
A prospective clinicopathologic study of venous invasion in
colorectal cancer. Am J Surg 1991; 162: 216–22.
93. Krasna MJ, Flancbaum L, Cody RP, Shneibaum S, Ben Ari G.
Vascular and neural invasion in colorectal carcinoma.
Incidence and prognostic significance. Cancer 1988; 61:
1018–23.
94. Chapuis PH, Fisher R, Dent OF, Newland RC, Pheils MT.
The relationship between different staging methods and
survival in colorectal carcinoma. Dis Colon Rectum 1985;
28: 158–61.
95. Freedman LS, Macaskill P, Smith AN. Multivariate analysis of
prognostic factors for operable rectal cancer. Lancet 1984; 2:
733–6.
96. Mulcahy HE, Toner M, Patchett SE, Daly L, O’Donoghue DP.
Identifying stage B colorectal cancer patients at high risk of
tumor recurrence and death. Dis Colon Rectum 1997; 40:
326–31.
97. Newland R, Dent O, Lyttle M, Chapuis P, Bokey E. Pathologi-
cal determinants of survival associated with colorectal cancer
with lymph node metastases. Cancer 1994; 73: 2076–82.
 colorectal cancer
98. Smith NJ, Barbachano Y, Norman AR, et al. Prognostic
significance of magnetic resonance imaging-detected extra-
mural vascular invasion in rectal cancer. Brit J Surg 2008; 95:
229–36.
99. Brown G, Daniels IR. Preoperative staging of rectal cancer:
the MERCURY research project. Recent Results Cancer Res
2005; 165: 58–74.
100. Harisinghani MG, Barentsz J, Hahn PF, et al. Noninvasive
detection of clinically occult lymph-node metastases in prostate
cancer. New Engl J Med 2003; 348: 2491–9.
101. Koh DM, Brown G, Temple L, et al. Rectal cancer: mesorectal
lymph nodes at MR imaging with USPIO versus histopatho-
logic findings—initial observations. Radiology 2004; 231: 91–9.
102. Beynon J, Mortensen NJ, Channer JL, Rigby H. Rectal endo-
sonography accurately predicts depth of penetration in rectal
cancer. Int J Colorectal Dis 1992; 7: 4–7.
103. Hildebrandt U, Schuder G, Feifel G. Preoperative staging of
rectal and colonic cancer. Endoscopy 1994; 26: 810–72.
104. Solomon MJ, McLeod RS. Endoluminal transrectal ultra-
sonography: accuracy, reliability, and validity. Dis Colon
Rectum 1993; 36: 200–5.
105. Massari M, De Simone M, Cioffi U, et al. Value and limits of
endorectal ultrasonography for preoperative staging of rectal
carcinoma. Surg Laparosc Endosc 1998; 8: 438–44.
106. Palacios Fanlo M, Ramirez Rodriguez J, Aguilella Diago V,
et al. Endoluminal ultrasography for rectal tumors: efficacy,
sources of error and limitations. Rev Esp Enferm Dig 2000;
92: 222–31.
107. Meyenberger C, Huch Boni RA, Bertschinger P, et al.
Endoscopic ultrasound and endorectal magnetic resonance
imaging: a prospective, comparative study for preoperative
staging and follow-up of rectal cancer. Endoscopy 1995; 27:
469–79.
108. Lindmark G, Elvin A, Pahlman L, Glimelius B. The value of
endosonography in preoperative staging of rectal cancer. Int
J Colorectal Dis 1992; 7: 162–6.
109. Akasu T, Sugihara K, Moriya Y, Fujita S. Limitations and
pitfalls of transrectal ultrasonography for staging of rectal
cancer. Dis Colon Rectum 1997; 40(10 Suppl): S10–S15.
110. Maier AG, Barton PP, Neuhold NR, et al. Peritumoral tissue
reaction at transrectal US as a possible cause of overstaging
in rectal cancer: histopathologic correlation. Radiology 1997;
203: 785–9.
111. Saitoh N, Okui K, Sarashina H, et al. Evaluation of echo-
graphic diagnosis of rectal cancer using intrarectal ultrasonic
examination. Dis Colon Rectum 1986; 29: 234–42.
112. Akasu T, Kondo H, Moriya Y, et al. Endorectal ultrasonogra-
phy and treatment of early stage rectal cancer. World J Surg
2000; 24: 1061–8.
113. Konishi K, Akita Y, Kaneko K, et al. Evaluation of endoscopic
ultrasonography in colorectal villous lesions. Int J Colorectal
Dis 2003; 18: 19–24.
114. Spinelli P, Schiavo M, Meroni E, et al. Results of EUS in
detecting perirectal lymph node metastases of rectal cancer:
the pathologist makes the difference. Gastrointest Endosc
1999; 49: 754–8.
115. Milsom JW, Czyrko C, Hull TL, Strong SA, Fazio VW. Pre-
operative biopsy of pararectal lymph nodes in rectal cancer
using endoluminal ultrasonography. Dis Colon Rectum
1994; 37: 364–8.
116. Quam JP RC, Charboneau JW. Transrectal sonographically
guided biopsy of a perirectal lymph node in recurrent rectal
carcinoma. Am J Roentgenol 1989; 153: 1101.
117. Choti MA, Sitzmann JV, Tiburi MF, et al. Trends in long-term
survival following liver resection for hepatic colorectal
metastases. Ann Surg 2002; 235: 759–66.
118. Geoghegan JG, Scheele J. Treatment of colorectal liver meta-
stases. Brit J Surg 1999; 86: 158–69.
119. Jaeck D, Bachellier P, Guiguet M, et al. Long-term survival
following resection of colorectal hepatic metastases. Association
Francaise de Chirurgie. Brit J Surg 1997; 84: 977–80.
120. Clavien PA, Selzner N, Morse M, Selzner M, Paulson E. Down-
staging of hepatocellular carcinoma and liver metastases from
colorectal cancer by selective intra-arterial chemotherapy.
Surgery 2002; 131: 433–42.
121. Shankar A, Leonard P, Renaut AJ, et al. Neo-adjuvant therapy
improves resectability rates for colorectal liver metastases.
Ann Roy Coll Surg Engl 2001; 83: 85–8.
122. Adam R, Avisar E, Ariche A, et al. Five-year survival following
hepatic resection after neoadjuvant therapy for nonresect-
able colorectal. Ann Surg Oncol 2001; 8: 347–53.
123. Giacchetti S, Itzhaki M, Gruia G, et al. Long-term survival of
patients with unresectable colorectal cancer liver metastases
following infusional chemotherapy with 5-fluorouracil, leuco-
vorin, oxaliplatin and surgery. Ann Oncol 1999; 10: 663–9.
124. Ridge JA, Bading JR, Gelbard AS, Benua RS, Daly JM. Perfu-
sion of colorectal hepatic metastases. Relative distribution of
flow from the hepatic artery and portal vein. Cancer 1987;
59: 1547–53.
125. Valls C, Andia E, Sanchez A, et al. Hepatic metastases from
colorectal cancer: preoperative detection and assessment of
resectability with helical CT. Radiology 2001; 218: 55–60.
126. Matsui O, Takashima T, Kadoya M, et al. Liver metastases
from colorectal cancers: detection with CT during arterial
portography. Radiology 1987; 165: 65–9.
127. Yamaguchi A, Ishida T, Nishimura G, et al. Detection by CT
during arterial portography of colorectal cancer metastases
to liver. Dis Colon Rectum 1991; 34: 37–40.
128. Soyer P, Levesque M, Elias D, Zeitoun G, Roche A. Detection
of liver metastases from colorectal cancer: comparison of
intraoperative US and CT during arterial portography.
Radiology 1992; 183: 541–4.
129. Oudkerk M, van Ooijen B, Mali SP, et al. Liver metastases
from colorectal carcinoma: detection with continuous CT
angiography. Radiology 1992; 185: 157–61.
130. Yamagami T, Nakamura T, Iida S, Kato T, Nishimura T. Non-
tumorous perfusion abnormalities of liver parenchyma adjacent
to the falciform ligament as revealed by angiographic helical
CT and angiography. Acta Radiol 2001; 42: 398–402.
131. Wong K, Paulson EK, Nelson RC. Breath-hold three-
dimensional CT of the liver with multi-detector row helical
CT. Radiology 2001; 219: 75–9.
132. Young SW, Bradley B, Muller HH, Rubin DL. Detection of
hepatic malignancies using Mn-DPDP (manganese dipyri-
doxal diphosphate) hepatobiliary MRI contrast agent. Magn
Reson Imaging 1990; 8: 267–76.
213
 primary tumor evaluation and staging
133. Blomley MJ, Sidhu PS, Cosgrove DO, et al. Do different types
of liver lesions differ in their uptake of the microbubble con-
trast agent SH U 508A in the late liver phase? Early experience.
Radiology 2001; 220: 661–7.
134. Wilson SR, Burns PN. Liver mass evaluation with ultrasound:
the impact of microbubble contrast agents and pulse inversion
imaging. Semin Liver Dis 2001; 21: 147–59.
135. Quaia E, Bertolotto M, Forgacs B, et al. Detection of liver
metastases by pulse inversion harmonic imaging during
Levovist late phase: comparison with conventional ultra-
sound and helical CT in 160 patients. Eur Radiol 2003; 13:
475–83.
136. Clouse ME. Current diagnostic imaging modalities of the
liver. Surg Clin N Am. 1989; 69: 193–234.
137. Staren ED, Gambla M, Deziel DJ, et al. Intraoperative ultra-
sound in the management of liver neoplasms. Am Surgeon
1997; 63: 591–6; discussion 6–7.
138. Torzilli G, Montorsi M, Donadon M, et al. “Radical but
conservative” is the main goal for ultrasonography-guided
liver resection: prospective validation of this approach. J Am
Coll Surgeons 2005; 201: 517–28.
139. Wildi SM, Gubler C, Hany T, et al. Intraoperative sonography
in patients with colorectal cancer and resectable liver metas-
tases on preoperative FDG-PET-CT. J Clin Ultrasound 2008;
36: 20–6.
140. Schiepers C, Penninckx F, De Vadder N, et al. Contribution
of PET in the diagnosis of recurrent colorectal cancer: com-
parison with conventional imaging. Eur J Surg Oncol 1995;
21: 517–22.
141. Bipat S, van Leeuwen MS, Comans EF, et al. Colorectal
liver metastases: CT, MR imaging, and PET for diagnosis–
meta-analysis. Radiology 2005; 237: 123–31.
142. Park KC, Schwimmer J, Shepherd JE, et al. Decision analysis
for the cost-effective management of recurrent colorectal
cancer. Ann Surg 2001; 233: 310–19.
143. Fernandez FG, Drebin JA, Linehan DC, et al. Five-year sur-
vival after resection of hepatic metastases from colorectal
cancer in patients screened by positron emission tomogra-
phy with F-18 fluorodeoxyglucose (FDG-PET). Ann Surg
2004; 240: 438–47; discussion 47–50.
144. Adloff M, Arnaud JP, Schloegel M, Thibaud D. Factors
influencing local recurrence after abdominoperineal
resection for cancer of the rectum. Dis Colon Rectum
1985; 28: 413–15.
145. Heimann TM, Szporn A, Bolnick K, Aufses AH Jr. Local
recurrence following surgical treatment of rectal cancer.
Comparison of anterior and abdominoperineal resection.
Dis Colon Rectum 1986; 29: 862–4.
146. Secco GB, Fardelli R, Rovida S, et al. Is intensive follow-up
really able to improve prognosis of patients with local recur-
rence after curative surgery for rectal cancer? Ann Surg Oncol
2000; 7: 32–7.
147. McCall JL, Cox MR, Wattchow DA. Analysis of local recur-
rence rates after surgery alone for rectal cancer. Int J Colorec-
tal Dis 1995; 10: 126–32.
148. Nesbakken A, Nygaard K, Westerheim O, Mala T, Lunde OC.
Local recurrence after mesorectal excision for rectal cancer.
Eur J Surg Oncol 2002; 28: 126–34.
214
149. Frykholm GJ, Pahlman L, Glimelius B. Treatment of local
recurrences of rectal carcinoma. Radiother Oncol 1995; 34:
185–94.
150. Holm T, Cedermark B, Rutqvist LE. Local recurrence of
rectal adenocarcinoma after “curative” surgery with and
without preoperative radiotherapy. Brit J Surg 1994; 81:
452–5.
151. Flamen P, Hoekstra OS, Homans F, et al. Unexplained rising
carcinoembryonic antigen (CEA) in the postoperative sur-
veillance of colorectal cancer: the utility of positron emission
tomography (PET). Eur J Cancer 2001; 37: 862–9.
152. Shirkhoda A, Staab EV, Bunce LA, Herbst CA, McCartney
WH. Computed tomography in recurrent or metastatic colon
cancer: relation to rising serum carcinoembryonic antigen.
J Comput Assist Tomo 1984; 8: 704–8.
153. Sugarbaker PH, Gianola FJ, Dwyer A, Neuman NR. A simplified
plan for follow-up of patients with colon and rectal cancer
supported by prospective studies of laboratory and radiologic
test results. Surgery 1987; 102: 79–87.
154. Husband JE, Hodson NJ, Parsons CA. The use of computed
tomography in recurrent rectal tumors. Radiology 1980;
134: 677–82.
155. Thoeni RF. Colorectal cancer: cross-sectional imaging for
staging of primary tumor and detection of local recurrence.
AJR Am J Roentgenol. 1991; 156: 909–15.
156. Brown G, Drury AE, Cunningham D, Husband JE. CT
detection of hydronephrosis in resected colorectal cancer:
a predictor of recurrent disease. Clin Radiol 2003; 58:
137–42.
157. Cho KC, Gold BM. Computed tomography of Krukenberg
tumors. AJR Am J Roentgenol 1985; 145: 285–8.
158. Birnkrant A, Sampson J, Sugarbaker PH. Ovarian metastasis
from colorectal cancer. Dis Colon Rectum 1986; 29: 767–71.
159. Kuhlman JE, Hruban RH, Fishman EK. Krukenberg tumors:
CT features and growth characteristics. Southern Med J 1989;
82: 1215–19.
160. Kim SH, Kim WH, Park KJ, Lee JK, Kim JS. CT and MR find-
ings of Krukenberg tumors: comparison with primary ovarian
tumors. J Comput Assist Tomo 1996; 20: 393–8.
161. Yamada K, Ishizawa T, Niwa K, et al. Patterns of pelvic inva-
sion are prognostic in the treatment of locally recurrent rectal
cancer. Brit J Surg 2001; 88: 988–93.
162. Boyle KM, Sagar PM, Chalmers AG, et al. Surgery for
locally recurrent rectal cancer. Dis Colon Rectum 2005; 48:
929–37.
163. Umpleby HC, Williamson RC. Anastomotic recurrence in
large bowel cancer. Brit J Surg 1987; 74: 873–8.
164. Sugarbaker PH. Recurrent and advanced primary colorectal
cancer: therapeutic implications of new concepts of gastro-
intestinal tumour biology. Baillieres Clin Gastroenterol 1989;
3: 699–712.
165. Sugarbaker PH. Mechanisms of relapse for colorectal cancer:
implications for intraperitoneal chemotherapy. J Surg Oncol
Suppl 1991; 2: 36–41.
166. Hruby G, Barton M, Miles S, et al. Sites of local recurrence
after surgery, with or without chemotherapy, for rectal cancer:
implications for radiotherapy field design. Int J Radiat Oncol
Biol Phys 2003; 55: 138–43.
 colorectal cancer
167. Pilipshen SJ, Heilweil M, Quan SH, Sternberg SS, Enker WE.
Patterns of pelvic recurrence following definitive resections
of rectal cancer. Cancer 1984; 53: 1354–62.
168. Marr R, Birbeck K, Garvican J, et al. The modern abdomino-
perineal excision: the next challenge after total mesorectal
excision. Ann Surg 2005; 242: 74–82.
169. Holm T, Ljung A, Haggmark T, Jurell G, Lagergren J. Extended
abdominoperineal resection with gluteus maximus flap
reconstruction of the pelvic floor for rectal cancer. Brit J Surg
2007; 94: 232–8.
170. West NP, Finan PJ, Anderin C, et al. Evidence of the oncologic
superiority of cylindrical abdominoperineal excision for low
rectal cancer. J Clin Oncol 2008; 26: 3517–22.
171. Sugihara K, Kobayashi H, Kato T, et al. Indication and ben-
efit of pelvic sidewall dissection for rectal cancer. Dis Colon
Rectum 2006; 49: 1663–72.
172. Renehan AG, Egger M, Saunders MP, O’Dwyer ST. Impact on
survival of intensive follow up after curative resection for
colorectal cancer: systematic review and meta-analysis of
randomised trials. BMJ (Clinical Research ed.) 2002; 324: 813.
173. Goldberg RM, Fleming TR, Tangen CM, et al. Surgery for
recurrent colon cancer: strategies for identifying resect-
able recurrence and success rates after resection. Eastern
Cooperative Oncology Group, the North Central Cancer
Treatment Group, and the Southwest Oncology Group.
Ann Int Med 1998; 129: 27–35.
174. Hida J, Yasutomi M, Shindoh K, et al. Second-look operation
for recurrent colorectal cancer based on carcinoembryonic
antigen and imaging techniques. Dis Colon Rectum 1996; 39:
74–9.
175. Saclarides TJ, Krueger BL, Szeluga DJ, et al. Thoracotomy for
colon and rectal cancer metastases. Dis Colon Rectum 1993;
36: 425–9.
176. Inoue M, Kotake Y, Nakagawa K, et al. Surgery for pulmonary
metastases from colorectal carcinoma. Ann Thorac Surg
2000; 70: 380–3.
177. Scheele J, Altendorf-Hofmann A, Stangl R, Gall FP. Pulmo-
nary resection for metastatic colon and upper rectum cancer.
Is it useful? Dis Colon Rectum 1990; 33: 745–52.
178. Baron O, Amini M, Duveau D, et al. Surgical resection of pul-
monary metastases from colorectal carcinoma. Five-year
survival and main prognostic factors. Eur J Cardiothorac
Surg 1996; 10: 347–51.
179. Girard P, Ducreux M, Baldeyrou P, et al. Surgery for lung
metastases from colorectal cancer: analysis of prognostic factors.
J Clin Oncol 1996; 14: 2047–53.
180. Valk PE, Abella-Columna E, Haseman MK, et al. Whole-body
PET imaging with [18F]fluorodeoxyglucose in management
of recurrent colorectal cancer. Arch Surg 1999; 134: 503–11;
discussion 11–13.
181. Flanagan FL, Dehdashti F, Ogunbiyi OA, Kodner IJ, Siegel
BA. Utility of FDG-PET for investigating unexplained plasma
CEA elevation in patients with colorectal cancer. Ann Surg
1998; 227: 319–23.
182. Delbeke D, Vitola JV, Sandler MP, et al. Staging recurrent
metastatic colorectal carcinoma with PET. J Nucl Med 1997;
38: 1196–201.
183. Huebner RH, Park KC, Shepherd JE, et al. A meta-analysis of
the literature for whole-body FDG PET detection of recurrent
colorectal cancer. J Nucl Med 2000; 41: 1177–89.
215
 14 Primary Tumors of the Liver and Biliary Tract
Richard L Baron and James V Ferris
INTRODUCTION
Liver tumors can arise from one of three basic cell lines of origin:
hepatocellular, cholangiocellular, and mesenchymal. The most
common primary liver tumor is hepatocellular (HCC), of hepato-
cyte origin, with cholangiocarcinoma (CCA), of cholangiocellular
origin, a distant second. Tumors of mesenchymal origin are rare,
with the most common in this group being angiosarcoma, epithe-
lioid hemangioendothelioma, and primary lymphoma. The major
part of this chapter will deal with HCC and CCA, the most com-
mon liver tumors, discussing predominately the role of imaging in
diagnosis and staging. The remaining rare primary liver tumors will
be presented briefly to introduce the reader to these entities and
their imaging appearances as they pertain to the oncological evalu-
ation of liver tumors and to aid in differentiating them from the
more common primary liver tumors. Tumors of the gallbladder
and large bile ducts will similarly stress the commonly encountered
tumors: gallbladder adenocarcinoma and CCA.
HEPATOCELLULAR CARCINOMA
One of the most common malignancies worldwide, HCC has been
reported to be responsible for one million deaths per year. In the
past, patients with these tumors had few treatment options, due
mainly to the presentation of patients at an advanced and inoper-
able stage. More recently, earlier detection of these lesions, mostly
due to technological developments, treatments such as resection,
transplantation, chemoembolization, and alcohol or thermal
ablation have become common, and successful cures or prolonged
survival are now reported (1–5).
Because up to 90% of patients with HCC have underlying cir-
rhosis or chronic viral infection (6), therapeutic options are often
limited due to the inability to resect large liver parenchymal vol-
umes or due to multiple tumor foci occurring in these patients. In
addition, in patients with cirrhosis, elevated alpha-fetoprotein
(AFP) levels can be found routinely, making screening with this
test for HCC more difficult. Conversely, patients with small tumors
often have normal AFP levels, being elevated in only a small
minority of such patients (7,8). For all of these reasons, despite
serious limitations, diagnostic imaging has come to play the key
role in detecting and staging HCC. The importance of making a
definitive imaging diagnosis of a liver lesion suspected of being
HCC is important, as in the United States, recent accepted criteria
allow for an imaging diagnosis of HCC (9), which when combined
with new organ transplantation candidate priority scoring (10)
can have serious implications in determining allocation of the few
available organs for transplantation.
Imaging Appearances
Like many liver neoplasms, these tumors often have non-specific
appearances, similar to metastatic neoplasms at computed
216
tomography (CT), ultrasound, or magnetic resonance imaging
(MRI). The underlying pathological changes, however, do allow
for some characteristic findings. The characteristic pathological
findings that affect imaging include:
• The presence of a surrounding fibrous capsule
• The heterogeneous nature of larger lesions (containing
scattered fibrous septae, necrosis, and focal accumula-
tions of fat)
• The vascular nature of the tumor resulting in marked
contrast enhancement at imaging
• Vascular invasion with portal or hepatic venous throm-
bosis are very suggestive findings of underlying HCC
and indicate an advanced stage
As these lesions do not cause symptomatic or clinically relevant
findings until large, in patients without chronic liver disease these
lesions are most often diagnosed late in their course when they are
large and then often with nonspecific features. In patients with
cirrhosis and chronic liver disease that are either undergoing imag-
ing screening for HCC, or imaged for other illness related reasons,
small and early lesions are seen with different appearances than
their large counterparts.
At ultrasound, the internal echo pattern is very variable and
lesions may appear hypoechoic, isoechoic, or hyperechoic
(Fig. 14.1) to normal liver, depending on the underlying patho-
logic composition of necrosis, fibrous tissue, or fat content.
Smaller tumors tend to be more homogeneous and larger tumors
heterogeneous, as with CT and MRI. The presence of a surround-
ing fibrous capsule, when present, will appear hypoechoic com-
pared to liver. Using intravenous contrast agents with ultrasound,
large advanced lesions have a heterogeneous and nonspecific
appearance similar to contrast enhanced CT and MR, but small
lesions will show increased vascularity and active enhancement in
up to 95% of cases, usually with subsequent rapid washout of
contrast material (11).
At CT and MR, the appearance of HCC will depend mainly on
the size of the tumor. Without intravenous contrast most small
(<3 cm) tumors are not visualized and when visualized are likely to
appear homogeneous [often isoattenuating (CT) or isointense
(MR) with liver]. Larger lesions usually demonstrate heterogeneity
with a mosaic appearance (Fig. 14.2) (12). The mosaic appearance
can be seen with ultrasound, CT, or MR and reflects a tumor com-
posed of multiple internal components of differing appearances
with internal enhancing septations and contrast-enhancement
patterns. Pathological evaluation has shown that internal heteroge-
neity is due to varying grades of:
• Tumor
• Necrosis
• Hemorrhage
• Fatty metamorphosis
• Fibrous elements
 primary tumors of the liver and biliary tract
Figure 14.1 Hepatocellular carcinoma (HCC). Sagittal ultrasound through the
liver shows a large HCC (arrows) at ultrasound as homogenously hyperechoic
compared to adjacent liver parenchyma, with a subtle peripheral hypoechoic zone
representing tumoral capsule.
Figure 14.2 Hepatocellular carcinoma (HCC). T1-weighted MR image shows a
large HCC with a mosaic appearance of internal organized regions of heterogeneity
and fibrous septations. The high signal intensity is due to intratumoral fat accumu-
lation. The heterogeneous appearance is typical of HCC, as is the surrounding low
signal intensity fibrous capsule (arrows), only rarely seen with other neoplasms.
The detection and appearance of HCC on CT or MR depends
greatly on the use and timing of intravenous contrast material.
Computed tomography features on non-contrast examinations
are typically hypo- or isoattenuating to adjacent liver, and a
peripheral capsule may appear as a rim of hypoattenuation. Calci-
fications are uncommon, but can occur in a variety of patterns in
approximately 5% to 10% of patients with large tumors in reported
series (13,14) but is very rare in small tumors. Fatty metamorpho-
sis, while common pathologically, is seen on CT in a small per-
centage of cases and appears as low attenuation regions similar to
fat (14). Contrast enhancement can be variable. Small lesions
often show homogeneous enhancement best seen during the arte-
rial phase of liver contrast enhancement (Fig. 14.3), although less
commonly they can appear hypovascular without enhancement.
Subsequent liver parenchymal enhancement during the portal
venous phase combined with the early washout of contrast in the
tumor results in these lesions becoming either hypoattenuating or
isoattenuating with liver. Delay equilibrium phase imaging can be
effective to demonstrate small tumor nodules when tumoral con-
trast washout is complete and the tumors appear hypoattenuating
to liver (15,16). In some instances this may be the only phase to
see small tumors as well as be helpful to differentiate benign
lesions that typically do not demonstrate washout greater than
adjacent liver. Higher rates of contrast administration (5 ml/sec)
(17) imaged during the late arterial phase (18) optimize small
lesion detection, but decrease diagnostic specificity (19).
Magnetic resonance imaging appearances are also variable.
Large lesions are most commonly seen as hypointense on
T1-weighted images and mildly hyperintense on T2-weighted
images, often with a heterogeneous, mosaic appearance; a vari-
ety of other patterns are also seen. Smaller lesions are often
isoattenuating on both T1- and T2-weighted images. Findings of
a peripheral capsule are more commonly seen than on CT,
appearing hypointense on T1-weighted images and T2-weighted
images in up to 65% of patients (20). Fatty metamorphosis is
visible more frequently than on CT with foci of high signal
intensity on T1-weighted images (Fig. 14.2) which will often lose
signal intensity when using T1 gradient echo out of phase images.
In up to one-third of HCC tumors, high-signal intensity on
T1-weighted images can be seen due to other causative factors
(21). This latter feature can be important for tumor detection as
many HCC in cirrhotic patients are isointense on T2-weighted
images. The enhancement characteristics of HCC with gadolin-
ium (gd) chelates are similar to that of iodine-based contrast
for CT, and results in increased tumor detection when using
arterial-phase imaging (20,22) due to the vascular nature of
most tumors.
Because the stage of HCC is so dependent on number and size
of the tumor nodules, an extensive discussion of optimizing HCC
nodule detection is presented under “Staging of HCC.”
Key Points: Imaging Findings in Hepatocellular
Carcinoma
■ On ultrasound, CT, and MR the appearances depend on
size. Large lesions are heterogeneous with a mosaic
appearance due to multiple confluent nodules and/or
internal septations
■ A surrounding fibrous capsule may be identified
■ Calcification is seen uncommonly, mostly in large tumors
■ Fatty metamorphosis is more frequently seen on MR than
CT
■ Arterial-phase imaging with CT and MR is the best non-
invasive method of detecting and delineating these tumors
■ Equilibrium-phase contrast imaging can be helpful in detecting
and characterizing small HCC
Staging (Table 14.1, Fig. 14.4)
Staging of HCC remains controversial as no algorithm to date
accurately stratifies patients based on survival statistics. The
pathology based TNM classification and group staging criteria for
primary liver carcinomas (Table 14.1), is widely accepted, but does
not take into consideration a patient’s underlying liver function
status, which dramatically impacts patient outcome in light of the
high incidence of cirrhosis. To accommodate this, tumor stage is
increased for the presence of severe fibrosis or cirrhosis in the
217
 primary tumor evaluation and staging

(A) (B)

(C) (D)
Figure 14.3 Small hepatocellular carcinoma (HCC). (A) Unenhanced CT does not discern the HCC seen on subsequent contrast enhanced images. (B) Arterial-phase
contrast CT shows homogeneous enhancement throughout the HCC nodule (arrow). (C) Portal venous-phase CT shows early washout of contrast within the tumor
combined with enhancement of surrounding liver parenchyma, resulting in the lesion being isoattenuating with liver parenchyma. (D) Delay equilibrium-phase images
show tumoral contrast washout greater than that of liver parenchyma with excellent visualization of the hypoattenuating tumor (arrow).

Table 14.1 TNM Classification and Group Staging Criteria for most recent revision (23). Additional significant changes from the
Primary Hepatocellular Carcinoma of the Liver prior TNM staging system are:

T1 Solitary tumor without vascular invasion

T2 Solitary tumor with vascular invasion, or multiple tumors, none >5 cm
• The classification of all solitary tumors without vascular
T3 Multiple tumors >5 cm or tumor involving a major branch of the portal
invasion, regardless of size as a T1 lesion, due to proven
or hepatic veins similar prognosis.
T4 Tumor(s) with direct invasion of adjacent organs other than the gallbladder • The classification of all solitary tumors with vascular
N0 No regional lymph node metastasis invasion and all patients with multiple tumors in any
N1 Regional lymph node metastasis number and distribution as T2 lesions, due to proven
M0 No distant metastasis
M1 Distant metastasis
similar prognosis.
Stage
I T1 N0 M0 The stage of tumor is upgraded by the presence of lymph node
II T2 N0 M0 (N) or distant metastases (M). The regional lymph nodes are the
IIIA T3 N0 M0 hilar, hepatoduodenal ligament lymph nodes, and caval lymph
IIIB T4 N0 M0 nodes, among which the most prominent are the hepatic artery
IIIC Any T N1 M0
and portal vein lymph nodes. Unfortunately, these nodes are very
IV Any T Any N M1
commonly enlarged from benign processes in patients with chronic

218
 primary tumors of the liver and biliary tract

T1

No vascular invasion

T2 T2

<5 cm

With vascular invasion

T3 T3

>5 cm
>5 cm

T4 T4

Invasion of adjacent organs

(A)

NI

(B)
Figure 14.4 Staging liver cancer in (A) primary tumor (T) and (B) lymph nodes (N).

219
 primary tumor evaluation and staging
liver diseases making it difficult for anatomic-based imaging to
stage lymph node disease (24).
The extent of tumor within the liver (T) dramatically affects the
stage of tumor, depending on:
• Number of tumor nodules present
• Size of tumor nodules
• Presence of vascular invasion
• Absence of vascular invasion
Accurate staging can be very important in selecting individual
therapeutic options. As an example, one report noted that no
Stage I or II patients with HCC who underwent transplantation
had developed recurrent tumor with a mean follow-up of three
years, while high rates of recurrence were found in Stage III or IV
patients (25). While older surgical literature showed poor long-
term survival for HCC patients following liver transplantation,
the advent of multidetector CT, and new MR contrast techniques
have improved the ability to detect small HCC tumor nodules by
approximately 30% to 40% (20,26,27). Despite continued limita-
tions in detecting small (particularly <1 cm) lesions at CT and MR
the improvements in imaging capabilities have led to more accu-
rate staging, resulting in more appropriate selection of lower stage
patients for surgery with better long-term survival results (4).
Recent advances in imaging ability to detect lesions have resulted
in an increasing reliance on imaging for the diagnosis of HCC
without biopsy. Accepted criteria for treatment planning by the
American Association for the Study of Liver Diseases (AASLD)
provide guidelines for diagnosing HCC and are shown in
Table 14.2 (9). Key to the modification from prior existing imag-
ing criteria is the use of equilibrium phase imaging to visualize
tumoral contrast washout in combination with arterial phase
hypervascularity. This substantially reduces the false positive diag-
nosis of HCC as most enhancing benign liver lesions do not wash
out greater than liver on delay phase imaging (28). These guide-
lines help in many clinical situations, but it is important to put in
perspective that 5% to 20% of HCC are hypovascular and will not
meet these criteria (26,29). In addition, differentiating HCC from
benign lesions by washout criteria is accurate but still not without
false positive and negative diagnoses (28,30). Nonetheless, the CT
and MR diagnosis of HCC has become accurate enough that the
AASLD criteria recommend diagnosing HCC when these specific
imaging criteria are met without proceeding to biopsy.
Table 14.2 Criteria for Imaging Diagnosis of HCC (9)
Imaging diagnosis Biopsy Follow
of HCC
>2 cm 1 contrast imaging Other solid lesions
technique shows lesion not meeting
enhancement and criteria
washout. Any solid lesion
with AFP > 200 ng/ml
1−2 cm 2 contrast imaging Solid lesion with
technique shows atypical findings
enhancement and on 1 of 2 imaging
washout techniques
<1 cm Follow at 3–6 mo
intervals with
ultrasound
220
The known process of malignant degeneration in dysplastic
cirrhotic regenerating nodules indicates that in cirrhotic patients
HCC is a diffuse multifocal process and may not be amenable to
surgical cure. In these patients, chemoembolization or ablation
(RF or alcohol) are commonly used. It becomes essential with
these treatments to document all possible tumor foci to allow for
complete treatment of all nodules. Accurate tumor staging therefore
becomes essential for patient management.
Primary Tumor (T) Staging
As with most abdominal neoplasms, imaging plays a critical role
in staging HCC. Unfortunately, detecting HCC tumor nodules is
often more complicated than with tumors located elsewhere in
the body. Despite some reports of abilities of conventional CT,
MR, and ultrasound to detect 80% to 90% of small HCC tumor
foci (22,31), studies with strong pathological correlation in
screening populations have shown that CT and contrast-enhanced
MR detect only approximately 75% of patients with HCC and
only 40% to 50% of tumor foci in a screening population (8,32).
Ultrasound reports with strong pathologic correlation in screen-
ing populations with underlying cirrhosis have reported even
worse results (33–36) with one study detecting only 30% of
patients with HCC and 20% of lesions (34). More recently, one
MR study with a small number of patients reported high success
with patient sensitivity of 93% for HCC detection (27). This study
used a combination of MR contrast agents, both superparamag-
netic iron oxide and gadolinium chelates, and had difficulty only
in detecting tumor nodules <1 cm in diameter. The high incidence
of HCC in their transplant population, however, raises the
question of a strong bias toward patient selection with HCC, and
whether this combination will increase sensitivity in a screening
population remains to be determined.
Cirrhosis is present in a high percentage of patients with HCC
and almost certainly is a major factor in making identification of
these neoplastic lesions difficult with any modality for the following
reasons:
• Differentiating large regenerative nodules and dysplastic
nodules of cirrhosis from HCC can be difficult with any
imaging modality
• Altered portal venous hemodynamics, coupled with the
increased hepatic arterial blood flow to the cirrhotic
liver, makes tumor detection with contrast-enhanced
CT more difficult in cirrhotic patients
• HCC is a vascular tumor, and it has been shown that
such vascular tumors can rapidly become isointense or
isoattenuating with the liver on contrast-enhanced CT
or MR
Computed Tomography
Computed tomography is the modality most frequently used to
detect and stage HCC in the United States as the entire chest and
abdomen can easily be screened at the same examination. Appro-
priate administration of intravenous contrast material is essential
for maximizing detection of tumor nodules on CT, requiring high
contrast material flow rates and optimal timing in the late arterial
phase to capture maximal tumor conspicuity (17,18). Due to the
vascular nature of these tumors, it is essential to image the liver
during the arterial phase of contrast administration which will
 primary tumors of the liver and biliary tract

detect an additional 30% to 40% of tumor nodules over portal

venous-phase imaging and will be the only CT technique to detect
tumor in 7% to 10% of patients (Figs. 14.3 and 14.5) (26,37). Fur-
thermore, the size of the tumor nodules is often shown to be larger
with arterial-phase imaging as portal venous-phase contrast CT
often detects only central necrosis within large tumors, with the
peripheral tumor appearing isoattenuating with the liver. By using
arterial-phase contrast imaging, the peripheral viable tumor sur-
rounding the necrosis can be appreciated, more accurately staging
the tumor (Fig. 14.6). If arterial-phase imaging is not possible in
patients with suspected HCC, then the second best contrast
sequence for tumor detection has been shown to be equilibrium-
phase images (22,38), which improves detection by approximately
5% when combined with arterial-phase imaging (39).
When using a multidetector CT scanner, the faster scan acquisi-
tion time allows one to tailor the timing of arterial phase images
and obtain two passes during the arterial phase (40,41). Early
arterial-phase images can be used to evaluate the arterial vascular
supply to the liver, and a late arterial phase (at approximately
35−40 seconds) has been found optimal to detect vascular tumor
nodules (18,41). Scanning during portal venous phase can evalu-
ate liver parenchyma for other abnormalities, venous structures of
the liver and abdomen, and other abdominal organs that need to
be evaluated as well as optimally visualize contrast washout in
HCC and hypovascular HCC.
While conventional MDCT techniques have reported sensitivi-
ties of approximately 75% patient detection and 40% to 50% Figure 14.5 Value of arterial-phase contrast CT in visualizing HCC tumor foci.
lesion detection, more invasive CT techniques to optimize con- Arterial-phase contrast CT image (top) shows numerous HCC foci throughout the
trast delivery to the liver have been used to increase tumor detec- right lobe and medial segment left lobe as homogeneously enhancing nodules.
tion. CT-arteriography (CT-A) is performed with contrast Most of these nodules become isoattenuating with liver and not visible during the
medium infused through an indwelling hepatic artery catheter to portal venous-phase imaging (bottom). Note the invasion of the portal vein with
an intravascular component of tumor (arrows) which enhances to the same degree
maximize arterial contrast delivery (42) (Fig. 14.7) and has been as adjacent tumor.
shown to increase the number of tumor nodules detected by as
much as 66% (43,44) but, as it is invasive, its use is generally
restricted to patients who are undergoing concurrent chemoem-
bolization treatment. Some centers still advocate the use of CT-
arterial portography (CT-AP) for patients with HCC as helpful in
tumor detection and characterization (45). However, limitations
in using this technique in patients with severe cirrhosis result in
contrast medium either failing to opacify the liver due to portal
hypertension or patchy enhancement resulting in too many
“pseudolesions” to be of clinical use in many cirrhotic patients
who are at risk for tumor (46).
A variant of CT-A, lipiodol-CT, utilizes the infusion of a lipid-
based iodine-contrast agent through the hepatic artery catheter,
as HCC retains the lipiodol contrast densely. When patients are
rescanned 7 to 14 days later, allowing time for clearance of the
contrast from the normal parenchyma, retention of lipiodol in
HCC foci can often be clearly seen. Unfortunately, despite initial
enthusiasm, more subsequent reports with pathological correla- Figure 14.6 Hepatocellular carcinoma size better depicted on arterial-phase CT
scan in a patient with cirrhosis. Arterial-phase image (left) shows enhancing
tion show that this technique only detects 50% to 70% of small peripheral viable tumor (arrows), allowing an accurate measurement of tumor
tumor foci (47,48). Nonetheless, this can be a helpful technique to size. Portal venous-phase image (right) only depicts central tumor necrosis and
either detect or stage HCC in selected patients. As chemoembo- significantly underestimates tumor size.
lization often uses this agent, in patients undergoing follow-up
imaging with CT, foci of retention in tumors will be encountered. Magnetic Resonance Imaging
An added advantage for this technique is that the delayed reten- While conventional MR has been shown to depict the early
tion within small tumor foci is an excellent target for biopsy under changes of HCC within dysplastic (formerly called adenomatous
CT guidance. hyperplastic) nodules (Fig. 14.8) (49) and generally excels over CT

221
 primary tumor evaluation and staging

Figure 14.7 Hepatocellular carcinoma foci seen best during

CT-arteriography. Three images (top row) obtained during an
arterial-phase CT examination fails to definitively identify
tumor. CT-arteriogram images (bottom row) at same three
levels shows three enhancing tumor foci (arrows).

(A) (B) (C)

(D) (E)
Figure 14.8 Hepatocellular carcinoma (HCC) arising within dysplastic nodule in a patient with cirrhosis. (A) T1-weighted image shows a small nodule predominately of increased
signal (arrow), typical of dysplastic nodule. A smaller lower signal nodule can be seen within the larger nodule (arrowhead), representing a contained focus of HCC within the
dysplastic nodule. (B) T2-weighted MR image shows only the small focus of HCC as increased signal intensity (arrowhead). (C) Late arterial-phase contrast enhanced CT shows
the peripheral dysplastic nodule region as hypoattenuating (arrow) compared with adjacent liver and the HCC focus as enhancing representing tumor neoangiogenesis.
(D) Arterial-phase contrast CT image six months later shows the tumor focus as enhancing (arrow) and has increased in size to encompass the entire nodule. (E) Equilibrium-
phase contrast CT at same examination shows contrast washout centrally in the tumor with a surrounding fibrous tumor capsule (arrow), both typical of HCC.

222
 primary tumors of the liver and biliary tract

in depicting changes of cirrhosis, there have been no controlled
large population studies with good pathological standards com-
paring CT and MR in detecting HCC. Similar to CT, optimal MR
detection of HCC requires the use of arterial-phase contrast-
enhanced imaging, detecting 21% more tumor nodules than
unenhanced MR (20) (Fig. 14.9). Recent studies comparing trans-
planted specimens with pretransplant MR imaging has shown
higher patient sensitivity in detecting HCC (27,32) with 77% (32)
and 93% (27) reported. Without controlled comparison studies
with CT, however, it is difficult to make direct comparisons as
the incidence of HCC in resected specimens in these studies was
37% (32) and 45% (27), far higher than the 11% to 14% expected
among transplant screening populations, indicating that a high
potential for patient selection bias existed in these studies. This
likelihood is corroborated when these studies reported lesion
detection rates of small lesions (<1 cm) that are virtually identical
to published CT detection rates. Nonetheless, these studies show
that increasing MR techniques and optimizing MR contrast has
resulted in increased sensitivity in tumor detection. Bhartia et al.
(27) achieved their reported higher rates using a dual-contrast
method of iron oxide contrast imaging T2, followed by T1 gradient-
echo gadolinium chelate dynamic contrast imaging to further
improve detection and characterization. In clinical practice, it
probably makes little difference whether screening is performed
with CT or MR imaging, as long as state-of-the-art contrast-
enhanced techniques are employed, and contrast material is used
appropriately.
Most centers in the United States screen patients with or at
risk for HCC with CT as CT affords the opportunity to survey
the entire chest, abdomen, and pelvis for tumor. MR is an excel-
lent tool for evaluating targeted single organs and is widely used
as a problem-solving tool, but remains problematic for use as a
widespread screen in a large number of patients, in part due to
limited scanner availability in comparison with CT.
Whether using MR or CT contrast, there are a large number of
enhancing vascular lesions that can simulate HCC in patients at
risk for tumor (50). Common amongst these are flash-filling
hemangiomas, arterio-portal shunts, peliosis, enhancing focal
fibrosis, and occasional regenerating or dysplastic nodules. By
evaluating the characteristics of enhancement through dynamic
images most of these lesions can be differentiated, looking for
washout of enhancement greater than liver in portal venous or
equilibrium delay phases in HCC, not commonly encountered in
benign lesions (28,51,52). In addition, following small lesions over
time can demonstrate enlargement, a sign most often seen with
malignancy.
Ultrasound
Ultrasound is a more controversial tool for use as a screening
tool in cirrhotic patients. While some have reported high success
in detecting HCC in cirrhosis with ultrasound, studies with
transplant correlation have repeatedly shown a low sensitivity
in detection (33–35,47). In part, these reported discrepancies
may be due to patient populations, as it has clearly been shown
that with advanced cirrhosis it is very difficult to accurately
differentiate HCC from the background liver parenchymal
changes seen with cirrhosis. The nonspecific appearance of
benign lesions in cirrhosis simulating HCC creates too many
false-positive benign lesions to be of clinical utility in an iso-
lated instance. Follow-up imaging with ultrasound, however, if
one has documented well the ultrasound appearance of the
parenchyma, can be helpful if evolutionary nodules are detected

(A) (B)
Figure 14.9 Hepatocellular carcinoma in a patient with cirrhosis seen only with dynamic contrast-enhanced imaging. (A) T1-weighted spin-echo image (top) and
T2-weighted spin-echo image (bottom) shows a cirrhotic liver morphology, but without evidence for underlying neoplasm; (B) dynamic gadolinium-enhanced gradient-
echo images obtained precontrast (upper left), and at approximately every 20 seconds thereafter, shows a 1 cm enhancing nodule (arrowheads) during the later arterial
phase. Note that the nodule is seen only briefly and at other times is isointense with liver parenchyma. Source: From Ref. 10.

223
 primary tumor evaluation and staging

(53,54). In addition, when a lesion is detected on CT or MR,
the lesion can often be identified at ultrasound by looking for
adjacent landmarks and locating specific nodules seen as sus-
picious on CT or MRI. This allows ultrasound to be used as the
procedure of choice for biopsy of liver masses to detect and
stage hepatocellular carcinoma. The addition of ultrasound
contrast agents has provided an excellent tool for characteriz-
ing lesions seen at ultrasound but remains difficult to utilize as
a screening tool for the liver and has not been adopted in the
United States.
Positron Emission Tomography (PET)
PET imaging with fluorine-18-fluorodeoxyglucose (FDG) is
increasingly being used with success to detect and stage various
tumors. The limited published studies using this technique for
evaluating patients with suspected HCC have not shown sufficient
success to warrant using this tool to search for primary tumors in
the liver. Reported sensitivities for using PET to detect HCC
ranged from 0% to 55% (55–57). Well differentiated tumors or
tumors of a lower grade were noted in one series to demonstrate
less FDG avidity and suggest it may be helpful in staging and
prognostication, as well as show slightly better utility to detect
metastases (58).
Vascular Invasion
Vascular invasion can be detected with CT, ultrasound, or MR when
present in the large portal vein (Figs. 14.5 and 14.10) or hepatic
vein branches. Because benign portal venous thrombi occur fre-
quently in patients with cirrhosis, caution must be used when
assuming that thrombus is always representative of malignant
invasion. Features that are associated with malignant invasion
include:
• Adjacent location to tumor
• Large diameter of the vein
• Enhancement of thrombus on CT
• Detection of intrathrombus arterial flow at either
Doppler ultrasound (59) or arterial phase-contrast CT
or MR (Fig. 14.10) (26,60)
Tublin et al. showed that the maximal diameter of veins with a
benign thrombus was 20 mm for right or left portal vein and
23 mm for the main portal vein, while the venous diameter was
expanded beyond these sizes in almost all malignant thrombosed
veins (60). Microscopic or small vessel vascular invasion cannot
be detected by any current imaging modality and remains one of
the major stumbling blocks to preoperative staging of HCC. Encap-
sulated tumors have been reported to have a better prognosis
and are more amenable to surgical resection (61), presumably due
to lack of vascular invasion. However, since HCC formation in
cirrhosis is a multifocal process, the lack of vascular invasion may
not guarantee a lower stage of tumor if unseen tumor nodules exist
elsewhere in the liver.
In addition to vascular invasion, evidence of advanced
tumor stage in the liver presents in the form of invasion of
HCC into the biliary tree (62). When present, such tumor foci
can simulate primary bile duct tumors in the absence of the
known history of HCC. The use of CT or MR can differentiate
these lesions, as cholangiocarcinoma does not typically enhance
vividly during the arterial phase, while HCC invading the bile
duct often does.

(A) (B)
Figure 14.10 Hepatocellular carcinoma with portal vein invasion. (A) Arterial-phase contrast CT images demonstrates tumor thrombus in the portal vein, with expan-
sion of the diameter of the vein. Arterial neovascularity within the tumor thrombus can be seen confirming the malignant nature of the thrombus. Arterioportal shunt-
ing through the tumor results in a large accumulation of contrast peripherally in the vein surrounding the tumor. (B) Malignant portal vein invasion in a different patient
shows diffuse enhancement of the thrombus, another appearance characteristic of malignancy.

224
 primary tumors of the liver and biliary tract
Extrahepatic Tumor (Nodal and Distant Metastases)
Despite voluminous publications over the past two decades con-
cerning HCC, relatively little is written about the manifestations
of extrahepatic disease. It has been stated that up to 50% of
patients with HCC have regional or distant metastases at the
time of death (63). In an autopsy study (64), lymph node metas-
tases were found in 42% of patients (Fig. 14.11) and the lung
and skeleton were the most common sites of distant metastases
(18% and 17%, respectively). Less common sites of metastases
included the adrenal gland (9%), and peritoneum (6%) with
rare occurrences in virtually any organ. Because complete lymph
node dissection is not routinely carried out in liver resection
surgery, the incidence of metastatic disease at time of presentation
or at resection for HCC is less well documented. It has been the
authors’ experience that imaging detects metastases in all of the
sites listed in the above autopsy series, although a lesser incidence
of skeletal metastases is seen upon an anecdotal review. Because
most of the metastatic spread is to lymph nodes, CT examination
of the chest, abdomen, and pelvis will detect enlarged lymph
nodes (Fig. 14.11) and the relatively more common distant met-
astatic deposits to the lung and other abdominal sites. Caution
must be exercised in diagnosing metastases to abdominal lymph
Figure 14.11 Metastases to the internal mammary lymph node chain from hepato-
cellular carcinoma (HCC). Contrast-enhanced CT examination shows an enlarged
lymph node (arrow) in the right internal mammary chain, proven to be metastatic
disease. Note that the node enhances substantially, often seen with vascular tumors
such as HCC, providing a clue to the malignant nature of lymph node enlargement.
nodes as benign enlarged lymph nodes are common in cirrhotic
patients (24). Such lymph node enlargement, while greatest in
size and prevalence with primary biliary cirrhosis (a low risk for
HCC), can be seen with virtually all etiologies of cirrhosis and
precludes the ability of diagnostic imaging studies to stage HCC
without the concomitant use of percutaneous biopsy of sus-
pected lymph nodes.
Key Points: Detection and Staging of HCC
■ Accurate tumor staging and treatment planning requires
accurate delineation of the number of intrahepatic tumor
foci
■ Contrast-enhanced CT and MR detect only approximately
50% of tumor foci in a screening population, and ultrasound
even less
■ Arterial-phase contrast imaging is critical for both CT and
MR to detect small tumor foci, and equilibrium-phase imaging
is extremely valuable to differentiate from benign enhancing
lesions
■ Cirrhosis, present in a high percentage of patients, is a major
factor resulting in difficulty in detection of small tumors
■ Computed tomography arteriography (CT-A) detects substantially
more HCC tumor nodules than arterial-phase CT
■ Ultrasound is the procedure of choice for biopsy of liver
masses
■ Vascular invasion can be detected with CT, ultrasound, or MR
FIBROLAMELLAR HEPATOCELLULAR CARCINOMA
Fibrolamellar hepatocellular carcinoma (FL-HCC) is a distinct
tumor with origin and differentiation different from HCC. The
neoplastic hepatocytes in this tumor are separated by lamellar
fibrous strands and lack the presence of AFP, typical of HCC.
FL-HCC is a tumor of young adults occurring in a noncirrhotic
liver. Some reports have shown a better prognosis than other
HCC types, with high resectability rates and cure rates approach-
ing 50% (61). Pathologically a fibrous central scar is present in
70% to 80% of cases (65) and much attention to this fact has
been made in the imaging appearance of the central scar for
characterizing these lesions. It has been reported that the central
scar in FL-HCC is hypointense on both T1-weighted and
T2-weighted MR imaging (Fig. 14.12) in contrast to focal nodu-
lar hyperplasia (FNH), where the fibrous central scar is dark on
T1-weighted imaging, but typically of high signal intensity on
T2-weighted imaging (66). Unfortunately, these are only guide-
lines, as FNH occasionally may have a low signal intensity
appearance to the central tumor region, and other HCC types
frequently may have central high signal intensity on T2-weighted
images due to central necrosis.
The CT characteristics suggestive of FL-HCC include the pres-
ence of calcifications within the central scar (Fig. 14.13), present
in approximately two-thirds of FL-HCC (65) and very uncom-
mon with FNH, and the presence of a well-defined vascular tumor,
particularly well shown during arterial-phase contrast imaging.
Most often these tumors are heterogeneous in their enhancement
unlike FNH which is very homogeneous except for the central scar
225
 primary tumor evaluation and staging

delineation. In problematic cases, differentiation between these

two lesions can often be resolved by nuclear scintigraphy (with
typical uptake of sulfur-colloid or hepatobiliary MR agents into
FNH lesions), or biopsy.
Staging of these tumors uses the TNM system as discussed
under HCC. Despite the better prognosis when compared with
HCC, extensive tumor can still be seen in the liver and elsewhere.
As with HCC, the use of dynamic contrast scanning, whether with
CT or MR, to achieve arterial-phase imaging is mandatory to
detect satellite nodules throughout the liver. Vascular invasion and
biliary tract invasion, as with HCC, can be present. Metastatic dis-
ease, when present, is most common to regional abdominal lymph
nodes, and remote metastases can be seen virtually anywhere, but
again lung deposits are most common.
Key Points: Fibrolamellar HCC
■ Fibrolamellar HCC is a tumor of young adults and occurs in
non-cirrhotic patients
■ Neoplastic hepatocytes are separated by lamellar fibrous
strands and there is a fibrous central scar
■ The central scar often contains calcification and has a varying
appearance on CT but a characteristic feature is low signal
intensity on T2-weighted MR
■ FL-HCC shows heterogeneous contrast enhancement on
arterial and portal venous-phase contrast imaging
CHOLANGIOCARCINOMA

Bile duct cancers are uncommon tumors, with approximately

3000 new cases reported annually in the United States (67).
Tumors arising in the bile ducts other than cholangiocarcinoma
(CCA) are rare. Cholangiocarcinoma is a tumor arising from the
epithelial lining of the bile ducts and occur most frequently in a
hilar or extrahepatic location, where between 70% and 90%
occur (68–70). The incidence is rising in the United States, with
increasing numbers of intrahepatic locations, perhaps due to
better awareness and differentiation from metastatic disease
(70). Of the extrahepatic locations, these are most common
proximally in a hilar location, often termed Klatskin tumors,
and less commonly distal in the common bile duct. Certain pre-
disposing conditions can dramatically increase the incidence of
CCA including:

• Choledochal cyst
Figure 14.12 Fibrolamellar HCC. T2-weighted fast spin-echo MR image shows a • Liver fluke Clonorchis senensis and Opisthorchis viverrini
large left lobe tumor (arrows) with a heterogeneous appearance. The central • Thorotrast deposition
fibrous scar (arrowheads) appears as a small, linear foci of signal void. • Primary sclerosing cholangitis (71)

(A) (B)
Figure 14.13 Fibrolamellar HCC (FL-HCC) with extensive peritoneal metastases. (A) Contrast-enhanced CT shows a typical appearance for FL-HCC. The lesion is
vascular with marked contrast enhancement and demonstrates a central scar appearing of low attenuation (arrows). Central calcification of high attenuation seen within
the scar is also frequently encountered in these tumors; (B) Pelvic images from the same examination demonstrate numerous masses arising in the peritoneum replacing
nearly the entire space of the pelvis. Note the marked vascularity of the masses with substantial contrast enhancement.

226
 primary tumors of the liver and biliary tract

Sclerosing cholangitis is the most common predisposing condi-
tion in western countries, and such patients have a lifetime risk of
approximately 10% of developing CCA (72). The higher incidence
of these tumors in the Far East and South East Asia is thought to
be due to live fluke infection endemic there (73).
The complex anatomic and pathologic variations seen in CCA
are reflected in difficulties in imaging detection and characteriza-
tion. In addition to differences in appearance at imaging from
tumors of marked different locations (intrahepatic versus extra-
hepatic), the tumors pathologically differ in their predominant
histologic stroma (fibrous versus glandular) which influences
their appearances at imaging. Gross morphologic appearances of
tumors can also vary and have been classified as extraductal
masses, periductal-infiltrating (formerly termed sclerotic), or
rarely intraductal (74). The rare intraductal form can take a
variety of appearances, including papillary, superficial mucosal
spreading, cast-like variants, and mucin-producing (similar to the
pancreatic counterpart) (75,76).
Intrahepatic Cholangiocarcinoma
Intrahepatic CCA, also called peripheral cholangiocarcinoma,
arises from biliary ductal epithelium from smaller ducts within
the liver parenchyma. It is far less common as a primary liver
tumor than HCC, representing only about 10% of all primary
hepatic malignancies (77). Although histological findings of
mucin-producing glands and a fibrous stroma can be suggestive
of the diagnosis, it can be difficult to differentiate intrahepatic
CCA from other metastatic adenocarcinoma lesions when such
liver lesions are biopsied. Clinically, the presence of such lesions in
the absence of any known primary lesion elsewhere should lead
one to suspect the diagnosis of CCA. This can be an important
distinction, as treatment options are very different, including
resection for peripheral, isolated CCA. These tumors can contain
predominately a fibrous stroma, a glandular mucin-producing
stroma, or a mixed stromal pattern. The imaging appearances will
vary depending on which stromal pattern predominates. All of the
anatomic and morphologic variants discussed above can be seen
in intrahepatic tumors.
Imaging Findings
Appearances of these lesions are dependent on the morphologic
type of tumor. In Europe and North America these lesions are
most often encountered as peripheral duct mass lesions occur-
ring peripheral to the right or left hepatic ducts. Such intrahe-
patic CCA mass lesions often lack characteristic findings on
imaging. On CT they can appear either with ill-defined or well-
defined tumor margins, and are most often hypodense or
isodense to liver parenchyma on non-contrast-enhanced images.
The lesions will either remain predominately hypoattenuating
or become isoattenuating (and not visualized) during the portal
venous-phase of contrast-enhanced CT (Figs. 14.14 and 14.15),
often with some mild to moderate peripheral contrast enhance-
ment. Caution must be taken not to mistake this enhancement
for that of hemangiomas and attention to the degree of enhance-
ment is important, as with CCA the enhancement will usually
not match that of appropriate blood vessels, typical of heman-
gioma. These lesions are usually nonenhancing during the arte-
rial phase of contrast enhancement, but some lesions may show
mild enhancement (78), usually peripherally. Dilated intrahe-
patic bile ducts may be seen peripheral to these lesions in some

(A) (B)
Figure 14.14 Cholangiocarcinoma (CCA) in a patient with primary sclerosing cholangitis (PSC). (A) Endoscopic retrograde cholangiography shows diffuse strictures
throughout the biliary tree typical of PSC. It is not possible to depict the region of tumor (arrow) as different from changes of PSC seen elsewhere throughout the biliary
tract; (B) Contrast-enhanced CT shows a large hypoattenuating mass (arrows) in the right lobe, proven, following transplantation, to be CCA with rich glandular stroma
(compare with Figs. 14.15 and 14.16). Scattered biliary ductal dilatation proximal to the mass is seen, typical of PSC.

227
 primary tumor evaluation and staging

(A) (B)
Figure 14.15 Cholangiocarcinoma (CCA) with progressive contrast enhancement. (A) CT scan obtained during arterial phase shows mild peripheral enhancement of
the lesion (arrows). In addition, capsular retraction overlying the lesion is seen both anteriorly and posteriorly (B) Scan at the same level during equilibrium phase shows
progressive enhancement centrally and retention of contrast within the lesion (arrows). All of these findings are commonly seen in CCA with a fibrous stroma
predominating (compare with Fig. 14.14).

(A) (B)
Figure 14.16 Common hepatic duct (CHD) cholan-
giocarcinoma (CCA) with proximal extension. (A)
Arterial-phase CT shows the CHD wall eccentrically
thickened and enhancing, representing CCA
(arrows). Note the liver parenchymal arterial
enhancement in segments 4 (arrowheads) represent-
ing transient hepatic attenuation difference (THAD)
due to left portal venous obstruction shown in (C).
(B) Portal venous-phase CT more cephalad shows
obstruction of multiple order branches of the left
hepatic ducts (arrowheads) but no obstructing mass
lesion is identified. (C) Delay equilibrium-phase CT
at same level as (B) shows washout of contrast in
liver parenchyma but retention of contrast in the
fibrous stroma of the CCA extension (arrows) into
the left lobe. Involvement into second order branches
or beyond classifies this lesion as a Bismuth 3b
tumor. (D) Coronal CT confirms the obstruction of
(C) (D) left portal vein at its origin (arrow).

228
 primary tumors of the liver and biliary tract
cases (Fig. 14.15), a less common finding in metastatic disease.
Overlying capsular retraction (Fig. 14.15) and atrophy of liver
parenchyma can be seen, due to either biliary or portal venous
obstruction, and fibrous scarring and retraction of associated
parenchyma during tumoral evolution (79). Associated with the
mucin content, calcifications may be present and identified on
CT or ultrasound, although in the authors’ experience this is
uncommon. Unlike hepatocellular carcinoma, a capsule sur-
rounding the tumor is not present (80). The characteristic CT
feature that allows for detection of these lesions with contrast
techniques is the delayed retention of the contrast medium during
mid and late equilibrium phase (Fig. 14.16) (81). This retention
of contrast medium has been hypothesized to be due to the
fibrous stroma present in these tumors, which is slow to accu-
mulate contrast and slow to release it. While many different
tumors can show heterogeneous marked retention of contrast,
homogeneous marked retention is uncommonly seen in other
tumors and is seen in approximately 40% of intrahepatic CCA
(81). In some patients the delayed images (best obtained from
10−20 minutes following initiation of contrast infusion) may be
the only sequence to demonstrate tumor. The implications of
this for detecting tumor and staging for potential resection are
obvious. In patients with subtle findings, or patients with scle-
rosing cholangitis and prominent dilated ducts without an obvious
mass seen on initial screening, we obtain delayed equilibrium
images for further evaluation.
Periductal infiltrating type cholangiocarcinomas are less com-
monly encountered in an intrahepatic location (more common in
hilar CCA) appearing as an elongated infiltration and soft tissue
thickening of the duct wall. Ducts proximal to the strictured
segment will appear dilated. In the authors’ experience, patients
with sclerosing cholangitis will show these types of lesions more
frequently. The tumor itself can be difficult to visualize at imaging
if the wall is not significantly thickened, and often the only visible
feature will be a strictured length of bile duct at cholangiography
or CT/MR bile duct reconstructions (74). These lesions do not
typically show arterial-phase contrast enhancement, but do show
(A)
Figure 14.17 Papillary cholangiocarcinoma. (A) Portal venous-phase CT scan shows dilated right hepatic ducts, which are obstructed at the level of the formation of the
main right hepatic duct. The right hepatic duct is dilated and, rather than appearing of water attenuation, an intraluminal papillary cholangiocarcinoma appears of soft
tissue attenuation (arrow); (B) Pathology specimen confirms the intraluminal papillary tumor (arrow). Source: From Ref. 92.
delay equilibrium-phase retention of contrast due to the fibrous
stroma commonly present.
Intraductal cholangiocarcinomas are rare and, when present,
are usually papillary, either solitary (most common) or, rarely,
multiple up to and including creating a cast of the biliary tree.
These lesions have a better prognosis as the tumor is often lim-
ited to mucosa and invades the wall later in its course (74).
These lesions are often too small to see at CT, but when large
can appear as soft tissue attenuation masses filling the lumen
of the ducts (Fig. 14.17). They do not typically show significant
arterial phase enhancement, but do show more delayed con-
trast enhancement typical of soft-tissue tumors. On rare occa-
sion these tumors can become large and diffuse but still
contained within the biliary ducts without extraductal exten-
sion, and can create a “cast” of the biliary tree in affected
regions (Fig. 14.18). Occasionally these tumors can produce
excessive amounts of mucin, distending the biliary tree focally
in the region of the tumor, occasionally simulating a cystic
mass (75) (Fig. 14.19).
Ultrasound findings in CCA are also non-specific, and intra-
hepatic mass lesions can appear hypo-, iso-, or hyperechoic to
liver parenchyma (82). Presumably, the hyperechoic nature is due to
the multiple tissue interfaces due to the fibrous stroma. Periductal-
infiltrating tumors may show thickening of the bile duct wall with
increased echogenicity.
MR imaging of intrahepatic mass-like CCA is also non-specific.
Typical lesions appear hypointense on T1-weighted and mildly
hyperintense on T2-weighted sequences. Varying with the underlying
histological nature, the tumors can appear to be of low central signal
intensity on T2 (if fibrous) or of high signal (if high mucin con-
tent or necrosis is present) (80). Following gadolinium-DTPA
administration, findings of contrast enhancement are similar to
that with iodine CT agents. Similar to CT, peripheral enhance-
ment with gadolinium chelate contrast material can initially be
seen, and delayed equilibrium enhancement can show dense con-
trast retention, aiding in detection and characterization of these
lesions (80,83).
(B)
229
 primary tumor evaluation and staging

(A) (B)
Figure 14.18 Intraductal cast-like cholangiocarcinoma in patient with recurrent pyogenic cholangitis (RPC). (A) Axial and (B) sagittal portal venous-phase CT shows
diffuse intrahepatic biliary duct dilatation with characteristic appearance of RPC. Soft tissue attenuation tumor (arrows) is seen contained diffusely but entirely within
the segment 6 and 7 duct system. Source: Case courtesy of Jae Hoon Lim, MD, Seoul, Korea.

(A) (B) (C)

Figure 14.19 Intraductal cholangiocarcinoma (CCA) with cystic duct expansion. (A) Portal venous-phase CT shows a large, near homogeneous cystic lesion (arrow) that
is contiguous with the left hepatic duct system. A flat papillary CCA tumor is evidenced by focal wall thickening (arrowhead). Marked mucin production into the ducts
creates the focal dilatation. (B) While the left hepatic duct system is most dilated (arrow), the marked mucin production produces distension of the entire biliary tree.
(C) Subsequent resected pathology specimen shows the papillary CCA (arrowhead) in the focally dilated cyst-like duct structure (arrow).

Extrahepatic Cholangiocarcinoma
The most common location for CCA is at the liver hilus, the
so-called Klatskin tumor, where up to 50% of all CCAs occur (84).
Less commonly they can be found distally, where they may be
difficult to differentiate clinically, pathologically, and at imaging
from pancreatic carcinoma. It is important to document the
location and extent of these tumors at imaging, as surgical treat-
ments will vary significantly depending on the tumor location,
because surgical treatments differ for tumors involving the duct
bifurcation, middle portions of the extraheptic duct, and the
periampullary/intrapancreatic region (84). Unlike intrahepatic
CCA, these tumors often cause biliary obstruction early in their
course and patients become symptomatic. Because these lesions
may be small, they are often missed on CT or ultrasound, although
the proximal biliary obstruction is often detected. Detection of
eccentric and occasionally focal thickening of the bile duct wall
just proximal to an obstructing mass can provide a clue to the
origin of the tumor as CCA rather than extrinsic metastatic
disease (Fig. 14.16) (85).
Masses pathologically can appear as three types:
• Most common is the stenosing or sclerosing variety,
resulting in strictures of the ducts at cholangiography,
usually with shouldered margins, although as with intra-
hepatic lesions, extrahepatic CCA can demonstrate
smooth tapered margins (Figs. 14.20 and 14.21)

230
 primary tumors of the liver and biliary tract

(A) (B) (C)

Figure 14.20 Cholangiocarcinoma (CCA) involving common hepatic duct (CHD) and extension into right hepatic ducts. (A) Cholangiogram shows proximal CHD
stricture typical of CCA with shouldered tumor margin (arrow). Proximally, the left hepatic duct (arrowhead) but not the second order branches of the left duct are
directly involved with tumor. The right hepatic ducts cannot be evaluated, so differentiating between a Bismuth 3b or Bismuth 4 lesion is not possible. (B) MRCP thick
slab image also shows the proximal CHD stricture (arrow) but, in addition, allows visualization of the right hepatic duct system, and obstruction is seen (arrowhead),
but it cannot be determined from this image whether this involves second order hepatic duct branches. (C) Axial T2-weighted fat-suppressed MR image shows the tumor
mass (white arrow) involving the right hepatic duct and obstructing multiple second and third order right hepatic ducts (black arrows) representing a Bismuth 4 lesion.
Metastatic subcapsular lesion is seen laterally. Abbreviation: P, portal vein.

(A) (B)
Figure 14.21 Hilar cholangiocarcinoma (CCA). (A) ERCP shows a central stricture (arrow) due to hilar CCA. The stricture has some tapered smooth margins (arrowhead),
and extends into the distal right and left hepatic ducts (Bismuth 2). Contrast the smooth tapered margin appearance with that of Figure 14.20. (B) Contrast CT examination
shows a small mass (white arrow) with direct extension into adjacent liver parenchyma (black arrow) and the portal vein (arrowhead), both indicative of advanced-stage
disease. Such extension cannot be predicted by cholangiography.

• Second most common is focal duct-wall thickening or Staging of Cholangiocarcinoma

nodule formation
• Least common is the papillary intraductal variety
(Fig. 14.17), comprising approximately 5% of tumors,
but affords the best prognosis, presumably due to a lower
incidence of adjacent tumor and spread being confined
to within the ducts
Intrahepatic cholangiocarcinoma is pathologically staged with the
same TNM system schema as HCC. Detection of satellite or remote
tumor nodules is an important aspect of tumor (T) stage as more
than half of patients with intrahepatic CCA will have satellite nod-
ules seen either at imaging or at pathological examination (82,86).
Delayed equilibrium contrast CT or MR contrast-enhanced imaging

231
 primary tumor evaluation and staging

Table 14.3 TNM Classification and Group Staging Criteria for Table 14.4 Bismuth Classification for Hilar and Perihilar
Extrahepatic Cholangiocarcinoma Biliary Strictures
Primary tumor (T) Type 1 Stricture limited to common hepatic duct
TX Primary tumor cannot be assessed Type 2 Stricture involves right and/or left hepatic duct but does not extend to
T0 No evidence of primary tumor second order hepatic duct branches
Tis Carcinoma in situ Type 3 Stricture involves second order branches of either right (3a) or left
T1 Tumor invades lamina propria or muscle layer (3b) hepatic ducts
T1a Tumor invades lamina propria Type 4 Stricture involves second order branches of both right and left hepatic
T1b Tumor invades muscle layer ducts
T2 Tumor invades perimuscular connective tissue; no extension
beyond serosa or into liver
T3 Tumor perforates the serosa (visceral peritoneum) and/or directly
invades the liver and/or one other adjacent organ or structure,
Apart from pathologic staging, patient treatment decisions are
such as the stomach, duodenum, colon, or pancreas, omentum based on clinical staging. Key to such decisions are
or extrahepatic bile ducts
T4 Tumor invades main portal vein or hepatic artery or invades • proximal and distal extent of biliary disease,
multiple extrahepatic organs or structures • potential vascular involvement (portal vein and hepatic
Regional lymph nodes (N) artery), and
NX
N0
Regional lymph nodes cannot be assessed
No regional lymph node metastasis
• distant metastases
N1 Regional lymph node metastasis Imaging plays the key role in this staging process. The most common
Distant metastasis (M) tumor locations in the porta hepatic and proximal CHD are staged
MX Distant metastasis cannot be assessed for extent using the widely accepted Bismuth classification (72,87)
M0 No distant metastasis
M1 Distant metastasis
(Table 14.4), which is based on determining the extent of biliary tract
Stage grouping involvement, most often determined by contrast or MR cholangiog-
Stage 0 Tis N0 M0 raphy, although occasionally axial CT or MR can better define the
Stage IA T1 N0 M0 extent of biliary duct involvement (Figs. 14.16, 14.20, and 14.21).
Stage IB T2 N0 M0
Stage IIA T3 N0 M0
Stage IIB T1 N1 M0 Extrahepatic/Extrabiliary Tumor Spread
T2 N1 M0 (Nodal and Distant Metastases)
T3 N1 M0 Little has been written specifically about the extrahepatic manifesta-
Stage III T4 Any N M0
tions and spread of intrahepatic CCA. Most of the studies detailing
Stage IV Any T Any N M1
the patterns of spread of CCA involve patients with hilar or proximal
common hepatic duct disease. In these central locations, direct inva-
sion of adjacent structures, in particular vascular encasement of
(discussed above) may be critical in defining an accurate tumor stage adjacent major vessels is a key component of staging to determine an
by detecting additional tumor nodules. Sclerosing varieties of this advanced, unresectable stage. Due to advanced surgical techniques,
tumor, particularly in patients with sclerosing cholangitis, may be hilar lesions that have local adjacent invasion may still, however, be
difficult to visualize tumor for detection or staging as it infiltrates resectable. It has been suggested that the following criteria be used to
along the bile ducts. The advantage of CT, ultrasound, and MR is suggest unresectability for local extension of tumor (88):
that they are able to detect masses beyond the duct lumen in patients
with primary sclerosing cholangitis (PSC) (Fig. 14.14). Cholangio- • Bilateral intrahepatic bile duct spread of tumor so
extensive as to preclude liver resection (typically Bismuth
graphically it can be very difficult to differentiate benign strictures
Classification IV)
typical of PSC from malignant ones.
Invasion of portal venous structures has been reported, usually • Tumor invasion of the main portal venous trunk
of small vessels and not appreciated on imaging studies. Occa- • Bilateral hepatic artery involvement
sionally, thrombi can be seen in hepatic or portal venous struc- • Portal vein branch involvement
tures on CT, MR, or ultrasound imaging (86), indicative of an Hepatic artery and portal vein involvement can best be docu-
advanced stage and not amenable to surgical cure. mented with CT, ultrasound, or MR allowing definition of tumor
The TNM staging criteria for extrahepatic biliary cancers and mass in relation to the vessels, and the techniques have generally
the resulting staging criteria are shown in Table 14.3. replaced the use of angiography for evaluating tumor extent.
Imaging cannot differentiate between disease limited to the duct Distant metastases denote an advanced stage and preclude sur-
wall and invading adjacent periductal connective tissue, and thus gical treatment. Like HCC, biliary tumors spread to lymph nodes
cannot differentiate T1 and T2 lesions. Invasion into adjacent along the hepatoduodenal ligament, and enlargement of these
structures (T3) results in a Stage IV tumor, as does the presence of nodes, in the absence of cirrhosis, should be treated as suspicious
distant metastases. These tumors spread via direct extension into for metastatic disease. Biliary tumors have a propensity to spread
adjacent organs (Fig. 14.21) as well as intraductal, blood-borne, to the portacaval lymph node chain (Fig. 14.22), and further down
peritoneal, and perineural extension. Multiplicity of lesions have to the anterior and posterior pancreaticoduodenal lymph node
been reported in 3% to 15% of cases (84), which may represent chain (89,90), occurring in about 50% of cases. In the authors’
either metastases or intraductal spread. experience, more distal lymph node metastases are uncommon.

232
 primary tumors of the liver and biliary tract
(A)
Figure 14.22 Biliary cystadenocarcinoma with lymph node metastases. (A, B) Contrast-enhanced CT scans at two levels show a large cystic lesion in the lateral segment,
with irregular septations and soft tissue enhancing mural nodules. Lymph node metastases are seen in the hepatoduodenal ligament (N) and in the portacaval space
(arrow); typical locations for spread of biliary tumors. Note that the portacaval lymph node is of similar attenuation to the cystic tumor. An incidental left adrenal
adenoma is present.
Metastatic spread via the bloodstream is less common than with
HCC (89). Remote tumor metastases (occasionally seen) include
disease to lung most commonly, and less commonly to bone, adre-
nal glands, and the peritoneum. Few series are large enough for
meaningful data on the relative incidence of distant metastases.
One series reported sites of tumor recurrence following curative
resection of hilar CCAs as follows (91):
• Lungs (71%)
• Liver (62%)
• Original tumor bed (42%)
Less common sites of involvement included:
• Bone (31%)
• Regional lymph nodes (20%)
• Peritoneum (16%)
CT can be an effective screen for disease in these regions and is
one of the main reasons why CT is the preferred staging tool over
ultrasound and MR.
Key Points: Cholangiocarcinoma
■ Fifty percent of all CCAs occur at the liver hilus—Klatskin
tumor
■ Intrahepatic CCAs may be well-defined or ill-defined tumors
on imaging
■ Imaging characteristics correlate with underlying tumor
stroma—fibrous, glandular, or mixed
■ Most often CCA shows no or only mild enhancement on
arterial-phase imaging
■ A characteristic CT and MR feature is delayed retention of
contrast medium during mid and late equilibrium
■ Extrahepatic CCAs cause biliary obstruction early
■ More than 50% of patients with intrahepatic CCA will have
satellite or remote intrahepatic tumor nodules
(B)
BILIARY CYSTADENOCARCINOMA
Biliary cystadenocarcinomas have a similar appearance and
morphology as their serous and mucinous counterparts in the
pancreas and ovary, and are seen predominately in women. Even
when benign these tumors have a propensity for malignant
degeneration, and any such tumors should be considered malig-
nant. They appear as unilocular or multilocular cystic masses,
with the typical anechoic and hypoechoic ultrasound appear-
ance and near water attenuation contents on CT, with peripheral
soft tissue nodularity and traversing septations (Fig. 14.22). The
greater the presence of papillary excrescences, soft tissue nodu-
larity, or septations, the more likely is the lesion to be malignant,
although this is a moot point as it has been shown that benign
lesions can undergo malignant degeneration (92). The cystic
areas at T1-weighted imaging are of variable signal intensity,
including hyperintense to liver, presumably due to proteinaceous
content (93). Coarse calcifications can be seen at ultrasound and
CT in both cystadenoma and cystadenocarcinoma and are not a
helpful differentiating feature. These lesions are usually intrahe-
patic in location, although rarely can occur in the porta hepatis
from the large central ducts. The differential diagnosis for these
lesions includes:
• Complicated hepatic cysts
• Liver abscesses
• Cystic metastases
• Hydatid cysts
When unilocular, they can be difficult to differentiate from large
hepatic cysts.
No large series has been published to provide data on incidence
and locations of metastatic disease. They usually appear as solitary
liver lesions but a search for the usual locations of metastatic
spread, such as the lungs and regional lymph nodes, should be
made (Fig. 14.21).
233
 primary tumor evaluation and staging
ANGIOSARCOMA
Hepatic angiosarcoma is a rare tumor derived from endothelial cells.
There is a strong association with carcinogens such as vinyl chloride
and Thorotrast, and it is also seen in patients with hemochromato-
sis, although in the majority of patients no known exposure to toxic
agents exists (94). Peak incidence of the tumor occurs in the fifth
through to the seventh decades with a male preponderance.
Pathologically angiosarcoma may appear as a large solitary mass
or with multiple tumor nodules of varying size (95). The tumors
contain blood-filled cavities and areas of internal hemorrhage
with fibrosis and hemosiderin deposition in the solid portions of
the tumor (61). Patients with angiosarcoma have a poor prognosis
with rapid growth of tumor; median survival being 5.5 months in
one review of 70 patients (94), and only 3% living longer than two
years. A striking clinical feature of angiosarcoma is the high inci-
dence of thrombocytopenia (up to 62%) with associated prob-
lems of hemorrhage (94). Cause of death in these patients often
relates to liver failure in almost half of the patients, and from hem-
orrhage in 30% (94). Distant metastases occur in about 50% of
patients (89), most common in the lungs and bone, typical of
bloodstream dissemination.
Computed Tomography
The imaging appearances of angiosarcoma are most often non-
specific, being hypoattenuating on unenhanced CT, and heteroge-
neous on postcontrast images. Tumor appearances can range from a
solid large tumor to numerous small lesions. The tumor often is char-
acterized by vascular channels that can create sinusoidal spaces that
can simulate cavernous hemangiomas. While potentially problematic
in that contrast enhancement characteristics of some angiosarcoma
can therefore rarely simulate that of benign hemangioma (Fig. 14.23),
in most cases the tumoral enhancement does not follow characteris-
tics of bloodpool at all phases (95,96). While some lesions may very
closely mimick the contrast enhancement characteristics of heman-
gioma, these well differentiated tumors are usually multiple in these
patients, and many of the lesions do not enhance similarly. The large
number of such lesions and atypical appearances for hemangioma of
many of the lesions are the key to avoid a mistaken diagnosis.
(A)
Figure 14.23 Diffuse multifocal angiosarcoma. (A) Arterial-phase CT scans from two levels show flash enhancement of a small nodule (arrowhead) and subtle enhance-
ment of a larger lesion (arrow); (B) Portal venous-phase CT scans at the same levels show these two lesions with more striking enhancement, as well as heterogeneous foci
of enhancement throughout the liver representing additional foci of tumor. In many respects, these enhancing tumor foci simulate hemangioma with near homogeneous
enhancement throughout the lesions.
234
Magnetic Resonance Imaging
On MR imaging, these lesions appear hypointense on T1-weighted
images, and moderate or high signal intensity on T2-weighted
images with a heterogeneous appearance. Occasionally fluid-fluid
levels, typical of hemorrhage can be seen (95). Similar contrast
enhancement effects with Gd-DTPA can be expected as with iodine-
enhanced CT. The combination of high signal intensity T2-weighted
characteristics and the occasional lesion that can show peripheral
discontinuous and progressive enhancement with gadolinium che-
late-based contrast can, similar to CT, simulate a diagnosis of benign
hemangioma. As with CT, there most often will be large numbers of
lesions, and many of which will not follow such enhancement
patterns that the diagnosis of hemangiomas can be excluded.
Documentation of metastatic disease has been limited in this rare
tumor in part due to the poor prognosis and rapid demise of patients.
In the review by Locker et al. (94) only 10% of patients had metastases
documented ante mortem, although this report is older and before
the widespread use of CT. Metastases in this series were greatest to
bone, with additional sites reported to the skin and pleura.
Key Points: Angiosarcoma
■ Hepatic angiosarcoma is a rare tumor
■ The peak incidence is in the fifth to seventh decades with a
male preponderance
■ There is a high incidence of thrombocytopenia in angiosarcoma
■ Imaging appearances are non-specific but most tumors are
heterogeneous on postcontrast CT and MR
■ Rarely can the tumoral enhancement patterns mimic that of
hemangioma
EPITHELIOID HEMANGIOENDOTHELIOMA
Epithelioid hemangioendothelioma (EHE) is a rare tumor of vas-
cular origin that occurs in a variety of organs, including the liver.
This adult tumor is not to be confused with infantile hemangioen-
dothelioma, a very different tumor. Soft tissue EHE tumors may
occur in the bone and lung as well and metastasize to the liver, and
(B)
 primary tumors of the liver and biliary tract
Figure 14.24 Epithelioid hemangioendothelioma (EHE). Contrast-enhanced CT
scan (portal venous-phase) shows the characteristic appearance of EHE with
numerous peripheral liver lesions becoming confluent. Capsular retraction (arrow-
head) over one of the lesions is a common finding, as are the concentric layers of
contrast enhancement seen in some of the lesions, which can help differentiate
these from metastatic lesions.
it can occur as a primary tumor in the liver. Liver primary tumors
are characterized by the presence of multiple, peripheral lesions
often growing slowly to become confluent masses. Histologically,
these are solid tumors composed of a fibrotic center and a cellular
hypervascular periphery. The tumor is one of middle-age, with the
average age ranging from 39 to 45 years (97).
Typical imaging findings include visualizing the peripheral
presence of the lesions along with overlying capsular retraction,
attributed to fibrosis and scarring within the tumor (97). The CT
attenuation or MR signal intensity characteristics are non-specific
and mimic other tumors, although rare calcifications may be seen
(97). Contrast enhancement with CT or MR often shows a central
zone of minimal or no enhancement and peripheral zones of
marked enhancement occasionally showing concentric zones of
marked enhancement (Fig. 14.24). The lesions often become con-
fluent and may grow large enough to replace nearly the entire liver
parenchyma. As this tumor can have a prolonged course, as the
liver parenchyma becomes replaced with large bulky tumor, sig-
nificant hypertrophy of normal regions of liver parenchyma can
occur (97). These patients may have symptoms of liver failure that
can be relieved by liver transplantation, which can also be a
successful treatment for localized tumor (61).
Reports of treatment relating to this type of tumor are limited;
however, the prognosis appears to be better than for HCC or
angiosarcoma. Ishak et al. (98) reported on 32 cases and found
extrahepatic metastases involving lungs, lymph nodes, spleen, and
bone in 28% of patients. The most common site of metastases, in
the authors’ experience, is in the lungs, easily visible on chest CT.
Key Points: Epithelioid Hemangioendothelioma
■ Epithelioid hemangioendothelioma is a rare vascular tumor
■ Liver primary tumors are characterized by multiple peripheral
lesions
■ CT and MRI characteristics are non-specific, mimicking
other tumors
LYMPHOMA
Hepatic lymphoma is most often seen as a secondary tumor in
patients with either non-Hodgkin’s or rarely Hodgkin’s disease. It
rarely can be seen as a primary liver tumor and is usually associ-
ated with an immunocompromised state such as AIDS, or post-
transplantation with immunosuppression therapy. Primary and
secondary hepatic lymphoma have a similar appearance and dif-
ferentiating between them depends on documenting the presence
of lymphoma elsewhere in the body.
Pathologically the lesions can be solid or cystic, focal, or diffusely
infiltrative (61), with varying imaging appearances. CT, MR, or
ultrasound show focal lesions with a non-specific appearance
similar to many other neoplastic lesions, although they are usually
large and well-defined with sharp margins. Infiltrating forms of
the tumor can be difficult to detect with any imaging modality,
although hepatomegaly, if present, may be a clue.
GALLBLADDER CARCINOMA
Gallbladder carcinoma is the sixth most common gastrointes-
tinal malignancy in the United States (99), and the most com-
mon malignancy of the biliary tract. It usually occurs in the sixth
decade or later and is more common in women than men, 3:1.
Risk factors include cholelithiasis in 65% to 95% of patients, pri-
mary sclerosing cholangitis, porcelain gallbladder, choledochal
cyst, and certain chronic infections such as Opisthorchis viverrini
and Salmonella typhii. Any of these may cause chronic biliary
stasis and inflammation that can lead to mucosal metaplastic
changes, a precursor to malignancy. Adenocarcinoma is the cell
type in 90% of patients, with other epithelial neoplasms such as
adenosquamous, squamous, and undifferentiated carinomas
accounting for most of the remainder (100). Metastases from
intrabiliary seeding from cholangiocarcinoma or hematogenous
dissemination from systemic malignancies such as melanoma
occur less frequently. The best prognosis occurs with papillary
adenocarcinomas, which tend to project into the lumen of the
gallbladder before invading its wall (101), or when an early stage
of gallbladder carcinoma is detected incidentally at pathology in
1% of cholecystectomy patients (102). Clinical symptoms such
as chronic abdominal pain, weight loss, and anorexia are non-
specific and can be confused with cholecystitis, cholelithiasis,
and biliary dyskinesia. Classic physical examination signs of
jaundice, palpable mass, and hepatomegaly tend to occur rela-
tively late. Unfortunately, diagnosis occurs at late stages in most
patients with a five-year prognosis of 5% and median survival of
six months from diagnosis (101).
Imaging Appearances
As with its clinical presentation, the imaging appearance of
gallbladder carcinoma can overlap with several other right upper
quadrant disease processes. Cholecystitis, benign gallbladder
polyps, adenomyomatosis, and even biliary sludge may simulate
gallbladder carcinoma. Further complicating diagnosis, 60% to
90% of gallbladder carcinoma patients have background chronic
cholecystitis (103). Ultrasound is often employed as the first
imaging modality in cases of suspected gallbladder disease due
235
 primary tumor evaluation and staging
Figure 14.25 Gallbladder carcinoma with direct invasion of the liver at ultrasound.
Ultrasound shows large hypoechoic mass (*) with entrapment of gallstones (thin
arrow) that confirms gallbladder location. Hypoechoic lesion in hepatic paren-
chyma (bold arrows) suggests direct invasion, confirmed at biopsy.
to relatively low cost and widespread availability, although com-
puted tomography is superior to ultrasound, MR and, obviously,
cholangiography for staging.
PET-CT has a promising role in the detection of unsuspected
metastases, which may alter staging and therapy (104), although
has been slow to gain acceptance because of high cost and limited
availability. The imaging appearance of gallbladder carcinoma at
first detection by any of these modalities has usually been mor-
phologically categorized and reported to occur in decreasing fre-
quency as:
• A large mass occupying most or all of the gallbladder
lumen
• Asymmetric gallbladder wall thickening (focal or diffuse)
• A polypoid mass projecting into the gallbladder lumen
• Diffuse symmetric thickening of the gallbladder wall
(infrequent)
The differential diagnosis of a mass filling or nearly replacing the
gallbladder lumen includes other malignancies that have invaded
the gallbladder fossa such as hepatocellular carcinoma, cholangio-
carcinoma, and metastatic disease, although entrapment of gall-
stones or porcelain segments of gallbladder wall if present helps
distinguish gallbladder carcinoma (Fig. 14.25). In cases of smaller
primary lesions, enlarged regional nodes from gallbladder carci-
noma metastasis can be confused with primary pancreatic and
duodenal malignancies.
Computed Tomography
The presence of a gallbladder mass, direct invasion of the liver with
a bulging contour of the anterior surface of the medial hepatic seg-
ment, and lymphadenopathy are the most specific CT findings
gallbladder carcinoma (105). Biliary obstruction at the level of the
236
Figure 14.26 Gallbladder carcinoma with direct invasion of the liver at CT. Portal
venous-phase contrast CT shows polypoid gallbladder carcinoma (thin arrow)
with direct liver invasion (bold arrow), the most common pathway of metastasis.
porta hepatis may be present. Diffuse or focal gallbladder wall
thickening (Fig. 14.26), stranded pericholecystic fat, thickening of
the hepatoduodenal ligament, and colonic or duodenal wall thick-
ening are nonspecific findings that may be seen in gallbladder car-
cinoma and other diseases including cholecystitis. Primary
gallbladder carcinoma tumors with direct and peripheral liver
metastases usually appear less dense than liver on noncontrast
enhanced images, but may show variable enhancement after IV
contrast administration. At contrast-enhanced CT or MR, intense
irregular enhancement may occur at the periphery of large primary
gallbladder cancer lesions during arterial phases. Contrast enhance-
ment may be retained within fibrous stromal components during
portal venous and delayed phases, aiding differentiation from large
central hepatocellular carcinomas, which tend to wash out contrast
(106). Focal or diffuse areas of gallbladder wall thickening may
enhance equal to or greater than the liver in up to 47% of gallblad-
der carcinoma patients; conversely, the lack of enhancement within
hypodense nodules comprising more than 60% of the gallbladder
wall helps distinguish the rare xanthogranulomatous cholecystitis
from carcinoma (107).
Ultrasound
Gallbladder carcinomas may appear by ultrasound as a large
mass replacing or surrounding the gallbladder in 42%, a mass
protruding into the gallbladder lumen in 23% (Fig. 14.25), or as
diffuse asymmetric wall thickening in 15% (108). Tumors
replacing the gallbladder lumen frequently have a heteroge-
neous echotexture from various degrees of tumor necrosis,
which aid in their distinction from mere sludge filling the gall-
bladder lumen. Lack of encapsulation and surface lobulations
or an irregular periphery may make margins of the primary
tumor lesions inseparable from direct invasion of the liver (109).
 primary tumors of the liver and biliary tract
(A)
Figure 14.27 Gallbladder carcinoma at MR. (A) Axial T2-weighted MR shows the gallbladder carcinoma as moderately high-signal intensity diffusely thickening the
gallbladder wall (arrows). (B) Image slightly lower shows the gallbladder wall thickening (arrows) and a gallstone centrally in gallbladder lumen appearing as a signal
void (arrowhead).
Gallstones, porcelain gallbladder, or tumoral calcifications may
be present in decreasing frequency and appear as echogenic foci
with acoustic shadowing. Adenomyomatosis, a benign prolifera-
tion of glandular and smooth muscle elements in the gallbladder
wall, can manifest as focal or diffuse thickening that simulates
malignancy. Shadowing caused by gallstones or porcelain gall-
bladders may also obscure carcinoma, while biliary sludge can
mimic a mass. Varying the scanning angle, decubitus views of
patient, and using a higher frequency probe may help eliminate
some of these pitfalls of ultrasound. In inoperable cases, ultra-
sound may be used for percutaneous image-guided biopsy of
primary gallbladder lesions or hepatic metastases to establish a
cytologic diagnosis.
MR Imaging
Primary gallbladder carcinomas typically show prolongation of
T1 and T2 relaxation times (110), while metastases often behave
similarly (111). The morphologic appearances of gallbladder car-
cinoma at MR are similar to those seen at CT—either focal wall
thickening, diffuse wall thickening (Fig. 14.27), or complete
replacement of gallbladder lumen by tumor. The signal character-
istics of the tumors are nonspecific to other soft tissues on T1
images, and on T2-weighted images appear of higher signal inten-
sity than other soft tissues or adjacent liver, but less than that of
fluid in the gallbladder lumen (Fig. 14.27). Gadolinium adminis-
tration may help distinguish carcinomas from chronic cholecysti-
tis during early-phase images as carcinomas may show irregular
areas of enhancement, while chronic cholecystitis usually shows
more uniform, smoothly delineated enhancement within a dif-
fusely thickened gallbladder wall (112). However, carcinomas may
become obscured or less conspicuous during late or delayed
phases when noncancerous portions of the gallbladder wall can
also enhance.
The ability of MR to provide cholangiographic reconstruc-
tions can demonstrate well the extent of tumoral extension as
(B)
it frequently dissects along the hepatic hilum and causes biliary
obstruction. Although an “all-in-one” protocol supplementing MR
imaging with cholangiographic (MRC) and contrast-enhanced
arterial and portal phase three-dimensional angiographic (MRA)
images may be up to 100% sensitive for bile duct and vascular
invasion, sensitivity falls to 67% for hepatic invasion and 56%
for lymph node metastases (113). MR imaging may be useful in
distinguishing gallbladder carcinoma from benign adenomyo-
matosis, which can have a focal, segmental, or diffuse distribu-
tion similar to malignancies. Breath-holding, T2-weighted pulse
sequences reportedly show the Rokitansky-Aschoff sinuses of
adenomyomatosis best, at times as a hyperintense “pearl neck-
lace” appearance within the gallbladder wall (114). Unenhanced
foci in the gallbladder wall on contrast-enhanced, T1-weighted
pulse sequences may also correspond to sinuses or mural
stones (115).
Other Imaging Modalities
At PET, an intense accumulation of 18F-FDG in the region of the
gallbladder suggests malignancy (Fig.14.28), although lacks speci-
ficity in distinguishing primary GBC from other malignant lesions,
as well as certain benign inflammatory lesions that can accumulate
18
F-FDG and result in false positive interpretations (116).
Gallbladder carcinomas may be apparent at cholangiography as
intraluminal filling defects in descending frequency in the gall-
bladder fundus, body, and neck. However, specificity is very lim-
ited as benign polyps, adenomyomatosis, sludge, and immobile
gallstones can appear similarly. Concomitant strictures of the
extrahepatic common duct or confluence of right and left ducts
help support a diagnosis of malignancy. Fluoroscopy or plain
radiographs of the abdomen in gallbladder carcinoma patients
may identify right upper quadrant calcifications that represent
gallstones, porcelain gallbladder, or tumoral calcifications in
decreasing order. Pneumobilia or unusual gas patterns may be
present after fistulization to or invasion of bowel.
237
 primary tumor evaluation and staging

GB

(A) (B)
Figure 14.28 Gallbladder carcinoma at CT and PET. (A) Contrast-enhanced CT shows asymmetric gallbladder wall thickening (*) with adjacent liver lesions (arrows).
(B) PET-CT image at same anatomic level shows intense fluorine-18 labelled fluoro-deoxyglucose (18F-FDG) uptake within gallbladder (GB) and extensive hepatic
metastases (H), underestimated by CT (A). Lack of uptake (arrow) denotes necrotic portion of tumor. Percutaneous biopsy confirmed T3 gallbladder carcinoma.

Staging Table 14.5 TNM Classification and Group Staging Criteria

The TNM classification and group staging criteria for primary gall- for Gallbladder Carcinoma
bladder carcinomas are shown in Table 14.5 (117) and Figure 14.29.
Primary tumor (T)
Anatomically the gallbladder lacks a muscularis mucosa and a sub-
TX Primary tumor cannot be assessed
mucosa, which facilitates its rapid spread and advanced stage at the
T0 No evidence of primary tumor
time of diagnosis. T1 lesions are confined to the lamina propria Tis Carcinoma in situ
(T1a) or muscle layer (T1b), whereas T2 lesions have invaded but T1 Tumor invades lamina propria or muscle layer
not surpassed the perimuscular connective tissue or serosa. When T1a Tumor invades lamina propria
tumor perforates the serosa and/or directly invades the liver and/or T1b Tumor invades muscle layer
invades one other adjacent organ or structure such as the duode- T2 Tumor invades perimuscular connective tissue; no extension
num, stomach, or pancreas, they are classified as T3 lesions. Venous beyond serosa or into liver
drainage of the gallbladder occurs through the liver parenchyma T3 Tumor perforates the serosa (visceral peritoneum) and/or directly
into the hepatic veins, which accounts for the high incidence of invades the liver and/or one other adjacent organ or structure,
direct invasion of the liver at the gallbladder margins. Most series such as the stomach, duodenum, colon, or pancreas, omentum or
extrahepatic bile ducts
cite direct hepatic invasion as the most common pathway of spread,
T4 Tumor invades main portal vein or hepatic artery or invades
followed by nodal metastasis (100,118). When tumor invades the multiple extrahepatic organs or structures
main portal vein or hepatic artery or invades multiple extrahepatic Regional lymph nodes (N)
organs or structures, it is classified as T4. Lymphatic drainage from NX Regional lymph nodes cannot be assessed
gallbladder carcinomas occurs first to cystic, pericholedochal, hilar, N0 No regional lymph node metastasis
periduodenal, peripancreatic, and superior mesenteric nodes, which N1 Regional lymph node metastasis
are considered regional or N1 nodes. Biliary obstruction may result Distant metastasis (M)
from enlarged metastatic nodes either encasing or directly invading MX Distant metastasis cannot be assessed
the common hepatic or common bile duct. M0 No distant metastasis
Portocaval, interaortocaval nodes, and more distant nodes are M1 Distant metastasis
considered the terminal lymphatic drainage from the gallbladder, Stage grouping
and hence are classified as distant metastasis, or M1 tumor. Stage 0 Tis N0 M0
Gallbladder carcinoma can also disseminate via intraductal spread Stage IA T1 N0 M0
along the cystic duct, hematogenous and neural pathways, and Stage IB T2 N0 M0
intraperitoneal “drop” metastases (119). T1 or T2 primary lesions Stage IIA T3 N0 M0
Stage IIB T1 N1 M0
without nodal metastasis are classified as Stage IA or IB disease,
T2 N1 M0
respectively. T3 lesions without nodal spread are Stage IIA. T1, T2,
T3 N1 M0
or T3 lesions with N1 lymph node involvement define Stage IIB. A
Stage III T4 Any N M0
T4 lesion without distant metastasis is considered Stage III. Any
Stage IV Any T Any N M1
patient with distant disease automatically becomes Stage IV.

238
 primary tumors of the liver and biliary tract

T1a T1b T2

Mucosa
Lamina propria
Muscle layer
Perimuscular
connective tissue
Serosa

T3 T3

T4 T4

(A)

N1 N2

(B)
Figure 14.29 Staging gallbladder cancer in (A) primary tumor (T) and (B) lymph nodes (N).

239
 primary tumor evaluation and staging

Accuracies of up to 85% have been reported using multidetec-

■ CT and MR appearances of HCC are variable depending on
tor CT (MDCT) to determine T-staging and predict resectability
tumor size
through its ability to delineate hepatic and vascular invasion,
■ Arterial phase imaging (CT, MR, or US) is essential for
lymphadenopathy, and distant metastases (120,121).
accurate HCC tumor detection and staging
Multiplanar and three-dimensional volume-rendered recon-
■ Equilibrium phase imaging is critical for characterization of
struction images may also be generated from MDCT to provide a
HCC tumor at CT and MR
vascular “road map” and coronal oblique images useful for surgical
■ Treatment of HCC includes resection, transplantation,
planning (120). As with other gastrointestinal malignancies, CT
chemoembolization, and thermal ablation
may be unreliable in demonstrating metastasis to the omentum,
■ Fibrolamellar hepatocellular carcinoma (Fl-HCC) is reported
bowel, and abdominal wall (100). Prospective studies comparing
to have a better prognosis than other types of HCC
MDCT, PET-CT, and MR in their ability to diagnose and stage
■ As with HCC, dynamic-contrast arterial-phase imaging is
gallbladder carcinoma have not been performed to date.
mandatory for Fl-HCC tumor staging
■ Cholangiocarcinoma (CCA) may be intrahepatic of
extrahepatic
Therapy
■ The most common location for CCA is the liver hilus—
Cholecystectomy and extended resection (partial resection of
Klatskin tumor
hepatic segments 4b and 5 bordering the gallbladder fossa and en
■ Cholangiocarcinoma often shows delayed retention of
bloc nodal dissection) may be curative for patients with Stage I
contrast medium during mid and late equilibrium phase on
gallbladder cancer (119,122). Patients with Stage IIA or IIB dis-
CT and MR contrast-enhanced imaging
ease may still undergo exploration and subsequent resection if
■ Detection of satellite or remote tumor nodules in CCA is an
metastatic disease is confined to regional nodes and adequate
important aspect of tumor staging
hepatic margins can be obtained as five-year survival rates of 45%
■ Biliary cyst adenocarcinomas are more common in women.
to 60% have been reported, although overall prognosis is only
They appear as unilocular or multilocular cystic masses
13% (123,124). External beam radiotherapy and systemic chemo-
■ Angiosarcoma and epithelioid hemangioendothleioma
therapy have improved survival in patients with negative resection
(EHE) are rare vascular tumors most often appearing with
margins, while patients with positive microscopic margins or
nonspecific findings on CT and MR. Occasionally characteristic
residual disease show no added benefit from chemotherapy and
findings of enhancement patterns (angiosarcoma) or
are offered adjuvant radiotherapy alone (125).
overlying capsular retraction (EHE) can be seen
■ Gallbladder carcinoma is the most common malignancy
Key Points: Gallbladder Carcinoma of the biliary tract with a five-year survival rate of 5%; spread
is most commonly directly into the liver
■ Gallbladder carcinoma is the most common malignancy of
■ Accurate gallbladder carcinoma staging is vital when
the biliary tract worldwide
radical surgery is contemplated for disease confined to
■ Associations include gallstones, porcelain gallbladder, and
regional nodes and hepatic resection is possible
other causes of chronic biliary stasis and inflammation
■ Gallbladder carcinoma is best staged using CT with acceptable
■ Peak incidence is in the elderly (sixth decade or later) with a
positive predictive values but poorer sensitivities
female predominance
■ Prognosis is poor as clinical presentation may be vague or
non-specific, delaying the diagnosis
■ Morphologies include a large mass replacing most or all of REFERENCES
the gallbladder lumen, focal or diffuse asymmetric gallbladder
wall thickening, polypoid lesions, and least often symmetric 1. Cabassa P, Donato F, Simeone F, Grazioli L, Romanini L.
wall thickening Radiofrequency ablation of hepatocellular carcinoma: long-
■ Direct invasion of the liver and lymphadenopathy are common term experience with expandable needle electrodes. Am J
pathways of spread Roentgenol 2006; 186: S316–S321.
■ All modalities lack sensitivity in detecting early stage tumors 2. Livraghi T, Giorgio A, Marin G, et al. Hepatocellular car-
■ MDCT is the most reliable modality for staging cinoma and cirrhosis in 746 patients: long-term results of
percutaneous ethanol injection. Radiology 1995; 197:
101–8.
Summary 3. Livraghi T, Goldberg SN, Lazzaroni S, et al. Hepatocellular
carcinoma: radio-frequency ablation of medium and large
■ Hepatocellular carcinoma (HCC) accounts for one million
lesions. Radiology 2000; 214: 761–8.
deaths per year worldwide
4. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation
■ Ninety percent of patients with HCC have underlying
for the treatment of small hepatocellular carcinomas in
cirrhosis or viral hepatitis
patients with cirrhosis. N Engl J Med 1996; 334: 693–9.
■ Although AFP levels are raised in most patients with large
5. Nakamura H, Hashimoto T, Oi H, Sawada S. Transcatheter
tumors, approximately one third of patients with small HCC
oily chemoembolization of hepatocellular carcinoma.
tumors have normal levels.
Radiology 1989; 170: 783–6.

240
 primary tumors of the liver and biliary tract
6. Hodgson HJF. Primary hepatocellular carcinoma. In:
Blumgart LH, ed. Surgery of the Liver and Biliary Tract.
Edinburgh: Churchill Livingstone, 1994: 1341–7.
7. Shinagawa T, Ohto M, Kimura K, et al. Diagnosis and clinical
features of small hepatocellular carcinoma with emphasis on
the utility of real-time ultrasonography. Gastroenterology
1984; 86: 495–502.
8. Peterson MS, Baron RL, Marsh JW Jr, et al. Pretransplanta-
tion surveillance for possible hepatocellular carcinoma in
patients with cirrhosis: epidemiology and CT-based tumour
detection rate in 430 cases with surgical pathologic correlation.
Radiology 2000; 217: 743–9.
9. Bruix J, Sherman M. Management of hepatocellular carci-
noma. Hepatology 2005; 42: 1208–36.
10. Liver transplant candidates with hepatocellular carcinoma.
United Network for Organ Sharing (UNOS) Policies 3.6.4.4
Accessed June 28, 2002. [Available at: http://wwwunosorg/
policiesandbylaws/policies/doc/policy_8doc].
11. Nicolau C, Catalá V, Vilana R, et al. Evaluation of hepatocellu-
lar carcinoma using SonoVue, a second generation ultrasound
contrast agent: correlation with cellular differentiation. Eur
Radiol 2004; 14: 1092–9.
12. Stevens WR, Gulino SP, Batts KP, Stephens DH, Johnson CD.
Mosaic pattern of hepatocellular carcinoma: histologic basis
for a characteristic CT appearance. J Comput Assist Tomogr
1996; 20: 337–42.
13. Freeny PC, Baron RL, Teefey SA. Hepatocellular carcinoma:
reduced frequency of typical findings with dynamic contrast-
enhanced CT in a non-Asian population. Radiology 1992;
182: 143–8.
14. Stevens WR, Johnson CD, Stephens DH, Batts KP. CT find-
ings in hepatocellular carcinoma: correlation of tumour
characteristics with causative factors, tumour size, and histo-
logic tumour grade. Radiology 1994; 191: 531–7.
15. Lim JH, Choi D, Kim SH, et al. Detection of hepatocellular
carcinoma: value of adding delayed phase imaging to dual-
phase helical CT. Am J Roentgenol 2002; 179: 67–73.
16. Iannaccone R, Laghi A, Catalano C, et al. Hepatocellular
carcinoma: role of unenhanced and delayed phase multi-
detector row helical CT in patients with cirrhosis. Radiology
2005; 234: 460–7.
17. Schima W, Hammerstingl R, Catalano C, et al. Quadruple-
phase MDCT of the liver in patients with suspected hepato-
cellular carcinoma: effect of contrast material flow rate. Am J
Roentgenol 2006; 186: 1571–9.
18. Kim MJ, Choi JY, Lim JS, et al. Optimal scan window for
detection of hypervascular hepatocellular carcinomas
during MDCT examination. Am J Roentgenol 2006; 187:
198–206.
19. Ichikawa T, Nakajima H, Nanbu A, Hori M, Araki T. Effect of
injection rate of contrast material on CT of hepatocellular
carcinoma. Am J Roentgenol 2006; 186: 1413–18.
20. Peterson MS, Baron RL, Murakami T. Hepatic malignancies:
usefulness of acquisition of multiple arterial and portal
venous phase images at dynamic gadolinium-enhanced MR
imaging. Radiology 1996; 201: 337–45.
21. Peterson MS, Baron RL. Radiologic diagnosis of hepato-
cellular carcinoma. Clin Liver Dis 2001; 5: 123–44.
22. Yamashita Y, Mitsuzaki K, Yi T, et al. Small hepatocellular
carcinoma in patients with chronic liver damage: prospective
comparison of detection with dynamic MR imaging and
helical CT of the whole liver. Radiology 1996; 200: 79–84.
23. Greene FL, Page DL, Fleming ID, et al. Liver (including intra-
hepatic bile ducts). In: AJCC Cancer Staging Manual, 6th edn.
New York: Springer-Verlag, 2002: 131–8.
24. Dodd GD, Baron RL, Oliver JH 3rd, Federle MP, Baumgartel
PB. Enlarged abdominal lymph nodes in end-stage cirrhosis:
CT- histopathologic correlation in 507 patients. Radiology
1997; 203: 127–30.
25. Ferris JV, Baron RL, Marsh JW Jr, et al. Recurrent hepatocellular
carcinoma after liver transplantation: spectrum of CT find-
ings and recurrence patterns. Radiology 1996; 198: 233–8.
26. Baron R, Oliver J 3rd, Dodd G 3rd, et al. Hepatocellular
carcinoma: evaluation with biphasic, contrast-enhanced,
helical CT. Radiology 1996; 199: 505–11.
27. Bhartia B, Ward J, Guthrie JA, Robinson PJ. Hepatocellular
carcinoma in cirrhotic livers: double-contrast thin-section
MR imaging with pathologic correlation of explanted tissue.
Am J Roentgenol 2003; 180: 577–84.
28. Holland AE, Hecht EM, Hahn WY, et al. Importance of small
(< or = 20-mm) enhancing lesions seen only during the hepatic
arterial phase at MR imaging of the cirrhotic liver: evaluation
and comparison with whole explanted liver. Radiology 2005;
237: 938–44.
29. Lee KH, O’Malley ME, Haider MA, Hanbidge A. Triple-phase
MDCT of hepatocellular carcinoma. Am J Roentgenol 2004;
182: 643–9.
30. Hayashida M, Ito K, Fujita T, et al. Small hepatocellular carci-
nomas in cirrhosis: differences in contrast enhancement
effects between helical CT and MR imaging during multipha-
sic dynamic imaging. Magn Reson Imaging 2008; 26: 65–71.
31. Takayasu K, Moriyama N, Muramatsu Y, et al. The diagnosis
of small hepatocellular carcinomas: efficacy of various imag-
ing procedures in 100 patients. Am J Roentgenol 1990; 155:
49–54.
32. Krinsky GA, Lee VS, Theise ND, et al. Hepatocellular carcinoma
and dysplastic nodules in patients with cirrhosis: prospective
diagnosis with MR imaging and explantation correlation.
Radiology 2001; 219: 445–54.
33. Dodd GD, Miller WJ, Baron RL, Skolnick ML, Campbell
WL. Detection of malignant tumors in end-stage cirrhotic
livers: efficacy of sonography as a screening technique. Am J
Roentgenol 1992; 159: 727–33.
34. Bennett GL, Krinsky GA, Abitbol RJ, et al. Sonographic detec-
tion of hepatocellular carcinoma and dysplastic nodules in
cirrhosis: correlation of pretransplantation sonography and
liver explant pathology in 200 patients. Am J Roentgenol
2002; 179: 75–80.
35. Kim CK, Lim JH, Lee WJ. Detection of hepatocellular carci-
nomas and dysplastic nodules in cirrhotic liver: accuracy of
ultrasonography in transplant patients. J Ultrasound Med
2001; 20: 99–104.
36. Liu WC, Lim JH, Park CK, et al. Poor sensitivity of sonogra-
phy in detection of hepatocellular carcinoma in advanced
liver cirrhosis: accuracy of pretransplantation sonography in
118 patients. Eur Radiol 2003; 13: 1693–8.
241
 primary tumor evaluation and staging
37. Oliver JH 3rd, Baron RL, Federle MP, Rockette HE Jr. Detect-
ing hepatocellular carcinoma: value of unenhanced or arterial
phase CT imaging or both used in conjunction with conventional
portal venous phase contrast-enhanced CT imaging. Am J
Roentgenol 1996; 167: 71–7.
38. Mitsuzaki K, Yamashita Y, Ogata I, et al. Multiple-phase heli-
cal CT of the liver for detecting small hepatomas in patients
with liver cirrhosis: contrast-injection protocol and optimal
timing. Am J Roentgenol 1996; 167: 753–7.
39. Monzawa S, Ichikawa T, Nakajima H, et al. Dynamic CT for
detecting small hepatocellular carcinoma: usefulness of
delayed phase imaging. Am J Roentgenol 2007; 188:
147–53.
40. Murakami T, Kim T, Takamura M, et al. Hypervascular
hepatocellular carcinoma: detection with double arterial
phase multi-detector row helical CT. Radiology 2001; 218:
763–7.
41. Laghi A, Iannaccone R, Rossi P, et al. Hepatocellular carci-
noma: detection with triple-phase multi-detector row helical
CT in patients with chronic hepatitis. Radiology 2003; 226:
543–9.
42. Baron RL. Understanding and optimizing use of contrast
material for CT of the liver. Am J Roentgenol 1994; 163:
323–31.
43. Oliver JH, Baron RL, Carr BI. CT imaging of hepatocellular
carcinoma: CT-arteriography versus triphasic helical contrast
CT. Radiology 1997; 205(P): 144.
44. Kanematsu M, Hoshi H, Yamawaki Y, et al. Angiographically
assisted helical CT of the liver. Am J Roentgenol 1999; 172:
97–105.
45. Miyayama S, Matsui O, Yamashiro M, et al. Detection of hepa-
tocellular carcinoma by CT during arterial portography using
a cone-beam CT technology: comparison with conventional
CTAP. Abdom Imaging 2008 (Epub ahead of print).
46. Oliver J, Baron R, Dodd G, Peterson M, Carr B. Does advanced
cirrhosis with portosystemic shunting affect the value of CT
arterial portography in the evaluation of the liver? Am J
Roentgenol 1995; 164: 333–7.
47. Taourel PG, Pageaux GP, Coste V, et al. Small hepatocellular
carcinoma in patients undergoing liver transplantation:
detection with CT after injection of iodized oil. Radiology
1995; 197: 377–80.
48. Merine D, Takayasu K, Wakao F. Detection of hepatocellular
carcinoma: comparison of CT during arterial portography
with CT after intraarterial injection of iodized oil. Radiology
1990; 175: 707–10.
49. Mitchell DG, Rubin R, Siegelman ES, Burk DL Jr, Rifkin MD.
Hepatocellular carcinoma within siderotic regenerative nod-
ules: appearance as a nodule within a nodule on MR images.
Radiology 1991; 178: 101–3.
50. Brancatelli G, Baron RL, Peterson MS, Marsh W. Helical CT
screening for hepatocellular carcinoma in patients with cir-
rhosis: frequency and causes of false-positive interpretation.
Am J Roentgenol 2003; 180: 1007–14.
51. O’Malley ME, Takayama Y, Sherman M. Outcome of small
(10-20 mm) arterial phase-enhancing nodules seen on tripha-
sic liver CT in patients with cirrhosis or chronic liver disease.
Am J Gastroenterol 2005; 100: 1523–8.
242
52. Jeong YY, Mitchell DG, Kamishima T. Small (<20 mm)
enhancing hepatic nodules seen on arterial phase MR imaging
of the cirrhotic liver: clinical implications. Am J Roentgenol
2002; 178: 1327–34.
53. Caturelli E, Pompili M, Bartolucci F, et al. Hemangioma-like
lesions in chronic liver disease: diagnostic evaluation in
patients. Radiology 2001; 220: 337–42.
54. Forner A, Vilana R, Ayuso C, et al. Diagnosis of hepatic nodules
20 mm or smaller in cirrhosis: prospective validation of the
noninvasive diagnostic criteria for hepatocellular carcinoma.
Hepatology 2008; 47: 97–104.
55. Jeng LB, Changlai SP, Shen YY, et al. Limited value of 18F-2-
deoxyglucose positron emission tomography to detect
hepatocellular carcinoma in hepatitis B virus carriers.
Hepatogastroenterology 2003; 50: 2154–6.
56. Liangpunsakul S, Agarwal D, Horlander JC, Kieff B,
Chalasani N. Positron emission tomography for detecting
occult hepatocellular carcinoma in hepatitis C cirrhotics
awaiting for liver transplantation. Transplant Proc 2003;
35: 2995–7.
57. Teefey SA, Hildeboldt CC, Dehdashti F, et al. Detection of
primary hepatic malignancy in liver transplant candidates:
prospective comparison of CT, MR imaging, US, and PET.
Radiology 2003; 226: 533–42.
58. Khan MA, Combs CS, Brunt EM, et al. Positron emission
tomography scanning in the evaluation of hepatocellular
carcinoma. J Hepatol 2000; 32: 792–7.
59. Pozniak MA, Baus KM. Hepatofugal arterial signal in the
main portal vein: an indicator of intravascular tumor spread.
Radiology 1991; 180: 663–6.
60. Tublin ME, Dodd GD, Baron RL. Benign and malignant por-
tal vein thrombosis: differentiation by CT characteristics.
Am J Roentgenol 1997; 168: 719–23.
61. Zimmerman A. Tumours of the liver - pathological aspects.
In: Blumgart LH, ed. Surgery of the Liver and Biliary Tract.
Edinburgh: Churchill Livingstone, 1994: 1277–323.
62. vanSonnenberg E, Ferrucci JT. Bile duct obstruction in hepa-
tocellular carcinoma (hepatoma) − clinical and cholangio-
graphic characteristics. Report of 6 cases and review of the
literature. Radiology 1979; 130: 7–13.
63. Huguet C, Stipa F, Gavelli A. Primary hepatocellular cancer:
Western experience. In: Blumgart LH, ed. Surgery of the
Liver and Biliary Tract. Edinburgh: Churchill Livingstone,
1994: 1365–9.
64. Kaczynski J, Hansson G, Wallerstedt S. Metastases in cases
with hepatocellular carcinoma in relation to cliicopathologic
features of the tumour. Acta Oncologica 1995; 34: 43–8.
65. Ichikawa T, Federle MP, Grazioli L, et al. Fibrolamellar hepa-
tocellular carcinoma: imaging and pathologic findings in 31
recent cases. Radiology 1999; 213: 352–61.
66. Powers C, Ros PR, Stoupis C, Johnson WK, Segel KH.
Primary liver neoplasms: MR imaging with pathologic
correlation. Radiographics 1994; 14: 459–82.
67. Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics,
1998. CA Cancer J Clin 1998; 48: 6–29.
68. Edmondson H. Tumors of the liver and intrahepatic bile
ducts. In: Atlas of Tumor Pathology. Washington, DC: Armed
Forces Institute of Pathology, 1958: Fascicle 25.
 primary tumors of the liver and biliary tract
69. Nakanuma Y, Minato H, Kida T, Terada T. Pathology of cho-
langiocellular carcinoma. In: Tobe T, Kameda H, Okudaira
M, Ohto M, eds. Primary Liver Cancer in Japan. Tokyo:
Springer-Verlag, 1994: 39–50.
70. Patel T. Increasing incidence and mortality of primary intra-
hepatic cholangiocarcinoma in the United States. Hepatol-
ogy 2001; 33: 1353–7.
71. Zimmerman A. Tumors of the bile duct − pathological
aspects. In: Blumgart LH, ed. Surgery of the Liver and Biliary
Tract. Edinburgh: Churchill Livingstone, 1994.
72. de Groen PC, Gores GJ, LaRusso NF, Gunderson LL, Nagorney
DM. Biliary tract cancers. N Engl J Med 1999; 341: 1368–78.
73. Lim JH. Cholangiocarcinoma: recent advances in imaging
and intervention. Abdom Imaging 2004; 29: 538–9.
74. Lim JH. Cholangiocarcinoma: morphologic classification
according to growth pattern and imaging findings. Am J
Roentgenol 2003; 181: 819–27.
75. Lim JH, Yoon KH, Kim SH, et al. Intraductal papillary mucinous
tumor of the bile ducts. Radiographics 2004; 24: 53–67.
76. Yoon KH, Ha HK, Kim CG, et al. Malignant papillary neo-
plasms of the intrahepatic bile ducts: CT and histopathologic
features. Am J Roentgenol 2000; 175: 1135–9.
77. Craig JR, Peters RL, Edmondson HA. Tumors of the liver and
intrahepatic bile ducts. In: Atlas of Tumor Pathology.
Washington, DC: Armed Forces Institute of Pathology, 1989:
Fascicle 26.
78. Kim T, Choi B, Han J, et al. Peripheral cholangiocarcinoma of
the liver: two-phase spiral CT findings. Radiology 1997; 204:
539–43.
79. Han JK, Choi BI, Kim AY, et al. Cholangiocarcinoma: pictorial
essay of CT and cholangiographic findings. Radiographics
2002; 22: 173–87.
80. Vilgrain V, Van Beers BE, Flejou JF, et al. Intrahepatic cholan-
giocarcinoma: MRI and pathologic correlation in 14 patients.
J Comput Assist Tomogr 1997; 21: 59–65.
81. Lacomis JM, Baron RL, Oliver JH 3rd, Nalesnik MA, Federle
MP. Cholangiocarcinoma: delayed CT contrast enhancement
patterns. Radiology 1997; 203: 98–104.
82. Ros PR, Buck JL, Goodman ZD, Ros AM, Olmsted WW.
Intrahepatic cholangiocarcinoma: radiologic-pathologic
correlation. Radiology 1988; 167: 689–93.
83. Lee WJ, Lim HK, Jang KM, et al. Radiologic spectrum of
cholangiocarcinoma: emphasis on unusual manifestations
and differential diagnoses. Radiographics 2001; 21 Spec No:
S97–S116.
84. Ahlgren JD. Neoplasms of the hepatobiliary system. In:
Calabresi P, Schein PS, eds. Medical Oncology. New York:
McGraw-Hill, 1993: 713–30.
85. Schulte SJ, Baron RL, Teefey SA, et al. CT of the extrahepatic
bile ducts: wall thickness and contrast enhancement in nor-
mal and abnormal ducts. Am J Roentgenol 1990; 154:
79–85.
86. Fan ZM, Yamashita Y, Harada M, et al. Intrahepatic cholang-
iocarcinoma: spin-echo and contrast-enhanced dynamic MR
imaging. Am J Roentgenol 1993; 161: 313–17.
87. Bismuth H, Nakache R, Diamond T. Management strategies
in resection for hilar cholangiocarcinoma. Ann Surg 1992;
215: 31–8.
88. Blumgart LH, Benjamin IS. Cancer of the bile ducts. In:
Blumgart LH, ed. Surgery of the Liver and Biliary Tract.
Edinburgh: Churchill Livingstone, 1994: 967–91.
89. Kew MC. Tumors of the liver. In: Zakim D, Boyer TD, eds.
Hepatology: A Textbook of Liver Disease. Philadelphia: WB
Saunders, 1996: 1513–48.
90. Engels JT, Balfe DM, Lee JK. Biliary carcinoma: CT
evaluation of extrahepatic spread. Radiology 1989; 172:
35–40.
91. Mitral B, Deutsch M, Iwatsuki S. Primary cancers of the
extrahepatic biliary passages. Int J Radiat Oncol Biol Phys
1985; 11: 849–55.
92. O’Shea JS, Shah D, Cooperman AM. Biliary cystadenoma of
extrahepatic duct origin arising in previously benign cysta-
denoma. Am J Gastroenterol 1987; 82: 1306–10.
93. Buetow PC, Buck JL, Pantongrag-Brown L, et al. Biliary cyst-
adenoma and cystadenocarcinoma: clinical-imaging-pathologic
correlations with emphasis on the importance of ovarian
stroma. Radiology 1995; 196: 805–10.
94. Locker GY, Doroshow JH, Zwelling LA, Chabner BA. The
clinical features of hepatic angiosarcoma: a report of four
cases and a review of the English literature. Medicine 1979;
58: 48–64.
95. Koyama T, Fletcher JG, Johnson CD, et al. Primary hepatic
angiosarcoma: findings at CT and MR imaging. Radiology
2002; 222: 667–73.
96. Peterson MS, Baron RL, Rankin SC. Hepatic angiosarcoma:
findings on multiphasic contrast-enhanced helical CT do not
mimic hepatic hemangioma. Am J Roentgenol 2000; 175:
165–70.
97. Miller W, Dodd G, Federle M, Baron R. Epithelioid hemangio-
endothelioma of the liver: imaging findings with pathologic
correlation. Am J Roentgenol 1992; 159: 53–7.
98. Ishak KG, Sesterhenn IA, Goodman ZD, Rabin L,
Stromeyer FW. Epithelioid hemangioendothelioma of the
liver: a clinicopathologic and follow-up study of 32 cases.
Hum Pathol 1984; 15: 839–52.
99. Greenlee RT, Hill-Harmon MB, Murray T, Thun M. Cancer
statistics, 2001. CA Cancer J Clin 2001; 51: 15–36.
100. Kumar A, Aggarwal S. Carcinoma of the gallbladder: CT
findings in 50 cases. Abdom Imaging 1994; 19: 304–8.
101. Henson DE, Albores-Saavedra J, Corle D. Carcinoma of the
gallbladder. Histologic types, stage of disease, grade, and
survival rates. Cancer 1992; 70: 1493–7.
102. Wanebo HJ, Vezeridis MP. Carcinoma of the gallbladder.
J Surg Oncol Suppl 1993; 3: 134–9.
103. Cotran RS, Kumar V, Collins T, Robbins SL. Robbins:
Pathologic Basis of Disease, 6th edn. Philadelphia: WB Saunders,
1999.
104. Rodriguez-Fernández A, Gómez-Rio M, Medina-Benitez A,
et al. Application of modern imaging methods in diagnosis
of gallbladder cancer. J Surg Oncol 2006; 93: 650–64.
105. Smathers RL, Lee JK, Heiken JP. Differentiation of compli-
cated cholecystitis from gallbladder carcinoma by computed
tomography. Am J Roentgenol 1984; 143: 255–9.
106. Yoshimitsu K, Honda H, Kaneko K, et al. Dynamic MRI of
the gallbladder lesions: differentiation of benign from malig-
nant. J Magn Reson Imaging 1997; 7: 696–701.
243
 primary tumor evaluation and staging
107. Chun K, Ha H, Yu E, et al. Xanthogranulomatous cholecysti-
tis: CT features with emphasis on differentiation from gall-
bladder carcinoma. Radiology 1997; 203: 93–7.
108. Weiner SN, Koenigsberg M, Morehouse H, Hoffman J.
Sonography and computed tomography in the diagnosis of
carcinoma of the gallbladder. Am J Roentgenol 1984; 142:
735–9.
109. Levy AD, Murakata LA, Rohrmann CA Jr. Gallbladder
carcinoma: radiologic-pathologic correlation. Radio-
Graphics 2001; 21: 295–314.
110. Sagoh T, Itoh K, Togashi K, et al. Gallbladder carcinoma:
evaluation with MR imaging. Radiology 1990; 174: 131–6.
111. Rooholamini SA, Tehrani NS, Razavi MK, et al. Imaging
of gallbladder carcinoma. RadioGraphics 1994; 14: 291–306.
112. Demachi H, Matsui O, Hoshiba K, et al. Dynamic MRI using
a surface coil in chronic cholecystitis and gallbladder carci-
noma: radiologic and histopathologic correlation. J Comput
Assist Tomogr 1997; 21: 643–51.
113. Kim JH, Kim TK, Eun HW, et al. Preoperative evaluation of
gallbladder carcinoma: efficacy of combined use of MR
imaging, MR cholangiography, and contrast-enhanced dual-
phase three-dimensional MR angiography. J Magn Reson
Imaging 2002; 16: 676–84.
114. Haradome H, Ichikawa T, Sou H, et al. The pearl necklace
sign: an imaging sign of adenomyomatosis of the gallbladder
at MR cholangiopancreatography. Radiology 2003; 227:
80–8.
115. Yoshimitsu K, Honda H, Jimi M, et al. MR diagnosis
of adenomyomatosis of the gallbladder and differentiation
from gallbladder carcinoma: importance of showing
Rokitansky-Aschoff sinuses. Am J Roentgenol 1999; 172:
1535–40.
244
116. Koh T, Taniguchi H, Yamaguchi A, Kunishima S, Yamagishi H.
Differential diagnosis of gallbladder cancer using positron
emission tomography with fluorine-18-labeled fluoro-
deoxyglucose (FDG-PET). J Surg Oncol 2003; 84: 74–81.
117. Greene FL, Page DL, Fleming ID, et al. AJCC Cancer Staging
Handbook. TNM Classification of Malignnt Tumors, 6th
edn. New York: Springer, 2002.
118. Franquet T, Montes M, Ruiz de Azua Y, Jimenez FJ,
Cozcolluela R. Primary gallbladder carcinoma: imaging find-
ings in 50 patients with pathologic correlation. Gastrointest
Radiol 1991; 16: 143–8.
119. Reid KM, Ramos-De la Medina A, Donohue JH. Diagnosis
and surgical management of gallbladder cancer: a review.
J Gastroint Surg 2007; 11: 671–81.
120. Kalra N, Suri S, Gupta R, et al. MDCT in the staging of
gallbladder carcinoma. Am J Roentgenol 2006; 186: 758–62.
121. Kim SJ, Lee JM, Lee JY, et al. Accuracy of preoperative T-staging
of gallbladder carcinoma using MDCT. Am J Roentgenol
2008; 190: 74–80.
122. Mekeel KL, Hemming AW. Surgical management of
gallbladder carcinoma: a review. J Gastrointest Surg 2007; 11:
1188–93.
123. Ito H, Matros E, Brooks DC, et al. Treatment outcomes associ-
ated with surgery for gallbladder cancer: a 20-year experience.
J Gastrointest Surg 2004; 8: 183–90.
124. Shirai Y, Yoshida K, Tsukada K, Muto T, Watanabe H. Radical
surgery for gallbladder carcinoma. Long-term results. Ann
Surg 1992; 216: 565–8.
125. Kresl JJ, Schild SE, Henning GT, et al. Adjuvant external beam
radiation therapy with concurrent chemotherapy in the
management of gallbladder carcinoma. Int J Radiat Oncol
Biol Phys 2002; 52: 167–75.
 15 Renal Tumors
Anju Sahdev and Rodney H Reznek
INTRODUCTION
The most common primary renal tumor is renal cell carcinoma
(RCC), with transitional cell carcinoma (TCC) of the upper uri-
nary tract being much less common. In this chapter the imaging
diagnosis and staging of these tumors is discussed, with emphasis
on the essential role of imaging in the preoperative evaluation of
patients.
PATHOLOGY
A representative list of renal tumors is given in Table 15.1 (1,2).
Renal cell carcinoma is the most frequent tumor of the kidney,
accounting for 80% to 90% of primary malignant neoplasms in
adults (1,2). The 2004 World Health Organization (WHO) classi-
fication recognized several distinct histological subtypes of RCC
(Table 15.2) (3). Clear cell carcinoma (CCRCC) is the commonest
subtype and accounts for more than 70% of all RCCs. Different
RCC subtypes are associated with specific and distinct genetic
abnormalities, which explains the diverse biological behavior of
the different RCC subtypes. Clear cell RCCs contain clear cells
that are lipid and glycogen-rich. A small percentage contain gran-
ular or spindle cells. Spindle cell carcinomas can be confused with
sarcomas but are distinguished by their expression of keratin. The
proximal convoluted tubule is thought to be the cell of origin for
RCC. Less common variants of RCC, such as papillary cystadeno-
carcinoma (10–15%), originate from the more distal nephron.
Papillary cystadenocarcinoma tends to have a less aggressive
clinical course.
Transitional cell carcinoma accounts for 5% to 7% of renal tumors
and may arise from the renal collecting system or ureter, with the
extrarenal pelvis most frequently affected.
RENAL CELL CARCINOMA
Incidence and Epidemiology
The American Cancer Society estimates that there will be about
54,390 new cases of kidney cancer (33,130 in men and 21,260 in
women) in the United States in the year 2008, and about 13,010
people (8100 men and 4910 women) will die from this disease.
These statistics include both renal cell carcinomas and transitional
cell carcinomas of the renal pelvis (4). In 2004, 6600 people were
diagnosed with renal cancer in the United Kingdom and there were
3600 deaths (5). Renal cancer is among the 10 most common can-
cers in both men and women. Overall, the lifetime risk for develop-
ing kidney cancer is about 1 in 75 (1.34%). This risk is higher in
men than in women. The incidence of RCC has increased by 40% in
the United States from 1974 to 1990 (6,7). There appears to be a
true increase in the incidence of RCC over and above that attribut-
able to the increased number detected by abdominal cross-sectional
imaging. This increase has been accompanied by improved five-
year survival as the tumors detected by imaging are diagnosed at an
earlier stage when they are still resectable (7). The male-to-female
ratio is approximately 2:1; the majority present in the fifth to sev-
enth decade of life and there is no racial predominance (8–10). The
majority of cases of RCC occur sporadically, but predisposing fac-
tors can sometimes be identified. Renal cell carcinoma occurs in
about 36% of patients with von Hippel–Lindau disease and invasive
RCC is three to six times more common among long-term dialysis
patients than in the general population (11). Recently, some envi-
ronmental factors have been associated with RCC. Obesity is a risk
factor and, in women, a linear relationship exists between body
weight and the risk of RCC (12,13). Cigarette smoking doubles the
likelihood of RCC (14,15) and occupational exposure to petroleum
products, heavy metals, or asbestos also increases the risk (16).
Clinical Presentation
Only 6% to 10% of patients with RCC present with the classic triad
of hematuria, flank pain, and a palpable mass. Many more will pres-
ent with one or two components of the triad (7,17). In recent years,
more than 50% of the RCCs have been detected incidentally using
non-invasive imaging techniques during investigations for a variety
of non-specific symptoms (18,19). Patients with RCC sometimes
present with paraneoplastic systemic symptoms unrelated to the
urinary tract, such as anorexia, lassitude, and weight loss. Fever may
be the only presenting symptom and some patients present with
hepatic dysfunction in the absence of liver metastases (Stouffer’s
syndrome) (20). Renal cell carcinomas may secrete humoral factors
such as erythropoietin, which causes erythrocytosis, or other factors
which cause hypercalcemia (20). Twenty-five percent of patients
still present with symptoms due to metastatic disease particularly
bone and brain metastases (6,18). This high incidence of advanced
renal cancer persists despite the increased use of cross-sectional
imaging and the increase detection of low stage renal cancer.
Key Points: RCC Epidemiology
■ Worldwide, renal cancer is among the 10 most common cancers
in men and women
■ Seventy percent of renal cancers are clear cell adenocarcinomas
arising from the proximal tubules
■ With the increasing use of modern cross-sectional imaging,
50% of RCC are incidentally detected
Staging Classifications
Two systems of clinical staging (Fig. 15.1 and Tables 15.3 and 15.4)
are in common use: the TNM classification (Table 15.3) (21) and
the Robson classification (Table 15.4) (22). The current consensus
is to use the TNM 2002 system developed by the International
Union Against Cancer and the American Joint Committee on
Cancer and recommended by the European Guidelines (23).
245
 primary tumor evaluation and staging

Table 15.1 Pathology of Renal Tumors specific and more detailed (24) but acknowledge that it is more
complicated than the Robson system (27).
Renal cell carcinomas
Table 15.2
Transitional cell carcinoma Staging and Prognosis
Oncocytoma Prognostic factors can be classified into anatomical (tumor size,
Rare renal neoplasms capsular and venous invasion, nodal and metastatic spread),
Epithelial––small cell, carcinoid, teratoma, etc. histological (histological subtype, Fuhrman grade, microvascu-
Mesenchymal––fibroma, liposarcoma, leiomyosarcoma, fibrosarcoma, etc.
Nephroblastoma (Wilm’s tumor)
lar invasion, invasion of the renal pelvis and/or sinus fat, and
Metastases sarcomatoid elements), clinical (age, performance status, systemic
Breast, bronchus, and malignant melanoma symptoms), and molecular.
Lymphoma The anatomical factors are represented within the staging clas-
sifications. A clear relationship exists between survival and the
macroscopic extent of tumor spread (Fig. 15.2). Opinions differ
regarding the value of tumor size for predicting survival. The
Table 15.2 WHO Classification of Renal Cell Carcinoma (3) overwhelming evidence is that tumor size alone is a poor indica-
Histological Prevalence Cell of origin Cytogenetic tor of prognosis in the absence of involved nodes or metastatic
subtype (%) findings disease and without local invasion of perirenal fat or other struc-
tures (28,29). However, a clear relationship exists between tumor
Clear cell RCC 70 Epithelium of 3p deletions,
size and the development of metastases (30–32), and because of
proximal tubule von-Hippel-
Lindau this the suggestion of a poorer prognosis for larger tumors is
gene mutations corroborated by several studies (33–35). Spread to the retroperi-
Papillary RCC 10 Epithelium of Trisomy of toneal nodes or beyond the renal fascia markedly reduces patients’
(chromophile) proximal tubule chromosomes 7 survival (21,36). Lymph node metastases are a very poor prognos-
and 17, loss of tic feature and demonstrate a strong correlation with the primary
Y chromosome,
7q34 chromosome
tumor stage. Canfield et al. demonstrated an almost linear
abnormality relationship between T stage and nodal disease. They showed the
Chromophobe RCC 5 Intercalated cell Loss of multiple incidence of nodal metastases was 3%, 17%, 30%, and 47% for
of collecting duct chromosomes: stage T1, T2, T3a, and T3b, respectively. Perinephric fat invasion is
1, 2, 6, 10, 13, 17, 21 a strong predictor of nodal metastases and 77% of patients with
Hereditary cancer 5 Variable
syndromes
perinephric fat invasion had nodal metastases in this study (37).
Multilocular cystic <1 Variable The importance of venous invasion is more controversial. Some
RCC patients with venous invasion, but without lymph node involve-
Collecting duct RCC <1 Medullary Loss of multiple ment, may survive as long as patients with tumors confined to the
collecting duct chromosomes: kidney but, more recently, it has been shown unequivocally that
1, 6, 14, 15, 22
and gain of
venous invasion reduces survival time (36,38–40). More recently,
chromosome 3 it has been shown that although successful removal of a tumor
Medullary carcinoma <1 Medullary Extracellular matrix thrombus in the renal vein and IVC may result in improved long-
collecting duct gene loss term survival in more than half of the affected patients, a higher
Mucinous tubular <1 Loop of Henle Loss of multiple level of thrombus appears to be a bad prognosticator for cancer
and spindle cell chromosomes:
carcinoma 1, 4, 6, 8, 13, 14
recurrence. A complete IVC thrombectomy, even in the metastatic
Neuroblastoma- <1 Multiple gene loss setting, provides a better quality of life and may prolong survival
associated RCC (41). There appears to be a difference between mobile, non-
Xp 11.2 translocation- <1 Translocations obstructive vena caval tumor thrombus and intracaval tumor
TFE3 carcinoma involving Xp11.2 thrombus with direct wall invasion. Patients with mobile tumors
Unclassified 4
have a median survival of 9.9 years, whereas in those with unre-
sectable venous wall involvement, the median survival is only 1.2
years (42).
There is an approximate correlation between these two systems Metastases are a strong indicator of poor patient survival. Com-
as shown in Table 15.5 (24). mon sites of metastases include the lungs, the bones, central ner-
Some urological surgeons continue to refer to Robson’s classifi- vous system (CNS), and adrenal glands. In general, patients with
cation, which is essentially a surgical staging approach. This distant metastases have five-year survival rates of 5% to 10% and
system includes the important staging variables that have survived 10-year survival rates of less than 5% (43,44).
scrutiny over the years (25). Confinement within the renal capsule, The Fuhrman nuclear grade remains the most widely accepted
penetration into the perirenal fat, invasion into the renal vein, and histological grading system and an independent prognostic factor
lymph node metastases are all important in determining prognosis (45). The WHO histological classification of renal tumors is based,
(Fig. 15.1 and Table 15.6) (25,26). in part, on the difference in prognosis of the various subtypes.
The TNM system uses the general principles employed for the Chromophobe carcinomas and papillary carcinomas have a better
staging of all tumors and its proponents argue that it is more prognosis than clear cell carcinomas. However, this prognostic

246
 renal tumors

T1a T1b T2

>7 cm

<4 cm 4–7 cm

T3a T3b T3c

Gerota’s fascia

Perinephric fat

T4

Gerota’s fascia

Perinephric fat

(A)

Figure 15.1 (A) Staging renal cell carcinoma using the TNM system for the primary tumor (T). (Continued)

247
 primary tumor evaluation and staging
Stage I
Stage II
Stage III
Stage IV
(B)
Figure 15.1 (B) (Continued) Staging renal cell carcinoma using the Robson system. (C) Staging renal cell carcinoma using the TNM system for the lymph nodes (N).
histological benefit is negated when stratified to tumor stage and
Fuhrman grade. Papillary carcinomas can be further subdivided
into type I and type II carcinomas, with type I tumors having a
more favorable prognosis (46,47). Clinically favorable prognostic
factors include a good patient performance status, low tumor
burden, absence of systemic symptoms, and a long disease-free
interval. Although currently limited to trials and research, bio-
chemical and molecular markers including p53, carbonic anhy-
drase IX, vascular endothelial growth factor, and hypoxia induced
growth factor have been proposed as prognostic factors and for
response assessment to therapy. In order to improve prognostic
estimations, nomograms that combine independent prognostic
factors have been developed to replace the TNM staging and
Fuhrman grade alone. The two main systems proposed have been
devised by the University of California Los Angeles (UCLA) and
Memorial Sloane-Kettering Cancer Centre (MSKCC) based on
the individual experience of each institution (48,49). These have
been evaluated but their use is currently limited to stratifying
patients within clinical trials.
248
N1
N2
(C)
Key Points: Staging and Prognosis
■ The TNM classification, Fuhrman grading system and WHO
histological subtype should be used for staging, prognosis,
and selecting therapy
■ Venous invasion reduces the survival time and unresectable
venous wall involvement further reduces median survival
■ A clear relationship exists between tumor size and the devel-
opment of metastases
■ Clinical nomograms and molecular prognostic factors are
presently limited to use in clinical and research trials
Staging and Surgery
Early work by Robson et al. (22) showed that survival rates are
significantly improved by radical nephrectomy compared with
simple or partial nephrectomy and, since then, “radical” nephrec-
tomy has been accepted as the gold standard treatment for RCC.
Increasingly, the detection of small incidental tumors has increased
 renal tumors

Table 15.3 TNM Staging System for Renal Cell Carcinoma (21) Table 15.6 Survival and Anatomical Extent of Renal Cell
Primary tumor (T)
Cancer (27)
TX Primary tumor cannot be assessed Anatomical extent of tumors Survival (%)
T0 No evidence of primary tumor
5-yr 10-yr
T1 T1a Tumor <4 cm in greatest dimension, limited to kidney
T1b Tumor >4 cm but not >7 cm in greatest dimension, Within renal capsule 65 56
limited to kidney Renal vein alone 55 49
T2 Tumor >7.0 cm in greatest dimension, limited to the kidney Renal vein + perinephric fat 50 33
T3 Tumor extends into major veins or invades adrenal gland or Renal vein + regional nodes 0 0
perinephric tissues but not beyond Gerota’s fascia Perinephric fat alone 47 20
T3a Invades adrenal gland or perinephric tissues but not Regional nodes alone 33 17
beyond Gerota’s fascia Invading nearby structures 0 0
T3b Grossly extends into renal vein(s) or vena cava below
diaphragm
T3c Grossly extends into vena cava above diaphragm 100
T4 Tumor invades beyond Gerota’s fascia 90
Nodal involvement (N) 80
The para-aortic and paracaval nodes are the regional lymph nodes
70
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis 60

Percentage of patients alive

N1 Metastasis in a single regional lymph node
50
N2 Metastasis in more than one regional lymph node
Distant metastases (M) 40
MX Distant metastasis cannot be assessed
M0 No distant metastases
M1 Distant metastases 30
TNM stage grouping
Stage I T1 N0 M0
Stage II T2 N0 M0
Stage III T3 N0 M0 20
T1,T2,T3 N1 M0
Stage IV T4 N0,N1 M0
Any T N2 M0
Any stage Any N M1

0
Table 15.4 Robson Staging of Renal Cell Carcinoma1 (22) 0 5 10 15 20 25 30
Time after surgery (yrs)
Stage Characteristics
I Tumor confined within capsule Stage I Stage IV
II Extracapsular spread to perinephric fat but confined Stage II Expected Stage I, II
to Gerota’s fascia Stage III Expected Stage III, IV
III Tumor involvement of renal vein, inferior vena cava,
or regional lymph nodes
IV Invasion of adjacent organs or distant metastases
Figure 15.2 Survival of patients with renal cell carcinoma according to stage.
“Expected” curves represent survival of similar populations without tumor.

Table 15.5 Robson’s Classification Versus TNM System (24) because the perinephric fat and Gerota’s fascia are routinely
Robson Disease extent TNM resected during radical nephrectomy, accurate differentiation
I Tumor confined to kidney (small, intrarenal) T1 between Stage I and Stage II (T1 versus T3a) has not been essential.
Tumor confined to kidney (large) T2 More recently, however, less aggressive surgery has been advocated
II Tumor spread to perinephric fat but within T3a for some patients with low-grade, non-invasive tumors and the
Gerota’s fascia need for routine ipsilateral adrenelectomy, lymphadenectomy,
IIIA Tumor spread to renal vein or cava T3b
IIIB Tumor spread to local lymph nodes N1–N2
and excision of the entire kidney is now controversial (50,51).
IIIC Tumor spread to local vessels and lymph nodes T3b, N1–N2 Current data indicate that for low-grade, low-stage RCC, 4 cm or
IVA Tumor spread to adjacent organs (excluding T4 smaller, conservative nephron-sparing surgery (either partial
ipsilateral adrenal) nephrectomy or tumor enucleation) gives an outcome comparable
IVB Distant metastasis M1 to that of radical nephrectomy (52). For these patients the distinc-
tion between Stage I and Stage II is important. Furthermore, the
the use of laparoscopic nephrectomy and nephron-sparing surgery diagnosis of Stage II disease (T3a: perirenal invasion, ipsilateral
(Fig. 15.3). The open radical nephrectomy is now usually reserved adrenal gland invasion) carries some prognostic significance.
for large, high stage tumors with perirenal invasion, vascular inva- Studies based on radical nephrectomy data showed about 6% of
sion, or central deep cortical tumors (Fig. 15.4). Until recently, patients with RCC have ipsilateral adrenal involvement, the risk

249
 primary tumor evaluation and staging
(A)
Figure 15.3 (A) Axial post-contrast enhanced CT image demonstrating an incidentally detected small <3 cm right RCC (arrow). (B) The coronal reformatted images
demonstrate the mainly parenchymal location of the tumor and its proximity to the renal hilum (arrow).
Figure 15.4 Coronal reformatted contrast enhanced CT showing a large right
sided RCC, too large for a laparoscopic procedure, with possible invasion of the
right psoas (arrow).
Figure 15.5 Axial post-contrast enhanced showing a T1A RCC in the left kidney
with a hypervascular enhancing retroperitoneal nodal metastasis (arrow).
250
(B)
being higher for tumors replacing the entire kidney and for upper
pole left-sided tumors (53). This figure is now lower due to the
preoperative CT detection of smaller, lower stage RCCs. Routine
adrenelectomy is no longer considered necessary as the cancer-
specific survival between patients with and without adrenelec-
tomy is similar (54,55). The long-term survival rates at 5 and
10 years after surgery is 66% and 50%, respectively, in patients
with no evidence of metastatic spread and 51% and 51% for
patients with isolated intraadrenal metastases (54).
The risk of nodal metastases is approximately 14% and although
lymphadenectomy confers a five-year survival benefit, the routine
use of lymphadenectomy is controversial (56). Resection of
ipsilateral and aortocaval lymph nodes is recommended by some
surgeons and there is evidence that it improves survival (37,56).
Nodal metastasis are an independent predictor of prognosis in
patients with M0 disease and it is recommended that patients with
positive nodes should be targeted for aggressive surgical resection
followed by selection into trials to assess the efficiency of adjuvant
chemotherapy (Fig. 15.5) (37). Local lymph node involvement
may be an ineffective barrier to tumor spread, as the incidence of
distant metastases is 50% higher in patients with infiltrated lymph
nodes (57).
Venous extension has been reported to occur in 20% to 25% of
patients with RCC at presentation and involvement of the renal
vein and inferior vena cava (IVC) in 5% to 10% (Figs. 15.6 and
15.7) (1). Recent data from 446 radical nephrectomies showed a
7.2% rate of IVC tumor thrombus (58). In one series of over
400 patients, there was no renal vein involvement in tumors
<2.5 cm in diameter (59). In a large multicenter European study
of 2000 patients, the level of thrombus within the renal vein and
IVC affects the five-year survival rate. Thrombus in the renal
vein alone confers a five-year survival of 60%, IVC invasion below
the diaphragm (T3b) 46%, and IVC invasion above the diaphragm
(T3c) 10% (60). Surgery remains the most effective therapeutic
option in patients with vascular invasion and IVC thrombectomy
results in an improved long-term survival in at least 50% of the
patients (41). Tumor extension into the renal vein only can be
 renal tumors
Figure 15.6 Axial post-contrast enhanced CT demonstrating a large left upper pole
RCC with invasion of the left renal vein. The thrombus is seen as a filling defect in
the renal vein (arrow). Metastatic para-aortic lymphadenopathy is seen in the
retroperitoneum (block arrow).
Figure 15.7 Axial post-contrast enhanced CT showing a right-sided RCC invading
the right renal vein and IVC. Thrombus of a similar CT attenuation and enhancement
to the primary tumor is present in the invaded vessels (arrows).
dealt with by routine ligation of the renal vein to prevent embo-
lization and an open radical nephrectomy is the surgery of choice.
Extension into the IVC necessitates a midline abdominal incision
for adequate access to the IVC so that it can be cleared. Delineat-
ing the upper margin of the tumor extent is very important. Forty
percent of tumor thrombi are within the intrahepatic portion of
the IVC and whether or not the tumor extends above the hepatic
veins is vital information, as this necessitates a thoracic surgical
approach. For the 5% to 10% of tumors with caval involvement
which extend into the right atrium, cardiopulmonary bypass is
necessary to remove the whole tumor thrombus (61).
Detection of all metastatic sites is important because the role of
radical nephrectomy in patients with metastastic RCC is limited.
Nephrectomy is only of value if surgery can excise all tumor
deposits and the patient has a good performance status but for
most patients with metastases surgery is a palliative procedure.
Nephrectomy improves survival if metastases are to one organ
only, particularly bone in combination with systemic interferon
therapy (41,62). The incidence of regression of multiple metastases
following nephrectomy is extremely low (0.3%) and the mortality
of surgery is significantly greater (63). Patients with solitary
metastases which can be completely excised may have a reasonable
five-year survival of 25–35%. The majority of these patients have
pulmonary metastases only (33).
Key Points: Staging and Surgery
■ Accurate assessment of perirenal, adrenal, nodal, and venous
invasion, particularly the upper extent of the thrombus, is
essential for planning surgery. In these patients, an open radical
nephrectomy is the surgery of choice and the presence of
any of the above features precludes a laparoscopic procedure
■ Detection of all metastatic sites preoperatively is important
because the role of nephrectomy in patients with metastatic
disease is usually palliative
Imaging in Staging
Interpretation of any imaging used to stage RCC must include
evaluation of:
• Tumor size
• Tumor location (e.g., exophytic, cortical, central)
• Tumor interface with the renal parenchyma
• Perinephric tumor extension
• Involvement of the adrenal glands
• The presence and extent of venous invasion
• Spread into contiguous organs
• Local and regional lymph node enlargement
• Local or distant metastatic spread
Over the past decade, CT has become the most widely used imaging
technique for the diagnosis and staging of RCC (8,61,64). Increas-
ingly, MR imaging has proved to be a valuable method for staging
and seems to be at least as accurate as CT (65,66). At present,
imaging time and scanner availability mean that MR is generally
used as a problem-solving tool. MR is used for surveillance in
patients with hereditary RCC syndromes and in those with renal
failure where iodine-based contrast cannot be administered.
Caution must now be taken in these patients, given the recent
studies associating gadolinium-based compounds and NSF. The
use of ultrasound is limited in staging RCC but in a relatively
high proportion of cases overlying bowel gas precludes adequate
visualization of the renal vessels, the infrahepatic IVC, and the
retroperitoneum (67,68).
Computed Tomography
The overall accuracy of CT in staging RCC ranges between 72%
and 90% (61,69,70). Multidetector CT has allowed improve-
ment in the accuracy of staging renal cancer, particularly in the
evaluation of perirenal fat invasion and vascular invasion (71)
(Figs. 15.6 and 15.7).
Technique
With helical and multidetector CT, choice of the optimal protocol
to maximize the sensitivity of detection, characterization, and staging
of RCC is important. Thin-section, non-contrast-enhanced imag-
ing followed by scans at 25 to 70 seconds after contrast medium
251
 primary tumor evaluation and staging

show cortical, but not medullary, enhancement (corticomedullary Perinephric Spread (T1/2 Vs. T3a)
phase) and scans at 100 to 120 seconds show homogeneous renal On CT, Stage T1–T2 (Robson’s Stage I) tumors are defined as being
parenchymal enhancement (nephrogram phase). Scans at 3 to entirely within the kidney with an intact renal capsule. The adja-
5 minutes after contrast medium show pelvicalyceal filling (excre- cent perinephric fat and renal fascia appear normal (Fig. 15.3).
tory phase). Both corticomedullary and nephrogram phase images Stage T3a tumors (Robson stage II) are diagnosed when there is
should be obtained for optimal detection of renal parenchymal extension of tumor into the perinephric space. The most specific
masses (72–74). sign of spread is the presence of a discrete mass measuring at least
For mass characterization, the nephrogram phase is more 1 cm in diameter within the perinephric space (Fig. 15.8). Although
sensitive than the corticomedullary phase, but characterization the specificity of this finding is 98% for Stage T3a tumor spread, its
is optimal when both are used. A few renal cell cancers enhance sensitivity is only 46% (70) because this finding is absent in the
very early, but some do not enhance fully until the nephrogram majority of patients with perinephric extension. Renal capsular
phase (74,75). When used alone, the vascular and corticomed- invasion is difficult to diagnose unless the tumor obviously extends
ullary phases are therefore less sensitive than nephrogenic and into the perinephric space. Recognized signs on CT include:
excretory phases as poorly enhancing masses may be difficult to
distinguish from the adjacent poorly enhancing medulla and • An indistinct tumor margin
hyperenhancing masses from avidly enhancing renal cortical • Blurring of the renal outline
tissues. In contrast, the corticomedullary phase is more sensi- • Thickening of the perirenal fascia
tive in detecting tumors in patients with renal impairment. In • Strands of soft tissue spreading into the perinephric fat
these patients, the tumor enhances avidly against a poorly resulting in “webs” or “wispy” densities
enhancing renal cortex (76).
Data on the best enhanced-phase for staging RCC are more lim-
ited. In the one published series of 90 tumors, staging accuracy
was 91% using non-contrast enhanced, corticomedullary, and
nephrogram phases, but was less when non-contrast-enhanced
plus corticomedullary phase only or non-contrast-enhanced plus
nephrogram phases only were used (81% and 86%, respectively)
(74). Using biphasic scans through the liver after contrast medium
increases the detection of liver metastases from RCC (77).
Our own technique for detection, characterization, and staging
of renal masses is to obtain a non-contrast enhanced scan and then
to give 100 to 150 ml of non-ionic contrast medium (300 mg I/ml)
intravenously at 2 to 3 ml/sec. Scans are obtained from below
upwards through the kidneys at 40 to 50 seconds (when filling of
the renal veins is optimal). A further series of scans is then obtained
through the liver and kidneys scanning from above downwards at
90 to 100 seconds. Using MDCT, images are routinely recon-
structed into narrow (1.5 mm) intervals and then reformatted in
the sagittal and coronal planes using the data from the arterial and Figure 15.8 Axial post-contrast enhanced CT showing a large left RCC with large
nephrogenic phases. tumor nodules in the perinephric fat (arrow).

(A) (B)
Figure 15.9 Right renal cell carcinoma. (A) Unenhanced and (B) enhanced CT scans. Enhancing upper pole mass containing a small focus of calcification. Perinephric
stranding (arrowed) was considered to indicate spread into perinephric fat (T3a) but the tumor was confined to the renal capsule at surgery.

252
 renal tumors
False positive diagnoses occur and in up to 6% to 50% of patients
with Stage T1–2 (Robson Stage I) disease, there is perirenal
stranding and fascial thickening without perinephric tumor
spread (Fig. 15.9) (61,64,71) caused by:
• Perinephric edema
• Fat necrosis
• Fibrosis from previous inflammation, stone disease, etc.
Renal cancers are responsible for about 60% of all cases of
spontaneous renal and perirenal hemorrhage, and blood in the
perirenal space may mask or simulate extracapsular extension
(78–80). Unenhanced vascular collaterals may also simulate
perinephric soft tissue nodules (Fig. 15.10) (8,61). Focal thick-
ening of Gerota’s fascia contiguous with the tumor tends to be a
more reliable indicator of invasion than generalized uniform
thickening alone.
Until recently, the sensitivity of CT for identifying Stage T3a
(Stage II) tumors has only been between 44% and 50% (61,70),
with a specificity of 90% when all the signs are present. Using
MDCT the detection of perirenal invasion has improved and has
been reported with sensitivity, specificity and accuracy of 96%,
93%, and 95%, respectively (71).
Key Points: Perinephric Spread
■ Early perinephric extension is often difficult to detect accurately
■ Failure to distinguish between T1 and T3a (Robson’s Stage I and
II) accounts for 50% of all staging errors
Figure 15.10 Coronal reformatted post-contrast CT. Large left RCC with large
perinephric collateral vessels around the tumor (arrows). These vessels may be
confused with tumor stranding but the coronal reformatted images are helpful in
demonstrating the serpiginous contour indicating that these represent vessels.
Venous Invasion (Stage T3b and T3c)
Evaluation of the venous system is an important function of imag-
ing in staging RCC. It is critical both for the detection of venous
invasion and for showing its extent. Studies performed several
years ago show that spiral CT had a reported sensitivity of 85%,
specificity of 98%, and accuracy of 96% for detecting venous
involvement by RCC (81). Our technique to demonstrate uniform
enhancement of the renal veins and IVC has already been described
(Fig. 15.11). Studies reporting the performance of MDCT are
small but MDCT has a much higher sensitivity, between 93% and
100%, whilst maintaining a high specificity of between 80% and
100% (Figs. 15.12 and 15.13) (82–84).
On CT, the most important sign of venous tumor invasion is a
persistent filling defect within the renal vein or IVC following
intravenous (IV) contrast medium administration. No false positive
results for the diagnosis of tumor thrombus have been reported for
this sign (85). Ipsilateral renal vein enlargement on CT without
identifiable tumor thrombus is not a reliable sign of venous tumor
extension (Fig. 15.14). This sign is associated with a 65% false pos-
itive rate and 90% false negative rate for diagnosing tumor, partly
because 78% of RCCs are hypervascular, causing increased flow
with enlargement of the renal vein (85). Conversely, tumor thrombus
does not necessarily cause enlargement of the veins.
Errors in the diagnosis of venous tumor extension on MDCT are
relatively infrequent. Triphasic imaging (described under the sec-
tion “Technique,” p. 253) has greatly diminished these potential
mistakes. Also, improved longitudinal reconstructions from axially
acquired images have largely overcome the previously encountered
difficulty in visualizing the upper extent of tumor in the IVC (Fig.
15.13). The cephalad extent of tumor related to the level of the
Figure 15.11 Coronal reformatted contrast enhanced CT showing a normally
enhancing renal vein and IVC (arrows) in a patient with a large lower pole RCC
(block arrow).
253
 primary tumor evaluation and staging

(A) (B)
Figure 15.12 (A) Contrast-enhanced CT of a left pelvic kidney with a large RCC (arrow). There is thrombus in the renal vein (block arrow) which does not enhance and
on histology was confirmed as bland thrombus only. (B) Ultrasound of the tumor shows the thrombus in the renal vein (block arrow) and the tumor (arrow), both with
similar echogenicity. No vascularity in the venous thrombus was present on ultrasound.

(A) (B)
Figure 15.13 (A) Axial post-contrast enhanced image demonstrating a left mid-pole RCC invading the renal vein (arrows). (B) A 3D volume-rendered image
demonstrating the tumor and the venous invasion. The cephalad extent of the tumor is better demonstrated on the 3D model and can be seen extending into the
IVC (arrows).

(A) (B)
Figure 15.14 Enlarged but patent renal vein draining a left renal cell carcinoma. (A) Contrast-enhanced CT shows a large hypervascular tumor. (B) Enhanced CT showed
that the engorged left renal vein is patent.

254
 renal tumors
hepatic veins is crucial for the planning of surgery and can now,
with MDCT, be shown with greater certainty (86). A recent MDCT
study showed a 93% accuracy in predicting the cephalad extent of
the thrombus when compared to the histological specimen (83).
The distinction between direct venous extension of malignancy
and bland thrombus on CT is usually extremely difficult, and does
not alter the patient’s management. The only reliable sign is neo-
vascularity or enhancing tumor vessels within the thrombus
(Fig. 15.15), but this may be difficult to recognize. A less reliable
distinction between the two can be made when bland thrombus is
seen within the IVC, separate from a patent entry of the renal vein,
and malignant thrombus is inferred because of direct continuity
of the filling defect. Diagnosis of direct invasion of the wall of the
IVC by malignant thrombus is also unreliable using CT.
Key Point: Venous Invasion
■ In patients with RCC, evaluation of the patency of the venous
system and determining the cephalad extent of thrombus,
when present, is an important purpose of imaging in staging
Lymph Nodes
The lymphatic drainage of the kidney is highly variable (Fig.
15.1C). Usually, there are collecting lymphatic vessels from an
intrarenal plexus, with four or five trunks, which follow the renal
veins and end in the ipsilateral para-aortic lymph nodes. Effer-
ents from the lateral aortic nodes pass to the contralateral side to
form the lumbar trunk, which terminates in the cisterna chyli.
However, direct connections to the thoracic duct and mediasti-
num do exist, accounting for the uncommon finding of mediasti-
nal and hilar lymph node involvement, particularly on the right
side, at presentation.
Demonstration of lymph node involvement identifies disease as
Robson Stage III or N1–N2 in the TNM system. As with all cross-
sectional imaging techniques, detection of lymph node involvement
on CT relies on detecting an increase in the size of the infiltrated
Figure 15.15 Axial contrast-enhanced CT showing a highly vascular and avidly
enhancing tumor in an expanded IVC (arrow). The enhancement of the thrombus
confirms tumor invasion into the IVC.
nodes and the limitation of using size criteria for identifying
lymphatic metastases in RCC is well recognized (70,87,88). False
positive rates as high as 43%, and caused by reactive hyperplasia and
other benign conditions when 1 cm was used as the upper limit of
normal, have been reported (89). Primary tumor necrosis or throm-
bus within the IVC is associated with a higher rate of reactive
lymphadenopathy, with a resultant increase in false positive results
(90). However, lymph nodes larger than 2 cm are almost always
involved by metastatic tumor (70,91). False negative results caused
by microscopic invasion of lymph nodes occur in only 4% to 5% of
patients (89). The overall accuracy of lymph node staging by CT in
RCC is reported to be between 83% and 89% (69,70).
When considered overall, and taking into account detection of
lymph node infiltration and venous invasion, the sensitivity of CT
in distinguishing between Robson’s Stage I and III is 88% to 95%,
and the specificity is 99% to 100% (69,70).
Key Points: Lymph Node Staging
■ False positive rates can be high due to reactive hyperplasia,
especially in the presence of IVC thrombus or tumor necrosis
■ The risk of nodal metastases increases with increasing T stage;
perinephric fat invasion is a strong independent factor
associated with a high risk of nodal metastases
Stage IV Disease (T4); M1
The diagnosis of Stage IV disease can be achieved accurately with
CT. Direct tumor invasion of adjacent muscles, including the dia-
phragm, psoas, quadratus lumborum, or erector spinae muscles is
well shown. Disease in the contralateral kidney or adrenal is well
delineated, as well as invasion of the liver, colon, pancreas, or
spleen (Figs. 15.16 and 15.17). Loss of fat planes between the
tumor and adjacent structures, such as the liver or psoas muscle, is
not necessarily a sign of tumor invasion (70). Invasion should be
suggested only when there is enlargement of or a density change
in the adjacent structure.
Figure 15.16 Axial contrast-enhanced CT showing an infiltrative poorly enhancing
left upper pole RCC inseparable from the splenic flexure on CT (arrows). Colonic
invasion was confirmed at surgery.
255
 primary tumor evaluation and staging
Figure 15.17 Axial contrast-enhanced CT showing a large T4 RCC invading the left
quadratus lumborum muscle and psoas (arrows). The infiltrating tumor margin
enhances in a similar manner to the primary tumor.
Computed tomography is an ideal method for detecting distant
metastases (M1). Adrenal metastases may be the only evidence of
Stage IV disease. Computed tomography has a very high sensitiv-
ity for the detection of ipsilateral adrenal involvement by RCC but
lower specificity (100% and 76%, respectively) (92). Occasionally,
confusion may arise between adrenal metastases and a benign
incidental adrenal cortical adenoma (Fig. 15.18). (The distinction
between these two is dealt with in chap. 16). Renal cell carcinoma
may also be associated with phaeochromocytomas as part of the
von Hippel–Lindau syndrome. A synchronous tumor occurs in
the contralateral kidney in about 2% of cases, but multifocal
lesions in the same kidney occur more frequently. Computed
tomography is also a sensitive technique for the detection of
hematogenous spread to the liver and lung. Metastases tend to be
vascular and enhance after IV injection of contrast medium (Fig.
15.19). Invasion of the IVC may result in the appearance of the
Budd–Chiari syndrome, which causes confusion when checking
for metastases (Fig. 15.20). The lung is the most common site of
metastases from RCC, with metastases to the lungs demonstrated
in 50% to 60% of cases at autopsy. The incidence of lung metasta-
ses is substantially higher in patients with extensive abdominal
disease, especially with IVC involvement, than in those with
limited renal disease. Accurate staging of lung disease is of great
importance as complete resection of a solitary pulmonary metas-
tasis can increase the five-year survival rate from 32% to 56% (64).
CT is the most sensitive technique for the detection of focal lung
lesions, including lung metastases, and is indicated for full staging
of all patients in whom surgery is planned. The sensitivity and
specificity for CT in the overall staging of Stage IV RCC are 98%
and 99%, respectively (69,70,87).
256
Figure 15.18 Coronal reformatted contrast enhanced CT with a RCC in the upper
pole of the right kidney (block arrow). A contra-lateral left adrenal mass (arrow)
with an irregular contour and heterogenous enhancement suggests a metastasis.
Figure 15.19 Axial contrast-enhanced CT showing a large left RCC with a vascular
metastasis in the tail of the pancreas (arrow). The avid enhancement of the metastasis
is typical for RCC metastases.
Magnetic Resonance
Magnetic resonance protocols for evaluation of patients with renal
cell cancer vary widely and have evolved in recent years with the
development of surface coils, gradients, and new pulse sequences.
At our institution, all renal examinations are performed with a
phased-array surface coil centered over the kidneys to increase
signal-to-noise ratio.
A series of axial, sagittal, and coronal T1-weighted localizer
images are obtained. From these a field-of-view is chosen, three-
fourths in the phase encoding direction and sized to the patient.
T1-weighted gradient-echo (GRE) sequences have now largely
replaced T1-weighted spin-echo sequences. These are performed
from the upper aspect of the liver to the lower margin of the
kidneys with a slice thickness of 5–6 mm with 1 mm intervals
between slices. The TE is altered when acquiring these T1-weighted
GRE sequences to allow chemical shift in- and out-of-phase
imaging. The in- and out-of-phase images detect any intracel-
lular lipid within renal or adrenal masses. Axial fat-suppressed
breath hold fast spin-echo (FSE) T2-weighted images are then
acquired through the same area. The fat-suppression increases
the conspicuity of the kidneys by reducing both the chemical
shift artifact and the dynamic range of abdominal signal inten-
sities (93–95). Gadolinium-enhanced sequences are performed
 renal tumors

as a two-dimensional (2D) or three-dimensional (3D) study.
Irrespective of whether 2D or 3D imaging is chosen, we prefer the
study to be performed in a coronal plane. For imaging renal
neoplasms this has the advantage of allowing assessment of both
kidneys, the renal arteries, the entire IVC, and the spine in a rela-
tively small number of slices. For 2D imaging, breath-hold fat-
saturated T1 GRE images are acquired before and 30 seconds after
IV injection of 10 ml gadolinium. Postcontrast axial sequences are
then acquired to evaluate the renal parenchyma in the corticome-
dullary and nephrographic phases (45 and 90 seconds). Later
coronal sequences are also acquired to visualize the IVC optimally.
We now perform the postcontrast examination using a 3D study,
which is of particular value for evaluating the IVC (93,96,97) and,
if required, also provides reliable, accurate images of the renal
parenchyma (97). As with the 2D examination, a breath-hold pre-
contrast set of images is acquired with the arms elevated to reduce
phase-wrap. A low flip-angle (10 B0) is applied using an enhanced
fast field-echo three-dimensional (3D FFE) sequence. The low
flip-angle improves soft tissue contrast. Seventy sections are
obtained in the coronal plane before the administration of con-
trast medium. The image volume is acquired in a single breath-
hold and includes the kidney and IVC. The total breath-hold
required is usually 17 to 20 seconds and the sequences are repeated
five times with a 10-second delay between repetitions.
Extension Into the Perirenal Space
Magnetic resonance has the same limitations as CT in identifying
early extension into the perinephric space. Although MR appears
slightly more sensitive than CT, it is equally non-specific for dis-
tinguishing between T1/2 and T3a (Robson’s Stage I and II) dis-
ease (Fig. 15.21). Thus tumor extension into the perinephric space
is suggested by strands of low signal intensity on T1-weighted
images and intermediate signal intensity on T2-weighted images.
Detection of perinephric invasion, or its absence, can be improved
by using fat-suppressed contrast-enhanced images, with enhance-
ment of previously low signal intensity areas in the perinephric

(A) (B)
Figure 15.20 Budd–Chiari syndrome caused by vena caval invasion by right renal cell carcinoma. Enhanced CT scans (A) and (B) show unenhanced inferior vena cava
filled with tumor (arrowed, A) and patchy right liver enhancement mimicking liver metastases.

(A) (B)
Figure 15.21 Renal cell carcinoma, Robson’s Stage II (T3a). (A) Enhanced CT shows a 3 cm tumor in the posterior left kidney with normal perirenal fat (arrow). (B)
Enhanced spin-echo T1-weighted MR shows abnormal soft tissue in the perirenal fat and perirenal fascial thickening (arrow). Spread into the perirenal fat was confirmed
histologically.

257
 primary tumor evaluation and staging
tissue indicating extrarenal tumor extension (95,98,99). Ergan
et al. used stricter criteria for perinephric fat invasion using the
disruption of the renal capsule, the presence of tumor nodules
greater than 5 mm and thick pericapsular stranding (>5 mm) to
diagnose T3a disease. This provided an accuracy of 81%. This
study also showed a very good kappa agreement (0.75) between
MRI T stage and pathological stage (100). When the tumors are
small (mean size 2.5 cm), the negative predictive value of MRI for
perinephric fat invasion has been reported as 100% (101). How-
ever, the inability to detect microscopic extension into the peri-
nephric space reduces the sensitivity to 60% to 81% (69,87,100).
As with CT, the specificity of MR is substantially higher than the
sensitivity at 94% (52,66,86,87).
Venous Invasion
A major advantage of MR in staging RCC includes direct imaging
in the sagittal and coronal planes, which is particularly helpful for
Figure 15.22 Coronal fat saturated T1-weighted post-gadolinium enhanced image.
A right mid-pole RCC invading the renal vein and IVC to the level of the intra-
hepatic IVC (arrows). The tumor thrombus and the primary tumor show poor
enhancement resulting in a lower signal intensity than the normally enhancing renal
vein and IVC.
(A)
Figure 15.23 MR pitfall in diagnosis of tumor extension into renal vein. (A) Magnetic resonance shows distended left renal vein containing signal suggesting tumor
extension. (B) Enhanced CT shows patent renal vein. Signal on the MR scan was caused by slow flow.
258
showing the full extent of IVC tumor thrombus. This advantage
has to a certain degree been negated by MDCT and CT volume
reconstruction and surface rendering software. However, the
ability of MRI to detect soft tissue signal intensity differences
between the renal tumor and the surrounding structures main-
tains its superior multiplanar ability. The most important role of
MR is in assessing venous involvement.
Tumor thrombus in the renal vein and IVC can be suspected on
T1-weighted spin-echo pulse sequences if the signal void of flow-
ing blood is replaced by relatively high signal produced by tumor
thrombus. Tumor thrombi emit signals of intensity similar to that
of the primary neoplasm on different pulse sequences (Fig. 15.22).
Occasionally, slow flow within a vessel causes confusion by
emitting a signal that is misinterpreted as tumor thrombus
(Fig. 15.23). On time-of-flight GRE images, flowing blood has
markedly increased signal intensity and appears white, whereas
tumor thrombus has medium signal intensity and appears as a
filling defect. Imaging in the sagittal and coronal planes is particu-
larly helpful for assessing the superior extent of caval tumor
thrombus in relation to the diaphragm, hepatic veins and right
atrium. A coronal 2D or 3D contrast medium-enhanced GRE
sequence centered on the renal vessels and IVC confirms the pres-
ence of thrombus. Administration of contrast medium may also
allow the distinction between direct tumor extension and bland
thrombus (Fig. 15.24).
Conventional spin-echo sequences have a very high accuracy
for detecting venous invasion. However, limited flip-angle GRE
techniques facilitate the imaging of vascular structures and their
use in RCC has allowed accuracies of 100% in assessing venal
caval invasion, 88% for renal vein tumor thrombus, and 80% for
atrial invasion (65,94,98,100). Intravenous administration of
gadopentate dimeglumine may improve the accuracy further,
particularly when combined with three-dimensional MR venog-
raphy (MRV) (98–101).
MDCT with coronal and sagittal reconstruction now approaches
the high sensitivity and specificity of MR in delineating the upper
extent of the tumor thrombus within the renal veins and IVC.
Stern et al. showed a 93% accuracy when compared with the sur-
gical findings, whilst Hallscheidt et al. showed a better perfor-
mance of MDCT compared to MRI with a sensitivity of CT and
(B)
 renal tumors

(A) (B) (C)

Figure 15.24 Inferior vena caval extension of renal cell carcinoma on MR. Coronal fat-suppressed images from a three-dimensional contrast-enhanced gradient-echo
sequence (repetition to echo time 8:1.4). (A) Early-phase: opacified aorta and large right lower pole tumor. (B) Delayed-phase: low signal in the inferior vena cava (IVC)
extending to the right atrium indicates thrombus. (C) Image slightly anterior to (B): enhancing tumor within the thrombosed IVC (arrowed). Thrombus and tumor were
easily removed surgically.

MR as 90% versus 85%, and specificity 80% versus 75%, respec-

tively (83,84). Detection of invasion of the IVC wall necessitates
resection of the affected segment and subsequent vascular recon-
struction. To date, wall invasion has not been reliably detected by
imaging but MR does appear able to make this diagnosis (96).
Breach of the wall allows a definite diagnosis of invasion, and
invasion may be suspected if there is thickening, altered signal
and/or enhancement of the vessel wall. The most reliable signs of
vessel wall invasion are a tumor signal on each side of the vessel
wall and vessel wall enhancement (Fig. 15.25).

Lymph Nodes
As with CT or ultrasound, the only criterion for lymph node infil-
tration on MR is an increase in size. The sensitivity and specificity
of MR for N staging in RCC, therefore, do not exceed those of CT
(99,102–104). A disadvantage of MR relates to the absence of a
universally acceptable bowel contrast agent, which in thin patients
particularly can result in confusion between bowel and lymph
node masses. However, MR has the advantage that it can distin-
guish between large collateral vessels and lymph nodes when the
CT findings are uncertain. The signal void of flowing blood on
spin-echo sequences usually enables the distinction to be made
accurately.
In recent years the use of ultra-small paramagnetic iron oxide
particles (USPIO) has been evaluated for the detection of lymph
node metastases. These do not depend on the lymph node size but Figure 15.25 Inferior vena caval invasion by right renal cell carcinoma
on MR. Coronal fat-suppressed contrast-enhanced spin-echo sequence.
rely on the change in nodal signal intensity. These particles consist Non-enhancing thrombus in the central inferior vena cava (IVC) with an
of an iron oxide core coated with a low-molecular weight dextran enhancing rim of tumor (arrowed), extending up the IVC, indicating wall
protein. After contrast injection, the USPIO particles are ingested invasion.

259
 primary tumor evaluation and staging
by macropages in healthy lymph nodes causing a decrease in the
signal intensity of normal nodes on T2 and T2*-weighted images.
Lymph node metastases replace the normal macrophages and
therefore do not show a decrease in signal intensity. To date, no
large studies have been published on the use of USPIOs in renal
cancer alone, but small number of patients with renal cancer have
been included in larger studies evaluating the use of USPIOs in
abdominal malignancies (105,106). A meta-analysis of these stud-
ies shows an overall improvement in the detection of lymph node
metastases when with the use of USPIOs (sensitivity and specific-
ity of 88% and 96%, respectively) compared to a sensitivity and
specificity of 63% and 93%, respectively, when USPIOs are not
used during the MR imaging (106).
Visceral Invasion
The accuracy of assessing visceral invasion of RCC with MR has been
reported to be between 97% and 98% (69,100) because the excellent
contrast resolution of MR allows assessment of the spread of Stage IV
tumors to neighboring organs (Fig. 15.26). By using chemical-shift
imaging, MR may be particularly helpful for distinguishing between
an incidentally detected benign cortical adenoma and a deposit in the
contralateral gland (see chap. 16). However, obtaining the true sensi-
tivity and specificity of MR and CT in determining T4 disease is
limited by the fact that these patients rarely proceed to surgery and no
confirmation of the suspected organ invasion is available. MR and
CT suffer from the limitation that an indistinct tumor-organ inter-
face is insufficiently accurate in diagnosing invasion and the only
reliable sign is the presence of a mass in the adjacent organ.
Key Points: MR in Staging
■ MR imaging is as accurate as CT for staging renal cancer and can
be used in patients unable to undergo contrast-enhanced CT
■ MR has similar performance to MDCT in the assessment of
perinephric invasion
■ Its strength lies in the ability to detect the cranial extent of
IVC thrombus and IVC wall invasion
Figure 15.26 Renal cell carcinoma invading the abdominal wall. Axial spin-echo
T2-weighted MR shows large inhomogeneous tumor invading posterior abdomi-
nal wall muscles and neural exit foramen.
260
Summary
Although ultrasound and CT are used more frequently in the
detection and characterization of renal masses, MR can be used in
cases where iodinated contrast media cannot be administered due
to renal impairment or contrast allergy. MR imaging is also used in
cases where radiation exposure needs to be limited, such as children,
pregnant women, and in young patients undergoing surveillance
for hereditary syndromes predisposing to renal cancer. Lastly, in
difficult cases where CT may be equivocal, MR imaging may be
used for problem-solving. The performance of CT and MR in
detection and staging of renal cancer is equivalent. The main
advantage of MR imaging is the assessment of IVC wall invasion
and, where USPIOs are included in the MR imaging, the sensitivity
for the detection of nodal metastases is greatly improved.
Ultrasound
Ultrasound is used extensively for characterizing space-occupying
lesions of the kidney and for detecting RCC, but it is less accu-
rate than CT or MR for detecting and staging tumors. This is
partly because of its inability to distinguish between Robson
Stage I and II (T1/2 versus T3a) tumors as it does not show the
perinephric fascia in most patients (68,107,108). In up to 50% of
patients, the central retroperitoneum, renal vessels, and infra-
hepatic cava cannot be visualized because of overlying bowel gas
(8,66,68). Metastases to regional lymph nodes are therefore
difficult to detect. Ultrasound is also unreliable for the detection
of muscle invasion, so that Stage IVA tumors may be incorrectly
assessed.
Sonography is, however, extremely useful for detecting tumor
extension into the IVC and right atrium (Fig. 15.27). Tumor
thrombus in the renal vein or IVC can be identified as a reflective
mass in the vessel lumen which may or may not be expanded (8).
Although the sensitivity of ultrasound for detecting tumor throm-
bus in the entire IVC (including the infrahepatic portion) or renal
vein may be as low as 54%, its specificity for detecting clinically
important tumor thrombus that extends into the intrahepatic
vena cava can be as high as 100% (59,109). Color Doppler appears
to increase the sensitivity of ultrasound for detecting tumor
extending into the renal veins, the IVC and the right side of the
heart (110,111). In one small series, the overall sensitivity for
detecting venous invasion was 75% and for detecting tumor
thrombus in the IVC only was 100% (110). Echocardiography,
either transthoracic or transesophageal, is necessary for full ultra-
sound assessment of right atrial extension of RCC (112). The
overall accuracy of ultrasound for staging RCC is as low as 50–70%
(8,67,69) and it is seldom used as the sole staging technique.
Radioisotopes
Positron Emission Tomography
The use of PET in renal cancer has been limited due to the physi-
ological uptake and excretion of 2-[F-18]fluoro-2-deoxy-D-glucose
(FDG) masking small renal tumors. There is relatively little data in
the literature on the use of FDG positron emission tomography
(18FDG PET) in RCC (113,114). 18FDG PET does not appear to
have advantages for detecting RCC. It has a sensitivity of only 77%
in the detection of renal cancers; mainly missing small and well-
differentiated tumors (115–117). It may also give false positive
diagnoses in the presence of other renal tumors, particularly
 renal tumors

(A) (B)
Figure 15.27 Renal cell carcinoma. Robson’s Stage IIIA (T3b). (A) Coronal spin echo T1-weighted MR. Note the left renal tumor with extension into the renal vein and
inferior vena cava (IVC), which spares the upper IVC and hepatic veins. (B) Longitudinal ultrasound scan shows expanded IVC containing tumor, with patent upper IVC
and left hepatic vein.

oncocytomas or adrenal tumors (115,118). When compared to

CT, PET has an equivalent accuracy of 94% in staging renal malig-
nancy. It has been suggested that the advantage of PET lies in the
evaluation of distant metastases, particularly in identifying lung
and bone metastases, which may alter the management of up to
40% of the patients with large tumors (119). However a recent
study by Dilhuydy et al. showed PET may have a significant false
negative rate and in their study PET missed four out of 10 meta-
static sites and one patient had a false positive PET study. This
provided a sensitivity of only 75% and a positive predictive value
of 92%. This suggests that management decisions should only be
modified in the presence of a positive PET study and a negative
study should not modify the clinical decision (120). Currently,
18
FDG PET is considered to have a potential role for examination
of the whole body for metastases at presentation (Fig. 15.28), for
monitoring metabolic activity of tumor during chemo- or immu-
notherapy, and in evaluating patients with suspected recurrent
disease (118). The development of PET-CT and newer tracers,
particularly fluorine-18-fluorothymidine (F-18 FLT), are likely to
improve the performance of PET in renal cancer, but currently
there is limited available data to support its routine use in the
staging of renal cancer.

Bone Scanning
The role of 99mtechnetium-methylene-diphosphonate bone scanning
in RCC for staging at presentation is considered to be limited
(121,122). Only 5% of 124 patients with clinically localized T1–2
disease had bone metastases detected, compared to rates of 35% in
patients with locally advanced or metastatic disease (122). It has
been suggested that bone scanning has no role in patients with Stage
T1–3a clinically localized tumors and who have no bone pain and
normal serum alkaline phosphatase (122). In patients with bone
pain, elevated alkaline phosphatase, or routine radiographic proce-
dures (CXR, IVU) suggesting bony metastases, the sensitivity and
Figure 15.28 Whole body 18FDG-PET image in a patient with a previous left neph-
rectomy for clear cell carcinoma. Recurrent disease (arrows) is seen in the left
supraclavicular and right renal hilar distributions. Multiple bony metastases are
also present in the lumbar spine.
specificity of radionuclide bone scans is 93% and 86%, respectively.
Bone scans should therefore be used to confirm the presence and to
determine the extent of osseous metastases in patients with renal cell
carcinoma but are unnecessary as a routine staging procedure (123).

261
 primary tumor evaluation and staging

NEPHRON-SPARING SURGERY the follow-up should be intensified to detect early intrarenal

recurrence (23).
Over recent years, nephron-sparing surgery has been increas- When comparing the open and laparoscopic partial nephrec-
ingly used for treating patients with RCC (123,124). Anxieties tomy techniques, the largest study to date with 1800 patients
about its success relating to the potential for multicentric shows the three-year cancer-specific survival rate was comparable
tumors and the risk of local recurrence have been addressed by at 99.3% and 99.2%, respectively. Laparoscopic partial nephrectomy
a number of follow-up studies (124–126). However, tumors less
than 4 cm in diameter have a less than 5% risk of being multi-
centric and show a lower recurrence rate and improved survival
after nephron-sparing surgery compared to larger tumors
(125,126). In a 10-year follow-up of 107 patients who had
nephron-sparing surgery, Fergany et al. found overall five-year
and 10-year cancer-specific survival rates of 98% and 92% in
patients with tumors measuring 4 cm or less (126). Indications
for nephron-sparing surgery may be absolute, relative, or elec-
tive (123). Absolute indications are a RCC in an anatomically or
functional single kidney, or bilateral RCCs. Relative indications
include a RCC where the contralateral kidney is threatened by
other conditions affecting its function (such as stone disease,
reflux nephropathy, renal artery disease, diabetes mellitus, or
glomerulonephritis) or in conditions where there is a heredi-
tary increased risk of multiple RCC (e.g., von Hippel–Lindau
disease, hereditary papillary RCC) (Table 15.7) (Figs. 15.29–15.31)
Figure 15.29 Axial T2-weighted image from a patient with VHL and a left nephre-
(127). Elective indications include small localized RCCs, which ctomy for a previous RCC. Within the residual right kidney, there is a third new
are often detected incidentally, or indeterminate cystic lesions RCC (arrow) adjacent to a scar from the second resected RCC in the right kidney.
considered to have malignant potential. These small RCCs
account for the majority of incidentally detected RCC and
nephron-sparing surgery is increasingly advocated for this
group of patients. The size of suitable solid small RCCs varies
between institutions. It has previously been shown that in
tumors smaller than 4 cm, complete resection can be achieved
at partial nephrectomy, but the incidence of incomplete resection
can be up to 22% in tumors over 4 cm (124). A more recent
study of 1048 patients contradicted this by showing no statistical
increase in the rate of positive surgical margins, local or distant
recurrence rates, and the cancer-specific survival was not sig-
nificantly different between tumors of 4 cm or less and those larger
than 4 cm. The authors conclude that careful patient selection
rather than the absolute tumor size ensures a good success with
nephron-sparing surgery (128). The current European guidelines
on renal cell carcinoma recognize nephron-sparing partial Figure 15.30 Coronal reformatted post-contrast enhanced CT image showing a
nephrectomy as an established curative treatment. They also state 3 cm right lower pole RCC suitable for nephron-sparing surgery in a patient with
partial nephrectomy for tumors 4–7 cm should be performed at chronic renal failure.
specialist centers with appropriate expertise. For these tumors

Table 15.7 Indications for Nephron-Sparing Surgery (122)

Indication Conditions

Absolute Anatomically or functionally solitary kidney

Bilateral tumors
Relative Unilateral RCC with diabetes mellitus, hypertension,
renovascular disease, connective tissue diseases
Renal dysfunction
Hereditory or familial RCC
Elective Incidental RCC < 4–7 cm (T1/2, N0, M0)
Type 3 or indeterminate cyst Figure 15.31 Axial contrast-enhanced CT from a patient with VHL with bilateral
small RCCs (arrows) suitable for enucleation surgery or RFA.

262

provides the added advantage of less operative time, and decreased
blood loss. However, in tumors less than 7 cm, laparoscopic partial
nephrectomy has a higher morbidity rate due to more intra- and
postoperative urological complications, and a longer warm renal
ischaemic time. The patients in the open group, despite being
a higher preoperative risk group with larger tumors, decreased
performance status, solitary kidneys, and impaired renal function,
had fewer postoperative complications. This would suggest
laparoscopic partial nephrectomy currently carries a greater
morbidity than open partial nephrectomy and the latter therefore
remains the standard of care (129,130).
Key Points: Nephron-Sparing Surgery
■ In patients with a solitary tumor less than 4 cm the
recurrence-free and long-term survival rates are similar to
those observed following radical surgery
■ Laparoscopic procedures can be expected to become widely
used but the current European guidelines suggest its use is
limited to centers treating renal tumors with laparoscopic
expertise
Imaging for Nephron-Sparing Surgery
Imaging plays a major role in the selection, preoperative evalua-
tion, and surveillance of patients for nephron-sparing surgery.
The surgeon needs to know the position of the kidney, the posi-
tion of the tumor within the kidney, as well as information about
the depth of renal parenchymal invasion, renal sinus invasion, the
relationship, and any invasion of the tumor into the pelvicalyceal
system, perinephric fat invasion the detailed anatomy of the renal
arteries and veins, and the presence of lymphadenopathy and
local or distant metastases (Table 15.8). All this information can
be satisfactorily provided by three-dimensional volume-rendered
CT (Fig. 15.32) and MR in those patients unable to undergo CT.
The current recommended CT technique for the imaging of
tumors suitable for nephron-sparing surgery ideally requires
Table 15.8 Features Assessed on Imaging of Renal Tumors
When Considering Suitability for Curative Nephron Sparing
Surgery (129–131)
Features Open
Tumor size Up to 7 cm
Tumor location in kidney Endophytic or exophytic
Endophytic RCC:
at least 1 cm clear
of calyces and vessels
Renal sinus invasion May be suitablea
Collecting system invasion May be suitablea
Perinephric invasion May be suitablea
Vascular invasion (renal vein Not suitable
and IVC)
Lymphadenopathy Not suitable
Local or distant metastases Not suitable
Document the number of arteries and veins supplying the kidney. Document any
early arterial branches arising less than 1 cm away from the renal ostium
a
Suitable only if solitary kidney, bilateral tumors, limited renal reserve.
renal tumors
MDCT. This provides high-resolution thin sections through the
kidneys at 1–1.5 mm, which can be reformatted for multiplanar
assessment (Fig. 15.33). Non-contrast-enhanced images are
essential to determine the pre-enhancement value of the renal
masses. Next a vascular phase, timed for peak enhancement of
the arteries and veins, to obtain renovascular information aiding
surgery are obtained. These are acquired at peak aortic enhance-
ment (identified by contrast agent bolus tracking) plus five sec-
onds. The third phase is the nephrogenic phase for maximal
lesion detection and enhancement typically at 120–150 seconds.
The arterial and nephrographic phase 1–1.5 mm source data
images are reconstructed as multiplanar coronal and sagittal
images. For complete evaluation of the renal vasculature, maxi-
mum intensity projections (MIPS), and 3D volume rendered
images may be required (131).
MR imaging has been infrequently used for the selection of
patients prior to partial nephrectomy. A small retrospective study
of 41 lesions in 38 patients using contrast-enhanced MR indicated
Figure 15.32 Left renal cell carcinoma. Volume-rendered three-dimensional CT
reformatted from images acquired at 1.25-mm intervals 30 seconds after intrave-
nous contrast medium. Relationship of the 2.5 cm tumor to the intrarenal arteries
and veins is well shown.
Laparoscopic
Up to 4 cm IVC
Exophytic
Aorta
RV
RA
Not suitable
Not suitable
Not suitable
Not suitable
Not suitable
Not suitable
Figure 15.33 Coronal CT reformatted and maximum intensity projection (MIP)
image showing a right upper pole renal cell carcinoma (arrow). The normal renal
vein, single renal artery and IVC are demonstrated. Abbreviations: IVC, inferior
vena cava; RA, renal artery; RV, renal vein.
263
 primary tumor evaluation and staging

(A) (B)

(C) (D)
Figure 15.34 Small renal cell carcinoma (Robson Stage I, T1) on MR. (A) Axial T2-weighted image. (B) Post-contrast enhanced axial T1 fat-saturated breath-hold
gradient-echo sequence. There is a 3.5 cm mid right renal tumor not invading perinephric fat. Volume acquisition three-dimensional gradient-echo MR shows the tumor
arterial supply in the coronal (C) and axial (D) planes. Source: Courtesy of Dr. Sheila Rankin, Guy’s and St. Thomas’ Hospital, London.

that this technique can also identify lesions suitable for partial
nephrectomy, but to date no further or larger studies have been
performed (Fig. 15.34) (101).
Intraoperative ultrasound may be helpful for finding small,
centrally located tumors not detected by the surgeon from the
surface of the kidney. Thus intraoperative ultrasound identified
additional tumors (2–4 cm in size) not detectable by the surgeon
in 25% of 68 patients with hereditary renal cell cancers undergoing
nephron-sparing surgery (132).
Key Points: Imaging for Nephron-Sparing Surgery
■ MDCT has the ability to provide additional neovascular
information to aid surgical planning and approach during
nephron-sparing surgery
■ 3D volume and surface rendering techniques provide the surgeon
with a virtual surface view of the location and size of the tumor,
and its relationship with important surrounding structures
Image-Guided Minimally Invasive Techniques
Multiple minimally invasive techniques are used in the treatment
of small renal cancers including radiofrequency ablation (RFA),
cryoablation, microwave ablation, laser ablation, and high-intensity
focused ultrasound ablation (HIFU). Of these the most widely
used is RFA. The potential benefits of these techniques include
reduced morbidity, the ability to treat patients with co-morbidity,
and to shorten treatment time by conducting the procedure as a
day case or as an outpatient (133–135). The current indications
for minimally invasive procedures include small, incidentally
found renal tumors in elderly patients, familial or multiple renal
tumors, solitary kidney, and bilateral tumors. Although at present
these procedures are reserved for patients not suitable for open
or laparoscopic surgery due to poor performance status, these
procedures are gaining popularity for small (<5 cm) exophytic
peripheral renal tumors (Fig. 15.35). Complete ablation is consis-
tently obtained in tumors smaller than 4 cm and tumors larger
than 5.5 cm rarely achieve complete ablation despite multiple
attempts. Ninety percent of tumors below 3 cm undergo complete
coagulation necrosis at the first attempt. After the second attempt
all tumors have been shown to be fully treated (136). Tumors with
a significant endophytic component and centrally located tumors
close to the collecting system are not usually recommended for RFA
as these present greater technical difficulties compared to the
exophytic tumors. The rich renal hilar blood supply is postulated to
be a source of significant heat loss (heat sink), which precludes the
complete heat ablation of any tumor margins close to the renal hila
(Fig. 15.36). Only 44% of tumors larger than 5.5 cm will be fully

264
 renal tumors

(A) (B)
Figure 15.35 (A) Axial post-contrast CT image demonstrating a small, less than 5 cm tumor in the right kidney (arrow). (B) Coronal CT reformatted images demonstrate
the tumor in the periphery enabling RFA access. Note the small, poorly enhancing left kidney with chronic renal impairment.

(A) (B) (C)

Figure 15.36 (A) Axial post-contrast image demonstrating a central left renal tumor prior to RFA treatment. The medial margins of the tumor lie at the renal hilum. (B)
Axial post-contrast CT acquired one day after RFA treatment with no areas of residual enhancement, pockets of air within the treated area which are almost always present
immediately after RFA. (C) Axial post-contrast image at nine months after treatment demonstrating nodular irregular enhancement along the periphery of the treated
area (arrows).

treated at the first ablation attempt and complete ablation will be
achieved in 61% to 78% of cases after multiple ablation attempts
(136–138). The largest RFA experience reported to date shows that
complications of RFA are infrequent and self-limiting:haemorrhage
(subcapsular hematoma, perinephric hemorrhage, hematuria) is
the commonest complication (5%). Other complications include
urinary leaks, bowel injury, ureteral strictures, skin burns, and
transient lumbar pain. Importantly, no cases of tumor seeding into
the ablation track have been reported (136,137). The contraindica-
tions include a poor life expectancy, multiple metastases, or difficulty
in accessing the tumor due to its location (23).
Key Point: Minimally Invasive Techniques
■ Radiofrequency ablation is a promising minimally invasive
therapy for renal cell carcinoma in patients who are not good
operative candidates and for patients requiring symptom
control of the local tumor in the context of metastatic dis-
ease. Small size and non-central location are favorable tumor
characteristics
Imaging for Radiofrequency Ablation and Post Treatment Surveillance
It is recommended that all patients undergoing RF ablation have a
contrast-enhanced CT or MR prior to treatment to allow compar-
ative evaluation following treatment (137). However, on imaging
alone, particularly in small renal masses, the distinction between
benign and malignant renal masses is often difficult. Up to 34%
of these masses may be benign (139). Most authors therefore
recommend a biopsy of either the renal mass or a metastatic
lesion to confirm RCC either prior to or at the time of RF ablation
(137,139). The CT and MR findings in residual or recurrent RCC
after RF ablation are similar. On CT the presence of enhancing
areas is taken to represent residual disease (Fig. 15.37) and the
pattern depends on the geometric shape of the ablation system
used. These areas of residual tumor may be in the form of multiple
peripheral nodules in the hooked systems or smooth crescent-shaped
enhancement, nodules, and mass-like change in the straight sys-
tems (137). On MR the enhancing tumor patterns are similar to
CT and are best identified and characterized on the T2-weighted
and T1 post-contrast-enhanced images (140). Areas of coagula-
tion necrosis (areas of ablation) are non-enhancing and low
attenuation on CT (Fig. 15.38) and hyperintense on T2-weighted

265
 primary tumor evaluation and staging
(A)
Figure 15.37 (A) Axial post-contrast CT acquired three months after RFA ablation of a small mid pole tumor. There is nodular enhancement in the periphery which is
suspicious of recurrent tumor (arrow). (B) Axial post-contrast CT acquired at nine months, showing the suspicious enhancement has increased in size and now appears
as a definite tumor recurrence in an ablated tumor (arrow).
Figure 15.38 Coronal reformatted post-contrast CT showing a completely treated
RCC (star), with residual perinephric stranding with no enhancement (arrows).
MR images. Immediate post-ablation imaging can demonstrate
a “blooming effect,” particularly on MR where the treated tumor
appears larger than on pre-treatment images. This is thought to
be secondary to a combination of hemorrhage and edema in the
treated tumor. In addition, a thin smooth rim of enhancement
may be observed around the zone of ablation, which disappears
on subsequent imaging. There is commonly non-enhancing
stranding in the perinephric space secondary to inflammatory
changes which slowly resolve and do not represent recurrent or
residual disease (Fig. 15.38) (137,140,141). The main reason for
performing surveillance imaging after RF ablation is the early
detection of residual or recurrent tumor. The optimal time for
follow-up imaging studies varies between institutions and remains
to be determined. Nonetheless, 96% of residual enhancing tumor
can be detected on contrast-enhanced CT or MR performed
266
(B)
between one and three months, and this would be a reasonable
strategy. Once fully treated, longer follow-up intervals of up to one
year are justified by the very low recurrence rates (137).
Key Point: Imaging Surveillance Following RFA
■ The most reliable sign of residual or recurrent disease is the
presence of enhancing soft tissue at the RF ablation site,
either as nodules or crescents. The pattern of enhancement
depends on the system of ablation used
RECURRENT RENAL CELL CARCINOMA
Twenty to thirty percent of patients with RCC that appear to be local-
ized at the time of surgery relapse following radical nephrectomy. However,
fewer than 5% have isolated local recurrence (142,143) and, in the
majority of cases, there are distant metastases (Fig. 15.39).
The stage of the tumor at the time of presentation is the most
important determinant of recurrent disease. The presence of
lymph node involvement, a high Fuhrman grade on histology, and
the presence of a sarcomatoid (spindle cell) architecture also
increase the risk of recurrence (142,144,145). Lymph node infil-
tration at surgery is a particularly strong predictor of recurrent
disease and, even if lymphadenectomy is performed, most tumors
relapse with distant metastases (146). This is of great importance
as up to 20% of patients who undergo radical nephrectomy for
RCC without metastases detected by imaging have regional lymph
node involvement at surgery (147,148).
The median time to relapse following nephrectomy is 15 to
18 months and 85% of relapses occur within three years (143,147).
Tumors with involved nodes tend to recur earlier (145). Very late
relapse, often solitary in the lung, bone, pancreas, or skeletal
muscle, can also occur (149). Lung metastases are the most fre-
quent site of distant relapse accounting for 50% to 60% (143,147).
 renal tumors

(A) (B)

(C)
Figure 15.39 Recurrent renal cell carcinoma following left nephrectomy. Enhanced CT. (A) Tumor nodule in left abdominal wall (arrowed). Normal appearance of left
renal bed containing bowel. (B) Bilateral retrocrural metastases and tumor nodule posterior to stomach (arrowed). (C) Anterior mediastinal node metatases (arrowed).

These metastases may either be hemorrhagic, producing consoli-

dation, or lymphatic (150). Mediastinal nodal infiltration may
accompany the lung metastases. Bone metastases occur less
frequently, are most commonly seen in the lumbar spine, tho-
racic spine, and ribs (145), and are usually lytic. Less commonly,
distant relapse occurs in the contralateral kidney, adrenal gland,
or brain (150–152).
Unusually, distant relapse, either solitary or multiple, occurs in
the pancreas (153) and typically appears hypervascular on
enhanced CT, unlike primary carcinoma of the pancreas, which is
typically hypovascular (Fig. 15.40). Pancreatic relapse may occur
many years following nephrectomy.
Local recurrence produces an enhancing mass at the site of nephre-
ctomy (Figs. 15.39 and 15.41). Following radical nephrectomy, nor-
mal structures, such as bowel, may simulate a recurrent mass.
Distortion of the tail of the pancreas as it drops into the left renal fossa
Figure 15.40 Axial CT image demonstrating ill-defined enhancing masses in the
can be particularly confusing. Recurrences may infiltrate the adjacent
pancreas (arrows) five years following a right nephrectomy for RCC. The patient
quadratus lumborum and psoas muscle. The lymph nodes close to also had lung and bone metastases.
the renal vascular pedicle are the most frequently involved by recur-
rence (151). Direct invasion of the colon or small bowel can occur and
when advanced can result in peritoneal carcinomatosis or mesenteric locally recurrent tumors tended to be diagnosed late when patients
nodal disease (150). were symptomatic and hence surgical treatment was often dan-
The management of isolated local recurrence in the renal fossa gerous with significant morbidity and mortality. However, early
remains controversial because of lack of evidence. In the past, detection by CT surveillance increases the diagnosis of small

267
 primary tumor evaluation and staging

(A) (B) (C)

Figure 15.41 Recurrent renal cell carcinoma on enhanced CT. (A) A 2.5 cm tumor in anterior mid right kidney. (B) Six months after radical nephrectomy there is a 1 cm
recurrent mass (arrowed) posterior to the inferior vena cava. (C) Nine months after resection of the tumor shown in (B) there is a large recurrent mass in the right
renal fossa.

recurrences, making surgery feasible and less dangerous (154,155). Table 15.9 Scoring Algorithm to Predict Metastases after Nephrec-
Although the majority of patients eventually develop metastases, tomy in Clear Cell RCC According to the Mayo Score (162)
surgical treatment of isolated renal fossa recurrence seems to
prolong survival (153,156,157). Feature Score
It has been recommended that routine follow-up after radical Primary tumor/T-stage
nephrectomy for RCC should be stage-dependent (158–160), so T1a 0
that regular follow-up is carried out in patients operated on for pT1b 2
pT2 3
locally advanced disease. Guidelines for follow-up also have to
pT3––pT4 4
take into account the cost-effectiveness of imaging. In recent years,
Tumor size
encouraging results have been achieved using immunotherapy in <10 cm 0
patients with relapse with metastatic disease following nephrec- > 10 cm 1
tomy (142), particularly with metastases located predominantly Regional lymph node status
in the lung. Response rates as high as 30% have been reported pNx/pNo 0
(161). For these reasons, follow-up of patients after radical pN1––pN2 2
nephrectomy is advisable. However, the frequency and duration Nuclear grade
Grade 1−2 0
of surveillance is controversial. We follow the Mayo risk scoring
Grade 3 1
system (Table 15.9) (162) whereby patients are stratified into low, Grade 4 3
intermediate, and high risk (Table 15.10). For low-risk patients, Tumor necrosis
annual chest X-ray and ultrasound of the abdomen are appropri- No necrosis 0
ate, and a CT is performed in cases of possible tumor-related Necrosis 1
symptoms only. In the intermediate to high risk group, CT of the
chest and abdomen are performed six months after nephrectomy,
and then annually for three years (163). The surveillance of late
metastases is controversial as the use of metastectomies and Table 15.10 Cumulative Risk of Metastases (%) in Clear Cell
contralateral renal nephron-sparing surgery would benefit RCC after Nephrectomy Using the Mayo Scores (162)
patients with solitary metastases.
Risk group Year 1 Year 3 Year 5 Year 10
Low 0.5 2.1 2.9 7.5
Key Points: Recurrent Renal Cell Carcinoma Intermediate 9.6 20.2 26.2 35.7
High 42.3 62.9 68.8 76.4
■ Following radical nephrectomy for RCC, 20% to 30% of
patients relapse with distant metastases; 5% develop local
recurrence only
■ Lung metastases are the most frequent site of distant relapse Summary: Renal Cell Carcinoma
■ High-stage, high-grade and lymph node infiltration at the
time of nephrectomy is a very strong predictor of relapse ■ Detailed epidemiological studies are still being conducted into
following nephrectomy those factors that most influence the prognosis of RCC but, in
■ The median time to relapse following nephrectomy is 15 to general, survival is influenced by the stage of disease
18 months ■ Modern non-invasive imaging is extremely important in
■ The management of isolated local recurrence should be surgical determining the form of surgery undertaken

268
 renal tumors

Risk factors for developing upper tract tumors are similar to

■ Detection of venous (particularly IVC) invasion and the
the risk factors for bladder TCC. These include increasing age
superior extent of a tumor thrombus is the most important
over 40 years, smoking, occupational exposure to chemicals
aspect of preoperative imaging assessment
containing hydrocarbons (aniline dyes, azo dyes, and rubber),
■ MR and CT appear to have similar accuracies in detecting
drugs such as cyclophosphamide and its metabolite acrolein,
venous invasion and lymph node involvement
phenacetin abuse, and patients with a strong familial history
■ Currently, CT is the most widely used technique, with MR
(166,167). Upper tract TCCs occur more frequently in men,
kept in reserve to solve particular problems. However, MR is
with a male-to-female ratio of 3:1, and more frequently in Cau-
the most accurate technique in assessing the whole IVC and
casians with a ratio of 2:1. There is an association with Balkan
appears to be able to identify invasion of the vessel wall
nephropathy, a degenerative nephropathy that confers a 100 to
■ Ultrasound is not usually used to stage RCC because of low
200 times increase in the incidence of upper tract TCC which are
accuracy, but is very accurate for assessing involvement of the
generally low grade, multiple, and bilateral. Lynch syndrome II
intrahepatic IVC
includes upper tract TCC, multiple proximal colonic non-polypoid
tumors, and multiple extra-colonic tumors (168,169).
NEOPLASMS OF THE UPPER URINARY TRACT
Tumor Multiplicity
COLLECTING SYSTEM Bilateral upper tract disease occurs in 1% to 5% of patients and
subsequent ipsilateral tumors occur in 14% to 30% of patients
Tumors of the renal calyces and pelvis and of the ureter are much
presenting with an upper tract TCC (166,170). Between 30% and
less common than RCC. Renal collecting system tumors account
75% of patients with upper tract TCC will have a bladder tumor,
for 5% to 8% of all renal tumors and over 90% are transitional cell
either previously, at the same time, or subsequently (165,166).
carcinomas (TCC). Ureteric TCCs are approximately a quarter
This multifocal involvement affects the choice of radiological
less frequent than pelvicalyceal transitional cell tumors. Other
investigation and planning treatment for upper tract TCC. Unlike
renal and ureteric epithelial tumors such as squamous cell carci-
bladder TCC, tumors in the upper tract are usually higher-grade
noma, adenocarcinoma and carcinosarcoma are rare. Mesodermal
(up to 79%), demonstrate a higher rate of unusual morphological
tumors arising from smooth muscle, neural tissue, fibrous tissue,
features (including squamous cell carcinoma, sarcomatoid, and
and blood vessels are very rare (164).
glandular differentiation) and squamous metaplasia. Whereas
85% of bladder TCC present as superficial (<T1) tumors, 45% of
Transitional Cell Carcinoma TCC of the renal pelvis present with locally advanced disease
Tumor Site (>pT2) (Fig. 15.43) (166,171,172). These features emphasize the
The extrarenal pelvis is the commonest site of origin of renal TCC need for more aggressive treatment to upper tract TCC.
(Fig. 15.42), with tumors arising from the infundibulo-calyceal
region less frequently (164). Ureteric tumors most commonly
arise from the lower ureter, followed by the midureter, with the
upper ureter an infrequent site [73%, 24%, and 3%, respectively,
in Babaian’s series (165)]. Upper tract TCCs are much less
frequent than bladder tumors and only account for 5% of all
urothelial tumors.

Figure 15.43 Reformatted post-contrast CT demonstrating an advanced Stage T4

TCC in the renal pelvis invading the renal parenchyma and extending into the
Figure 15.42 Coronal reformatted post-contrast CT showing a poorly enhancing TCC perinephric fat (arrows). An enlarged metastatic lymph node is noted in the left
occupying the renal pelvis (arrow) with resultant hydronephrosis within the kidney. para-aortic region (block arrow).

269
 primary tumor evaluation and staging

Tumor Spread Treatment

Upper tract TCCs spread by direct invasion and by the lymphatic The accepted management for upper tract TCC is a nephro-
route more commonly than hematogenously. Invasion of the renal ureterectomy with removal of the bladder cuff and mucosa, and
veins and IVC occurs but is rare. local lymphadenectomy. Lymphadenectomy is particularly ben-
eficial in detecting microscopic lymph node metastases, which
Clinical and Laboratory Findings dictates the use of adjuvant chemotherapy (175,176). In the
Hematuria is the commonest presenting symptom, occurring in absence of nodal disease, systemic chemotherapy can be avoided.
approximately three quarters (164). Although the hematuria is Lymphadenectomy of macroscopically involved nodes has been
often painless, dull flank pain, and/or ureteric colic are recognized shown to have no therapeutic benefit (175,176). Local excision
presentations. There may also be pyuria, dysuria, and urinary and minimally invasive surgical techniques can be performed
frequency. Urine cytology is more likely to be positive with for patients with a solitary kidney, bilateral tumors, low grade
larger and higher-grade tumors. In one series, 67% of upper tumors or for palliative symptom control in patients unfit for
tract TCCs were diagnosed using urine cytology and 20% were definitive surgery with results comparable to definitive surgery
suspected (173). (177–179). Laparoscopic and percutaneous resection of tumors
are sometimes performed but are not yet widely practised (180).
Accurate preoperative staging is essential before conservative
Staging and Prognosis
surgery is undertaken.
Although no staging system is universally accepted, the TNM
system is the most frequently used (Table 15.11 and Fig. 15.44).
Key Points: TCC Epidemiology and Management
■ TCCs account for 90% of all renal collecting system cancers
but only 5% of all TCCs
Table 15.11 TNM Clinical Classification and Group Staging ■ Smoking, a strong family history, and bladder TCC are the
for Upper Tract Transitional Cell Carcinoma strongest risk factors
■ Invasion of the renal vein and IVC is unusual
Primary tumor (T)
■ Nephro-ureterectomy is the treatment of choice. Adjuvant
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor chemotherapy is beneficial in patients with microscopic nodal
Ta Non-invasive papillary carcinoma metastases
Tis Carcinoma in situ
T1 Tumor invades subepithelial connective tissue
T2 Tumor invades muscularis Imaging in the Evaluation and Staging of Upper
T3 (Renal pelvis) Tumor invades beyond muscularis into Urinary Tract Transitional Cell Carcinoma
peripelvic fat or renal parenchyma Intravenous urography (IVU) and direct pyelography currently
(Ureter) Tumor invades beyond muscularis into periureteric
fat
are the best methods for detecting upper tract TCC (Fig. 15.45),
T4 Tumor invades adjacent organs or through the kidney into although they may be replaced in this role by new techniques
perinephric fat of CT urography. Conventional CT has a role in the diagnosis
Regional lymph nodes (N) of upper tract TCC by demonstrating that lucent filling defects
NX Regional lymph nodes cannot be assessed in the pelvicalyceal system and ureter are caused by soft tissue
N0 No regional lymph node metastasis tumor masses rather than by “lucent” calculi (e.g., urate) or
N1, N2 Metastasis in a single lymph node £2 cm in greatest
dimension
blood clot (Figs. 15.42 and 15.45). Ultrasound can detect
N3 Metastasis in a single lymph node >2 cm but >5 cm in larger tumors and the obstruction they secondarily cause, but
greatest dimension, or multiple lymph nodes, none >5 cm does not show the mucosa and cannot detect most early TCCs.
in greatest dimension Computed tomography is the method of choice for staging
N3 Metastasis in a lymph node >5 cm in greatest dimension TCCs, with MR usually only used if CT is not possible or not
Distant metastasis (M) diagnostic.
MX Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis Intravenous Urography
pTNM pathological classification Meticulous IVU is essential to detect upper tract TCCs and to
The pT, pN, and pM categories correspond to the T, N, and M categories show whether they are multifocal. If conservative surgery is
Group staging criteria
planned, the extent of mucosal involvement is also important.
Stage 0 Ta–Tis N0 M0
Stage I T1 N0 M0
Rarely, speckled calcification is seen in relation to a pelvicalyceal
Stage II T2 N0 M0 tumor on the plain film. Early pelvicalyceal TCCs are seen as single
Stage III T3 N0 M0 or multiple filling defects (Fig. 15.45), usually papillary but some-
Stage IV T4 N0 M0 times flat, and often with an irregular surface giving a stippled
Any T N1–N3 M0 appearance where contrast medium enters the interstices of the
Any T Any N M1
tumor (Fig. 15.46). With tumor growth there may be calyceal
The 5-yr survival for non-infiltrating upper tract TCC without metastases is infundibular stenosis, producing a hydrocalyx (Fig. 15.47), or a
approximately 50%. With invasion, survival decreases to 5% or less (174). tumor mass within the dilated calyx (oncocalyx). Obstruction of

270
 renal tumors

T3

Ta T1 T2

Epithelium

Subepithelial
connective tissue

Muscularis

Periureteric fat
Peripelvic fat

T4

T4 T4

Vertebral body
Figure 15.44 Staging transitional cell cancer of the renal pelvis––primary tumor (T).

Figure 15.46 Coronal reformatted post-contrast enhanced CT demonstrating a

Figure 15.45 IVU tomogram showing a right renal pelvis fixed filling defect large left upper pole TCC with stippled enhancement within the tumor and pools
(arrow) with the typical irregular margins of a TCC. of contrast within the invaded calyces (arrow).

271
 primary tumor evaluation and staging
the calyceal infundibulum produces calyceal amputation (phantom
calyx) and the same process at the pelviureteric junction causes
pelviureteric junction obstruction (181,182). In one series, filling
defects occurred in 35%, with oncocalyx in 26%, calyceal amputation
in 19%, and pelviureteric junction obstruction in 19% (183).
Ureteric TCCs are also seen as single or multiple filling defects
which, if large, may cause dilatation of the ureter and pelvicalyceal
system (Fig. 15.48). If the growth pattern of the tumor is not
papillary, there may be ureteric stricture, usually irregular but
sometimes smooth, and these may also be associated with proximal
dilatation. With larger tumors which obstruct the ureter, no filling
of the pelvicalyceal system and ureter occurs (182).
Direct Pyelography
Direct pyelography, either retrograde or antegrade, may also be
used to define upper tract TCCs. Retrograde pyelography (Fig. 15.49)
Figure 15.47 IVU showing a solitary dilated right lower pole calyx (hydrocalyx)
(arrow) due to a small infundibular TCC seen in the surgical specimen.
Figure 15.48 Distal left ureteric transitional carcinoma. Intravenous urography
shows rounded lucent filling defect causing obstruction.
272
is used when the IVU is not diagnostic and antegrade pyelography
is used when an obstructed kidney has been drained percutane-
ously. Most of the signs are identical to those on IVU. In ureteric
TCC, there is the additional “goblet” sign when the ureter dilates
around the tumor, reflecting the slow tumor growth and differen-
tiating it from other types of filling defect (lucent stone, clot).
Computed Tomography
CT urography includes triple-phase CT, consisting of an unen-
hanced scan, nephrographic phase (100–120 seconds), and excretory
phase (5–7 minutes) after contrast enhancement are all essential.
The addition of the cortico-medulllary phase (27–70 seconds) aids
in the assessment of venous infiltration when the opacification of
the IVC is optimal. Multidetector CT protocols vary at every stage
and currently no consensus exists to the most appropriate protocol.
The most frequently used is a three-phase protocol which typically
includes an initial unenhanced phase, a second enhanced phase
acquired 100 seconds (nephrographic phase) after administration
of 100 ml of intravenous contrast medium and, finally, the pyelo-
graphic phase typically taken 5 to 15 minutes after administration
of contrast medium. Differences exist between institutions at all
stages and the use of saline bolus, use of compression, intravenous
frusemide administration, additional phases (cortico-medullary
phase, cystogram), and timing of the pyelographic phase are some
examples of current variations (184).
Early upper tract TCCs (T1–2) are seen as a focal mass or focal
area of wall-thickening (Fig. 15.50), which shows slight enhance-
ment after contrast medium. The mean unenhanced attenuation
in one series was 39 HU and the mean enhanced attenuation was
65 (185). Masses within dilated calyces (oncocalyces) may be seen,
corresponding with the IVU finding. When a pelvicalyceal mass is
separated from renal parenchyma by sinus fat or contrast medium
Figure 15.49 Left pelvicalyceal transitional cell tumor. Retrograde pyelogram
shows lucent tumor in the pelvis, dilated oncocalyx containing tumor (arrowed)
and no filling of upper pole calyx.
 renal tumors
in the pelvicalyceal system, it can be classified as T1 or T2 (186)
(Fig. 15.50). Secondary dilatation of the calyces or renal pelvis are
considered to be good criteria for non-invasive tumor (187).
With T3 tumors there is loss of the peripelvic fat and areas of
abnormal parenchymal enhancement caused by tumor growth
into the parenchyma. Tumor in the parenchyma has an infiltrative
growth pattern, with maintenance of the reniform contour and
enlargement rather than the rounded mass seen typically with
RCC (Fig. 15.51). Difficulties may occur if there is sinus fat com-
pression which is misinterpreted as invasion, or if there is abnor-
mal parenchymal enhancement for reasons other than invasion
(e.g., obstruction, infection, or vascular occlusion) (188).
T4 tumors extend into the perinephric fat, invade adjacent
structures and/or the renal vein and IVC (Fig. 15.52). Lymph node
involvement can also be detected with the same limitations as
described in the RCC section.
Figure 15.50 Axial post-contrast enhanced CT showing two enhancing TCC nod-
ules (arrows). Both are limited to the renal pelvis and no invasion of the renal
pelvic fat is seen indicating stage T1/T2 lesions.
Figure 15.51 Axial contrast-enhanced CT showing a large upper pole right renal
TCC invading the full thickness of renal parenchyma (Stage T3) but maintaining
the reniform shape (block arrow). Extensive nodal metastases are seen in the
retroperitoneum (arrows).
Staging Accuracy with CT
CT has limited value in staging TCC as it cannot reliably differ-
entiate between low-stage pTa and pT2 tumors, where it may
under- or overstage peripelvic and parenchymal invasion
(187–189). The overall staging accuracy for CT is between 50%
and 60% and early stage tumors remain undetected on conven-
tional CT in 24% to 80% of cases (187,188). With multidetector
CT (MDCT), images collimated down to 1 mm, and multiplanar
imaging, the detection rate of small TCCs has increased to almost
90% but the staging accuracy and, in particular, the differentia-
tion between stages Ta, T1, and T2 remains poor with significant
therapeutic implications (190,191). Patients with Stage Ta–T1
tumors are candidates for nephron-sparing treatment but
patients with T2 tumors require nephro-ureterectomy. Tumor
stage in various studies has been confirmed as an independent
predictor of recurrence and tumors Stage T2 and above do not
benefit from a conservative approach (192–195).
The value of CT lies in demonstrating peripelvic or peri-
ureteral tumor extension in advanced disease (191,195). It
remains the modality of choice to detect direct parenchymal
invasion, extrarenal extension, nodal and venous involvement.
The detection of enlarged lymph nodes is important as it sug-
gests high-stage disease and in this group of patients no benefit
of routine lymphadenectomy has been shown (175,176).
Magnetic Resonance
Although there are no large series, it appears that MR provides
similar morphological findings to CT for the diagnosis of upper
tract TCC. On T1-weighted sequences, TCC has signal intensity
similar to or slightly less than normal parenchyma, and on
T2-weighted sequences signal intensity is similar or slightly more
than normal parenchyma. After gadolinium, TCCs enhance
slightly (93). In one series, MR was reported to be better than CT
for staging upper tract TCC (196), but there are relatively limited
data available. With state-of-the-art equipment, performance of
the two techniques is probably similar and CT is therefore the
technique of choice for staging the disease. More recently, MR has
Figure 15.52 Axial post-contrast enhanced CT showing an infiltrative anterior mid
polar TCC invading the renal cortex, renal vein, and IVC (arrows).
273
 primary tumor evaluation and staging
been advocated as a problem-solving modality in patients with a
high risk of upper tract TCC for evaluating hydronephrosis unex-
plained by standard investigations (196). Targeted high-resolution
T2-weighted images demonstrated ureteral and renal pelvic TCC
in a significant number of patients in whom routine investiga-
tions with IVU and endoscopic techniques had failed to provide a
diagnosis.
Key Points: Transitional Cell Carcinoma
■ Transitional cell tumors may be multicentric, a feature
important in planning treatment
■ The vast majority of TCCs will be detected on IVU, with the
commonest finding being a filling defect within the collecting
system or ureter
■ CT is widely used to stage the disease; however, it is relatively
inaccurate and the major cause of the inaccuracy is its inability
to distinguish Stages 0, I, and II disease
■ MR currently does not have a significant role in staging TCC
of the renal collecting system
Summary: Renal Tumors
■ CT is the most widely used technique in the staging of RCC
and TCC
■ The overall accuracy for MDCT and MR in staging RCC is
similar, varying between 90% and 85%
■ In RCC, both MDCT and MR are extremely accurate in dem-
onstrating venous invasion (>90%) and visceral invasion
(>90%)
■ CT, MR, and ultrasound are relatively inaccurate in detecting
early perinephric spread in RCC
■ Transitional cell tumors are most commonly detected at IVU
or direct pyelography
■ In patients with TCC, CT is the study of choice to detect
parenchymal invasion, extrarenal extension, nodal and
venous involvement
■ Although CT is accurate for staging advanced TCC of the
pelvis and ureter, it is relatively inaccurate in distinguishing
between tumor that is confined to the submucosa (T1) and
tumor that invades the muscularis (T2)
REFERENCES
1. Malkowicz SB. Clinical aspects of renal tumors. Semin Roent-
genol 1995; 30: 102–15.
2. Tomaszewski JE. The pathology of renal tumors. Semin
Roentgenol 1995; 30: 115–27.
3. Lopez-Beltran A, Scarpelli M, Montironi R, Kirkali Z. 2004
WHO classification of the renal tumors of the adults. Eur
Urol 2006; 49: 798–805.
4. American Cancer Society. [Available from: www.cancer.org/
docroot/CRI/content/CRI]. Accessed 8.03.08.
5. Cancer Research UK. [Available from: http://info.cancerresearchuk.
org/cancerstats]. Accessed 8.03.08.
274
6. Hock LM, Lynch J, Balaji KC. Increasing incidence of all
stages of kidney cancer in the last two decades in the United
States: an analysis of surveillance, epidemiology and end
results program data. J Urol 2002; 157: 57–60.
7. Patard JJ, Shvarts O, Lam JS, et al. Safety and efficacy of
partial nephrectomy for all T1 tumours based on an inter-
national multicenter experience. J Urol 2004; 171(6 Pt 1):
2181–5.
8. Levine E. Renal cell carcinoma: clinical aspects, imaging
diagnosis, and staging. Semin Roentgenol 1995; 30: 128–48.
9. Bennington JL, Beckwith JB. Tumors of the kidney, renal pel-
vis and ureter (Fascicle 12). Atlas of Tumor Pathology. Armed
Forces Institute of Pathology, Washington, DC, 1975.
10. McLaughlin JK, Lipworth L, Tarone RE. Epidemiologic aspects
of renal cell carcinoma. Semin Oncol 2006; 33: 527–33.
11. Levine E, Collins DL, Horton WA, Schimke RN. CT screen-
ing of the abdomen in von Hippel–Lindau disease. Am J
Roentgenol 1982; 139: 505–10.
12. Mellemgaard A, Lindblad P, Schlehofer B, et al. International
renal-cell cancer study. III. Role of weight, height, physical
activity, and use of amphetamines. Int J Cancer 1995; 60:
350–4.
13. Wolk A, Lindblad P, Adami HO. Nutrition and renal cell cancer.
Cancer Cause Control 1996; 7: 5–18.
14. McLaughlin JK, Mandel JS, Blot WJ, et al. A population-based
case-control study of renal cell carcinoma. J Natl Cancer Inst
1984; 72: 275–84.
15. Yu MC, Mack TM, Hanisch R, Cicioni C, Henderso BE. Ciga-
rette smoking, obesity, diuretic use, and coffee consumption as
risk factors for renal cell carcinoma. J Natl Cancer Inst 1986;
77: 351–6.
16. Mandel JS, McLaughlin JK, Schlehofer B, et al. International
renal-cell cancer study. IV. Occupation. Int J Cancer 1995; 61:
601–5.
17. de Kernion JB, Belldegrun A. Renal tumors. In: Walsh PC,
Retik AB, Stamey TA, et al., eds. Campbell’s Urology. Philadelphia:
W B Saunders, 1982: 1053–62.
18. Lee CT, Katz J, Fearn PA, Russo P. Mode of presentation of
renal cell carcinoma provides prognostic information. Urol
Oncol 2002; 7: 135–40.
19. Smith SJ, Bosniak MA, Megibow AJ, et al. Renal cell carci-
noma: earlier discovery and increased detection. Radiology
1989; 170: 699–703.
20. Holland JM. Proceedings: cancer of the kidney: natural history
and staging. Cancer 1973; 32: 1030–42.
21. Greene FL, Page DL, Fleming ID, et al., eds. AJCC Cancer
Staging Handbook, 6th edn. TNM Classification of Malig-
nant Tumors. New York: Springer-Verlag, 2002.
22. Robson CJ, Churchill BM, Anderson W. The results of radical
nephrectomy for renal cell carcinoma. J Urol 1969; 101:
297–301.
23. Ljungberg B, Hanbury DC, Kuczyk MA, et al. European
Association of Urology Guideline Group for renal cell carci-
noma. Renal cell carcinoma guideline. Eur Urol 2007; 51:
1502–10.
24. Guinan P, Saffrin R, Stuhldreher D, Frank W, Rubenstein M.
Renal cell carcinoma: comparison of the TNM and Robson
stage groupings. J Surg Oncol 1995; 59: 186–9.
 renal tumors
25. Montie JE. Prognostic factors for renal cell carcinoma. J Urol
1994; 152: 1397–8.
26. Skinner DG, Vermillion CD, Colvin RB. The surgical man-
agement of renal cell carcinoma. J Urol 1972; 107: 705–10.
27. Guinan P, Frank W, Saffrin R, Rubenstein M. Staging and
survival of patients with renal cell carcinoma. Semin Surg
Oncol 1994; 10: 47–50.
28. Targonski PV, Frank W, Stuhldreher D, Guinan PD. Value of
tumor size in predicting survival from renal cell carcinoma
among tumors, nodes and metastases stage 1 and stage
2 patients. J Urol 1994; 152: 1389–92.
29. Reis M, Faria V. Renal carcinoma. Reevaluation of prognostic
factors. Cancer 1988; 61: 1192–9.
30. Bell ET. Tumors of the kidneys: Renal Disease. Philadelphia:
Lea & Febiger, 1950: 424–42.
31. Lieber MM, Tomera FM, Taylor WF, Farrow GM. Renal
adenocarcinoma in young adults: survival and variables
affecting prognosis. J Urol 1981; 125: 154–8.
32. Fuhrman SA, Lasky LC, Limas C. Prognostic significance of
morphologic parameters in renal cell carcinoma. Am J Surg
Pathol 1982; 6: 655–63.
33. Ljungberg B, Joanssen H, Stenling R. Prognostic factors in
renal cell carcinoma. Int Urol Nephrol 1988; 20: 115–21.
34. Selli C, Hinshaw WM, Woodard BH, Paulson DF. Stratifica-
tion of risk factors in renal cell carcinoma. Cancer 1983; 52:
899–903.
35. Strohmeyer T, Ackermann R. Classic and modern prognostic
indicators in renal cell carcinoma. Review of the literature.
Urol Int 1991; 47: 203–12.
36. Cherrie RJ, Goldman DG, Lindner A, deKernion JB. Prog-
nostic implications of vena caval extension of renal cell
carcinoma. J Urol 1982; 128: 910–12.
37. Canfield SE, Kamat AM, Sánchez-Ortiz RF, et al. Renal cell
carcinoma with nodal metastases in the absence of distant
metastatic disease (clinical stage TxN1-2M0): the impact of
aggressive surgical resection on patient outcome. J Urol 2006;
175(3 Pt 1): 864–9.
38. Waters WB, Richie JP. Aggressive surgical approach to renal
cell carcinoma: review of 130 cases. J Urol 1979; 122: 306–9.
39. McNichols DW, Segura JW, DeWeerd JH. Renal cell carci-
noma: long-term survival and late recurrence. J Urol 1981;
126: 17–23.
40. Virdi JS, Kelly DG. Prognostic value of renal venous involve-
ment in renal carcinoma. Br J Urol 1992; 69: 481–5.
41. Kirkali Z, Van Poppel H. A critical analysis of surgery for
kidney cancer with vena cava invasion. Eur Urol 2007; 52:
658–62.
42. Maldazys JD, deKernion JB. Prognostic factors in metastatic
renal carcinoma. J Urol 1986; 136: 376–9.
43. Boxer RJ, Waisman J, Lieber MM, Mampaso FM, Skinner
DG. Renal carcinoma: computer analysis of 96 patients
treated by nephrectomy. J Urol 1979; 122: 598–601.
44. Thrasher JB, Paulson DF. Prognostic factors in renal cancer.
Urol Clin North Am 1993; 20: 247–62.
45. Lang H, Lindner V, de Fromont M, et al. Multicenter determina-
tion of optimal interobserver agreement using the Fuhrman
grading system for renal cell carcinoma: assessment of
241 patients with >15-year follow-up. Cancer 2005; 103: 625–9.
46. Cheville JC, Lohse CM, Zincke H, Weaver AL, Blute ML.
Comparisons of outcome and prognostic features among
histologic subtypes of renal cell carcinoma. Am J Surg Pathol
2003; 27: 612–24.
47. Patard JJ, Leray E, Rioux-Leclercq N, et al. Prognostic value
of histologic subtypes in renal cell carcinoma: a multicenter
experience. J Clin Oncol 2005; 23: 2763–71.
48. Zisman A, Pantuck AJ, Figlin RA, Belldegrun AS. Validation
of the UCLA integrated staging system for patients with renal
cell carcinoma. J Clin Oncol 2001; 19: 3792–3.
49. Motzer RJ, Mazumdar M, Bacik J, et al. Survival and prog-
nostic stratification of 670 patients with advanced renal cell
carcinoma. J Clin Oncol 1999; 17: 2530–40.
50. Wickham JE. Conservative renal surgery for adenocarcinoma.
The place of bench surgery. Br J Urol 1975; 47: 25–36.
51. Zincke H, Engen DE, Henning KM, McDonald MW. Treat-
ment of renal cell carcinoma by in situ partial nephrectomy
and extracorporeal operation with autotransplantation. Mayo
Clin Proc 1985; 60: 651–62.
52. Lerner SE, Hawkins CA, Blute ML, et al. Disease outcome in
patients with low stage renal cell carcinoma treated with nephron-
sparing or radical surgery. J Urol 1996; 155: 1868–73.
53. Robey EL, Schellhammer PF. The adrenal gland and renal cell
carcinoma: is ipsilateral adrenalectomy a necessary compo-
nent of radical nephrectomy? J Urol 1986; 135: 453–5.
54. Kuczyk M, Wegener G, Jonas U. The therapeutic value of
adrenalectomy in case of solitary metastatic spread originating
from primary renal cell cancer. Eur Urol 2005: 48: 252–7.
55. Yokoyama H, Tanaka M. Incidence of adrenal involvement
and assessing adrenal function in patients with renal cell
carcinoma: is ipsilateral adrenalectomy indispensable during
radical nephrectomy? BJU Int 2005; 95: 526–9.
56. Terrone C, Cracco C, Porpiglia F, et al. Reassessing the current
TNM lymph node staging for renal cell carcinoma. Eur Urol
2006; 49: 324–31.
57. McClennan BL. Computed tomography in the diagnosis and
staging of renal cell carcinoma. Semin Urol 1985; 3: 111–31.
58. Zini L, Destrieux-Garnier L, Leroy X, et al. Renal vein ostium
wall invasion of renal cell carcinoma with an inferior vena
cava tumor thrombus: prediction by renal and vena caval
vein diameters and prognostic significance. J Urol 2008; 179:
450–4.
59. Kallman DA, King BF, Hattery RR, et al. Renal vein and inferior
vena cava tumor thrombus in renal cell carcinoma: CT, US, MRI
and venacavography. J Comput Assist Tomogr 1992; 15: 240–7.
60. Ficarra V, Galfano A, Guillé F, et al. A new staging system for
locally advanced (pT3-4) renal cell carcinoma: a multicenter
European study including 2,000 patients. J Urol 2007; 178:
418–24.
61. Zagoria RJ, Bechtold RE, Dyer RB. Staging of renal adenocar-
cinoma: role of various imaging procedures. Am J Roentgenol
1995; 154: 363–70.
62. Johnson DE, Kaesler KE, Samuels ML. Is nephrectomy justi-
fied in patients with metastatic renal carcinoma? J Urol 1975;
114: 27–9.
63. Montie JE, Stewart BH, Straffon RA, et al. The role of
adjunctive nephrectomy in patients with metastatic renal
cell carcinoma. J Urol 1977; 117: 272–5.
275
 primary tumor evaluation and staging
64. Parks CM, Kellett MJ. Staging renal cell carcinoma. Clin
Radiol 1994; 49: 223–30.
65. Kabala JE, Gillatt DA, Persad RA, et al. Magnetic resonance
imaging in the staging of renal cell carcinoma. Br J Radiol
1991; 64: 683–9.
66. Hricak H, Thoeni RF, Carroll PR, et al. Detection and staging
of renal neoplasms: a reassessment of MR imaging. Radiol-
ogy 1988; 156: 643–9.
67. Webb JA, Murray A, Bary PR, Hendry WF. The accuracy and
limitations of ultrasound in the assessment of venous exten-
sion in renal carcinoma. Br J Urol 1987; 60: 14–17.
68. Levine E, Maklad NF, Rosenthal SJ, Lee KR, Weigel J.
Comparison of computed tomography and ultrasound in
abdominal staging of renal cancer. Urology 1980; 15:
317–22.
69. London NJ, Messios N, Kinder RB, et al. A prospective study
of the value of conventional CT, dynamic CT, ultrasonogra-
phy and arteriography for staging renal carcinoma. Br J Urol
1989; 64: 209–17.
70. Johnson CD, Dunnick NR, Cohan RH, Illescas FF. Renal ade-
nocarcinoma: CT staging of 100 tumors. Am J Roentgenol
1987; 148: 59–63.
71. Catalano C, Fraioli F, Laghi A, et al. High-resolution multide-
tector CT in the preoperative evaluation of patients with
renal cell carcinoma. Am J Roentgenol 2003; 180: 1271–7.
72. Cohan RH, Sherman LS, Korobkin M, Bass JC, Francis IR.
Renal masses: assessment of corticomedullary-phase and
nephrographic-phase CT scans. Radiology 1995; 196:
445–51.
73. Szolar DH, Kammerhuber F, Altziebler S, et al. Multiphasic
helical CT of the kidney: increased conspicuity for detection
and characterization of small (<3 cm) renal masses. Radiol-
ogy 1997; 202: 211–17.
74. Kopka L, Fischer U, Zoeller G, et al. Dual-phase helical CT
of the kidney: value of the corticomedullary and nephro-
graphic phase for evaluation of renal lesions and preopera-
tive staging of renal cell carcinoma. Am J Roentgenol 1997;
159: 1573–8.
75. Birnbaum BA, Jacobs JE, Ramchandani P. Multiphasic renal
CT: comparison of renal mass enhancement during the cor-
ticomedullary and nephrographic phases. Radiology 1996;
200: 753–8.
76. Takebayashi S, Hidai H, Chiba T, et al. Using helical CT
to evaluate renal cell carcinoma in patients undergoing
hemodialysis: value of early enhanced images. Am J Roent-
genol 1999; 172: 429–33.
77. Raptopoulos VD, Blake SP, Weisinger K, et al. Multiphase
contrast-enhanced helical CT of liver metastases from renal
cell carcinoma. Eur Radiol 2001; 11: 2504–9.
78. McClennan BL. Oncologic imaging. Staging and follow-up
of renal and adrenal carcinoma. Cancer 1991; 67: 1199–208.
79. Singer J, McClennan BL. The diagnosis, staging, and
follow-up of carcinomas of the kidney, bladder, and prostate:
the role of cross-sectional imaging. Semin Ultrasound CT
MR 1989; 10: 481–97.
80. Zagoria RJ, Wolfman NT, Karstaedt N, et al. CT features of
renal cell carcinoma with emphasis on relation to tumor size.
Invest Radiol 1990; 25: 261–6.
276
81. Welch TJ, LeRoy AJ. Helical and electron beam CT scanning
in the evaluation of renal vein involvement in patients with
renal cell carcinoma. J Comput Assist Tomogr 1997; 21:
467–71.
82. Lawrentschuk N, Gani J, Riordan R, Esler S, Bolton DM.
Multidetector computed tomography vs magnetic resonance
imaging for defining the upper limit of tumour thrombus in
renal cell carcinoma: a study and review. BJU Int 2005; 96:
291–5.
83. Stern Padovan R, Perkov D, Smiljanic R, Oberman B, Potocki
K. Venous spread of renal cell carcinoma: MDCT. Abdom
Imaging 2007; 32: 530–7.
84. Hallscheidt PJ, Fink C, Haferkamp A, et al. Preoperative stag-
ing of renal cell carcinoma with inferior vena cava thrombus
using multidetector CT and MRI: prospective study with his-
topathological correlation. J Comput Assist Tomogr 2005;
29: 64–8.
85. Zeman RK, Cronan JJ, Rosenfield AT, et al. Renal cell carcinoma:
dynamic thin-section CT assessment of vascular invasion and
tumor vascularity. Radiology 1988; 157: 393–6.
86. Wyatt SH, Urban BA, Fishman EK. Spiral CT of the kidneys:
role in characterization of renal disease. Part II: Neoplastic
disease. Crit Rev Diagn Imaging 1995; 36: 39–72.
87. Fein AB, Lee JK, Balfe DM, et al. Diagnosis and staging of
renal cell carcinoma: a comparison of MR imaging and CT.
Am J Roentgenol 1987; 148: 749–53.
88. Birnbaum BA, Bosniak MA. MRI of Renal Cell Carcinoma.
CT and MRI of the Genitourinary Tract. Edinburgh:
Churchill Livingstone, 1990: 25–42.
89. Studer UE, Scherz S, Scheidegger J, et al. Enlargement of
regional lymph nodes in renal cell carcinoma is often not due
to metastases. J Urol 1990; 144: 243–5.
90. Hatcher PA, Paulson DF, Anderson EE. Accuracy in staging
of renal cell carcinoma involving vena cava. Urology 1992;
39: 27–30.
91. Levine E, Lee KR, Weigel J. Preoperative determination of
abdominal extent of renal cell carcinoma by computed
tomography. Radiology 1979; 132: 395–8.
92. Sawai Y, Kinouchi T, Mano M, et al. Ipsilateral adrenal
involvement from renal cell carcinoma: retrospective study
of the predictive value of computed tomography. Urology
2002; 59: 28–31.
93. Pretorius ES, Wickstrom ML, Siegelman ES. MR imaging of
renal neoplasms. Magn Reson Imaging Clin N Am 2000; 8:
813–36.
94. Semelka RC, Shoenut JP, Magro CM, et al. Renal cancer staging:
comparison of contrast-enhanced CT and gadolinium-
enhanced fat-suppressed spin-echo and gradient-echo MR
imaging. J Magn Reson Imaging 1993; 3: 597–602.
95. Semelka RC, Hricak H, Stevens SK, et al. Combined gadolinium-
enhanced and fat-saturation MR imaging of renal masses.
Radiology 1991; 178: 803–9.
96. Sohaib SA, Teh J, Nargund VH, et al. Assessment of tumour
invasion of the vena caval wall in renal cell carcinoma cases
by magnetic resonance imaging. J Urol 2002; 157: 1271–5.
97. Choyke PL, Walther MM, Wagner JR, et al. Renal cancer:
preoperative evaluation with dual-phase three-dimensional
MR angiography. Radiology 1997; 205: 767–71.
 renal tumors
98. Semelka RC, Shoenut JP, Kroeker MA, MacMahon RG,
Greenberg HM. Renal lesions: controlled comparison between
CT and 1.5-T MR imaging with nonenhanced and gadolinium-
enhanced fat-suppressed spin-echo and breath-hold FLASH
techniques. Radiology 1992; 182: 425–30.
99. Krestin GP. Magnetic resonance imaging of the kidneys:
current status. Magn Reson Q 1994; 10: 2–21.
100. Ergen FB, Hussain HK, Caoili EM, et al. MRI for preoperative
staging of renal cell carcinoma using the 1997 TNM classifi-
cation: comparison with surgical and pathologic staging. Am
J Roentgenol 2004; 182: 217–25.
101. Pretorius ES, Siegelman ES, Ramchandani P, Cangiano T,
Banner MP. Renal neoplasms amenable to partial nephrectomy:
MR imaging. Radiology 1999; 212: 28–34.
102. Eilenberg SS, Lee JK, Brown J, Mirowitz SA, Tartar VM. Renal
masses: evaluation with gradient-echo Gd-DTPA-enhanced
dynamic MR imaging. Radiology 1990; 176: 333–8.
103. Hricak H, Demas BE, Williams RD, et al. Magnetic resonance
imaging in the diagnosis and staging of renal and perirenal
neoplasms. Radiology 1985; 154: 709–15.
104. Patel SK, Stack CM, Turner DA. Magnetic resonance imaging
in staging of renal cell carcinoma. Radiographics 1987; 7:
703–8.
105. Harisinghani MG, Saksena MA, Hahn PF, et al. Ferumoxtran-
10-enhanced MR lymphangiography: does contrast-enhanced
imaging alone suffice for accurate lymph node characterization?
Am J Roentgenol 2006; 186: 144–8.
106. Will O, Purkayastha S, Chan C, et al. Diagnostic precision of
nanoparticle-enhanced MRI for lymph-node metastases: a
meta-analysis. Lancet Oncol 2006; 7: 52–60.
107. Fritzsche PJ, Millar C. Multimodality approach to staging
renal cell carcinoma. Urol Radiol 1992; 14: 3–7.
108. Didier D, Racle A, Etievent JP, Weill F. Tumour thrombus of
the inferior vena cava secondary to malignant abdominal
neoplasms: US and CT evaluation. Radiology 1987; 152:
83–9.
109. Schwerk WB, Schwerk WN, Rodeck G. Venous renal tumour
extension: a prospective US evaluation. Radiology 1985; 156:
491–5.
110. Habboub HK, Abu-Yousef MM, Williams RD, See WA,
Schweiger GD. Accuracy of color Doppler sonography in
assessing venous thrombus extension in renal cell carcinoma.
Am J Roentgenol 1997; 158: 267–71.
111. Spahn M, Portillo FJ, Michel MS, et al. Color Duplex sono-
graphy vs. computed tomography: accuracy in the preoperative
evaluation of renal cell carcinoma. Eur Urol 2001; 40:
337–42.
112. Sun JP, Asher CR, Xu Y, et al. Inferior vena caval masses identi-
fied by echocardiography. Am J Cardiol 1999; 84: 613–15, A9.
113. Hoh CK, Seltzer MA, Franklin J, et al. Positron emission
tomography in urological oncology. J Urol 1998; 159:
347–56.
114. Hofer C, Kubler H, Hartung R, Breul J, Avril N. Diagnosis and
monitoring of urological tumors using positron emission
tomography. Eur Urol 2001; 40: 481–7.
115. Bachor R, Kotzerke J, Gottfried HW, et al. Positron emission
tomography in diagnosis of renal cell carcinoma. Urologe A
1996; 35: 146–50.
116. Goldberg MA, Mayo-Smith WW, Papanicolaou N, Fischman
AJ, Lee MJ. FDG PET characterization of renal masses:
preliminary experience. Clin Radiol 1997; 52: 510–15.
117. Montravers F, Grahek D, Kerrou K, et al. Evaluation of FDG
uptake by renal malignancies (primary tumor or metastases)
using a coincidence detection gamma camera. J Nucl Med
2000; 41: 78–84.
118. Blake MA, McKernan M, Setty B, Fischman AJ, Mueller PR.
Renal oncocytoma displaying intense activity on 18F-FDG
PET. Am J Roentgenol 2006; 186: 269–70.
119. Ramdave S, Thomas GW, Berlangieri SU, et al. Clinical role
of F-18 fluorodeoxyglucose positron emission tomography
for detection and management of renal cell carcinoma. J Urol
2001; 156: 825–30.
120. Dilhuydy MS, Durieux A, Pariente A, et al. PET scans for
decision-making in metastatic renal cell carcinoma: a single
institution evaluation. Oncology 2006; 70: 339–44.
121. Staudenherz A, Steiner B, Puig S, Kainberger F, Leitha T. Is
there a diagnostic role for bone scanning of patients with a
high pretest probability for metastatic renal cell carcinoma?
Cancer 1999; 85: 153–5.
122. Koga S, Tsuda S, Nishikido M, et al. The diagnostic value of
bone scan in patients with renal cell carcinoma. J Urol 2001;
156: 2126–8.
123. Uzzo RG, Novick AC. Nephron sparing surgery for renal
tumors: indications, techniques and outcomes. J Urol 2001;
156: 6–18.
124. Gschwend JE, Vogel U, Bader C, Mattfeldt T, Hautmann RE.
Predictive value of magnetic resonance imaging and com-
puterized tomography for conservative renal surgery in an
ex vivo tumor enucleation study followed by step-sectioning.
J Urol 1996; 155: 451–4.
125. Hafez KS, Novick AC, Campbell SC. Patterns of tumor recur-
rence and guidelines for follow up after nephron sparing surgery
for sporadic renal cell carcinoma. J Urol 1997; 157: 2067–70.
126. Fergany AF, Hafez KS, Novick AC. Long-term results of
nephron sparing surgery for localized renal cell carcinoma:
10-year follow-up. J Urol 2000; 153: 442–5.
127. Herring JC, Enquist EG, Chernoff A, et al. Parenchymal spar-
ing surgery in patients with hereditary renal cell carcinoma:
10-year experience. J Urol 2001; 155: 777–81.
128. Patard JJ, Pantuck AJ, Crepel M, et al. Morbidity and clinical
outcome of nephron-sparing surgery in relation to tumour
size and indication. Eur Urol 2007; 52: 148–54.
129. Gill IS, Matin SF, Desai MM, et al. Comparative analysis of
laparoscopic versus open partial nephrectomy for renal
tumors in 200 patients. J Urol 2003; 170: 64–8.
130. Gill IS, Kavoussi LR, Lane BR, et al. Comparison of 1,800
laparoscopic and open partial nephrectomies for single renal
tumors. J Urol 2007; 178: 41–6.
131. Coll DM, Uzzo RG, Herts BR, et al. 3-dimensional volume
rendered computerized tomography for preoperative evalua-
tion and intraoperative treatment of patients undergoing
nephron sparing surgery. J Urol 1999; 151: 1097–102.
132. Choyke PL, Pavlovich CP, Daryanani KD, et al. Intraopera-
tive ultrasound during renal parenchymal sparing surgery
for hereditary renal cancers: a 10-year experience. J Urol
2001; 155: 397–400.
277
 primary tumor evaluation and staging
133. Lui KW, Gervais DA, Arellano RA, Mueller PR. Radiofrequency
ablation of renal cell carcinoma. Clin Radiol 2003; 58: 905–13.
134. Merkle EM, Nour SG, Lewin JS. MR imaging follow-up
after percutaneous radiofrequency ablation of renal cell
carcinoma: findings in 18 patients during first 6 months.
Radiology 2005; 235: 1065–71.
135. Gill IS, Remer EM, Hasan WA, et al. Renal cryoablation:
outcome at 3 years. J Urol 2005; 173: 1903–7.
136. Gervais DA, McGovern FJ, Arellano RS, McDougal WS,
Mueller PR. Radiofrequency ablation of renal cell carcinoma:
part 1. Indications, results, and role in patient management
over a 6-year period and ablation of 100 tumors. Am J Roent-
genol 2005; 185: 64–71.
137. Gervais DA, Arellano RS, McGovern FJ, McDouglas WS,
Mueller PR. Radiofrequency ablation of renal cell carcinoma:
part 2. Lessons learned with ablation of 100 tumors. Am J
Roentgenol 2005; 185: 72–80.
138. Farrell MA, Charboneau WJ, DiMarco DS, et al. Imaging-
guided radiofrequency ablation of solid renal tumors. Am J
Roentgenol 2003; 180: 1509–13.
139. Tuncali K, vanSonnenberg E, Shankar S, et al. Evaluation of
patients referred for percutaneous ablation of renal tumors:
importance of a preprocedural diagnosis. Am J Roentgenol
2004; 183: 575–82.
140. Merkle EM, Nour SG, Lewin JS. MR imaging follow-up after
percutaneous radiofrequency ablation of renal cell carcinoma:
findings in 18 patients during first 6 months. Radiology 2005;
235: 1065–71.
141. Farrell MA, Charboneau WJ, DiMarco DS, et al. Imaging-
guided radiofrequency ablation of solid renal tumors. Am J
Roentgenol 2003; 180: 1509–13.
142. Motzer RJ, Russo P, Nanus DM, Berg WJ. Renal cell carci-
noma. Curr Probl Cancer 1997; 21: 185–232.
143. Sandock DS, Seftel AD, Resnick MI. A new protocol for the
followup of renal cell carcinoma based on pathological stage.
J Urol 1995; 154: 28–31.
144. Zisman A, Pantuck AJ, Wieder J, et al. Risk group assessment
and clinical outcome algorithm to predict the natural history
of patients with surgically resected renal cell carcinoma.
J Clin Oncol 2002; 20: 4559–66.
145. Saidi JA, Newhouse JH, Sawczuk IS. Radiologic follow-up of
patients with T1–3a,b,c or T4N+M0 renal cell carcinoma
after radical nephrectomy. Urology 1998; 52: 1000–3.
146. Phillips E, Messing EM. Role of lymphadenectomy in the
treatment of renal cell carcinoma. Urology 1993; 41: 9–15.
147. Rabinovitch RA, Zelefsky MJ, Gaynor JJ, Fuks Z. Patterns of
failure following surgical resection of renal cell carcinoma:
implications for adjuvant local and systemic therapy. J Clin
Oncol 1994; 12: 206–12.
148. Herrlinger A, Schrott KM, Schott G, Sigel A. What are the ben-
efits of extended dissection of the regional renal lymph nodes in
the therapy of renal cell carcinoma. J Urol 1991; 146: 1224–7.
149. Newmark JR, Newmark GM, Epstein JI, Marshall FF. Solitary
late recurrence of renal cell carcinoma. Urology 1994; 43:
725–8.
150. Scatarige JC, Sheth S, Corl FM, Fishman EK. Patterns of
recurrence in renal cell carcinoma: manifestations on helical
CT. Am J Roentgenol 2001; 177: 653–8.
278
151. Johnsen JA, Hellsten S. Lymphatogenous spread of renal cell
carcinoma: an autopsy study. J Urol 1997; 157: 450–3.
152. Saitoh H, Nakayama M, Nakamura K, Satoh T. Distant meta-
stasis of renal adenocarcinoma in nephrectomized cases.
J Urol 1982; 127: 1092–5.
153. Ghavamian R, Klein KA, Stephens DH, et al. Renal cell carci-
noma metastatic to the pancreas: clinical and radiological
features. Mayo Clin Proc 2000; 75: 581–5.
154. Schrodter S, Hakenberg OW, Manseck A, Leike S, Wirth MP.
Outcome of surgical treatment of isolated local recurrence
after radical nephrectomy for renal cell carcinoma. J Urol
2002; 157: 1530–3.
155. Esrig D, Ahlering TE, Lieskovsky G, Skinner DG. Experience
with fossa recurrence of renal cell carcinoma. J Urol 1992;
147: 1491–4.
156. Itano NB, Blute ML, Spotts B, Zincke H. Outcome of isolated
renal cell carcinoma fossa recurrence after nephrectomy.
J Urol 2000; 154: 322–5.
157. Campbell SC, Novick AC. Management of local recurrence
following radical nephrectomy or partial nephrectomy. Urol
Clin North Am 1994; 21: 593–9.
158. Levy DA, Slaton JW, Swanson DA, Dinney CP. Stage specific
guidelines for surveillance after radical nephrectomy for local
renal cell carcinoma. J Urol 1998; 159: 1153–7.
159. Ljungberg B, Alamdari FI, Rasmuson T, Roos G. Follow-up
guidelines for nonmetastatic renal cell carcinoma based on
the occurrence of metastases after radical nephrectomy. Br J
Urol Int 1999; 84: 405–11.
160. Bromwich E, Aitchison M. How should patients be followed
up after radical nephrectomy for renal cell cancer? Br J Urol
Int 2002; 89: 1–4.
161. Neidhart JA, Anderson SA, Harris JE, et al. Vinblastine fails to
improve response of renal cancer to interferon alfa-n1: high
response rate in patients with pulmonary metastases. J Clin
Oncol 1991; 9: 832–6.
162. Leibovich BC, Blute ML, Cheville JC, et al. Prediction of pro-
gression after radical nephrectomy for patients with clear cell
renal cell carcinoma: a stratification tool for prospective clin-
ical trials. Cancer 2003; 97: 1563–71.
163. Junaid I, Barua J. North East London Cancer Network Guide-
lines: Urology. Renal Cancer, 2006.
164. Nocks BN, Heney NM, Daly JJ, et al. Transitional cell carci-
noma of renal pelvis. Urology 1982; 19: 472–7.
165. Babaian RJ, Johnson DE. Primary carcinoma of the ureter. J
Urol 1980; 123: 357–9.
166. Olgac S, Mazumdar M, Dalbagni G, Reuter VE. Urothelial
carcinoma of the renal pelvis: a clinicopathologic study of
130 cases. Am J Surg Pathol 2004; 28: 1545–52.
167. Jensen OM, Knudsen JB, McLaughlin JK, Sorensen BL. The
Copenhagen case-control study of renal pelvis and ureter
cancer: role of smoking and occupational exposures. Int J
Cancer 1988; 41: 557–61.
168. Greenland JE, Weston PM, Wallace DM. Familial transitional
cell carcinoma and the Lynch syndrome II. Br J Urol 1993;
72: 177–80.
169. Stefanovic V, Toncheva D, Atanasova S, Polenakovic M.
Etiology of Balkan endemic nephropathy and associated
urothelial cancer. Am J Nephrol 2006; 26: 1–11.
 renal tumors
170. Stewart GD, Bariol SV, Grigor KM, Tolley DA, McNeill SA. A
comparison of the pathology of transitional cell carcinoma
of the bladder and upper urinary tract. BJU Int 2005; 95:
791–3.
171. Perez-Montiel D, Wakely PE, Hes O, Michal M, Suster S.
High-grade urothelial carcinoma of the renal pelvis: clinico-
pathologic study of 108 cases with emphasis on unusual
morphologic variants. Mod Pathol 2006; 19: 494–503.
172. Highman WJ. Transitional carcinoma of the upper urinary
tract: a histological and cytopathological study. J Clin Pathol
1986; 39: 297–305.
173. Guinan P, Vogelzang NJ, Randazzo R, et al. Renal pelvic cancer:
a review of 611 patients treated in Illinois 1975–1985. Cancer
Incidence and End Results Committee. Urology 1992; 40:
393–9.
174. Miyake H, Hara I, Gohji K, Arakawa S, Kamidono S. The
significance of lymphadenectomy in transitional cell carci-
noma of the upper urinary tract. Br J Urol 1998; 82: 494–8.
175. Miyao N, Masumori N, Takahashi A, et al. Lymph node
metastasis in patients with carcinomas of the renal pelvis and
ureter. Eur Urol 1998; 33: 180–5.
176. Elliott DS, Segura JW, Lightner D, Patterson DE, Blute ML. Is
nephroureterectomy necessary in all cases of upper tract
transitional cell carcinoma? Long-term results of conserva-
tive endourologic management of upper tract TCC in indi-
viduals with a normal contralateral kidney. Urology 2001; 58:
174–8.
177. Chen GL, Bagley DH. Ureteroscopic management of upper
tract transitional cell carcinoma in patients with normal
contralateral kidneys. J Urol 2000; 154: 1173–6.
178. Keeley FX Jr, Bibbo M, Bagley DH. Ureteroscopic treatment
and surveillance of upper urinary tract transitional cell carci-
noma. J Urol 1997; 157: 1560–5.
179. Richie JP. Urothelial neoplasia of the upper urinary tract.
In: Whitfield HN, Hendry WF, Kirby RS, Duckett JW, eds.
Textbook of Genitourinary Surgery. Oxford: Blackwell,
1998.
180. Caoili EM, Cohan RH, Korobkin M, et al. Urinary tract
abnormalities: initial experience with multi-detector row CT
urography. Radiology 2002; 222: 353–60.
181. Kawashima A, Goldman SM. Neoplasms of the renal collecting
system, pelvis and ureters. In: Pollack HM, McLennan BL,
eds. Neoplasms of the Renal Collecting System, Pelvis and
Ureters. Philadelphia: W B Saunders, 2000.
182. Lowe PP, Roylance J. Transitional cell carcinoma of the kidney.
Clin Radiol 1976; 27: 503–12.
183. O’Connor OJ, McSweeney SE, Maher MM. Imaging of hema-
turia. Radiol Clin North Am 2008; 46: 113–32.
184. Nyman U, Oldbring J, Aspelin P. CT of carcinoma of the
renal pelvis. Acta Radiol 1992; 33: 31–8.
185. Urban BA, Buckley J, Soyer P, Scherrer A, Fishman EK. CT
appearance of transitional cell carcinoma of the renal pelvis:
part 1. Early-stage disease. Am J Roentgenol 1997; 159:
157–61.
186. Buckley JA, Urban BA, Soyer P, Scherrer A, Fishman EK.
Transitional cell carcinoma of the renal pelvis: a retrospective
look at CT staging with pathologic correlation. Radiology
1996; 201: 194–8.
187. Scolieri MJ, Paik ML, Brown SL, Resnick MI. Limitations of
computed tomography in the preoperative staging of upper
tract urothelial carcinoma. Urology 2000; 56: 930–4.
188. McCoy JG, Honda H, Reznicek M, Williams RD. Computer-
ized tomography for detection and staging of localized and
pathologically defined upper tract urothelial tumors. J Urol
1991; 146: 1500–3.
189. Caoili EM, Cohan RH, Inampudi P, et al. MDCT urography
of upper tract urothelial neoplasms. Am J Roentgenol 2005;
184: 1873–81.
190. Fritz GA, Schoellnast H, Deutschmann HA, Quehenberger F,
Tillich M. Multiphasic multidetector-row CT (MDCT) in
detection and staging of transitional cell carcinomas of the
upper urinary tract. Eur Radiol 2006; 15: 1244–52.
191. Goel MC, Mahendran V, Roberts JG. Percutaneous manage-
ment of renal urothelial tumours: long-term follow-up.
J Urol 2003; 159: 925–9.
192. Deligne E, Colombel M, Badet L, et al. Conservative manage-
ment of upper urinary tract tumors. Eur Urol 2002; 42: 43–8.
193. Hatch TR, Hefty TR, Barry JM. Time-related recurrence rates
in patients with upper tract transitional cell carcinoma.
J Urol 1988; 140: 40–1.
194. Hallscheidt P, Wagener N, Gholipour F, et al. Multislice com-
puted tomography in planning nephron-sparing surgery in a
prospective study with 76 patients: comparison of radiologi-
cal and histopathological findings in the infiltration of renal
structures. J Comput Assist Tomogr 2006; 30: 869–74.
195. Weeks SM, Brown ED, Brown JJ, et al. Transitional cell carci-
noma of the upper urinary tract: staging by MRI. Abdom
Imaging 1995; 20: 365–7.
196. Chahal R, Taylor K, Eardley I, Lloyd SN, Spencer JA. Patients
at high risk for upper tract urothelial cancer: evaluation of
hydronephrosis using high resolution magnetic resonance
urography. J Urol 2005; 174: 478–82.
279
 16 Primary Adrenal Malignancy
Rodney H Reznek and Priya Narayanan
INTRODUCTION
The adrenal glands are composed of cortex derived from the
mesoderm and medulla from the neural crest ectoderm. The cor-
tex comprises 90% of the normal adult adrenal gland and is made
up of three zones. Starting from the superficial to the deep these
are the outer zona-glomerulosa, the middle zona fasciculata, and
the inner zona reticularis.
The majority of adrenocortical tumors are benign and non-
functioning (1). Adrenal cortical carcinoma (ACC) is a malignant
neoplasm of the adrenal cortical cells demonstrating partial or
complete histological and functional differentiation. Pheochromo-
cytomas are rare tumors that arise from the chromaffin cells in the
adrenal medulla and elsewhere.
ADRENAL CORTICAL CARCINOMA
Epidemiology
Adrenal cortical carcinomas (ACC) are rare tumors and
account for only 0.05% to 0.20% of all cancers (2). There is a
bimodal age distribution, with the first peak before the age of
five years and the second in the fourth to fifth decade. There is
a female predominance of functional carcinomas but men
develop non-functioning malignant adrenal tumors more
often than women (2). The overall incidence of functional car-
cinomas is 59.3% (3). Functional tumors in males tend to occur
before the age of 20 years (4). Bilateral tumors have been
reported in 2% to 10% of cases (5). The tumor is slightly more
common on the left side (3).
Although most malignant adrenal tumors in childhood are
neuroblastomas or ganglioneuroblastomas, ACC does have a
worldwide incidence of 0.3 per 1,000,000 in children younger
than 15. In southern Brazil, the annual incidence is 3.4 to 4.2 per
1,000,000 children (6).
Etiology
The myriad of genetic changes seen in different studies of these
tumors may explain the association of ACC with complex hered-
itary syndromes. These include the Li–Fraumeni syndrome
(familial susceptibility to a variety of cancers including breast,
brain, lung, larynx, sarcomas, and leukemias); Carney complex
(primary pigmented nodular adrenal dysplasia, cardiac myxomas,
cutaneous myxomas, testicular tumors, and other endocrine
neoplasms); and Beckwith–Wiedmann syndrome. Furthermore,
prevalence of heterozygous genetic mutations in the P-450 CZ1
gene is increased in patients with adrenocortical tumors (7,8).
Cytogenetic analysis suggests that loss of heterozygosity on chro-
mosomes 11p, 13q, or 17p may be important in pathogenesis
(9). Other studies have implicated mutations in p53 gene as a
cause in sporadic ACC (10). There is also evidence to suggest
280
that environmental pollutants may play a causative role in some
forms of childhood ACC (11).
Pathology
Although the difference in the natural history between benign
and malignant adrenal cortical neoplasms is clear, it is not always
possible to separate one from the other histologically. Nevertheless,
the most reliable signs histologically for malignancy are:
• Venous invasion
• Capsular invasion
• Necrosis, hemorrhage, and calcification
• Marked nuclear pleomorphism
The mitotic rate is also an important criterion, not only for dis-
tinguishing malignant from benign tumors but also for predict-
ing the clinical aggressiveness of ACC. Patients with a higher
mitotic rate, that is, more than 20 mitoses per 40 HPF, have a
shorter disease-free survival period compared to those with
mitotic rates less than 20 mitoses per 40 HPF (6). In general, an
adenoma does not exceed 5 cm in diameter and 100 g in weight
(12,13). Adrenal carcinomas tend to be greater than 6 cm in size
and weigh between 100 and 5000 g. Areas of necrosis and hem-
orrhage are common. Invasion and metastases also occur.
Immunohistochemically, the tumors are frequently positive for
vimentin. They do not consistently express keratin, a-1 antit-
rypsin, alpha-fetoprotein (AFP), b2-microglobulin, or lectins
in contrast to other malignant neoplasms. Clinically, the only
definitive single criterion is the presence of nodal or distant
metastases.
Key Points: Epidemiology, Etiology, and Pathology
■ Adenocortical carcinoma has a bimodal age distribution—
before five years and fourth to fifth decades
■ It is associated with several complex hereditary syndromes
including the Li-Fraumeni syndrome, Carney Complex, and
the Beckwith-Wiedemann syndrome
■ It is often difficult to distinguish carcinomas from adenomas
histologically
Clinical Presentation
Approximately 50% of adrenal carcinomas in adulthood are non-
functional and these patients present with abdominal or flank
pain, or an incidentally discovered adrenal mass. A palpable mass
is present in 40% to 50% and, in a significant proportion (about
30%), metastatic disease to the lungs, liver, or bones may cause
symptoms (14,15). These patients usually present at an older age
than patients with functioning tumors and there is a male pre-
dominance (16). Patients presenting with a large mass may have
associated symptoms like unexplained fever, anemia, and weight
loss in the presence of obesity. Unlike adrenal adenomas, which
 primary adrenal malignancy

predominantly secrete cortisol, functioning carcinomas often
secrete a variety of other hormones, including:
• Androgens
• Cortisol
• Estrogens
• Aldosterone
Thirty percent of adults with adrenal carcinoma present with
Cushing’s syndrome (20–30% of cases of adrenal Cushing’s are due
to a carcinoma) (Fig. 16.1), 20% with virilization and a combination
of the two in 10% to 20%. Feminization and hyperaldosteronism
are relatively rare manifestations accounting for about 2% each (12)
and even rarer are hypoglycemia and polycythemia (5).
Adrenal carcinomas are often functioning in children where the
majority present with virilization (72%) (17). In order of frequency,
ACCs produce:
• Virilization
• Cushing’s syndrome
• Feminization
• Conn’s syndrome
Some children may also present with precocious puberty. Elevated
blood pressure is seen in >50% of childhood adrenal carcinomas,
mostly associated with cortisol hypersecretion. The median age at
diagnosis in children is 4.3 years with girls predominating over
boys (5.3:1) below the age of four years (5,12,13).

L L

(A) (B)

(C)
Figure 16.1 Adrenal cortical carcinoma presenting with Cushing’s syndrome. (A) Unenhanced CT shows a right adrenal tumor (arrow) containing foci of calcification.
The liver demonstrates marked fatty change (L). (B) Contrast medium-enhanced CT. There is inhomogeneous enhancement of the right adrenal mass (arrow). (C) On
a heavily T2-weighted MRI, the IVC is compressed but not invaded (arrows).

281
 primary tumor evaluation and staging

Table 16.1 Staging of Adrenocortical Carcinoma

Stage Criteria
Primary tumor (T)
T1 Tumor <5 cm, invasion absent
T2 Tumor >5 cm, invasion absent
T3 Tumor outside adrenal in fat
T4 Tumor invading adjacent organs
Lymph nodes (N)
N0 No positive lymph nodes
N1 Positive lymph nodes
Metastases (M)
M0 No distant metastases
M1 Distant metastases
Staging group
I T1, N0, M0
II T2, N0, M0
III T1–2, N1, M0: T3, N0, M0
IV Any T, any N, M1: T3, T4, N1 (A)
The surgical staging of adrenal carcinoma is as follows:
I Tumor less than 5 cm without local invasion, nodal or distant metastases
II Same as stage I except tumor more than 5 cm
III Tumor with local invasion or positive lymph nodes
IV Tumor with local invasion and positive lymph nodes or distant
metastases

Staging
The American Joint Committee on Cancer (AJCC) and the Inter-
national Union Against Cancer (UICC) have no published TNM
staging system for adrenal malignancies. The system initially pro-
posed by MacFarlane (18) and modified by Sullivan et al. (19) is
most commonly utilized for ACCs. This is given in Table 16.1.
Seventy percent of patients with adrenal cancer have either
Stage III or IV disease at the time of diagnosis (Fig. 16.2). The
most frequent sites of metastases are (20):

• Lymph nodes (25–46%) (B)

• Lungs (47–97%)
• Liver (53–96%) (Fig. 16.2)
• Abdomen (35–43%)
• Bone (11–33%)
Treatment
The definitive treatment for all stages of disease including locally
aggressive Stage III disease is an en bloc resection, which may
include removal of other invaded organs such as the adjacent kidney
or spleen and a regional lymphadenectomy. The procedure may
require a combined thoraco-abdominal approach. Untreated, the
median survival is less than three months. When en bloc resection
is not possible due to local extension into other structures, tumor
debulking to the maximum degree possible is indicated. This
decreases the amount of cortisol-secreting tissue and also minimizes
complications due to tumor mass.
At present, open adrenalectomy is preferred to a laparoscopic
procedure as the latter is associated with a high rate of local recur-
rence (21,22). Surgery is carried out even when there is tumor
invasion of the inferior vena cava (IVC), with tumor extending
from the IVC bifurcation to the right atrium. Cardiac bypass tech-
niques may be used in supradiaphragmatic extension of the tumor.
In general, the great majority of patients show local invasion with
Figure 16.2 Adrenal cortical carcinoma. (A) Contrast medium-enhanced CT scan
in the arterial phase shows a large left-sided adrenal carcinoma with multiple
hepatic metastases. (B) Follow-up arterial phase contrast-enhanced CT image of
the same patient after treatment with adrenolytic drug, mitotane, shows a dramatic
response of both the primary tumor and hepatic metastases.
or without metastases and, despite aggressive surgical therapy, the
five-year survival is only 15% to 25% (23).
Therapy with the adrenolytic drug orthopara-DDD (mitotane)
may improve survival (24,25) (Fig. 16.2). Its specific cytotoxic
effect on the adrenal cortex has led to its use as both primary ther-
apy and adjuvant therapy in patients with ACC. The drug acts by
blocking 11b-hydroxylation and altering the extra-adrenal metab-
olism of cortisol and androgens. It also exerts a direct tumoricidal
effect. Another possible mechanism mediating the adrenolytic
effect of mitotane is oxidative damage through production of free
radicals. Mitotane has been used in the treatment of primary met-
astatic, as well as recurrent, ACC. The use of mitotane as adjuvant
therapy in patients with Stage I and II ACC is controversial because
of lack of convincing data that the drug can prevent tumor recur-
rence. However, a recent multicenter, retrospective study has
shown that patients who received adjuvant mitotane had a signifi-
cantly longer recurrence-free survival compared with those who

282
 primary adrenal malignancy
had radical surgery alone. Further randomized prospective stud-
ies are needed however to corroborate these results (26). This drug
is associated with significant toxicity, particularly, affecting the
gastro-intestinal, neuromuscular, and hepatobiliary systems.
Different studies have shown that patients with ACC demonstrate
a partial response to mitotane ranging from 14% to 35% (3,12).
Treatment with mitotane not only affects the tumor but also the
function of the contralateral adrenal gland. Hence, patients under-
going treatment with this drug need hydrocortisone replacement
therapy.
Adrenocortical carcinomas are generally resistant to radiation
therapy. Conventional abdominal irradiation is associated with
tumor response in only 15% of the cases (6). Radiotherapy is
occasionally used to treat the adrenal bed after surgery, to treat
unresectable recurrences and for palliation of bone metastases.
Patients with invasion of contiguous structures at presentation
have a median survival of 2.3 years (4).
Prognosis
The prognosis for patients with untreated ACC is very poor, with
mean survival being only three months (18). The overall five-year
survival rate is 22% (15). In most series, the survival rate is between
20% and 35% (27). The prognosis in patients with ACC depends
largely on tumor stage. The five-year survival for patients with
Stage I and II disease has been reported as 54%, that for Stage III
disease 21% and that for Stage IV disease 7% (28). Children tend
to have a better prognosis if complete surgical cure is possible.
Recurrence and metastatic disease is common in ACC. Of
patients undergoing complete resection, 85% will develop recur-
rent or metastatic disease (29). The treatment for recurrent dis-
ease is reoperation as survival figures are better when compared to
medical treatment—56 months for reoperation in contrast to
19 months for medical therapy (29).
Key Points: Adrenal Carcinoma—Clinical Features,
Prognosis, and Treatment
■ Excess hormone production is present in more than 50% of
patients with adrenal carcinoma
■ Cushing’s syndrome is the most common endocrine
abnormality in adult patients with adrenal carcinoma
■ Adrenal carcinoma has a poor prognosis. Most patients
present with advanced disease and the mean survival time in
untreated patients is three months
■ Although surgery is the definitive treatment for patients with
adrenal carcinoma, medical treatment with the adrenolytic
drug, mitotane, as an adjuvant therapy, has had mixed results
PHEOCHROMOCYTOMAS AND PARAGANGLIOMAS
Pheochromocytomas are tumors that arise from the chromaffin
cells of the adrenal medulla. Those that arise from extra-adrenal
chromaffin tissue are called paragangliomas. Most extra-adrenal
chromaffin cells are found in the abdominal pre-aortic sympathetic
chain (46%), the organ of Zuckerkandl at the aortic bifurcation
(29%), thoracic paraspinal region (10%), bladder (10%), and head
and neck (2–4%) (30). In the head and neck, 80% are carotid body
or glomus vagale tumors (31). Pheochromocytomas have been
estimated to be present in approximately 0.3% of the patients
undergoing evaluation for secondary causes of hypertension (32).
Epidemiology
Pheochromocytomas occur with equal frequency in both sexes
and at any age from childhood to the seventh decade, although
most commonly in the third to fourth decades. Extra-adrenal
paragangliomas commonly occur in the second to third decades.
Ninety percent are sporadic, the remainder being inherited as
an isolated disorder or as part of a systemic disease. Inherited
tumors are often bilateral, multicentric, and multiple (Fig. 16.3).
Pheochromocytomas may be associated with endocrine and non-
endocrine inherited disorders. They may occur in the autosomal
dominant multiple endocrine neoplasia type 2 (MEN 2a or b)
syndrome (which show a 50% prevalence of pheochromocytoma)
(Fig. 16.4), neurofibromatosis Type I (NFI)—also an autosomal
dominant condition and von Hippel–Lindau disease (VHL), in
which it occurs in 15%. In addition, familial tumors can also occur
as a dominant inherited trait. Pheochromocytomas can be the
only manifestation in about 25% of the carriers of MEN 2, a mutation,
and in about 40% of carriers of the VHL syndrome (33). Germline
mutations of the genes encoding succinate dehydrogenase sub-
units B (SDHB) and D (SDHD) predispose to pheochromocy-
tomas and paragangliomas (34).
Pathology and Prognosis
Pheochromocytomas are usually solitary, being multiple in 10%
of sporadic cases, and in approximately 30% to 75% of the cases
that occur in association with inherited conditions (35,36). Ninety-
eight percent of pheochromocytomas arise in the abdomen, with
90% in the adrenal medulla (37). Between 10% and 13% of tumors
are malignant, although this is probably underestimated (33).
Other studies have reported malignancy to occur in 36% to 40%
of cases (38,39). Malignancy is thought not to occur in association
with the MEN syndrome. Extra-adrenal paragangliomas show a
greater tendency to display malignant behavior (33).
Pheochromocytomas are composed of small round nests of cells
surrounded by rich vascular septa. The cells can be small and regular,
or have marked pleomorphism. Whereas a diagnosis of malignancy
is clear-cut in the presence of metastatic lesions to the bone, liver,
lungs, and within the tumor bed, presence of necrosis, cytologic aty-
pia, increased mitotic atypia, or vascular invasion can be seen in both
benign and malignant tumors. This makes histological determina-
tion of malignancy impossible (40). Capsular invasion and vascular
penetration are not proof of malignancy. Malignant tumors are usu-
ally large with an irregular contour and demonstrate some degree of
necrosis or locoregional invasion. They tend to have a slow and indo-
lent course. Evidence of malignancy such as metastases or recurrence
may occur years (median 5–6 years) after surgical resection of an
apparently benign lesion. Pheochromocytomas resected from hyper-
tensive patients usually measure between 3 and 5 cm and weigh
approximately 100 g (41). The five-year survival rate for malignant
pheochromocytomas is between 40% and 74% (42).
Clinical Presentation
Ninety percent of adrenal pheochromocytomas are hormonally
active compared with 50% of extra-adrenal tumors (43).
283
 primary tumor evaluation and staging

(A)

(D)

(B)

(E)

(C) (F)
Figure 16.3 Carney’s triad. (A) Contrast-enhanced CT scan showing a mediastinal paraganglioma (arrow). (B) The paragangliomas are of similar attenuation (white
arrows) to vessels following contrast medium administration (p, portal vein; i, inferior vena cava). (C) Contrast-enhanced CT of the upper abdomen showing another
paraganglioma in the same patient (arrow). (D) Planar MIBG study showing uptake within the paragangliomas (arrows). (E) CT scan of the lung showing a pulmonary
chondroma (arrow). (F) CT scan of the abdomen showing a GIST tumor (arrow). Both pulmonary chondromas and GIST tumors are components of this complex.

Patients present with a number of symptoms probably due to • Parathyroid hormone

the variety of active metabolic substances secreted. Elevation of • Calcitonin
blood pressure is the most consistent manifestation due to cat- • Gastrin
echolamine secretion. In addition, pheochromocytomas may • Serotinin
also secrete: • Adrenocorticotrophic hormone (ACTH)

284
 primary adrenal malignancy

(B)

(A)

(C) (D)

Figure 16.4 Malignant pheochromocytoma in association with MEN 2A. (A) Sagittal T2-weighted MRI shows a large heterogeneous suprarenal mass (white arrows)
which was confirmed to be a malignant pheochromocytoma. (B) Bilateral enlarged lymph nodes are present in the neck (white arrows) with a medullary cell carcinoma
in the left lobe of the thyroid gland (black arrow). (C) A parathyroid adenoma was demonstrated on longitudinal ultrasound (arrow). (D) T-1-weighted MRI in the same
patient showing a dural metastatic deposit (arrow).

A significant number of pheochromocytomas (>50%) are found Chemotherapy using cyclophosphamide, vincristine, and
at autopsy having escaped the diagnosis during life. dacarbazine has resulted in a 57% tumor response and a 79%
biochemical response (45). Palliation of bony metastases with
Staging irradiation has been successful. A number of indicators have been
The TNM staging of pheochromocytomas is the same as that for linked with poor prognosis, including young patients, females,
ACC (Table 16.1). extra-adrenal tumors, familial lesions, and tumors associated with
other endocrine or neoplastic disorders.
Diagnosis
Recent evidence advocates the measurement of plasma-free meta-
nephrines for the diagnosis of pheochromocytoma and this is a Key Points: Pheochromocytomas
highly sensitive test. It is, however, less specific than the combination
■ Malignant pheochromocytomas account for 13% of all pheo-
of 24-hour urinary total metanephrines and free catcholamines.
chromocytomas and are more common when extra-adrenal
Urinary free metanephrines have been found to be 100% sensitive
or familial
and 94% specific for the diagnosis of pheochromocytoma and
■ Ninety-eight percent arise in the abdomen, 90% in the adrenal
are superior to urinary vanillyl mandelic acid (VMA), urinary
medulla
catecholamines, and plasma catecholamines (44).
■ Ninety percent occur sporadically (of which 10% are multiple),
10% occur in association with certain inherited syndromes
Treatment
■ Multiplicity occurs more commonly (30–75% of cases) when
The treatment of pheochromocytomas is surgical. Surgery should
associated with inherited conditions
also be considered in patients with metastatic disease as the
■ Plasma free metanephrines measurement is the best
reduction of tumor bulk may relieve symptoms and may increase
biochemical test
the efficacy of other therapeutic modalitites; 131I-MIBG can be used
■ Adrenal tumors are more commonly active than those which
as a therapeutic option in cases of incomplete removal or meta-
occur in extra-adrenal sites
static disease. Medical management with alpha- and beta-blockade
■ Tumors are usually slow-growing
using phenoxybenzamine is effective in controlling symptoms.

285
 primary tumor evaluation and staging

tumor by local extension into the renal veins and IVC, and also
IMAGING TECHNIQUES
to the liver, lung, and bones (49) (Fig. 16.7). Computed tomog-
raphy is an excellent modality for staging adrenal carcinoma.
Computed Tomography Preservation of the fat planes around the tumor indicates that
Computed tomography is generally the preferred primary modal-
there is no local invasion. Where there is a paucity of retroperi-
ity for the evaluation of the adrenal glands as it is quick, widely
toneal fat, it may be impossible to determine tumor invasion in
available, and offers the highest spatial resolution. Computed
the absence of a clear fat plane, unless there is obvious distortion
tomography is now able to detect adrenal masses as small as 5 mm
of the adjacent organ.
in diameter and, therefore, is the only imaging investigation nec-
Lymph nodes are involved in 25% to 46% of cases, usually in
essary to make a diagnosis in most cases. Multidetector CT using
the high para-aortic or paracaval regions. Nodes in this area are
3 to 5 mm thick slices will reduce volume averaging sufficiently to
considered enlarged if they are 10 mm or larger in their short
improve the accuracy of density measurements. Scans performed
axis. Adrenal carcinomas commonly invade the draining vein
immediately after intravenous (IV) injection of contrast medium
and may extend up the IVC to the heart (14). Lesions that
and delayed imaging will not only help characterize the lesion but
involve the IVC tend to arise from the right side (83%) and also
also optimize the staging of malignant lesions. Multidetector CT
tend to be large (50). Large lesions on the left commonly involve
can provide exquisite reformatted images in any plane allowing
the left renal vein. Contrast-enhanced CT will usually demon-
for more accurate determination of invasion of surrounding
strate this extension. The IV extension of the tumor is usually
structures (Fig. 16.5).
well-encapsulated, such that it can be withdrawn often intact
from the vein (51). However, as with renal cell carcinoma, it is
Adrenal Cortical Carcinoma (AAC)
important to delineate the cephalad extent of the tumor pre-
Adrenal cortical carcinomas are usually large at presentation,
cisely, particularly in relation to the level of the hepatic veins, so
ranging in size from 3 to 25 cm with an average size of approxi-
that surgery can be planned. The most common sites of
mately 9 cm. Approximately 70% are >6 cm at presentation
hematogenous spread are liver and lungs, but virtually any
(46). Smaller lesions are usually homogeneous but become het-
organ may be involved. Hepatic metastases tend to be hypervas-
erogeneous when they enlarge. Calcification is present in about
cular and are usually best seen on the arterial phase following
30% and is usually central (Figs. 16.1 and 16.6) (46). The het-
IV injection of contrast medium (Fig. 16.2). Recurrence and
erogeneity of the tumor is accentuated following IV injection of
metastatic disease are common in ACC. Of patients undergoing
contrast medium with peripheral enhancement surrounding
complete resection, 85% will develop recurrence or metastatic
areas of central necrosis or hemorrhage (47) (Fig. 16.7). ACCs
disease (29).
retain contrast medium on delayed contrast-enhanced CT
images; they have a relative percentage washout of contrast of
less than 40% (48). With the increasing use of multidetector CT, Pheochromocytomas and Paragangliomas
this could be useful in differentiating smaller ACCs, that will Computed tomography is accurate in the detection of pheochro-
inevitably be discovered, from benign adrenal adenomas. Com- mocytoma with a sensitivity ranging from 93% to 100% (52,53).
puted tomography will also be of value in showing spread of the Sporadic pheochromocytomas tend to be large at the time of

(A) (B)

Figure 16.5 Multidetector CT reformatting. (A) Coronal reformat shows that the large left adrenal adrenocortical tumor (arrow) depresses the left kidney but does not
invade the left kidney or spleen. This is also demonstrated on (B) the sagittal reformatted image. The white arrows indicate the adrenal mass.

286
 primary adrenal malignancy

(A) (B)

(C)
Figure 16.6 Adrenal cortical carcinoma. Thirty-year-old male patient presenting with Cushing’s syndrome. (A) Axial postcontrast CT scan showing a left adrenal carcinoma
(solid arrows) containing calcification (open arrows); (B) coronal T1-weighted MR showing low signal adrenal carcinoma (arrows) depressing the left kidney but sepa-
rated from it by an intact fat plane; (C) axial T2-weighted MR showing high signal intensity adrenal carcinoma (arrows). Note normal right adrenal gland behind inferior
vena cava (curved arrow).

(A) (B)

Figure 16.7 Adrenal cortical carcinoma. Forty-five-year-old female patient presenting with right flank pain. (A) Axial postcontract CT scan showing large right adrenal
cancer, enhancing peripherally (arrows) but necrotic centrally. The mass is invading the inferior vena cava and is inseparable from the liver; (B) axial postcontract CT
scan at the level of the pancreas. Necrotic adrenal cancer (straight arrows) invading the right renal hilum (curved arrow) and displacing the pancreas anteriorly.

287
 primary tumor evaluation and staging

diagnosis, rarely being smaller than 3 cm and with an average size
of 5 cm (54). However, they are often smaller if they are found as
a result of screening a patient with a familial risk of pheochromo-
cytoma. On precontrast CT, they are usually of soft tissue attenu-
ation similar to liver, sometimes with central low attenuation due
to necrosis or cystic change (Fig. 16.8A). Very rarely, extensive
necrosis of the tumor may result in a cystic appearance resembling
a simple adrenal cyst (55). Calcification occurs in about 12% of
pheochromocytomas (56). Pheochromocytomas enhance mark-
edly following IV injection of contrast medium. There has been a
widely held concern about the release of catecholamine following
IV injection of contrast medium, in the light of studies showing
that catecholamines can be elevated using ionic contrast
media (57). However, injection of non-ionic low osmolar contrast
agent is not associated with an increase in catecholamines, and
premedication is not necessary prior to injection of contrast
medium when investigating an adrenal mass (58).
Extra-adrenal paragangliomas account for about 15% of chro-
maffin cell tumors. Retroperitoneal paragangliomas are usually
closely related to the aorta and IVC, following the distribution of
the aorto-sympathetic chain, and are seen in the paravertebral
sympathetic chain (46%) (Fig. 16.9), organ of Zuckerkandl (29%),
thoracic paraspinal region (10%), and bladder (10%). Retroperi-
toneal paragangliomas are usually large and show heterogeneous
appearances on non-contrast CT. Following IV injection of con-
trast medium, the tumors show avid uptake and enhancement
(Fig. 16.10A). Small (<2 cm) tumors show diffuse homogeneous
enhancement, while larger tumors show enhancement of the solid
components. There are no specific imaging features of retroperi-
toneal paragangliomas and their appearances overlap with other

(A) (B)

Figure 16.8 Malignant adrenal pheochromocytoma. Forty-year-old male patient presenting with metastatic deposits within the ribs. (A) Large right adrenal pheochro-
mocytoma with marked central necrosis invading the inferior vena cava (IVC, arrow) and liver (arrowheads); (B) Axial T2-weighted MR showing large right adrenal
pheochromocytoma which has heterogeneous high signal intensity (straight arrows). It is invading the IVC, which shows a slit-like flow void (curved arrow).

(A) (B)
Figure 16.9 Malignant extra-adrenal pheochromocytoma. (A) Contrast-enhanced arterial phase images show a large intensely enhancing mass in the left para-aortic area
with central necrosis. (B) Coronal reformat showing the entire extent of the mass and its relationship to the aorta and surrounding bowel.

288
 primary adrenal malignancy

(A) (B) (C)

(D)

Figure 16.10 Malignant paraganglioma. (A) Contrast medium-enhanced CT. There is an

avidly enhancing mediastinal mass with a necrotic center (arrow). (B) The mass is of high
signal intensity on T2-weighted imaging (arrow) and (C) Is also of high signal on the T2
fat-suppressed image (arrow). (D) It does not exhibit MIBG avidity. (E) FDG-PET—the
(E) paraganglioma Is FDG-avid (arrow).

retroperitoneal tumors, particularly neurofibromas, neuromas,
and sarcomas (59).
Magnetic Resonance
Magnetic resonance can also be used to detect and stage adrenal
tumors and is usually used as a complementary tool to CT, espe-
cially in the display of the relationship of large adrenal tumors to
the adjacent organs using its multiplanar capability. Magnetic
resonance has excellent contrast resolution for the evaluation of
adrenal tumors and the spatial resolution is adequate for the
detection of tumors as small as 1 cm (49).
imaging using breath-hold gradient-echo and fast spin-echo
sequences further improves image quality by minimizing motion
artifacts. Axial T1-weighted images are used initially to assess
adrenal morphology, followed by T2-weighted scans for tissue
characterization. Post-contrast images are also useful in further
characterization of adrenal tumors and in evaluating invasion of
adjacent structures (60). Chemical shift imaging using gradient-
echo in- and out-of-phase T1-weighted sequences is also
employed to differentiate benign from malignant masses by
demonstrating intracytoplasmic lipid in the former (see chap. 45
“Adrenal Metastases”) (60–62).

Imaging Technique Adrenal Cortical Carcinoma

Adrenal imaging may be performed using a body coil. However, Adrenocortical carcinoma is typically heterogeneous in signal
phased-array surface coils are preferable due to improved visual- intensity on MR due to the presence of central hemorrhage or
ization and up to threefold increased signal-to-noise ratio. Rapid necrosis. On T1-weighted sequences, the tumor is isointense or of

289
 primary tumor evaluation and staging

(A) (B)

(C)
Figure 16.11 Adrenal cortical carcinoma. A 50-year-old female patient presenting with a three-year history of high blood pressure. (A) Axial T1-weighted MR showing
right adrenal cancer (straight arrows) containing high signal intensity hemorrhage, with extension into the inferior vena cava (IVC, curved arrow); (B) Axial
T2-weighted MR showing right adrenal cancer with higher signal than adjacent liver (straight arrows). Note extension into the IVC (curved arrow); (C) CT scan
reformatted coronally showing right adrenal cancer invading the perinephric fat (arrowheads) and the liver (straight arrow) with extension superiorly into the IVC
(curved arrow).

slightly low signal when compared to the liver (Fig. 16.6B). How-
ever, they can have central high-signal intensity secondary to the
presence of hemorrhage (Figs. 16.11 and 16.12). On T2-weighted
imaging, these tumors usually have higher signal intensity than
liver and appear heterogeneous due to the presence of fluid in
areas of necrosis and also hemorrhage (63) (Figs. 16.11 and 16.13).
On the chemical-shift MR, these tumors do not uniformly lose
signal on the out-of-phase T1-weighted images due to a lack of
intracytoplasmic lipid. However, as these tumors are functional,
they may contain regions that lose signal on out-of-phase
images (64). On postcontrast scans, the tumor periphery shows
enhancement with the central necrotic area remaining low in sig-
nal intensity. Peripheral mural-based nodules, although unusual,
have also been described (64). Magnetic resonance gives infor-
mation similar to that of CT and hence remains complementary
in differentiating benign from malignant adrenal tumors (65).
However, as in renal cancer, MR has been shown to be superior in
delineating the IVC invasion by the tumor and depicting the
entire extent of the thrombus from the right atrium to the IVC
bifurcation.
Pheochromocytoma
On T1-weighted imaging, pheochromocytoma has signal inten-
sity similar to or slightly lower than liver. On T2-weighted images,
these tumors are said to be typically hyperintense (66) (Fig. 16.8B).
This pattern, though not always present, helps distinguish a pheo-
chromocytoma from a benign adenoma. Although pheochromo-
cytoma may appear very bright, giving a “light bulb” appearance
on T2-weighted images, the majority are heterogeneous and of
moderately high signal (67). Pheochromocytomas enhance after IV

290
 primary adrenal malignancy

(A) (B)

(C)
Figure 16.12 A 16-year-old boy presenting with sudden onset of left loin pain shown to have an adrenocortical carcinoma complicated by hemorrhage. (A) Coronal
T1-weighted MRI shows an adrenal mass comprised predominantly of material which is of intermediate to high signal intensity on T1-weighted imaging compat-
ible with hemorrhage (h). Soft tissue is present at the inferior margin of the mass (arrow). (B) Coronal T2-weighted image shows a suprarenal mass containing hemor-
rhage (arrows). (C) T1 fat-saturated sequence following administration of contrast medium, the peripheral rim of soft tissue enhances (arrow) without enhancement
of the hemorrhagic contents (h).

(A) (B)
Figure 16.13 Adrenal cortical carcinoma. A 13-year-old female presenting with precocious puberty and hirsutism. (A) Coronal T1-weighted MR showing a left adrenal
carcinoma of intermediate signal intensity (straight arrow) invading the left kidney inferiorly and spleen superiorly (arrowheads). Note the signal void in the patent aorta
and inferior vena cava (IVC, curved arrows); (B) Axial T2-weighted MR showing large heterogeneous high signal intensity left adrenal cancer (arrows), with a high signal
intensity metastasis in the liver (arrowhead). Note multiple lung metastases.

291
 primary tumor evaluation and staging

gadolinium-DTPA but may be heterogeneous due to necrosis or

cyst formation. The enhancement may be minimal on immediate
post-gadolinium images and then become progressively of greater
intensity on later interstitial-phase images. On chemical-shift
imaging, pheochromocytomas do not lose signal intensity on the
out-of-phase images. Magnetic resonance is also reported to be
more sensitive than CT in detecting recurrent tumor; the sensitiv-
ity of CT is reported to be 57% and that of MR 86% (68).
Magnetic resonance appears to be equivalent to CT in diagnos-
ing adrenal pheochromocytoma, but is more accurate in detecting
extra-adrenal pheochromocytoma, and also provides more
detailed anatomical and vascular information for resectability and
surgical planning. On MR, paragangliomas have signal intensity
equal to or slightly higher than muscles on T1-weighted images
and appear hyperintense on T2-weighted images. Their signal
intensity on T2-weighted images is higher than liver and equal to
or slightly higher than muscle, but lower than urine and cerebro-
spinal fluid. Rare tumors occurring in the bladder (Fig. 16.14) or
in the heart (Fig. 16.15) are particularly well shown (69).
Key Points: Adrenal Malignancy on Computed
Tomography and Magnetic Resonance
■ Adrenal carcinomas range in size from 3 to 25 cm; 30% are
calcified, heterogeneous, and may contain fluid or hemorrhage
■ Sporadic pheochromocytomas are rarely smaller than 3 cm at
diagnosis, but are often smaller when detected on screening in
patients with pheochromocytomas associated with syndromes
■ Pheochromocytomas enhance markedly following IV injec-
tion of contrast medium on CT or MR
■ On T2-weighted MR, adrenal carcinomas are usually of higher
signal intensity than the liver and do not show significant
signal loss on the out-of-phase chemical-shift imaging
■ Pheochromocytomas are typically, but not always, hyperintense
on T2-weighted MR
■ MR is of value in demonstrating extra-adrenal pheochromocy-
tomas seen in the paravertebral sympathetic chain (46%),
organ of Zuckerkandl (29%), thoracic paraspinal region
(10%), and bladder (10%)

(A) (B)
Figure 16.14 Bladder pheochromocytoma. (A) Axial FSE T2-weighted MR (TR 4000; TE 105 msec) scan shows at least two separate lobulated masses within the bladder.
The anteriorly situated mass shows areas of central necrosis. (B) Sagittal T1-weighted MR (FMPSPGR TR 150; TE 4.2 msec) post-gadolinium enhanced sequence with
fat saturation shows intense enhancement of both the anterior and posterior bladder masses.

(A) (B)
Figure 16.15 Cardiac pheochromocytoma. (A) Axial T2-weighted and (B) coronal T2-weighted scans show a large intracardiac pheochromocytoma within the left
atrium (white arrows).

292
 primary adrenal malignancy

Radionuclide Imaging Pheochromocytoma

Scintigraphy is complementary to biochemical tests and anatomic
imaging in identifying adrenal tumors, as specific tracers produce
functional information. However, CT and MR are still needed for
anatomical localization (70).
Adrenal Cortical Carcinoma
Adrenocortical scintigraphy uses radiocholesterol such as
131
I-6-beta-iodomethyl-19-norcholesterol (NP59) or 75Se-6-
selenomethyl-19-norcholesterol, to evaluate adrenocortical tumors.
These agents are concentrated in tissues secreting steroid hor-
mones. The positive predictive value (PPV) of the nor choles-
terol scan to characterize an adrenal mass as an adenoma has
been reported as 89% with a corresponding negative predictive
value (NPV) to rule out this type of tumor as 100% (71). Imaging
with NP59 is time-consuming, the isotope is not widely avail-
able, and it has limited spatial resolution. It does not appear to
confer any diagnostic value over CT and MRI and therefore is
not routinely used.
Meta-iodobenzylguanidine is an analogue of guanethidine that
concentrates in sympatho-adrenal medullary tissue. 123I-MIBG is
the radiopharmaceutical of choice for the imaging of neural crest
tumors, particularly pheochromocytoma and paraganglioma (Figs.
16.3D and 16.16). Conventional planar or single photon emission
computed tomographic (SPECT) images may be obtained. When
such tumors are seen to take up the tracer, 131I-MIBG can be used
as a therapeutic option. Meta-iodobenzylguanidine imaging is also
useful for the detection of metastatic and recurrent sites of disease
or when whole-body imaging is important (72).
A study comparing CT/MRI versus 123I-MIBG in 83 primary
pheochromocytomas (60 adrenal and 23 extra-adrenal) showed
that the overall sensitivity of 123I-MIBG for tumor detection was
75%. Tumor detection rate was higher in adrenal (85%) compared
with extra-adrenal (58%) pheochromocytomas. Tumor size cor-
related with 123I-MIBG uptake for adrenal tumors. However, two
large tumors which contained necrosis or hemorrhage produced a
negative 123I-MIBG result (73). A further study found that MIBG

R
L

(A) (B)

(C)
Figure 16.16 Bilateral pheochromocytoma. (A) A posterior view of a planar 24-hour 123I-MIBG Scan shows intense uptake in the left adrenal pheochromocytoma. Less
marked uptake is also visualized in the right suprarenal area. (B) CT scan shows bilateral necrotic pheochromocytomas with the left smaller than that on the right
(arrow). (C) Ultrasound examination in the same patient showing the large right-sided pheochromocytoma.

293
 primary tumor evaluation and staging
scintigraphy does not appear to identify foci of disease that are
not seen on cross-sectional imaging (74). MIBG scintigraphy
may only be useful in patients with biochemical evidence of a
pheochromocytoma in whom CT/MRI have failed to identify
the tumor.
111
Indium-pentrotide, an octreotide analogue, may also be used
for the detection of pheochromocytoma with sensitivities as high
as 97%, but is of limited value for non-metastatic, solitary adrenal
pheochromocytomas (75). It may be of value in the detection of
metastatic disease (Fig. 16.17) and extra-adrenal disease.
Key Points: Meta-Iodobenzylguanidine
■ 123I-MIBG has a relatively low sensitivity for identification of
a pheochromocytoma and CT/MRI are used as first-line
investigations
■ MIBG is particularly of value in planning 131I-MIBG therapy
for malignant tumors that take up the tracer, in detecting
metastatic disease,and in confirming recurrence
Positron Emission Tomography
Adrenocortical Carcinoma and Pheochromocytoma
Whole-body 2-[F-18]fluoro-2-deoxy-D-glucose positron emission
tomography (18FDG PET) is able to characterize adrenal masses
(see chap. 45). Abnormally increased 18FDG uptake in malignant
adrenal lesions allows differentiation of these abnormalities from
benign tumors. In addition, whole-body 18FDG PET allows detec-
tion of extra-adrenal tumor sites for accurate disease staging in
patients with malignant adrenal tumors.
(A)
Figure 16.17 Malignant pheochromocytoma with metastases. (A) Sagittal T1-weighted SE (TR 500; TE 11 msec) MR scan of the cervical and thoracic spine shows mul-
tiple soft tissue deposits in the vertebral bodies and posterior elements in a patient with malignant pheochromocytoma. (B) Twenty-four-hour 111in-octreotide sagittal
spet image corresponding to the above MR shows increased tracer uptake in the mid and lower thoracic region.
294
18
FDG PET imaging is based on increased glucose metabolism
in malignant lesions. It is important for the patients to fast for at
least four to six hours prior to 18FDG PET examination. If the
blood sugar levels are high, as in diabetic patients, transport of
18
FDG into malignant cells can be competitively inhibited, poten-
tially decreasing its ability to detect and characterize adrenal
lesions (76). PET combined with CT (FDG PET-CT) allows for
superior anatomic localization.
To date, data on the use of 18FDG PET in the detection of ACC
specifically are sparse. A small study on the use of PET-CT and
contrast enhanced CT (CECT) in 28 patients with ACC showed
that the intensity of FDG uptake and the FDG uptake volume
were related to tumor size and mitotic rate. Thirty-eight percent
of local relapses were seen only with PET-CT. Both PET-CT and
CECT had similar sensitivities for the detection of ACC metasta-
ses (90% and 88%, respectively). Twelve and ten percent of lesions
were seen only by PET-CT or CECT, respectively, and it therefore
appears that these are complementary techniques (77).
Positron emission tomography using 11C-metomidate (MTO)
as a tracer targets the adrenal cortex. It has a high sensitivity and
specificity in differentiating adrenal cortical lesions from non-
adrenocortical lesions and, therefore, could be of use in charac-
terizing adrenal incidentalomas, which have not been adequately
characterized by CT or MRI (78). All adrenocortical lesions (ade-
nomas, hyperplasia, and carcinomas) have been shown to take up
MTO. The clinical application of this technique may therefore be
in its ability to detect metastases and stage the disease. In a study
comparing MTO-PET with CT in 11 patients with known ACC,
MTO-PET detected two more lesions than CT. However, there
was no uptake in three necrotic tumors (79).
(B)
 primary adrenal malignancy
18
FDG PET is positive in the majority of pheochromocytomas,
both benign and malignant, and intra-adrenal or extra-adrenal
(Fig. 16.10E). 18FDG-PET is especially useful in defining the dis-
tribution of those pheochromocytomas that fail to concentrate
MIBG and is also of use in rapidly growing tumors (80,81). A
study by Shulkin and colleagues found that FDG uptake was
more common in malignant than benign pheochromocy-
tomas (80). Other positron-emitting agents that have been used
to visualize pheochromocytoma include 11C-hydroxy-ephedrine
(a catecholamine analogue), 6-(18F)-fluoro-dopamine, and
18
F-DOPA. Although the image quality is good, the short half-
life of 11C isotope hardly allows whole-body examinations and
necessitates on-site production of the radiopharmaceutical
agent. 18F-DOPA has been shown to have 100% sensitivity and
specificity for detecting pheochromocytomas. 18F-DOPA is superior
to MIBG scintigraphy in evaluation of pheochromocytomas
(82). The advantages of 18F-DOPA include a higher spatial reso-
lution, excellent image quality and a much shorter wait time of
four hours before imaging in contrast to MIBG scintigraphy,
which requires imaging at 24 hours. The uptake of 18F-DOPA
is based on the fact that pheochromocytomas show dopamine
synthesis by means of DOPA decarboxylation. It is particularly
useful in imaging extra-adrenal pheochromocytomas and neck
paragangliomas (82).
Key Points: 18FDG PET and Radionuclide Imaging
■ Abnormally increased uptake of 18FDG PET is seen in
malignant adrenal tumors and in both benign and malignant
pheochromocytomas
■ PET using newer tracers such as 11C-metomidate and
18
F-DOPA in the assessment of ACCs and pheochromocytomas,
respectively, have shown promise but further evaluation is
necessary
Ultrasound
Ultrasound is a useful modality for the evaluation of adrenal
tumors in children or adults with a paucity of fat. Sonography can
detect adrenal masses of 1 cm or less but the technique is very
operator-dependent and image quality can be variable if the
patient is obese or if bowel gas obscures the field-of-view (83).
The sonographic features of ACC and pheochromocytoma are
very similar, with small adrenal tumors having low reflectivity and
large tumors becoming more heterogeneous. Central necrosis or
hemorrhage may produce a central echo-free area.
STAGING
As surgery is the most effective treatment for ACC and pheochro-
mocytoma, precise tumor delineation is essential for preoperative
assessment. The aim of staging is to assess accurately the size and
position of the tumor, and to identify local spread into the adjacent
organs, such as liver, spleen, pancreas, and kidneys. It is also
important to evaluate venous invasion of tumor, especially into
the IVC. Metastatic disease to local lymph nodes, liver, and lungs
must also be assessed.
Local Invasion
Local invasion of an ACC or pheochromocytoma beyond the adre-
nal gland capsule and into the adjacent organs is usually first evalu-
ated on CT. Preservation of the fat plane around the tumor indicates
no local invasion (Fig. 16.6). However, distortion of adjacent
organs, such as the liver or kidney, is suspicious for local invasion,
which can sometimes be confirmed on enhanced scans (14).
Invasion of adjacent organs is often better assessed on MR and
ultrasound, as the relationship of a tumor to either more superior
(e.g., liver) or more inferior (e.g., kidney) structures can be demon-
strated in the sagittal and coronal planes (84) (Figs. 16.6 and 16.13).
Multidetector CT with multiplanar reformatting, however, may be
equally accurate in assessing invasion of adjacent structures.
Lymph Node and Venous Invasion
Adrenal cortical carcinoma and pheochromocytoma can metasta-
size to local lymph nodes, and are identified on CT by enlargement
to more than 10 mm in the retroperitoneum and greater than 6 mm
in the retrocrural space (85). Magnetic resonance demonstrates
nodal metastases with equal accuracy to CT.
Tumor thrombus into the adrenal vein and IVC occurs in up to
10% of patients with ACC. It occurs less frequently in malignant
pheochromocytoma.
Contrast medium-enhanced CT, especially with modern multi-
detector CT, can accurately demonstrate invasion of the adrenal
vein, and extension into the renal vein on the left and IVC on the
right (51,86). Tumor thrombus is seen as a filling defect in the renal
vein and IVC. It is crucial to establish the superior extent of tumor
thrombus, precisely as this is a key issue in surgical planning. The
tumor thrombus is usually well-encapsulated and can be withdrawn
intact from the vein. However, if tumor thrombus extends into the
heart, a cardiothoracic surgeon will be needed for its extraction.
Magnetic resonance is as accurate as contrast-enhanced CT in
demonstrating tumor thrombus in vena cava, and more accurate in
defining the superior extent of the thrombus than spiral CT (87–89)
(Figs. 16.8B and 16.11). Magnetic resonance may be used if CT is
inconclusive due to flow artifacts or mistiming of the bolus enhance-
ment of the IVC. It can also be used to evaluate the vena cava in
patients with contraindications to the use of iodinated contrast.
Magnetic resonance has been shown to determine accurately not
only the extent of the thrombus in the IVC, but also to demonstrate
wall invasion and to differentiate tumor thrombus from a pure
thrombus in patients with renal cell carcinoma (RCC) (68). The
sensitivity, specificity, and accuracy of IVC wall invasion in patients
with RCC has been reported as 100%, 89%, and 92%, respectively
(68). The mechanism of tumor invasion of IVC is similar in ACC.
Hence, MR is an excellent modality for not only detecting but also
determining the superior extent and wall invasion, and for differen-
tiating bland from tumor thrombus in patients with ACC. The
accuracy of CT and MR in detecting venous invasion in ACC and
pheochromocytoma is likely to be similar to that for RCC.
There have also been recent reports of tumor thrombus from
ACC being detected on 18F-FDG-PET-CT (90,91).
Ultrasound can also be used to detect tumor thrombus within
the vena cava (92–94). Ultrasound is more accurate than CT for
evaluating tumor thrombus within the intrahepatic vena cava, but
is less sensitive than CT and MR in evaluating the abdominal IVC,
where it is obscured by bowel gas.
295
 primary tumor evaluation and staging
Metastases
Metastatic spread hematogenously to the liver and lungs is most
accurately evaluated on CT (14). Technetium-99m diphosphonate
radionuclide imaging is used to identify bone metastases.
Because the whole body is imaged radiopharmaceutically,
123
I-MIBG scintigraphy is useful in the detection of pheochromo-
cytoma metastases (Fig. 16.17). These most commonly occur in
the (95) skeleton, but also occur in the
• liver,
• lymph nodes,
• peritoneum, and
• lung
The functional nature of the information also helps identify recur-
rent tumor within postoperative scar tissue (96). 123I is the primary
scintigraphic diagnostic tool as it provides better demonstration
of small or metastatic lesions, and is performed as an essential
prelude to 131I-MIBG therapy. It must be stressed, however, that
standard bone scintigraphy using technetium-99m diphosphonate
is still the most sensitive method for detection of bone metastases
in pheochromocytoma (97).
Summary
■ Adrenocortical carcinoma has a bimodal age distribution,
occurring before the age of five years and in the fourth to
fifth decades
■ About 50% of adrenal carcinomas are functional in adult-
hood and most commonly cause Cushing’s syndrome
■ The definitive treatment for adrenal carcinoma is surgery; the
prognosis is nevertheless poor
■ CT remains the most widely used imaging technique to iden-
tify and stage adrenal carcinomas; 70% are >6 cm, 30% are
calcified and heterogeneous in appearance after IV injection
of contrast medium
■ Thirteen percent of pheochromocytomas are malignant,
most commonly when extra-adrenal or familial
■ Ninety-eight percent of pheochromocytomas are intra-
abdominal and on CT are usually large, intensely vascular and
often necrotic, and 12% contain calcium
■ MR is ideally suited to the detection of extra-adrenal pheochro-
mocytomas, the majority of which appear heterogeneous and
of moderately high signal intensity on T2-weighted images
■ Radiopharmaceuticals such as MIBG, 123I-MIBG, or even
18
FDG PET are ideally suited to the detection of meta-
static disease in malignant pheochromocytoma, although
MIBG has a relatively low sensitivity for the detection of
pheochromocytomas, particularly when small, necrotic, or
extra-adrenal
REFERENCES
1. Ross NS, Aron DC. Hormonal evaluation of the patient with
an incidentally discovered adrenal mass. N Engl J Med 1990;
323: 1401–5.
2. Norton JA, Le HN. Adrenal tumors. In: de Vita VT, Hellman S,
Rosenberg SA, eds. Cancer: Principles and Practice of Oncology,
296
6th edn. Philadelphia: Lippincott Williams & Wilkins, 2001:
1777–88.
3. Wooten MD, King DK. Adrenal cortical carcinoma. Epidemi-
ology and treatment with mitotane and a review of the literature.
Cancer 1993; 72: 3145–55.
4. Cohn K, Gottesman L, Brennan M. Adrenocortical carcinoma.
Surgery 1986; 100: 1170–7.
5. Latronico AC, Chrousos GP. Extensive personal experience: adre-
nocortical tumors. J Clin Endocrinol Metab 1997; 82: 1317–24.
6. Schteingart DE. Current perspective in the diagnosis and
treatment of adrenocortical carcinoma. Rev Endocr Metab
Disord 2001; 2: 323–33.
7. Lynch HT, Katz DA, Bogard PJ, Lynch JF. The sarcoma,
breast cancer, lung cancer, and adrenocortical carcinoma
syndrome revisited. Childhood cancer. Am J Dis Child 1985;
139: 134–6.
8. Beuschlein F, Schulze E, Mora P, et al. Steroid 21-hydroxylase
mutations and 21-hydroxylase messenger ribonucleic acid
expression in human adrenocortical tumors. J Clin Endocrinol
Metab 1998; 83: 2585–8.
9. Henry I, Grandjouan S, Couillin P, et al. Tumor-specific loss of
11p15.5 alleles in del11p13 Wilms tumor and in familial adre-
nocortical carcinoma. Proc Natl Acad Sci USA 1989; 86:
3247–51.
10. McNicol AM, Nolan CE, Struthers AJ, et al. Expression of
p53 in adrenocortical tumours: clinicopathological correlations.
J Pathol 1997; 181: 146–52.
11. Sandrini R, Ribeiro RC, DeLacerda L. Childhood adrenocortical
tumors. J Clin Endocrinol Metab 1997; 82: 2027–31.
12. Pommier RF, Brennan MF. An 11-year experience with adreno-
cortical carcinoma. Surgery 1992; 112: 963–70.
13. Barzilay JI, Pazianos AG. Adrenocortical carcinoma. Urol Clin
North Am 1989; 16: 457–68.
14. Dunnick NR. Adrenal carcinoma. Radiol Clin North Am 1994;
32: 99–108.
15. Luton JP, Cerdas S, Billaud L, et al. Clinical features of adreno-
cortical carcinoma, prognostic factors, and the effect of mitotane
therapy. N Engl J Med 1990; 322: 1195–201.
16. Samaan NA, Hickey RC. Adrenal cortical carcinoma. Semin
Oncol 1987; 14: 292–6.
17. Mendonca BB, Lucon AM, Menezes CA, et al. Clinical, hormonal
and pathological findings in a comparative study of adreno-
cortical neoplasms in childhood and adulthood. J Urol 1995;
154: 2004–9.
18. MacFarlane DA. Cancer of the adrenal gland; the natural history,
prognosis and treatment in a study of fifty-five cases. Ann R
Coll Surg Engl 1958; 23: 155–86.
19. Sullivan M, Boileau M, Hodges CV. Adrenal cortical carcinoma.
J Urol 1978; 120: 660–5.
20. Flack MR, Chrousos GP. Neoplasms of the adrenal cortex. In:
Holland JF, Bast RC Jr, Morton DL, et al., eds. Cancer Medicine.
Baltimore: Williams and Wilkins, 1997: 19.
21. Gonzalez RJ, Shapiro S, Sarlis N, et al. Laparoscopic resection
of adrenal cortical carcinoma: a cautionary note. Surgery 2005;
138: 1078–86.
22. Cobb WS, Kercher KW, Sing RF, Heniford BT. Laparoscopic
adrenalectomy for malignancy. Am J Surg 2005; 189:
405–11.
 primary adrenal malignancy
23. Schteingart DE. Treating adrenal cancer. Endocrinologist
1992; 2: 149–57.
24. Kasperlik-Zaluska AA, Migdalska BM, Zgliczynski S, Makowska
AM. Adrenocortical carcinoma. A clinical study and treatment
results of 52 patients. Cancer 1995; 75: 2587–91.
25. Dickstein G, Shechner C, Arad E, Best LA, Nativ O. Is there a role
for low doses of mitotane (o,p’-DDD) as adjuvant therapy in adre-
nocortical carcinoma? J Clin Endocrinol Metab 1998; 83: 3100–3.
26. Terzolo M, Angeli A, Fassnacht M, et al. Adjuvant mitotane for
adenocortical carcinoma. N Engl J Med 2007; 356: 2372–80.
27. Demeure MJ, Somberg LB. Functioning and nonfunctioning
adrenocortical carcinoma: clinical presentation and therapeutic
strategies. Surg Oncol Clin N Am 1998; 7: 791–805.
28. Crucitti F, Bellantone R, Ferrante A, Boscherini M, Crucitti P.
The Italian Registry for Adrenal Cortical Carcinoma: analysis
of a multiinstitutional series of 129 patients. The ACC Italian
Registry Study Group. Surgery 1996; 119: 161–70.
29. Pommier RF, Brennan MF. Management of adrenal neoplasms.
Curr Probl Surg 1991; 28: 657–739.
30. Whalen RK, Althausen AF, Daniels GH. Extra-adrenal pheo-
chromocytoma. J Urol 1992; 147: 1–10.
31. Bradley WG Jr. MR of the brain stem: a practical approach.
Radiology 1991; 179: 319–32.
32. Walther MM, Keiser HR, Linehan WM. Pheochromocytoma:
evaluation, diagnosis, and treatment. World J Urol 1999; 17: 35–9.
33. Dahia PL, Toledo SP, Mulligan LM, et al. Mutation analysis of
glial cell line-derived neurotrophic factor (GDNF), a ligand
for the RET/GDNF receptor alpha complex, in sporadic phaeo-
chromocytomas. Cancer Res 1997; 57: 310–13.
34. Neumann HP, Pawlu C, Peczkowska M, et al. Distinct clinical
features of paraganglioma syndromes associated with SDHB
and SDHD gene mutations. JAMA 2004; 292: 943–51.
35. Atuk NO, McDonald T, Wood T, et al. Familial pheochromo-
cytoma, hypercalcemia, and von Hippel–Lindau disease. A ten
year study of a large family. Medicine 1979; 58: 209–18.
36. Thomas JL, Bernardino ME. Pheochromocytoma in multiple
endocrine adenomatosis. Efficacy of computed tomography.
JAMA 1981; 245: 1467–9.
37. Radin DR, Ralls PW, Boswell WD Jr, et al. Pheochromocy-
toma: detection by unenhanced CT. Am J Roentgenol 1986;
146: 741–4.
38. Scott HW Jr, Halter SA. Oncologic aspects of pheochromocy-
toma: the importance of follow-up. Surgery 1984; 96: 1061–6.
39. Beierwalters WH, Sisson JC, Shapiro B, et al. Malignant potential
of pheochromocytoma. Proc Am Assoc Cancer Res 1986; 27: 617.
40. Page DL, de Lessis RA, Hough AJ. Tumors of the adrenal pheo-
chromocytoma. Atlas of Tumor Pathology. Washington, DC:
Armed Forces Institute of Pathology, 1986: Fascicle 23, 183.
41. Sutton MG, Sheps SG, Lie JT. Prevalence of clinically unsus-
pected pheochromocytoma. Review of a 50-year autopsy
series. Mayo Clin Proc 1981; 56: 354–60.
42. Fitzgerald PA, Goldsby RE, Huberty JP, et al. Malignant pheo-
chromocytomas and paragangliomas: a phase II study of therapy
with high dose 131I-metaiodobenzylguanidine (131I-MIBG).
Ann N Y Acad Sci 2006; 1073: 465–90.
43. Dunn GD, Brown MJ, Sapsford RN, et al. Functioning middle
mediastinal paraganglioma (phaeochromocytoma) associated
with intercarotid paragangliomas. Lancet 1986; 1: 1061–4.
44. Boyle JG, Davidson DF, Perry CG, Connell JM. Comparison of
diagnostic accuracy of urinary free metanephrines, vanillyl
mandelic acid and catecholamines and plasma catecholamines
for diagnosis of pheochromocytoma. J Clin Endocrinol Metab
2007; 92: 4602–8.
45. Averbuch SD, Steakley CS, Young RC, et al. Malignant pheo-
chromocytoma: effective treatment with a combination of
cyclophosphamide, vincristine, and dacarbazine. Ann Intern
Med 1988; 109: 267–73.
46. Fishman EK, Deutch BM, Hartman DS, et al. Primary adreno-
cortical carcinoma: CT evaluation with clinical correlation.
Am J Roentgenol 1987; 148: 531–5.
47. Dunnick NR, Heaston D, Halvorsen R, Moore AV, Korobkin
M. CT appearance of adrenal cortical carcinoma. J Comput
Assist Tomogr 1982; 6: 978–82.
48. Slattery JM, Blake MA, Kalra MK, et al. Adrenocortical carci-
noma: contrast washout characteristics on CT. Am J Roentgenol
2006; 187: W21–4.
49. Sohaib SA, Reznek RH. Adrenal imaging. Br J Urol Int 2000;
86(Suppl 1): 95–110.
50. Hedican SP, Marshall FF. Adrenocortical carcinoma with
intracaval extension. J Urol 1997; 158: 2056–61.
51. Geelhoed GW, Dunnick NR, Doppman JL. Management of
intravenous extensions of endocrine tumors and prognosis
after surgical treatment. Am J Surg 1980; 139: 844–8.
52. Quint LE, Glazer GM, Francis IR, Shapiro B, Chenevert TL.
Pheochromocytoma and paraganglioma: comparison of MR
imaging with CT and I-131 MIBG scintigraphy. Radiology
1987; 165: 89–93.
53. Velchik MG, Alavi A, Kressel HY, Engelman K. Localization of
pheochromocytoma: MIBG, CT, and MRI correlation. J Nucl
Med 1989; 30: 328–36.
54. Moulton JS, Moulton JS. CT of the adrenal glands. Semin
Roentgenol 1988; 23: 288–303.
55. Bush WH, Elder JS, Crane RE, Wales LR. Cystic pheochromo-
cytoma. Urology 1985; 25: 332–4.
56. Sohaib SA, Bomanji J, Evanson J, Reznek RH. Imaging of
the endocrine system. In: Grainger RG, Allison DJ, Adam A,
Dixon AK, eds. Diagnostic Radiology: A Textbook of Medical
Imaging. New York: Churchill Livingstone, 2001: 1389.
57. Raisanen J, Shapiro B, Glazer GM, Desai S, Sisson JC. Plasma
catecholamines in pheochromocytoma: effect of urographic
contrast media. Am J Roentgenol 1984; 143: 43–6.
58. Mukherjee JJ, Peppercorn PD, Reznek RH, et al. Pheochromo-
cytoma: effect of nonionic contrast medium in CT on circulating
catecholamine levels. Radiology 1997; 202: 227–31.
59. Hayes WS, Davidson AJ, Grimley PM, Hartman DS. Extra-
adrenal retroperitoneal paraganglioma: clinical, pathologic,
and CT findings. Am J Roentgenol 1990; 155: 1247–50.
60. Ichikawa T, Ohtomo K, Uchiyama G, Fujimoto H, Nasu K.
Contrast-enhanced dynamic MR of adrenal masses: classifica-
tion of characteristic enhancement patterns. Clin Radiol 1995;
50: 295–300.
61. Korobkin M, Lombardi TJ, Aisen AM, et al. Characterization of
adrenal masses with chemical shift and gadolinium-enhanced
MR imaging. Radiology 1995; 197: 411–18.
62. Bilbey JH, McLoughlin RF, Kurkjian PS, et al. MR imaging of
adrenal masses: value of chemical-shift imaging for distinguishing
297
 primary tumor evaluation and staging
adenomas from other tumors. Am J Roentgenol 1995; 164:
637–42.
63. Smith SM, Patel SK, Turner DA, Matalon TA. Magnetic reso-
nance imaging of adrenal cortical carcinoma. Urol Radiol
1989; 11: 1–6.
64. Schlund JF, Kenney PJ, Brown ED, et al. Adrenocortical carci-
noma: MR imaging appearance with current techniques. J Magn
Reson Imaging 1995; 5: 171–4.
65. Korobkin M, Brodeur FJ, Yutzy GG, et al. Differentiation of
adrenal adenomas from nonadenomas using CT attenuation
values. Am J Roentgenol 1996; 166: 531–6.
66. Korobkin M, Francis IR. Adrenal imaging. Semin Ultrasound
CT MR 1995; 16: 317–30.
67. Varghese JC, Hahn PF, Papanicolaou N, et al. MR differentia-
tion of phaeochromocytoma from other adrenal lesions based
on qualitative analysis of T2 relaxation times. Clin Radiol
1997; 52: 603–6.
68. Aslam Sohaib SA, Teh J, Nargund VH, et al. Assessment of tumor
invasion of the vena caval wall in renal cell carcinoma cases by
magnetic resonance imaging. J Urol 2002; 167: 1271–5.
69. Sahdev A, Sohaib SA, Kaniyur S, et al. MR appearances of
functioning extra-adrenal paragangliomas (pheochromocy-
tomas). Radiology 2001; 221(P): 438.
70. Gelfand MJ. Meta-iodobenzylguanidine in children. Semin
Nucl Med 1993; 23: 231–42.
71. Maurea S, Klain M, Mainolfi C, Ziviello M, Salvatore M. The
diagnostic role of radionuclide imaging in evaluation of
patients with nonhypersecreting adrenal masses. J Nucl Med
2001; 42: 884–92.
72. Maurea S, Cuocolo A, Reynolds JC, et al. Iodine-131-metaiodo-
benzylguanidine scintigraphy in preoperative and postoperative
evaluation of paragangliomas: comparison with CT and MRI.
J Nucl Med 1993; 34: 173–9.
73. Bhatia KS, Ismail MM, Sahdev A, et al. 123I-metaiodobenzyl-
guanidine (MIBG) scintigraphy for the detection of adrenal and
extra-adrenal phaeochromocytomas: CT and MRI correlation.
Clin Endocrinol (Oxf) 2008; 69: 181–8.
74. Greenblatt DY, Shenker Y, Chen H. The utility of metaiodo-
benzylguanidine (MIBG) scinitigraphy in patients with phaeo-
chromocytoma. Ann Surg Oncol 2008; 15: 900–5.
75. Shulkin B, Ilias I, Sisson J, Pacak K. Current trends in functional
imaging of phaeochromocytomas and paragangliomas. Ann N Y
Acad Sci 2006: 1073; 374–82.
76. Maurea S, Mainolfi C, Bazzicalupo L, et al. Imaging of adrenal
tumors using FDG PET: comparison of benign and malignant
lesions. Am J Roentgenol 1999; 173: 25–9.
77. Leboulleux S, Dromain C, Bonniaud G, et al. Diagnostic and
prognostic value of 18-fluordeoxyglucose positron emission
tomography in adrenocortical carcinoma: a prospective com-
parison with computed tomography. J Clin Endocrinol Metab
2006; 91: 920–5.
78. Hennings J, Hellman P, Ahlström H, Sundin A. Computed
tomography, magnetic resonance imaging and (11)C-
metomidate positron emission tomography for evaluation of
298
adrenal incidentalomas. Eur J Radiol 2007; Dec 13 (Epub
ahead of print).
79. Khan TS, Sundin A, Juhlin C, et al. 11C-metomidate PET
imaging of adrenocortical cancer. Eur J Nucl Med Mol Imaging
2003; 30: 403–10.
80. Shulkin BL, Thompson NW, Shapiro B, Francis IR, Sisson JC.
Pheochromocytomas: imaging with 2-[fluorine-18]fluoro-2-
deoxy-D-glucose PET. Radiology 1999; 212: 35–41.
81. Pacak K, Eisenhofer G, Ilias I. Diagnostic imaging of pheochro-
mocytoma. Front Horm Res 2004; 31: 107–20.
82. Hoegerle S, Nitzsche E, Altehoefer C, et al. Pheochromocytomas:
detection with 18F-DOPA whole body PET - initial results.
Radiology 2002; 222: 507–12.
83. Yeh HC. Adrenal gland and nonrenal retroperitoneum. Urol
Radiol 1987; 9: 127–40.
84. Shady KL, Brown JJ. MR imaging of the adrenal glands. Magn
Reson Imaging Clin N Am 1995; 3: 73–85.
85. Castellino RA, Hoppe RT, Blank N, et al. Computed tomography,
lymphography, and staging laparotomy: correlations in initial
staging of Hodgkin disease. Am J Roentgenol 1984; 143: 37–41.
86. Dunnick NR, Doppman JL, Geelhoed GW. Intravenous exten-
sion of endocrine tumors. Am J Roentgenol 1980; 135: 471–6.
87. Fein AB, Lee JK, Balfe DM, et al. Diagnosis and staging of
renal cell carcinoma: a comparison of MR imaging and CT.
Am J Roentgenol 1987; 148: 749–53.
88. Hricak H, Amparo E, Fisher MR, Crooks L, Higgins CB.
Abdominal venous system: assessment using MR. Radiology
1985; 156: 415–22.
89. Soler R, Rodriguez E, Lopez M F, Marini M. MR imaging in
inferior vena cava thrombosis. Eur J Radiol 1995; 19: 101–7.
90. Cheng MF, Wu YW, Tzen KY, Yen RF. F-18 FDG PET-CT illus-
trating tumor invasion in the IVC from adrenocortical carci-
noma. Clin Nucl Med 2007; 32: 891–2.
91. Lai P, Bomanji JB, Mahmood S, et al. Detection of tumour
thrombus by 18F-FDG-PET/CT imaging. Eur J Cancer Prev
2007; 16: 90–4.
92. Park JH, Lee JB, Han MC, et al. Sonographic evaluation of
inferior vena caval obstruction: correlative study with vena
cavography. Am J Roentgenol 1985; 145: 757–62.
93. Schwerk WB, Schwerk WN, Rodeck G. Venous renal tumor
extension: a prospective US evaluation. Radiology 1985; 156:
491–5.
94. Didier D, Racle A, Etievent J P, Weill F. Tumor thrombus of the
inferior vena cava secondary to malignant abdominal neoplasms:
US and CT evaluation. Radiology 1987; 162: 83–9.
95. Shapiro B, Sisson JC, Lloyd R, et al. Malignant phaeochromo-
cytoma: clinical, biochemical and scintigraphic characterization.
Clin Endocrinol (Oxf) 1984; 20: 189–203.
96. Boland GW, Goldberg MA, Lee MJ, et al. Indeterminate adrenal
mass in patients with cancer: evaluation at PET with 2-[F-18]-
fluoro-2-deoxy-D-glucose. Radiology 1995; 194: 131–4.
97. Lynn MD, Braunstein EM, Wahl RL, et al. Bone metastases in
pheochromocytoma: comparative studies of efficacy of imaging.
Radiology 1986; 160: 701–6.
 17 Pancreatic Malignancy
Matilde Nino-Murcia and R Brooke Jeffrey
INTRODUCTION
Despite impressive advances in basic molecular biology and the
continued evolution of high-resolution imaging techniques for
the pancreas, the inescapable fact remains that the most common
type of pancreatic cancer—ductal adenocarcinoma—continues
to be a highly lethal disease with few long-term survivors. This
dismal prognosis is due in large part to the lack of serum markers
to detect subclinical disease, and the paucity of early symptoms
prior to the development of metastases. Although surgical resec-
tion with tumor-free margins does confer a modest degree of sur-
vival benefit, actual survival following “curative resection” is only
in the order of 11% to 25% after five years (1–4). Overall, fewer
than 4% of patients with pancreatic carcinoma survive five years
(5–7). Throughout the industrialized world, pancreatic surgery is
now largely performed at specialized centers by experienced pan-
creatic surgeons. This has contributed to a significant reduction in
the morbidity and mortality from pancreaticoduodenectomy;
however, it has not resulted in a substantial improvement in the
long-term survival. Thus, surgery cannot truly be considered
curative for pancreatic cancer.
A variety of imaging studies, including endoscopic ultra-
sound (EUS), MR, and positron emission tomography with
18
F-fluorodioxyglucose (18FDG PET), have important roles to play
in the initial staging and follow-up of patients with pancreatic can-
cer. However, at most centers, the mainstay of radiologic diagnosis
remains contrast-enhanced computed tomography (CT). The
development of multidetector CT (MDCT), with its substantially
increased speed of scan acquisition, improves both temporal and
spatial resolution of pancreatic imaging. Thin collimation, breath-
held imaging (1.25 mm) is utilized routinely, enabling volumetric
data acquisition. Specialized multiplanar reconstructions are useful
adjuncts to interpretation of axial images, including curved planar
reformations, maximum and minimum intensity projections,
and volume-rendered images. The primary goals of imaging
include accurate diagnosis and staging and, in patients with locally
advanced and/or metastatic disease, avoidance of inappropriate
radical surgery. CT and MR are highly accurate for detecting
pancreatic tumors and indicating nonresectabililty. CT and MR
are not as reliable in predicting resectability. Patients deemed
resectable may still have peritoneal seeding and/or surface studding
of the liver with metastases, which are impossible to detect with
any imaging technique at this point in time.
INCIDENCE AND EPIDEMIOLOGY
The incidence of pancreatic cancer is higher in North America,
Europe, and Japan than in other countries, and overall higher in
developed than developing countries. There are regional varia-
tions in the incidence of this disease, with only two new cases per
100,000 patients in South Eastern and South Central Asia compared
to nine per 100,000 in Eastern Europe (8). The incidence of pan-
creatic cancer has changed over time, increasing in some countries
while decreasing in others. The reported incidence of pancreatic
cancer over the last two decades has increased in France and Japan,
has decreased in Sweden, and has remained stable in the United
States (2,6). In the United States there are approximately 37,000
new cases of pancreatic carcinoma yearly and 34,000 deaths, mak-
ing it the fourth leading cause of cancer-related mortality (5,7).
Pancreatic carcinoma is largely a disease of elderly patients aged
60 to 80 and is rare under the age of 45 (6).
The etiology of pancreatic carcinoma has yet to be established;
however, research in molecular biology has implicated a number
of oncogene mutations (mainly the K-RAS gene), tumor suppres-
sor gene mutations (p53, p16, and others), as well as overexpres-
sion of various growth factors (including epidermal growth factor,
EGF, and transforming growth factor, TGF) (9–11). Cigarette
smoking is a well-established environmental risk factor for pan-
creatic cancer, with recent studies suggesting an association
between K-RAS mutation and smoking (10). Other risk factors
include older age, African American ethnicity, and genetic factors
such as familial pancreatic cancer (12,13). Although diabetes mel-
litus and chronic pancreatitis have been associated with an
increased risk of pancreatic cancer, it is unclear at this point in
time whether there is a causal relationship (14,15). A number of
dietary factors have been implicated in increasing the risk for
pancreatic carcinoma. Consumption of fat, meat, and sugar are
associated with an increased risk and, conversely, consumption of
whole-grain bread, fruits, and vegetables appear to have protective
effects (16,17). A recent study suggests that the increased risk of
pancreatic carcinoma associated with consumption of red and
processed meats may be due to carcinogenic substances related to
meat preparation methods (16).
PATHOLOGY AND PROGNOSIS
Primary epithelial neoplasms of the pancreas arise from either
the endocrine islet cells or the exocrine parenchymal tissues
(Table 17.1). Ductal adenocarcinoma is the most common pan-
creatic primary epithelial malignancy, accounting for 75% to 92%
of all pancreatic neoplasms (18–20). Approximately 70% of ductal
adenocarcinomas arise in the head of the gland, neck, and unci-
nate process; 15% in the body of the pancreas; 5% to 10% in the
pancreatic tail; and 5% to 15% diffusely involve the gland (19).
Most ductal adenocarcinomas are solid, but cystic changes, prob-
ably due to necrosis, may be seen in larger lesions. In other cases,
retention cysts may be seen adjacent to the carcinoma due to
localized dilatation of obstructed ducts. The clinical diagnosis of
ductal adenocarcinoma of the pancreas is quite challenging due to
the lack of early clinical symptoms and the current inability to
299
 primary tumor evaluation and staging

Table 17.1 Pathology of Pancreatic Malignancies Table 17.2 Staging of Carcinoma of the Pancreas
Origin Type of tumor TNM group staging system
I T1–2, N0, M0 No direct extension with no regional nodal
Ductal epithelium Adenocarcinoma, giant cell carcinoma, adenosquamous, involvement
mucinous, microcarcinoma, cystadenocarcinoma,
II T3, N0, M0 Direct extension into adjacent tissue with no lymph
papillary cystic tumor, mucinous ductal ectasia
node involvement
Acinar cells Acinar cell carcinoma
III T1–3, N1, M0 Regional lymph node involvement with or without
Islet cells Malignant insulinoma, gastrinoma, vipoma, gluca- direct tumor extension
gonoma, and others
IVA T1–4; N0–1, M0
Non-epithelial tissue Fibrosarcoma, leiomyosarcoma, hemangiopericytoma,
IVB T1–4, N0–1, M1 Distant metastatic disease spread
lymphoma (extremely rare)
TNM classification
TX Primary tumor cannot be assessed
detect preclinical disease by serum markers. At the time of diagno- T1 Tumor limited to the pancreas, 2 cm or less
sis, 80% of pancreatic carcinoma patients have unresectable or T2 Tumor limited to the pancreas, more than 2 cm
T3 Tumor extends directly into any of the following: duodenum, bile duct,
metastatic disease (21). Ductal adenocarcinoma of the pancreas
peripancreatic tissues
characteristically spreads by direct perivascular and perineural T4 Tumor extends directly into any of the following: stomach, spleen,
invasion. Perineural invasion is seen in 75% of surgically resected colon, adjacent large vessels
ductal adenocarcinomas and is associated with the presence of NX Regional lymph nodes not assessed
perineural invasion in the extrapancreatic retroperitoneal nerve N0 Regional lymph nodes not involved
N1 Regional lymph nodes involved
plexus (18,20). Early micrometastasis to peripancreatic lymphatics,
N1a Metastasis in a single regional lymph node
the liver, and peritoneal surfaces are common. Lymph node metas- N1b Metastasis in multiple regional lymph nodes
tases are present in 70% of resected carcinomas of the head and in M0 No distant metastases
80% of resected carcinomas of the body or tail of the pancreas (18). M1 Distant metastasis present
Because of the small size of the metastatic deposits to the liver and MX Distant metastasis not assessed
peritoneal surfaces, it is not uncommon for these to be undetected
by current imaging methods. This has led some authorities to
recommend laparoscopic staging of patients with the diagnosis of
pancreatic carcinoma prior to formal laparotomy (22,23). Key Points: Pathology and Prognosis
The prognosis of ductal adenocarcinoma of the pancreas remains
exceedingly poor. Despite the progress in surgical treatment, the ■ Over 80% of patients presenting with ductal adenocarcinoma
true figures for cure are below 3% (24). Looking beyond five years, have extrapancreatic extension at the time of presentation
there are few long-term survivors of this disease. In fact, some and are incurable
authorities claim that it is essential to review the pathology of long- ■ At presentation, 40% have lymph node metastases, 50% have
term survivors of presumed pancreatic ductal adenocarcinoma. In liver metastases, and 35% peritoneal implants
up to 49% of these patients, re-examination demonstrates that the ■ Five-year survival after curative resection is approximately
original pathology was in error, and that the correct diagnosis was 11% to 25%
either an islet cell tumor or chronic pancreatitis (25).
In North America and Europe, surgical resection for carcinoma of
the head of the pancreas (pancreaticoduodenectomy) in the past two STAGING CLASSIFICATION
decades has largely been performed at centers specializing in pancre-
The Joint American Committee for Cancer Consensus on Staging
atic surgery. This has led to a reduction in morbidity and mortality
Classification, sixth edition, is outlined in Table 17.2 and Figure 17.1.
following pancreatic resection. The median operative time, blood
loss, and postoperative length of stay have decreased. Postoperative
complications such as hemorrhage, anastomotic leaks, and intra- IMAGING GOALS
abdominal abscess have also decreased with a perioperative mortal-
ity of less than 4% (4,26). However, despite apparently successful Given the grim prognosis of pancreatic carcinoma and the rela-
“curative resections,” the five-year survival in patients with pancre- tively high morbidity and mortality of pancreatic resection, physi-
atic carcinoma following surgery is only between 11% and 25% cians caring for patients with ductal adenocarcinoma must always
(1–4). Surgery, therefore, even in patients with negative margins, bear in mind specific imaging and clinical goals. One of the most
affords only a modest improvement in survival and cannot be truly important goals is to accurately stage patients with imaging, in
considered curative. The main factors that influence long-term prog- order to avoid inappropriate attempted radical resection for cure.
nosis of ductal adenocarcinoma of the pancreas include the size and Surgery in patients with ductal adenocarcinoma that has positive
grade of the tumor and the presence or absence of lymph node margins provides no survival benefit (27). Similarly, because there
involvement (1,2,4,26–28). In patients with negative margins and is no effective systemic chemotherapy for this disease, evidence of
negative lymph node involvement the prognosis appears better, with extrapancreatic extension to the peritoneal surface or liver is an
reported five-year survivals in the order of 41% (26). The use of absolute contraindication to attempted surgical resection. Accu-
adjuvant chemotherapy in combination with surgical resection is rate preoperative staging with imaging is essential to identify the
still controversial and more studies are needed to determine if they small number of patients in whom attempted pancreaticoduo-
can improve patient survival (1,29,30). denectomy should be performed. In general, only lesions in the

300
 pancreatic malignancy

T1 T2 T3 T3

≤2 cm
>2 cm

Peripancreatic - also
extending to
Common bile duct retroperitoneal fat or
mesentery, omentum
or peritoneum

T3 T4 T4

Spleen

Duodenum

N1a - Single node

N1b - Multiple nodes

Figure 17.1 Staging pancreatic cancer—primary tumor (T) and lymph nodes (N).

head and uncinate process of the pancreas are amenable to surgical percutaneous biopsy in lesions that appear resectable for cure
resection as tumors of the body and tail almost always have remains controversial; however, the use of EUS can improve the
perineural or perilymphatic metastasis and, unless the tumors are diagnostic yield of fine-needle aspiration biopsy for small tumors.
small (<2 cm), surgery should be avoided in these patients.
Another important goal of imaging is to diagnose mimics of ductal
adenocarcinoma that may have a significantly better prognosis. Key Points: The Goals of Imaging
These include tumors of the ampulla of Vater, neuroendocrine or
■ The goals of imaging include avoidance of inappropriate
islet cell tumors (see chap. 32), cystic pancreatic neoplasms,
attempts at radical resection, identification of the small
peripancreatic lymphoma, and metastasis to the pancreas from
number of tumors amenable to pancreaticoduodenectomy,
renal cell carcinoma.
and diagnosis of mimics of ductal adenocarcinoma
At many centers patients with obvious extrapancreatic tumor
■ The most widely held criteria for nonresectability include
extension, liver, or peritoneal metastasis have fine-needle aspiration
vascular encasement, lymphatic, peritoneal, or hepatic
biopsy of the pancreas performed under CT or ultrasound guidance
metastasis, and direct organ invasion
as standard procedure to confirm the imaging diagnosis. The role of

301
 primary tumor evaluation and staging

patient may initially be screened with abdominal ultrasound to

DIAGNOSTIC IMAGING TECHNIQUES
An expanding array of diagnostic imaging techniques has proven
to be useful in the diagnosis and staging of ductal adenocarcinoma
of the pancreas. These include CT, EUS, 18FDG PET, and MR
imaging. All of these methods have their strengths and weaknesses,
and diagnostic assessment of pancreatic lesions is often a matter
of institutional bias and local expertise. In general, CT and MR are
the most widely used modalities for pancreatic carcinoma, and
have proven to be roughly equivalent in their accuracy for tumor
detection, local staging, and identification of distant metastasis
(31–33). Endoscopic ultrasound appears to be of particular value
in the assessment of small tumors with possible invasion of the
portal venous system. At the time of writing, the role of 18FDG
PET is evolving, and this technique may potentially play a more
significant role in differentiating benign from malignant pancre-
atic neoplasms, and in detecting distant metastasis.
Due to the variability of institutional practices, it is not uncom-
mon to use a combination of the above techniques. The jaundiced
determine whether biliary ductal dilatation is present. Once a
pancreatic neoplasm is suspected on the basis of a prior imaging
study or strong clinical evidence, contrast-enhanced MDCT is the
most common modality used for the initial evaluation of a possible
pancreatic malignancy.
Multidetector Computed Tomography of the Pancreas
When introduced in the early 1990s, helical CT substantially
improved image quality through the use of breathheld acquisi-
tions and the ability to perform scanning during predominantly
arterial and venous phases. A decade later, MDCT became widely
available, and this major hardware upgrade now permits up to
16 slices of CT data to be acquired with a single gantry rotation.
This dramatic increase in the speed of scan acquisition not only
substantially improves temporal resolution optimally to acquire
images during the peak phase of contrast enhancement, but also
significantly improves spatial resolution through the routine use
of thinner collimation to scan the entire upper abdomen at 1.0
to 1.25 mm. When overlapping reconstructions are performed, a
nearly isotropic voxel volumetric dataset is acquired that can be
used to generate high-quality two-dimensional and three-
dimensional reformations of the pancreas and peripancreatic
vasculature (Fig. 17.2) (34).

Computed Tomography Technique

Figure 17.2 Normal curved planar reformation of the pancreas on MDCT. Note
uniform parenchymal enhancement and normal calibre pancreatic duct (arrow)
and common bile duct (open arrow).
Immediately prior to scanning, the stomach and duodenum are
distended with neutral contrast material such as water or 0.1%
barium sulfate suspension (VoLumen, E-Z-EM) to more clearly
depict gastric and duodenal invasion (Fig. 17.3). Initial non-
contrast scans are obtained of the upper abdomen to delineate the
target volume to be scanned. Following a rapid intravenous (IV)
injection of 150 ml of non-ionic contrast delivered via a power

D T

(A) (B)
Figure 17.3 Value of water distension to demonstrate duodenal invasion by pancreatic carcinoma in two patients. In (A), note hypoattenuating tumor of uncinate process
(T) encasing the superior mesenteric artery (curved arrow). Tumor directly invades and obstructs second duodenum (D). In (B) (a minimum intensity projection), note
hypoattenuating tumor (T) in the head of the pancreas invading the medial wall of the water-distended duodenum (D) (arrows indicates tumor invasion).

302
 pancreatic malignancy

T L

(A) (B)
Figure 17.4 Hypoattenuating pancreatic carcinoma in two patients. (A) Curved planar reformation of the pancreas demonstrating a normal proximal pancreatic duct
(arrow) and hypoattenuating tumor (T) in the body of the pancreas. Note distal atrophy of pancreas and obstructed distal pancreatic duct (open arrow). Cluster of
peripancreatic nodes are noted, which had proven micrometastases at surgery (curved arrow). In another patient (B), a curved planar reformation demonstrates a small
hypoattenuating carcinoma (arrow) with slight distal pancreatic ductal dilatation (open arrow).

phase is essential to confirm liver metastases, portal venous

occlusion, and venous collaterals from complete or partial
obstruction (Fig. 17.8).

Imaging Processing of the Computed Tomography Data

Figure 17.5 Late arterial-phase scan (pancreatic phase) shows peripheral rim
enhancement around 5 mm liver metastasis from pancreatic carcinoma (arrow).
injector at 4 ml/sec, the entire upper abdomen, including the liver
and pancreas, is scanned during a single breath-hold at 1.0 to
1.25 mm following a 40-second injector delay. This late arterial-
phase has been termed the “pancreatic phase,” and improves visu-
alization of pancreatic carcinoma, which is characteristically
hypoattenuating relative to the intensely enhancing normal pan-
creas (Fig. 17.4) (35–47). The late arterial injection is also valuable
to detect subtle liver metastases by demonstrating peripheral rim
enhancement (Fig. 17.5). The peripancreatic vasculature is also
more clearly depicted during this phase of scanning (Fig. 17.6). In
addition, islet cell tumors, which are characteristically hypervas-
cular, are more readily detected and characterized during this
phase (Fig. 17.7) (see chap. 32).
Following the late arterial-phase acquisition (i.e., pancreatic
phase), venous-phase scanning is performed with a single
breath-hold at 70 seconds after the onset of the IV bolus. This
As an adjunct to interpretation of axial images alone, a variety of
CT and MR display techniques have been found useful to depict
the peripancreatic vasculature, ductal structures, and pancreatic
masses. These include maximum and minimum intensity projec-
tion images as well as volume-rendered images (34,39). Maxi-
mum intensity projection images are most useful to display
high-attenuation structures, such as the peripancreatic vascula-
ture. Conversely, minimum-intensity projection images aid in
depicting low-attenuation structures, such as the bile duct, pan-
creatic duct, and hypoattenuating tumors. Both types of image
display are often performed on a thin “slab” of stacked axial
images (Fig. 17.9). In addition to these techniques, curved planar
reformations have proven to be quite useful in the display of the
pancreatic duct and common bile duct, as well as the peripancre-
atic vasculature. Soft-tissue extension of tumors adjacent to
blood vessels is particularly well demonstrated by these images,
which preserve the soft tissue contrast of the original axial data
set (38,39). Curved planar reformations are two-dimensional
displays of tubular structures traversing through the three-
dimensional volume (Fig. 17.6A). These are generated by placing
cursors on the specific anatomic structure through a stack of
axial images, and displaying the designated anatomic structure in
two planes. The voxel dimension perpendicular to the curved
plane determines the thickness of the curved planar reformation.
Curved planar reformations are routinely obtained through the
pancreatic duct (Fig. 17.10), common bile duct, and peripancre-
atic blood vessels including the celiac axis, hepatic artery, splenic
artery, superior mesenteric artery, portal vein, superior mesen-
teric vein, and splenic vein. A blinded review by Prokesch et al.
demonstrated that curved planar reformations were equivalent
in diagnostic accuracy to axial images for local staging of pancre-
atic carcinoma, and more time efficient than reviewing a large
number of axial images (39).

303
 primary tumor evaluation and staging
(A)
Figure 17.6 Normal peripancreatic vasculature on late arterial-phase scan and MDCT. In (A), note normal curved planar reformation of splenic artery (arrow), and in
(B) coronal reformation of the portal venous system (arrows).
(A)
Figure 17.7 Value of arterial-phase images to detect liver metastases from islet cell tumor. (A) Note multiple hypervascular liver lesions in arterial phase. (B) Lesions are
much less conspicuous in venous phase.
Figure 17.8 Portal vein occlusion by pancreatic carcinoma. Maximum intensity
projection image of venous-phase scan demonstrates portal vein occlusion (arrow)
and numerous periportal collaterals (open arrow) in hepatoduodenal ligament.
304
(B)
(B)
Key Points: Multidetector Computed Tomography
in Pancreatic Cancer
■ The speed of scan acquisitions in MDCT allows optimal timing
to the phase of contrast medium enhancement, improves
spatial resolution, and high-quality two-dimensional and
three-dimensional reformations
■ Maximum intensity projections for high-attenuation structures,
minimum intensity projections for low-attenuation structures,
and curved planar reformations are all valuable in staging the
tumor
Computed Tomography Findings in Pancreatic Carcinoma
On late arterial-phase images, approximately 90% of ductal
adenocarcinomas are hypoattenuating compared to the normally
intensely enhancing pancreatic parenchyma (35–47) (Figs. 17.4 and
17.10). However, approximately 10% of lesions are similar in atten-
uation to the pancreatic parenchyma and may be considered isoat-
tenuating (40). Small isoattenuating lesions that do not deform to
the contour of the pancreatic parenchyma may be difficult to detect
without secondary signs such as obstruction of the pancreatic duct
or common bile duct. The majority of pancreatic lesions, however,
are large enough to extend from the normal glandular contour and
produce obvious mass effect. Unless located in the uncinate process,
 pancreatic malignancy

Body of pancreas
thin slab minip

(A) (B)

(C)
Figure 17.9 Value of minimum-intensity displays (MINIP) in three different patients with pancreatic carcinoma. (A) Minimum-intensity image of pancreatic carcinoma.
Note hypoattenuating tumor (T) in head of pancreas obstructing the common bile duct (arrow). (B) MINIP display in second patient reveals isoattenuating carcinoma
(arrowhead) invading SMV (arrow). (C) MINIP display in third patient demonstrates obstruction of pancreatic duct by small pancreatic carcinoma (arrow).

(A) (B)
Figures 17.10 Value of curved planar reformations in two different patients with pancreatic carcinoma. (A) Hypoattenuating pancreatic carcinoma obstructing the
pancreatic duct. Curved planar reformation demonstrates tumor (T) in neck of pancreas and atrophy of distal gland due to pancreatic ductal obstruction (arrow indi-
cates obstructed pancreatic duct). (B) Curved planar reformation in second patient demonstrates obstruction of common bile duct (arrowhead) by hypoattenuating
carcinoma in head of pancreas (arrow).

305
 primary tumor evaluation and staging

(A) (B)

(C) (D) (E)

Figure 17.11 Arterial encasement in five patients. (A) Hypoattenuating tumor in the uncinate process circumferentially encases the superior mesenteric artery (arrow)
and markedly narrows the superior mesenteric vein (open arrow). Note dilated gastrocolic venous trunk (curved arrow). In another patient (B), note large tumor infil-
trating root of mesentery and encasing the superior mesenteric artery (arrow). In another patient (C), curved planar reformation of the superior mesenteric artery
demonstrates soft tissue infiltration obliterating normal mesenteric fat planes (arrows). In another patient (D), curved planar reformation reveals narrowing of splenic
artery by encasing tumor (arrow). (E) Curved planar reformation in fifth patient demonstrates soft-tissue infiltration along SMA (arrows).

pancreatic masses typically obstruct the pancreatic duct and/or

common bile duct. Curved planar reformations of the pancreatic
and common bile ducts are quite useful in displaying partial or
complete ductal obstruction (40). Neuroendocrine tumors may
also produce isoattenuating lesions in the pancreas that may be
indistinguishable from isoattenuating ductal adenocarcinoma.

Extrapancreatic Extension
Vascular Involvement. A characteristic pattern of the spread of
ductal adenocarcinoma is infiltration along peripancreatic blood
vessels. Arterial encasement by tumor is a critical finding repre-
senting an absolute contraindication to surgical resection (Fig.
17.11) (41,42). Some authorities feel that invasion of the portal
or superior mesenteric vein is not a contraindication to surgery
and can be managed with the use of venous bypass grafting.
Others emphasize that resection in patients with venous invasion
has no apparent survival advantage unless tumor-free margins are
obtained (Figs. 17.12 and 17.13) (48–51). In defining criteria for
vascular encasement, many authorities use the observation that
tumor extension beyond 50% of the circumference of a vessel is
a reliable indicator of invasion (37). Using this criterion, Lu et al.
found, in 25 patients undergoing surgical dissection, a sensitivity
Figure 17.12 Venous compression from pancreatic carcinoma. Curved planar ref-
ormation of splenic vein demonstrates marked narrowing (arrow) from pancreatic
carcinoma (open arrow) in the body of the pancreas.
of 84%, a specificity of 98%, positive predictive value (PPV) for
unresectability of 95%, and negative predictive value (NPV) of
93% for unresectability (37). In an attempt to achieve a 100%
PPV for unresectability and, therefore, never deny surgery for a
potentially resectable patient, O’Malley et al. used the criterion of
tumor encasement to be >75% of the circumference of the
involved vessel (41). In 25 patients undergoing surgery for

306
 pancreatic malignancy

(A) (B) (C)

Figure 17.13 Venous encasement from pancreatic carcinoma. Coronal (A) and sagittal (B) curved planar reformations of the superior mesenteric vein demonstrate
circumferential narrowing from encasing tumor (arrow). (C) In another patient, note encasement of SMV on curved planar reformation (arrow).

(A) (B)
Figure 17.14 Interval development of teardrop sign of SMV invasion. (A) Note normal configuration of uncinate process and SMV (arrow). (B) Five years later, note
teardrop configuration of SMV (arrow) and subtle rounding of uncinate process due to small pancreatic carcinoma.

pancreatic carcinoma, 16 were resectable and nine were not (41).
All four patients with vascular encasement >75% of the vessel
circumference were found to be surgically unresectable, yielding
a PPV of 100% for unresectability in these patients (41).
Tumors in the body and tail of the pancreas characteristically
infiltrate the celiac, hepatic, or splenic arteries, while tumors in
the head and uncinate process typically extend along the superior
mesenteric artery and the root of the mesentery. Although in some
instances tumor infiltration and encasement may narrow the
lumen of peripancreatic arteries and produce an irregular outer
contour to the artery, it is not uncommon for the contour of the
artery to be preserved, while tumor is noted to infiltrate along the
periarterial fat planes. Purely angiographic techniques, such as
maximum intensity projections, may not provide adequate soft
tissue display and thus may not reveal tumor encasement in the
absence of arterial narrowing or irregularity.
Venous involvement, particularly of the superior mesenteric vein,
is often a key factor in determining the resectability of pancreatic
carcinoma. Adventitial infiltration of the venous wall may result in
retraction of the vein and a “tethered” contour, referred to as the
“teardrop sign” (Fig. 17.14). In the absence of this finding, >50%
circumferential involvement may also be used as a reliable criterion
to determine venous invasion (52,53). Superior mesenteric venous
obstruction by tumor may result in gastrocolic varices that are an
important secondary finding (Fig. 17.11A). Short gastric and peris-
plenic varices characteristically occur with splenic vein occlusion.

307
 primary tumor evaluation and staging
(A)
Figure 17.15 Gastric invasion from pancreatic carcinoma in two patients. (A) Note large hypoattenuating tumor (T) directly infiltrating the gastric antrum (curved
arrow). Mass obstructs pancreatic duct (black arrow). (B) On coronal MINIP in second patient, note serosal infiltration of the stomach (arrow) by adjacent mucinous
cystadenocarcinoma (arrowhead).
Figure 17.16 Lymph node metastasis from pancreatic carcinoma. Curved planar
reformation of superior mesenteric artery demonstrates enlarged mesenteric
lymph node from pancreatic carcinoma (arrow).
Key Points: Vascular Involvement
■ Arterial encasement is an absolute contraindication to resection
■ Extension beyond 50% of the vessel circumference is a reliable
indicator of vessel invasion
Invasion of Adjacent Organs. Due to its propensity for direct infiltra-
tion of adjacent structures, locally advanced ductal adenocarcinoma
may invade the stomach, duodenum, and retroperitoneal tissues.
The CT diagnosis of invasion of the luminal gastrointestinal tract
308
(B)
is improved with the use of water as negative contrast agent. The
normal bowel wall enhances avidly with IV contrast during a late
arterial injection and tumor invasion focally interrupts this area
of enhancement. Although duodenal invasion is not a contraindi-
cation to pancreaticoduodenectomy, it is associated with regional
lymph node metastasis and, therefore, a poorer prognosis. Gastric
invasion through the lesser sac is a direct contraindication to
pancreatic surgery, and can be diagnosed when there is focal inter-
ruption of the enhancing mucosa of the stomach wall with associated
gastric mural thickening (Fig. 17.15).
Key Points: Invasion of Adjacent Organs
■ Gastric invasion is a direct contraindication to surgery
■ Duodenal invasion does not contraindicate surgery but is
associated with a poorer prognosis
Lymph Node Involvement. Pancreatic carcinoma drains to five
major peripancreatic lymph node groups: superior, inferior, ante-
rior, posterior, and splenic (Fig. 17.16). Secondary drainage then
occurs to lymph nodes in the porta hepatis, the common hepatic
artery, celiac axis, and region of the root of the mesentery around
the superior mesenteric artery and vein. Third-order drainage is
to the periaortic and distal superior mesenteric nodes. Only
nodal metastasis into the second and third echelon can be reli-
ably detected by CT. Nodes >1 cm in short axis are suspicious
for metastases (Fig. 17.16). Nevertheless, because of the high
prevalence of micrometastases, nodal enlargement is a relatively
poor predictor of nodal involvement in pancreatic carcinoma.
Roche et al., using thin-section helical CT, performed a detailed
correlation between nodes detected at CT and pathology speci-
mens in nine patients (54). Using a criterion of >10 mm in short
axis diameter, the authors found only a 14% sensitivity, 85%
specificity, 17% PPV, and 82% NPV (54). Likewise, Maithel et al.
found no correlation between the CT size and presence of metas-
tases in a study of 42 common bile duct and 49 gastroduodenal
artery lymph nodes resected in patients with periampullary
tumors (55). It is therefore clear that CT is not accurate in
 pancreatic malignancy
Figure 17.17 Subtle peritoneal metastases from pancreatic carcinoma. Note nodular
implants on liver surface (open arrows), left lobe liver metastasis (arrow), and
porta hepatis adenopathy (curved arrow).
assessing nodal metastases. In some patients, there is a component
of pancreatitis associated with tumors that may result in reactive
lymphadenopathy. This is particularly true with postendoscopic
retrograde cholangiopancreatography (ERCP) or stent place-
ment, and therefore it is not uncommon to see moderately
enlarged peripancreatic nodes in these patients.
Distant Metastasis. Metastases to the liver and peritoneal surfaces
are the most frequently observed intra-abdominal distant metastases.
With MDCT, small (<1 cm) metastatic deposits to the liver may
on occasion be detected during late arterial-phase imaging acqui-
sitions by their peripheral rim enhancement (Fig. 17.5). This
peripheral rim enhancement is relatively specific for either metas-
tasis or an abscess, and in the appropriate clinical setting can be
a reliable diagnostic sign for metastatic disease. Peripheral rim
enhancement often is not evident on scans obtained during the
portal venous phase. Peritoneal involvement frequently involves
the omentum, liver surface, and serosal surface of the gastroin-
testinal tract. Many of these smaller areas of tumor “studding” are
not able to be detected by current imaging, but on rare occasion
may be visualized on the surface of the liver as nodular deposits
(Fig. 17.17). The presence of subtle peritoneal thickening and
ascites is often an indication of early carcinomatosis.
Magnetic Resonance
The recent development of faster MR techniques, such as echo-
planar and three-dimensional volumetric breath-held imaging,
have established MR as an equivalent imaging technique to CT
in initial diagnosis and staging of pancreatic carcinoma (31–33,56,57).
In many instances, the most useful sequences include gadolinium-
enhanced breath-held scans using gradient-echo techniques.
In addition, MR cholangiopancreatography (MRCP) may be a
very useful adjunctive technique to visualize obstruction of
either the pancreatic or common bile duct. In some instances,
the pattern of ductal dilatation may be useful to distinguish
inflammatory pancreatic masses from malignant obstruction.
The “duct penetrating sign” showing luminal narrowing of the
duct, as opposed to an abrupt termination of a dilated duct, may
indicate a greater likelihood of an inflammatory mass from focal
chronic pancreatitis (58).
Appearance of Pancreatic Carcinoma on Magnetic Resonance
Pancreatic ductal carcinoma generally has lower signal intensity
than the normal pancreas on T1-weighted fat-saturated and non-
fat-saturated images, and on arterial phase (20−40 seconds after
contrast injection) post-gadolinium T1-weighted images. Rim
enhancement has been reported in small tumors (31,33,57,59). In
some cases, the pancreatic parenchyma “upstream” of tumor may
appear hypointense on T1-weighted images secondary to changes
from duct obstruction or chronic inflammation, limiting tumor
conspicuity (59). Similar to imaging characteristics with iodinated
contrast media, the majority of pancreatic neoplasms will be
hypointense relative to the normal pancreas. However, approxi-
mately 10% will be isoattenuating, and are most clearly evident due
to secondary signs of obstruction of the pancreatic duct or bile duct.
While T2-weighted sequences often demonstrate little contrast dif-
ference between the tumor and normal pancreas, this sequence is
still important for the detection of liver metastases. Fast spin-echo
techniques have largely supplanted routine spin-echo techniques
because of their shorter acquisition. The most useful sequence for
detecting vascular invasion with MR is the use of gadolinium-
enhanced gradient-echo techniques (Figs. 17.18–17.20) (31,33,57).
Angiographic techniques such as maximum intensity projection
images may be useful to highlight vascular invasion.
Accuracy of Local Staging with Computed
Tomography and Magnetic Resonance
A variety of studies have demonstrated relatively comparable accu-
racy of CT and MR (31–33). Multidetector CT, due to its widespread
availability, is generally the screening technique utilized at many
centers. However, MR is the imaging method of choice in patients
who cannot receive IV contrast, due to either renal sufficiency or
allergic history. Computed tomography and MR are highly reliable
in predicting unresectability when there is clear-cut evidence of local
invasion or distant metastasis. Authors Lu et al. and O’Malley et al.
assessed the resectability of pancreatic carcinoma using criteria that
focused on the vascular extent of tumor involvement. Vessels were
graded in quartiles, with categories of 0% to 25%, 26% to 50%, 51%
to 75%, and 76% to 100% of circumferential involvement (37,41).
Both authors found that no vessels with >75% circumferential
involvement were resectable, yielding a 100% specificity and 100%
PPV. Lu et al. noted that using a lower threshold circumferential
involvement of >50% was 98% specific for unresectable tumor (37).
Using these specific criteria for vascular invasion, CT and MR are
highly reliable in predicting vascular involvement (31,35,41,56).
As noted previously, arterial involvement with encasement of the
celiac, splenic, hepatic, or superior mesenteric artery is an absolute
309
 primary tumor evaluation and staging
(A)
Figure 17.18 Vascular encasement demonstrated by gadolinium-enhanced MR. (A) T1-weighted sequence demonstrates mass in the body of the pancreas (arrow) and
perihepatic ascites (open arrow). Following injection of gadolinium, multiplanar-spoiled gradient-echo sequence (B) demonstrates hypointense mass (M), encasement
of superior mesenteric artery (arrow), and liver metastases (open arrow).
Figure 17.19 Vascular encasement demonstrated by gadolinium-enhanced MR.
Arterial phase three-dimensional breath-held scan following injection of gadolin-
ium demonstrates hypointense mass (curved arrow) in the head of the pancreas
with encasement of the superior mesenteric artery and vein (arrow). Source: Case
courtesy of Dr. Richard Semelka.
contraindication to surgery. The obliteration of fat planes around
50% of the circumference of these vessels has a high degree of
predictive value in establishing unresectability.
Computed tomography and MR have proven to be less reliable in
predicting resectability, as a small percentage of patients will have
surface studding of the liver, peritoneal surfaces, and serosa of the
bowel with tumor that will go undetected prior to surgery
(31,33,42,56,59). In rare instances, if a tumor is <50% of the cir-
cumference of the vessel, there is actual infiltration of the adventitia,
making the patient not resectable for cure. Lymph node metastases
continue to be problematic, as there is a low sensitivity for involve-
ment, given the frequent micrometastases that occur (18,54,55).
Lymph node enlargement may also be due to reactive lymphoid
hyperplasia in patients with post-ERCP pancreatitis.
Although limited data are available, the use of MDCT (includ-
ing 4-, 8-, 16-, and 64 row CT scanners) with multiplanar refor-
mations has shown improvement in accuracy for local staging of
310
(B)
pancreatic carcinoma with excellent (100%) NPV for vascular
invasion (44–47). The problem of undetected micrometastases to
the liver and peritoneum remains. Subtle rim enhancement may
detect liver metastases that might otherwise be misdiagnosed as
small cysts.
Key Points: CT and MR in Staging
■ CT and MR are comparable in accuracy for staging pancreatic
carcinoma
■ Biphasic MDCT with distension of the stomach and duodenum
with neutral contrast, rapid IV injection of contrast medium
and thin collimation during the late arterial and venous
phase is the most widely used technique
■ Arterial encasement remains the most widely accepted
contraindication for surgery
■ Using specific criteria for vascular invasion, CT and MR are
highly reliable in predicting vascular involvement
■ CT and MR cannot reliably detect peritoneal studding and
micrometastases to lymph nodes and the liver
■ MR of the pancreas should be performed with a combination
of fat-suppressed T1 images, gadolinium-enhanced breath-held
gradient-recalled sequences, and T2-weighted images
Endoscopic Ultrasound (EUS)
Endoscopic ultrasound has rapidly emerged as a useful imaging
tool for the diagnosis and staging of pancreatic carcinoma
(60–62). Pancreatic carcinoma is characteristically hypoechoic on
EUS (Fig. 17.21), and in most instances ductal obstruction is
clearly evident distal to the tumor. Endoscopic ultrasound has
been reported to be more sensitive than CT for detection of
tumors, particularly for lesions <25 mm (61). The EUS detection
of pancreatic carcinoma is known to be limited in patients with
chronic or recent pancreatitis and in cases of diffusely infiltrating
carcinoma. In patients with lesions felt to be resectable based on
CT or MR, EUS may be used to further confirm this, and to guide
fine-needle aspiration biopsy when clinically indicated (60,61).
 pancreatic malignancy

(A) (B)

(C) (D)

Figure 17.20 Ductal obstruction in two patients with pancreatic carcinoma.(A) A fat-suppressed image demonstrating dilated intrahepatic bile ducts (arrows). (B) Note dilated
pancreatic duct (open arrow) due to small obstructing hypointense pancreatic carcinoma (arrow). (C) MR cholangiogram in another patient demonstrates dilated pancreatic
duct (arrow). (D) T2-weighted axial image in same patient as (C) reveals obstructed pancreatic duct (arrowhead) from small isointense pancreatic carcinoma (arrow).

In a recent study by DeWitt et al., EUS was found to be superior for

tumor detection and T staging, but similar for nodal staging and
resectability of nonmetastatic pancreatic cancer (61). Endoscopic
ultrasound is useful for detection of vascular invasion of the
portal, splenic, and superior mesenteric veins but limited in the
visualization and detection of vascular invasion of other vessels (62).

Figure 17.21 Endoscopic ultrasound (EUS) of pancreatic cancer. Note lobulated
hypoechoic tumor (T) in the head of the pancreas. Fine needle aspirate under EUS was
positive for adenocarcinoma. Source: Case courtesy of Jacques Van Dam, MD, PhD.
18
FDG PET
18
FDG PET is an emerging functional imaging modality with
potential applications in the diagnosis, staging, and management
of patients with pancreatic malignancy (63–70). 18FDG PET
appears sensitive and specific for pancreatic malignancy, with
sensitivities in the order of 88% to 97%, and specificities of 78%
to 83% (63,66). 18FDG PET may be useful in differentiating benign
from malignant pancreatic masses, which have been problematic
on CT (67). The major impact of 18FDG PET on staging pancre-
atic carcinoma has been its ability to identify distant metastases, as
it may demonstrate not only liver metastases that are suspected on
the basis of CT findings, but also lung and other sites of distant
metastasis (68). In addition to the initial diagnosis and staging,
18
FDG PET may be very useful in evaluation of patients receiving
adjuvant therapy and in the follow-up of patients who present
with a rising CA 19-9 serology and an equivocal or non-diagnostic

311
 primary tumor evaluation and staging
(A) (B)
Figure 17.22 18FDG PET in pancreatic carcinoma in two patients. (A) Note large
central hypermetabolic focus (arrow) representing primary tumor and adjacent
smaller focus from nodal metastases (open arrow). In another patient (B), focus
of hypermetabolic activity is noted in the bed of surgical resection, indicating
recurrent disease (arrow) (open arrow indicates right renal pelvis). Source: Cases
courtesy of Hossein Jadvar, MD, PhD.
CT (64,66). Jadvar et al. (64) demonstrated that 18FDG PET
may identify metastasis that changed therapeutic management
(Fig. 17.22). 18FDG PET, however, does not appear to provide an
imaging solution to the small peritoneal metastasis that can only
be detected by direct laparoscopy.
The combination of anatomic and biologic (18FDG PET/CT
fusion) data appears to be advantageous. A recent study by Lemke
et al. showed that retrospective fusion of CT and 18FDG PET images
resulted in an improvement in the sensitivity of both imaging
modalities (CT 76%; PET 84%; fused 89%) (69). The strength of
18
FDG PET/CT is its ability to detect pathology and characterize
lesion morphology in a single examination. A study by Heinrich
et al. with an integrated PET/CT scanner showed that the overall
accuracy of 18FDG PET/CT for detecting pancreatic carcinoma
was similar to that of previous studies that used 18FDG PET alone
(70). Although 18FDG PET/CT appears to be useful in the routine
evaluation of pancreatic cancer, its exact role has yet to be fully
determined.
Summary
■ Ductal adenocarcinoma of the pancreas is a highly lethal
disease that continues to carry an exceedingly poor prognosis,
due to the inability to detect the lesion at an early stage
■ Accurate preoperative local staging is essential to identify
the small subset of patients in whom attempted resection is
indicated
■ The most important criteria for non-resectability include the
evidence of arterial encasement and distant metastasis
312
■ MDCT has emerged as the imaging method of choice for
local staging. However, MR, EUS and 18FDG PET all have
important roles to play in the diagnostic work-up
■ MR is equivalent to CT in terms of overall accuracy of staging
but has not gained widespread acceptance due to its relative
lack of availability and the complexity of the examination
■ EUS is useful for detection of vascular invasion of the portal,
splenic, and superior mesenteric veins but limited in the
visualization and detection of vascular invasion of other
vessels
■ 18FDG PET is an emerging technology that is likely to play a
pivotal role in the evaluation of pancreatic masses. When
18
FDG PET is positive, it is highly likely to be a malignant
lesion. 18FDG PET may detect distant metastasis not clearly
evident on CT. Its exact role has yet to be defined
REFERENCES
1. Butturini G, Stocken DD, Wente MN, et al. Influence of
resection margins and treatment on survival in patients with
pancreatic cancer: meta-analysis of randomized control trials.
Arch Surg 2008; 143: 75–83.
2. Linder S, Boström L, Nilsson B. Pancreatic carcinoma inci-
dence and survival in Sweden in 1980–2000: a population-
based study of 16,758 hospitalized patients with special
reference to different therapies. Eur J Surg Oncol 2007; 33:
616–22.
3. Winter JM, Cameron JL, Campbell KA, et al. 1423 pancreati-
coduodenectomies for pancreatic cancer. A single-institution
experience. J Gastrointest Surg 2006; 10: 1199–210.
4. Richter A, Niedergethmann M, Sturm JW, et al. Long-term
results of partial pancreatoduodenectomy for ductal adeno-
carcinoma of the pancreatic head: 25 years experience. World
J Surg 2003; 27: 324–9.
5. Jemal A, Murray T, Ward E, et al. Cancer statistics, 2005. CA
Cancer J Clin 2005; 55: 10–30.
6. Ries LA, Melbert D, Krapcho M, et al., eds. SEER Cancer
Statistics Review, 1975–2004, Bethesda, MD: National Cancer
Institute, 2007 (based on November 2006 SEER data sub-
mission, posted to the SEER website, 2007). [Available from:
http:/seer.cancer.gov/csr/1975_2004/].
7. American Cancer Society. Cancer Facts & Figures 2008.
Atlanta: American Cancer Society, 2008.
8. Parkin DM, Pisani P, Ferlay J. Estimates of the worldwide inci-
dence of 25 major cancers in 1990. Int J Cancer 1999; 80:
827–41.
9. Saif MW, Karapanagiotou L, Syrigos K. Genetic alterations of
pancreatic cancer. World J Gastroenterol 2007; 13: 4423–30.
10. Hassan MM, Bondy ML, Wolff RA, et al. Risk factors for
pancreatic cancer: case-control study. Am J Gastroenterol
2007; 102: 2696–707.
11. Jiao L, Zhu J, Hassan MM, et al. K-ras mutation and p16 and
preproenkephalin promoter hypermethylation in plasma
DNA of pancreatic cancer patients: in relation to cigarette
smoking. Pancreas 2007; 34: 55–62.
12. Chang KJ, Parasher G, Christie C, Largent J, Anton-Culver H.
Risk of pancreatic adenocarcinoma: disparity between African
 pancreatic malignancy
Americans and other race/ethnic groups. Cancer 2005; 103:
349–57.
13. Klein AP, Hruban RH, Brune KA, Petersen GM, Goggins M.
Familial pancreatic cancer. Cancer J 2001; 7: 266–73.
14. Gullo L, Pezzilli R, Morselli-Labate AM. Diabetes and the risk
of pancreatic cancer. N Engl J Med 1994; 331: 81–4.
15. Chow W-H, Gridley G, Nyren O, et al. Risk of pancreatic
cancer following diabetes mellitus: a nationwide cohort study
in Sweden. J Natl Cancer Inst 1995; 87: 930–41.
16. Nöthlings U, Wilkens LR, Murphy SP, et al. Meat and fat intake
as risk factors for pancreatic cancer: the multiethnic cohort
study. J Natl Cancer Inst 2005; 19: 1458–65.
17. Nkondjock A, Krewski D, Johnson KC, Ghadirian P. Dietary
patterns and risk of pancreatic cancer. Int J Cancer 2005; 114:
817–23.
18. Hruban RH, Pitman Bishop M, Klimstra DS. Tumours of the
pancreas. Atlas of tumour pathology, 4th Series, Fascicle 6.
Washington, DC: Armed Forces Institute of Pathology,
2007.
19. Cubilla AL, Fitzgerald PJ. Pancreas cancer. I. Duct adenocarci-
noma. A clinical-pathologic study of 380 patients. Pathol Ann
1978; 13: 241–89.
20. Hira I, Kimura W, Ozawa K, et al. Perineural invasion in
pancreatic cancer. Pancreas 2002; 24: 15–25.
21. Li D, Xie K, Wolff R, Abbruzzese J. Pancreatic cancer. Lancet
2004; 363: 1049–57.
22. Liu RC, Traverso LW. Diagnostic laparoscopy improves staging
of pancreatic cancer deemed locally unresectable by computed
tomography. Surg Endosc 2005; 19: 638–42.
23. White R, Winston C, Gonen M, et al. Current utility of staging
laparoscopy for pancreatic neoplasms. J Am Coll Surg 2008;
206: 445–50.
24. Beger HG, Rau B, Gansauge F, Poch B, Link KH. Treatment of
pancreatic cancer: challenge of the facts. World J Surg 2003;
27: 1075–84.
25. Carpelan-Holmströn M, Nordling S, Pukkala E, et al. Does
anyone survive pancreatic ductal adenocarcinoma? A nation-
wide study re-evaluating the data of the Finnish cancer registry.
Gut 2005; 54: 385–7.
26. Cameron JL, Riall TS, Coleman J, Belcher KA. One thousand
pancreaticoduodenectomies. Ann Surg 2006; 244: 10–15.
27. Wagner M, Redaelli C, Lietz M, et al. Curative resection is
the single most important factor determining outcome in
patients with pancreatic adenocarcinoma. Br J Surg 2004; 91:
586–94.
28. Lim JE, Chien MW, Earle CC. Prognostic factors following
curative resection for pancreatic adenocarcinoma: a population-
based, linked database analysis of 396 patients. Ann Surg 2003;
237: 74–85.
29. Kleeff J, Michalski C, Friess H, Büchler M. Pancreatic cancer:
from bench to 5-year survival. Pancreas 2006; 33: 111–18.
30. Bilimoria KY, Bentrem DJ, Ko CY, et al. Multimodality therapy
for pancreatic cancer in the U.S.: utilization, outcomes, and
the effect of hospital volume. Cancer 2007; 110: 1227–34.
31. Mehmet Erturk S, Ichikawa T, Sou H, et al. Pancreatic adeno-
carcinoma: MDCT versus MRI in the detection and assess-
ment of locoregional extension. J Comput Assist Tomogr 2006;
30: 583–90.
32. Schima W, Ba-Ssalamah A, Kölblinger C, et al. Pancreatic
adenocarcinoma. Eur Radiol 2007; 17: 638–49.
33. Tamm EP, Bhosale PR, Lee JH. Pancreatic ductal adenocarci-
noma: ultrasound, computed tomography, and magnetic
resonance imaging features. Semin Ultrasound CT MR 2007;
28: 330–8.
34. Fishman EK, Horton KM. Imaging pancreatic cancer: the role
of multidetector CT with three-dimensional CT angiography.
Pancreatology 2001; 1: 610–24.
35. Diehl SJ, Lehmann KJ, Sadick M, Lachmann R, Georgi M.
Pancreatic cancer: value of dual-phase helical CT in assessing
resectability. Radiology 1998; 206: 373–8.
36. Lu DS, Vedantham S, Krasny RM, et al. Two-phase helical CT
for pancreatic tumours: pancreatic versus hepatic phase
enhancement of tumour, pancreas, and vascular structures.
Radiology 1996; 199: 697–701.
37. Lu DS, Reber HA, Krasny RM, Kadell BM, Sayre J. Local stag-
ing of pancreatic cancer: criteria for unresectability of major
vessels as revealed by pancreatic-phase, thin-section helical
CT. Am J Roentgenol 1997; 168: 1439–43.
38. Nino-Murcia M, Jeffrey RB Jr, Beaulieu CF, Li KC, Rubin GD.
Multidetector CT of the pancreas and bile duct system: value
of curved planar reformations. Am J Roentgenol 2001; 176:
689–93.
39. Prokesch RW, Chow LC, Beaulieu CF, et al. Local staging of
pancreatic carcinoma with multi-detector row CT: use of
curved planar reformations – initial experience. Radiology
2002; 225: 759–65.
40. Prokesch RW, Chow LC, Beaulieu CF, Bammer R, Jeffrey RB Jr.
Isoattenuating pancreatic adenocarcinoma at multi-detector
row CT: secondary signs. Radiology 2002; 224: 764–18.
41. O’Malley ME, Boland GW, Wood BJ, et al. Adenocarcinoma of
the head of the pancreas: determination of surgical unresect-
ability with thin-section pancreatic-phase helical CT. Am J
Roentgenol 1999; 173: 1513–18.
42. Balci NC, Semelka RC. Radiologic diagnosis and staging of
pancreatic ductal adenocarcinoma. Eur J Radiol 2001; 38:
105–12.
43. McNulty NJ, Francis IR, Platt JF, et al. Multi-detector row
helical CT of the pancreas: effect of contrast-enhanced multi-
phasic imaging on enhancement of the pancreas, peripancre-
atic vasculature, and pancreatic adenocarcinoma. Radiology
2001; 220: 97–102.
44. Catalano C, Laghi A, Fraioli F, et al. Pancreatic carcinoma:
the role of high resolution multislice spiral CT in the diagno-
sis and assessment of respectability. Eur Radiol 2003; 13:
149–56.
45. Vargas R, Nino-Murcia M, Trueblood W, Jeffrey RB Jr. MDCT
in pancreatic adenocarcinoma: prediction of vascular invasion
and respectability using a multiphasic technique with curved
planar reformations. Am J Roentgenol 2004; 182: 419–25.
46. Brügel M, Link TM, Rummeny EJ, et al. Assessment of vascu-
lar invasion in pancreatic head cancer with multislice spiral
CT: value of multiplanar reconstructions. Eur Radiol 2004; 14:
1188–95.
47. Zamboni GA, Kruskal JB, Vollmer CM, et al. Pancreatic
adenocarcinoma: value of multidetector CT angiography in
preoperative evaluation. Radiology 2007; 245: 770–8.
313
 primary tumor evaluation and staging
48. Kawada M, Kondo S, Okushiba S, Morikawa T, Katoh H.
Reevaluation of the indications for radical pancreatectomy
to treat pancreatic carcinoma: is portal vein infiltration a
contraindication? Surg Today 2002; 32: 598–601.
49. Allema JH, Reinders ME, van Gulik TM, et al. Portal
vein resection in patients undergoing pancreatoduo-
denectomy for carcinoma of the pancreatic head. Br J Surg
1994; 81: 1642–6.
50. Fukuda S, Oussoultzoglou E, Bachellier P, et al. Significance
of the depth of portal vein wall invasion after curative resec-
tion for pancreatic adenocarcinoma. Arch Surg 2007; 142:
172–9.
51. Nakao A, Takeda S, Inoue S, et al. Indications and techniques
of extended resection for pancreatic cancer. Worl J Surg 2006;
30: 976–82.
52. Valls C, Andia E, Sanchez A, et al. Dual-phase helical CT of
pancreatic adenocarcinoma: assessment of resectability before
surgery. Am J Roentgenol 2002; 178: 821–6.
53. Horton KM, Fishman EK. Multidetector CT angiography of
pancreatic carcinoma: part 2, evaluation of venous involve-
ment. Am J Roentgenol 2002; 178: 833–6.
54. Roche CJ, Hughes ML, Garvey CJ, et al. CT and pathologic
assessment of prospective nodal staging in patients with
ductal adenocarcinoma of the head of the pancreas. Am J
Roentgenol 2003; 180: 475–80.
55. Maithel SK, Khalili K, Dixon E, et al. Impact of regional node
evaluation in staging patients with periampullary tumours.
Ann Surg Oncol 2007; 14: 202–10.
56. Arslan A, Buanes T, Geitung JT. Pancreatic carcinoma: MR,
MR angiography and dynamic helical CT in the evaluation of
vascular invasion. Eur J Radiol 2001; 38: 151–9.
57. Elias J Jr, Semelka RC, Altun E, et al. Pancreatic cancer:
correlation of MR findings, clinical features, and tumour
grade. J Magn Reson Imaging 2007; 26: 1556–63.
58. Ichikawa T, Sou H, Araki T, et al. Duct-penetrating sign at MRCP:
usefulness for differentiating inflammatory pancreatic mass
from pancreatic carcinomas. Radiology 2001; 221: 107–16.
59. Pamuklar E, Semelka RC. MR imaging of the pancreas. Magn
Res Imag Clin North Am 2005; 13: 313–30.
314
60. Tierney WM, Francis IR, Eckhauser F, et al. The accuracy of
EUS and helical CT in the assessment of vascular invasion by
peripapillary malignancy. Gastrointest Endosc 2001; 53:
182–8.
61. DeWitt J, Devereaux B, Chriswell M, et al. Comparison of
endoscopic ultrasonography and multidetector computed
tomography for detecting and staging pancreatic cancer. Ann
Int Med 2004; 141: 753–63.
62. Aslanian H, Salem R, Lee J, et al. EUS diagnosis of vascular
invasion in pancreatic cancer: surgical and histology corre-
lates. Am J Gastroenterol 2005; 100: 1381–5.
63. Keogan MT, Tyler D, Clark L, et al. Diagnosis of pancreatic carci-
noma: role of FDG PET. Am J Roentgenol 1998; 171: 1565–70.
64. Jadvar H, Rischman AJ. Evaluation of pancreatic carcinoma
with FDG PET. Abdom Imaging 2001; 26: 254–9.
65. Rose DM, Delbeke D, Beauchamp RD, et al. 18Fluorodeoxy-
glucose-positron emission tomography in the management of
patients with suspected pancreatic cancer. Ann Surg 1999; 229:
729–38.
66. Bang S, Chung HW, Park SW, et al. The clinical usefulness of
18-fluorodeoxyglucose positron emission tomography in the
differential diagnosis, staging, and response evaluation after
concurrent chemoradiotherapy for pancreatic cancer. J Clin
Gastroenterol 2006; 40: 923–9.
67. Nakamoto Y, Higashi T, Sakahara H, et al. Delayed (18)
F-fluoro-2-deoxy-D-glucose positron emission tomography
scan for differentiation between malignant and benign lesions
in the pancreas. Cancer 2000; 89: 2547–54.
68. Pakzad F, Groves AM, Ell PJ. The role of positron emission
tomography in the management of pancreatic cancer. Semin
Nucl Med 2006; 36: 248–56.
69. Lemke AJ, Niehues SM, Hosten N, et al. Retrospective digital
image fusion of multidetector CT and 18F-FDG PET: clinical
value in pancreatic lesion-a prospective study with 104 patients.
J Nucl Med 2004; 45: 1279–86.
70. Heinrich S, Goerres GW, Schäfer M, et al. Positron emission
tomography/computed tomography influences on the manage-
ment of resectable pancreatic cancer and its cost-effectiveness.
Ann Surg 2005; 242: 235–43.
 18 Bladder Cancer
David MacVicar, Janet E Husband, and Dow-Mu Koh
INTRODUCTION
The goals of imaging patients with bladder cancer are to define
the extent of tumor spread within the bladder wall and into adja-
cent tissues, to detect pelvic and retroperitoneal nodal metastases
and, in advanced disease, to identify distant metastases. Treatment
of invasive tumors includes cystectomy, radiotherapy, and chemo-
therapy, and imaging has a role in radiotherapy treatment planning,
the post-treatment evaluation of these tumors and in the detection
of recurrence. In current practice, magnetic resonance (MR)
imaging and computed tomography (CT) have pre-eminent roles
in the assessment of bladder cancer.
INCIDENCE AND ETIOLOGY
After prostate cancer, bladder cancer is the second most common
malignancy of the urinary tract worldwide, accounting for an esti-
mated 6% to 8% of all male malignancies and 2% to 3% of all
female malignancies. Incidence rates are highest in industrially
developed countries, particularly in North America and Western
Europe, and in areas associated with endemic schistosomiasis in
Africa and the Middle East. The highest reported rates are in Egypt
(37 per 100,000 population) and low rates (less than five per
100,000 population) are reported in India and China. However,
world incidence rates for bladder cancer show comparatively little
variation compared to other malignancies. In the United Kingdom,
10,278 new cases were reported in 2005, accounting for one in
every 28 new cases of cancer each year in the United Kingdom. It
is more common in men with a male to female ratio of 5:2. It is the
fourth most common cancer in males and tenth most common
cancer in females. Few cases occur under the age of 50, and peak
incidence is in the sixth and seventh decades. A small deprivation
gradient has been noted, with lowest bladder cancer rates recorded
for the most affluent and the highest rates for the most deprived
socio-economic groups. Time trends in bladder cancer incidence
rates are difficult to interpret as a result of changing pathological
classifications and coding practices, but it appears that the age-
standardized incidence rates in the United Kingdom rose throughout
the 1970s and 1980s to reach a peak incidence of 31 per 100,000
population in men and nine per 100,000 population in women
in the early 1990s. Since that time incidence rates have fallen by
one-third. It is possible that this is a result of reduction in expo-
sure to environmental risk factors such as smoking and industrial
chemicals. Mortality figures have also been falling, and in 2006
there were 3177 male deaths and 1636 female deaths from bladder
cancer in the United Kingdom (1,2). In the United States in 2005
there were an estimated 63,200 new cases and 13,200 deaths were
attributable to bladder cancer. Higher incidence rates are noted in
white than non-white populations in the United States, and the
age-adjusted incidence rates in 2000–2003 were 40 per 100,000
population for white males compared to 19.8 in black males.
Overall incidence and mortality rates are similar in western Europe
and north America (1,3).
An association between environmental factors and the develop-
ment of bladder cancer was first described over 100 years ago by
Rehn, a German physicist (4) who documented an increased inci-
dence of the disease in aniline dye workers. Since that time aromatic
amines have also been shown to be associated with the development
of bladder cancer, thereby introducing an occupational hazard for
those working with organic chemicals, certain dyes, rubber, and
paint materials. Diesel fumes and the long-term abuse of the drug
phenacetin are also implicated in the development of the disease
(5). Today, however, cigarette smoking is the single most important
factor known to increase incidence of urothelial cancer, increasing
individual risk by at least threefold. The length of time that an indi-
vidual smokes appears to be an important predictor of risk, and
individuals who cease smoking have a declining probability, and it
is estimated that after four years of abstinence, an ex-smoker’s risk
falls by 40%. After 25 years of abstinence, an ex-smoker still has a
higher risk than the general population and aromatic amines pres-
ent in cigarette smoke are the most likely substance responsible.
Acetylation of chemicals is a common pathway for inactivating
toxic substances, and the genetically coded acetylation status of the
individual may also be relevant with “slow acetylators” being more
likely to develop bladder cancer as a result of smoking (6,7).
Cystitis and chronic urinary tract infection predispose to blad-
der cancer and in those areas where schistosomiasis is prevalent
there is also a strong association with the development of squamous
carcinoma of bladder (8). Approximately 7% of all bladder tumors
occur within diverticula (9).
Bladder cancer does not appear to follow a strong family history,
but the variations in sex and racial incidence indicate that genetic
factors have a role. An overview of the molecular biology of blad-
der carcinoma is beyond the scope of this text, but it appears that
certain chromosomal lesions are associated with tumor grade,
stage and vascular invasion (10–14).
CLINICAL PRESENTATION AND DIAGNOSTIC APPROACH
The majority of patients with bladder carcinoma present with pain-
less hematuria which may be frank, microscopic, or detectable by
dipstick. Less common presentations of bladder cancer include blad-
der irritability, frequency, urgency of micturition, and flank pain
associated with ureteric obstruction. Advanced disease may present
with a pelvic mass and symptoms of longstanding bladder outflow
obstruction, and this clinical presentation is associated with a poor
prognosis. In the United Kingdom, there has been an effort to detect
bladder cancer at an early clinico-pathological stage. Patients of any
age with frank hematuria and those over 50 with microscopic hema-
turia can be referred to hematuria clinics which endeavor to perform
all relevant diagnostic tests at a single visit. In the region of 25% of
patients with frank hematuria, and almost 4% of patients with
315
 primary tumor evaluation and staging

microscopic hematuria will prove to have a urological malignancy. Table 18.1 Who Histological Classification of Tumors
In these fast-track hematuria clinics, patients will be assessed by of the Urinary Tract (Modified) (17)
clinical history, urine cytology, upper tract imaging, and flexible cys-
toscopy. There appears to be some difference in detection rates of Urothelial tumors
Infiltrating urothelial carcinoma
urological malignancy in patients with dipstick hematuria who are with squamous differentiation
investigated in primary care compared with those referred to hospi- with glandular differentiation
tal hematuria clinics (15,16). Urine cytology alone is of limited use- micropapillary
fulness in diagnosing low-grade and low-stage tumors, and must be sarcomatoid
combined with other procedures. High-grade malignant urothelial Non-invasive urothelial neoplasias
cancer has tumor cells with lower cohesive potential which are more urothelial carcinoma in situ (CIS)
non-invasive papillary urothelial carcinoma, high grade
readily shed and therefore detected in the voided cytology samples. non-invasive papillary urothelial carcinoma, low grade
Imaging is most useful in detecting upper tract neoplasms such as non-invasive papillary urothelial neoplasm of low malignant potential
renal cell carcinoma or ureteric obstruction with hydronephrosis in (PUNLMP)
patients with advanced muscle-invasive bladder tumors. Ultrasound urothelial papilloma
or intravenous urography (or both) is used. Cystoscopy in fast-track inverted urothelial papilloma
hematuria clinics is carried out with a flexible cystoscope under local Squamous neoplasms
Squamous cell carcinoma
anaesthetic. It allows visualization of the bladder mucosa and biopsy Verrucous carcinoma
of suspicious areas. In patients with a known history of bladder Squamous cell papilloma
cancer treatment of small volume disease and low-grade superficial Glandular neoplasms
tumors can be undertaken using laser ablation. Rigid cystoscopy is Adenocarcinoma
carried out under general or regional anaesthesia and is usually Enteric
reserved for bladder lesions previously detected on imaging, or if Mucinous
Signet ring cell
there is a high index of suspicion that multiple biopsies or resection
Villous adenoma
of extensive superficial tumor will be required.
Neuroendocrine tumors
Blue light cystoscopy is an innovation which involves pre- Small cell carcinoma
installation of a protoporphyrin precursor known as delta-5- Carcinoid
amino-levulonic acid. Tumor cells retain this fluorescent agent Paraganglioma
and when cystoscopy is carried out under blue-light, tumors Melanocytic tumors
will fluoresce resulting in increased sensitivity of detection. It is Malignant melanoma
Naevus
not in general use, but has a role in patients who have positive
Mesenchymal tumors
cytology in the absence of obvious urothelial tumor.
Rhabdomyosarcoma
Leiomyosarcoma
Angiosarcoma
PATHOLOGY Other
Hemopoietic and lymphoid tumors
The vast majority of primary bladder tumors, over 90%, are epithe- Lymphoma
Plasmacytoma
lial in origin. Of the epithelial tumors, transitional cell carcinoma in
Miscellaneous tumors
most parts of the world is the commonest type. It should be noted
Carcinoma of Skene, Cowper and Littre glands
that the term “transitional cell carcinoma (TCC)” is being replaced Metastatic tumors and tumors extending from other organs
by “urothelial carcinoma.” Pathologists prefer the term urothelial
carcinoma, but radiologists, surgeons and indeed pathologists con-
tinue to use both terms interchangeably. However, a variety of rela- infiltrative, ulcerative, or polypoid. These patterns of tumor growth
tively rare neoplasms may be found in the bladder, and the WHO are well demonstrated on imaging with CT and MR (Fig. 18.1).
classification (2004) is given in modified form in Table 18.1 (17). The majority of urothelial carcinomas arise on the lateral bladder
The urothelium is the lining epithelium of the urinary collect- walls (approximately 47%) or in the region of the trigone (approx-
ing system, including the renal pelvis, ureters, bladder, and part of imately 20%). At the time of presentation, approximately one-third
the urethra. Depending on the state of distension of the bladder, of patients with urothelial bladder tumors have multifocal disease
its thickness varies from three to seven cell layers. Under normal and indeed the whole of the bladder epithelium may be abnormal
circumstances, these cells have a slow turnover rate, in the region showing areas of squamous metaplasia and carcinoma in situ. The
of three to six months, and will desquamate but very few cells are presence of carcinoma in situ is associated with an increased
seen in normal urine cytology specimens. When malignant trans- incidence of recurrence and an increased risk of development of
formation takes place, shedding of cells and hematuria will invasive disease (18). Urothelial cancers may be associated with
develop. Urothelial cell tumors account for 90% of all epithelial synchronous or metachronous development of tumors elsewhere
bladder cancers. These tumors show a variable pattern of growth in the urinary tract including the renal pelvis and ureter.
and are classified as papillary lesions which have delicate frond- Squamous cell carcinomas, mixed transitional and squamous
like projections into the bladder lumen, non-papillary, or mixed cell tumors, adenocarcinomas, and undifferentiated lesions account
papillary and infiltrative tumors. Papillary tumors are usually for less than 10% of bladder cancers. Squamous cell carcinomas
solitary intraluminal masses; non-papillary tumors may be are the most prevalent histological type in patients with chronic

316
 bladder cancer

inflammatory disease of the bladder; they are often found arising

in bladder diverticula and have a poor prognosis. Squamous
differentiation may occur in urothelial tumors and is an unfavorable
prognostic indicator (19).
Adenocarcinomas which account for 2% to 3% of all bladder
tumors are often associated with a persistent urachus and are
seen arising exophtically from the bladder dome. The trigone is a
typical site of origin for non-urachal adenocarcinomas (20).
Urachal adenocarcinomas have a better prognosis than non-urachal
adenocarcinomas (21).
Other rare pathological types of bladder cancer include the carci-
nosarcomas which are usually large and show a polypoid growth
pattern and the sarcomas which are very aggressive carrying a poor
prognosis. Non-epithelial tumors of the bladder are rare and include
primary bladder sarcomas (rhabdomyosarcomas and leiomyosarco-
mas), phaeochromocytomas, lymphoma, and melanoma. Direct
invasion of the bladder by other pelvic tumors is well recognized, but
(A)
haematogenous metastases to the bladder are distinctly unusual.
The grade of malignancy of urothelial carcinoma varies from well-
differentiated, low-grade tumors (Grade I) to poorly differentiated,
high-grade tumors (Grade III). There is a close correlation between
tumor grade and the pattern of growth, thus most well-differentiated
tumors (Grade I) are papillary, whereas most undifferentiated tumors
(Grade III) are solid, sessile, and infiltrating and have a much poorer
prognosis (9,22). Grading of bladder cancer also correlates well with
tumor stage; most Grade III tumors (about 80%) are invasive cancers,
whereas the majority of Grade I tumors are superficial (22,23).
Grading from I to III follows the WHO 1973 grading system
which most pathologists and urologists still use. However, the
future trend is to grade urothelial carcinoma as low-grade or high-
grade which is believed to be more relevant clinically. Grading is
subjective, and a more simple low/high-grade system might reduce
interobserver variability, and the WHO 2004 grading system
(B)
incorporates this approach (17).
Bladder cancers can be broadly divided into two main patho-
logical groups on the basis of prognosis; i.e., superficial and
invasive disease. Superficial tumors are those which do not invade
the muscle layer of the bladder wall; they have a significantly
better prognosis than invasive disease. Invasive tumors are those
which infiltrate the muscle layers of the bladder wall. Superficial
tumors have a propensity to recur and 10% to 20% of lesions
will progress to invasive cancers (22,24,25).

Key Points: General Features

■ Bladder cancer is more common in males than in females
■ Cigarette smoking is the single most important known cause
of urothelial cancer
■ Cystitis and chronic urinary infection and inflammation
predispose to squamous bladder cancer
■ Over 90% of bladder tumors are epithelial and the vast
majority of these are urothelial carcinomas
(C) ■ One-third of bladder tumors are multifocal at the time of

Figure 18.1 Patterns of tumor growth. (A) Coronal T2-weighted MR image presentation
showing solitary papillary intraluminal mass. (B) CT scan showing an infiltrating ■ Superficial tumors have a propensity to recur and to progress
pattern of tumor growth. (C) Coronal T2-weighted MR image showing a mixed to invasive disease
pattern of papillary and infiltrating growth. ■ High grade, sessile tumors have a worse prognosis

317
 primary tumor evaluation and staging
PATTERNS OF TUMOR SPREAD
Primary bladder tumors infiltrate the mucosa, lamina propria,
superficial, and deep muscle layers of the bladder wall. Eventually
the tumor breaks through the bladder wall into the surrounding
perivesical fat and then invades the pelvic organs and pelvic sidewall
structures by direct tumor spread.
Lymph node metastases are rare in superficial tumors but if deep
muscle is involved the incidence of lymph node deposits rises to
about 30% and when extravesical invasion is present, between 50%
and 60% of patients will have lymph node metastases (26). The
distinction between those patients with nodal metastases and those
without nodal spread has important prognostic significance as
patients with invasive tumors with nodal involvement have a five-
year survival of approximately 11% compared with a five-year
survival of 28% in patients without nodal involvement (27).
In bladder cancer, lymphatic spread is first to the anterior and
lateral perivesical nodes, and then the lateral sacral, presacral,
hypogastric, obturator, and external iliac nodes. Further spread is
to the common iliac and para-aortic nodes. Spread to inguinal
nodes is unusual. Lymph node metastases are also occasionally
seen above the diaphragm.
Distant metastases usually occur late in the clinical course of
bladder cancer. The predominant sites of metastatic spread are
the bone, lungs, brain, and liver. Squamous cell tumors have a
predilection to spread to bone. Occasionally, bone metastases may
be identified at presentation in patients with aggressive high-grade
tumors. Treatment of patients with metastatic disease is palliative
and imaging is only required to detect disease in patients suspected
of having metastases based on clinical symptoms; occasionally, they
are detected incidentally on survey of the abdomen and pelvis at
staging, during follow-up or at the time of relapse.
TREATMENT OPTIONS
The major factors influencing prognosis and therefore treatment
choice include:
• Histological cell type
• Grade of malignancy
• Tumor volume
• Growth pattern
• Depth of bladder wall infiltration
• Presence of metastases in lymph nodes
• Metastases in blood-borne sites
• Genetic factors
In patients with superficial urothelial tumors, the prognosis is
good with a mean five-year survival rate of approximately 80%
( Table 18.2) (22,28–30). However, the outlook deteriorates
significantly with advancing stage of the primary tumor and the
Table 18.2 Prognosis of Bladder Cancer
Pathology Incidence (%) Overall 5-yr survival (%)
Superficial tumors 80 70–80
Invasive tumors 20 <50
318
presence of metastases; thus, invasive tumors have an overall
five-year survival of less than 50% irrespective of therapeutic
approach and, in patients with nodal metastases, only 15% of
patients survive one year (31,32). If blood-borne metastases are
present, only about 5% of patients survive one year (31,32). His-
tological type also has a bearing on disease outcome. Genetic
mutations are linked to bladder cancer but as yet no clear view has
been reached regarding the prognostic significance of known
oncogenes such as P53, Rb, and P21 (33).
Cystoscopic procedures are the mainstay of therapy for early
bladder cancer. The diagnosis of bladder cancer is confirmed by
cystoscopic examination and biopsy. Multiple biopsies of obvious
lesions are taken as well as biopsies from areas remote from visible
tumor because carcinoma in situ may coexist with superficial or
invasive disease.
Although superficial non-invasive bladder cancer can be success-
fully treated by cystadiathermy or transurethral resection, impor-
tant factors determining therapeutic choice are the occurrence of
multiple lesions and the propensity to develop recurrences (22,24).
Because grade and stage progression is seen in up to 30% of
patients with recurrence (24), a more aggressive approach using
intravesical chemotherapy, immunomodulators, or radical cystec-
tomy is frequently adopted in patients with a history of multiple
recurrences and high-grade lesions, as well as in selected patients
with carcinoma in situ (29). Treatment is also influenced by clinical
assessment as the age and fitness of the patient may determine
whether surgical or conservative therapy is the most appropriate
way forward.
There is no general consensus regarding the optimum manage-
ment of patients with invasive bladder cancer because no clear
survival benefit is seen with different therapeutic approaches
(30–32,34,35). Thus treatment options include radical external
beam irradiation with curative intent, external beam irradiation
followed by cystectomy (or partial cystectomy) and chemotherapy
(methotrexate, cisplatinum, Adriamycin) combined with radio-
therapy. Cystectomy alone may be offered to patients with invasive
tumors confined to the bladder wall or with only minimal extra-
vesical spread but preoperative radiotherapy has also been used to
down-stage disease prior to cystectomy (34).
As is the case with many common solid tumors, it is difficult to
organize a large truly randomized trial to compare, for example,
neoadjuvant chemotherapy followed by radical radiotherapy with
current techniques of cystectomy with or without orthotopic
bladder reconstructions. Historically there has been a tendency
for proponents of one treatment technique to compare their
results with historical data from other techniques and conclude
that apparent improvement in survival is due to the new treat-
ment rather than to other factors such as improved supportive
care and more accurate pre-treatment staging. In the absence of
hard data, it seems reasonable that the choice between cystectomy
and radiotherapy may be made on the basis of the patient’s per-
ceptions and preferences, including the acceptability of potential
side-effects of surgery or radiotherapy/chemotherapy.
With advances in surgical techniques it is now generally con-
sidered that surgery offers a good treatment option for muscle-
invasive tumors and may also be considered as first-line
treatment in cases of superficial tumors with severe anaplasia
(36,37). It involves en bloc excision of the bladder, prostate, and
 bladder cancer

seminal vesicles with pelvic nodal dissection. Because the bladder
is completely removed at radical cystectomy, urinary diversion
is an essential part of the procedure. This may be a cutaneous
ureterostomy, ileal conduit with ureteroileocutaneostomy, ure-
terosigmoidostomy, or orthotopic neobladder reconstruction
with ileal or ileocaecal segments (Fig. 18.2). Orthotopic neo-
bladder reconstruction is the preferred option if the urethral
sphincter can be conserved at surgery without compromise to
the clearance of tumor (38,39).
The ileal conduit with a cutaneous stoma is a long-established
form of urinary diversion. About 10 to 15 cm of distal ileum is
mobilized and isolated on a vascular pedicle, and ileo-ileal anas-
tomosis is performed to reinstate continuity of the remainder of
the bowel. The ileal conduit is traditionally placed in the right
side of the abdomen, and the left ureter is mobilized and brought
to the right side of the abdomen. The ureters can be anastomosed
to the ileum separately (Bricker technique) or the terminal ends
of the ureters can be anastomosed to each other to form a ure-
teric plate which is then anastomosed to the ileum (Wallace
technique). The advantage of the Bricker technique is that if
there is tumor recurrence in one ureter there is no direct physical
channel for spread to the other ureter. The disadvantage of this
technique is the higher anastomotic stricture rate of approxi-
mately 7%, twice that of the Wallace anastomosis. Both types of
anastomoses reflux, and in longterm survival there is frequently
concern about upper tract dilatation and accompanying loss of
renal function. Other complications include prolapse of the
stoma, parastomal herniation, stomal stenosis, and parastomal
dermatitis. Urinary leakage and recurrent urinary infections are
also relatively frequent.
Orthotopic reconstruction involves the use of the patient’s
native urethra and urethral sphincter as an outlet and continence

(A) (B) i (B) ii

(C) (D)
Figure 18.2 (A) and (B) Diagrams to show methods of urinary diversion. (A) Ileal conduit. (B) Orthotopic neobladder reconstruction: i. Bladder substitute attached to
urethra, ii. Urinary reservoir attached to terminal ileum with stoma. (C) CT scan showing ileal conduit (arrow). (D) CT scan shows an orthotopic bladder reconstruction
containing urine. A length of bowel has been resected, laid out and reconfigured into a spheroid shape, then re-anastomosed to the ureters and urethral orifice.

319
 primary tumor evaluation and staging

mechanism. All reconstructions require a segment of bowel which

STAGING
is detubularized, opened out to form a plate and then reconfigured
into a spheroid. This allows a relatively large volume low pressure
system to be constructed and peristaltic waves within the reservoir
Classifications
There are two main staging classifications used for evaluating
are limited in their motor activity, potentially decreasing the risk
bladder cancer, the TNM system (Table 18.3 and Fig. 18.3) (45)
of incontinence. The commonest small bowel reservoir used in
and the Jewett–Strong–Marshall system (Table 18.4) (46,47). The
clinical practice is the Studer J-reservoir, constructed from 50 to
first of these classifications to be used in clinical management was
60 cm of ileum. The daytime continence rate of this technique has
that described by Jewett and Strong in 1946 (46) which was subse-
been reported as 90%, while the nighttime continence rate is
quently modified by Marshall (47) to take into account the results
estimated at 60%. The most demanding form of reconstructive
of bimanual examination and biopsy at cystoscopy. This system
surgery is the Mitrofanoff procedure. The Mitrofanoff principle
has been widely used throughout the United States for several
refers to a system whereby a fine caliber tube, usually the appen-
decades, but the TNM system is now uniformly accepted and has
dix, acts as a catheterizable channel. One end is implanted via a
the advantage that nodal disease is distinguished from locally
submucosal tunnel into an orthotopic reconstructed bladder res-
advanced tumors and from distant metastatic spread. The AJCC
ervoir and the other is brought out to the surface as a cutaneous
staging classification (48) uses the same TNM staging classification
continent catheterisable stoma. Bladder filling causes the tube to
as the latest UICC version of 2002.
act as a flap valve, rendering the system continent in 90% of
patients. However, the complication rate of this procedure is high,
with 25% of patients developing stenosis of the Mitrofanoff tube Methods
and 10% developing calculi in the reservoir. At the time of presentation, cystoscopic evaluation and biopsy will
Ureterosigmoidostomy in its traditional form had a high inci- reveal the pattern of tumor growth, histological cell type, and tumor
dence of ascending infection, metabolic disturbance and renal grade. When a papillary tumor is removed and disease is confined
deterioration, but the Mainz 2 ureterosigmoidostomy has resur- to the stalk, full pathological staging is possible without any further
rected the principle. This procedure uses 30 cm of sigmoid colon assessment. Depth of infiltration within the bladder wall is deter-
which are reconfigured as a sphere. Good continence rates are mined pathologically by deep biopsy but in advanced disease, with
reported, but many patients require oral alkanizing agents to tumor spread beyond the bladder, staging of the disease relies on
prevent hyperchloraemic acidosis (40,41). the results of the bimanual assessment of tumor bulk, the presence
In those patients with fixed tumors which have spread to the or absence of tumor fixation to adjacent structures, as well as on
pelvic sidewall or into adjacent organs, systemic chemotherapy, histopathological examination.
using single- or multi-agent regimens, may induce tumor response, Clinicopathological staging is highly accurate in the evalua-
but palliative radiotherapy also has an important role in patient tion of superficial tumors. However, in patients with invasive
management (30,31,34). Systemic chemotherapy may induce an lesions, clinical staging has been shown to be inaccurate with
objective response in patients with metastatic or recurrent locally errors ranging from 25% to 50%, (46,47,49) and other methods
advanced disease (42). Overall, response rates ranging from 30%
to 60% with a complete remission rate of 25% to 60% have been
reported with multi-agent chemotherapy which includes metho- Table 18.3 TNM Classification for Bladder Cancer
trexate and cisplatin (42–44). The results of a large intergroup
TX Primary tumor cannot be assessed
study of neo-adjuvant chemotherapy (cisplatin, methotrexate, T0 No evidence of primary tumor
and vinblastine) before definitive treatment versus no chemother- Ta Non-invasive papillary carcinoma
apy showed only a 5.5% survival advantage at three years in the Tis Carcinoma in situ: “flat tumor”
chemotherapy arm (31). T1 Tumor invades subepithelial connective tissue
T2 Tumor invades muscle
T2a Tumor invades superficial muscle (inner half)
Key Points: Therapy T2b Tumor invades deep muscle (outer half)
T3 Tumor invades perivesical tissue
T3a microscopically
■ Superficial bladder tumors have a good prognosis in the
T3b macroscopically (extravesical mass)
majority of patients and cystoscopic techniques are the T4 Tumor invades any of the following: prostate, uterus, vagina, pelvic
mainstay of treatment wall, abdominal wall
■ In patients with superficial bladder cancer, treatment may be by T4a Tumor invades prostate or uterus or vagina
local resection but, with multiple recurrences and high-grade T4b Tumor invades pelvic wall or abdominal wall
NX Regional lymph nodes cannot be assessed
lesions, cystectomy may be the preferred option
N0 No regional lymph node metastasis
■ No clear survival benefit is seen with different therapeutic
N1 Metastasis in a single lymph node <2 cm in greatest dimension
approaches for invasive bladder cancer. These include surgery, N2 Metastasis in a single lymph node >2 cm but <5 cm in greatest
radiotherapy, and chemotherapy dimension, or multiple lymph nodes, none >5 cm in greatest
■ Radical cystectomy involves en bloc resection of the bladder, dimension
N3 Metastasis in a lymph node >5 cm in greatest dimension
seminal vesicles, prostate, and pelvic lymph nodes
MX Distant metastasis cannot be assessed
■ A variety of surgical reconstructive procedures can be
M0 No distant metastasis
performed M1 Distant metastasis

320
 bladder cancer

T2a

T1
T2b

Ta

T3a
Tis

T3b ≤5 cm
Mucosa <2 cm
Lamina propria >2–5 cm >5 cm
Superficial muscle
T4a Deep muscle
T4b N1
N2
Prostate N2
N3

(A) (B)
Figure 18.3 Staging bladder cancer (A) primary tumor (T), (B) lymph nodes (N).

Table 18.4 Jewett–Strong–Marshall Classification
for Bladder Tumor
0 Preinvasive
A Submucosal invasion
B1 Superficial muscle
B2 Deep muscle
C Extravesical spread
D1 Fixed to or invading prostate, uterus, vagina or pelvic lymph nodes
D2 Spread to extrapelvic lymph nodes or distant metastases
of determining the extent of local tumor spread therefore play a
central role in patient management. These include ultrasound,
CT, and MR imaging.
Over the last 20 years there have been major advances in
ultrasound techniques, with improvement in image quality of
transabdominal ultrasound and the introduction of transurethral,
transrectal, and transvaginal techniques. Computed tomography,
first introduced for body imaging in the mid 1970s, has also
improved substantially, particularly with the recent developments
of multidetector CT (MDCT). Magnetic resonance provides a
superb modality for assessing primary pelvic tumors because it
combines high-quality imaging with flexible and versatile infor-
mation. Increasingly powerful computing techniques now allow a
variety of reconstructions and three-dimensional displays such as
“virtual cystoscopy.”
IMAGING THE PRIMARY TUMOR
Once the diagnosis of a malignant bladder tumor has been made
at cystoscopy, the principal role of imaging is to evaluate tumor
spread to assist selection of the most appropriate treatment. The
choice of imaging technique is not greatly influenced by the
pathology which has been discovered, although it should be noted
that urothelial carcinoma may be multifocal, which might result
in a greater emphasis being placed on imaging techniques which
visualize the entire urinary tract. MR imaging and CT both have
strengths in demonstration of extent of tumor spread, but in cur-
rent U.K. practice, the choice is often made on the basis of avail-
ability of machine-time and local expertise.
Ultrasound
Transabdominal, transurethral, transvaginal, and transrectal ultra-
sound have been used to stage bladder cancer (50–52). Transab-
dominal ultrasound is no longer used for staging because the
results are inaccurate and visualization of the tumor is often
obscured in obese patients and by air-containing bowel loops
adjacent to the bladder wall (50). Further problems relate to inac-
cessibility of tumors arising in the region of the bladder neck and
to the evaluation of lymph node metastases. Intravesical ultra-
sound is superior to the transabdominal approach, with reported
accuracies ranging from 62% to 92% (51,52). The accuracy depends
upon the local stage of disease because intravesical ultrasound is
more accurate for staging superficial than advanced tumors due to
poor penetration of the ultrasound beam beyond the bladder wall
(50). Because clinical staging is also highly accurate for staging
early tumors, transvesical ultrasound is rarely performed routinely.
Transrectal ultrasound provides good quality images of the trig-
one, but tumors at the bladder dome and anteriorly are poorly
visualized and this technique is therefore seldom used.
Ultrasound assessment with color Doppler has demonstrated
an association between bladder tumor size and vascularity, with
tumors of less than 2 cm in size failing to show increased vascular-
ity. However, there has been no demonstrable association between
the presence or pattern of vascularity demonstrated by Doppler
ultrasound with tumor stage or histological grade (53,54). Carbon
dioxide microbubbles have been used as a contrast medium, and
it has been reported that tumor visualization is improved com-
pared to conventional ultrasonography. Enhancement of bladder
tumor by microbubbles is prolonged compared to normal bladder

321
 primary tumor evaluation and staging
wall. Extravesical disease can be visualized, but differentiation
between deep muscle invasion and extravesical spread can be
hampered as a result of the high echogenicity of the primary
tumor after microbubble enhancement, which generates posterior
acoustic shadowing which can obscure deeper muscle in the
region of interest (55).
A refinement of transurethral ultrasonography where an ultra-
sound probe is inserted via the cystoscope sheath is endoluminal
ultrasonography (ELUS). ELUS involves a 2 mHz miniature trans-
ducer which is passed through the working channel of the cysto-
scope, allowing the tumor to stay under direct vision while
ultrasound is performed. The authors claim that individual muscle
layers can be depicted and the accuracy of distinguishing muscle-
invasive from non-muscle-invasive tumor is 84% to 88% (56,57).
Such instruments are clearly most useful for diagnosing small early
stage tumors, as the low penetration of the high frequency
ultrasound beam means that deep invasion will be more difficult to
evaluate. Broad-based tumor larger than 2 cm proved more difficult
to stage accurately using endoluminal ultrasound (57).
Despite refinements of technique over the years, ultrasound
remains somewhat peripheral in diagnosis and staging of bladder
cancer.
In general, bladder tumors are echogenic, but adjacent bladder
wall has a more intense echo pattern than tumor tissue. Early
superficial lesions can be distinguished, but with all ultrasound
based techniques problems arise in discriminating tumors involv-
ing the superficial muscle (T2a) from those invading deep muscle
(T2b). Inability to assess deeper infiltrating tumors is a funda-
mental disadvantage for ultrasound, as is inability to assess lymph
node status unless the lymph nodes are grossly enlarged.
Computed Tomography
Technique of Examination
As with all pelvic CT examinations, a full bladder is desirable, but
in patients with bladder cancer this is not always possible and only
moderate filling may be achieved. Approximately one liter of
dilute oral contrast medium (e.g., 2% gastrografin; 2% sodium
meglumine diatrizoate—Schering Healthcare Ltd.) is given at
least one hour before the examination to ensure that the small-
bowel loops within the pelvis are adequately opacified. Alterna-
tively, water may be given as an oral contrast agent provided the
technique is combined with intravenous (IV) contrast enhance-
ment to opacify the bowel wall.
The technique for staging bladder cancer has evolved considerably
over the last two decades. Initially in the 1970s, several authors advo-
cated bladder catheterization with the introduction of negative and
positive contrast agents (58,59). However, catheterization increases
the risk of urinary tract infection, prolongs examination time, is
unpleasant for the patient, and does not improve delineation of
tumor spread within the bladder wall or beyond it. These techniques
have therefore been abandoned.
Intravenous contrast medium is employed routinely for staging
bladder cancer and should be given as a bolus injection. A dose of
100 to 150 ml of iodinated contrast medium (300–350 mg iodine/
ml) is appropriate using an injection rate of approximately 3 ml/
second with a delay of 60 to 90 seconds, thus allowing images to be
obtained through the primary tumor at the time of maximum tis-
sue enhancement (Fig. 18.4). Using this technique, good vascular
322
opacification is also achieved which facilitates the distinction
of enlarged nodes from blood vessels.
When assessing patients with bladder cancer, a survey of the
abdomen as well as the pelvis is recommended. Data acquisition
can be undertaken using 1 to 5 mm collimation. Modern MDCT
machines allow coronal and sagittal reformats (Fig. 18.5) (60).
Reformatting in alternative planes may be helpful for demonstrating
tumor extension into structures beyond the bladder wall or the
relationship of normal structures to tumor.
The radiologist should always review the CT study before the
examination is judged as complete because certain manoeuvres may
facilitate interpretation. For example, altering the patient’s position
may elucidate whether a loop of bowel is adherent to tumor or
whether an apparent soft tissue mass represents a loop of bowel or an
enlarged lymph node. Sometimes it is helpful to rescan the patient
(Fig. 18.6) with the bladder empty to determine the fixation of adja-
cent structures to the bladder wall (61). It may also be useful to scan
the patient after a delay of 5 to 10 minutes to show the bladder lumen
and distal ureters opacified, thus permitting more precise detection of
tumor spread. This is also a useful manoeuvre in patients with a large
bladder diverticulum in whom it is difficult to determine whether the
tumor arises in the true bladder wall or within the diverticulum.
Refinements of the basic CT technique described above are so-
called computed tomography urography (CTU) and CT virtual
cystoscopy (CTVC). Given the propensity of urothelial carcinoma
to produce multiple lesions, CTU has the attraction of being able
to visualize the entire urinary tract. The CT technique is tailored
to visualize principally the urinary tract. Protocols of CTU should
incorporate precontrast images as well as images in the nephro-
graphic phase of enhancement, using a time delay of approxi-
mately 10 to 120 seconds from commencement of injection, and
finally in the excretory phase. The technique should allow detailed
assessment of the renal parenchyma as well as the collecting
systems, thereby allowing detection of co-existing urothelial
tumors. It should be possible to complete the examination in a
shorter time than standard excretory urography and has been
Figure 18.4 CT showing enhancement of tumor on the left bladder wall. Note
retraction of the outer bladder wall at the site of the tumor (arrow). Good opacifi-
cation of the vessels has been achieved. Stage T2b disease.
 bladder cancer

(A) (B)

(C)

(D)
Figure 18.5 Multidetector CT with multiplanar reformats. (A) Axial scan shows a large tumor lying on the posterior bladder wall. (B) Sagittal reformat demonstrates a
fat plane between the tumor and the seminal vesicles. The degree of thickening indicates that perivesical spread is highly likely. (C) Paracoronal reformat demonstrates
that the tumor is causing almost circumferential thickening of the bladder and involves the dome and both lateral walls. (D) Right hydronephrosis. Cystoprostatectomy
confirmed pT3b disease, but without invasion of prostate or seminal vesicles. Reprinted with permission from Contemporary Issues in Cancer Imaging: Carcinoma of
the bladder. MacVicar D, ed. Cambridge University Press, 2008.

Figure 18.6 (A) and (B) CT showing tumor at the bladder base
which is well-demonstrated on delayed scans with the bladder lumen
(A) (B) partly opacified. Note opacified ureters (A).

323
 primary tumor evaluation and staging

demonstrated to have improved accuracy (62). CTU has replaced
the combination of excretory urography and ultrasound in the
assessment of hematuria in some centers.
A range of CTU protocols are in use, largely based on personal
preference. No clear advantage of any particular protocol has
been demonstrated. An example of a three-phase protocol (used
at our institution at the time of writing) begins with intravenous
hydration with 250 ml of normal saline administered 10 to
15 minutes before imaging. No oral contrast is given. Images are
acquired as thin section precontrast axial scans through the entire
urinary tract. A further thin section acquisition is made follow-
ing 150 ml of intravenous iodinated contrast medium, from the
top of the kidneys to the pubic symphysis at 100 seconds after
commencement of injection (nephrographic phase) and then at
7.5 minutes (excretory phase). Axial reconstructions and orthogonal
plane reformats are then prepared for interpretation.
CT virtual cystoscopy (CTVC) similarly involves acquisition of
a three-dimensional imaging dataset, and also requires applica-
tion of volume and surface rendering algorithms. Early protocols
for CTVC involved filling the bladder with air or carbon dioxide
(pneumocystoscopy) or iodinated contrast medium (63,64).
These techniques have the disadvantage of requiring urethral
catheterization with its associated risks. An alternative method of
acquisition of CTVC images involves injection of intravenous
contrast medium with delayed acquisition of images when the
bladder feels full, usually at 90 to 120 minutes after injection. The
patient is manoevured to ensure mixing of contrast with urine in
the bladder. The sensitivity of CTVC for detecting bladder tumors
is reported to be in the region of 90%, even for lesions of less than
5 mm (65,66). Use of CTVC is said to be superior to viewing of
multiplanar reformatted images as a result of its better demon-
stration of superficial lesions (Fig. 18.7). The technique is designed

(A) (B)

(C)
Figure 18.7 CT virtual cystoscopy for bladder carcinoma. Axial contrast-enhanced CT in arterial phase (A) demonstrates early enhancement of polypoidal tumor
(arrow). Delayed imaging (B) with contrast medium in the bladder lumen outlines intraluminal growth pattern (arrow). Virtual cystoscopy reconstructed images (C)
show two polypoidal growths (black arrows) on the bladder wall. Behind the polypoidal growths is an indentation from the enlarged prostate (white arrow) with urethral
orifice (white arrowhead) in the middle. Reprinted with permission from Contemporary Issues in Cancer Imaging: Carcinoma of the bladder MacVicar D, ed.
Cambridge University Press, 2008.

324
 bladder cancer

to evaluate the bladder mucosa. Some authors claim that further

refinement with color mapping of the entire thickness of the bladder
wall will improve the sensitivity of detection of small flat and
sessile lesions (67,68). CTVC is a technique mainly performed in
specialist centers, and its principal advantage is in assessment of
early or multifocal disease. Large volume and locally advanced
disease can be effectively assessed using standard CT techniques.

Key Points: Computed Tomography Technique

■ For suspected locally advanced disease, standard CT technique
is appropriate and should include abdomen and pelvis
■ CTU and CTVC are more specialized techniques aimed at
imaging the whole of the urinary tract

CT Features of Bladder Carcinoma Figure 18.8 Axial CT shows a mass on the anterior bladder wall extending into the
CT staging of bladder cancer is usually undertaken following cys- perivesical fat and demonstrating stranding of the fat (arrow). Stage T3b.
toscopic evaluation. In patients with superficial lesions, the tumor
may have been resected and the only abnormality seen at the site
of resection is thickening of the bladder wall representing edema
or inflammatory reaction (69). If the primary tumor has not been
resected or the tumor is a large invasive lesion which has simply
been biopsied, the CT examination may reveal an intraluminal
mass (Figs. 18.1, 18.4, and 18.6). Tumors enhance following injec-
tion of IV contrast medium, usually to a greater degree than the
adjacent normal bladder wall (Fig. 18.4) (70,71). The intralumi-
nal surface of the tumor may be encrusted with calcium, which is
clearly visible on CT, but blood clots, either on the surface of the
tumor or within the mass, cannot be differentiated reliably from
tumor. Occasionally, fresh blood clots within the bladder may be
distinguished from tumor by altering the patient’s position which
allows the blood clot to fall into the most dependent part of the
bladder. Early tumors confined to the mucosal layer of the blad-
der can only be identified on CT if scanning is undertaken before
cystoscopic resection and even then small lesions less than 1 to Figure 18.9 Locally advanced bladder cancer. There is a large enhancing soft tissue
2 cm are likely to be missed, particularly at the bladder base. mass extending into the extravesical fat. Stage T3b.
Bladder cancers invading superficial and deep muscle usually
produce bladder wall thickening but distinction between T2a and
T2b lesions is extremely difficult on CT (69–74). Residual bladder
wall thickening, following resection of Ta and T1 lesions, is also
indistinguishable from muscle invasive disease (69,70).
The most important role of CT is to distinguish invasive tumors
confined to the bladder wall from those that spread into the
perivesical fat (69). The region of the bladder wall known to be the
site of the primary tumor must therefore be carefully scrutinized
for perivesical spread. A smooth outer border of the bladder wall
suggests that the tumor is confined to the bladder although the
deep muscle may be invaded. Retraction of the bladder wall at the
site of the tumor is often seen and probably indicates muscle inva-
sion (Fig. 18.4). An irregular ill-defined outer edge to the bladder
wall with soft tissue stranding into the perivesical fat is highly sus-
picious of perivesical disease (Stage T3b) (Fig. 18.8) (70,73,75).
Tumor enhancement is helpful for delineating such early perivesi-
cal spread because contrast enhancement increases the tissue con-
Figure 18.10 CT showing a mass in the right lateral bladder wall which extends
trast between tumor and fat. In more advanced disease, an obvious through the bladder wall and is causing convexity of the outer border and strand-
soft tissue mass extending beyond the bladder wall is seen as ing within the perivesical fat. Note also enlarged lymph nodes in the external iliac/
well as infiltrating strands of tumor tissue (Figs. 18.9 and 18.10). obturator group (arrow). Stage T3b N2.

325
 primary tumor evaluation and staging

Caution should be exercised if CT is performed shortly after cysto-
scopic resection of apparently early stage tumor, as it may cause
transient mural thickening and perivesical stranding (Fig. 18.11).
Tumor extension to within 3 mm of the anterior abdominal wall
muscles and/or obturator internus is classified as Stage T4b on
CT. In advanced Stage T4b disease, direct tumor spread into these
muscles is seen as an enhancing mass which invades, enlarges, and
distorts the muscle contours (Fig. 18.12) (76).
Invasion of adjacent organs is frequently difficult to identify on
CT because there are no clear fat planes between such structures
as the posterior bladder wall and the rectum, prostate, uterus,
cervix and vagina (70–72,75). Invasion of bowel may be shown in
advanced tumors. Tumor may abut against an organ without
necessarily invading it. Invasion of the seminal vesicles is more
readily detected than invasion of other organs because there is a
clear, well-defined fat angle between the anterior surface of the
seminal vesicles and the posterior bladder wall (Fig. 18.13) (72,75).
Posterior bladder wall tumors extending beyond the bladder
obliterate the fat angle and invasion of the seminal vesicles is seen
as an enhancing tumor mass directly invading these structures
(Fig. 18.13). However, obliteration of the seminal vesicle fat angle
is also seen if the rectum is overdistended or if there is hyperemia
around the bladder base due to coexistent infection (77). In the
detection of tumor invasion of the vaginal vault, cervix, and
uterus, attention should be paid to the pattern of contrast enhance-
ment because the normal uterus shows homogeneous enhance-
ment, whereas tumor usually shows a more heterogeneous pattern
of enhancement thereby allowing distinction between tumor and
normal tissue. Early organ invasion is difficult to identify, as loss
of the fat plane between an organ and tumor does not necessarily
imply tumor invasion.
In patients with tumors at the bladder base, spread inferiorly
into the perineum may be identified on CT, tumor enhancing to a
greater degree than the normal pelvic floor tissues (Fig. 18.14).

(A) (B)
Figure 18.11 (A) CT showing considerable thickening of the left bladder wall following transurethral resection for a Stage T2a tumor. Note apparent infiltration of the
perivesical fat. (B) Four weeks later the bladder wall thickening has almost completely resolved. The appearances on the initial scan were due to edema/inflammation
following resection.

(A) (B)
Figure 18.12 CT of Stage T4b bladder cancer. (A) Tumor is seen arising from the anterior bladder wall extending into the extravesical fat as far as the anterior abdominal
wall. (B) In another patient tumor is seen extending into the left obturator internus muscle.

326
 bladder cancer

(A) (B)
Figure 18.13 CT of advanced bladder cancer. (A) Tumor is present on the posterior wall of the bladder, with evidence of extravesical extension (arrow). (B) The angle
between bladder and seminal vesicles has been obliterated and there is invasion of the seminal vesicles (arrowhead). Reprinted with permission from Contemporary
Issues in Cancer Imaging: Carcinoma of the bladder. MacVicar D, ed. Cambridge University Press, 2008.

(A) (B)

(C)
Figure 18.14 CT of bladder carcinoma arising at the base, involving the posterior wall. (A) Tumor extends into the perivesical fat posteriorly, and is seen to thicken the
mesorectal fascia and presacral fascia (arrow). (B) and (C) Tumor extends into the pelvic floor, and no clear fat plane is identifiable between the tumor and anterior
rectal wall just above the anal canal (arrow).

Tumor arising within a bladder diverticulum may be difficult to are more likely to spread into the perivesical fat. With MDCT the
delineate with CT because the diverticulum may lie at an angle to use of reconstructions in the coronal and sagittal planes may be
the main bladder wall. It should be noted that the wall of a diver- helpful in defining local spread of tumors at the bladder base
ticulum usually lacks the muscle layer and therefore these tumors and dome and in assessing diverticular tumors. There are several

327
 primary tumor evaluation and staging
limitations and pitfalls associated with CT staging of bladder
cancer, summarized below:
• T1, T2, and T2a tumors are usually indistinguishable
• Tumors at the bladder base may involve the ureteric
orifices which may be difficult to image in the transaxial
plane
• Edema following cystoscopic resection or coexistent infec-
tion leads to thickening of the bladder wall (Fig. 18.11)
• Microscopic and minimal macroscopic tumor spread
beyond the bladder wall cannot be identified on CT
• Organ invasion is difficult to evaluate due to the lack of
fat planes between normal structures and tumor and
also due to partial volume averaging in the axial plane
• Tumors in unusual sites, e.g., within a diverticulum, are
difficult to assess due to poor visibility of the relation-
ship of the diverticulum to the bladder and to tumor
Key Points: Computed Tomography Findings
■ Bladder tumors enhance following injection of IV contrast
medium to a greater degree than the normal bladder wall
■ A smooth outer bladder wall usually indicates organ-confined
disease
■ Early perivesical spread is best demonstrated on
contrast-enhanced images
■ Advanced disease with spread to the pelvic sidewall or
seminal vesicles is well demonstrated on CT, but early
organ invasion may be difficult to identify
■ MDCT with alternative plane reconstructions provides
useful additional information
Magnetic Resonance Imaging
Magnetic resonance has been established as the method of choice
for evaluating several pelvic malignancies such as prostate,
uterus and cervix, and has challenged the role of CT for staging
bladder cancer. However, the recent introduction of MDCT has
once again improved the quality of CT information and there-
fore both techniques should be regarded as appropriate imaging
techniques for bladder cancer evaluation. The major advantages
of MR compared with CT include the ability to image tumor
directly in any plane and to obtain images with high soft tissue
contrast using different imaging parameters with and without
IV contrast medium.
Technique
The procedure for staging bladder cancer with MR will vary
according to the field strength of the magnet and the availability
of surface coils and of high-speed gradients which permit rapid
dynamic scanning. Some general comments apply to all pelvic
examinations and include the need to image the patient with a
moderately full bladder, and the use of an antiperistaltic agent
(e.g., glucagon) to reduce motion artefacts. A survey of the abdo-
men primarily to identify enlarged retroperitoneal nodes is also
required. To reduce respiratory motion an adjustable belt can be
wrapped around the abdomen which produces slight abdominal
compression (78) but sequences (e.g., respiratory ordered phase
328
encoding, ROPE; phased-encoded artefact reduction, PEAR; and
Navigator echoes) are now available to minimize respiratory
artefacts although these are not routinely employed in imaging
of the bladder.
Imaging Coils
The image quality of pelvic MR has been considerably enhanced
by the use of phased-array surface coils (79). Endorectal coils have
also been used for staging bladder cancer but have the disadvan-
tage that the field of view is limited to the bladder base and the
dorsal bladder wall, and therefore the technique is not suitable for
the majority of patients.
Imaging Sequences
Because MR is a highly flexible and versatile system, many differ-
ent imaging sequences and imaging planes are used for pelvic
scanning. The choice will depend largely upon the type of scanner
used and the ability to obtain fast images. However, irrespective
of the scanner features, T1- and T2-weighted sequences are usu-
ally performed. For T1-weighted sequences, conventional two-
dimensional spin-echo, fast (turbo) spin-echo, or three-dimensional
gradient-echo imaging can be used [e.g., three-dimensional
magnetization prepared rapid gradient-echo (MP-RAGE)]
(80,81). The two-dimensional spin-echo sequences have high
spatial and contrast resolution but have relatively long acquisi-
tion times; fast (turbo) spin-echo sequences allow the whole pelvis
to be imaged in under five minutes. Gradient-echo images (two-
and three-dimensional) have much shorter acquisition times and
three-dimensional imaging has the advantage that reconstruc-
tions can be obtained in any plane during postprocessing. Using
three-dimensional imaging combined with dynamic IV contrast
enhancement, Barentsz et al. (81) reported an improved staging
accuracy compared with conventional two-dimensional spin-echo
sequences.
T2-weighted images can also be obtained using conventional
spin-echo, fast spin-echo (turbo spin-echo), or gradient-echo
sequences. Fast or turbo spin-echo sequences are preferable to
standard spin-echo sequences because the acquisition time is
reduced. Gradient-echo images are highly susceptible to motion
and are therefore generally unsatisfactory for evaluating the pri-
mary tumor, but can be helpful for demonstrating pelvic sidewall
vessels and for distinguishing these from enlarged nodes using
MR angiography (time-of-flight) sequences.
Other sequences which may be of benefit include fat-suppression
techniques such as short tau inversion recovery (STIR) or chemical
shift imaging (CSI). STIR is particularly useful for highlighting
bone marrow metastases and lymphadenopathy. Fat saturation
using chemical shift may be used in conjunction with IV contrast
medium to increase the conspicuity of tumor enhancement.
Early studies reporting the accuracy of MR for staging bladder
cancer were all carried out without injection of IV contrast
medium, but as imaging has developed, the important role of IV
contrast medium in evaluating pelvic cancers has been recognized
and it has been the subject of rigorous investigation (80,82–85).
Bladder tumors enhance following injection of IV contrast
medium. The pattern of enhancement in relation to time can be
studied and signal intensity–time curves produced (85). Studies in
bladder cancer have revealed that these tumors show a greater
 bladder cancer
(A)
Figure 18.15 Bladder cancer involving the lateral and posterior walls of the bladder (Stage T3b). (A) T2-weighted MR image showing bladder cancer involving the lateral
and posterior bladder walls. (B) Early enhancement of the bladder tumor is seen on the right bladder wall only using dynamic scanning with fat saturation (image at
60 seconds).
degree of enhancement after injection than surrounding normal
tissues and the washout of contrast medium is also earlier than for
non-malignant tissue. Contrast medium uptake by the tumor can
be shown visually on dynamic scans taken through the bladder
at 30, 60, and 90 seconds postinjection of contrast material (Fig.
18.15). However, using fast dynamic scanning with gradient-
echo T1-weighted sequences, time–intensity curves can be
obtained through a slice(s) of the tumor with images obtained
every 2 to 10 seconds (Fig. 18.16) (85). These images are of
relatively poor resolution compared with the more conventional
approach of dynamic scanning and subtraction of the postcon-
trast from the precontrast images is recommended for better
visualization of tumor morphology. However, signal intensity–
time curves provide semiquantitative information regarding
the pattern of uptake of contrast material and, based on these
patterns, tumor tissue can be recognized (Fig. 18.16). There is,
however, overlap between signal intensity time curves of tumor
tissue and benign tissue. Absolute values of gadolinium concen-
tration can be derived from signal intensity–time curves from
which measurements of capillary permeability and extracellular
leakage space can be deduced. These semiquantitative and quan-
titative measurements reflect tumor vascularity and, although
they are currently undertaken only in research centers, a more
quantitative approach to staging and assessing treatment
response is likely to be introduced into clinical practice in the
not too distant future.
A recent development alongside CT virtual cystoscopy has
been the extension of three-dimensional MR imaging to MR
virtual cystoscopy (MRVC). MRVC can be conducted without
the need for external bladder filling, and no intravenous contrast
(B)
is required. A variety of imaging sequences have been described,
and most of those in current use are based on T2-weighted turbo
spin-echo sequences (86). Studies evaluating MRVC have shown
a detection rate of 100% for tumors greater than 1 cm, but for
lesions below this threshold the detection rate reduces to 70%
(87). As with CTVC, flat bladder tumors with minimal elevation
from the bladder surface cause the greatest difficulties. Differen-
tiation between small flat tumors and inflammatory swelling of
the mucosa is also problematical, especially if the bladder was
not fully distended. An advantage of MRVC is that it can be used
in patients with gross hematuria. Operative cystoscopy and
CTVC are impaired by blood clots in the bladder and bleeding
bladder tumors, but signal characteristics of blood on MR imag-
ing are usually distinctive. Both CT and MRVC are particularly
useful in assessment of tumors in bladder diverticula and on the
anterior bladder wall, areas which may be misinterpreted at
operative cystoscopy.
In general, axial images are obtained using T1- and
T2-weighted sequences followed by imaging in an orthogonal
plane, the exact protocol depending upon the site of the primary
bladder tumor. For example, coronal images are particularly
helpful for visualizing tumors arising from the lateral bladder
wall, whereas sagittal images are useful for evaluation of lesions
at the bladder base and dome. If three-dimensional techniques
are used then images can be obtained in any plane. This facility
is an advantage for investigating patients with suspected fistula
because images can be obtained along the plane of the fistula
thus demonstrating it optimally. An important use of recon-
struction in the oblique plane is in the demonstration of possible
enlarged nodes (81).
329
 primary tumor evaluation and staging

(A) (B)

500
450
400
350
Signal intensity

300
250
200
150
100
50
0
0 Image time (secs) 44
Tumor
Fat
(C) (D)

500
450
400
350
Signal intensity

300
250
200
150
100
50
0
0 44
Image time (secs)
Tumor
Fat
(E) (F)
Figure 18.16 MR imaging in the axial plane of a patient with bladder cancer treated with neoadjuvant chemotherapy. (A) T2-weighted MR image showing large intra-
luminal tumor prior to treatment. (B) Early subtraction image showing enhancement of the bladder tumor (region of interest shown in red). (C) Signal intensity-time
(SI) curve (region of interest) showing early enhancement bladder cancer and a steep SI gradient, characteristic of malignant tissue. (D) Following chemo-radiation there
has been complete resolution of the intraluminal bladder mass but bladder wall thickening persists. (E) Early contrast-enhanced subtraction image shows minimal
uptake of contrast medium (region of interest shown in red). (F) Signal intensity-time curve from a region of interest in the enhancing area of the posterior bladder wall
shows that the gradient of the SI curve is more gradual, typical of benign tissue. These results imply an excellent response to treatment.

330
 bladder cancer

On T2-weighted images, the bladder wall can be distinguished

Key Points: Magnetic Resonance Technique
■ A moderately distended bladder is necessary
■ An antiperistaltic agent helps to reduce artefacts on movement
■ Flexible phased-array pelvic coils are the technique of choice
■ Sequence selection will depend upon individual equipment but
T2-weighted images are the mainstay of imaging the bladder
■ Intravenous contrast medium may be helpful using con-
ventional or fast dynamic scanning
■ Axial images should be followed by coronal or sagittal images
depending upon the site of the primary tumor
■ 3D techniques and MR virtual cystoscopy are useful adjuncts
MR Imaging Features of Bladder Carcinoma
On T1-weighted images, the normal urinary bladder appears as a
low signal intensity structure on axial imaging. The bladder wall
has a slightly higher signal intensity than urine but differentia-
tion of the wall from urine is not always possible on T1 weight-
ing. The perivesical fat has a high signal intensity and the
pelvic sidewall muscles and vessels have a low signal intensity.
from urine within the bladder because it has a relatively low sig-
nal intensity compared with the high signal intensity of urine
(70,77,88–91). The individual layers of the bladder wall cannot
be discerned reliably on MR but occasionally a higher signal
intensity inner layer representing the submucosa is seen on
contrast-enhanced studies (92).
Bladder tumors have a low signal intensity on T1-weighted
images similar to that of muscle but slightly higher than that of
urine. On T2-weighted sequences, bladder tumors have an inter-
mediate to relatively high signal intensity (Fig. 18.17). On fast
(turbo) spin-echo T2-weighted images, bladder tumors have
lower signal intensity than on spin-echo sequences. The signal
intensity of the tumor is usually higher than that of the adjacent
normal bladder wall but lower than that of urine (Fig. 18.17). The
tumor has a lower signal intensity than perivesical fat (70,77,88–91).
A combination of T1- and T2-weighted images are principally
used to evaluate invasion of tumor within the bladder wall and
spread beyond the bladder wall into the perivesical fat and adja-
cent tissues. However, the image quality of T2-weighted images on
current scanners often obviates the need to perform T1-weighted

(A) (B)

(C) (D)
Figure 18.17 MR imaging of bladder cancer. Axial (A) T1-weighted and (B) T2-weighted images in the same patient with advanced bladder carcinoma. The tumor in the
left lateral wall returns intermediate homogeneous signal on T1-weighted imaging. T2-weighted imaging demonstrates mixed intermediate and high signal in the tumor.
(C) and (D) demonstrate an advanced bladder tumor in a different patient. T2-weighted axial and coronal images demonstrate a fairly uniform intermediate to high
signal in the mass, contrasting with the high signal return from urine.

331
 primary tumor evaluation and staging

images. Intravenous contrast medium given as a bolus shows con-
trast enhancement of the tumor and is a useful technique, not
only for obtaining dynamic signal intensity–time curves, but also
for evaluating the visual extent of tumor invasion within and
beyond the bladder wall (88,93,94). If IV contrast medium is used
then a T1-weighted sequence before and after administration of
contrast medium is recommended (Fig. 18.18).
Magnetic resonance cannot reliably detect tumors smaller than
1 cm in diameter (93,94). As with CT, bladder wall thickening
may be the only sign of a bladder tumor, particularly in patients
who have undergone transurethral resection of early superficial
disease.
In the early days of MR imaging, considerable enthusiasm was
based on the belief that MR would be able to distinguish between
T1 and T2a lesions reliably. However, as experience has been
gained it is clear that MR imaging is inaccurate for the evaluation
of these early lesions, but there is some evidence that lesions
involving the superficial muscle only (T2a) can be distinguished
from those invading the deep muscle (T2b) (70,90). This is based
on the criterion that if the “black line” of the bladder wall remains
intact on T2-weighted images the deep muscle is not invaded but
is disrupted if the deep muscle is involved (Figs. 18.19 and 18.20).
The thin black line of the bladder wall is also distinguished from
tumor on contrast-enhanced images as the muscular layer does
not enhance to the same degree as tumor (Fig. 18.18) (94–96).
Recently, Hayashi et al. (92) published data on enhancement of
the bladder wall using an endorectal coil and IV contrast medium.
These authors found that they were able to distinguish T1 tumors
from T2 tumors by virtue of the enhancement of the submucosa.
In T1 tumors, mucosal enhancement remains intact throughout
the region of the tumor, whereas in T2 tumors, submucosal
enhancement is interrupted. Submucosal enhancement may also
be shown using a pelvic phased-array coil (Fig. 18.21).
Tumor spread beyond the bladder is well demonstrated on
both T1- and T2-weighted images on current scanners because
there is high contrast between tumor and perivesical fat (Fig.
18.22) (70,89,90). The high-contrast resolution of MR and the
ability to obtain images in multiple planes facilitates perivesical
tumor detection (Fig. 18.23), but it should be remembered that
microscopic disease cannot be identified with imaging and that
early macroscopic spread beyond the bladder wall may be
missed on MR. Furthermore, hyperaemic blood vessels, edema,
and inflammatory tissue may be misinterpreted as perivesical
tumor spread in patients with coexistent infection or following

(B)

(A)

(C)
Figure 18.18 (A) T2-weighted coronal MR image shows tumor on left bladder wall with questionable extension of tumor into perivesical fat. Precontrast T1-weighted
imaging (B) and postcontrast T1-weighed imaging (C) have been performed demonstrating enhancement of the tumor which extends into the deep layers of the bladder
wall indicating deep muscle invasion and possible early extravesical spread (arrow). There is also linear enhancement of adjacent bladder submucosa which indicates
possible T1 tumor, but makes muscle invasive disease at this site very unlikely (arrowheads).

332
 bladder cancer

(A) (B)
Figure 18.19 Sagittal T2-weighted MR imaging. (A) There is a small polypoid intraluminal bladder tumor lying on the posterior wall of the bladder (arrow). The black
line of the bladder muscle is in tact, and this is an early stage tumor. (B) At the dome of the bladder in the same patient, there is infiltrative tumor disrupting the black
line of the bladder wall (arrows) and at the anterior aspect of the dome there is evidence of stranding into the perivesical fat (arrowheads). The patient has co-existent
early stage and T3b locally advanced tumor.

Figure 18.20 T2-weighted axial image showing advanced bladder cancer. Postero-
laterally to the left of the midline, the black line of the muscle layer is preserved
(arrowheads). More anteriorly, the muscle layers are seen to be engulfed by tumor
(arrows). Figure 18.21 Sagittal T1-weighted postcontrast MR image of a tumor at the bladder
base obtained with a phased-array coil. Presumed submucosal enhancement is
demonstrated (arrows).

(A) (B)
Figure 18.22 (A) Coronal and (B) sagittal T2-weighted MR images showing extensive locally advanced bladder cancer extending into the extravesical fat. Stage T3b.

333
 primary tumor evaluation and staging

cystoscopic resection (Fig. 18.24) (69). If contrast enhancement

is used, then fat suppression may be helpful for assessing
perivesical spread because enhancement of tumor reduces the
difference in signal intensity between tumor and perivesical fat
(Fig. 18.15). However, the addition of fat suppression lengthens
the acquisition time and artefacts due to movement are there-
fore more likely.
As disease advances, staging with MR becomes more accurate.
Spread of tumor to the pelvic sidewall is detected on the same
basis as CT, i.e., the demonstration of tumor extending to the
pelvic sidewall, pelvic floor, or anterior abdominal wall (Fig. 18.25).

(A)

(A)

(B)
Figure 18.23 T2-weighted MR images of a large intraluminal bladder cancer. (A)
Axial image showing intraluminal tumor with no obvious evidence of extravesical
spread. (B) Coronal image showing extravesical spread inferiorly (arrow).

(B)
Figure 18.24 T2-weighted axial MR image showing extensive soft tissue extending Figure 18.25 Advanced bladder cancer. (A) and (B) T2-weighted axial images with a
into the extravesical fat anteriorly 21 days following biopsy. This abnormal tissue urethral catheter in situ demonstrates that the urethra is surrounded by tumor, which
completely resolved without treatment in this patient with a superficial tumor. is invading the pelvic floor and the antero-lateral wall of the anal canal (arrows).

334
 bladder cancer

Organ invasion by direct tumor spread is also readily appreci-
ated on MR due to the difference in signal intensity between
tumor and the involved organ (Figs. 18.25 and 18.26) (70,80,93).
However, it may be difficult to diagnose direct tumor invasion of
an organ unless tumor enlarges the organ or produces a change
in signal intensity (Fig. 18.26). Tumor spread into the prostate,
seminal vesicles, and cervix is best shown on T2-weighted images
which highlight the signal intensity differences. An alternative
approach is to image the patient following injection of IV con-
trast medium using dynamic or postcontrast T1-weighted
sequences (Fig. 18.27) (88,93). Magnetic resonance has some
advantages over CT in the depiction of organ involvement due
to its multiplanar capability and superior contrast resolution
(Fig. 18.28).
In common with CT, MR imaging has important limitations with
regard to staging bladder tumors; these are summarized below:
• Edema and fibrosis cannot be distinguished reliably from
tumor within the bladder wall on unenhanced images
and, as with CT, this may lead to errors of overstaging
• Over or under distension of the bladder wall makes
delineation of the contiguity of the thin black line of the
bladder wall not entirely reliable
• Assessment of submucosal enhancement may distinguish
T1 from T2 tumors
• Understaging results from the inability to demonstrate
microscopic or minimal perivesical spread and early
adjacent organ invasion

(A) (B)
Figure 18.26 T2-weighted axial (A) and sagittal (B) MR images demonstrate multifocal locally advanced bladder tumor. The lesion on the posterior bladder wall is clearly
in contact with the anterior uterus. It is highly likely that the uterus is invaded, but in the absence of disruption of uterine morphology, caution must be exercised in
diagnosing invasion of the uterus.

(A) (B)
Figure 18.27 (A) T2-weighted coronal MR image shows infiltrating circumferential bladder tumor with possible invasion of the prostate (arrows). (B) Dynamic contrast-
enhanced sequence with subtraction images shows early enhancement of the primary bladder tumor and within the prostatic urethra (arrows). Urethral involvement was
confirmed at cystoscopic biopsy.

335
 primary tumor evaluation and staging

(A) (B)

(D)

(C)
Figure 18.28 A female patient with a urethral tumor. (A) and (B) CT through the tumor has not clearly demonstrated the anatomical relationship of the tumor to the
bladder, urethra and pelvic floor. (C) Sagittal and (D) coronal T2-weighted MR images clearly depicting tumor within the urethra.

Accuracy of Imaging for Staging Bladder Cancer Table 18.5 CT and MR Accuracies for Staging Bladder Cancer
Ultrasound techniques for staging bladder cancer have been
Reference Date CT No. Accuracy MR No. Accuracy
largely abandoned in the light of information now derived from
patients (%) patients (%)
CT and MR imaging (Table 18.5). However, using intravesical
Fisher et al. (91) 1985 12 64 14 85
ultrasound, accuracies in the region of 90% have been achieved
Amendola et al. (89) 1986 10 40 11 73
(50–52). The best results are achieved for staging early superficial Bryan et al. (74) 1987 9 89 10 80
tumors—tumors in which clinical staging is also highly accurate— Rholl et al. (90) 1987 19 85 23 96
and for this reason the technique is not used today as a routine Buy et al. (77) 1988 30 60 40 73
procedure. Husband et al. (70) 1989 30 80 30 73
Barentsz et al. (80) 1993 60 45 60 85
Considerable debate has focused on the relative accuracies of
Tachibana et al. (95) 1991 57 72 57 91
CT and MR imaging for staging bladder cancer throughout the Kim et al. (93) 1994 36 55 36 75
last two decades. During this time, technological aspects of CT
have continued to improve and this in part explains the wide
range of accuracies reported with CT staging of bladder cancer a greater number of patients were included with early disease
over the last 20 years, of between 40% and 92% (70–75,90,91,97,98). which tended to reduce the overall accuracy. In some studies, CT
These results also reflect the differences in study design, the tech- was evaluated following radiotherapy which led to errors of over-
niques employed, and the experience and expertise of the observ- staging due to the difficulty of distinguishing bladder wall thick-
ers. In addition, selection of patients included in the studies had ening, due to radiotherapy fibrosis, from tumor (98,99). For
an important impact on the results. For example, in some studies example, Vock et al. (99) reported overstaging in 18% of patients

336
 bladder cancer
who had previously undergone radiotherapy and, in a study
reported by Kellett et al. (98), 14% of patients were overstaged.
With CT, errors of understaging usually represent difficulties in
detecting early perivesical tumor spread and organ invasion, but
in patients with obvious advanced disease, CT is highly accurate.
Studies in which the accuracy of CT and MR imaging have been
compared in the same patients have shown a similar range of
accuracy for CT as those carried out in the early 1980s despite the
introduction of fast scanners with high image quality (70,90,93).
The accuracies reported from MR range from 73% to 96%, which
is superior to those for CT (70,74,88,90,93,96). The major differ-
ences between the techniques lie in the greater ability of MR to
assess penetration of the muscle layers of the bladder and to identify
early invasion of adjacent tissues.
In these comparative studies, patients with superficial lesions
have been included as well as patients with more advanced tumors,
thus when each pathological stage is analyzed separately with
regard to CT and MR, it is not surprising that the results of CT
have been poor. However, if Ta to T2b are grouped together, results
of CT are considerably improved.
In other studies, similar results have been obtained where MR is
either equal or slightly better than CT in distinguishing tumors
confined to the bladder from those extending into the perivesical
spread, but few studies have shown statistically significant
improvement (77,90).
Intravenous contrast medium is now advocated for MR staging
of bladder cancer by most authors. However, only a few studies
have been reported comparing unenhanced MR with dynamic
contrast-enhanced studies. Barentsz et al. showed improved stag-
ing from 67% to 84%, when IV contrast medium was used in a
fast dynamic scanning mode (85). Kim et al. (93) also showed an
improved accuracy of 9% when dynamic contrast-enhanced MR
images were compared with unenhanced images. In such studies,
the extent of invasion of the bladder wall was better demonstrated
on contrast-enhanced T1-weighted images compared with con-
ventional images and the inclusion of contrast-enhanced sequences
was the major factor in improving results. Furthermore, Hayashi
et al. (92) have also shown that contrast-enhanced MR can distin-
guish T1 from T2 tumors. A drawback of this study, however, was
the need to use an endorectal coil to obtain high-resolution
images. However, from a clinical point of view, the distinction of
early tumors confined to the bladder is less important than the
distinction of tumor spread beyond the bladder from that con-
fined to the bladder wall. Therefore, the differences in accuracy of
tumor staging with CT and MR for early disease are not central to
patient management.
Following treatment with radiotherapy, patients may require
re-staging at the time of relapse. Radiotherapy produces edema,
inflammation and fibrosis with resultant thickening of the blad-
der wall. Distinction of recurrent tumor from radiation-induced
fibrosis is frequently impossible with CT and MR unless an
obvious mass lesion can be visualized (98,99). Fast dynamic con-
trast-enhanced studies using semiquantitative analysis of signal
intensity–time curves may be useful for distinction of tumor from
biopsy tissue or fibrosis by showing earlier onset of enhancement
of tumor than benign tissue (Fig. 18.16). A study by Dobson et al.
(100) showed that dynamic contrast-enhanced MR has a high
negative predictive value (NPV 100%) in detecting residual tumor
following radiotherapy. The positive predictive value (PPV),
however, is only 48%.
Key Points: Computed Tomography Versus
Magnetic Resonance
■ Overall, MR is slightly superior to CT for staging bladder
cancer but in many patients with obvious advanced
disease, staging by both techniques is similar
■ MR has the advantage of demonstrating perivesical extension
and organ invasion in multiple planes and may therefore
determine the extent of disease better than CT. This information
is valuable for radiotherapy planning but does not necessarily
lead to upstaging of the tumor
■ Following treatment, problems are encountered with both
MR and CT in the distinction of radiation effects such as
inflammation and fibrosis from persistent or recurrent
tumor
Imaging Features of Unusual Bladder Tumors
Squamous cell carcinoma (SCC) is a major health problem in
countries where schistosomiasis is endemic, but accounts for
around 5% of bladder neoplasms in the United Kingdom. Other
risk factors for SCC include chronic infection, bladder calculi, and
indwelling catheters. The usual presentation is as a single sessile
mass lesion causing diffuse or focal bladder wall thickening. They
occur most commonly around the trigone or along the lateral
bladder wall, and are not multiple. Surface calcification may
encrust the tumor, and this is readily demonstrated on CT. A poly-
poid growth pattern is very rarely seen, and 80% of SCC demon-
strate muscle invasion at diagnosis, and extensive extravesical
spread is common. However, distant metastases at the time of
diagnosis are unusual (101).
Primary bladder adenocarcinoma accounts for around 2% of
bladder cancers. These lesions may be primary or secondary,
non-urachal, or urachal.
Urachal adenocarcinoma is associated with a persistent urachus
or more severe congenital anomalies such as bladder extrophy.
Urothelial metaplasia from chronic irritation, urinary diversions,
and pelvic lipomatosis are also risk factors, and around 25% of
patients with urachal adenocarcinomas will have some mucus in
the urine. The imaging characteristics of a urachal adenocarci-
noma are typically a large mixed solid and cystic lesion (Fig. 18.29),
and approximately 70% of lesions demonstrate some calcification
which is usually around the edge of the tumor and is patchy rather
than continuous unlike the surface calcification in SCC (102).
Mucin secretion in these tumors results in a high signal on
T2-weighted MR imaging. They commonly arise at the dome of
the bladder and along the course of the urachus, and the bulk of
the tumor may be outside the bladder. Extravesical spread and
peritoneal metastases are common (102).
Non-urachal adenocarcinoma characteristically gives diffuse
bladder wall thickening, most commonly at the bladder base.
Locally advanced disease is common at presentation and a high
proportion of patients have distant metastases with perito-
neum, lymph nodes, and lung the most commonly involved
sites (103).
337
 primary tumor evaluation and staging

Metastatic adenocarcinoma is at least as common as primary
bladder adenocarcinoma. Direct invasion of the bladder may
occur from primaries of prostate, ovary, colon, and rectum.
Hematogenous spread may occur from breast, lung, and stomach.
In the presence of a known primary, it is important to discrimi-
nate secondary carcinoma as treatment may be significantly dif-
ferent, and cell morphology and tumor markers are important in
these clinical circumstances.
Primary lymphoma may involve the bladder; this is almost invari-
ably non-Hodgkin’s lymphoma. Lymphoid tissue within the blad-
der wall may give rise to a malignant clone which thickens the wall
of the bladder. Disease may become bulky by the time of presenta-
tion, and lymphoma may remain submucosal for a prolonged
period with the result that hematuria is not pronounced. As the
mucosal surface at cystoscopy may have remained intact, deep
biopsy may be necessary to confirm the diagnosis. Cross-sectional
imaging may be helpful in demonstrating a bulky mass with rela-
tively few clinical symptoms. Bladder involvement may also be seen
as a result of metastatic lymphoma, but this is rare and is usually
seen in the clinical context of high grade or aggressive lymphoma
(104). Treatment of primary bladder lymphoma with chemother-
apy will usually result in a favorable response, and the morphology
may return to give an imaging appearance very close to normal.
Very rare bladder tumors include small cell carcinoma, neu-
roendocrine tumors such as carcinoid, paraganglioma, leiomy-
oma, melanoma, and sarcoma (Fig. 18.30). Non-malignant
lesions such as endometriosis and haemangioma may mimic
bladder cancer. Some clinical clues may be available, for example,

(A) (B)
Figure 18.29 Urachal adenocarcinoma. (A) The bladder wall component of the tumor may be limited (arrow), but (B) shows bulky mass lesions (T) along the line of the
urachus which are typical and may have solid and cystic components.

(A) (B)
Figure 18.30 (A) Axial CT with (B) sagittal reformatted image in a child aged six years shows a bizarre enhancing intraluminal lesion with thickening of the adjacent wall.
The clinical presentation and radiological appearance are unlike transitional cell carcinoma. Rhabdomyosarcoma was diagnosed at biopsy.

338
 bladder cancer

cyclical hematuria is the classical clinical presentation of endo-
metriosis affecting the bladder. Magnetic resonance imaging may
reveal subtle signal changes which suggest hemorrhage in asso-
ciation with endometriosis (105). A previous history of relatively
common aggressive tumor such as small cell carcinoma and mel-
anoma may hint at an esoteric diagnosis such as metastatic lesions
to the urinary bladder, but the diagnosis of such rare tumors is
frequently a surprise following cystoscopic biopsy.
NODAL METASTASES
Although lymph node metastases can be detected by CT and MR
imaging in the pelvis in patients with bladder cancer, both tech-
niques rely mainly on size criteria for diagnosing nodal involve-
ment. The detection of nodal metastases is discussed in detail in
chapter 40 but a few points relevant to the detection of nodal
metastases in bladder cancer are made here.
Firstly, metastases from bladder cancer frequently replace the
normal node causing little, if any, nodal enlargement and there-
fore high false negative rates are recorded with both CT and MR
imaging. Therefore it is important to scrutinize carefully the sites
of locoregional lymph node spread. Magnetic resonance appears
to be superior in the detection of obturator and presacral enlarged
lymph nodes due to improved contrast resolution (Fig. 18.31). In
one study with CT, a false negative rate of 40% was reported (75).
Secondly, lymph node metastases may enhance avidly following
injection of IV contrast medium which may cause difficulty in
the distinction of contrast-enhanced lymph nodes from adjacent
vessels. The degree of enhancement may be related to tumor
aggressiveness (85). The accuracy of CT for the detection of
lymph node deposits in pelvic cancers ranges from 70% to 92%
(75,106) and for MR ranges from 80% to 98% (74,77,90,107).
Using criteria to distinguish round nodes from oval nodes, Jager
et al. (107) investigated 134 patients with bladder or prostate can-
cer and found an accuracy of 90% in the detection of pathologi-
cally involved nodes, a specificity of 90%, a sensitivity of 75% and
a PPV of 94%. Microscopic metastatic deposits in normal-sized
nodes were not recognized in 11 patients but correct identifica-
tion of pathological nodes was possible in 33 cases. In this series,
there were two false positive cases due to benign nodal enlarge-
ment. These data were based on three-dimensional MR using the

(A) (B)

(C)

Figure 18.31 Nodal metastases. T2-weighted axial (A) and (B), and coronal (C) MR images show a diffuse locally advanced bladder tumor with prominent and enlarged
lymph nodes in the obturator, internal iliac and presacral lymph nodal chains. Presacral node arrowed.

339
 primary tumor evaluation and staging
three-dimensional magnetization-prepared rapid gradient-echo
(MP-RAGE) sequence (107). The same group has investigated
the use of dynamic contrast MR techniques to evaluate both
primary bladder cancer as well as lymph node metastases and
there is some evidence to suggest that early enhancement of
lymph nodes may indicate the presence of tumor deposits even in
nodes which are not enlarged on MR criteria (85). The current
consensus is that CT and MR are of approximately equal accu-
racy in the detection of pelvic nodal metastases (74–76,78). Nodal
metastases frequently mimic the characteristics of the primary,
not only in terms of enhancement but also with reference to such
entities as calcification and cyst formation.
Magnetic resonance lymphography using contrast agents is an
exciting new technique which is currently being investigated in
bladder cancer. Preliminary results indicate that MR lymphography
is likely to improve nodal staging significantly. Further discussion of
this technique can be found in chapter 40.
IMAGING IN FOLLOW-UP OF BLADDER CANCER
The biological behavior of urothelial malignancies is fundamen-
tally influenced by stage and grade at time of diagnosis. Follow-up
strategies are therefore tailored accordingly. For superficial
tumors resected at cystoscopy, the risk of a second bladder tumor
is greater than the risk of distant disease dissemination. Direct
inspection of the bladder mucosa is achieved by regular check
cystoscopy. Based on clinical and pathological features of the
initial tumor, patients are stratified into low, intermediate and
high-risk groups. Frequency and duration of cystoscopic follow-up
vary with the high-risk group being cystoscoped at three-
monthly intervals for two years, and if they remain clear of
disease followed at decreasing intervals until five years have
(A)
Figure 18.32 Recurrence following total cystectomy. (A) CT and (B) T1-weighted MR image. Advanced nodal recurrence is demonstrated bilaterally. There is involve-
ment of the mesorectal fascia and extension of tumor into the rectal wall.
340
elapsed. There is a case to be made for surveillance of the upper
urinary tract. Historically, this has been achieved using intra-
venous urography, but increasingly CT urography (CTU) and
MR urography (MRU) have been employed. Although more
expensive than intravenous urography (IVU), CTU and MRU
have the advantage of accurate anatomical delineation and
assessment of extraluminal disease. In terms of frequency and
duration of screening, some authors suggest a single baseline
study with re-imaging only if symptoms or positive cytology
dictate, while others advocate imaging every 6 or 12 months for
anything from two years to life (108).
In patients who present with or subsequently develop invasive
disease, radical cystectomy is frequently undertaken. The risk of
disease relapse following radical cystectomy is reportedly 5% to
70%, the majority occurring within two years of surgery (109,110).
Slaton et al. found that recurrence occurred in 5%, 20%, and 40%
of patients with Stage T1, T2, and T3 bladder cancer, respectively.
They also reported that the median times to recurrence were 53,
19, and 12 months for Stage T1, T2, and T3, respectively (109).
In a study from our own institution we also observed that tumor
stage has a relationship to the time of relapse. In our study, patients
with stage T3 and T4 disease had a shorter mean time to recurrence
compared to patients with stage T2 disease (12.9 versus 22.7 months)
(111). The reported median time to recurrence following cystec-
tomy is approximately 10 to 12 months, although this ranges widely
between 1 and 100 months. The majority of local recurrence occurs
within two years after surgery (54–82%) (109,110).
Despite pelvic nodal dissection, which is carried out routinely as
part of the radical cystectomy procedure, pelvic lymphadenopathy
is the most frequent site of relapse, occurring in 55% of our cases
(Fig. 18.32) (111). Pelvic nodal relapse occurs most frequently
along the common iliac group of lymph nodes and along the
internal iliac chains. These nodal stations are not routinely
(B)
 bladder cancer
removed at lymphadenectomy. Nodal relapse is frequently greater
than 2 cm in size, and typically appears as homogeneous soft tis-
sue masses on CT and MR. Retroperitoneal lymphadenopathy is
also a common site of relapse in our series, occurring in 33% (Fig.
18.33) (111). Although the majority of cases of retroperitoneal
lymphadenopathy are associated with pelvic nodal disease, they
may be an isolated finding in 10% of patients. We found that half
of the cases in our study with isolated retroperitoneal disease had
undergone previous pelvic radiotherapy.
Pelvic soft tissue recurrence is also common, accounting for
about 50% of relapses. The majority of pelvic soft tissue recur-
rence in our study appeared as a circumscribed soft tissue mass
(58%) (Fig. 18.34), although diffuse soft tissue thickening was
Figure 18.33 CT showing large retroperitoneal nodal recurrence in a patient with
bladder cancer. Note that a large mass invades the psoas muscle and right kidney.
The inferior vena cava is obliterated.
(A)
Figure 18.34 (A) Axial and (B) sagittal MR images showing recurrence (arrows) in the periurethral tissues following cystectomy.
also common (42%) (111). Local relapse may be subtle on imaging,
particularly peritoneal disease, and detection of disease can be
made more difficult by the persistent but variable asymmetrical
soft tissue changes following surgery. Hence, it is imperative to
compare each new scan with previous imaging to scrutinize for
any interval change. On CT, recurrent lesions may be indistinct
and difficult to identify with certainty. In these cases, dynamic
gadolinium-enhanced MR may be useful for distinguishing
abnormal tumor tissue from normal adjacent tissue (112). In our
study (111), local recurrent disease was associated with nodal
disease in only 47%, a figure that is substantially lower than the
80% observed by Ellis et al. (113).
Bladder cancer may metastasize at the time of recurrence
(114–116). The most common sites of metastatic disease in our
study were the liver (19%), bones (12%), and lungs (10%) (Fig.
18.35) (111). Bone may also be involved by direct spread from
local tumor recurrence (Fig. 18.36). The majority of patients with
liver metastases have coexisting nodal disease within the pelvis or
abdomen.
Historical data from autopsy series have demonstrated that, in
common with other solid tumors, bladder carcinoma is capable of
metastasizing to any organ. The most common sites from an
autopsy series are listed in Table 18.6 (117). Data from the era of
cross-sectional imaging confirms that nodes, liver, lung, and bone
remain the commonest sites, and a variety of extremely rare sites
of metastasis have been the subject of small series or case reports.
These include skin, eye, and meninges, and it is worth noting that
CNS deposits are relatively rare in bladder cancer (118).
The usefulness of surveillance CT after cystectomy remains a
subject of controversy. One report suggests that routine CT
surveillance can identify only 14% of recurrences that are not
symptomatic or apparent on physical examination (110). Another
study suggested that CT could detect up to 30% of those with
pelvic or retroperitoneal recurrence before the development of
(B)
341
 primary tumor evaluation and staging

(A) (B)
Figure 18.35 (A) CT showing typical liver metastases with retroperitoneal nodal involvement in a patient with advanced disseminated metastatic disease. (B) Coronal
T1-weighted MR image showing a large metastasis from bladder cancer in the sacrum.

(A) (B)
Figure 18.36 (A) and (B) CT showing extensive bony invasion by soft tissue recurrence in the pelvis following cystectomy.

Table 18.6 Sites of Metastatic Bladder Cancer (117) In current practice, FDG PET with or without CT is not rou-
tinely employed in the staging or follow-up of bladder cancer.
Site Incidence (%) FDG is subject to urinary excretion and high levels of activity are
Lymph node 78 normally found within the urinary bladder, which causes diffi-
Liver 38 culty in distinguishing normal bladder activity from tumor or
Lung 36 regional spread. As is the case in other common solid tumors,
Bone 27
PET-CT is a useful problem-solving tool in the assessment of
Adrenal gland 21
Intestine 13 distant metastatic disease.

THE EFFECTS OF TREATMENT

symptoms (109). Most of the cases of relapse in our own study
have been detected through surveillance imaging following cys-
tectomy (111).
The American College of Radiology has attempted to rationalize
follow-up imaging strategies by assigning appropriateness crite-
ria to various investigations (119). They recommend that patients
with invasive bladder cancer should have investigation of the
upper renal tract every one to two years. In addition, those patients
requiring cystectomy should have MR imaging or CT at 6, 12, and
24 months, and chest radiographs at regular intervals up to five
years postoperatively.
A significant proportion of patients with bladder cancer are unsuit-
able for cystectomy, or choose to undergo combinations of cyto-
toxic chemotherapy and radiotherapy. Response evaluation of
bladder tumors is based on a subjective assessment of tumor vol-
ume and, as with other hollow viscera, it can be difficult to measure
disease response following treatment (Fig. 18.37) Chemotherapy
and radiotherapy can generate fibrosis in the primary tumor.
Cross-sectional imaging and cystoscopy are both used in follow-up
assessment but have limitations. Schrier et al. (120) have examined
the use of dynamic contrast-enhanced MR imaging in evaluating

342
 bladder cancer
(A)
Figure 18.37 (A) CT of patient with locally advanced urothelial carcinoma on right postero-lateral bladder wall. (B) Following treatment there has clearly been reduction
in tumor bulk, but measurement is difficult, and exact characterization of subtle perivesical abnormalities (arrow) is difficult.
tumor response to chemotherapy and found that changes in the
enhancement pattern of a residual bladder tumor were more
accurate than tumor size criteria in determining response of disease
after two courses of chemotherapy. Early contrast enhancement is
related to tumor neovascularity, the persistence of which after
chemotherapy appears to be a predictor of failure to respond to
treatment (120). Assessment of residual mass lesions following treat-
ment also presents a challenge, and similar dynamic enhancement
techniques have been used to assess the irradiated bladder (100).
Radiation effects on normal tissues are also of clinical impor-
tance. Because of its rapid cell turnover, the gastrointestinal tract
is relatively radiosensitive. During radiotherapy, efforts are made
to displace bowel wall from the radiation field, but nevertheless
an acute effect of gut edema or delayed effect of gut fibrosis may
be visible on imaging. Pelvic muscle and fat will be oedematous
in the acute phase of radiation treatment, displaying high signal
on T2-weighted MR images. Abnormal signal within muscle
may persist for months or years, and fibrosis of the pelvic fascial
planes is common (121). Familiarity with the expected effects of
treatment will prevent overdiagnosis of local and peritoneal
recurrence.
Key Points: Recurrence
■ The likelihood of local recurrence is strongly influenced by
stage and grade of tumor at presentation
■ Despite pelvic nodal dissection, the pelvic lymph nodes remain
a frequent site of disease relapse following radical cystectomy
■ Local pelvic recurrence may present as a circumscribed mass
or as diffuse soft tissue thickening. There is wide variation in
practice with respect to surveillance and follow-up tech-
niques. Cross-sectional imaging is frequently used to detect
local and distant metastatic disease
■ Common sites of metastatic disease are nodes, liver, lungs,
and bone
■ The American College of Radiology has published Appropri-
ateness Criteria for follow-up investigation
■ Effects of chemotherapy and radiotherapy on bladder tumor
and surrounding tissues can be demonstrated on imaging
(B)
Summary
■ Bladder cancer can be divided into two main groups: super-
ficial tumors with a good prognosis and invasive tumors with
a poor prognosis
■ Bladder tumors are multifocal in one-third of patients and
approximately one-third of patients with superficial disease
develop recurrences which tend to progress in stage and grade
■ Clinical staging is accurate in early stage disease but inaccurate
for evaluating invasive tumors spreading beyond the bladder
■ Ultrasound has been superseded by CT and MR for staging
bladder tumors
■ CT is unreliable for staging tumors confined to the bladder wall
■ CT is accurate for staging advanced disease
■ MR imaging is superior to CT for staging early tumors
■ Contrast-enhanced MR is probably superior to unenhanced
MR for staging bladder cancer
■ CT and MR both have important limitations leading to
overstaging and understaging
■ CT and MR are equal in their ability to detect lymph node
involvement
■ CT and MR may be useful for monitoring response
■ CT and MR are valuable for detection of recurrence
REFERENCES
1. Cancer Research UK. [Available from: http://info.cancerresearchuk.
org/cancerstats/types/bladder/incidence].
2. Cancer Research UK. [Available from: http://info.cancerresearchuk.
org/cancerstats/types/bladder/mortality].
3. Jemal A, Murray T, Ward E, et al. Cancer statistics, 2005. CA
Cancer J Clin 2005; 55: 10–30.
4. Rehn L. Blasengeschülste bei Fuchsin-Arbeitern. Arch Klinik
Chirurgie 1985; 50: 558–600.
5. Iyer V, Harris RE, Wynder EL. Diesel exhaust exposure and
bladder cancer risk. Eur J Epidemiol 1990; 6: 49–54.
6. Brennan P, Bogillot O, Cordier S, et al. Cigarette smoking and
bladder cancer in men: a pooled analysis of 11 case-control
studies. Int J Cancer 2000; 86: 289–94.
343
 primary tumor evaluation and staging
7. Marcus PM, Hayes RB, Vineis P, et al. Cigarette smoking,
N-acetyltransferase 2 acetylation status, and bladder cancer
risk: a case-series meta-analysis of a gene-environment inter-
action. Cancer Epidemiol Biomarkers Prev 2000; 9: 461–7.
8. Kantor AF, Hartge P, Hoover RN, et al. Epidemiological char-
acteristics of squamous cell carcinoma and adenocarcinoma
of the bladder. Cancer Res 1988; 48: 3853–5.
9. Droller MJ. Transitional cell cancer: upper tracts and bladder. In:
Walsh PC, Gittes RF, Perlmutter AD, eds. Campbell’s Urology,
6th edn. Philadelphia: WB Saunders Stamey, 1992: 1343–440.
10. Kiemeney LA, Moret NC, Witjes JA, Schoenberg MP, Tulinius
H. Familial transitional cell carcinoma among the popula-
tion of Iceland. J Urol 1997; 157: 1649–51.
11. Tsai YC, Nichols PW, Hiti AL, et al. Allelic losses of chromo-
somes 9, 11, and 17 in human bladder cancer. Cancer Res
1990; 50: 44–7.
12. Fradet Y, Lacombe L. Can biological markers predict recur-
rence and progression of superficial bladder cancer? Curr
Opin Urol 2000; 10: 441–5.
13. Esrig D, Elmajian D, Groshen S, et al. Accumulation of
nuclear p53 and tumour progression in bladder cancer.
N Engl J Med 1994; 331: 1259–64.
14. Baffa R, Letko J, McClung C, et al. Molecular genetics of
bladder cancer: targets for diagnosis and therapy. J Exp Clin
Cancer Res 2006; 25: 145–60.
15. Alishahi S, Byrne D, Goodman CM, Baxby K. Haematuria
investigation based on a standard protocol: emphasis on the
diagnosis of urological malignancy. J R Coll Surg Edinb 2002;
47: 422–7.
16. National Institute for Clinical Excellence (NICE). Guidance
on cancer services: improving outcomes in urological cancers
2002; 12.
17. Eble JN, Sauter G, Epstein JL, Sesterhenn IA, eds. World
Health Organisation Classification of Tumours, Pathology
and Genetics of Tumours of the Urinary System and Male
Genital Tract Organs. Lyon: IARC Press, 2004.
18. Pode D, Fair W. The development of bladder cancer. In: AUA
Update 1987. Texas: Urological Associated Office of Education,
1987; lesson 40.
19. Akdas A, Turkeri L. The impact of squamous metaplasia in
transitional cell carcinoma of the bladder. Int Urol Nephrol
1991; 23: 333–6.
20. Rafal RB, Markisz JA. Urachal carcinoma: the role of magnetic
resonance imaging. Urol Radiol 1991; 12: 184–7.
21. Balci NC, Semelka RC, Siegelman ES. Tumours of the bladder
and urethra. In: Bragg DG, Rubin P, Hricak H, eds. Oncologic
Imaging, 2nd edn. Philadelphia: WB Saunders, 2002: 629–45.
22. Gilbert HA, Logan JL, Kagan AR, et al. The natural history of
papillary transitional cell carcinoma of the bladder and its
treatment in an unselected population on the basis of histologic
grading. J Urol 1978; 119: 488–92.
23. Haas GP, Grignon DJ, Montie JE. Benign and malignant
tumors of the lower urinary tract. In: Resnick IM, Older RA,
eds. Diagnosis of Genitourinary Disease, 2nd edn. New York:
Thieme, 1997: 397.
24. Heney NM, Nocks BN, Daly JJ, et al. Ta and T1 bladder
cancer: location, recurrence and progression. Br J Urol 1982;
54: 152–7.
344
25. Jakse G, Loidl W, Seeber G, et al. Stage T1, grade 3 transi-
tional cell carcinoma of the bladder: an unfavorable tumor?
J Urol 1987; 137: 39–43.
26. van der Werf-Messing B, Schroeder RH, Bush H. Part II.
Clinical practice: bladder. In: Halnan KE, ed. Treatment of
Cancer. London: Chapman and Hall, 1982: 457–74.
27. Raghavan D, Shipley WU, Garnick MB, et al. Biology and
management of bladder cancer. N Engl J Med 1990; 322:
1129–38.
28. Kulkarni JN, Gupta R. Recurrence and progression in stage
T1G3 bladder tumour with intravesical bacille Calmette–
Guerin (Danish 1331 strain). Br J Urol Int 2002; 90: 554–7.
29. Lamm DL. Superficial bladder cancer. Curr Treat Options
Oncol 2002; 3: 403–11.
30. Millikan R, Dinney C, Swanson D, et al. Integrated therapy
for locally advanced bladder cancer: final report of a
randomized trial of cystectomy plus adjuvant M-VAC versus
cystectomy with both preoperative and postoperative
M-VAC. J Clin Oncol 2001; 19: 4005–13.
31. de Wit R. Overview of bladder cancer trials in the European
Organization for Research and Treatment. Cancer 2003; 97:
2120–6.
32. Crawford ED, Wood DP, Petrylak DP, et al. Southwest
Oncology Group studies in bladder cancer. Cancer 2003;
97: 2099–108.
33. Stein JP, Ginsberg DA, Grossfeld GD, et al. Effect of p21WAF1/
CIP1 expression on tumour progression in bladder cancer.
J Natl Cancer Inst 1998; 90: 1072–9.
34. Cole CJ, Pollack A, Zagars GK, et al. Local control of muscle-
invasive bladder cancer: preoperative radiotherapy and
cystectomy versus cystectomy alone. Int J Radiat Oncol Biol
Phys 1995; 32: 331–40.
35. Waxman J, Barton C, Biruls R, et al. Bladder cancer: inter-
relationships between chemotherapy and radiotherapy. Br J
Urol 1992; 69: 151–5.
36. Wishnow KI, Levinson AK, Johnson DE, et al. Stage B (P2/3A/
N0) transitional cell carcinoma of bladder highly curable by
radical cystectomy. Urology 1992; 39: 12–16.
37. Stein JP, Lieskovsky G, Cote R, et al. Radical cystectomy in the
treatment of invasive bladder cancer: long-term results in
1,054 patients. J Clin Oncol 2001; 19: 666–75.
38. Hautmann RE, Volkmer BG, Schumacher MC, Gschwend JE,
Studer UE. Long-term results of standard procedures in urology:
the ileal neobladder. World J Urol 2006; 24: 305–14.
39. Sandhu S, Thompson A. Surgery for bladder cancer. In:
Contemporary Issues in Cancer Imaging: Carcinoma of the
Bladder. MacVicar D, ed. Cambridge: Cambridge University
Press, 2008: 93–105.
40. Perimenis P, Burkhard FC, Kessler TM, Gramann T, Studer
UE. Ileal orthotopic bladder substitute combined with an
afferent tubular segment: long-term upper urinary tract
changes and voiding pattern. Eur Urol 2004; 46: 604–9.
41. Wiesner C, Bonfig R, Stein R, et al. Continent cutaneous
urinary diversion: long-term follow-up of more than
800 patients with ileocecal reservoirs. World J Urol 2006; 24:
315–18.
42. Raghavan D. Progress in the chemotherapy of metastatic
cancer of the urinary tract. Cancer 2003; 97: 2050–5.
 bladder cancer
43. Sternberg CN, Yagoda A, Scher HI, et al. M-VAC (methotrexate,
vinblastine, doxorubicin and cisplatin) for advanced transitional
cell carcinoma of the urothelium. J Urol 1988; 139: 461–9.
44. Vale C. Neoadjuvant chemotherapy in invasive bladder cancer:
a systematic review and meta-analysis. Lancet 2003; 361:
1927–34.
45. Sobin LH, Wittekind CH, eds. International Union Against
Cancer (UICC). TNM classification of malignant tumours,
6th edn. New York: John Wiley & Sons, 2002.
46. Jewett H, Strong G. Infiltrating carcinoma of the bladder:
relation of depth of penetration of the bladder wall to incidence
of local extension in metastases. J Urol 1946; 55: 366–72.
47. Marshall V. The relation of the preoperative estimate to the
pathologic demonstration of the extent of vesical neoplasms.
J Urol 1952; 68: 714–23.
48. Greene FL, Page DL, Fleming ID, et al., eds. AJCC Cancer
Staging Handbook. New York: Springer-Verlag, 2002.
49. Whitmore WF Jr, Batata MA, Ghoneim MA, et al. Radical
cystectomy with or without prior irradiation in the treat-
ment of bladder cancer. Trans Am Assoc Genitourin Surg
1977; 69: 100–3.
50. Dershaw DD, Scher HI. Sonography in evaluation of carci-
noma of bladder. Urology 1987; 29: 454–7.
51. Schuller J, Walther V, Schmiedt E, et al. Intravesical ultra-
sound tomography in staging bladder carcinoma. J Urol
1982; 128: 264–6.
52. Abu-Yousef MM, Narayana AS, Brown RC, et al. Urinary
bladder tumors studied by cystosonography. Part II: Staging.
Radiology 1984; 153: 227–31.
53. Karahan OI, Yikilmaz A, Ekmekcioglu O, Ozturk F, Sevinc H.
Color Doppler ultrasonography findings of bladder tumors:
correlation with stage and histopathologic grade. Acta Radiol
2004; 45: 481–6.
54. Horstman WG, McFarland RM, Gorman JD. Color Doppler
sonographic findings in patients with transitional cell carci-
noma of the bladder and renal pelvis. J Ultrasound Med
1995; 14: 129–33.
55. Akimoto T, Matsumoto M, Mitsuhashi N, Mashimo T, Niibe
H. Evaluation of effect of treatment for invasive bladder can-
cer by ultrasonography with intra-arterial infusion of carbon
dioxide microbubbles. Invest Radiol 1997; 32: 396–400.
56. Saga Y, Numata A, Tokumitsu M, et al. Comparative study
of novel endoluminal ultrasonography and conventional
transurethral ultrasonography in staging of bladder cancer.
Int J Urol 2004; 11: 597–601.
57. Horiuchi K, Tsuboi N, Shimizu H, et al. High-frequency
endoluminal ultrasonography for staging transitional cell
carcinoma of the bladder. Urology 2000; 56: 404–7.
58. Hildell JG, Nyman UR, Norlindh ST, et al. New intravesical
contrast medium for CT: preliminary studies with arachis
(peanut) oil. Am J Roentgenol 1981; 137: 777–80.
59. Seidelmann FE, Cohen WN, Bryan PJ, et al. Accuracy of CT
staging of bladder neoplasms using the gas-filled method:
report of 21 patients with surgical confirmation. Am J Roent-
genol 1978; 130: 735–9.
60. Bonomo L, Foley D, Imhof H, et al., eds. Multidetector
computed tomography technology: advances in imaging
techniques. London: Royal Society of Medicine Press, 2003.
61. Havard AC. Technical report: the postmicturition CT scan as
an aid to staging bladder cancer. Clin Radiol 1992; 45:
201–2.
62. Caoili EM, Cohan RH, Inampudi P, et al. MDCT urography
of upper tract urothelial neoplasms. AJR Am J Roentgenol
2005; 184: 1873–81.
63. Kishore TA, George GK, Bhat S. Virtual cystoscopy by intra-
vesical instillation of dilute contrast medium: preliminary
experience. J Urol 2006; 175: 870–4.
64. Kawai N, Mimura T, Nagata D, Tozawa K, Kohri K. Intra-
venous urography-virtual cystoscopy is a better preliminary
examination than air virtual cystoscopy. BJU Int 2004; 94:
832–6.
65. Kim JK, Ahn JH, Park T, et al. Virtual cystoscopy of the
contrast material-filled bladder in patients with gross hema-
turia. AJR Am J Roentgenol 2002; 179: 763–8.
66. Nambirajan T, Sohaib SA, Muller-Pollard C, Reznek R,
Chineqwundoh FI. Virtual cystoscopy from computed
tomography: a pilot study. BJU Int 2004; 94: 828–31.
67. Kim JK, Park SY, Kim HS, Kim SH, Cho KS. Comparison of
virtual cystoscopy, multiplanar reformation, and source CT
images with contrast material-filled bladder for detecting
lesions. AJR Am J Roentgenol 2005; 185: 689–96.
68. Fielding JR, Hoyte LX, Okon SA, et al. Tumor detection by
virtual cystoscopy with color mapping of bladder wall thick-
ness. J Urol 2002; 167: 559–62.
69. Husband JE. Staging bladder cancer. Clin Radiol 1992; 46:
153–9.
70. Husband JE, Olliff JF, Williams MP, et al. Bladder cancer: staging
with CT and MR imaging. Radiology 1989; 173: 435–40.
71. Jeffrey RB, Palubinskas AJ, Federle MP. CT evaluation of
invasive lesions of the bladder. J Comput Assist Tomogr 1981;
5: 22–6.
72. Hodson NJ, Husband JE, MacDonald JS. The role of com-
puted tomography in the staging of bladder cancer. Clin
Radiol 1979; 30: 389–95.
73. Morgan CL, Calkins RF, Cavalcanti EJ. Computed tomography
in the evaluation, staging, and therapy of carcinoma of the
bladder and prostate. Radiology 1981; 140: 751–61.
74. Bryan PJ, Butler HE, LiPuma JP, et al. CT and MR imaging in
staging bladder neoplasms. J Comput Assist Tomogr 1987;
11: 96–101.
75. Koss JC, Arger PH, Coleman BG, et al. CT staging of bladder
carcinoma. AJR Am J Roentgenol 1981; 137: 359–62.
76. Husband JE. Computed tomography of the bladder. In: Jafri
AJ, Amendola MA, Diokno A, eds. Genito Urinary Radiology,
Diagnostic and Therapeutic. New York: Springer-Verlag,
1997.
77. Buy JN, Moss AA, Guinet C, et al. MR staging of bladder
carcinoma: correlation with pathologic findings. Radiology
1988; 169: 695–700.
78. Barentsz JO. MR imaging of urinary bladder carcinoma. In:
Jafri AJ, Amendola MA, Diokno A, eds. Genito Urinary Radi-
ology, Diagnostic and Therapeutic. New York: Springer-Verlag,
1997.
79. Barentsz JO, Lemmens JA, Ruijs SH, et al. Carcinoma of the
urinary bladder: MR imaging with a double surface coil. AJR
Am J Roentgenol 1988; 151: 107–12.
345
 primary tumor evaluation and staging
80. Barentsz JO, Ruijs SH, Strijk SP. The role of MR imaging in
carcinoma of the urinary bladder. AJR Am J Roentgenol
1993; 160: 937–47.
81. Barentsz JO, Jager G, Mugler JP 3rd, et al. Staging urinary
bladder cancer: value of T1-weighted three-dimensional
magnetization prepared-rapid gradient-echo and two-
dimensional spin-echo sequences. AJR Am J Roentgenol
1995; 164: 109–15.
82. Doringer E, Joos H, Forstner R, et al. MRT of bladder carci-
noma: tumor staging and gadolinium contrast behavior.
Rofo Fortschr Geb Rontgenstr Neuen Bildgeb Verfahr 1991;
154: 357–63.
83. Nicolas V, Spielmann R, Maas R, et al. The diagnostic value of
MR tomography following gadolinium-DTPA compared to
computed tomography in bladder tumors. Rofo Fortschr
Geb Rontgenstr Neuen Bildgeb Verfahr 1990; 153: 197–203.
84. Neuerburg JM, Bohndorf K, Sohn M, et al. Staging of urinary
bladder neoplasms with MR imaging: is Gd-DTPA helpful?
J Comput Assist Tomogr 1991; 15: 780–6.
85. Barentsz JO, Jager GJ, van Vierzen PB, et al. Staging urinary
bladder cancer after transurethral biopsy: value of fast
dynamic contrast-enhanced MR imaging. Radiology 1996;
201: 185–93.
86. Beer A, Saar B, Rummeny EJ. Tumors of the urinary bladder:
technique, current use, and perspectives of MR and CT cys-
tography. Abdom Imaging 2003; 28: 868–76.
87. Lammle M, Beer A, Settles M, et al. Reliability of MR imaging-
based virtual cystoscopy in the diagnosis of cancer of the
urinary bladder. AJR Am J Roentgenol 2002; 178: 1483–8.
88. Barentsz JO, Jager GJ, Witjes JA, et al. Primary staging of uri-
nary bladder carcinoma: the role of MR and a comparison
with CT. Eur Radiol 1996; 6: 129–33.
89. Amendola MA, Glazer GM, Grossman HB, et al. Staging of
bladder carcinoma: MR-CT-surgical correlation. Am J Roent-
genol 1986; 146: 1179–83.
90. Rholl KS, Lee JK, Heiken JP, et al. Primary bladder carcinoma:
evaluation with MR imaging. Radiology 1987; 163: 117–21.
91. Fisher MR, Hricak H, Tanagho EA. Urinary bladder MR
imaging. Part II. Neoplasm. Radiology 1985; 157: 471–7.
92. Hayashi N, Tochigi H, Shiraishi T, et al. A new staging crite-
rion for bladder carcinoma using gadolinium-enhanced
magnetic resonance imaging with an endorectal surface coil:
a comparison with ultrasonography. Br J Urol Int 2000; 85:
32–6.
93. Kim B, Semelka RC, Ascher SM, et al. Bladder tumor staging:
comparison of contrast-enhanced CT, T1- and T2-weighted
MR imaging, dynamic gadolinium-enhanced imaging, and
late gadolinium-enhanced imaging. Radiology 1994; 193:
239–45.
94. Tanimoto A, Yuasa Y, Imai Y, et al. Bladder tumor staging:
comparison of conventional and gadolinium-enhanced
dynamic MR imaging and CT. Radiology 1992; 185: 741–7.
95. Tachibana M, Baba S, Deguchi N, et al. Efficacy of gadolinium-
diethylenetriaminepentaacetic acid-enhanced magnetic
resonance imaging for differentiation between superficial
and muscle-invasive tumor of the bladder: a comparative
study with computerized tomography and transurethral
ultrasonography. J Urol 1991; 145: 1169–73.
346
96. Narumi Y, Kadota T, Inoue E, et al. Bladder wall morphology:
in vitro MR imaging–histopathologic correlation. Radiology
1993; 187: 151–5.
97. Sager EM, Talle K, Fossa S, et al. The role of CT in demon-
strating perivesical tumor growth in the preoperative staging
of carcinoma of the urinary bladder. Radiology 1983; 146:
443–6.
98. Kellett MJ, Oliver RT, Husband JE, et al. Computed tomogra-
phy as an adjunct to bimanual examination for staging blad-
der tumours. Br J Urol 1980; 52: 101–6.
99. Vock P, Haertel M, Fuchs WA, et al. Computed tomography
in staging of carcinoma of the urinary bladder. Br J Urol
1982; 54: 158–63.
100. Dobson MJ, Carrington BM, Collins CD, et al. The assessment
of irradiated bladder carcinoma using dynamic contrast-
enhanced MR imaging. Clin Radiol 2001; 56: 94–8.
101. Shokeir AA. Squamous cell carcinoma of the bladder: pathol-
ogy, diagnosis and treatment. BJU Int 2004; 93: 216–20.
102. Thali-Schwab CM, Woodward PJ, Wagner BJ. Computed
tomographic appearance of urachal adenocarcinomas: review
of 25 cases. Eur Radiol 2005; 15: 79–84.
103. Hughes MJ, Fisher C, Sohaib SA. Imaging features of primary
nonurachal adenocarcinoma of the bladder. AJR Am J Roent-
genol 2004; 183: 1397–401.
104. Bates AW, Norton AJ, Baithun SI. Malignant lymphoma
of the urinary bladder: a clinicopathological study of 11
cases. J Clin Pathol 2000; 53: 458–61.
105. Umaria N, Olliff JF. MRI appearances of bladder endometriosis.
Br J Radiol 2000; 73: 733–6.
106. Golimbu M, Morales P, Al-Askari S, et al. CAT scanning in
staging of prostatic cancer. Urology 1981; 18: 305–8.
107. Jager GJ, Barentsz JO, Oosterhof GO, et al. Pelvic adenopathy
in prostatic and urinary bladder carcinoma: MR imaging
with a three-dimensional TI-weighted magnetization-
prepared-rapid gradient-echo sequence. Am J Roentgenol
1996; 167: 1503–7.
108. Bradford TJ, Montie JE, Hafez KS. The role of imaging in
the surveillance of urologic malignancies. Urol Clin North
Am 2006; 33: 377–96.
109. Slaton JW, Swanson DA, Grossman HB, Dinney CP. A stage
specific approach to tumor surveillance after radical cystec-
tomy for transitional cell carcinoma of the bladder. J Urol
1999; 162: 710–14.
110. Westney OL, Pisters LL, Pettaway CA, et al. Presentation,
methods of diagnosis and therapy for pelvic recurrence
following radical cystectomy for transitional cell carcinoma
of the bladder. J Urol 1998; 159: 792–5.
111. Koh DM, Husband JE. Patterns of recurrence of bladder
carcinoma following radical cystectomy. Cancer Imaging
2003; 3: 96–100.
112. Barentsz JO, Engelbrecht M, Jager GJ, et al. Fast dynamic
gadolinium-enhanced MR imaging of urinary bladder
and prostate cancer. J Magn Reson Imaging 1999; 10:
295–304.
113. Ellis JH, McCullough NB, Francis IR, et al. Transitional
cell carcinoma of the bladder: patterns of recurrence after
cystectomy as determined by CT. Am J Roentgenol 1991;
157: 999–1002.
 bladder cancer
114. Lee JK, McClennan BL, Stanley RJ, et al. Use of CT in evalu-
ation of postcystectomy patients. Am J Roentgenol 1981; 136:
483–7.
115. Oliva L, Cariati M, Reggiani L, et al. CT evaluation of the
pelvic cavity after cystectomy: observation in 40 cases.
J Comput Assist Tomogr 1984; 8: 734–8.
116. Montie JE. Follow-up after cystectomy for carcinoma of the
bladder. Urol Clin North Am 1994; 21: 639–43.
117. Babaian RJ, Johnson DE, Llamas L, Ayala AG. Metastases
from transitional cell carcinoma of urinary bladder. Urology
1980; 16: 142–4.
118. Berry J, MacVicar D. Imaging of metastatic bladder cancer.
In: Contemporary Issues in Cancer Imaging: Carcinoma of
the Bladder. MacVicar D, ed. Cambridge: Cambridge University
Press, 2008: 79–92.
119. American College of Radiology Appropriateness Criteria –
Follow-up imaging of bladder carcinoma 2003. [Available from:
http://www.acr.org/].
120. Schrier BP, Peters M, Barentsz JO, Witjes JA. Evaluation of
chemotherapy with magnetic resonance imaging in patients
with regionally metastatic or unresectable bladder cancer.
Eur Urol 2006; 49: 698–703.
121. Taylor B, Bonington S, Carrington B. Imaging of treated
bladder cancer. In: Contemporary Issues in Cancer Imaging:
Carcinoma of the Bladder. MacVicar D, ed. Cambridge:
Cambridge University Press, 2008: 147–73.
347
 19 Prostate Cancer
Jingbo Zhang, Tvrtko Hudolin, and Hedvig Hricak
INTRODUCTION
Prostate cancer is the most commonly diagnosed non-cutaneous
cancer in men and a leading cause of cancer-related mortality (sec-
ond only to lung cancer) in industrialized countries. The American
Cancer Society estimated that in 2008, 186,320 cases of prostate can-
cer would be diagnosed in the United States and 28,660 men would
die from the disease (1). In the United Kingdom there are approxi-
mately 35,000 new cases diagnosed annually and about 10,000
deaths. The difference in incidence and mortality in the United
States compared with the United Kingdom is accounted for by the
large number of patients who undergo screening and are diagnosed
with early disease. However, in Europe the incidence of cancer has
been rising steadily over the last decade due, in part at least, to the
increased detection of early disease in asymptomatic patients (2).
The risk of developing prostate cancer increases with age and
approximately 60% of 60-year-old men have prostate cancer (3).
Despite the extensive clinical experience with this particular dis-
ease, its management, from screening, to diagnosis, to treatment
selection, continues to be one of the most controversial areas in
oncology. Prostate cancer is frequently multifocal and ranges greatly
in tumor volume and biological aggressiveness. Some patients carry
significant cancers that threaten their health or even their lives,
whereas others have clinically insignificant cancers that they will die
with, rather than die of. The five-year survival rate is virtually 100%
for local or regional disease, but decreases to 32% when distant
metastases are present (1). With modern prostatic serum antigen
(PSA) screening, a downward trend in tumor stage and volume at
the time of diagnosis has been witnessed. Because most patients are
diagnosed with early disease in the era of modern medicine in the
United States, for patients of all stages the relative survival rate is
98% at five years, 91% at 10 years, and 76% at 15 years (1).
CLINICAL FEATURES
Early prostate cancer is often asymptomatic at presentation. When
symptoms are present, they involve the urinary system (e.g., uri-
nary frequency and/or obstruction of urine flow). Patients with
advanced disease who have osseous metastases may experience
bone pain. On physical examination, the most common finding is
an enlarged prostate gland with indurations. Unfortunately, although
these findings may indicate the possibility of prostate cancer in an
elderly man, none of them is specific. They do, however, frequently
trigger further clinical investigations leading to serum PSA testing
and prostate biopsies for a definitive diagnosis.
PATHOLOGY AND BIOMARKERS
Ninety-five percent of prostate cancers are adenocarcinomas that
arise from the acini of the prostatic ducts. Other histological types of
348
malignant prostate tumors include small cell, mucinous, squamous,
transitional cell, and undifferentiated carcinomas, carcinosarcoma,
and malignant mesenchymal tumors such as rhabdomyosarcomas
in children and leiomyosarcomas in adults. Occasionally metastatic
tumors may be encountered in the prostate gland (4).
Prostate adenocarcinoma is currently characterized by its clinical
stage, histological grade, and serum PSA level (5–7). The TNM
staging system is the most widely applied staging system for pros-
tate cancer (Fig. 19.1 and Table 19.1) (8). There are several systems
for classifying the tumor grade. The most commonly used system
was devised by Donald F Gleason (9). This grading system is based
on the appearance of the glandular architecture under a low-power
microscope. The specimen is assigned a primary grade on the basis
of the most dominant pattern of glandular cell differentiation, and
a secondary grade based on the second most dominant pattern,
both on a scale of 1 to 5. The two grades are then added together to
produce the “Gleason score.” The higher the Gleason score the less
differentiated and more biologically aggressive is the tumor.
Patients with a Gleason score of 8 to 10 have the worst prognosis
and the highest risk probability of recurrence (10). The serum PSA
level is a strong indicator of disease severity, frequently correlates
with prostate cancer stage and prognosis, and is helpful in moni-
toring response to therapy. However, absolute serum PSA levels in
individual patients must be interpreted carefully with regard to
patient age, the size of the prostate gland, and the presence or
absence of prostatitis (11). In addition, some of the rare high-grade
undifferentiated tumors actually produce little or no PSA making
PSA of little value as a biomarker for early diagnosis in these cases.
Algorithms or nomograms that combine prostate cancer stage,
grade, and PSA level perform better than individual factors alone
in predicting disease severity and prognosis (12,13).
ANATOMY OF THE PROSTATE
For tumor localization, the prostate gland is usually divided into
three zones:
• Peripheral zone
• Central zone
• Transition zone (Figs. 19.2 and 19.3)
These three zones contain approximately 70% to 80%, 20% to
30%, and 5% to 10% of the glandular tissue, respectively, with the
frequency of disease in each zone corresponding to the per-
centage of glandular tissue it contains (14). Benign prostatic
hyperplasia (BPH) arises in the transition zone, although occa-
sionally well-defined BPH nodules can be seen in the periph-
eral zone. Cranio-caudally the prostate gland is often divided
into three sections—base, midgland, and apex, with the base
of the prostate gland being superior at the level of the bladder
neck, and the apex being inferior just above the urogenital
diaphragm (15). The prostate gland is partially enveloped by
 prostate cancer

T2a T2c

T3a T3b Seminal vesicle

T4
Levator ani muscle

Rectum

T4

Figure 19.1 Staging of prostate cancer—primary tumor (T).

a fibrous “prostate capsule” which separates the prostate gland

Table 19.1 TNM Classification: Primary Tumor (T) (2002) (8)
from the periprostatic connective tissue. It is an important
T—primary tumor landmark for assessing extraprostatic tumor extension. The
TX Primary tumor cannot be assessed neurovascular bundles course posterolateral to the prostate
T0 No evidence of primary tumor capsule bilaterally and send penetrating branches through
T1 Clinically inapparent tumor, not palpable or visible by imaging the capsule at the apex and the base, an important consider-
T1a Tumor is incidental histological finding in 5% or less of tissue
ation for modern surgical planning to minimize postoperative
resected
T1b Tumor is incidental histological finding in more than 5% of complications (16).
tissue resected
T1c Tumor identified by needle biopsy (e.g., due to elevated
PSA level) TREATMENT OPTIONS
T2 Tumor palpable or visible by imaging confined to the prostate
T2a Tumor involves one half of one lobe or less
Currently a variety of treatment options are available for pros-
T2b Tumor involves more than half of one lobe, but not both lobes
T2c Tumor involves both lobes tate cancer. The more definitive, potentially curative modali-
T3 Tumor extends through the prostatic capsule ties include surgical radical prostatectomy, external beam
T3a Extracapsular extension (unilateral or bilateral) radiation therapy, and brachytherapy. Medical treatment,
T3b Tumor invades seminal vesicle(s) including chemotherapy and hormonal therapy, is used either
T4 Tumor is fixed or invades adjacent structures other than seminal vesicles: as adjuvant therapy or, in patients with metastatic disease, as
bladder neck, external sphincter, rectum, levator muscles, or pelvic wall
the cornerstone of management. In addition, with advances in

349
 primary tumor evaluation and staging

Urethra
Ejaculatory ducts
Transition zone
Central zone

Axial Peripheral zone

Anterior fibromuscular stroma

Coronal Sagittal

Figure 19.2 Anatomy of the prostate gland.

technology, imaging-guided local therapies such as radiofre-

quency ablation (RFA), cryotherapy, and high-intensity focused
ultrasound (HIFU) have raised much clinical interest and are
undergoing investigation. “Watchful waiting,” or more appro-
A priately, deferred therapy, has also been proposed by some
experts in the field for selected patients with clinically low-risk
prostate cancers. Therefore, in the current era, the major
objective of prostate cancer imaging is to achieve more pre-
T
U cise disease characterization. Improvements are being sought
in cancer detection and localization, staging, and assessment of
tumor biological aggressiveness through the synthesis of ana-
tomic, functional, and molecular imaging information, so that
P
appropriate treatment can be selected based on individualized
P risk stratification. The appropriateness of an imaging modality
for an individual patient will depend on the cost-effectiveness
E and specific performance characteristics of the test, as well as
on the patient’s pretest probability of positive findings. It
is important that the physician be familiar with the indica-
Figure 19.3 Whole-mount section of prostate showing anatomy of the gland. The
left neurovascular bundle is marked with blue dye (arrowhead). Abbreviations: A, tions for the available staging modalities as well as test perfor-
anterior fibromuscular stroma; T, transition zone; P, peripheral zone; E, ejaculatory mance characteristics in order to proceed in an appropriate
ducts; U, urethra. and economically judicious fashion (17).

350
 prostate cancer
Key Points: General
■ Prostate cancer is the most commonly diagnosed cancer
in men
■ With PSA screening, a downward trend in tumor stage and
volume at diagnosis has been observed
■ Ninety-five percent of prostate cancers are adenocarcinomas
■ Prostate cancer is characterized for management by
clinical stage, histological grade, and PSA
■ Seventy to eighty percent of tumors arise in the peripheral zone
■ Potentially curable treatments for prostate cancer include
surgical radical prostatectomy, external beam radiation therapy,
and brachytherapy
IMAGING TECHNIQUES
There are several established imaging modalities for the evaluation
of prostate cancer. Transrectal ultrasonography has been used to
guide needle biopsy and brachytherapy seed implant. Improved
results have been reported with color and power Doppler and
administration of sonographic contrast agents. The role of elastog-
raphy with transrectal ultrasound in prostate cancer remains to be
elucidated. Magnetic resonance (MR) imaging, especially endorectal
MR imaging, is being used at a growing number of medical centers
for local staging before treatment. Accumulating data show that MR
spectroscopic imaging (MRSI) can improve this evaluation while
providing an indication of tumor aggressiveness. MR imaging with
superparamagnetic nanoparticles has high sensitivity and specificity
in depicting lymph node metastases, but guidelines have not yet
been developed for its use which remains restricted to the research
setting. Advances in MR technology during the past few years have
led to newer imaging techniques such as diffusion-weighted imaging
(DWI) and dynamic contrast-enhanced or perfusion MR imaging
that are under active investigation for their potential roles in the
assessment of prostate tumors. Computed tomography (CT) is the
modality of choice for whole-body staging and follow-up in patients
with metastatic disease. Positron emission tomography (PET), alone
or in combination with CT, using the new radiotracers 11C-choline,
18
F-fluorocholine, 11C-acetate, and 18F-fluoride has also shown prom-
ising results. Although its utility is limited in the assessment of pri-
mary disease, combined PET-CT is gaining acceptance in prostate
cancer treatment follow-up (18). In addition, imaging is playing an
increasingly important role in the guidance and follow-up of local-
ized prostate cancer therapy. Evidence-based guidelines for the use
of imaging in assessing the risk of distant spread of prostate cancer
are available (11), but controversy still exists regarding the use of
imaging for evaluating primary prostate cancers. This chapter
will review the optimal role of modern imaging in prostate cancer
detection, staging, treatment planning, and follow-up.
Detection
Transrectal Ultrasound (TRUS)
Transrectal ultrasound (TRUS) produces high-resolution images
of the prostate using a high-frequency (5–10 MHz) endorectal
transducer. With Doppler imaging, detailed assessment of the
morphology and vascularity of the prostate gland and seminal
vesicles and tumors can be made. The most important roles of
transrectal ultrasound are in guiding prostate biopsy and
brachytherapy seed implant.
Approximately 60% to 75% of prostate tumors are hypoechoic
compared with normal prostate parenchyma on ultrasound; about
12% to 30% are isoechoic and therefore cannot be detected by
grayscale sonography (Fig. 19.4). A small number of prostate
tumors are hyperechoic (19,20). However, finding a hypoechoic
lesion on TRUS is not specific for cancer as certain benign pro-
cesses such as prostatitis may also appear as hypoechoic. It has been
reported that the sensitivity of transrectal ultrasound for the detec-
tion of prostate cancer ranges between 30% and 85%, depending
on the patient’s presenting serum PSA level. Transrectal ultrasound
alone has limited utility for the identification of prostate cancer,
especially in patients with serum PSA levels lower than 20 ng/ml.
Thus, grayscale sonography is inappropriate for cancer screening,
and increasing numbers of biopsy cores are being taken in the set-
ting of systematic TRUS-guided biopsy to improve prostate cancer
detection (21). Rather than the traditional six biopsy cores, 10 to 14
cores are now routinely obtained and in some practices as many as
100 cores may be obtained.
Alternative or additional imaging methods can be performed to
help direct TRUS-guided biopsy. For example, a prospective study
showed that color Doppler imaging was more sensitive and specific
in predicting prostatic malignancy than was conventional gray-
scale imaging when areas of increased flow on Doppler imaging
were targeted for biopsy (22). Another study showed that abnormal
color flow was strongly associated with Gleason score 8 to 10
lesions but not with lower-grade lesions (23).
Ultrasound-based real-time elastography imaging, a new tech-
nique for the assessment of tissue elasticity, is being investigated as
a tool for detecting prostate cancer based on the hypothesis that
solid tumors differ in their consistency compared with the adjacent
normal tissue. Promising results have been reported recently show-
ing elastography can detect prostate cancer foci within the prostate
with good accuracy and has potential to improve ultrasound-based
prostate cancer detection (24,25). Targeted core biopsies based on
grayscale, color Doppler, and elastographic imaging have been
reported to be more likely to return positive biopsy results than
systematic core biopsies. Although color Doppler imaging and
elastography are helpful adjuncts for improving cancer detection,
targeted biopsy alone is not sufficient to replace the traditional
sextant biopsy technique (23).
Another new technique in the field of ultrasound is the use of
intravenous contrast material to enhance the visualization of
focal lesions under real-time ultrasound. For example, a study in
patients with at least one previous negative biopsy for prostate
carcinoma showed that contrast-enhanced ultrasound allowed
reliable differentiation of prostate cancer from normal prostate
tissue with a very high sensitivity, thus providing a good basis for
targeted prostate biopsy in this group of patients (26). Compari-
sons between systematic and contrast-enhanced targeted biop-
sies have shown that the targeted approach detects more cancers
and cancers with higher Gleason scores with a reduced number
of biopsy cores (27). Therefore, although systematic prostate
biopsy is now the “gold standard” of prostate cancer diagnosis, it
351
 primary tumor evaluation and staging

(A) (B)

(C)
Figure 19.4 Biopsy-confirmed prostate cancer of Gleason score 7 (4 + 3). (A) Transrectal ultrasound of prostate showing hypoechoic area (arrows) in the left peripheral
zone. (B) The baseline color Doppler image demonstrates flow along the margins of the mid-gland on both sides, with slightly increased flow in the left peripheral zone
(arrow). (C) The post-contrast color image demonstrates marked enhancement of capsular vessels feeding the lesion on the left side (arrow). Source: Courtesy of
Dr. Ethan Halpern, Jefferson Prostate Diagnostic Center, Philadelphia, U.S.A.

fails to detect some prostate cancers. Contrast-enhanced color
Doppler ultrasound and elastography may have the potential
to improve prostate cancer detection, grading, and staging.
However, further clinical trials will be needed to determine the
potential of these new ultrasound techniques (27,28).
Key Points: Transrectal Ultrasound (TRUS)
■ Sixty to seventy percent of prostate cancers are hypoechoic
on ultrasound but 12% to 30% are isoechoic with normal
parenchyma and cannot be seen on grayscale ultrasonography
■ Sensitivity of TRUS for detecting prostate cancer ranges from
30% to 85%
■ Color Doppler, real-time elastography, and contrast-
enhanced ultrasound are promising techniques for improving
tumor detection
Computed Tomography
In recent years computed tomography (CT) has undergone sub-
stantial technical improvements. With the introduction of high-
speed multidetector helical scanners, it is now possible to acquire
a CT study with high spatial resolution in a very short time. How-
ever, CT has relatively poor soft-tissue resolution in the pelvis and
is inadequate for differentiating tumor from adjacent normal
parenchyma and for delineating the prostatic anatomy. Therefore,
CT is not the modality of choice for evaluating primary prostate
cancer. A prostate that contains tumor confined within the
capsule may manifest as a normal-sized or enlarged prostate gland
on CT and cannot be differentiated from a benign enlarged
prostate gland that contains no tumor. Due to the inability of CT
to detect cancer and to visualize the prostatic capsule, a smooth
outer prostatic margin does not exclude the presence of cancer
within the gland.
One area under active investigation is the role of perfusion or
“functional” imaging in the evaluation of prostate cancer (29).
Microvessel density within the prostate is associated with the
presence of cancer, disease stage, and disease-specific survival
(30). Both dynamic contrast-enhanced (DCE) CT and DCE
MR imaging have been used for evaluating cancer angiogenesis.
On DCE CT, unlike DCE MR imaging, there is a direct linear
relationship between changes in iodine concentration and
enhancement. However, compared with DCE MR imaging, DCE
CT has had far less validation using accepted surrogate markers

352
 prostate cancer
for angiogenesis, and the substantial radiation exposure associ-
ated with DCE CT remains an important drawback. In addition,
the signal-to-noise ratio obtained with DCE CT remains poorer
than that obtained with DCE MR imaging (31).
Despite earlier studies that showed suboptimal results using
quantitative CT perfusion in localizing prostate cancer (30), a
more recent study demonstrated that it is potentially feasible to
detect both small and large prostatic lesions using 3D quantitative
blood flow mapping of the prostate obtained from DCE multi-
detector CT, with a spatial resolution as high as 0.1 cc (32). Formal
prospective studies are needed to determine the accuracy, sensi-
tivity and specificity of contrast-enhanced multi-slice helical CT
in the detection and localization of primary prostate cancer.
Key Points: Computed Tomography
■ Unenhanced CT is inadequate for differentiating tumor from
normal prostatic parenchyma
■ Three-dimensional quantitative DCE CT has potential in the
discrimination of tumor from normal gland tissue
Magnetic Resonance Imaging and Magnetic Resonance
Spectroscopic Imaging
Compared with other imaging modalities, magnetic resonance
has superior soft-tissue resolution. It can show the anatomy of the
prostate in detail and can enhance the staging of local prostate
cancer, allowing concurrent evaluation of prostatic, periprostatic,
and pelvic anatomy. Many technological advances have been
developed recently in the field of body MR imaging, such as MR
spectroscopic imaging (MRSI), dynamic contrast-enhanced MR
imaging (DCE-MRI), and diffusion-weighted imaging (DWI), for
metabolic and functional evaluation of the prostate and prostate
cancer. Furthermore, it is possible to fuse conventional MR images
with metabolic and functional images to improve the evaluation
of cancer location, size, extent, and aggressiveness. Pretreatment
(A)
Figure 19.5 Enlarged pelvic lymph nodes. (A) Axial T1-weighted and (B) axial T2-weighted MR images showing enlarged left obturator and presacral lymph nodes (arrows).
Note that the nodes are round in configuration and heterogeneous on T2-weighted imaging. Source: Imaging in Oncology, 2nd edition, chapter 18.
knowledge of these prognostic variables is essential for achieving
minimally invasive patient-specific therapy (33).
Conventional MR imaging of the prostate typically includes an
axial T1-weighted sequence of the pelvis and small-field, thin-
section, high-resolution T2-weighted images in three orthogonal
planes of the prostate. The role of T1-weighted imaging is to pro-
vide evaluation of the presence or absence of pelvic adenopathy
(Figs. 19.5 and 19.6) and osseous lesions (Fig. 19.7) as well as post-
biopsy artifacts in the prostate gland, e.g., hemorrhage (Fig. 19.8).
The prostate demonstrates homogeneous medium signal intensity
on T1-weighted imaging and tumors are impossible to discern.
T2-weighted imaging provides superb delineation of the
prostate and pelvic anatomy and is the cornerstone of prostate
tumor detection and localization. The peripheral zone of the
prostate demonstrates high signal intensity on T2-weighted
imaging (Fig. 19.9). The transition zone is often heterogeneous,
especially in older patients, due to the presence of benign pros-
tatic hypertrophy (Fig. 19.10). Prostate cancer typically manifests
as focal decreased signal on T2-weighted imaging (Fig. 19.11).
However, small-volume and low-grade prostate cancer may not
always be detectable on T2-weighted imaging. In addition, the
T2-hypointensity is not specific for prostate tumor, as certain
benign conditions such as prostatitis, fibrotic changes, or post-
biopsy changes of the prostate may lead to decreased T2 signal,
mimicking the appearance of prostate cancer. On T1-weighted
imaging post-biopsy changes manifest as T1-hyperintensity,
whereas tumors are isointense to the background parenchyma.
However, post-biopsy changes and prostate cancer may coincide
at the same location and thus MR imaging cannot always differ-
entiate biopsy changes from tumor. Therefore, a delay of six to
eight weeks between biopsy and MR imaging is recommended
(34–36).
At present, the commercially available MR scanners most com-
monly used for prostate imaging have a magnetic field strength of
1.5 T. At this field strength, the combined use of an endorectal coil
and an anterior pelvic phased-array coil appears to provide optimal
(B)
353
 primary tumor evaluation and staging

Figure 19.7 Bone metastases. Paracoronal T1-weighted MR image through the

sacrum showing multiple low signal intensity metastases from prostate cancer.
Source: Imaging in Oncology, 2nd edition, chapter 18.

Figure 19.6 Lymph node metastases. Axial T2-weighted MR image showing cluster
of nodes in the posterior external iliac chain on left (arrows). Only one of the nodes
is enlarged (>8 mm) and round, but at surgery all showed metastatic deposits.

(A) (B)
Figure 19.8 Signal changes following transrectal biopsy. (A) Axial T1-weighted and (B) axial T2-weighted MR images both show high signal intensity likely from
blood-related products (arrows). Source: Imaging in Oncology, 2nd edition, chapter 18.

(A) (B) (C)

Figure 19.9 Normal anatomy of prostate shown on T2-weighted MR images acquired with an endorectal coil. (A) Axial image; note the high signal intensity of the
peripheral zone (P). (B) Coronal image showing peripheral zone (P), central zone (C), the verumontanum (V), prostatic urethra (PU), and membranous urethra (MU).
(C) Sagittal image showing peripheral zone (P), central zone (C), and transition zone (T) of prostate.

354
 prostate cancer

(A) (B)

(C)

Figure 19.10 Seventy-three-year-old patient with elevated PSA level. Benign prostatic hyperplasia shown on T2-weighted (A) axial, (B) coronal, and (C) sagittal endorec-
tal MR images. The transition zone is enlarged by a number of glandular hyperplastic nodules and interposed stromal elements. Surgical pseudocapsule (arrowheads) is
seen at the interface of the transition and peripheral zones. The distal prostatic urethra can be seen as well (arrow).

(A) (B)
Figure 19.11 Stage T3 prostate carcinoma. (A) Axial T2-weighted MR image obtained using an endorectal coil shows anterior tumor (T) with extraprostatic extension.
(B) Whole-mount section of the prostate confirms an anterior transition zone tumor with extraprostatic extension.

355
 primary tumor evaluation and staging

(A) (B)

(C) (D)

Figure 19.12 Forty-seven-year-old patient with a PSA level of 5.3 ng/ml and biopsy-confirmed Gleason score 7 and Gleason score 6 cancer in the right and left prostate
base, respectively. T2-weighted axial (A), (B), and coronal (C), (D) MR images acquired with an endorectal coil at 3 T show the prostate anatomy and seminal vesicles in
exquisite detail; bilateral tumor (T) can be seen at the base.

signal and spatial resolution. Scanners of higher field strengths such
as 3T are becoming more widely available for clinical use (Fig.
19.12). Some investigators believe that the endorectal coil may not
be necessary at 3T for the generation of diagnostic-quality images,
since the higher field strength itself is associated with a higher signal
(37). However, other investigators have shown that image quality
and tumor localization improved significantly with endorectal coil
imaging compared with body phased-array coil imaging at 3T. For
experienced radiologists, the staging performance was significantly
better with endorectal coil imaging (38). The gradual introduction
of 3T scanners into clinical practice may provide an opportunity to
improve the quality and usefulness of prostate imaging. Increased
signal-to-noise allows for imaging at higher spatial resolution,
higher temporal resolution, or higher bandwidth. Although this
may improve the quality of conventional T2-weighted prostate
imaging, which is the standard sequence for detecting and localiz-
ing prostate cancer, the potential for improvement at 3T is of
greater significance for advanced techniques such as spectroscopy,
DWI, DCE MR imaging, and susceptibility imaging (39).
The reported accuracy of prostate cancer detection on MR imaging
varies widely, possibly due to readers’ experience levels and technical
factors. Nonetheless, MR imaging has been shown to contribute sig-
nificant incremental value to both digital rectal examination and
transrectal ultrasound-guided biopsy in cancer detection and local-
ization in the prostate (40). In addition, it has been shown that signal
intensity ratios on T2-weighted MR images correlate significantly
with tumor aggressiveness, with higher Gleason grades being
associated with lower tumor-to-muscle signal intensity ratios (41).
Traditionally, MR imaging has been thought to be inadequate
for detecting tumors in the transition zone. However, recent
research has shown that MR imaging can be used to detect, local-
ize, and stage transition zone prostate cancers (42). In addition, it
has been shown that MRSI can characterize transition zone
tumors based on their metabolic abnormality (a higher choline/

356

citrate ratio compared to BPH in the transition zone), and hence
yield high specificity, sensitivity, and accuracy in discriminating
between cancer and BPH in this zonal area (43).
Magnetic resonance spectroscopic imaging (MRSI) is an estab-
lished advanced imaging technique for metabolic and functional
evaluation of the prostate gland and displays the relative con-
centrations of chemical compounds within the imaged voxels. To
perform combined MR imaging/MRSI, a magnetic field strength
of at least 1.5 T is required. The combined use of endorectal and
pelvic phased-array coils is recommended at 1.5 T, although it has
been shown that at a higher field strength of 3T an external radio-
frequency surface coil may be sufficient for discrimination between
prostate cancer and healthy tissue (44). A number of different
MR spectroscopic techniques have been described. At present, a
three-dimensional spectroscopic imaging technique with water
and lipid suppression is routinely performed at our institution.
(A)
1500
1000
500
–365
4.30 3.71
(C)
Figure 19.13 Sixty-five-year-old patient presenting with a PSA level of 4.8 ng/ml, clinical stage T1c, and biopsy Gleason score 6 (3 + 3). (A) Axial T2-weighted MR image
with corresponding MR spectroscopic imaging (MRSI) grid overlaid; (B) corresponding MRSI spectral grid with all healthy voxels; (C) representative healthy spectrum
showing citrate (cit), creatine (cr), polyamine (PA), and choline (cho).
prostate cancer
The set-up for spectroscopic imaging is the same as that for
morphologic imaging, and both datasets are usually acquired in
the same examination so that the metabolic information can be
overlaid directly on the corresponding anatomic images. Cur-
rently, three-dimensional (3D) proton MR spectroscopic meta-
bolic mapping of the entire gland is possible with a resolution of
0.24 cc at 1.5 T. The combined MR imaging/MR spectroscopic
examination takes approximately 50 minutes.
Proton MRSI displays concentrations of citrate, creatine, and
choline. Normal prostate tissue contains high levels of citrate and
low levels of choline. In the presence of prostate cancer, the citrate
level is diminished for increased energy metabolism, and the cho-
line level is elevated owing to a high phospholipid cell membrane
turnover in the proliferating malignant tissue. Hence, an increased
choline/citrate or (choline + creatine)/citrate ratio distinguishes
prostate cancer from healthy tissue (Figs. 19.13 and 19.14). When
(B)
cit
PA
cho cr
3.09 2.48 1.87 1.25 0.64
357
 primary tumor evaluation and staging

(A) (B)

2800

2400

2000

1600 cit

1200 cho

800

400

–400
–624
4.30 3.71 3.09 2.48 1.87 1.25 0.64 0.39
(C)
Figure 19.14 Sixty-year-old patient presenting with a PSA level of 7.10 ng/ml, clinical stage T1c, and Gleason score 7 (3 + 4). (A) Axial T2-weighted MR image with MR
spectroscopic imaging (MRSI) grid overlaid; (B) corresponding MRSI spectral grid with voxels suspicious for cancer marked by asterisks; (C) representative spectrum
suggestive of cancer showing reduced citrate (cit) and elevated choline (cho).

combined with conventional MR imaging, 3D MRSI has been
reported to detect and localize prostate cancer in the entire pro-
state with high sensitivity and specificity that exceed the sensitivity
and specificity of sextant biopsy of the prostate. In addition, MR
imaging and MRSI have the advantages of being non-invasive,
radiation-free, and repeatable, and therefore provide a valuable tool
for the planning of biopsy and therapy, and for post-treatment
follow-up (45).
The addition of MRSI to conventional MR imaging signifi-
cantly improves the accuracy of prostate cancer localization
and decreases interobserver variability (46,47). With advances in
MRSI techniques, more metabolic peaks are being discovered
and studied. A recently published study by Shukla-Dave et al.
showed that polyamines (predominantly spermine) also have an
important role to play in the detection of peripheral zone prostate
cancer (48). The authors generated a statistically based voxel clas-
sification tree using a 24-patient training set (584 voxels). The first
split in the tree was based on the polyamine peak. When the
polyamine peak was undetectable or lower than the choline peak,
the voxel was considered malignant. When the polyamine peak
was higher than the choline peak, then the diagnosis was based
on the conventional metabolic ratio. In a 26-patient test set (667
voxels), the new criteria had high specificity (85%) but low sensi-
tivity (42%) for cancer detection. Additional analysis of all cancer
voxels showed that the percentage of cancer in the voxel at histo-
pathological analysis correlated positively with the sensitivity of
the classification rule, which was 75% in voxels with more than
90% malignant tissue (48).
As prostate cancer is a multifocal and histologically heteroge-
neous disease, biopsy is limited in defining all cancer sites and
grades. When biopsy results for tumor localization by sextant were
compared with pathology findings from radical prostatectomy
specimens, the positive predictive value of biopsy was 83.3% and
the negative predictive value was as low as 36.4% (49). The use of

358
 prostate cancer

combined MR imaging and MRSI improves the detection of tumors
and increases sensitivity in the preoperative localization of prostate
cancer (47,49,50). One study found that the number of abnormal
voxels on MRSI correlated significantly with histopathologic tumor
volume for tumors >0.5 cc, with the accuracy of volume prediction
being higher for larger tumors (51).
Screening for prostate cancer using serum PSA determination has
a positive predictive value of only 30% to 42% in patients with PSA
levels between 4 and 10 ng/ml. A study of 155 men showed that pros-
tate biopsy can be deferred in patients with an increased serum PSA
of 4 to 10 ng/ml if MRSI does not show any malignant voxels (52).
One of the most challenging characteristics of prostate cancer
is its variability in biologic aggressiveness. Gleason scores obtained
from biopsy specimens are not accurate predictors of Gleason
scores determined at surgical pathology. MR spectroscopy has
shown promise for the assessment of tumor aggressiveness. In
one study a trend of increasing (choline + creatine)/citrate
ratios with increasing Gleason scores was found in lesions identified
correctly with MRSI; in addition, tumor volumes determined
with MRSI increased with increasing Gleason scores (53).
Diffusion-weighted imaging (DWI) is an MR technique that mea-
sures the Brownian motion of water molecules in biologic tissues,
which is inversely proportional to cellular density, presumably
because increased cellular density limits water diffusion in the
interstitial space. The apparent diffusion coefficient (ADC), a
quantitative parameter measured from DWI, has been shown to be
useful for differentiating abdominal tumors (54–58) and assessing
the biological aggressiveness of brain tumors (59). The combina-
tion of T2-weighted imaging and DWI has been found to be better
than T2-weighted imaging alone in the detection of significant
prostate cancer (i.e., cancer with a Gleason score of at least six and
a diameter >4 mm) within the peripheral zone (Fig. 19.15) (60).
Similarly, it has been shown that the combination of MRSI and
DWI has significantly higher accuracy than does MRSI alone in
differentiating benign from malignant voxels in the peripheral
zone (61). In one study, the combination of conventional

(A) (B)

(C)
Figure 19.15 Sixty-one-year-old patient with a PSA level of 9.41 ng/ml, clinical stage T1c, and Gleason score 9 (4 + 5). (A) T2-weighted MR image acquired with an
endorectal coil showing prostate cancer in the peripheral zone with extracapsular extension and neurovascular bundle infiltration (arrow). (B) Corresponding diffusion-
weighted image obtained using a spin-echo echo-planar imaging (SE-EPI) sequence showing tumor (arrow). (C) Whole-mount section of the same prostate. Because of
the MR imaging findings, the surgeon made a wide excision in order to achieve negative surgical margins.

359
 primary tumor evaluation and staging

T2-weighted imaging and DWI had significantly higher sensitiv-
ity in prostatic tumor detection than did T2-weighted MR imaging
alone, especially in the transition zone. Less differentiated pros-
tate cancers were associated with lower ADC values and thus were
more likely to be detected by this technique (62). A similar study
showed that the addition of DWI to T2-weighted imaging with a
phased-array coil at 3T improved the differentiation of malig-
nant and benign tissues in both the peripheral and the transi-
tion zone (63). However, a recent study in Japanese men found
that ADC values were significantly different in different zones of
the prostate and increased with age, considerations that must be
taken into account when using DWI in the diagnosis of prostate
cancer (64).
Dynamic contrast-enhanced MR imaging. As in many other
cancers, angiogenesis is key to the growth and metastasis of pros-
tate cancer, and can be used as a diagnostic marker of disease.
With advances in technology, it is now possible to perform rapid
scanning with high temporal and reasonable spatial resolution
after rapid injection of contrast bolus. This type of dynamic
contrast-enhanced MR imaging (DCE-MRI) using small molecular
weight gadolinium chelates enables non-invasive imaging charac-
terization of tissue vascularity. Depending on the technique used,
data reflecting tissue perfusion, microvessel permeability and
extracellular leakage space can be obtained. Two dynamic MR
imaging techniques (T2*-weighted or susceptibility based and
T1-weighted or relaxivity-enhanced methods) for prostate gland
evaluations have been used (65).
Prostate cancer often demonstrates early nodular enhance-
ment before the rest of the prostatic parenchyma, and early
washout of signal intensity. However, this pattern is not pathog-
nomonic, as angiogenesis is also an integral part of benign pros-
tatic hyperplasia, and is associated with prostatic intraepithelial
neoplasia (PIN) (65). Prostatitis can also demonstrate increased
vascularity. In addition, some prostate cancers are mildly or
moderately hypervascular and thus are not detectable with DCE-
MRI. Despite these limitations, DCE-MRI has been shown
to have sensitivity of 73% and specificity of 81% in detecting
prostate cancers (66). Comparable results in diagnosing pro-
state cancer with this technique were reported at 3T (67,68).
A computer-aided diagnostic system applied to DCE-MRI to facili-
tate the detection of prostate cancer has also shown promising
results (69,70).
The aforementioned advanced MR imaging techniques each
have inherent advantages and disadvantages. In the future,
the best characterization of prostate cancer most likely will
result from a comprehensive, multiparametric 60-minute
examination, combining all or several of the available tech-
niques (Fig. 19.16). However, questions remain as to how to
analyze and display this large amount of imaging data, and
how to optimally combine the data for the most accurate
assessment of prostate cancer. Histological correlations or
clinical outcomes are required to determine the sensitivity
and specificity of each method and optimal combinations of
these approaches (71).

cho

cr

(A) (B) (C)

(D) (E)

Figure 19.16 Multi-parametric approach in prostate cancer imaging combining endorectal MR imaging, MR spectroscopic imaging (MRSI), and diffusion-weighted
imaging. (A) Axial T2-weighted MR image showing prostate tumor on the left side, (B) corresponding MRSI voxel, (C) metabolic map of (Cho + Cre)/Cit, (D) apparent
diffusion coefficient map, and (E) whole-mount pathologic section of the same prostate. Abbreviations: cho, choline; cr, creatine.

360
 prostate cancer
Key Points: MRI and MRSI
■ T1-weighted imaging is used to detect lymph node involve-
ment and bone metastases
■ T2-weighted imaging provides superb delineation of the
prostate anatomy and tumor localization
■ At 1.5 T endorectal imaging combined with an anterior pelvic
phased-array coil provides optimum images with high spatial
resolution
■ Proton MRSI demonstrates citrate, creatine, and choline in
prostatic tissue
■ Normal prostatic tissue has low levels of choline and high
levels of citrate
■ In prostate cancer the citrate level is reduced and the choline
level is elevated
■ The addition of MRSI to conventional MR imaging
significantly improves cancer localization
■ The combination of T2-weighted imaging and DWI is better
than T2-weighted imaging alone for the detection and
localization of prostate cancer
■ DCE-MRI provides information on tumor angiogenesis,
reflecting tumor perfusion, microvessel permeability, and
the volume of extracellular leakage space
■ DCE-MRI has a sensitivity of 73% and a specificity of 81% in
the detection of prostate cancers
Positron Emission Tomography
18
F-fluoro-2-deoxy-D-glucose (FDG) PET imaging in prostate can-
cer is challenging because glucose utilization in well-differentiated
prostate cancer is often lower than in other tumor types. There-
fore, there is an overlap in the degree of uptake between prostate
cancer, benign prostatic hyperplasia, and inflammation. In addition,
normal urinary excretion of radioisotope can mask pathological
uptake, further limiting the role of FDG PET in the identification
of primary prostate tumors (72). Generally, FDG PET has been
found to have low sensitivity for detecting primary prostate
cancer (11), except in patients with advanced-stage and more
aggressive tumors (73).
Due to the limitations of FDG PET in the evaluation of prostate
cancer, investigations are being performed with new tracers.
Promising early results have been found for 11C-choline, the
uptake of which is increased in malignant tissue due to increased
synthesis of membranal phosphatidylcholine in tumor cells (74),
and C-11 acetate, which assesses oxidative metabolism in the tis-
sue. 11C-choline has the advantage of reduced urinary excretion,
and thus may provide more accurate information for the localiza-
tion of dominant primary prostate cancer lesions (72). A recent
study retrospectively compared the sensitivity and specificity of
MR imaging, MRSI, combined MRI/MRSI, and 11C-choline
PET-CT for intraprostatic tumor sextant localization, using
histological findings as the reference standard. This study
showed that when positive results were found at both MRSI and
MR imaging, specificity in the localization of prostate cancer was
comparable to that obtained with 11C-choline PET-CT; however,
the sensitivity of 11C-choline PET-CT was lower than that of MRSI
alone or combined with MR imaging (75).
Key Points: Positron Emission Tomography
■ PET has major limitations for imaging prostate tumors
■ Glucose utilization in prostate tumors is low and therefore
there is overlap in degree of FDG uptake between normal,
benign, and malignant tissue
■ Excretion of 18FDG via the urinary tract obscures vision of
the prostate gland and masks pathological uptake in the
gland
■ 11C-choline PET has yielded promising early results in
the detection of prostate cancer, but these results need to be
validated in larger studies
Staging and Treatment Planning
The American Joint Committee on Cancer (AJCC) TNM (Tumor-
Node-Metastasis) staging system is currently the most widely used
staging system for prostate cancer (7).
Primary Tumor Staging
For local staging, MR imaging is the modality of choice. On high-
spatial-resolution T2-weighted MR imaging, signs of extracapsu-
lar extension include capsular irregularity or disruption, contour
deformity, obliteration of the rectoprostatic angle, and asymme-
try or direct involvement of the neurovascular bundle(s). Signs of
seminal vesical invasion include direct extension of low-signal-
intensity tumor into and around the seminal vesicle(s). Adjacent
organ invasion can also be visualized directly (Fig. 19.17). The
addition of MRSI allows combined anatomical and metabolic
evaluation of prostate cancer; it has been shown to improve stag-
ing by MR imaging and appears to have incremental prognostic
value in patients with moderate and high-risk tumors. For exam-
ple, the finding of more than 5 mm of extracapsular extension
before radiation seems to be of particular negative prognostic
significance, and patients with this finding may be candidates for
more aggressive supplementary therapy. The use of MR imaging
to assist radiation treatment planning has been shown to improve
outcomes (76). The presence and degree of extracapsular exten-
sion at MR imaging prior to external-beam radiation therapy are
important predictors of post-treatment metastatic recurrence
(77). A recent study showed that three-dimensional transrectal
ultrasonography (3D-TRUS) can be used to reconstruct the
prostate and seems to be an accurate technique for staging local-
ized prostate cancer. If 3D-TRUS indicates locally advanced dis-
ease, the probability of capsular perforation or seminal vesicle
invasion is very high (78). However, this technique is not widely
used and larger studies are needed to confirm the preliminary
findings.
As noted earlier, high spatial resolution dynamic contrast-
enhanced MR imaging (DCE-MRI) is a newer MR technique
undergoing active investigation. It has been shown that the
combination of this technique and conventional T2-weighted
MR imaging yields significantly improved assessment of extra-
capsular extension (ECE) and better prostate cancer staging
than does either technique independently. In a study in which
images were independently interpreted by two readers, the
mean sensitivity, specificity, positive predictive value, and
negative predictive value for ECE were 86%, 95%, 90%, and
361
 primary tumor evaluation and staging

(A) (B) (C)

(D) (E) (F)

Figure 19.17 Seventy-four-year-old man with PSA 37 ng/ml, with biopsy Gleason scores 8 (from right side) and 9 (from left side). T2-weighted MR images acquired with
an endorectal coil. (A) Axial image showing extracapsular extension on the left side (arrow) and invasion of neurovascular bundle on the right side (*). (B) Axial image
showing extracapsular extension (arrow) and neurovascular bundle invasion (*) on the right side. (C) Axial and (D) coronal images showing seminal vesicle invasion on
both sides (more prominent on left). (E) Axial image showing thickening of rectal wall (arrow). (F) Sagittal image showing low signal intensity in rectal wall (arrow). At
surgery, rectal wall invasion was confirmed.

93%, respectively, when the DCE-MRI and T2-weighted MR
imaging datasets were combined. The combined datasets had
a mean overall staging accuracy of 95%, as determined by the
area under the receiver operating characteristic curve (AUC). A
computer-generated color-coded scheme was used to facilitate
analysis of the DCE MR images (79).
Nodal Staging
In the TNM system, the regional lymph nodes (metastasis
to which is classified as N1) are considered to be the nodes
of the true pelvis, which essentially are the pelvic nodes
below the bifurcation of the common iliac arteries. They
include the following groups (laterality does not affect the
N classification):
• Pelvic [not otherwise specified (NOS)]
• Hypogastric
• Obturator
• Iliac (i.e., internal, external, or NOS)
• Sacral [lateral, presacral, promontory (e.g., Gerota),
or NOS]
Distant lymph nodes (involvement of which is classified as M1a)
are outside the confines of the true pelvis. They can be imaged
using ultrasound, CT, MR imaging, or even lymphangiography
and include the following groups:
• Aortic (para-aortic, periaortic, or lumbar)
• Common iliac, inguinal (deep)
• Superficial inguinal (femoral)
• Supraclavicular
• Cervical
• Scalene
• Retroperitoneal (NOS) nodes
Although involved lymph nodes can be identified with imaging if they
are enlarged, false-positive rates are high because the widespread use of
PSA screening has markedly reduced the incidence of nodal disease at
presentation. In lieu of imaging, risk tables are used to determine
individual patient risk of nodal involvement at the time of screening.
In the detection of lymph node metastases, conventional imag-
ing modalities are limited by both poor sensitivity and poor spec-
ificity. This is because a lymph node harboring micrometastases
may be normal in size, whereas a benign lymph node may be
enlarged due to benign etiologies, such as reactive or granuloma-
tous changes. A recent meta-analysis of 24 studies showed that CT
had a pooled sensitivity of 0.42 and a pooled specificity of 0.82 for

362
 prostate cancer

diagnosing lymph node metastases in patients with prostate cancer,
whereas for MR imaging, the pooled sensitivity was 0.39 and the
pooled specificity was 0.82. The differences in the performance of
CT and MR imaging were not statistically significant. Since nei-
ther CT nor MR imaging is reliable for determining the patient’s
status regarding nodal metastases, these techniques are not help-
ful for directing the therapeutic strategies offered to the patient
(80). Novel lymphotropic contrast agents such as superparamag-
netic nanoparticles for MR imaging may be useful for non-invasive
detection of clinically occult lymph node metastases in prostate
cancer. Superparamagnetic nanoparticles gain access to lymph
nodes by means of interstitial-lymphatic fluid transport. Normal
lymph nodes that take up these nanoparticles will demonstrate
susceptibility artefacts and therefore become darker on MR images,
whereas malignant deposits within a lymph node will not take up
the superparamagnetic agent and therefore the node will remain
partially or completely bright after administration of the contrast
material (see chap. 40). The preliminary studies of this technique
showed that high-resolution MR imaging with lymphotropic
superparamagnetic nanoparticles correctly identified all prostate
cancer patients with nodal metastases, and in a node-by-node
analysis, the technique had a significantly higher sensitivity than
conventional MR imaging (90.5% versus 35.4%, P < 0.001) or clin-
ical nomograms (81). However, the new technique, although
promising, still needs further validation and refinement of the
criteria for its use (e.g., in patients in specific risk categories or
with lymph nodes meeting specific size criteria).
tests, including CT (11). Because of widespread PSA testing and
the resultant downstaging of prostate cancer at diagnosis, the
majority of patients with newly diagnosed localized prostate can-
cer are at low risk for metastases and the diagnostic yield of CT is
low in these patients. On the other hand, high-risk patients with
clinically apparent, grossly advanced local disease, such as gross
extraprostatic extension or seminal vesical invasion, and invasion
of adjacent structures, will almost always meet the recommended
clinical criteria for the appropriate use of CT imaging for staging.
It has been shown that Gleason score, PSA, and clinical stage are
independent predictors for a positive CT scan of the abdomen
and pelvis in patients with newly diagnosed prostate cancer (85).
In asymptomatic patients with newly diagnosed, untreated pros-
tate cancer and serum PSA levels of less than 20 ng/ml the likeli-
hood of positive findings on abdominal/pelvic CT is extremely
low (<1.0%) (86,87). Therefore abdominal/pelvic CT does not
appear necessary in this setting. With more than 200,000 cases of
prostate cancer being diagnosed each year in the United States,
elimination of unnecessary staging abdominal/pelvic CT could
reduce medical expenditures by $20 to $50 million per year (86).
It is generally recommended that CT should be performed only
in patients with a PSA level greater than 15 to 20 ng/ml, Gleason
score greater than 7, and/or clinical tumor stage T3 or higher, or
probability of lymph node involvement >20% as predicted by
clinical nomograms (85,86,88–91). One exception is patients
with the anaplastic or small cell variant of prostate cancer (92,93).
Unlike patients with advanced typical adenocarcinoma of the

Metastases
Prostate cancer is one of the cancers that most frequently metasta-
sizes to the bone (classified as M1b), and bone is the most common
site of hematogenous spread from prostate cancer. Osseous metas-
tases from prostate cancer are typically osteoblastic (80%) and less
commonly osteolytic (5%) or mixed osteoblastic-osteolytic (10–15%).
Radionuclide bone scanning is the established imaging modality for
detection of osseous metastases in patients with prostate cancer
(Fig. 19.18). However, if the patient’s PSA level is less than 10 ng/ml,
the chances of a positive bone scan are less than 1% (82). Therefore,
bone scanning is generally reserved for patients with PSA levels
greater than 10 ng/ml (11). Osteoblastic bone metastases from pros-
tate cancer appear as focally increased tracer uptake, usually in the
axial skeleton. Less commonly, an area of reduced uptake may be
present, when the metastasis is mostly osteolytic. Bone scans are
more reliable than clinical symptoms or conventional radiographs
in detecting metastatic osseous lesions (83). However, with recent
advances in MR techniques that allow faster scanning of the whole
body, a one-step MR imaging examination of the axial skeleton
may be more sensitive than the traditional work-up for identifying
bone metastases in high-risk prostate cancer patients (84).
For detection of soft tissue metastases in distant organs (classi-
fied as M1c), contrast-enhanced CT is the modality of choice due
to its wide availability, low cost, and fast speed. Although all
patients with newly diagnosed prostate cancer should be assessed
for risk of metastatic disease using clinical parameters, CT is
indicated only in selected patients of higher risk categories.
Nomograms based on clinical data (PSA level, Gleason score,
digital rectal examination findings, etc.) provide risk stratifica-
tion estimates that guide the ordering of appropriate imaging Figure 19.18 Whole-body radionuclide bone scan showing bone metastases.

363
 primary tumor evaluation and staging

prostate, patients with the anaplastic or small cell variant of pros- to 100% has been reported in detecting local recurrence after
tate cancer may have extensive metastatic disease at CT despite radical prostatectomy (95,96). In a recent study, MRSI and
relatively low PSA levels. DCE-MRI also showed promising diagnostic performance in this
For detection of soft tissue metastases, a CT study is typically clinical setting (97).
acquired approximately 70 seconds after injection of intravenous
contrast medium to maximize the detection of metastatic lesions
and to differentiate between blood vessels and lymph nodes. Axial
images are obtained through the abdomen and pelvis to assess for
retroperitoneal and pelvic lymphadenopathy as well as distant
metastases to the liver or other organs (9). Using helical CT
technology, thin (5 mm collimation) slices can now be obtained
quickly through the entire abdomen and pelvis during one
breath-hold with little motion artifact.
Although limited in evaluating the primary prostate tumor,
FDG PET has a high positive predictive value for detecting
untreated metastases in viscera, but not in lymph nodes. A posi-
tive FDG PET study can provide the physician with useful infor-
mation for clinical decision-making. 11C-choline PET has shown
promise in providing sensitive and accurate preoperative staging
of pelvic lymph nodes in prostate cancer; however, at present only
a few studies have been performed and further investigations with
large numbers of patients are needed (72).

Key Points: Staging

■ MR imaging is the modality of choice for local staging
■ MRSI combined with MR imaging improves staging accuracy
in patients with moderate and high-risk tumors
■ DCE-MRI combined with T2 imaging may demonstrate
extracapsular extension with improved accuracy compared
with T2 imaging alone
Figure 19.19 Local recurrence of prostate cancer after radical prostatectomy.
■ 3D-transrectal ultrasonography (3D-TRUS) can be used to
Sagittal T2-weighted MR image acquired with an endorectal coil, showing local
reconstruct the prostate, and seems to be a promising technique recurrence between bladder and rectum with infiltration of rectum (arrow).
for staging localized prostate cancer
■ CT has a sensitivity of 42% and a specificity of 82% in the
detection of nodal spread; results for MR imaging are similar
with a sensitivity of 39% and specificity of 82%
■ MR lymphography shows promise in the detection of nodal
disease in prostate cancer
■ Bone is the most common site of metastatic spread
■ Contrast-enhanced CT is the modality of choice for detecting
metastases in distant organs

Post-Treatment Follow-up
Currently the follow-up of prostate cancer patients after treat-
ment is largely based on serum PSA levels and disease-specific
history, with imaging being performed only when indicated by
elevated PSA levels or the occurrence of symptoms (94).
Traditional methods for detecting local recurrence (i.e., digital
rectal examination, transrectal ultrasound, and transrectal ultrasound-
guided biopsy) have limited accuracy in determining the pres-
ence and extent of local recurrence after radical prostatectomy or
radiation therapy, and therefore have limited ability to guide sal-
vage therapy. For detecting local recurrence of prostate cancer
after radical prostatectomy or radiation therapy in patients
with clinical biochemical progression, MR imaging appears to be Figure 19.20 Local recurrence after brachytherapy. Coronal T2-weighted MR
the modality of choice (Figs. 19.19 and 19.20). Using conven- image showing local recurrence at superior part of prostate (T). The seeds from
tional T2-weighted endorectal MR imaging, an accuracy of close brachytherapy can be seen as well.

364
 prostate cancer

A study on a small series of patients showed that clinically
significant post-radiotherapy local recurrence occurs at the site of
the primary tumor, thus supporting the practice of boosting the
radiation dose within the primary tumor using imaging guidance.
The results of this study also suggested that monitoring of the
primary tumor site with pre- and post-radiotherapy MR imaging
might lead to early detection of local recurrence amenable to
salvage treatment (98). DCE-MRI may perform better than
T2-weighted imaging in the detection and localization of prostate
cancer in the peripheral zone after external beam radiotherapy,
and hence may be helpful in the planning of salvage therapy (99).
The combination of MR imaging and MRSI can also be applied
for the detection of local recurrence after various other thera-
peutic treatments, including hormone ablation therapy and cryo-
therapy of the prostate, since the distinction between healthy
tissue and prostate cancer is largely maintained. The additional
advantages of being non-invasive, radiation-free and repeatable
render combined MR imaging and MRSI of the prostate a valuable
tool for post-therapeutic follow-up (45).
As in the setting of pretreatment staging, CT is the modality of
choice for detection of lymph node and distant organ metastases
in post-treatment patients. Furthermore, in post-treatment
patients, PSA is a reliable follow-up tool. A study showed that the
post-treatment detection of progressive disease by imaging was
always preceded by an abnormal PSA (100). Therefore, in patients
whose PSA levels fail to become undetectable after surgery and in
patients who achieve undetectable PSA levels with subsequent
detectable PSA levels that rise on at least two measurements after
surgery, the National Comprehensive Cancer Network (NCCN)
recommends that CT, among other imaging modalities, be con-
sidered for detection of remaining disease and selection of patients
for salvage therapy (88). The NCCN also recommends that CT be
considered for patients who have a rising PSA or positive digital
rectal examination after radiation therapy who are still considered
candidates for local salvage therapy (88).
PET imaging is also being actively investigated for its poten-
tial role in evaluating recurrence. Uptake on FDG-PET is
indicative of viable tumor (Figs. 19.21 and 19.22). However,
the vast majority of studies show a relatively poor yield of pos-
itive scans with PSA values <4 ng/ml. So far, no tracer has been
shown to be able to detect local recurrence within the clinically
useful 1 ng/ml PSA threshold, clearly limiting the use of PET

(A) (B)
18
Figure 19.21 Local recurrence. (A) CT and (B) F-FDG PET-CT after radiation therapy. Accumulation of radiotracer in the right posterior part of the prostate can be
seen (arrow).

(A) (B)
Figure 19.22 Clinical stage T4 prostate cancer. (A) CT and (B) 18F-FDG PET-CT showing invasion of the pelvic sidewall on the right side.

365
 primary tumor evaluation and staging
imaging in the post-surgical setting. Preliminary evidence,
however, suggests that 11C-choline PET may be useful in select-
ing patients with early biochemical relapse (PSA < 2 ng/ml)
who have pelvic nodal oligometastasis that may be amenable to
local treatment. The role of PET imaging in prostate cancer is
gradually evolving but still remains within the experimental
realm. Well-conducted studies comparing the merits of differ-
ent tracers are needed (101). Another study demonstrated that
11
C-choline PET-CT seems to be useful for detecting clinical
recurrence after curative therapy (including radical prostatec-
tomy, external beam radiation, and interstitial brachytherapy),
of prostate cancer with a sensitivity of 91% at PSA levels
<2.5 ng/ml (102).
Key Points: Post-Treatment Follow-up
■ MR imaging is used to detect and localize recurrence in
patients with elevated PSA following therapy
■ DCE-MRI appears to be better than unenhanced T2-weighted
MR imaging for the detection of local recurrence within the
prostate
■ CT is used for detection of nodal and distant organ metastases
after treatment
Imaging-Guided Interventions
Based on the contemporary epidemiological and pathological
characteristics of prostate cancer, it is clear that in regions with a
high prevalence of PSA screening, the over-detection and subse-
quent overtreatment of prostate cancer is common. Although
many of the cancers now diagnosed pose too small a threat to
warrant radical therapy, many men are reluctant to accept watch-
ful waiting or active surveillance. However, the available curative
treatments for prostate cancer can result in morbidity, leaving
many men either impotent or incontinent, or both. Interventional
image-guided procedures have a potentially paradigm-changing
role to play in the treatment of prostate cancer by markedly
reducing the morbidity traditionally associated with manage-
ment of this disease (3). Traditional thinking holds that prostate
cancer is multifocal and therefore is not amenable to focal treat-
ment. However, histopathologic findings from published data
have indicated that up to 25% of prostate cancers are solitary
and unilateral. Furthermore, the significance of minute second-
ary cancers might be minimal (103). The growing interest in
focal therapy targeting unifocal or biologically unifocal tumors
in the prostate is related to improved biopsy strategies and imag-
ing techniques that can provide more precise tumor localization
and characterization. Several emerging technologies seem capable
of focal destruction of prostate tissue with minimal morbidity;
these include:
• High-intensity focused ultrasound (HIFU)
• Cryotherapy
• Radiofrequency ablation
• Photodynamic therapy
The major arguments against focal therapy are the multifocal
nature of prostate cancer, the limited accuracy of staging, the
unpredictable aggressiveness of secondary foci, and the lack of
established technology for focal ablation. Therefore, the investigation
366
of focal therapy in low-risk prostate cancer with prospective clini-
cal trials that carefully document safety, functional outcomes, and
cancer control is needed (104).
The principle of transrectal HIFU ablation is to focus multiple
ultrasound beams on a given target lesion in the prostate gland,
causing intensive heating and coagulation necrosis. This process is
truly non-invasive in the sense that no incisions or needle inser-
tions are needed for the procedure. Preliminary experiences show
that this may be a potential option for the the treatment of local-
ized prostate cancer in non-surgical patients, with medium-term
oncologic results broadly comparable to those of standard thera-
pies. It is also a promising salvage therapy for local recurrence after
radiation therapy. In addition, a synergistic effect between HIFU
ablation and chemotherapy has recently been reported, opening
up possibilities for treatment of high-risk or clinically advanced
tumors. However, further studies are needed to improve patient
selection and non-invasive assessment of the target tumor(s) before
and after HIFU treatment. Whereas HIFU ablation of tumors used
to be performed under TRUS guidance, MR guidance with real-time
monitoring of temperature has become available (105).
In cryoablation, freezing probes are inserted via a percutaneous
transperineal approach under TRUS guidance, leading to damage
of the target tissue. This technique has shown promise for local-
ized prostate cancer therapy and is referred to by some investiga-
tors as “the male lumpectomy.” With cryoablation, potency appears
to be preserved in a majority of patients, and other complications
are limited as well. In a study on patients who were followed up
for up to 10 years, no local recurrences were noted in treated areas.
Potency was maintained in 86% of patients and continence was
retained in all patients without previous prostate surgery or radio-
therapy (103). Therefore, this treatment approach could have a
profound effect on prostate cancer management (106). Prelimi-
nary results have also shown that cryoablation may be used as an
effective and safe salvage treatment modality for local recurrence
after radical prostatectomy. However, larger cohorts and longer
follow-up are needed to assess the viability of this treatment (107).
Radiofrequency ablation takes a transperineal approach similar to
that of cryoablation, but uses radiofrequency energy to heat tar-
geted lesions, causing irreversible coagulative necrosis. This
approach is not widely used in current clinical practice. Photody-
namic therapy uses a photosensitizing drug that is activated by
light of a specific wavelength. It requires tissue oxygen for the
treatment effect, with the activated drug forming reactive oxygen
species, which are directly responsible for damage to the treated
volume. This technique is undergoing investigation (108).
MR imaging is emerging as an ideal modality for guiding and
monitoring imaging-guided interventions due to its detailed
rendering of the prostate and its sub-structure, prostate tumors,
and surrounding tissues. MR-compatible robotic assistant systems
have been developed to allow prostate biopsy and other interven-
tional procedures including brachytherapy and the above-mentioned
local therapy techniques to be performed with improved precision
inside an MRI scanner (109). Due to the advantages of MR imag-
ing, the role of MR-guided prostate interventions in prostate can-
cer care is expected to grow (110). Attempts have also been made to
fuse real-time TRUS and previously acquired MR images of the
prostate to enable MR imaging-guided interventions outside of the
MR imaging suite. The fusion technique allows for navigation
 prostate cancer
within dynamic contrast-enhanced maps, or T2-weighted or MR
spectroscopic images. It shows promise as a way to facilitate MR
imaging-guided prostate therapies without the cost, throughput,
or equipment compatibility issues associated with an MR imaging
suite (111).
In short, energy-based ablative techniques are of growing interest
for treating the heterogeneous spectrum of prostate cancers. They
have the potential to be delivered as minimally invasive, outpatient
procedures that offer effective cancer control with low morbidity. At
present, photodynamic therapy is in its infancy and longer follow-up
with prospectively designed trials is warranted. HIFU and cryosur-
gery have emerged as forerunners in this field. However, long-term
outcome data from controlled trials with uniform definitions of dis-
ease control and consistency in reporting morbidity outcomes will
help these technologies be accepted into the mainstream (108,112).
Summary
■ Prostate cancer is the most commonly diagnosed non-
cutaneous cancer in the western world
■ Prostate cancer is frequently multifocal and varies widely in
tumor volume and biological aggressiveness
■ Seventy to eighty percent of tumors arise in the peripheral zone
■ On ultrasound, 60% to 75% of prostate tumors are
hypoechoic compared with normal prostatic tissue
■ At 1.5T T2-weighted MR images obtained with an endorectal
coil combined with a pelvic phased-array coil provide superb
delineation of the prostate
■ Combining MRSI, DWI and DCE-MRI with T2-weighted
imaging improves tumor assessment
■ FDG PET has major limitations in the assessment of
primary prostate cancer
■ Prostate cancer most frequently metastasizes to bone.
Approximately 80% of bone metastases are sclerotic
■ If the PSA level is less than 10 ng/ml the chance of a
positive bone scan is less than 1%
■ Although PSA measurement remains the primary method
for clinical surveillance of prostate cancer treatment, imaging
has shown promising results in detecting local recurrence
after radical prostatectomy or radical radiotherapy
■ CT is the best modality for identifying nodal disease and
distant organ spread after therapy
■ Novel techniques, such as high-intensity focused ultrasound
are being developed for focal destruction of tumor with
minimal morbidity
REFERENCES
1. American Cancer Society. Cancer Facts & Figures 2008.
Atlanta, GA: American Cancer Society, 2008, Publication No.
500808.
2. UK Prostate Cancer incidence statistics. Cancer Research UK
2008. [Available from: http://info.cancerresearchuk.org/
cancerstats/types/prostate/incidence/].
3. Onik G. Percutaneous image-guided prostate cancer treat-
ment: cryoablation as a successful example. Tech Vasc Interv
Radiol 2007; 10: 149–58.
4. Wheeler TM. Anatomy of the prostate and the pathology of
prostate cancer. In: Vogelzang NJ, Shipley WU, Scardino PT,
Coffey DS, eds. Comprehensive Textbook of Genitourinary
Oncology. Philadelphia, PA: Lippincott Williams & Wilkins,
2000: 587–604.
5. Allsbrook WC Jr, Mangold KA, Yang X, Epstein JI. The
Gleason grading system: an overview. J Urol Pathol 1999; 10:
141–57.
6. Gleason DF, Mellinger GT. Prediction of prognosis for
prostatic adenocarcinoma by combined histological grading
and clinical staging. J Urol 1974; 111: 58–64.
7. Green FL, Page DL, Fleming ID, et al., eds. AJCC Cancer
Staging Manual. New York: Springer-Verlag, 2002.
8. Sobin LH, Wittekind CH. TNM Classification of Malignant
Tumours, 6th edn. New York: Wiley-Liss, 2002.
9. Gleason DF. Classification of prostatic carcinomas. Cancer
Chemother Rep 1966; 50: 125–8.
10. D’Amico AV, Moul JW, Kattan MW. Emerging prognostic
factors for outcome prediction in clinically localized pro-
state cancer: prostate-specific antigen level, race, molecular
markers, and neural networks. In: Vogelzang NJ, Shipley
WU, Scardino PT, Coffey DS, eds. Comprehensive Textbook
of Genitourinary Oncology. Philadelphia, PA: Lippincott
Williams & Wilkins, 2000; 680–700.
11. Hricak H, Choyke PL, Eberhardt SC, Leibel SA, Scardino PT.
Imaging prostate cancer: a multidisciplinary perspective.
Radiology 2007; 243: 28–53. Erratum in: Radiology 2007;
245: 302.
12. Kattan MW, Stapleton AM, Wheeler TM, Scardino PT. Evalu-
ation of a nomogram used to predict the pathologic stage of
clinically localized prostate carcinoma. Cancer 1997; 79:
528–37.
13. Kattan MW, Zelefsky MJ, Kupelian PA, et al. Pretreatment
nomogram for predicting the outcome of three-dimensional
conformal radiotherapy in prostate cancer. J Clin Oncol
2000; 18: 3352–9.
14. Coakley FV, Hricak H. Radiologic anatomy of the prostate
gland: a clinical approach. Radiol Clin North Am 2000; 38:
15–30.
15. Ishii J, Ohori M, Scardino P, et al. Significance of the
craniocaudal distribution of cancer in radical prostatectomy
specimens. Int J Urol 2007; 14: 817–21.
16. Kundra V, Silverman PM, Matin SF, Choi H. Imaging in
oncology from the University of Texas M.D. Anderson
Cancer Center: diagnosis, staging, and surveillance of
prostate cancer. AJR Am J Roentgenol 2007; 189: 830–44.
17. Lacy GL 2nd, Soderdahl DW, Hernandez J. Optimal cost-
effective staging evaluations in prostate cancer. Curr Urol
Rep 2007; 8: 190–6.
18. Oehr P, Bouchelouche K. Imaging of prostate cancer. Curr
Opin Oncol 2007; 19: 259–64.
19. Shinohara K, Wheeler TM, Scardino PT. The appearance of
prostate cancer on transrectal ultrasonography: correlation
of imaging and pathological examinations. J Urol 1989; 142:
76–82.
20. Smith JA Jr. Transrectal ultrasonography for the detection
and staging of carcinoma of the prostate. J Clin Ultrasound
1996; 24: 455–61.
367
 primary tumor evaluation and staging
21. Tamsel S, Killi R, Hekimgil M, et al. Transrectal ultrasound
in detecting prostate cancer compared with serum total
prostate-specific antigen levels. J Med Imaging Radiat Oncol
2008; 52: 24–8.
22. Sen J, Choudhary L, Marwah S, et al. Role of colour Doppler
imaging in detecting prostate cancer. Asian J Surg 2008; 31:
16–19.
23. Nelson ED, Slotoroff CB, Gomella LG, Halpern EJ. Targeted
biopsy of the prostate: the impact of color Doppler imaging
and elastography on prostate cancer detection and Gleason
score. Urology 2007; 70: 1136–40.
24. Kamoi K, Okihara K, Ochiai A, et al. The utility of tran-
srectal real-time elastography in the diagnosis of prostate
cancer. Ultrasound Med Biol 2008; 34: 1025–32.
25. Salomon G, Köllerman J, Thederan I, et al. Evaluation of
prostate cancer detection with ultrasound real-time elastog-
raphy: a comparison with step section pathological analysis
after radical prostatectomy. Eur Urol 2008; 54: 1354–62.
26. Taymoorian K, Thomas A, Slowinski T, et al. Transrectal
broadband-Doppler sonography with intravenous contrast
medium administration for prostate imaging and biopsy
in men with an elevated PSA value and previous negative
biopsies. Anticancer Res 2007; 27: 4315–20.
27. Pallwein L, Mitterberger M, Pelzer A, et al. Ultrasound
of prostate cancer: recent advances. Eur Radiol 2008; 18:
707–15.
28. Heijmink SW, Barentsz JO. Contrast-enhanced versus
systematic transrectalultrasound-guided prostate cancer
detection: an overview of techniques and a systematic review.
Eur J Radiol 2007; 63: 310–16.
29. Henderson E, Milosevic MF, Haider MA, Yeung IW. Func-
tional CT imaging of prostate cancer. Phys Med Biol 2003;
48: 3085–100.
30. Ives EP, Burke MA, Edmonds PR, Gomella LG, Halpern EJ.
Quantitative computed tomography perfusion of prostate
cancer: correlation with whole-mount pathology. Clin
Prostate Cancer 2005; 4: 109–12.
31. Padhani AR, Harvey CJ, Cosgrove DO. Angiogenesis imaging
in the management of prostate cancer. Nat Clin Pract Urol
2005; 2: 596–607.
32. Jeukens CR, van den Berg CA, Donker R, et al. Feasibility
and measurement precision of 3D quantitative blood flow
mapping of the prostate using dynamic contrast-enhanced
multi-slice CT. Phys Med Biol 2006; 51: 4329–43.
33. Fuchsjäger M, Shukla-Dave A, Akin O, Barentsz J, Hricak H.
Prostate cancer imaging. Acta Radiol 2008; 49: 107–20.
34. Ikonen S, Kivisaari L,Vehmas T, et al. Optimal timing of post-
biopsy MR imaging of the prostate. Acta Radiol 2001; 42:
70–3.
35. Qayyum A, Coakley FV, Lu Y, et al. Organ-confined prostate
cancer: effect of prior transrectal biopsy on endorectal MRI
and MR spectroscopic imaging. AJR Am J Roentgenol 2004;
183: 1079–83.
36. White S, Hricak H, Forstner R, et al. Prostate cancer: effect of
postbiopsy hemorrhage on interpretation of MR images.
Radiology 1995; 195: 385–90.
37. Park BK, Kim B, Kim CK, Lee HM, Kwon GY. Comparison of
phased-array 3.0-T and endorectal 1.5-T magnetic resonance
368
imaging in the evaluation of local staging accuracy for pros-
tate cancer. J Comput Assist Tomogr 2007; 31: 534–8.
38. Heijmink SW, Fütterer JJ, Hambrock T, et al. Prostate
cancer: body-array versus endorectal coil MR imaging at
3 T—comparison of image quality, localization, and staging
performance. Radiology 2007; 244: 184–95.
39. Cornfeld DM, Weinreb JC. MR imaging of the prostate: 1.5T
versus 3T. Magn Reson Imaging Clin N Am 2007; 15:
433–48, viii.
40. Mullerad M, Hricak H, Kuroiwa K, et al. Comparison of
endorectal magnetic resonance imaging, guided prostate
biopsy and digital rectal examination in the preoperative
anatomical localization of prostate cancer. J Urol 2005; 174:
2158–63.
41. Wang L, Mazaheri Y, Zhang J, et al. Assessment of biologic
aggressiveness of prostate cancer: correlation of MR signal
intensity with Gleason grade after radical prostatectomy.
Radiology 2008; 246: 168–76.
42. Akin O, Sala E, Moskowitz CS, et al. Transition zone prostate
cancers: features, detection, localization, and staging at
endorectal MR imaging. Radiology 2006; 239: 784–92.
43. Li SY, Chen M, Wang R, Zhou C. Differentiation between
benign prostatic hyperplasia and prostate cancer in the
transitional zone evaluated by 1H magnetic resonance
spectroscopic imaging. Chin Med Sci J 2007; 22: 238–42.
44. Scheenen TW, Heijmink SW, Roell SA, et al. Three-dimensional
proton MR spectroscopy of human prostate at 3T without
endorectal coil: feasibility. Radiology 2007; 245: 507–16.
45. Mueller-Lisse UG, Scherr MK. Proton MR spectroscopy of
the prostate. Eur J Radiol 2007; 63: 351–60.
46. Jung JA, Coakley FV, Vigneron DB, et al. Prostate depiction
at endorectal MR spectroscopic imaging: investigation of a
standardized evaluation system. Radiology 2004; 233:
701–8.
47. Scheidler J, Hricak H, Vigneron DB, et al. Prostate cancer:
localization with three-dimensional proton MR spectroscopic
imaging—clinicopathologic study. Radiology 1999; 213:
473–80.
48. Shukla-Dave A, Hricak H, Moskowitz C, et al. Detection of
prostate cancer with MR spectroscopic imaging: an expanded
paradigm incorporating polyamines. Radiology 2007; 245:
499–506.
49. Wefer AE, Hricak H, Vigneron DB, et al. Sextant localization
of prostate cancer: comparison of sextant biopsy, magnetic
resonance imaging and magnetic resonance spectroscopic
imaging with step section histology. J Urol 2000; 164: 400–4.
50. Westphalen AC, Coakley FV, Qayyum A, et al. Peripheral
zone prostate cancer: accuracy of different interpretative
approaches with MR and MR spectroscopic imaging. Radiology
2008; 246: 177–84.
51. Coakley FV, Kurhanewicz J, Lu Y, et al. Prostate cancer tumor
volume: measurement with endorectal MR and MR spectro-
scopic imaging. Radiology 2002; 223: 91–7.
52. Kumar R, Nayyar R, Kumar V, et al. Potential of magnetic
resonance spectroscopic imaging in predicting absence of
prostate cancer in men with serum prostate-specific antigen
between 4 and 10 ng/ml: a follow-up study. Urology 2008;
72: 859–63.
 prostate cancer
53. Zakian KL, Sircar K, Hricak H, et al. Correlation of proton
MR spectroscopic imaging with gleason score based on
step-section pathologic analysis after radical prostatectomy.
Radiology 2005; 234: 804–14.
54. Ichikawa T, Haradome H, Hachiya J, Nitatori T, Araki T.
Diffusion-weighted MR imaging with a single-shot echopla-
nar sequence: detection and characterization of focal hepatic
lesions. AJR Am J Roentgenol 1998; 170: 397–402.
55. Namimoto T, Yamashita Y, Sumi S, Tang Y, Takahashi M.
Focal liver masses: characterization with diffusion-weighted
echo-planar MR imaging. Radiology 1997; 204: 739–44.
56. Yamada I, Aung W, Himeno Y, Nakagawa T, Shibuya H.
Diffusion coefficients in abdominal organs and hepatic
lesions: evaluation with intravoxel incoherent motion echo-
planar MR imaging. Radiology 1999; 210: 617–23.
57. Yoshikawa T, Kawamitsu H, Mitchell DG, et al. ADC measure-
ment of abdominal organs and lesions using parallel imaging
technique. AJR Am J Roentgenol 2006; 187: 1521–30.
58. Zhang J, Tehrani YM, Wang L, et al. Renal masses: character-
ization with diffusion-weighted MR imaging—a preliminary
experience. Radiology 2008; 247: 458–64.
59. Al-Okaili RN, Krejza J, Wang S, Woo JH, Melhem ER.
Advanced MR imaging techniques in the diagnosis of
intraaxial brain tumors in adults. Radiographics 2006;
26(Suppl 1): S173–S189.
60. Haider MA, van der Kwast TH, Tanguay J, et al. Combined
T2-weighted and diffusion-weighted MRI for localization of
prostate cancer. AJR Am J Roentgenol 2007; 189: 323–8.
61. Mazaheri Y, Shukla-Dave A, Hricak H, et al. Prostate cancer:
identification with combined diffusion-weighted MR
imaging and 3D 1H MR spectroscopic imaging—correlation
with pathologic findings. Radiology 2008; 246: 480–8.
62. Yoshimitsu K, Kiyoshima K, Irie H, et al. Usefulness of
apparent diffusion coefficient map in diagnosing prostate
carcinoma: correlation with stepwise histopathology. J Magn
Reson Imaging 2008; 27: 132–9.
63. Kim CK, Park BK, Lee HM, Kwon GY. Value of diffusion-
weighted imaging for the prediction of prostate cancer
location at 3T using a phased-array coil: preliminary results.
Invest Radiol 2007; 42: 842–7.
64. Tamada T, Sone T, Toshimitsu S, et al. Age-related and zonal
anatomical changes of apparent diffusion coefficient values
in normal human prostatic tissues. J Magn Reson Imaging
2008; 27: 552–6.
65. Alonzi R, Padhani AR, Allen C. Dynamic contrast enhanced
MRI in prostate cancer. Eur J Radiol 2007; 63: 335–50.
66. Jager GJ, Ruijter ET, van de Kaa CA, et al. Dynamic Turbo-
FLASH subtraction technique for contrast-enhanced MR
imaging of the prostate: correlation with histopathologic
results. Radiology 1997; 203: 645–52.
67. Kim CK, Park BK, Kim B. Localization of prostate cancer
using 3T MRI: comparison of T2-weighted and dynamic
contrast-enhanced imaging. J Comput Assist Tomogr 2006;
30: 7–11.
68. Ocak I, Bernardo M, Metzger G, et al. Dynamic contrast-
enhanced MRI of prostate cancer at 3 T: a study of
pharmacokinetic parameters. AJR Am J Roentgenol 2007;
189: 849.
69. Puech P, Betrouni N, Viard R, et al. Prostate cancer
computer-assisted diagnosis software using dynamic
contrast-enhanced MRI. Conf Proc IEEE Eng Med Biol Soc
2007: 5567–70.
70. Vos PC, Hambrock T, Hulsbergen-van de Kaa CA, et al.
Computerized analysis of prostate lesions in the peripheral
zone using dynamic contrast enhanced MRI. Med Phys 2008;
35: 888–99.
71. Kurhanewicz J, Vigneron D, Carroll P, Coakley F. Multipara-
metric magnetic resonance imaging in prostate cancer: pres-
ent and future. Curr Opin Urol 2008; 18: 71–7.
72. Takahashi N, Inoue T, Lee J, Yamaguchi T, Shizukuishi K. The
roles of PET and PET/CT in the diagnosis and management
of prostate cancer. Oncology 2007; 72: 226–33.
73. Larson SM, Schöder H. Advances in positron emission
tomography applications for urologic cancers. Curr Opin
Urol 2008; 18: 65–70.
74. Mishani E, Ben-David I, Rozen Y. Improved method for the
quality assurance of [C-11]choline. Nucl Med Biol 2002; 29:
359–62.
75. Testa C, Schiavina R, Lodi R, et al. Prostate cancer: sextant
localization with MR imaging, MR spectroscopy, and 11C-
choline PET/CT. Radiology 2007; 244: 797–806.
76. Westphalen A, McKenna DA, Kurhanewicz J, Coakley FV.
Role of magnetic resonance imaging and magnetic resonance
spectroscopic imaging before and after radiotherapy for
prostate cancer. J Endourol 2008; 22: 789–94.
77. McKenna DA, Coakley FV, Westphalen AC, et al. Prostate
cancer: role of pretreatment MR in predicting outcome
after external-beam radiation therapy—initial experience.
Radiology 2008; 247: 141–6.
78. Mitterberger M, Pinggera GM, Pallwein L, et al. The value of
three-dimensional transrectal ultrasonography in staging
prostate cancer. BJU Int 2007; 100: 47–50.
79. Bloch BN, Furman-Haran E, Helbich TH, et al. Prostate
cancer: accurate determination of extracapsular extension
with high-spatial-resolution dynamic contrast–enhanced
and T2-weighted MR imaging--initial results. Radiology
2007; 245: 176–85.
80. Hövels AM, Heesakkers RA, Adang EM, et al. The diagnostic
accuracy of CT and MRI in the staging of pelvic lymph nodes
in patients with prostate cancer: a meta-analysis. Clin Radiol
2008; 63: 387–95.
81. Harisinghani MG, Barentsz J, Hahn PF, et al. Noninvasive
detection of clinically occult lymph-node metastases in pros-
tate cancer. N Engl J Med 2003; 348: 2491–9. Erratum in:
N Engl J Med 2003; 349(10): 1010.
82. Lin K, Szabo Z, Chin BB, Civelek AC. The value of a baseline
bone scan in patients with newly diagnosed prostate cancer.
Clin Nucl Med 1999; 24: 579–82.
83. Palmer E, Henrikson K, McKusick K, Strauss HW, Hochberg
F. Pain as an indicator of bone metastasis. Acta Radiological
1988; 29: 445–9.
84. Lecouvet FE, Geukens D, Stainier A, et al. Magnetic resonance
imaging of the axial skeleton for detecting bone metastases
in patients with high-risk prostate cancer: diagnostic and
cost-effectiveness and comparison with current detection
strategies. J Clin Oncol 2007; 25: 3281–7.
369
 primary tumor evaluation and staging
85. Lee N, Newhouse JH, Olsson CA, et al. Which patients with
newly diagnosed prostate cancer need a computed tomogra-
phy scan of the abdomen and pelvis? An analysis based on
588 patients. Urology 1999; 54: 490–4.
86. Huncharek M, Muscat J. Serum prostate-specific antigen as a
predictor of staging abdominal/pelvic computed tomogra-
phy in newly diagnosed prostate cancer. Abdom Imaging
1996; 21: 364–7.
87. Spencer JA, Chng WJ, Hudson E, Boon AP, Whelan P. Pro-
state specific antigen level and Gleason score in predicting
the stage of newly diagnosed prostate cancer. Br J Radiol
1998; 71: 1130–5.
88. Mohler J, Babaian RJ, Bahnson RR, et al. NCCN Clinical
Practice Guidelines in Oncology: Prostate Cancer. [Available
from: http://www.nccn.org/professionals/physician_gls/PDF/
prostate.pdf 2007; V.2. Accessed September 21, 2007].
89. Flanigan RC, McKay TC, Olson M, et al. Limited efficacy of
preoperative computed tomographic scanning for the evalu-
ation of lymph node metastasis in patients before radical
prostatectomy. Urology 1996; 48 : 428–32.
90. Levran Z, Gonzalez JA, Diokno AC, Jafri SZ, Steinert BW.
Are pelvic computed tomography, bone scan and pelvic
lymphadenectomy necessary in the staging of prostatic
cancer? Br J Urol 1995; 75: 778–81.
91. O’Dowd GJ, Veltri RW, Orozco R, Miller MC, Oesterling JE.
Update on the appropriate staging evaluation for newly
diagnosed prostate cancer. J Urol 1997; 158: 687–98.
92. Moul JW, Kane CJ, Malkowicz SB. The role of imaging studies
and molecular markers for selecting candidates for radical
prostatectomy. Urol Clin North Am 2001; 28: 459–72.
93. Schwartz LH, LaTrenta LR, Bonaccio E, et al. Small cell and
anaplastic prostate cancer: correlation between CT findings
and prostate-specific antigen level. Radiology 1998; 208:
735–8.
94. Heidenreich A, Aus G, Bolla M, et al. European Association
of Urology. EAU guidelines on prostate cancer. Eur Urol
2008; 53: 68–80.
95. Sella T, Schwartz LH, Swindle PW, et al. Suspected local
recurrence after radical prostatectomy: endorectal coil MR
imaging. Radiology 2004; 231: 379–85.
96. Silverman JM, Krebs TL. MR imaging evaluation with a tran-
srectal surface coil of local recurrence of prostatic cancer in
men who have undergone radical prostatectomy. AJR Am J
Roentgenol 1997; 168: 379–85.
97. Sciarra A, Panebianco V, Salciccia S, et al. Role of dynamic
contrast-enhanced magnetic resonance (MR) imaging and
proton MR spectroscopic imaging in the detection of local
recurrence after radical prostatectomy for prostate cancer.
Eur Urol 2008; 54: 589–600.
98. Pucar D, Hricak H, Shukla-Dave A, et al. Clinically signifi-
cant prostate cancer local recurrence after radiation therapy
occurs at the site of primary tumor: magnetic resonance
imaging and step-section pathology evidence. Int J Radiat
Oncol Biol Phys 2007; 69: 62–9.
370
99. Haider MA, Chung P, Sweet J, et al. Dynamic contrast-
enhanced magnetic resonance imaging for localization of
recurrent prostate cancer after external beam radiotherapy.
Int J Radiat Oncol Biol Phys 2008; 70: 425–30.
100. Strohmaier WL, Keller T, Bichler KH. Follow-up in prostate
cancer patients: which parameters are necessary? Eur Urol
1999; 35: 21–5.
101. Greco C, Cascini GL, Tamburrini O. Is there a role for positron
emission tomography imaging in the early evaluation of
prostate cancer relapse? Prostate Cancer Prostatic Dis 2008;
11: 121–8.
102. Rinnab L, Mottaghy FM, Blumstein NM, et al. Evaluation of
[11C]-choline positron-emission/computed tomography in
patients with increasing prostate-specific antigen levels after
primary treatment for prostate cancer. BJU Int 2007; 100:
786–93.
103. Onik G, Vaughan D, Lotenfoe R, Dineen M, Brady J. “Male
lumpectomy”: focal therapy for prostate cancer using
cryoablation. Urology 2007; 70: 16–21.
104. Eggener SE, Scardino PT, Carroll PR, et al. International
Task Force on Prostate Cancer and the Focal Lesion Paradigm.
Focal therapy for localized prostate cancer: a critical appraisal
of rationale and modalities. J Urol 2007; 178: 2260–7.
105. Rouvière O, Souchon R, Salomir R, et al. Transrectal high-
intensity focused ultrasound ablation of prostate cancer:
effective treatment requiring accurate imaging. Eur J Radiol
2007; 63: 317–27.
106. Onik G. Rationale for a “male lumpectomy,” a prostate
cancer targeted approach using cryoablation: results in
21 patients with at least 2 years of follow-up. Cardiovasc
Intervent Radiol 2008; 31: 98–106.
107. Siddiqui SA, Mynderse LA, Zincke H, et al. Treatment of
prostate cancer local recurrence after radical retropubic
prostatectomy with 17-gauge interstitial transperineal
cryoablation: initial experience. Urology 2007; 70: 80–5.
108. Ahmed HU, Moore C, Emberton M. Minimally-invasive
technologies in uro-oncology: the role of cryotherapy, HIFU
and photodynamic therapy in whole gland and focal therapy
of localised prostate cancer. Surg Oncol 2009; 18: 219–32.
109. Fischer GS, DiMaio SP, Iordachita II, Fichtinger G. Robotic
assistant for transperineal prostate interventions in 3T closed
MRI. Med Image Comput Comput Assist Interv Int Conf
Med Image Comput Comput Assist Interv 2007; 10(Pt 1):
425–33.
110. Zangos S, Eichler K, Thalhammer A, et al. MR-guided
interventions of the prostate gland. Minim Invasive Ther
Allied Technol 2007; 16: 222–9.
111. Singh AK, Kruecker J, Xu S, et al. Initial clinical experience
with real-time transrectal ultrasonography-magnetic reso-
nance imaging fusion-guided prostate biopsy. BJU Int 2008;
101: 841–5.
112. Marberger M. Energy-based ablative therapy of prostate
cancer: high-intensity focused ultrasound and cryoablation.
Curr Opin Urol 2007; 17: 194–9.
 20 Testicular Germ Cell Tumors
S Aslam Sohaib, Dow-Mu Koh, and Janet E Husband
INTRODUCTION
Testicular tumors, of which the vast majority is of germ cell origin,
are an important group of neoplasms because most of them are
curable. The management of testicular cancer has been a major
oncological success story and provides a model for the management
of curative solid tumors. In recent years, attention has focused not
only on improving cure rates in patients where treatment has
historically been unsuccessful but also on optimizing treatment in
the good prognosis groups with the aim of limiting long term
adverse effects of treatment.
Imaging plays a pivotal role in the management of these patients.
It is occasionally useful in the diagnosis of testicular tumors, but
in most cases the diagnosis is made by biopsy or at orchidectomy.
Once the diagnosis of a testicular neoplasm is established, imaging
is crucial for determining the presence and extent of metastatic
disease, and subsequently for assessing response to treatment,
evaluating suitability for surgery of residual masses, and detecting
sites of relapse. Computed tomography (CT) and plain chest radio-
graphs remain the preferred radiological techniques used although
magnetic resonance (MR) imaging, positron emission tomography
with 18-fluoro-2-deoxyglucose (18FDG PET), and ultrasound also
have a place in certain clinical situations.
EPIDEMIOLOGY AND ETIOLOGY
Testicular germ cell tumors (GCT) comprise 1% to 2% of all
cancers but are the most common malignant tumors in males
aged between 15 and 44 years. In the United States, the incidence
of testicular cancer is approximately 7900 new cases per annum
and in the United Kingdom, there were 2109 new cases in 2004
(1,2). The incidence of testicular cancer has been rising, particu-
larly in the peak age group between 20 and 40 years in which the
incidence has almost doubled in the past 40 years (3).
The incidence of testicular cancer shows considerable geographic
and racial variance. The highest incidence rates are in northern
Europe, Denmark, Norway, Switzerland, Germany, and New
Zealand, whereas intermediate rates of the disease are reported
from the United States and the United Kingdom. A much lower
incidence is seen in Asia, Africa, and North American blacks (4).
The persistently low rates of testicular cancer reported in black
Americans compared with white Americans suggests a genetic
basis for this difference in incidence.
Risk factors for the development of GCT include prior history
of GCT, cryptorchidism, infertility, testicular dysgenesis, and a
positive family history (3). A previous diagnosis of testicular cancer
increases the risk of developing a subsequent (metachronous) tes-
ticular tumor by around 12-fold (5). Cryptorchidism is associated
with a two- to four-fold increased risk of testicular cancer (6).
Correction of cryptorchidism at a young age by orchidopexy,
particularly before the age of four years and at latest by the age of
10 (i.e., before puberty) reduces risk of testicular cancer, but it
still remains higher than that for the general population. Other
urological mal-developments associated with an increased risk of
testicular cancer include inguinal hernia and hydrocoele.
In 1% to 3% of patients a first-degree family member is also
affected with the disease. This is usually a father and son or brothers.
Brothers of patients with a testicular tumor have a relative risk of 8
to 10 (7). This is higher than for most other cancer types where the
relative risk rarely exceeds four, and suggests that predisposition
genes are important in this disease (7). Testicular microlithiasis has
been associated with an increase in risk of testicular cancer, although
the precise relationship remains to be determined (8). Recently we
have shown that testicular microlithiasis is present at a higher fre-
quency in relatives of GCT cases than expected by chance indicating
that testicular microlithiasis is a familial risk factor for GCT (9).
The etiology of testicular cancer is unknown but almost all cases
of testicular cancer display amplification of the short arm of chro-
mosome 12. This suggests that genes in this region are important
in the development of GCT (3). GCTs are thought to be derived
from cells in the germ cell lineage that are blocked in maturation.
In adults, GCTs are thought to initiate during foetal development
and involve changes to the primordial germ cells. All GCTs prog-
ress through a non-invasive lesion called carcinoma in situ (CIS)
as the frequency of CIS and GCT are similar. CIS is thought to
progress around or after puberty (3). Carcinoma in situ is also
called intratubular germ-cell neoplasia unclassified (IGCNU) and
testicular intraepithelial neoplasia (TIN).
Key Points: Epidemiology and Etiology
■ The vast majority of testicular tumors are GCTs
■ GCTs are the most common malignancy in males between 15
and 44 years
■ Cryptorchidism and carcinoma in situ may be important
aetiological factors
PATHOLOGY
Ninety-five percent of testicular tumors are germ cell tumors, 4% are
lymphomas and 1% are rare tumors such as Sertoli cell tumors,
interstitial (Leydig cell) tumors, and paratesticular embryonal sarco-
mas. Lymphomas are nearly always found in men aged over 50 years
and are generally treated as a different disease entity from GCT.
GCTs can be divided into two main groups: about 40% to 45%
are seminomas and a similar percentage are nonseminomatous
GCTs (NSGCT). Some GCTs (10–15%) are a mixture of seminoma
and nonseminomatous GCT, and are usually classified and treated
as nonseminomatous GCT. GCTs occasionally occur in an extra-
gonadal primary site (such as the mediastinum or retroperitoneum)
but are still managed in the same way as testicular GCT.
There are two main classifications used in the histopathological
examination of testicular tumors, the World Health Organization
371
 primary tumor evaluation and staging

Table 20.1 Comparison of Two Classifications of Germ patients with advanced NSGCT tumors but in only 10% to 20% of
Cell Tumors patients with clinical Stage I disease. Advanced pure seminoma
produces raised levels of HCG in 15% to 25% of patients. Lactate
2004 WHO classification BTTP classification dehydrogenase is raised in the majority of patients with advanced
Tumors of one histologic type NSGCT and seminoma. At least one marker is raised in 56% to
Seminoma Seminoma 84% of patients with testicular tumors (10,11).
With syncytiotrophoblastic giant cells Spermatocytic seminoma
Spermatocytic seminoma Malignant teratoma,
Embryonal carcinoma undifferentiated (MTU) Key Points: Pathology
Yolk sac tumor Yolk sac tumor (pure neoplasms
Choriocarcinoma only) ■ GCTs are classified as seminomas or non-seminomatous germ
Other trophoblastic tumors Malignant teratoma, trophoblastic cell tumors (NSGCT). About 40% to 45% are seminomas
Monophasic choriocarcinoma (MTT)
■ NSGCTs contain more than one cell type
Placental site trophoblastic tumor Teratoma, differentiated (TD)
■ AFP is raised in up to 65% of NSGCT cases
Teratoma
Dermoid cyst ■ HCG is raised in up to 60% of advanced NSGCT and in 15%
Monodermal teratoma to 20% of seminoma cases
Teratoma with somatic transformation
Tumors of more than one histologic type
Embryonal carcinoma/yolk sac and Malignant teratoma intermediate
PATTERN OF SPREAD
teratoma (MTI)
Choriocarcinoma and other Malignant teratoma, trophoblastic
non-seminoma (MTT) Lymphatic drainage of the testes occurs along efferent lymphatic
Combined tumor Seminoma/ channels, which pass from the mediastinum of the testis through
Seminoma and non-seminoma non-seminoma the internal inguinal ring accompanying the spermatic cord. They
then join up to form major lymphatic channels which accompany the
testicular vessels and after crossing the ureter, the lymphatics fan
(WHO) system and the British Testicular Tumor Panel classification out to enter the retroperitoneal lymph nodes. Left-sided tumors
(Table 20.1). The British Testicular Tumor Panel classification is spread to the left para-aortic nodes and the pre-aortic nodes
widely used in the United Kingdom and Australia, whereas the initially (Fig. 20.1). The upper para-aortic nodes, just below the
WHO classification is most commonly used in North America renal vessels are the most commonly involved first sites of spread in
and some European countries. left-sided tumors (Fig. 20.2). Right-sided tumors spread into the
NSGCTs tend to occur on average ten years earlier than semino- inter-aortico-caval nodes, the precaval nodes and the right para-
mas. The incidence of NSGCT peaks in the 20 to 35 years age group caval and retrocaval nodes. Right-sided tumors spread preferen-
while the incidence of seminomas peaks in the 30 to 45 years age tially to nodes below the right renal hilum, the first nodal site to be
group. NSGCTs are clinically more aggressive and consist of more demonstrated frequently being an inter-aortico-caval node or a
than one cell type which include malignant teratoma undifferenti- right paracaval node in the lower retroperitoneum (Fig. 20.3).
ated (MTU) (embryonal carcinoma), malignant teratoma differen- Lymphatic spread may also occur to nodes lateral to the para-
tiated (MTD) (teratoma), malignant teratoma intermediate (MTI) caval para-aortic group, the so-called “echelon” node. Lymph node
and malignant teratoma trophoblastic (choriocarcinoma), and yolk metastases lying on the anterior surface of the iliopsoas muscles
sac tumor and malignant teratomas intermediate (mixed germ cell are considered to represent echelon node deposits (Fig. 20.4).
tumors). Elements of trophoblastic teratoma are usually associated These are an unusual site of disease, more frequently demonstrated
with undifferentiated teratoma, but tumors consisting of pure tro- at the time of relapse than at initial staging (12).
phoblastic teratoma can occur. These latter tumors metastasize The consistency with which right-sided tumors spread to the right-
widely and produce very high levels of human chorionic gonado- sided retroperitoneal nodes and left-sided tumors to left-sided nodes
trophin (HCG). Yolk sac elements produce alpha-fetoprotein (AFP) is such that contralateral lymph node involvement in the absence of
and in children this is the most common variety of GCTs. ipsilateral node involvement is very rare (13). If a single enlarged node
is demonstrated on the contralateral side and is the only possible evi-
SERUM TUMOR MARKERS dence of metastatic disease, then histological verification should be
obtained before commencing systemic treatment. Crossover to
Serum tumor markers, alpha-fetoprotein (AFP), human chorionic contralateral nodes is unusual when ipsilateral nodes are less than
gonadotrophin (HCG), and lactate dehydrogenase (LDH), are 2 cm in diameter and is more frequently seen as lymphadenopathy
critical for diagnosing testicular tumors, for determining prog- becomes increasingly bulky (Fig. 20.5), particularly with right-sided
nosis and for assessing treatment response. Alpha-fetoprotein is a tumors. Direct spread to iliac or inguinal nodes alone is rare and
glycoprotein produced by the liver and gastrointestinal tract. The usually associated with an identifiable predisposition such as cryp-
normal adult concentration of AFP in the blood is less than 15 ng/ml torchidism or previous scrotal incision (Fig. 20.6A). However, pel-
but it is frequently raised in patients with NSGCTs, e.g., MTU and vic nodes may become involved in the presence of bulky
yolk sac tumors. In these tumor types an elevated AFP is seen in retroperitoneal lymphadenopathy due to retrograde flow of lymph
up to 65% of cases. Human chorionic gonadotrophin is also a resulting from obstruction by tumor (Fig. 20.6B). By a similar
glycoprotein and may be found in patients with pure seminoma as mechanism, nodes in the mesentery may also become involved,
well as NSGCT. Elevated levels of HCG are seen in up to 60% of resulting in a “pseudo lymphoma” appearance (Fig. 20.7).

372
 testicular germ cell tumors

RIGHT LEFT
Aorto caval nodes Pre aortic nodes
Precaval nodes

Para aortic nodes Echelon

Paracaval Echelon node
nodes node

Echelon Echelon node

node
Retrocaval nodes

(A) (B)
Figure 20.1 Schematic representation of lymphatic drainage of the testes to the retroperitoneum. (A) Axial representation of nodal distribution just below the level of
the renal vessels. (B) A plane drawn down the center of the aorta separates left- from right-sided nodes. Right-sided nodal groups include the aortocaval nodes. “Echelon”
nodes lie more laterally. On the left, lymphatic drainage is initially to the node groups immediately below the left renal vessels. On the right, the lymphatics fan out more,
and there tends to be more variability in the initial site of metastatic nodes from right-sided tumors.

(A) (B)

(C)
Figure 20.2 Left-sided nodal disease (A) CT, (B) T1-weighted and (C) T2-weighted MR images in a patient with a left testicular NSGCT showing a 4 cm left
para-aortic node.

373
 primary tumor evaluation and staging

Figure 20.3 Right-sided nodal disease. (A) In

this patient with a right-sided testicular semi-
noma, there is a 10 mm node in the aorto-
caval group (arrow). This is a characteristic
site of initial nodal metastasis from right-
sided tumors. (B) In another patient with a
right-sided testicular NSGCT, note the pres-
ence of an 8 mm retrocaval lymph node,
which is also a common site of metastasis
(A) (B) from right-sided tumor.

Figure 20.4 There is a 3.5 cm nodal metastasis, lying anterior to the left psoas
muscle, typical of an “echelon” node (arrow).
Figure 20.5 In this patient with a right-sided NSGCT, there is a 2 cm nodal mass in the
left para-aortic group, in addition to a right-sided 1.5 cm retrocaval node (arrow).

Figure 20.6 The pelvic lymph node chain is

an uncommon site of disease in patients with
testicular tumors. (A) There is a large right
pelvic mass in this 47 yr old man who was
previously treated with an orchidectomy for a
right undescended testis. The mass was con-
firmed to be a seminoma at histopathology.
(B) In this patient who was previously treated
for retroperitoneal nodal metastasis from
NSGCT, there is disease relapse in a 1.5 cm
(A) (B) right hypogastric lymph node.

374
 testicular germ cell tumors

(A) (B)
Figure 20.7 (A) and (B) Bulky nodes are present in the retroperitoneum, accompanied by mesenteric nodes, resulting in a “pseudo lymphoma” appearance.

Lymph nodes above the renal hila are involved by direct spread
from lower para-aortic nodes and extension of disease is then to the
retrocrural lymph nodes (Fig. 20.8). Supradiaphragmatic spread of
testicular tumors occurs via the thoracic duct, which leads to
involvement of the supraclavicular nodes and, occasionally, supe-
rior mediastinal prevascular nodes (Fig. 20.9). Direct spread through
the diaphragm from the retroperitoneal space leads to posterior
mediastinal and subcarinal nodal involvement.
Hematogenous spread in testicular cancer is predominantly to the
lungs. Multiple small metastases in a peripheral location are typical
features of NSGCT (Fig. 20.10) but, in seminoma, pulmonary metas-
tases tend to be large lesions of at least 1 to 2 cm in diameter. Other
sites of metastases in patients with advanced aggressive tumors
include the brain (Fig. 20.11), bone, and liver (Fig. 20.12). Brain
metastases are more common in patients with trophoblastic tera-
tomas than any other histological type. Other sites of hemato-
genous spread are rare and include the kidneys, adrenal glands,
muscle, spleen, pericardium, pleura, and peritoneum (Fig. 20.12).
These unusual sites of disease are more frequently observed at the
time of relapse in patients who have been previously treated.

Figure 20.8 Involved retrocrural nodes over 1 cm in maximum transverse diameter.

Key Points: Patterns of Tumor Spread The upper limit of normal for retrocrural nodes is 6 mm.

■ Testicular tumors spread by the lymphatic route via channels

which accompany the testicular vessels to the retroperitoneal
lymph nodes
■ Right-sided tumors spread to the inter-aortico-caval nodes,
the precaval nodes, and the right paracaval and retrocaval
nodes
■ Left-sided tumors spread to the left para-aortic nodes and
the pre-aortic nodes
■ Hematogenous spread is predominantly to the lungs
■ Unusual patterns of spread are more likely to be seen at relapse

STAGING CLASSIFICATION

Until recently, multiple staging classifications have been used for

classifying testicular tumors. The use of multiple systems frequently
leads to confusion but now the stage groupings of the American Figure 20.9 Mediastinal lymphadenopathy in the prevascular space and paratracheal
Joint Committee on Cancer (AJCC) and the Union Internationale region in NSGCT.

375
 primary tumor evaluation and staging
Figure 20.10 CT showing a small peripheral pulmonary nodule in the left lung
base resulting from metastatic NSGCT.
Figure 20.11 Unenhanced T1-weighted MR image of the brain shows a hemor-
rhagic metastatic mass in the left occipital lobe.
Contre le Cancer (UICC) has been adopted by both organizations
(Table 20.2). This system, initially updated in 1997, is similar to
the simpler system introduced by the Royal Marsden Hospital
which takes account of tumor volume as well as the sites of met-
astatic spread (Table 20.3 and Fig. 20.13). The Royal Marsden sys-
tem is used widely in the United Kingdom and other European
countries, and has been approved by the European Organization
for Research and Treatment of Cancer (EORTC).
PROGNOSTIC GROUPING
Patients with metastatic disease are further classified into prog-
nostic groups. In 1997, the International Germ Cell Cancer Col-
laborative Group (IGCCCG) published a prognostic classification
376
system (Table 20.4) that is now widely accepted around the world
and has been incorporated into the TNM classification and the
American Joint Committee on Cancer (AJCC) classification.
Patients are categorized into good, intermediate, and poor prog-
nostic groups based on histology, location of primary tumor and
metastases, and levels of serum markers (14). This classification
resulted from worldwide collaborative effort in which clinical data
were collected from approximately 6000 patients with metastatic
germ cell cancer from 10 countries (10% seminoma and 90%
NSGCT). All patients were treated between 1975 and 1990 with
cisplatin containing chemotherapy and the median follow-up at
the time of analysis was five years.
CLINICAL FEATURES
Patients with testicular tumors present with a variety of clinical
features including testicular pain, swelling, or an obvious mass.
Sometimes there is a history of recent trauma which has prob-
ably brought a pre-existing condition to light rather than
trauma having a causal effect. Occasionally, a patient may pres-
ent with symptoms due to metastatic disease such as backache
from retroperitoneal lymphadenopathy or general debility from
disseminated disease.
TREATMENT
The management of GCT depends on the pathology, staging,
and prognostic grouping of the tumor. Treatment guidelines
and reviews of the management of testicular cancer have been
published by the European Germ Cell Consensus Group (EGCCG)
(15,16).
Seminoma
Seminomas are more radiosensitive and more chemosensitive
than NSGCT and survival rates have always been high. Seminoma
patients also tend to present with earlier stage disease than those
with NSGCT.
Approximately 80% of seminoma patients present with Stage I
disease. Following orchidectomy, management options for Stage I
disease includes surveillance or adjuvant treatment with either
radiotherapy or a single cycle of carboplatin chemotherapy. For
many years the standard treatment for Stage 1 seminoma in the
United Kingdom has been inguinal orchidectomy followed by adju-
vant radiotherapy (3). However evidence gained from clinical trials
indicated that both the radiation field and the amount of radiation
needed were reduced to minimize long-term effects (17). A further
randomized trial has shown that orchidectomy followed by a single
cycle of carboplatin is equivalent to orchidectomy followed by
radiotherapy in reducing the risk of recurrence of testicular cancer,
and has lower toxicity (18). Recently concern about the long-term
toxicity of radiotherapy has led to the adoption of orchidectomy
plus carboplatin as the standard treatment for seminomas in the
United Kingdom (19). An alternative to either adjuvant chemo-
therapy or radiotherapy is surveillance followed by treatment of
any relapse. Patients with Stage I disease have an approximately
20% chance of relapse with surgery and no further treatment thus
 testicular germ cell tumors

(A)

(B)

(C)

(E) (D)

Figure 20.12 Metastatic disease. (A) There is a mixed attenuation metastasis in the left hepatic lobe. Note also the extensive retroperitoneal lymphadenopathy at the
level of the renal veins. (B) There is bilateral adrenal enlargement of homogenous soft tissue density resulting from adrenal metastases. (C) Diffuse pericardial thickening
from metastatic infiltration is seen encasing the heart. (D) There is nodular pleural thickening within the right hemithorax due to pleural disease. (E) There is a 4 cm
low-density metastasis within the right psoas muscle.

377
 primary tumor evaluation and staging

Table 20.2 TNM Staging Classification of Testicular Tumors Table 20.3 The Royal Marsden Hospital Staging Classification
Primary tumor
for Testicular Germ Cell Tumors
The extent of the primary tumor is classified after radical orchidectomy (pT) Stage Definitions
pTX Primary tumor cannot be assessed (if no radical orchidectomy has
been performed, TX is used) I No evidence of metastases
pT0 No evidence of primary tumor (e.g., histological scar in testis) IM Rising serum markers with no other evidence of metastases
pTis Intratubular germ cell neoplasia (carcinoma in situ) II Abdominal node metastases
pT1 Tumor limited to testis and epididymis without vascular/ A <2 cm in diameter
lymphatic invasion; tumor may invade into the tunica B 2–5 cm in diameter
albuginea but not tunica vaginalis C >5 cm in diameter
pT2 Tumor limited to testis and epididymis with vascular/lymphatic III Supradiaphragmatic node metastases
invasion, or tumor extending through tunica albuginea with M Mediastinal
involvement of tunica vaginalis N Supraclavicular
pT3 Tumor invades spermatic cord with or without vascular/lymphatic O No abdominal node metastases
invasion ABC Node size defined as in Stage II
pT4 Tumor invades scrotum with or without vascular/lymphtic IV Extralymphatic metastases
invasion Lung
L1 ≤3 metastases
Regional lymph nodes
L2 >3 metastases, all <2 cm in diameter
Clinical involvement
L3 >3 metastases, one or more >2 cm in diameter
NX Regional nodes cannot be assessed
H+ Liver metastases
N0 No regional lymph node metastasis
Br+ Brain metastases
N1 Metastasis with a lymph node mass ≤2 cm in greatest dimension
Bo+ Bone metastases
or multiple lymph nodes none >2 cm in greatest dimension
N2 Metastasis with a lymph node mass >2 cm but <5 cm in greatest
dimension, or multiple lymph nodes, any one mass >2 cm but
≤5 cm in greatest dimension
N3 Metastasis with a lymph node mass >5 cm in greatest dimension
Pathological involvement avoiding treatment related toxicity in the remaining 80%. Risk of
pN0 No regional lymph node metastasis relapse is higher if tumor size is >4 cm and there is evidence of rete
pN1 Metastasis with a lymph node mass ≤2 cm in greatest dimension testis invasion (20). If neither risk factor is present then the risk of
and 5 or fewer positive nodes, none >2 cm in greatest dimension
pN2 Metastasis with a lymph node mass >2 cm but ≤5 cm in greatest
relapse is less than 12%. This increases to 15% if one factor is pres-
dimension; or more than 5 nodes positive, none >5 cm; or ent and over 30% if both are present. The disease specific survival
evidence of extranodal extension of tumor for Stage I disease approaches 99% independent of the management
pN3 Metastasis with a lymph node mass >5 cm in greatest dimension strategy used.
Distant metastasis The treatment options for Stage IIa/b seminoma include para-
MX Distant metastasis cannot be assessed aortic and iliac node radiotherapy, chemotherapy, or a combina-
M0 No distant metastasis
M1 Distant metastasis
tion of chemotherapy and radiotherapy. All three of the above
M1a Non-regional lymph node or puylmonary metastasis options for Stage IIa/b provide high rates of cure, but with
M1b Distant metastasis other than to non-regional lymph nodes differing toxicity profiles. There is general agreement that the
and lungs best treatment for Stage IIc and above involves multi-agent platinum
Serum tumor markers (S) based chemotherapy.
SX Tumor marker studies not available or not performed
S0 Tumor marker levels within normal limits
S1 LDH <1.5 × normal and HCG <5000 iu/l and AFP <1000 ng/ml Non-Seminomatous GCT (NSGCT)
S2 LDH 1.5–10 × normal or HCG 5000–50,000 iu/l or AFP
Between one-third and one-half of NSGCT patients have Stage I
1000–10,000 ng/ml
S3 LDH >10 × normal or HCG >50,000 iu/l or AFP >10,000 ng/ml disease at presentation and again inguinal orchidectomy is the
Stage groupings mainstay of treatment. For further management in the United
Stage I pT1–4, N0, M0, SX Kingdom cases are divided into low- and high-risk according to
Stage II Any pT/Tx, N1–3, M0, SX the presence or absence of vascular invasion detected on patho-
Stage IIA Any pT/Tx, N1, M0, S0 logical examination. Low-risk patients are managed with surveil-
Any pT/Tx, N1, M0, S1
lance, while high-risk patients receive either adjuvant chemotherapy
Stage IIB Any pT/Tx, N2, M0, S0
Any pT/Tx, N2, M0, S1 or undergo surveillance. In North America primary retroperito-
Stage IIC Any pT/Tx, N3, M0, S0 neal lymph node dissection (RPLND) may also be considered in
Any pT/Tx, N3, M0, S1 the management of Stage I disease. Retroperitoneal lymphadenec-
Stage III Any pT/Tx, Any N, M1, SX tomy is curative in the majority of patients and surgical mortality
Stage IIIA Any pT/Tx, Any N, M1a, S0 is less than 1%. However, serious complications may ensue, such as
Any pT/Tx, Any N, M1a, S1
Stage IIIB Any pT/Tx, N1-3, M0, S2
hemorrhage and pulmonary emboli in the short term, and in the
Any pT/Tx, any N, M1a, S2 longer term, ejaculatory failure and infertility. The cure rates for
Stage IIIC Any pT/Tx, N1-3, M0, S3 Stage I NSGCT is about 99%.
Any pT/Tx, any N, M1a, S3 The standard treatment for metastatic NSGCT is cisplatin-
Any pT/Tx, any N, M1b, any S based chemotherapy, which has an overall cure rate of approximately

378
 testicular germ cell tumors
Stage II A
<2 cm
Left sided tumor
Stage II C
>5 cm
Left sided tumor
Figure 20.13 Staging testicular cancer—lymph nodes (Royal Marsden Hospital system).
85%. Usually this is with a schedule called BEP (consisting of
three drugs, bleomycin, etoposide, and cisplatin). Patients in a
good prognostic group receive three courses whilst poor prog-
nostic group have four cycles. In patients with limited residual
masses following chemotherapy (about 30%), resection of
residual masses forms an important role in management.
Residual masses following chemotherapy are seen in approxi-
mately 25% of cases. These masses frequently contain mature
differentiated teratoma or may consist purely of fibrosis, necro-
sis, and hemorrhage, but in approximately 15% to 20% of
Stage II B
>2.5 cm
Left sided tumor
Stage II B
Right sided tumor
masses active malignancy is found. Resection of residual masses
at other sites, such as the mediastinum and lung, may also be
performed.
Although the majority of patients have an excellent prognosis,
about 10% to 15% with metastatic disease fail to achieve sustained
response on standard combination chemotherapy. This group has
an overall survival rate of between 20% and 30%, and new
approaches to therapy are being evaluated, including more inten-
sive chemotherapy schedules as well as high-dose therapy with
hemopoietic stem cell rescue.
379
 primary tumor evaluation and staging

Table 20.4 International Germ Cell Tumor Consensus Diagnosis

Conference Classification (14) Testicular tumors are usually diagnosed clinically and pathologi-
cally at surgery. Imaging of the testis with ultrasound can help to
Non-seminoma Seminoma
confirm the presence of an intra-testicular mass or if there is
Good Testis/retroperitoneal primary and Any primary site and
uncertainty of the clinical features. Testicular ultrasound is also
prognosis No pulmonary, visceral metastases and No non-pulmonary
Good markers—all of: visceral metastases helpful in patients who present with metastatic disease in whom
AFP <1000 ng/ml, and an occult primary tumor of the testis is suspected, or for examin-
hCG <5000 iu/l and Normal AFP, any hCG, ing the contralateral testis to identify the small number of patients
LDH <1.5 × upper limit of any LDH with bilateral synchronous tumors.
normal
MR imaging has been reported to be able to distinguish between
56% of non-seminomas 90% of seminomas seminoma and non-seminomatous GCT (21). However, this is of
5-yr PFS = 89% 5-yr PFS = 82% little clinical value as appropriate management dictates orchidec-
5-yr survival = 92% 5-yr survival = 86% tomy to obtain detailed pathology of the tumor. MR imaging of the
Intermediate Testis/retroperitoneal primary and Any primary site and scrotum may help if clinical and sonographic assessment cannot
prognosis No non-pulmonary visceral No non-pulmonary differentiate between an intra- or extratesticular mass (22).
metastases and visceral metastases
Intermediate markers—any of: and
AFP 1000 to 10,000 ng/ml, or Normal AFP, any hCG,
Key Points: Diagnosis
hCG 5000 iu/l to 50,000 iu/l, or any LDH ■ Diagnosis is made clinically and at pathology following
LDH 1.5–10 × upper limit of
orchidectomy
normal
■ Testicular ultrasound may be used to identify an occult pri-
28% of non-seminomas 10% of seminomas mary in a patient presenting with metastatic disease or small
5-yr PFS = 75% 5-yr PFS = 67% synchronous tumor in the contralateral testis
5-yr survival = 80% 5-yr survival = 72% ■ MR imaging of the scrotum may be helpful if clinical and
Poor Mediastinal primary or No patients classified as sonographic assessment cannot differentiate between an
prognosis Non-pulmonary visceral metastases poor prognosis
intra- or extratesticular mass
or
Poor markers—any of:
AFP >10,000 ng/ml Staging
hCG >50,000 iu/l
(10,000 ng/ml), or
Computed Tomography
LDH >10 × upper limit of normal CT remains the imaging modality of choice in staging GCTs.
The effective use of CT relies on good technique and a detailed
16% of non-seminomas knowledge of the patterns of tumor spread, the characteristic
5-yr PFS = 41% appearances of metastatic disease, and familiarity with potential
5-yr survival = 48%
diagnostic pitfalls.
Lymph node metastases vary in size from a single small node
to huge intra-abdominal retroperitoneal masses. Masses from
seminoma are usually of soft tissue density (Fig. 20.14A) but occa-
sionally may contain areas of relatively low density due to central
necrosis. However, large volume masses of NSGCT are frequently
Key Points: Treatment heterogeneous in density (Fig. 20.14B), being composed of multi-
loculated complex cystic areas, as well as soft tissue elements. Whilst
■ Approximately 95% of patients with GCTs are curable the diagnosis of large volume disease is readily made on CT, the
■ NSGCTs are managed by surveillance for Stage I and diagnosis of small volume metastatic disease may be extremely dif-
cisplatin-based chemotherapy for metastatic disease ficult, i.e., distinguishing Stage I from Stage II disease. Such distinc-
■ Treatment options for Stage I seminoma include single cycle tion is critical to patient management since a surveillance policy
carboplatin, surveillance or radiotherapy may be deployed in patients with Stage I disease, whereas patients
with Stage II disease need treatment usually with chemotherapy.
Studies performed to assess the effect of different thresholds of
IMAGING significance for lymph node size have been performed (23,24).
Essentially, they confirm the concept that by reducing the lymph
Imaging is central to the multidisciplinary approach to manage- node size accepted as normal, the likelihood of detecting positive
ment of testicular tumors and, together with serum marker esti- nodes increases, but the specificity of the test decreases. It has
mations, forms the basis on which virtually all major treatment been shown that by using 10 to 15 mm as the upper limit of nor-
choices are made. Following orchidectomy, staging with CT is mal up to 44% of scans were false negative (25–27). A further
undertaken to identify the presence or absence of metastatic dis- complication of trying to standardize upper limits of normal is
ease, the sites of spread and an overall estimate of tumor bulk. After that normal nodes in the superior retroperitoneum are smaller
treatment CT continues to direct and influence management during than those in the inferior retroperitoneum on CT (28,29). Stan-
the course of the disease and even during long-term follow-up. dardization of normality as such has not been agreed; thus

380
 testicular germ cell tumors

(A) (B)
Figure 20.14 Nodal disease. (A) In this patient with disseminated testicular seminoma, note the large volume nodal disease along the left pelvic sidewall. Nodal disease
resulting from seminoma is usually of near uniform soft tissue density, and may be ill-defined or plaque-like. (B) A patient with NSGCT metastatic to retroperitoneal
nodes. There is a bulky nodal mass below the level of the renal vessels containing cystic areas and solid soft tissue elements, typical of nodal dissemination from NSGCT.

(A) (B)

Figure 20.15 Lymph nodes of uncertain significance should be followed up with interval scanning. (A) In this patient with a right-sided NSGCT, there is a solitary 8 mm
aortocaval node seen on the initial staging CT, which is of uncertain significance. (B) A repeat CT scan performed eight weeks later showed an interval increase in nodal
size consistent with metastatic infiltration.

institutions vary in their practice. At the Royal Marsden Hospital
a threshold of 10 mm is used to differentiate between normal
and abnormal lymph nodes. Those measuring between 8 and
10 mm are treated as suspicious. These measurements must
however be taken in context of the overall patient’s situation such
as risk of disease, marker levels and laterality of the tumor. Sites
suspicious of disease warrant further investigation; this could
include tissue sampling, biochemical markers, additional imaging
such as FDG PET imaging (see below) or further follow-up
imaging (Fig. 20.15).
Using a size of criteria of 8 mm or larger in the maximum
short axis diameter to define a suspicious retroperitoneal node
is associated with a high specificity but low sensitivity (30).
However, it is well established that between 25% and 30% of
patients harbor occult microscopic metastases which cannot
be detected by CT (31–35). False-negative examinations are
therefore inevitable, but the number of false-negative exami-
nations can be minimized by elimination of observer error and
recognition of the limitations of imaging. There are various well-
known pitfalls in the diagnosis of retroperitoneal lymphadenopathy.

381
 primary tumor evaluation and staging

(A) (B)

(C) (D)
Figure 20.16 (A)–(D) Intravenous contrast-enhanced CT images demonstrating the presence of a left sided inferior vena cava (arrows), which drains into the left renal
vein. In addition, a 3 cm paracaval node is identified adjacent to the anomalous inferior venous cava (arrowhead). Venous anomalies may be mistaken for nodal disease,
especially when intravenous contrast medium has not been administered. The surgeon should be alerted to the presence of such venous anomalies, particularly if surgery
is contemplated.

The following vascular anomalies may be found (Figs. 20.16 and
20.17):
• Large gonadal veins
• Duplication of the inferior vena cava (IVC)
• Left-sided IVC
• Retro-aortic and circumaortic renal vessels
• Left ascending lumbar communicating veins
These may be readily apparent if intravenous (IV) contrast
medium is given and multiplanar reformats are performed. Other
problems in the diagnosis of lymphadenopathy relate to loops of
unopacified bowel which may even be seen between the aorta and
IVC or in the left para-aortic region.
CT is the most sensitive technique for the detection of pulmonary
metastases and may also identify nodal spread to the supra-
clavicular fossa and mediastinum. Mediastinal nodal disease
usually occurs by direct contiguous spread of tumor via the
thoracic duct into the posterior mediastinum through the dia-
phragmatic hiatus in seminoma, but in NSGCT tumor spread is
382
more random (36). Nodal disease can involve the anterior medi-
astinum, aortopulmonary window, or hilar regions without evi-
dence of spread to the posterior mediastinal or subcarinal lymph
nodes (Fig. 20.18). Similarly, tumor spread of disease to the supra-
clavicular fossae and to lymph nodes in the neck is also more com-
mon in NSGCT. Pleural masses and effusions are a well-recognized
feature of seminoma (37) and are usually accompanied by other
manifestations of metastatic spread.
CT of the brain is not undertaken as part of routine staging but
is indicated in those with high-risk factors and in patients with
suspected metastatic disease on clinical grounds. Brain metasta-
ses are usually hemorrhagic and are evident as lesions of high
attenuation on unenhanced scans. The metastases typically show
enhancement following intravenous contrast medium.
Metastases in other sites, such as the liver and bone, may be
missed if these regions are not carefully scrutinized on the initial
staging scan and at subsequent investigation.
Unusual sites of disease in patients who relapse are not
uncommon and it is important, therefore, to question every
 testicular germ cell tumors

(A) (B)
Figure 20.17 Gonadal veins (arrows) may mimic lymphadenopathy. (A) On this unenhanced CT, the unopacified left gonadal vein may be misinterpreted as lymph-
adenopathy. (B) However, after administration of intravenous contrast medium, there is enhancement of the veins indicating their vascular nature.

Figure 20.18 In this patient with NSGCT, axial CT shows lymphadenopathy within
the aortopulmonary window as the only site of intra-thoracic disease.
Figure 20.19 In this patient previously treated for NSGCT, there is peritoneal
relapse of disease with multiple peritoneal nodules seen in the left upper abdomen
(arrows). Peritoneal dissemination is an unusual manifestation of testicular
tumors, and may result from surgical implantation or spontaneous rupture of
nodal disease into the peritoneal cavity.

abnormality and to refer to previous CT studies in the same

patient, which should always be available for comparative
purposes (Fig. 20.19).
Magnetic Resonance Imaging
MR imaging, despite technical developments with faster acquisi-
tions, is not routinely used for staging, in part due to longer exami-
nation times, higher cost, and limited availability compared with CT.
However, MR imaging is useful for the detection and characteriza-
tion of central nervous system disease, as well as musculoskeletal,
and hepatic metastases. Magnetic resonance is particularly useful for
assessing involvement of the IVC by tumor (Figs. 20.20 and 20.21).
MR imaging may also be valuable as a problem solving technique in
the presence of equivocal CT findings, e.g., the demonstration of a

383
 primary tumor evaluation and staging
(A)
Figure 20.20 (A) and (B) T2-weighted turbo spin-echo MR images showing loss of the normal flow void within the inferior vena cava, due to the presence of tumor
thrombus within the lumen of the inferior vena cava. The caval tumor returns a heterogeneous signal intensity (arrows).
fistula between the large retroperitoneal mass and the small bowel
which could not be diagnosed with confidence on CT (Fig. 20.22).
In the detection of retroperitoneal lymph nodes MR imaging is
comparable with CT (Fig. 20.2) and has the same important limi-
tation, i.e., inability to identify disease in normal sized nodes or
distinguish reactive from malignant enlarged nodes. Recently, MR
imaging with lymphotrophic nanoparticles (LNMRI) has been
shown to be an effective method for evaluating lymph nodes in
different cancers (38–41). A recent study, in 18 patients with tes-
ticular cancer, showed that lymphotrophic nanoparticle-enhanced
MR imaging demonstrated higher sensitivity (88%) and specificity
(92%) for detecting nodal metastases when compared with MR
imaging alone which had sensitivity and specificity of 71% and
68% respectively (39). The role of LNMRI needs to be evaluated
in a large prospective study.
FDG PET
The potential advantage of FDG PET over CT is that it is a functional
imaging technique that identifies metabolically active sites of disease
and thus provides different information from anatomical imaging.
Studies comparing FDG PET with CT in primary staging of GCT
show that FDG PET is useful for detecting viable tumor in lesions
that are visible on CT and may also prevent false-positive diagnoses
on CT (42). However it does not improve staging in patients with
clinical Stage I disease because in common with CT, it is poor at
detecting small volume (sub-centimeter) metastases (42,43). Fur-
thermore, FDG PET is not able to identify mature teratoma; FDG
PET is therefore not recommended in the primary staging of GCT.
Chest Radiography
If chest CT is performed, a chest radiograph is not needed for
staging. However, plain chest radiographs play an important role
in the management of testicular cancer patients as lung metastases
greater than 1 cm can be recognized and followed, mediastinal
masses can be evaluated, and pleurally-based tumor and effusions
can also be detected. Chest radiographs provide a baseline for
evaluating the presence and extent of tumor prior to treatment
384
(B)
and are also valuable as a cost-effective method of follow-up in the
interval between serial CT studies.
Ultrasound
Ultrasound is not routinely used in staging. The retroperitoneum
is difficult to visualize due to overlying bowel gas and intra-
abdominal fat and small-volume disease is likely to be “missed.”
Ultrasound is only used in specific clinical situations as a
problem-solver in the evaluation of testicular tumor patients. For
example, in the investigation of focal liver lesions demonstrated
on staging CT when it has not been possible to reach a definitive
diagnosis. Ultrasound is also useful for guidance of biopsy of
retroperitoneal masses, liver lesions or masses in other sites.
Key Points: Staging
■ Lymph node metastases from seminoma are usually masses
of soft tissue density
■ Lymph node metastases from NSGCTs are frequently com-
posed of soft tissue and cystic elements giving rise to a het-
erogeneous density
■ A lymph node greater than 8 mm in diameter should be con-
sidered as suspicious of harboring a metastasis
■ Lung metastases are the commonest site of hematogenous spread
■ Mediastinal nodal involvement is usually by direct spread in
seminoma to the posterior mediastinum but more random
in NSGCT
■ Testicular tumors may also spread to liver, bone and other sites
■ CT is ideally suited to routine staging of testicular tumors
■ Ultrasound and MR imaging are used for problem-solving
■ Imaging of the brain should be routine in high-risk patients
SURVEILLANCE
In patients with Stage I disease, surveillance following orchidec-
tomy as a management strategy is increasingly recognized as the
 testicular germ cell tumors

(A) (B)

(C) (D)

(E)
Figure 20.21 (A)–(D) T2-weighted True-FISP gradient echo axial and (E) coronal MR images showing a large nodal mass, which is causing anterior and lateral displace-
ment of the inferior vena cava (arrows).

preferred option (19,44). This is as a result of growing aware-
ness of long-term treatment related complications (see below).
Surveillance protocols are designed to identify relapse at the
earliest stage thereby enabling earlier treatment. Treatment at
this earlier stage results in disease-free survival rates of over 98%
and in compliant patients, surveillance should be considered
the treatment option of choice. In addition to clinical and serum
marker assessment, imaging with CT forms the basis of surveil-
lance strategies but there is great variation in the frequency of CT
studies between centers (45).

385
 primary tumor evaluation and staging
(A)
Figure 20.22 (A) Fistula between retroperitoneal mass and bowel. CT shows a large cystic retroperitoneal metastasis with a possible communication with bowel.
(B) Coronal MR image clearly demonstrates continuity of tumor mass into a bowel loop (arrow).
In Stage I non-seminomatous GCT, approximately 30% of
patients will relapse, thus to treat all patients would risk toxicity
in over 70% of cases (31,34). Vascular or lymphatic invasion are
the most powerful predictors of relapse. The absence of yolk sac
elements and the presence of undifferentiated cells are also adverse
independent prognostic variables. Relapse rates approach 50% in
high-risk patients compared to approximately 20% in those with-
out high risk factors. In a large prospective study on surveillance
in NSGCT, 45% of those that relapsed did not have raised markers
at the time of discovery of recurrent disease (34). Sixty-one percent
of relapses occurred in the para-aortic nodes and 10% in medi-
astinal or supraclavicular nodes. Ninety-five percent of those who
did relapse were in the IGCCCG good prognostic group and over-
all survival from GCT was 99%. Approximately 80% of relapses
occur within the first year, 90% by year two and almost all by year
three of surveillance (34,46). Hence number of scans should be
the greatest during the first year (45). Surveillance is performed
rigorously with clinical follow-up, serum marker analysis, and
imaging of the thorax and abdomen is routinely performed.
The value of chest CT compared to chest radiography has been
studied. In a series of 168 Stage I non-seminomatous GCT patients
on surveillance chest radiograph rather than chest CT was per-
formed (47). Nineteen percent (42 patients) of these patients
relapsed, of which eight of 42 relapsed with chest disease. Seven
out of eight of these latter patients had evidence of disease else-
where which was identified on abdominal CT. The one patient in
this series who had only chest disease at relapse was clearly diag-
nosed by chest radiography. This led the authors to conclude that
chest imaging with CT would not have changed the prognosis of
those who relapsed in the chest.
The role of pelvic CT has also been called into question. In one
series of patients with testicular GCT pelvic lymphadenopathy
was seen in 16 of 167 patients (9.6%). The presence of bulky
para-aortic lymphadenopathy was the only significant predictor
for pelvic disease and was present in 11 of 16 patients. Other risk
factors for pelvic disease include previous scrotal or inguinal surgery,
386
(B)
maldescent, tunica vaginalis invasion, and retroperitoneal lymph
node dissection. In the absence of these risk factors routine pelvic
CT for patients on surveillance for Stage I disease may constitute
unnecessary irradiation (48).
Centers vary in their preference, but the majority will under-
take abdominal CT between two and six times during the first
year. As yet no consensus on optimal strategy has been reached
but it should be noted that those centers which scan patients
more frequently do not detect relapse at a significantly earlier
stage than those using less rigorous schedules. Indeed, in one
study of 46 patients, all relapses detected after the first CT at
three months were picked up on the basis of clinical suspicion,
raised tumor markers, or chest radiograph (49). Furthermore,
results from a recent prospective randomized trial of two ver-
sus five CT scans in patients with Stage I non-seminomatous
GCT, showed that there was no difference in the outcome in
patients in the five-scan schedule compared to the two-scan
schedule (50).
Is there a role for FDG PET in identifying patients suitable for
surveillance? Early studies in patients with NSGCT suggested that
patients with a negative FDG PET were unlikely to relapse and
therefore did not require adjuvant treatment and could be moni-
tored with surveillance alone whereas FDG PET positive patients
would require treatment (51,52). However this has not been con-
firmed in a large prospective multi-center study which showed
that the relapse rate amongst FDG PET negative patients remained
as high as FDG PET positive patients (53). Thus FDG PET was
not able to identify patients suitable for surveillance.
For Stage I NSGCT surveillance protocols focus on the first year
with investigations reducing in intensity in subsequent years (45).
Serum markers are checked monthly for the first year, with two-
monthly chest radiographs and clinical examination and CT scans
(abdomen only unless pelvis deemed high risk) at three months
and one year. This is broadly similar to the recent national com-
prehensive cancer network (NCCN) guidelines though reduces
the frequency of CT (54).
 testicular germ cell tumors

In seminoma, the wide-scale adoption of surveillance was

ASSESSMENT OF TUMOR RESPONSE, RESIDUAL
limited until recently mainly due to the lack of a reliable serum
tumor marker. Furthermore, the predominant intra-abdominal AND RECURRENT DISEASE
site of relapse meant that regular cross-sectional imaging was
CT remains the primary imaging modality for assessing response
needed. However, surveillance has recently been popularized
to treatment. Reduction in size of metastases is the main change
after publication of a new predictive model for relapse in Stage
on CT indicating response to therapy even if malignant cells
I seminoma. A multivariate analysis of patients from Canadian,
persist within the residuum. The CT findings may parallel reduc-
U.K. and Danish centers has identified tumor size (>4 cm) and
tion in serum marker levels and interval CT scanning during and
invasion of the rete testis as significant predictors for relapse. In
following completion of therapy is important to assess response.
the absence of both these factors, patients have no more than a
Imaging to assess residual disease allows selection of patients who
12% risk of relapse, suggesting that there is a group of patients
may benefit from further treatment such as surgical resection
at particularly low risk where surveillance might be an attrac-
(traditionally those with residual masses greater than 1 cm). In
tive option. Relapses are rare after two years but have been
those patients with large volume residual masses, CT, and MR
reported to occur up to six years after initial diagnosis (20,55).
imaging may be useful for planning the operative approach.
The majority of relapses are in the para-aortic nodes followed
Seminoma is extremely sensitive to chemo- and radiotherapy,
by mediastinal, supraclavicular nodes, and lung metastases
such that residual masses post-treatment usually only constitute
(55,56). Only 30% of seminoma relapses will be marker posi-
fibrosis and necrosis (Fig. 20.23). CT reveals these residual masses
tive. No studies have addressed the optimal scanning or follow-up
as soft tissue density which are poorly defined and frequently
frequency with widely differing policies (19). The policy at our
obscure adjacent fat planes. In the retroperitoneum, the residual
hospital is for six-monthly abdominal CT and chest radiographs
mass is usually closely applied to the aorta and IVC. Calcification
for the first two years and the pelvis is only imaged if there has
may be observed within these residual masses (Fig. 20.24). How-
been previous pelvic surgery. Annual abdominal CT and chest
ever it is important to identify any residual active disease as this
radiograph are then performed until five years following the
will need further treatment usually with surgery and FDG PET
diagnosis (45).
may have a role in this regard. Recently a large prospective study,
SEMPET trial, in which FDG PET was used to assess residual
Key Points: Surveillance tumors in patients with seminoma treated with chemotherapy,
showed that FDG PET imaging was more accurate for assess-
■ Surveillance for Stage I disease is increasingly recognized as
ment than other modalities (57). They reported that FDG PET
the preferred option for both seminoma and NSGCT in
correctly identified all cases of residual tumor in lesions greater
compliant patients
than 3 cm and in 95% of cases with lesions less than 3 cm. This
■ Surveillance avoids unnecessary treatment in 50% to 90% of
gave an overall specificity and sensitivity of 100% and 80% respec-
patients
tively for FDG PET, compared with 74% and 70% for CT. The
■ Disease-free survival of 98% can be achieved in patients who
100% negative predictive value in this and other studies implies
relapse on surveillance
that if FDG PET is negative for a residual mass, no further treatment

(A) (B)
Figure 20.23 Seminoma nodal disease. (A) Pre-chemotherapy and (B) Post-chemotherapy axial CT images showing response to treatment in the large para-caval nodal
metastasis.

387
 primary tumor evaluation and staging

is needed (Fig. 20.25) (58,59). False positive FDG PET imaging
can occur and in order to minimize this, it is important to per-
form FDG PET at least six weeks after completion of chemo-
therapy. If the FDG PET is positive then follow-up FDG PET
imaging at six to eight weeks should be performed to see if the
activity is decreasing or alternatively a biopsy should be consid-
ered. If biopsy is positive or there is persistent or increased FDG
PET activity, then treatment options include surgical excision, fur-
ther chemotherapy, or radiotherapy.
Non-seminomatous germ cell tumor nodal masses may
become cystic on therapy and, if so, frequently enlarge initially,
a phenomenon first demonstrated on CT (60). Simple cysts with
no soft tissue nodules in the wall following therapy are usually
lined by mature differentiated teratoma (Fig. 20.26), whereas
residual masses which are only partially cystic with solid elements
may contain undifferentiated active cancer as well as necrosis,
fibrosis, and differentiated tissue. Soft tissue residua may contain
active cancer or may simply be composed of benign residual tis-
sue. CT demonstrates reduction in tumor volume after therapy in
the majority of patients, even if active malignancy persists within
the residual mass (Fig. 20.27).
In the chest, small pulmonary metastases frequently disappear
on therapy but scars are occasionally seen which are irregular in
shape at the site of previous metastases. In NSGCT, metastases
may cavitate, leaving an air-containing space with a thin rim of
soft tissue (Fig. 20.28) (61).
The purpose of CT in NSGCT at this time is to document
response to therapy and to delineate the presence and extent of
residual disease. CT provides a useful method of distinguishing
between those patients who will go forward to retroperitoneal

Figure 20.26 Cystic NSGCT nodal metastasis following chemotherapy. Note a

large low-density unilocular thin-walled cystic left para-aortic lymph node follow-
ing chemotherapy. Histopathology revealed only mature teratoma.
Figure 20.24 Calcified residual node in the left para-aortic region (arrow). This
appearance was unchanged on subsequent imaging.

(A) (B)
Figure 20.25 Residual mass following chemotherapy for seminoma. (A) Unenhanced CT shows a residual retroperitoneal mass (arrow). (B) The corresponding FDG PET
image shows no activity in this mass. Subsequent follow-up over two years has shown no evidence of recurrent disease. Source: Reprinted from the American Journal of
Roentgenology.

388
 testicular germ cell tumors

(A) (B)
Figure 20.27 Response of NSGCT nodal disease to chemotherapy. (A) Pre-chemotherapy and (B) post-chemotherapy axial CT images showing a partial response in the
large right para-caval nodal metastasis from a right testicular NSGCT.

(A) (B)
Figure 20.28 (A) CT of the lungs demonstrating multiple pulmonary metastases, the largest being in the left lung base, measuring 1.5 cm in size. (B) There was complete
response of the metastases to chemotherapy. However, note the cystic air spaces that persist in the left lung base corresponding to the sites of previous metastases.

lymphadenectomy and those who will not require intervention, as
surgery is based on the size of the residual mass; masses greater
than 1 cm in diameter are resected because there is a risk of subse-
quent relapse in patients with demonstrable residual disease (62).
In patients with large residual masses or multiple sites of residual
disease, surgery may be impossible or may need to be carried out
in stages. A combined thoraco-abdominal approach to resect both
lung and intra-abdominal lesions may be performed in specialized
centers. Both CT and MR imaging have an important role in
determining operability of these complex residual masses and in
planning the surgical approach. The coronal plane images obtained
with MR are particularly useful in patients undergoing resection
when there is concern regarding the presence or extent of inferior
vena caval involvement (Fig. 20.21) (63).
In patients with residual masses following chemotherapy for
non-seminomatous GCT, the use of FDG PET is limited as
mature differentiated teratoma has variable low or no uptake
and cannot be distinguished from fibrosis or necrosis (64–66).
Patients with residual mature differentiated teratoma require
surgery as there is a risk of the mass undergoing malignant
transformation. The crucial decision here is whether the response
requires surgery or not, and FDG PET is unable to help in this
regard.
Detection of recurrent disease relies on careful follow-up with
a combination of clinical assessment, serum markers, chest
radiographs, and abdominal CT. Follow-up protocols vary
depending on the type of tumor, stage, treatments given, and
individual institutions (45). They are based on the known patterns

389
 primary tumor evaluation and staging

(A) (B)

(C) (D)
Figure 20.29 Recurrent disease on FDG PET. A patient previously treated for metastatic NSGCT had slowly rising tumor markers but no apparent disease on contrast-
enhanced CT. FDG PET-CT was performed. (A) and (B) The fused color coded FDG PET-CT images show increased uptake in the nodes in the supraclavicular fossa
(arrow) and posterior mediastinum (arrow). In retrospect the small nodes can be seen on the CT images (C) and (D) in the supraclavicular fossa and posterior mediasti-
num (arrows). Source: Reprinted from the American Journal of Roentgenology.

of disease relapse in testicular GCT (54,67). FDG PET has been

investigated in the detection of recurrent disease and may have
a role in patients with raised tumor markers but no active disease
seen on other imaging such as CT (Figs. 20.29 and 20.30). In
one study, 47 18FDG PET scans were performed for the investi-
gation of residual masses and 23 scans were undertaken for the
investigation of raised markers without evidence of disease on
CT. The positive predictive value (PPV) of 18FDG PET was 96%
and the negative predictive value (NPV) was 90% in patients
with residual masses. In this study the PPV was equivalent to
that of serum markers but 18FDG PET has the added advantage
of locating the site of relapse (65). The authors conclude that
18
FDG PET is a highly sensitive and specific technique for
detecting relapse in patients with raised markers and residual
masses (65). Furthermore, in the presence of persistent raised
marker levels and negative imaging (including negative FDG
PET) the most appropriate follow-up imaging may be to repeat
FDG PET imaging after an interval.
Key Points: Assessment of Tumor Response,
Residual, and Recurrent Disease
■ CT is the main imaging technique used in routine follow-up
■ MR imaging may be useful as a problem-solving exercise,
e.g., to detect IVC involvement
■ A negative 18FDG PET scan of a residual mass following
chemotherapy for seminoma excludes any viable disease
■ In the presence of raised tumor marker levels and a nega-
tive CT, FDG PET has a high predictive value for identifying
the site of recurrent disease
LONG-TERM FOLLOW-UP
As most patients with testicular GCT are being cured, long-term
follow-up for treatment-related toxicity and late relapse are
becoming important issues. Late treatment-related side effects

390
 testicular germ cell tumors

(A) (B)

(C)
Figure 20.30 Recurrent disease on FDG PET. A patient previously treated for metastatic NSCGT had slowly rising tumor markers. The left retrocrural residual mass was
unchanged on (A) contrast-enhanced CT. (B) Three months later a follow-up combined FDG PET-CT still showed no active disease. However after another three months
with continuing rising markers, a further (C) FDG PET-CT showed activity and recurrent disease was confirmed at surgery.

(A) (B)
Figure 20.31 Late relapse in a patient previously treated for Stage III NSGCT. Contrast-enhanced CT shows (A) a low density lesion (arrow) behind the inferior vena cava
and (B) a further low density lesion (arrow) behind the aorta. Both lesions proved to be differentiated teratoma.

391
 primary tumor evaluation and staging

have been more recently appreciated (3). Long-term survivors of

■ Testicular tumors spread predominantly to the retroperito-
testicular cancer have a two-fold risk of cardiovascular disease
neal lymph nodes and to the lungs
(68,69). In addition to the acute myeloid leukemia seen in up to
■ Right-sided tumors spread predominately to right-sided
2% of patients treated with Etoposide (70), there is an 10% excess
nodes and left-sided tumors spread to left-sided nodes
lifetime risk of second malignancy in patients treated with radio-
■ Patients are grouped according to prognostic risk (good,
therapy, chemotherapy or both after 30 years of follow-up (71).
intermediate, and poor) based on histology, serum marker
Long-term endocrine disturbance is also recognized with increased
levels, and CT findings
risk of hypogonadism and metabolic syndrome (which includes
■ Approximately 80% of seminoma patients are Stage I whereas
obesity, hypertension, diabetes, and hypercholesterolemia) (72).
only about 30% to 50% of those with non-seminomatous
Long-term sensory neuropathy and Raynaud’s phenomenon
germ cell tumors present with Stage I disease
are also commonly seen (73). To date, detection and manage-
■ CT is an accurate technique for identifying all common sites of
ment of toxicity has been a minor component of most oncolo-
metastatic spread and is central to patient management
gists’ practice and has by default been delegated to primary care.
■ 18FDG PET is unhelpful for detecting small volume disease in
Recommendations for monitoring have been made but the evi-
patients considered to be Stage I on CT
dence base is limited and the role of imaging remains to be
■ CT has a pivotal role in surveillance of patients with Stage I
determined.
disease
Late relapse is defined as relapse occurring more than two years
■ MR imaging has a limited but useful role in the detection and
after obtaining a complete response to treatment, in the absence of
assessment of metastatic disease
a second primary testicular tumor (74). Late relapse of non-
■ CT is the imaging modality of choice for assessing response to
seminomatous GCT is increasingly being recognized (Fig. 20.31),
treatment in both seminoma and non-seminomatous tumors
occurring in up to 7% of patients (75), partly as a result of improved
■ Seminoma is exquisitely sensitive to chemoradiation. Residual
treatment and long-term survival. Late relapse occurs at a median
masses are usually composed of fibrotic and necrotic tissue
time interval of approximately six years after initial treatment (74)
■ Studies to date show that 18FDG PET is highly accurate in
with an annual recurrence rate for non-seminomatous GCT of 1%
determining the presence or absence of residual tumor in
between five and 10 years (76). The timing of late relapse appears to
treated seminomatous masses
be independent of initial histology and it behaves as a separate clin-
■ In non-seminomatous germ cell tumors 18FDG PET may have
ical entity with patients experiencing a different clinical course and
a role in identifying relapse in patients with raised serum
having different histopathological features compared with those
markers but no evidence of disease on CT
who relapse early (56,74,77). It is also less likely to respond to
chemotherapy and is best treated by surgical excision. The most
common sites of late relapse are the retroperitoneum in 49%,
followed by the lungs in 21%, and mediastinum in 14% of cases (75). REFERENCES
Currently there is no consensus on the optimal long-term
surveillance regime of patients treated for metastatic disease. 1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2007. CA
Controversy exists regarding frequency and length of imaging Cancer J Clin 2007; 57: 43–66.
follow-up, as well as the imaging method and protocol, but most 2. UK Testicular Cancer incidence statistics. Cancer Research
institutions do not routinely follow-up patients beyond 10 years. UK, 2008. [Available from: http://info.cancerresearchuk.org/
It may be that routine CT surveillance in high-risk patients will cancerstats/types/testis/incidence/].
prove highly valuable in the early detection of late relapse. 3. Horwich A, Shipley J, Huddart R. Testicular germ-cell cancer.
Lancet 2006; 367: 754–65.
Key Points: Long-Term Follow-up 4. McGlynn KA, Devesa SS, Sigurdson AJ, et al. Trends in the
incidence of testicular germ cell tumors in the United States.
■ Long-term survivors of testicular cancer have a two-fold risk
Cancer 2003; 97: 63–70.
of cardiovascular disease
5. Fossa SD, Chen J, Schonfeld SJ, et al. Risk of contralateral
■ There is a 10% excess lifetime risk of second malignancy in
testicular cancer: a population-based study of 29,515 U.S.
patients treated with radiotherapy, chemotherapy, or both
men. J Natl Cancer Inst 2005; 97: 1056–66.
after 30 years of follow-up
6. Garner MJ, Turner MC, Ghadirian P, Krewski D. Epidemiol-
■ Late relapse of non-seminomatous GCT may occur in up to
ogy of testicular cancer: an overview. Int J Cancer 2005; 116:
7% of patients
331–9.
7. Lutke Holzik MF, Rapley EA, Hoekstra HJ, et al. Genetic
Summary predisposition to testicular germ-cell tumours. Lancet Oncol
2004; 5: 363–71.
■ Germ cell tumors of the testis account for only 1% of all male
8. Miller FN, Rosairo S, Clarke JL, et al. Testicular calcification
cancers but are the most common malignant tumors in males
and microlithiasis: association with primary intra-testicular
between 15 and 44 years of age
malignancy in 3,477 patients. Eur Radiol 2007; 17: 363–9.
■ Over 95% of testicular tumors are curable
9. Coffey J, Huddart RA, Elliott F, et al. Testicular microlithiasis
■ Serum markers (AFP and HCG) are frequently elevated in
as a familial risk factor for testicular germ cell tumour. Br J
NSGCT; HCG may be elevated in seminoma
Cancer 2007; 97: 1701–6.
392
 testicular germ cell tumors
10. Mason MD. Tumour markers. In: Horwich A, ed. Testicular
Cancer: Investigation and Management. London: Chapman
and Hall, 1996: 35–51.
11. Mencel PJ, Motzer RJ, Mazumdar M, et al. Advanced semi-
noma: treatment results, survival, and prognostic factors in
142 patients. J Clin Oncol 1994; 12: 120–6.
12. Williams MP, Cook JV, Duchesne GM. Psoas nodes—an over-
looked site of metastasis from testicular tumours. Clin Radiol
1989; 40: 607–9.
13. Dixon AK, Ellis M, Sikora K. Computed tomography of
testicular tumours: distribution of abdominal lymphade-
nopathy. Clin Radiol 1986; 37: 519–23.
14. International germ cell consensus classification: a prognostic
factor-based staging system for metastatic germ cell cancers.
International germ cell cancer collaborative group. J Clin
Oncol 1997; 15: 594–603.
15. Krege S, Beyer J, Souchon R, et al. European consensus confer-
ence on diagnosis and treatment of germ cell cancer: a report
of the second meeting of the european germ cell cancer con-
sensus group (EGCCCG): Part I. Eur Urol 2008; 53: 478–96.
16. Krege S, Beyer J, Souchon R, et al. European consensus confer-
ence on diagnosis and treatment of germ cell cancer: a report of
the second meeting of the european germ cell cancer consensus
group (EGCCCG): Part II. Eur Urol 2008; 53: 497–513.
17. Jones WG, Fossa SD, Mead GM, et al. Randomized trial of
30 versus 20 Gy in the adjuvant treatment of stage I Testicular
Seminoma: a report on medical research council trial TE18,
European organisation for the research and treatment of cancer
trial 30942 (ISRCTN18525328). J Clin Oncol 2005; 23: 1200–8.
18. Oliver RT, Mason MD, Mead GM, et al. Radiotherapy versus
single-dose carboplatin in adjuvant treatment of stage I semi-
noma: a randomised trial. Lancet 2005; 366: 293–300.
19. Huddart RA, Joffe JK. Preferred treatment for stage I semi-
noma: a survey of Canadian radiation oncologists. Clin Oncol
(R Coll Radiol) 2006; 18: 693–5.
20. Warde P, Specht L, Horwich A, et al. Prognostic factors for
relapse in stage I seminoma managed by surveillance: a pooled
analysis. J Clin Oncol 2002; 20: 4448–52.
21. Tsili AC, Tsampoulas C, Giannakopoulos X, et al. MRI in the
histologic characterization of testicular neoplasms. AJR Am J
Roentgenol 2007; 189: W331–W337.
22. Kim W, Rosen MA, Langer JE, et al. US MR imaging correla-
tion in pathologic conditions of the scrotum. Radiographics
2007; 27: 1239–53.
23. Lien HH, Stenwig AE, Ous S, Fossa SD. Influence of different
criteria for abnormal lymph node size on reliability of com-
puted tomography in patients with non-seminomatous
testicular tumor. Acta Radiol Diagn (Stockh) 1986; 27: 199–203.
24. Stomper PC, Fung CY, Socinski MA, et al. Detection of retro-
peritoneal metastases in early-stage nonseminomatous testic-
ular cancer: analysis of different CT criteria. AJR Am J
Roentgenol 1987; 149: 1187–90.
25. Thomas JL, Bernardino ME, Bracken RB. Staging of testicular
carcinoma: comparison of CT and lymphangiography. AJR
Am J Roentgenol 1981; 137: 991–6.
26. Rowland RG, Weisman D, Williams SD, et al. Accuracy of
preoperative staging in stages A and B nonseminomatous
germ cell testis tumors. J Urol 1982; 127: 718–20.
27. Richie JP, Garnick MB, Finberg H. Computerized tomogra-
phy: how accurate for abdominal staging of testis tumors?
J Urol 1982; 127: 715–17.
28. Dorfman RE, Alpern MB, Gross BH, Sandler MA. Upper
abdominal lymph nodes: criteria for normal size determined
with CT. Radiology 1991; 180: 319–22.
29. Magnusson A. Size of normal retroperitoneal lymph nodes.
Acta Radiol Diagn (Stockh) 1983; 24: 315–18.
30. Hilton S, Herr HW, Teitcher JB, Begg CB, Castellino RA. CT
detection of retroperitoneal lymph node metastases in patients
with clinical stage I testicular nonseminomatous germ cell
cancer: assessment of size and distribution criteria. AJR Am J
Roentgenol 1997; 169: 521–5.
31. Freedman LS, Parkinson MC, Jones WG, et al. Histopathology
in the prediction of relapse of patients with stage I testicular tera-
toma treated by orchidectomy alone. Lancet 1987; 2: 294–8.
32. Thompson PI, Nixon J, Harvey VJ. Disease relapse in patients
with stage I nonseminomatous germ cell tumor of the testis
on active surveillance. J Clin Oncol 1988; 6: 1597–603.
33. Nicolai N, Pizzocaro G. A surveillance study of clinical stage I
nonseminomatous germ cell tumors of the testis: 10-year
follow-up. J Urol 1995; 154: 1045–9.
34. Read G, Stenning SP, Cullen MH, et al. Medical research
council prospective study of surveillance for stage I testicular
teratoma. Medical Research Council Testicular Tumors Working
Party. J Clin Oncol 1992; 10: 1762–8.
35. Peckham MJ, Barrett A, Husband JE, Hendry WF. Orchidec-
tomy alone in testicular stage I non-seminomatous germ-cell
tumours. Lancet 1982; 2: 678–80.
36. Wood A, Robson N, Tung K, Mead G. Patterns of supradia-
phragmatic metastases in testicular germ cell tumours. Clin
Radiol 1996; 51: 273–6.
37. Williams ME, Husband JE, Heron CW. Intrathoracic manifes-
tations of metastatic testicular seminoma: a comparison of
chest radiographic and CT findings. AJR Am J Roentgenol
1987; 149: 473–5.
38. Rockall AG, Sohaib SA, Harisinghani MG, et al. Diagnostic per-
formance of nanoparticle-enhanced magnetic resonance imag-
ing in the diagnosis of lymph node metastases in patients with
endometrial and cervical cancer. J Clin Oncol 2005; 23: 2813–21.
39. Harisinghani MG, Saksena M, Ross RW, et al. A pilot study of
lymphotrophic nanoparticle-enhanced magnetic resonance
imaging technique in early stage testicular cancer: a new
method for noninvasive lymph node evaluation. Urology
2005; 66: 1066–71.
40. Bellin MF, Lebleu L, Meric JB. Evaluation of retroperitoneal
and pelvic lymph node metastases with MRI and MR lymp-
hangiography. Abdom Imaging 2003; 28: 155–63.
41. Koh DM, Brown G, Temple L, et al. Rectal cancer: mesorectal
lymph nodes at MR imaging with USPIO versus histopathologic
findings—initial observations. Radiology 2004; 231: 91–9.
42. Albers P, Bender H, Yilmaz H, et al. Positron emission
tomography in the clinical staging of patients with Stage I and
II testicular germ cell tumors. Urology 1999; 53: 808–11.
43. Spermon JR, Geus-Oei LF, Kiemeney LA, Witjes JA, Oyen WJ.
The role of (18)fluoro-2-deoxyglucose positron emission
tomography in initial staging and re-staging after chemotherapy
for testicular germ cell tumours. BJUInt 2002; 89: 549–56.
393
 primary tumor evaluation and staging
44. Sohaib SA, Husband J. Surveillance in testicular cancer: who,
when, what and how? Cancer Imaging 2007; 7: 145–7.
45. van As NJ, Gilbert DC, Money-Kyrle J, et al. Evidence based prag-
matic guidelines for the follow-up of testicular cancer: optimising
the detection of relapse. Br J Cancer 2008; 98: 1894–902.
46. Daugaard G, Petersen PM, Rorth M. Surveillance in stage I
testicular cancer. APMIS 2003; 111: 76–83; discussion 83–75.
47. Harvey ML, Geldart TR, Duell R, Mead GM, Tung K. Routine
computerised tomographic scans of the thorax in surveillance
of stage I testicular non-seminomatous germ-cell cancer—a
necessary risk? Ann Oncol 2002; 13: 237–42.
48. White PM, Howard GC, Best JJ, Wright AR. The role of com-
puted tomographic examination of the pelvis in the management
of testicular germ cell tumours. Clin Radiol 1997; 52: 124–9.
49. Crawford SM, Rustin GJ, Begent RH, Newlands ES, Bagshawe KD.
Safety of surveillance in the management of stage I anaplastic
germ cell tumours of the testis. Br J Urol 1988; 61: 250–3.
50. Rustin GJ, Mead GM, Stenning SP, et al. Randomized trial of
two or five computed tomography scans in the surveillance of
patients with stage I nonseminomatous germ cell tumors of
the testis: Medical Research Council Trial TE08, ISRCTN
56475197—the National Cancer Research Institute Testis Can-
cer Clinical Studies Group. J Clin Oncol 2007; 25: 1310–15.
51. Lassen U, Daugaard G, Eigtved A, et al. Whole-body FDG-PET
in patients with stage I non-seminomatous germ cell tumours.
Eur J Nucl Med Mol Imaging 2003; 30: 396–402.
52. Cremerius U, Wildberger JE, Borchers H, et al. Does positron
emission tomography using 18-fluoro-2-deoxyglucose improve
clinical staging of testicular cancer?—Results of a study in
50 patients. Urology. 1999; 54: 900–4.
53. Huddart RA, O’Doherty MJ, Padhani AR, et al. 18fluorode-
oxyglucose positron emission tomography in the prediction
of relapse in patients with high-risk, clinical stage 1 nonsemi-
nomatous germ cell tumors: preliminary report of MRC Trial
TE22—the NCRI Testis Tumour Clinical Study Group. J Clin
Oncol 2007; 25: 3090–5.
54. Kondagunta GV, Sheinfeld J, Motzer RJ. Recommendations of
follow-up after treatment of germ cell tumors. Semin Oncol
2003; 30: 382–9.
55. Oldenburg J, Martin JM, Fossa SD. Late relapses of germ cell
malignancies: incidence, management, and prognosis. J Clin
Oncol 2006; 24: 5503–11.
56. Dieckmann KP, Albers P, Classen J, et al. Late relapse of
testicular germ cell neoplasms: a descriptive analysis of 122
cases. J Urol 2005; 173: 824–9.
57. De Santis M, Becherer A, Bokemeyer C, et al. 2-18fluoro-
deoxy-D-glucose positron emission tomography is a reliable
predictor for viable tumor in postchemotherapy seminoma:
an update of the prospective multicentric SEMPET trial. J Clin
Oncol 2004; 22: 1034–9.
58. Lewis DA, Tann M, Kesler K, . Positron emission tomography
scans in postchemotherapy seminoma patients with residual
masses: a retrospective review from Indiana University
Hospital. J Clin Oncol 2006; 24: e54–55.
59. Hinz S, Schrader M, Kempkensteffen C, et al. The role of
positron emission tomography in the evaluation of residual
394
masses after chemotherapy for advanced stage seminoma.
J Urol 2008; 179: 936–40; discussion 940.
60. Husband JE, Hawkes DJ, Peckham MJ. CT estimations of
mean attenuation values and volume in testicular tumors: a
comparison with surgical and histologic findings. Radiology
1982; 144: 553–8.
61. Charig MJ, Williams MP. Pulmonary lacunae: sequelae of metas-
tases following chemotherapy. Clin Radiol 1990; 42: 93–6.
62. Hendry WF, A’Hern RP, Hetherington JW, et al. Para-aortic
lymphadenectomy after chemotherapy for metastatic non-
seminomatous germ cell tumours: prognostic value and
therapeutic benefit. Br J Urol 1993; 71: 208–13.
63. Ng CS, Husband JE, Padhani AR, et al. Evaluation by magnetic
resonance imaging of the inferior vena cava in patients with
non-seminomatous germ cell tumours of the testis metastatic
to the retroperitoneum. Br J Urol 1997; 79: 942–51.
64. Cremerius U, Effert PJ, Adam G, et al. FDG PET for detection
and therapy control of metastatic germ cell tumor. J Nucl Med
1998; 39: 815–22.
65. Hain SF, O’Doherty MJ, Timothy AR, et al. Fluorodeoxyglu-
cose positron emission tomography in the evaluation of germ
cell tumours at relapse. Br J Cancer 2000; 83: 863–9.
66. Stephens AW, Gonin R, Hutchins GD, Einhorn LH. Positron
emission tomography evaluation of residual radiographic
abnormalities in postchemotherapy germ cell tumor patients.
J Clin Oncol 1996; 14: 1637–41.
67. Flechon A, Culine S, Theodore C, Droz JP. Pattern of relapse
after first line treatment of advanced stage germ-cell tumors.
Eur Urol 2005; 48: 957–63.
68. Huddart RA, Norman A, Shahidi M, et al. Cardiovascular dis-
ease as a long-term complication of treatment for testicular
cancer. J Clin Oncol 2003; 21: 1513–23.
69. van den Belt-Dusebout AW, Nuver J, de Wit R, et al.
Long-term risk of cardiovascular disease in 5-year survivors of
testicular cancer. J Clin Oncol 2006; 24: 467–75.
70. Baldwin EL, Osheroff N. Etoposide, topoisomerase II and
cancer. Curr Med Chem Anticancer Agents 2005; 5: 363–72.
71. Travis LB, Fossa SD, Schonfeld SJ, et al. Second cancers
among 40,576 testicular cancer patients: focus on long-term
survivors. J Natl Cancer Inst 2005; 97: 1354–65.
72. Nuver J, Smit AJ, Wolffenbuttel BH, et al. The metabolic
syndrome and disturbances in hormone levels in long-term
survivors of disseminated testicular cancer. J Clin Oncol 2005;
23: 3718–25.
73. Fossa SD. Long-term sequelae after cancer therapy—survivorship
after treatment for testicular cancer. Acta Oncol 2004; 43: 134–41.
74. Baniel J, Foster RS, Einhorn LH, Donohue JP. Late relapse of
clinical stage I testicular cancer. J Urol 1995; 154: 1370–2.
75. Lipphardt ME, Albers P. Late relapse of testicular cancer. World
J Urol 2004; 22: 47–54.
76. Shahidi M, Norman AR, Dearnaley DP, et al. Late recurrence
in 1263 men with testicular germ cell tumors. Multivariate
analysis of risk factors and implications for management.
Cancer 2002; 95: 520–30.
77. Gerl A, Clemm C, Schmeller N, et al. Late relapse of germ cell tumors
after cisplatin-based chemotherapy. Ann Oncol 1997; 8: 41–7.
 21 Ovarian Cancer
S Aslam Sohaib and Rodney H Reznek
INTRODUCTION
Ovarian cancer remains the most lethal of the gynecological
cancers partly because the majority of patients present with
advanced disease. A multidisciplinary approach is central to the
management of patients with ovarian neoplasms. Expert pathologi-
cal review is needed in this widely diverse group of often complex
neoplasms. Careful case selection and advanced surgical techniques
is required for best surgical results. The surgical options have to be
managed with the chemotherapy available for optimum outcome
for the patients. Imaging is central to this multidisciplinary team.
Imaging in conjunction with tumor markers and clinical assessment
is used in the detection and characterization of adnexal masses, in
the selection of initial treatment options between surgery and/or
chemotherapy, and in the subsequent follow-up of these patients.
EPIDEMIOLOGY
Ovarian cancer accounts for 3% to 4% of all female cancers (1,2).
In the developed world, it is the second most common gyneco-
logical cancer after cancer of the uterine corpus but the most fre-
quent cause of death from gynecological malignancy (1,2). An
estimated 21,650 new cases and 15,520 deaths are expected in the
United States in 2008; in the United Kingdom there were 6615
new cases diagnosed in 2004 and 4447 death in 2005 (1,2). The
lifetime risk of developing ovarian cancer is one in 48 (approxi-
mately 2%) in England and Wales (1). Over recent years there has
been a steady decline in the number of new cases annually; in the
United States, between 1987 and 2004, ovarian cancer incidence
declined at a rate of 0.9% per year (2).
The age distribution varies according to tumor histology; epithe-
lial ovarian cancer is a disease of postmenopausal women, whereas
germ cell tumors and sex cord stromal tumors are most prevalent
in the second and third decades of life.
The causes of ovarian cancer are unknown, but several factors are
considered to exert an influence over its development. Based on several
epidemiological studies there is good evidence that increased parity,
use of the oral contraceptive pill, tubal ligation, and hysterectomy
reduce the risk of ovarian cancer (3). Lactation has a weaker effect on
risk reduction. The effects of endometriosis, infertility, diet, and
polycystic ovary syndrome on ovarian cancer risk are unclear (3).
A hereditary link is observed in less than 5% of cases (4). These
tumors tend to occur at an earlier age than non-hereditary cancers
but the disease is similar in stage and grade at presentation (4,5).
Two distinct familial cancer syndromes are observed:
• Breast-ovarian familial cancer syndrome
• Hereditary non-polyposis colorectal cancer (HNPCC)
or Lynch syndrome
A gene that confers increased susceptibility to ovarian cancer
alone has not yet been isolated and so site-specific familial ovarian
cancer and hereditary breast ovarian cancer syndrome are con-
sidered to be part of the same spectrum (3). Most cases of heredi-
tary breast/ovarian cancer families are associated with one of
two genes: BRCA1 (on chromosome 17q12-21) and BRCA2 (on
chromosome 13q12-13). The lifetime risk for developing ovarian
cancer for BRCA1 carriers is 16% to 44% and for BRCA2 carriers
is 27% (3). The Lynch syndrome is characterized by colon cancer
(unrelated to polyposis), endometrial cancer, breast cancer,
urothelial tumors, and ovarian cancer clusters in first and second
degree relatives (6). Most of the ovarian cancers in this syndrome
are serous cystadenocarcinomas.
CLINICAL FEATURES
The clinical presentation of all ovarian neoplasms is similar despite
the great histological diversity. Patients are usually asymptomatic
until the tumor is large and consequently the vast majority pres-
ent with disease which has spread beyond the ovary. The most
frequent presenting symptoms are abdominal pain and swelling.
Gastrointestinal symptoms such as indigestion, urinary frequency,
weight loss, backache, and a feeling of pelvic pressure are all
recognized non-specific features.
Key Points: Epidemiology and Clinical Presentation
■ Ovarian cancer accounts for 3% to 4% of all female malig-
nancy and is the most common cause of death from a
gynecological cancer
■ Epithelial cancer is a disease of postmenopausal women and
usually presents with advanced disease
■ Germ cell tumors and sex cord stromal tumors are most
prevalent in the second and third decades of life
■ There are two hereditary forms of ovarian cancer—breast-
ovarian familial cancer syndrome and hereditary non-polyposis
colorectal cancer (HNPCC) or Lynch syndrome
■ Abdominal pain and swelling are the presenting features
PATHOLOGY
A simplified version of the World Health Organisation (WHO)
classification of ovarian tumors is shown in Table 21.1 (7). This
classification categorizes tumors according to the tissue of origin
and whether they are benign, borderline, or overtly malignant. Pri-
mary ovarian tumors arise from one of three ovarian components:
• Surface epithelium
• Germ cells
• Stroma of the ovary
The sites of development of ovarian tumors are shown in Fig. 21.1.
The frequency of the most common epithelial histological types
of cancer, the percentage that are malignant, and the percentage of
395
 primary tumor evaluation and staging

Table 21.1 Ovarian Tumors (WHO Classification, 1993) serous tumors are usually predominantly cystic and may be either
unilocular or multilocular. The cyst content varies but is often
Surface epithelial tumors made up of thin fluid with variable amount of fibrous stroma.
Serous tumor
Benign, borderline, and malignant
Malignant serous lesions tend to have a larger component of
Mucinous tumor solid tissue compared with the benign forms; areas of hemor-
Benign, borderline, and malignant rhage and necrosis are also more frequently seen. Microscopic
Endometrioid tumor calcification referred to as “psammoma bodies” are seen in up to
Benign, borderline, and malignant 30% of serous tumors (8). Although psammoma bodies are
Epithelial-stromal
Adenosarcoma, mesodermal (mullerian) mixed tumor
characteristic of serous tumors they may be seen in other neoplasms
Clear cell tumor (e.g., papillary cancer of the thyroid gland) or non-neoplastic
Benign, borderline, and malignant processes.
Transitional cell tumor
Brenner tumor (Benign, borderline, and malignant)
Non-Brenner type Mucinous Tumors
Mixed and unclassified tumor • Adenocarcinoma
Sex cord-stromal tumors
Granulosa stroma cell tumor
• Cyst adenocarcinoma
Tumors of the thecoma-fibroma group
• Malignant adenofibroma
Sertoli-stromal cell tumor (androblastoma) • Cyst adenofibroma
Sex cord tumor with annular tubules Mucinous tumors are analogous to the serous tumors but differ in
Gynandroblastoma
that the epithelium consists of mucin-secreting cells. As in serous
Steroid (lipid) cell tumor
tumors, most mucinous neoplasms present in postmenopausal
Germ cell tumors
Teratoma women. They differ from serous tumors in that they are less likely
Immature to be bilateral and 80% are benign compared with 60% of serous
Mature tumors (8). Mucinous tumors are typically multilocular with
Monodermal (e.g., struma ovarii, carcinoid) numerous thin-walled cysts. Mucoid material is found within the
Dysgerminoma
cysts, sometimes complicated by hemorrhagic or cellular debris.
Yolk sac tumor
Embryonal cell tumor This gives the cystic fluid an echogenic appearance on ultrasound
Choriocarcinoma and may give a variable signal on MRI. Malignant lesions tend to
Mixed germ cell tumors have proportionately greater solid elements. Metastasis within the
Metastatic tumors (from non-ovarian primary) peritoneal cavity or rupture of a mucinous tumor gives rise to
pseudomyxoma peritonei which is seen most often with border-
line or well-differentiated cancers (8). The peritoneal cavity
becomes filled with mucinous material resembling the cystic
tumors that are bilateral are shown in Table 21.2. In addition to
content of the tumor. Multiple tumor implants are found on the
the histological types, histological grading (0–4) is designated
serosal surfaces of abdominal structures and the viscera becomes
according to the degree of cellular differentiation.
matted together.
Surface Epithelial Tumors Endometrioid Cancers
Neoplasms of surface epithelial origin account for 65% to 70% of Carcinoma
all primary ovarian tumors and almost 90% of malignant ovarian
cancers; hence, they are sometimes referred to as common epithe- • Adenocarcinoma
lial tumors (7). The most common are serous tumors followed by • Adenoacanthoma
mucinous and endometrioid cancers. Clear and transitional cell • Malignant adenofibroma
tumors are rare. In addition to the definitely benign and definitely • Cystadenofibroma
malignant tumors, some epithelial neoplasms occupy an interme- Endometrioid stromal sarcomas
diate category and are called borderline tumors or tumors of low
malignant potential. • Mesodermal (Müllerian)
• Mixed tumors
Serous Tumors
Endometrioid cancers are almost always invasive and are the second
• Adenocarcinoma most common malignant ovarian neoplasm. They are associated
• Papillary adenocarcinoma with hyperplasia or cancer of the uterine endometrium in 20% to
• Papillary cyst adenocarcinoma 33% of cases (8) and microscopically have a tubular glandular
• Surface papillary carcinoma pattern, which mimics endometrial cancer. Despite histology
• Malignant adenofibroma similar to the latter, most of these tumors are thought to represent
• Cystadenofibroma independent primary tumors (8). The gross morphology is simi-
Serous tumors are the most frequent of the ovarian tumors. Benign lar to other epithelial tumors with a variable cystic and solid com-
and borderline tumors are most common between 20 and 50 years ponent. Occasionally they are completely solid, unlike other
of age with malignant tumors occurring later. Macroscopically, epithelial tumors.

396
 ovarian cancer

Hilar cells
Cells of origin of
Corpus luteum stromal (sex cord)
Theca cells
tumors
Granulosa cells

Follicle

Tunica albuginea

Mesothelial inclusion cyst

Cells of origin of
epithelial tumors
Surface coelomic mesothelium

Germ cell Cells of origin of

Germ cell germ cell tumor

Figure 21.1 Diagrammatic representation of the sites of origin of ovarian neoplasms.

Table 21.2 Frequency of Major Ovarian Tumors Clear cell tumors are histologically similar to clear cell tumors
of the endometrium, vagina, and cervix but are not associated with
Histological tumor Percentage of malignant Bilateral tumors (%) exposure to diethylstilboestrol in utero (8). These tumors have a
type ovarian tumors (%)
good overall prognosis because they tend to remain confined to the
Serous 40 ovary. Approximately 75% are Stage I and over 85% are Stage I or II
Benign (60%) 25
at the time of diagnosis. Clear cell tumors are frequently unilocular
Borderline (15%) 30
Malignant (25%) 65 cysts with one or two mural nodules protruding into the lumen.
Mucinous 10 Multilocular cysts, however, may also be seen occasionally and
Benign (80%) 5 sometimes the tumors are predominantly solid.
Borderline (10%) 10
Malignant (10%) <5 Brenner Tumors
Endometrioid 20 40 Brenner tumors are solid, homogeneous neoplasms which are fre-
carcinoma
Undifferentiated 10 –
quently small (typically 1–2 cm in diameter) and are only malig-
Clear cell carcinoma 6 40 nant in a small proportion of cases. They are characterized by
Granulosa cell tumor 5 5 nests and columns of epithelial cells embedded in ovarian stroma.
Teratoma 15 They show extensive calcification and are seldom bilateral. Cystic
Benign (96%) areas are unusual and, when present, are likely to be due to co-
Malignant (4%) 1 rare
Metastatic 5
existent cystadenoma; about 20% of these neoplasms are associated
Others 3 with mucinous cystadenomas or other epithelial tumors (8).

Undifferentiated Cancers
Undifferentiated cancers are tumors in which cellular differentia-
tion is not sufficient to categorize their cellular origin, although
small areas of various histological elements may be seen in most
Malignant mixed mesodermal (Müllerian) tumors are included lesions. This group has the poorest outcome and are often extensive
in the endometrioid classification but differ in that endometrioid at the time of presentation.
cancers have a better prognosis than these mixed tumors. They
are endometrioid tumors containing epithelial and mesenchymal Mixed Epithelial Tumors
elements. Mixed epithelial tumors are neoplasms composed of two or more
of the major components of epithelial tumors. Their most frequently
Clear Cell Tumors encountered combinations are transitional cells with mucinous
• Malignant carcinoma cells (Brenner tumors) and endometrioid cells with mucinous,
• Adenocarcinoma serous, or clear cells.

397
 primary tumor evaluation and staging
Borderline Ovarian Tumors
Borderline tumors refer to ovarian neoplasms which have some or
all of the features of malignant tumor but no stromal invasion (9).
These tumors behave more aggressively than benign neoplasms
but have a better prognosis than invasive malignancy. Recently, a
further category of borderline tumor with microinvasion has been
made as this has a prognosis between that of borderline tumors
and frankly invasive tumors (9). In the histological diagnosis of
borderline tumor, sampling of large ovarian tumors may be prob-
lematic and the possibility that an invasive component has not
been sampled should be kept in mind.
Borderline tumors are estimated to comprise 5% to 15% of all
ovarian malignancies, with women presenting about 10 to 15 years
earlier compared to the invasive ovarian neoplasm (8). Most
borderline tumors are either serous or mucinous but other histo-
logical types are occasionally seen (10). Risk factors for these
tumors are similar to those of overt ovarian malignancy but their
link with the use of oral contraceptives is less distinct and they are
more common in women with a history of infertility (10). In
general, these tumors present in a similar manner to other epithe-
lial ovarian tumors and the serum CA-125 level may be elevated.
Long-term follow-up is required since these tumors can recur up
to 20 years after the initial diagnosis (10).
Borderline serous ovarian neoplasms are the commonest bor-
derline ovarian tumors. They are usually multilocular cysts with
fine papillary processes. Implants of borderline ovarian cell in
peritoneal, omental, and lymph node may be invasive or non-in-
vasive (both types may be found in the same patient). Patients
with invasive implants have a worse prognosis. Borderline muci-
nous ovarian tumors are large multilocular masses with mucoid
material. There is a strong association between a borderline muci-
nous tumors and similar tumor involving the appendix. As well as
appendiceal disease, other features that indicate aggressive behav-
ior include invasive implants and pseudomyxoma peritonei.
Key Points: Surface Epithelial Cancers
■ Epithelial cancer accounts for 65% to 70% of all ovarian neo-
plasms; serous tumors are the most frequent, followed by
mucinous and endometrioid tumors
■ Serous tumors are predominantly cystic, either unilocular or
multilocular, and may contain psammoma bodies. Approximately
40% are malignant
■ Mucinous tumors are usually benign and are less likely to be
bilateral than serous tumors. Metastases may rupture
producing pseudomyxoma peritonei
■ Endometrioid tumors are always invasive. They are solid/cystic
masses and may be associated with endometrial cancer in up
to one third of cases
■ Clear cell tumors are usually benign and present as unilocu-
lar cysts with one or two soft tissue nodules protruding into
the lumen
■ Brenner tumors are solid neoplasms. They are usually benign,
unilateral and may be associated with other tumors such as
mucinous cyst adenomas
■ Borderline ovarian tumors are estimated to comprise 5% to
15% of all ovarian malignancies and have a better prognosis
than their frankly malignant ovarian neoplasms.
398
Germ Cell Tumors
• Teratoma
• Dysgerminoma
• Yolk sac tumors
• Choriocarcinoma
Germ cell tumors comprise 15% to 20% of all ovarian neo-
plasms and most are benign cystic teratomas (7).. They are most
commonly seen in the first two decades of life when they
account for 70% of all ovarian tumors and are rare after the
third decade of life. Germ cell malignancies grow rapidly and
are often characterized by pain secondary to torsion, hemor-
rhage, or necrosis. They frequently reach a large size and the
patient may therefore present with bladder symptoms such as
frequency of micturition or pelvic pain. Dysgerminomas are
the most common malignant germ cell tumor and are bilateral
in 10% to 15% of cases. Other germ cell tumors of the ovary
are usually unilateral.
Teratoma
Teratomas are divided into three categories:
• Mature (benign)
• Immature (malignant)
• Monodermal (or specialized) teratomas
Mature Teratoma
The vast majority of ovarian teratomas are mature cystic teratomas
(dermoid cysts) and are the commonest benign ovarian neoplasms.
Dermoid cysts have a variety of appearances on imaging depend-
ing on the composition of the tumor but a fat-fluid or hair-fluid
level is characteristic, as is the demonstration of calcification, bone
or teeth. About 1% of dermoids may undergo malignant transfor-
mation, usually to a squamous cell carcinoma, of any one of the
component elements (7).
Immature Teratomas
These teratomas are rare and contain components which resemble
fetal or embryonic tissues (7). They are aggressive malignant
lesions which grow rapidly and frequently penetrate the capsule,
which results in widespread dissemination of disease with distant
metastases. Morphologically they are bulky masses with a smooth
external surface, predominantly solid but may contain areas of
hemorrhage and necrosis.
Monodermal Teratomas
These teratomas are a rare group, the most common of these being
the struma ovarii and carcinoid tumors.
Dysgerminoma
Dysgerminomas are composed of undifferentiated germ cells and
are comparable histologically to testicular seminoma. They may
be associated with congenital malformations of the genital tract,
Turner syndrome, and with gonadoblastoma in patients with
dysgenic gonads. Dysgerminomas are uncommon, accounting
for only 2% of primary malignant ovarian cancers with 80%
of them occur during the second and third decades of life (7).
Morphologically these tumors are usually solid masses containing
cystic areas due to hemorrhage and necrosis (Fig. 21.2).
 ovarian cancer

(A) (B)

(C)
Figure 21.2 Ovarian dysgerminoma. Axial (A) T1-weighted, (B) T2-weighted, and (C) contrast-enhanced fat-suppressed T1-weighted images show a heterogeneous
solid cystic mass (arrows).

Yolk Sac Tumors

Yolk sac tumors are also rare but are in fact the second most
common malignant germ cell tumor. They usually occur during
the second and third decades of life and, like immature terato-
mas, are predominantly solid although cystic degeneration
frequently occurs. They are usually unilateral rapidly growing
tumors.
Choriocarcinoma
Choriocarcinomas are rare and aggressive tumors which usually
have metastasized widely to the lungs, liver, and bone by the time
of presentation. Most of these tumors present below the age of
20 years and the tumor occurs in combination with other forms of
malignant germ cell neoplasia, such as immature teratoma (7).
Key Points: Germ Cell Tumors
■ Germ cell tumors account for 15% to 20% of all ovarian
neoplasms
■ Germ cell tumors usually present in the first or second
decades of life and grow rapidly
■ Teratomas may be mature (benign), immature (malignant), or
monodermal
■ The vast majority of ovarian teratomas are benign
■ Dysgerminomas are the most common malignant germ cell
tumor. They are composed of undifferentiated germ cells
and are bilateral in 10% to 15% of cases, are usually solid,
containing cystic areas due to hemorrhage after necrosis
■ Yolk sac tumors are the second most common malignant
germ cell tumor
■ Choriocarcinomas are rare, aggressive tumors which have
usually metastasized widely by the time of presentation. They
are often composed of mixed cell types including immature
teratoma
Sex Cord-Stromal Tumors
This category includes all tumors that develop from the sex cords
and the specialized stroma of the ovary. They are capable of
differentiating in an ovarian direction (granulosa-theca cells), in
a testicular direction (Sertoli cells or Leydig cells), or in a stromal
direction to remain fibromatous. They account for between 5%
and 10% of all ovarian malignancies and are seen throughout
the reproductive phase and also in postmenopausal women (7).
They also occur in childhood but are uncommon before the
menarche and account for only approximately 5% of all childhood
malignancies. This group of ovarian neoplasms are also referred
to as “functioning tumors” in that as many as 85% to 90% of them
synthesize steroids such as estrogen, progesterone, testosterone,
and corticosteroids (7).

399
 primary tumor evaluation and staging
Granulosa Cell Tumors
Granulosa cell tumors are the most common of the sex-cord
tumors and are associated with endometrial cancer. The peak age
of presentation is in the postmenopausal years and they may
secrete estrogen, causing postmenopausal bleeding. If they occur
in prepubertal girls they produce sexual precocity. Characteristi-
cally these tumors are unilateral and usually solid (7). The behavior
of these tumors and their prognosis is impossible to predict from
the histological features. The most reliable predictor is the stage of
the tumor at operation. Recurrence may occur in 5% to 25% of
patients and this may happen up to 30 years later (9).
Fibroma and Thecoma
These are benign tumors composed of either fibroblasts (fibromas) or
more pulp spindle cells with lipid droplets (thecomas). They are rela-
tively common accounting for 4% of all ovarian tumors (7). These
tumors are usually unilateral, solid encapsulated masses seen in the
fourth and fifth decades of life. As many of these tumors contain a
mixture of both these cells they are sometimes termed fibroma-
thecoma. Pure thecomas are rare and tumors where these cells pre-
dominate may be hormonally active and secrete estrogen and, as in the
case with granulosa cell tumors, are associated with endometrial can-
cer. Ovarian fibromas are associated with Meig’s syndrome (ovarian
tumor, ascites, and pleural effusion) and basal cell nevus syndrome (7).
Sertoli–Leydig Cell Neoplasm (Androblastoma)
These tumors are thought to represent masculine differentiation
of primitive mesenchymal elements within the ovary, synthesis a
variety of androgens and cause masculinization. They are rare,
partly cystic but mostly solid, unilateral, large tumors and usually
present in young females within the reproductive age group (7).
They have a potential for aggressive behavior which cannot be
predicted from the histological features.
Key Points: Sex Cord-Stromal Tumors
■ Sex cord tumors are derived from the sex cord and special-
ized stroma of the ovary and differentiate in an ovarian
direction, in a testicular direction, or in a stromal direction,
and account for 5% to 10% of all ovarian malignancies
■ Granulosa cell tumors (ovarian direction) are the most
common sex cord tumors and usually present in the
postmenopausal age group
■ Fibromas and thecomas are benign tumors and ovarian
fibromas may be associated with Meig’s syndrome and basal
cell nevus syndrome
■ Sertoli–Leydig cell tumors (testicular direction) are rare and
tend to occur in young females in the reproductive age and
commonly produce masculinization
Metastases
About 5% to 15% of ovarian neoplasms are metastases (11). The
most common tumors, which metastasize to the ovary, are breast,
endometrial, and gastrointestinal malignancies. Krukenberg tumor
refers to bilateral ovarian metastases characterized by mucin-
producing signet ring cells, most commonly seen in stomach can-
cer. Morphologically most of these tumors are complex, consisting
of solid elements and cystic areas (11). Solid tumor deposits within
the ovaries may be seen in leukemia or lymphoma (12).
400
TUMOR MARKERS
The most commonly used serum marker for ovarian epithelial
cancer is CA-125 (13). It is raised in over 80% of advanced ovarian
cancer but only 25% to 50% of stage I disease (14). A CA-125 ele-
vated to greater than 35 U/ml is not specific for ovarian cancer as it
is also raised in 1% of healthy individuals, in 40% of patients with
advanced intra-abdominal non-ovarian malignancy, and in benign
conditions is associated with inflammation of the peritoneum, such
as peritonitis, endometriosis, and pelvic inflammatory disease (13).
As more than 90% of false-positive findings are encountered in pre-
menopausal age, in this patient group only a serial rise of
CA-125 should raise the concern of malignancy (14). In postmeno-
pausal women, CA-125 is a better indicator of malignancy, and a
threshold value of 65 U/ml is predictive of malignancy in 75% of
women with pelvic masses (15). In mucinous ovarian cancers
CA-125 levels may not be markedly elevated. Carcinoembryonic
antigen (CEA) may be elevated in mucinous cystadenocarcinoma,
again illustrating the non-specificity of many serum markers in
malignant disease.
Many germ cell tumors produce serum markers. Yolk sac tumors
and choriocarcinoma produce alpha-fetoprotein (AFP) and
human chorionic gonadotrophin (HCG), respectively. Embryonal
carcinomas are capable of producing both AFP and HCG, while
mixed tumors and immature teratomas may produce both markers,
one of these or neither of them.
Key Points: Tumor Markers
■ CA-125 is the best and most commonly used serum marker
for epithelial ovarian cancer but lacks sufficient sensitivity and
specificity to be used alone as a screening test
■ Germ cell tumors may produce alpha-fetoprotein (AFP) and
human chorionic gonadotrophin (HCG)
PATTERNS OF TUMOR SPREAD
Ovarian cancer spreads by local extension, transcoelomic spread,
and by the lymphatic and hematogenous routes (Fig. 21.3).
Contiguous tumor spread from the ovary occurs along the
Fallopian tube to involve the broad ligament and uterus directly.
In more advanced disease, direct tumor invasion of the rectum,
sigmoid colon, bladder, and lateral pelvic wall is seen.
Transcoelomic spread occurs when the ovarian cancer breaks
through the serosal epithelial surface of the ovary and tumor cells are
shed into the peritoneal cavity. These malignant cells are distributed
through the peritoneal cavity via the peritoneal fluid circulation.
Most of these cells are destroyed due to host-immune mechanisms
but those that survive adhere to peritoneal surfaces where aggre-
gates of tumor cells grow into vascularized tumor deposits. Perito-
neal metastases are therefore commonly seen in such sites as the:
• Under surface of the diaphragm
• Omentum
• Surfaces of the small and large bowel
• Surfaces of the liver
• Pouch of Douglas
 ovarian cancer

Perenchymal Peritoneal
pulmonary seeding of
metastases diaphragm
and liver
serosa
Perenchymal
hepatic
metastases

Peritoneal Seeding of
Spread via seeding of pouch
portal vein omentum of douglas
Spread via and gut
ovarian vein serosa

Direct extension
of tumor to
neighboring
organs (bladder,
uterus, fallopian tubes,
rectum)

Hematogenous spread primarily to lung via ovarian vein

(A) and vena cava and to liver via portal venous system (B)

Malignant cells Transdiaphragmatic

in peritoneal fluid communication
embolize to of pleural and
lymphatic vessels abdominal
of right lymphatic vessels
hemidiaphragm results in
pleural effusion

Subdiaphragmatic
cell flow Para-aortic
nodes
Flow over
omentum Occlusion of
lymphatic vessels
Flow along causes ascites
Para-aortic gutters

Pelvic nodes

Peritoneal seeding of free-floating malignant cells Lymphatic spread primarily to pelvic and
(C) most common mode of spread para-aortic lymph node chains
(D)
Figure 21.3 (A–D) Diagrammatic patterns of tumor spread in ovarian neoplasms.

401
 primary tumor evaluation and staging

The right side of the diaphragm is affected more frequently than
the left (16).
Lymphatic-borne metastases result from direct invasion of
ovarian lymphatics or by absorption from the peritoneal fluid
into diaphragmatic lymphatic channels. From the ovary direct
lymphatic tumor spread passes via three main pathways along:
• Ovarian vessels to the upper common iliac and para-aortic
lymph nodes
• The broad ligament and parametria to the external iliac
and obturator nodes
• The round ligaments drainage to external iliac and
inguinal nodes
The lymphatic channels that accompany the ovarian vessels lie on
the anterior surface of the psoas muscles. On the right side these
lymphatic vessels fan out to drain into the precaval and lateral
caval lymph nodes, which are situated between the right renal
hilum and the aortic bifurcation. On the left the lymphatic chan-
nels do not diverge from each other as extensively as on the right
and usually terminate in lymph nodes around the renal hilum.
The frequency of lymph node involvement in ovarian cancer is
seen as follows (17).
Stage Percentage of cases
Stage I/II disease 5–20%
Stage III disease 30–40%
Stage IV disease >50%
FIGO system is based on a formal staging laparotomy which has
specified parameters for sampling high risk areas such as the
omentum and peritoneal reflections. The FIGO system of staging
is based on the concept that ovarian cancer spreads first to sites
within the pelvis and then to the peritoneal cavity, only metasta-
sizing outside the peritoneal cavity in advanced disease. The
staging of all histological types of ovarian cancer follows this
system. The TNM classification (Table 21.3) for ovarian cancer
has also been defined and is based on the FIGO system (19).
The regional lymph nodes for ovarian cancer are defined as
follows:
• Hypogastric (obturator) nodes
• Common iliac nodes
• External iliac nodes
• Lateral iliac nodes
• Para-aortic nodes
• Inguinal nodes
PROGNOSIS
The 10-year relative survival rate for all stages combined is 38%
for ovarian cancer in the United States (2). Overall, the one- and
five-year relative survival of ovarian cancer patients is 75% and
45%, respectively. Relative survival varies by age: 56% of women
younger than 65 years survive five years following diagnosis; only
29% of women aged 65 years and older do (2).

Hematogenous spread occurs late during the course of disease

and less than 1% of patients with epithelial cancers have paren- Table 21.3 FIGO and TNM Classification for Ovarian Cancer
chymal liver metastases at presentation. However, the liver is a
FIGO stage TNM stage Extent of disease
common site of hematogenous spread. Other sites of meta-
static spread in the terminal stages include the lungs, pleura, I T1 Tumor limited to ovaries
IA T1a Tumor limited to one ovary; capsule intact, no
and bone. tumor on ovarian surface; no malignant cells
Although the majority of ovarian cancers spread according to in ascites or peritoneal washings
the patterns described above, some tumors have a predilection for IB T1b Tumor limited to both ovaries; capsule intact, no
a particular route. For example, dysgerminomas spread to lymph tumor on ovarian surface; no malignant cells
nodes more frequently than epithelial tumors but hematogenous in ascites or peritoneal washings
IC T1c Tumor limited to one or both ovaries with any
spread is uncommon. The more aggressive yolk sac tumors, embry- of the following; capsule ruptured, tumor on
onal tumors, and choriocarcinomas predominantly metastasize ovarian surface; malignant cells in ascites or
by the hematogenous route. peritoneal washings
Ovarian cancers are bilateral in up to 50% of patients but, in II T2 Tumor involves one or both ovaries with pelvic
about half of these patients, involvement of both ovaries prob- extension
IIA T2a Extension and/or implants on the uterus and/or
ably represents extra-ovarian spread from the initial tumor.
tube(s); no malignant cells in ascites or
Thus, in about 25% of cases, ovarian cancer is presumed to be peritoneal washings
metastastic. IIB T2b Extension to other pelvic tissue; no malignant
cells in ascites or peritoneal washings
IIC T2c Pelvic extension (IIa or IIb); malignant cells in
Key Point: Tumor Spread ascites or peritoneal washings
III T3 ± N1 Tumor involves one or both ovaries with
■ Ovarian cancer spreads directly into adjacent tissues, by microscopically confirmed peritoneal
the transcoelomic route and by lymphatic and hematogenous metastases outside the pelvis and/or regional
pathways lymph node metastasis
IIIA T3a Microscopic peritoneal metastasis beyond pelvis
IIIB T3b Macroscopic peritoneal metastasis beyond pelvis
2 cm or less in greatest dimension
STAGING (TABLE 21.3 AND FIG. 21.4) IIIC T3c ± N1 Peritoneal metastasis beyond pelvis more than
2 cm in greatest dimension and/or regional
The staging system used for ovarian cancer is that of the Interna- lymph node metastasis
IV M1 Distant metastasis (excludes peritoneal metastasis)
tional Federation of Gynecology and Obstetrics (FIGO) (18). The

402
 ovarian cancer

IA IB IC
T1a T1b T1c

Malignant cells
in ascites

IIA IIB IIC

T2a T2b T2c

Rectum

Aorta Aorta

Malignant cells
in ascites

III III IV
T3 T3 M1
IIIA/3a
microscopic only
IIIC/3c
peritoneal
metastases IIIB/3b
<2 cm macroscopic
peritoneal
metastases
≤2 cm

Parenchymal

Liver capsule

(A)
Figure 21.4 (A) Staging ovarian cancer—primary tumor and metastases (FIGO and TNM systems). (Continued)

403
 primary tumor evaluation and staging
Initial spread
NI
(B)
Figure 21.4 (Continued) (B) Staging ovarian cancer—lymph nodes (N) (TNM
system).
The stage of disease at the time of diagnosis carries important
prognostic significance. Women diagnosed with localized stage
disease have a five-year survival rate of 92% but only about a fifth
of all cases are detected at this stage. In those women with regional
and distant disease, five-year survival rates are 71% and 30%,
respectively (2). Although 60% to 70% of patients with malignant
epithelial tumors present with Stage III or IV disease, the stage
distribution of borderline and the other non-epithelial cancers is
different with most cancers presenting at an earlier stage.
The histological cell type of an epithelial cancer is not a prognostic
indicator but mucinous and endometrioid tumors are often associ-
ated with an earlier stage of disease at diagnosis and lower grade of
malignancy than serous cyst adenocarcinomas. The other main
prognostic factor in epithelial ovarian cancer is the extent of residual
disease after primary surgery. Multiple studies have demonstrated
that the amount of residual tumor after cytoreductive surgery cor-
relates inversely with progression-free and overall survival (20). The
median survival can be approximately doubled from 17 months to
39 months when cytoreductive efforts are successful (20).
Prognostic factors in malignant germ cell tumors are FIGO
stage, residual disease, histologic type, and elevation of serum tumor
markers (21,22). Advanced FIGO stage and non-dysgerminoma/
immature teratoma histology were associated with a significantly
increased risk of treatment failure. Non-dysgerminoma/immature
histology and bulky residual disease after salvage surgery were
significantly associated with a worse overall survival (21,22).
In granulosa cell tumors, patients with advanced disease have a
poorer survival rate. The five-year survival rate for patients with
stage I granulosa cell tumor is greater than 90%; with stage II this
drops to 55% to 75%, and in stage IV disease the rate is between
22% and 50% (23). Age less than 40 years, tumor size greater than
404
10 to 15 cm, high mitotic index, and tumor rupture before surgery
may confer a worse prognosis but the data are conflicting (23).
Key Points: Prognosis
■ The stage of disease at diagnosis carries important prognostic
significance
■ The histological cell type of an epithelial cancer is not in itself
a prognostic indicator
■ The extent of residual disease following primary surgery for
epithelial cancers carries important prognostic significance
TREATMENT
Surgery forms the cornerstone of the treatment options in the man-
agement of all types of ovarian cancer. Surgical exploration allows
• Confirmation of the histological diagnosis
• The spread of disease to be documented and the disease
to be staged
• Removal of all tumor if possible
Surgery may be followed by further adjuvant therapy usually with
chemotherapy depending on the surgical findings.
Epithelial Cancers
Surgery
The aim of surgery in the treatment of ovarian cancer is the removal
of all macroscopic tumor. In patients with Stage I and early Stage II
disease this is usually possible but in those with Stage III and IV
disease, surgical resection is frequently complex and in most cases
some macroscopic residual tumor is left behind. In addition, micro-
scopic deposits which cannot be resected are likely to be present.
The pattern of spread in ovarian cancer is such that surgical staging
remains the key for determining optimum further management.
Thus the role of surgery in ovarian cancer is two-fold:
• Removal of all tumor where possible. This may be cura-
tive in early stage disease
• Surgical staging of abdomino-pelvic disease
Surgical staging of ovarian cancer includes the following procedures:
• Cytology of ascites and peritoneal washings
• Careful exploration of all abdominal structures and
surfaces
• Total abdominal hysterectomy with bilateral salpingo-
oophorectomy (TAH/BSO)
• Infracolic omentectomy, with or without an appen-
dectomy
• Selective pelvic and aortic lymph node sampling
• Selective biopsies of the pelvis and abdominal peritoneum
and diaphragm
Primary surgical cytoreduction is a key component of the manage-
ment of advanced ovarian cancer and optimal tumor reduction
surgery is loosely defined as the largest residual tumor diameter
being less than 1 cm but preferably even less than 0.5 cm in maxi-
mum diameter. Several studies have shown a direct relationship
between the amount of residual tumor remaining and clinical
outcome, larger volume residua being associated with a poorer
 ovarian cancer
prognosis (20,24–27). If more than 2 cm of residual tumor is left
after the operation, cytoreduction is deemed suboptimal and
irrespective of the tumor bulk prior to surgery the outcome
is poor. Patients who have required bowel surgery as part of
cytoreduction have a particularly poor outlook (28,29).
Surgery may also be performed in a number of other clinical
settings in women with ovarian cancer (20):
• In patients not suitable for optimal primary surgical
cytoreduction, delayed primary surgery may be per-
formed following neoadjuvant chemotherapy
• Women who have initial suboptimal cytoreduction,
because the ovarian cancer was not suspected prior to
the initial operation or the initial operation was per-
formed by a non-gynecological surgeon, may undergo
secondary debulking surgery. This operation is usually
performed following some chemotherapy after the initial
suboptimal cytoreduction
• The term interval debulking surgery has been used to
refer to both delayed primary surgery and secondary
debulking surgery
• Second-look laparotomy refers to surgical re-evaluation
after primary cytoreductive surgery and adjuvant chemo-
therapy. This procedure was initially used to verify disease
status and establish an end-point for chemotherapy treat-
ment. In assessing the overall value of second-look laparo-
tomy, no survival benefit has been demonstrated and the
procedure has therefore largely been abandoned (20,30)
• Secondary cytoreductive surgery is a subsequent surgical
debulking after primary treatment and a treatment-free
interval. In this setting of recurrent disease the standard
management remains poorly defined, particularly the
role of surgery. Some studies suggest that the longer
the progression-free interval after primary treatment,
the less residual disease the patient had following pri-
mary surgery, and the better the patient’s performance
status, the more likely that the patient will benefit from
secondary cytoreductive surgery (20)
Chemotherapy
Ovarian cancer is chemosensitive and most patients with ovarian
cancer undergo some form of treatment with chemotherapy. Platinum-
based agents (cisplatin and carboplatin) are the most important
chemotherapeutic agents. In early stage ovarian cancer following
surgery a meta-analysis of five trials of adjuvant chemotherapy
compared with no further treatment showed an improvement in
both overall survival and disease-free survival (31). In advanced
ovarian cancer improved survival has been reported when pacli-
taxel is used combined with a platinum agent (32,33). However, a
larger study, ICON3, showed no difference in outcome with combi-
nation therapy (34). The current recommendations are that women
requiring chemotherapy should have a platinum agent adminis-
tered and the possible addition of paclitaxel should be discussed on
an individual basis (35).
In recurrent ovarian cancer there are many chemotherapeutic
options available with overall response rates of 15% to 30% and
median response duration of six to eight months (36). The interval
between completion of first-line treatment and relapse is strongly
predictive of subsequent response and survival. Disease which
develops within six months from the end of treatment would be
deemed resistant to that therapy and further treatment needs to be
individualized. In those patients with relapses occurring after six
months, further responses to platinum can be anticipated. A recent
randomized controlled study (ICON4) showed that in relapsed
disease (occurring at least six months after previous treatment)
the combination of carboplatin and paclitaxel afforded a better
survival when compared to single agent carboplatin (37).
Radiotherapy
The role of radiotherapy has a very limited role in the management
of ovarian epithelial cancer. It may be helpful in the palliative
setting for symptom relief.
Germ Cell Tumors
Unlike other ovarian tumors, malignant germ cell neoplasms can be
cured with chemotherapy and limited surgery. Unilateral salpingo-
ophorectomy may be performed in the majority of patients, there-
fore preserving future fertility. The primary treatment following
surgery is chemotherapy, which is given in most cases with the
possible exception of Stage I (Grade 1) lesions. As in epithelial cancers,
first-line chemotherapy is a platinum-based regimen (38).
Sex Cord Tumors
In most cases, tumors of stromal origin (thecomas, fibromas) and
Sertoli–Leydig cell tumors follow a relatively benign course and
surgery alone is adequate treatment (23). Postoperative adjunctive
platinum-based chemotherapy is sometimes given to patients
with Sertoli–Leydig cell tumors with poor differentiation.
Key Points: Treatment
■ The role of primary surgery in ovarian cancer is two-fold: (i)
for staging purposes, (ii) for therapeutic purposes
■ The aim of primary cytoreductive surgery is to remove all
visible tumor and is only considered optimum if tumor less
than 1 cm in diameter remains
■ Chemotherapy is used in the vast majority of patients with
epithelial cancers following primary surgery
■ Where optimal primary cytoreduction is not feasible neoad-
juvant chemotherapy may be followed by delayed primary
surgery
■ Most patients with ovarian germ cell tumor can be cured
with chemotherapy and limited surgery
SCREENING
The overall poor outcome of ovarian cancer is mainly related to
the delayed presentation and, therefore, earlier diagnosis of ovar-
ian cancer is likely to be one of the most effective ways of improv-
ing prognosis. Ovarian cancer can be detected in asymptomatic
women using a variety of screening tests (39,40). Early diagnosis
by pelvic examination, biochemical, morphological, vascular, and
cytological tumor markers have all been explored (40–43). How-
ever, two screening strategies have emerged as promising (44); one
ultrasound-based with transvaginal scanning as the primary test,
and the other based on measurements of serum tumor marker
405
 primary tumor evaluation and staging
Clinical assessment, CA-125 assay, US
Adnexal mass + ascites Adnexal mass
appears malignant
Staging CT Staging CT
Surgery not possible
Surgery appropriate
or inappropriate
Image guided core biopsy
Figure 21.5 Imaging pathway for a suspected ovarian cancer. Abbreviations: CT, computed tomography; MR, magnetic resonance; US, ultrasound.
CA125 as the primary test and ultrasound as the secondary test
(multimodal screening).
The aim of ultrasound is to detect the earliest possible architec-
tural changes in the ovary that accompany carcinogenesis. Most
screening protocols use a scoring system based on ovarian vol-
ume, outline, presence of papillary projections, and cyst complex-
ity. Serum CA-125 is the tumor maker most extensively studied in
ovarian cancer screening. CA-125 can be elevated in the preclini-
cal asymptomatic phase of the disease. CA-125 alone is a poor
indicator of ovarian cancer since it is elevated in less than 50% of
patients with Stage 1 disease (13). However, combined with the
patient’s age, the CA-125 profile with time and pelvic ultrasound,
the sensitivity has been reported as 79% to 100% (45,46).
Several large prospective studies of screening for ovarian cancer
in the general population have been performed (44). However,
there is a need for a randomized control trail to establish the impact
of screening on mortality as well as issues of target population,
health, economic, and psychological morbidity. Currently, there
are two large randomized control trials of ovarian cancer screening
in the general population: the U.K. Collaborative Trial of Ovarian
Cancer screening (UKCTOCS) and, in the United States, the
National Institute of Health’s prostate, lung, colon, and ovary (NIH
PLCO) study (44,47,48). The UKCTOCS is a three-armed ran-
domized controlled trial screening 200,000 postmenopausal
women aged 50 to 74 years, randomized in a 1:1:2 ratio to ultra-
sound screening, multimodal screening, and a control group who
will not be screened. The primary end-point of this study is ovar-
ian cancer mortality at seven years after randomization. The trial
has a 90% power to detect a 30% reduction in ovarian cancer mor-
tality in the screened group compared with the control group.
Ovarian cancer screening in high-risk population is frequently
advocated although the efficacy of this is unknown (44). Screen-
ing can be problematic as this population often includes pre-
menopausal women who have a higher incidence of false positive
CA-125 results and ultrasound abnormalities. Currently, 5000
women aged over 35 with a significant family history of ovarian
cancer are being invited to participate in U.K. Familial Ovarian
Cancer Screening Study (UKFOCSS), assessing the utility of
annual screening with CA-125 measurement and ultrasound.
Key Point: Screening
■ The role for screening in ovarian cancer remains to be defined and
data from a large randomized controlled trial is currently awaited
406
Indeterminate mass Adnexal mass
appears benign
MR imaging Remove if symptomatic or
follow up with US
IMAGING OF OVARIAN CANCER
The Purpose of Imaging
Imaging is used along all parts of the patient pathway in ovarian
cancer:
• At initial diagnosis
• In staging prior to cytoreductive surgery or neoadjuvant
chemotherapy
• Following cytoreductive surgery and prior to chemo-
therapy
• Assessing response during chemotherapy including
patients being considered for debulking surgery
• Suspected relapse
• Assess complication of disease or its treatment
Figure 21.5 shows the pathway for imaging for the initial diagnosis
and staging in ovarian cancer patient (49).
Diagnosis/Characterization of a Pelvic Mass
Adnexal masses are a common clinical problem, with an estimated
5% to 10% of women undergoing surgery for a suspected adnexal
mass, but in only 13% to 21% of these women will the mass prove to
be malignant (30). The accurate evaluation of such lesions is impor-
tant as it affects subspecialty referral and surgical decisions. Benign
disease can be managed conservatively or operated with a “simple”
excision of the mass. For malignant disease radical surgery is required,
that is, a staging laparotomy (see Treatment Epithelial Cancer Sur-
gery, pg. 407) in addition to optimal debulking. This is best per-
formed by a surgeon specialized in gynecological oncology as the
outcomes of surgery for ovarian cancer performed by a specialist
gynecologic oncologist are better than by a non-oncological surgeon
(50,51). As referral to a cancer center and a gynecologic oncologist is
not possible or appropriate for every adnexal mass lesion, it is
important to identify masses that are likely to be malignant.
Clinical and imaging assessment plays an important role in the
management of such patients. Imaging has a valuable role in
determining the presence of a mass, its organ of origin, and can
provide information on the character of the mass and the like-
lihood of it being benign or malignant. Ultrasound (abdominal,
transvaginal, Doppler), CT, MRI, and radionuclide imaging may
all be used in this way. Of these, transvaginal ultrasound (TVS)
and Doppler techniques are preferred as the initial investigation
with MRI indicated in certain circumstances. TVS ultrasound has
 ovarian cancer
the advantage of being highly sensitive for malignancy, relatively
quick, widely available, relatively inexpensive, and does not use
ionizing radiation; an important factor when investigating young
female patients many of whom will have benign lesions.
Ultrasound
Sonographic evaluation of pelvic masses can be performed via
a transabdominal (TAS) or transvaginal (TVS) approach. The
morphologic information may be further supplemented with
Doppler studies. Transvaginal ultrasound is a sensitive method
of detecting ovarian masses and is probably the best method of
detecting small tumors (52). It provides additional diagnostic
information in 70% of cases and has a higher specificity in the
diagnosis of ovarian cancer than transabdominal ultrasound
(53,54).
A unilocular simple cystic mass less than 5 cm in maximum
diameter with a thin wall is likely to be benign and such lesions
can be followed with imaging (55,56). Multilocular cysts may be
benign or malignant. Malignant lesions range from entirely cystic
masses to homogenous solid masses (57). The morphological
features which suggest malignancy on ultrasound include:
• Vegetation on the cyst wall which appears as soft tissue
thickening or excrescences into the cyst lumen
• Irregular thickening of the wall
• Ovarian cystic mass >10 cm in diameter
• Partly cystic, partly solid mass
• Homogenous solid mass
• Presence of ascites
• Presence of peritoneal nodules (53,58)
The sensitivity of morphological analysis with ultrasound in
predicting malignancy has been reported to be very high at 85%
to 97%, whereas the specificity which ranges from 56% to 95%
tends to be lower due to the overlap between the appearance of
benign and malignant lesions (59–63).
Doppler ultrasound studies provide useful information on
tumor vascularity (64). Color Doppler US helps identify vascular-
ized tissue and can assist in differentiating solid tumor from non-
vascularized structures. It can be used in conjunction with pulsed
Doppler US to identify vessels for waveform analysis. Benign
lesions tend to initiate new tumor vessel peripherally from pre-
existing host vessels whereas malignant tumors tend to initiate
new tumor vessels centrally (63,65,66). In analyzing the waveform,
the pulsatility and resistive index increase with increasing distal
vascular resistance. A resistive index (RI) less than 0.4 to 0.8 and a
pulsatility index (PI) of less than 1 are indicative of a malignant
lesion (63,67–72). In distinguishing benign from malignant
masses Doppler US has yielded variable results with sensitivity
of 50% to 100% and a specificity of 46% to 100% (59,60,62,63,
69,73,74). The differing results are in part due to the varying
thresholds used in different studies.
The limitations of Doppler US include operator-dependence
and lack of standard criteria in distinguishing benign from
malignant waveform. Some common benign conditions such
as acute inflammatory adnexal disease and endometriosis may
be associated with malignant waveform and Doppler indices
(75). In premenopausal women Doppler indices have a lower
specificity due to physiologic alteration in the ovary due to
the menstrual cycle. The spectral waveform in malignancy is
similar to that of the follicle in the periovulatory period of the
menstrual cycle or due to a persistent corpus luteum. Recogni-
tion of this feature has resulted in the recommendation that
ovarian Doppler studies in premenopausal patients should
only be carried out between the third and eleventh day of the
menstrual cycle.
The use of a combination of morphological analysis and
Doppler US may overcome some of these problems. Sensitivity and
specificity in the 90% have been reported with such a combined
approach (59,62,63,75,76).
Key Points: Characterization of Masses—Ultrasound
■ Ultrasound is a useful method for characterizing pelvic
masses and determining an ovarian origin
■ Several characteristic features on ultrasound may suggest
malignancy but there is considerable overlap between the
appearances of benign and malignant lesions
■ Transvaginal ultrasound is probably the best method for
detecting small ovarian tumors
■ Color-flow Doppler ultrasound provides useful informa-
tion on tumor vascularity and may be helpful in distin-
guishing benign from malignant neoplasms
Magnetic Resonance Imaging
Magnetic resonance imaging (MRI) offers potential benefits in
the investigation of ovarian neoplasms because of its superior
contrast resolution and ionizing radiation is not utilized.
For characterization of adnexal masses, images should be
obtained in at least two planes. Both T1- and T2-weighted images
are important for pelvic anatomy and tissue characterization. The
use of small field-of-view high-resolution images improves the
delineation of small structures such as papillary projections.
Fat-suppressed T1-weighted images help distinguish fatty
from hemorrhagic masses. Gadolinium-enhanced fat-suppressed
T1-weighted images improves lesion characterization by increasing
the conspicuousness of nodules and septa in complex adnexal
masses (77–80). Contrast-enhanced scans also improve detection
of peritoneal and omental implants.
Several types of tissue and fluid can be distinguished at
MRI from their signal intensity characteristics. The signal
intensities of an individual tumor depend upon the presence,
type, and extent of solid tumor, and cystic components of the
mass. The soft tissue components are of intermediate or low sig-
nal intensity on T2- weighted images (Fig. 21.6). Tumors with
predominantly smooth muscle or fibrotic component, such as
fibroma, fibrothecoma, cystadenofibroma, Brenner tumor, and
leiomyoma, have low to intermediate signal on T2-weighted
sequences (81,82). Predominantly or uniformly low signal inten-
sity on T2-weighted sequences within a lesion is, therefore, a
feature of benign tumors (83). The signal intensity of the cystic
component of an ovarian neoplasm may vary depending upon
protein content; such variations in signal intensity are commonly
seen in mucinous tumors and cystic lesions containing hemor-
rhage and cellular debris (Figs. 21.7 and 21.8). Fat, hemorrhage,
and some high viscosity mucin-containing lesions have high
signal on T1-weighted images (Figs. 21.7–21.9).
407
 primary tumor evaluation and staging

(A) (B)
Figure 21.6 Carcinoma of the ovary in association with the separate primary carcinoma of the cervix. (A) T2-weighted sagittal image and (B) axial MR image show a
large, well-defined mass lying above the uterus. The central high signal intensity seen on both sequences was due to necrosis within the predominantly solid mass. On
the sagittal scan, a separate carcinoma of the cervix is demonstrated (arrowed).

(A) (B)
Figure 21.7 A 48-year-old women with an endometrioma. (A) Axial T1- and (B) T2-weighted scans shows a well defined thick walled mass (arrow) lying anterior to
the bladder. The central component of this is of high signal on T1- and of low signal on T2-weighted scans. This finding on this combination of sequences is typical of
the appearance of the altered products of blood.

(A) (B)
Figure 21.8 A 50-year-old woman with an ovarian carcinoma. (A) T1-weighted spin-echo, and (B) T2-weighted fast spin-echo scans show bilateral solid cystic mass. The
cystic components show varying signal intensities. Small amount of ascites is also present.

408
 ovarian cancer

(A) (B)

(C) (D)
Figure 21.9 Benign cystic teratoma which appears suspicious for malignancy on ultrasound but has a characteristic benign MR appearance. (A) Transabdominal ultra-
sound shows a heterogeneous predominantly solid mass. Axial (B) T1-weighted, (C) T2-weighted, and (D) contrast-enhanced fat-suppressed T1-weighted image show
a mass (arrow) anterior to the bladder. The mass contains material of high signal intensity on both the T1- and T2-weighted scans which shows loss of signal on the fat
saturated image.

MRI has an overall accuracy of 60% to 93% in distinguishing a
benign from a malignant lesion. As with US and CT, MRI relies on
similar morphological features to identify lesions as malignant.
Analysis of the imaging features has shown that the characteristics
most predictive of malignancy are vegetation in a cystic lesion,
presence of ascites, maximal diameter greater than 6 cm, and
necrosis in a solid lesion (Figs. 21.6 and 21.10) (83,84). Studies
that have directly compared US and MRI have shown that contrast-
enhanced MRI is superior to US in characterizing adnexal mass
lesions (85–88). Both techniques are highly sensitive but MR
imaging is more specific than ultrasound at identifying malignant
masses. The greater specificity of MRI is due to its ability to char-
acterize dermoid (Fig. 21.9), endometrotic cysts (Fig. 21.7), and
fibroids which may appear malignant on US, particularly when
pedunculated (88).
A recent meta-analysis evaluated the performance of com-
bined gray-scale and Doppler US, CT, and non-enhanced or
contrast material-enhanced MR imaging after initial gray-
scale US with indeterminate results. This showed that in
women with an indeterminate ovarian mass at gray-scale US,
MR imaging findings contributed to a change in probability
of ovarian cancer in both pre- and postmenopausal women
more than did CT or combined gray-scale and Doppler US
results (89).
Key Points: Characterization of Masses—MRI
■ MRI shows the internal characteristics of an ovarian mass on
T2-weighting
■ Fat-suppressed contrast-enhanced images improve lesion
characterization
■ MRI and US are both highly sensitive for characterization of
malignancy, but MRI has greater specificity than US
■ If a lesion is indeterminate on grayscale sonography,
contrast-enhanced MRI is the best test to perform
Computed Tomography
CT relies on the same morphological features as ultrasound to
characterize andexal lesions: findings suggestive of malignancy
include solid masses and partially solid/cystic masses, as well
as the presence of papillary projections into a cystic lesion
(Figs. 21.11–21.14) (90). Ascites and lymphadenopathy in the
retroperitoneum or pelvis also indicates the presence of malignancy.

409
 primary tumor evaluation and staging
(A)
Figure 21.10 Ovarian endometroid cancer associated with uterine endometrial cancer. Sagittal (A) T2- and (B) contrast-enhanced fat-suppressed T1-weighted images
show behind the uterus a large heterogeneous mass with areas of necrosis. The endometrial cavity is distended and contains a focal mass that was an endometrial
cancer.
Figure 21.11 Primary serous adenocarcinoma of the ovary. Post-contrast CT scan
showing a large septate cystic mass in the right iliac fossa. The mass also contains a
soft tissue nodule in its right lateral aspect (arrowed).
Contrast enhancement is variable and is seen in septae, cyst
walls, and solid components. CT has an accuracy in the detec-
tion of ovarian masses of up to 95% and in distinguishing benign
from malignant lesions of between 66% and 94% (91). MRI is
therefore preferred to CT in the presence of an equivocal ultra-
sound or where ultrasound findings suggest a neoplasm but the
patient is young and the CA 125 is not elevated (88,89,92).
Key Point: Characterization of Masses—CT
■ CT may show features characteristic of malignancy but there
is considerable overlap in CT findings between benign and
malignant lesions
410
(B)
Radionuclide Imaging
Positron Emission Tomography (PET)
Imaging with FDG-PET has been used to characterize pelvic mass
lesions. On FDG-PET most malignant ovarian tumors show
increased glucose metabolism and are visualized as increased
uptake once lesions have reached a critical tumor cell mass. How-
ever, early carcinomas and particularly borderline tumors may
lack the typical pattern of glucose uptake as a result of the small
amount of transformed tissue. The sensitivity and specificity of
FDG-PET in the detection of ovarian carcinomas are 58% to 86%
and 54% to 86%, respectively (87,93).
Radioimmunoscintigraphy
Radioimmunoscintigraphy (RIS) uses radiolabelled monoclonal
antibody directed against tumor-specific antigen for imaging (94).
A potential role for radioimmunoscintigraphy may lie in the char-
acterization of complex or indeterminate pelvic mass. A recent
study comparing ultrasound, MR imaging, and radioimmunoscin-
tigraphy found the sensitivity and specificity were 98% and 52% for
US, 93% and 84% for MRI, and 85% and 86% for RIS (92).
Key Points: Characterization of Masses—
Radionuclide Imaging
■ Early carcinoma and borderline tumors lack uptake of
FDG-PET
■ Radioimmunoscintigaphy lack sensitivity for the detection of
ovarian malignancy
Role of Imaging in the Characterization
of Pelvic Masses
In practice, ultrasound and Doppler techniques are performed
as the initial investigation for a clinically suspected adnexal
mass. No other imaging is required if the mass has features
clearly indicating it is benign or if the ultrasound findings,
 ovarian cancer

(A) (B)

(C)
Figure 21.12 Primary carcinoma of the ovary. (A) A mixed solid and cystic mass showing a typical appearance of multiple soft tissue nodules and masses (arrowed)
within a predominantly cystic lesion. Ascites is also seen within the right and left iliac fossa. Peritoneal masses are also noted in the left iliac fossa (curved arrow). There
is also internal and external iliac lymph node enlargement. (B) Abdominal CT scan in the same patient as (A) showing ascites and left para-aortic lymph node enlarge-
ment. (C) CT scan in the same patient showing mesenteric infiltration with mesenteric nodal enlargement. Abbreviations: u, uterus.

(A) (B)
Figure 21.13 Predominantly solid primary carcinoma of the ovary. (A) Post-contrast CT scan shows a predominantly solid mass. (B) CT scan taken slightly superior to
(A) shows superior aspect of the mass encasing a loop of bowel (arrowed) resulting in bowel obstruction.

411
 primary tumor evaluation and staging
(A)
Figure 21.14 CT scan of nine-year-old child with a carcinoma of the ovary (small cell). (A) There is a large, contrast-enhanced mass lying centrally in the pelvis behind
the bladder. The mass contains a relatively low density center probably representing necrosis/cystic change. It has an ill-defined contour anteriorly suggesting local spread.
(B) There is a large para-aortic lymph node mass which also shows contrast enhancement and a low density center. Note hydronephrosis on the left.
together with tumor marker and clinical findings, strongly indi-
cate malignancy. However, if the ultrasound features are equivo-
cal or suspicious for malignancy but the patient is young or the
CA-125 is normal or minimally elevated, then the patient needs
further evaluation in order to decide subspecialty referral. In
such cases a risk of malignancy index (RMI) scoring can be used
to predict the likelihood of a mass being malignant. The RMI
combines the results of transvaginal ultrasound examination
(U), menopausal status (M), and blood levels of the ovarian can-
cer marker CA125 (measured in U/ml). All RMI use the basic
formula: RMI = U × M × CA125, but differ in the scores that are
assigned to U and M. It has been shown that using a cut-off
value for the RMI of 200 (regardless of scoring system) achieves
sensitivities ranging from 70% to 87% and specificities ranging
from 89% to 97% (95–98).
The RM index is widely used in the United Kingdom in selec-
tive referral of women from local cancer units to specialized
cancer centers. A RMI score of less than 25 has a 3% chance
of malignancy and a RMI greater than 250 has a 75% chance of
malignancy. In a prospective study we investigated the value of
further specialist imaging in 196 women referred to a teaching
hospital with an adnexal mass with RMI values of 25 to 1000 (3).
Sensitivity and specificity for specialist US were 100% and 57%,
for MRI 92% and 86%, respectively. Analysis of 123 patients
with RMI of between 25 and 1000 managed sequentially with US
and MRI provided a sensitivity of 94% and a specificity of 90%.
We concluded that rather than using the traditional RMI thresh-
old value of 250 to refer to a cancer center; for patients with an
RMI of between 25 and 1000 imaging by specialist US and MR,
imaging can increase the proportion of patients with cancer
appropriately referred to a cancer center with no change in the
proportion of patients with benign disease being managed in a
local unit (92).
Specific Diagnosis
The primary role for radiological imaging of an adnexal mass is to
characterize the mass and distinguish whether it is benign or
412
(B)
malignant. The diverse histological types of ovarian cancer combined
with the fact that many tumors show mixed cell types results in a
wide range of appearances. Although definite diagnosis of the dif-
ferent ovarian masses cannot be made with imaging, certain fea-
tures may suggest a particular pathology.
Cyst adenocarcinomas are usually large multilocular masses
that contain soft tissue projections extending into the cystic spaces.
The cystic spaces themselves may contain echogenic material on
ultrasound.
Endometrioid tumors and clear cell carcinomas have a variable
appearance on imaging ranging from entirely cystic masses to
complex masses with solid and cystic components.
Brenner tumors are solid masses, which are usually benign.
They frequently appear as hypoechoic lesions on ultrasound, may
contain calcifications, and are sometimes indistinguishable from
uterine fibroids on ultrasound.
Ovarian cystic teratomas have characteristic features on ultra-
sound, CT, and MRI often permitting definitive diagnosis on
imaging. The classic features of ultrasound include a cystic mass
containing a central echogenic focus and a fat fluid level may
occasionally be identified. Calcification is best shown on CT and
the fatty component of the tumor is elegantly shown both on CT
and MRI.
Dysgerminomas are malignant and usually appear on ultra-
sound as solid masses but may contain small cystic areas as well as
areas of hemorrhage and necrosis. On CT and MRI these tumors
appear as soft tissue masses, occasionally showing areas of high or
low density/signal intensity due to fresh blood, the breakdown prod-
ucts of hemoglobin, and fluid (Figs. 21.15 and 21.16). The appear-
ances of yolk sac tumors are similar to those of dysgerminomas
on imaging.
Granulosa cell tumors, Sertoli–Leydig cell tumors, thecomas,
and fibromas have variable features on imaging and may therefore
appear as small solid masses on imaging or as large multilocular
cystic lesions similar to cyst adenocarcinomas.
Metastases to the ovary may be solid, partially solid, and cystic,
or rarely as a multiloculated cystic lesion on ultrasound, CT, and
 ovarian cancer

(A) (B)

(C)
Figure 21.15 CT scans in a 30-year-old patient with a dysgerminoma of the ovary. (A) The primary tumor (t) is solid/cystic. It occupies the pelvis centrally, lying between
the cervix/vaginal vault (c) and the rectum which is compressed. (B) There is a large metastatic retroperitoneal lymph node mass which is also partly cystic and partly
solid. Flecks of calcification are noted within the mass. Note a liver metastasis arising on the tip of the right lobe of the liver. There is ascites and peritoneal thickening.
(C) The liver is grossly enlarged and contains multiple metastases. The largest lesion contains calcification.

MRI (Fig. 21.17). They are usually bilateral but on imaging alone
they may be indistinguishable from primary ovarian tumors.
Preoperative Assessment of Disease Extent
Once a clinical/imaging diagnosis of ovarian malignancy has been
made further pathological confirmation should be obtained. This
is especially important if the patient is to go on to chemotherapy
prior to any surgery. Occasionally benign pathology such as
tuberculosis or other malignancy such as lymphoma may mimic
ovarian cancer with elevated CA-125, pelvic masses and perito-
neal disease. Image-guided biopsy of the omentum or pelvic mass
or ascites aspiration for cytology can be performed either under
CT or ultrasound guidance. If imaging-guided biopsy is not pos-
sible, then pathological diagnosis may need to be obtained at a
staging laparotomy or at laparoscopy for a patient not suitable for
laparotomy.
Image-Guided Biopsy
Image-guided biopsy is emerging as a new tool in the manage-
ment of ovarian cancer (99). Historically, patients with suspected
ovarian cancer underwent surgery without prior histological
confirmation. This is still valid for the majority of patients
presenting with typical clinical, imaging, and biochemical find-
ings. However, this patient pathway may be modified in selected
cases and, based on a multidisciplinary consensus, patients can
be selected who will benefit from biopsy (100). Patients whose
treatment may be radically altered are those found to have peri-
toneal metastases from non-ovarian primaries including breast
cancer, gastrointestinal tract malignancies, uterus, and rarely
lymphoma.
Image-guided biopsy can provide a rapid diagnosis allowing
administration of chemotherapy when a patient is unfit for surgery
or considered to have more extensive tumor than can be optimally
debulked. If there is a history of a cancer that might metastasize
in a pattern similar to ovarian cancer or the clinico-radiological
pattern is not clear, biopsy is essential. For women found to have
alternative diagnoses there is a significant impact on patient
management as these will undergo chemotherapy instead of
surgery.
Biopsies are usually taken from omental metastases, the
paracolic gutters, or other mass-like peritoneal implants
under image guidance with 18-gauge core needles (99,101). It

413
 primary tumor evaluation and staging

(A) (B)

(C)
Figure 21.16 A 23-year-old patient with a left dysgerminoma of the ovary. (A) Contrast-enhanced CT scan. (B) T1-weighted MR image. (C) Contrast-enhanced
T1-weighted MR image. On contrast-enhanced CT, a multiloculated ovarian cystic mass is shown. On MR the mass has low signal intensity on T1-weighting. Following
injection of intravenous contrast medium a soft tissue nodule and septae are seen within the mass.

(A) (B)
Figure 21.17 (A) and (B) Contrast-enhanced CT showing bilateral Krukenberg tumors from carcinoma of the colon. These tumors are partly cystic and partly solid.
The uterus (u) shows homogeneous contrast enhancement.

414
 ovarian cancer

is a safe procedure and renders site-specific histological diag- implants (77). With the advent of multidectector CT, high
noses using immunochemical information in more than 90% resolution multiplanar reformats in the coronal and sagittal
of cases. planes improve the anatomical analysis, especially of surface
lesions (Figs. 21.18–21.20) (102).

Key Point: Image-Guided Biopsy

■ Image-guided biopsy can provide a histological diagnosis in
patients prior to neoadjuvant chemotherapy or those unsuit-
able for primary cytoreductive surgery

Imaging in Staging
If malignancy is suspected on clinical and imaging grounds, then
radiological staging is performed prior to surgery. Surgery provides
tissue for histology and, as described above, is the gold standard for
staging and as well as being therapeutic.

Computed Tomography
Computed tomography (CT) is the most widely used imaging
technique for staging ovarian cancer. The abdomen and pelvis
should be scanned from the dome of the diaphragm to the
symphysis pubis. Bowel opacification is important for the dif-
ferentiation of bowel loops from peritoneal implants. At least
1000 ml of diluted contrast media or water is given orally one
hour prior to the CT. Rectal opacification is also helpful for
distension of the rectosigmoid. Intravenous contrast medium
is recommended routinely for evaluation of these patients Figure 21.18 Stage III ovarian cancer. Contrast-enhanced coronal reformatted CT
since it improves tumor delineation and tumor characteriza- shows disease on the surface of the liver and serosal thickening of small bowel
tion and also increases the conspicuousness of peritoneal loops.

(A) (B)
Figure 21.19 Ovarian cancer. (A and B) Contrast-enhanced coronal reformatted CT shows thick nodular disease on the right hemidiaphram surface and thick omental
cake (arrow).

415
 primary tumor evaluation and staging

(A) (B)

(C) (D)
Figure 21.20 Stage IV ovarian cancer. Contrast-enhanced CT shows (A) a pericardiac node (arrow); (B) multiple small peritoneal nodules in the left flank (oblique
arrows) and Sister Joseph nodule (arrow) at the umbilicus. Reformatted (C) coronal and (D) sagittal images shows the peritoneal nodules in the left flank the umbilical
node and the ovarian tumor in the pelvis.

As a method of staging, CT is useful for detecting tumor involve-
ment of many intra-abdominal and pelvic structures. These include:
• Small and large bowel (Figs. 21.21–21.24)
• Urinary tract
• Peritoneum and mesentery
• Liver (Figs. 21.18, 22.22, 21.25, 21.26, 21.29)
• Lymph nodes (Figs. 21.14, 21.27, and 21.28)
• Ascites and pseudomyxoma peritonii
When interpreting CT, care should be taken to assess all the
sites of potential metastatic disease since small deposits less
than 1 cm in diameter, and which are detectable on CT, can be
overlooked easily unless the areas of likely spread are carefully
scrutinized.
Imaging Patterns of Tumor Spread
Peritoneal tumor spread, the most common pathway of dissemi-
nation in ovarian cancer, is found in approximately 70% at initial
diagnosis. Although all peritoneal, parietal, and visceral surfaces
may be involved, common sites of peritoneal implants in ovarian
cancer include the greater omentum, paracolic gutters, the pouch
of Douglas, liver, diaphragmatic, and bowel surfaces. Less frequent
implants in ovarian cancer are found in the mesentery, splenic
surface, along the porta hepatis, lesser sac, and the gastrosplenic
ligament (14,103). The detection of peritoneal tumor deposits is
dependent on their location, their size, and the presence of ascites,
which increases their conspicuousness (Figs. 21.19 and 21.29)
(16,104,105). On CT, peritoneal metastases may appear as
rounded, “cake-like,” stellate, or ill-defined masses (106). These

416
 ovarian cancer

tumor deposits usually show contrast enhancement and appear as

Figure 21.21 Small bowel infiltration due to carcinoma of the ovary. A CT scan
showing diffuse thickening of the serosal surface of the small bowel in the presence
of ascites (arrowed). At surgery, there is extensive small bowel infiltration of the
serosa due to adenocarcinoma of the ovary.
soft tissue nodules along the peritoneum or the whole of the peri-
toneal surface may be thickened. CT can identify calcification in
plaque-like peritoneal metastases from serous cyst adenocarci-
noma even if there is no associated soft tissue component to
the deposit (Fig. 21.30) (107). Rarely, mixed solid and cystic or
purely cystic lesions are found. The latter may mimic loculated
fluid; however, tiny mural nodules may indicate its malignant
nature.
Omental involvement is common and is seen as a netlike pattern,
nodules of various size and omental caking under the anterior
abdominal wall or as complete replacement of the omentum by a
soft tissue tumor mass (Figs. 21.29, 21.31, and 21.32).
Bowel infiltration from ovarian cancer results from serosal involve-
ment resulting in thickening of the bowel wall (Figs. 21.21–21.23
and 21.32). Bowel surface or mesenteric implants can cause tether-
ing of loops and may lead to obstruction. This may cause intermit-
tent chronic small bowel obstruction with dilatation of small bowel

(A)

(B) (C)

Figure 21.22 Large bowel infiltration in carcinoma of the ovary. (A) There is extensive asymmetric thickening of loop of sigmoid due to infiltration by primary
carcinoma of the ovary. (B) Same patient as in (A) also showing a typical peritoneal deposit on the lateral aspect of the liver together with celiac lymph node enlarge-
ment (arrowed). (C) CT scan in the same patient showing a typical splenic deposit and a deposit in the left adrenal gland.

417
 primary tumor evaluation and staging
loops intermingled with regions of stenosis. Bowel obstruction is
more commonly seen in recurrent ovarian cancer (108).
A major limitation of CT is the inability to detect small (less
than 1 cm) peritoneal deposits reliably and a complete inability
to identify microscopic lesions. Intraperitoneal contrast media
increases the detection of peritoneal tumor implants and
smaller tumor deposits less than 5 mm in diameter can be iden-
tified, but the technique is seldom practical on a routine basis
(109). Compartmentalization of the peritoneal cavity may be
apparent and it may also be possible to determine whether the
lesion is intra- or extraperitoneal. This is useful for determin-
ing the utilization of intraperitoneal chemotherapy, which is
sometimes used in patients with advanced intraperitoneal disease.
(A detailed account of peritoneal metastatic disease is given
in chap. 46).
Figure 21.23 Small bowel obstruction due to carcinoma of the ovary. This patient
with known carcinoma of the ovary presented with symptoms of small bowel
obstruction. The CT scan showed a typical appearance of small bowel dilatation
together with ascites and peritoneal thickening.
(A)
Figure 21.24 Large bowel infiltration due to carcinoma of the ovary. (A) CT scan shows typical asymmetric encasement of a loop of a large bowel (arrowed). Extensive
peritoneal thickening is seen lying anterior to the bowel infiltration (arrowheads). (B) The corresponding appearance on the barium enema (arrowed).
418
The distinction between Stage III and IV has important con-
sequences for patient management. The commonest finding to
result in the assignment of Stage IV disease is a malignant pleu-
ral effusion. However, the radiological detection of an effusion
is not itself sufficient for Stage IV disease as the effusion must
be shown to be malignant. CT or MR can rarely distinguish
between a benign or malignant effusion unless there is pleural
thickening or nodularity. Another important distinction is the
differentiation of liver surface implants (Stage III) from true
parenchymal metastases (Stage IV). Surface implants are usu-
ally well defined, biconvex, and peripheral, and indent the liver
rather than replace the liver parenchyma. True intraparenchy-
mal implants are often ill-defined circular and partially or com-
pletely surrounded by liver tissue (see chap. 46, Fig. 46.xx).
Pelvic organ invasion by ovarian cancer may be difficult to
diagnose accurately as the mass or masses may abut adjacent
structures, for example uterine invasion is particularly difficult
to diagnose because the para-uterine fat plane may be lost with-
out necessarily inferring invasion of the uterine serosa (90).
Indeed, in patients with large ovarian masses it may be difficult
to identify the uterus, as it may be partially or completely sur-
rounded by tumor. This is a common finding in postmenopausal
women in whom the uterus is atrophied. Pelvic sidewall invasion
should be suspected when the primary tumor lies within 3 mm
of the pelvic sidewall or when the iliac vessels are surrounded or
distorted by tumor (77). Focal obliteration of the fat plane or
tumor encasement of the bladder or rectosigmoid is highly sus-
picious of involvement of these structures (110).
Much of the literature on CT in ovarian cancer relates to studies
performed before the advent of multislice or spiral CT. A more
recent study with spiral CT has demonstrated a sensitivity of 85%
to 93% and a specificity of 91% to 96% for the detection of peri-
toneal metastases greater than 1 cm (111). The improved accuracy
is likely to be due to use of thinner sections and the absence of
slice misregistration artefact on spiral CT. This trend is likely to
continue with multislice CT.
(B)
 ovarian cancer

Magnetic Resonance Imaging

Key Points: CT for Staging When MR imaging is used for staging ovarian cancer, imaging of
■ CT is the most widely used imaging technique for staging the whole abdomen and pelvis should be performed as in CT.
ovarian cancer Axial T1- and T2-weighted scans are used to cover the abdomen
■ CT is superior to ultrasound in demonstrating extra-ovarian and pelvis. Coronal sections are helpful to examine spread to the
spread liver surface, diaphragm, and pelvic sidewall involvement. Sagittal
■ CT can identify peritoneal metastases down to the size of images in the pelvis outline the relationship of the ovarian neo-
approximately 5 mm plasm to the uterus, bladder, and rectum. Contrast-enhanced
■ The detection of peritoneal deposits is dependent upon their fat-suppressed T1-weighted images are essential in staging ovarian
location and the presence of ascites cancer as it improves tumor delineation, tumor characterization,
■ Contrast enhancement increases the conspicuousness of increases the conspicuousness of peritoneal implants, and facili-
peritoneal nodules tates detection of bowel wall infiltration. Antiperistaltic agents
■ CT may also demonstrate tumor involvement of the bowel may be helpful to reduce bowel motility (e.g., glucagon 1 mg
wall, omentum, liver, and lymph nodes administered intravenously or intramuscularly). The body coil

Figure 21.25 and Figure 21.26 Liver deposits in two different patients with carcinoma of the ovary. Figure 21.25 shows a well-demarcated, irregular, lobulated mass of
inhomogeneous enhancement. Figure 21.26 shows a typical well-defined cystic lesion.

(A) (B)
Figure 21.27 Nodal enlargement in carcinoma of the ovary. (A) A large nodal mass is seen in the right para-aortic region with a smaller mass in the left para-aortic
region. There is also ascites, an omental “cake,” and extensive peritoneal thickening. The mass is also resulting in marked hydronephrosis on the left side. (B) The primary
carcinoma in the same patient with a complex central pelvic mass. Note the right obturator lymph node enlargement (arrowed).

419
 primary tumor evaluation and staging
Figure 21.28 CT scan showing paracardiac lymph node enlargement (arrowed).
Lymph node enlargement in the left perisplenic region. Note too the liver and
splenic deposits.
will suffice for imaging the pelvis but phased-array coils provide
superior signal to noise. We do not use a vaginal tampon routinely
and have not observed any difficulty in image interpretation.
Respiratory compensation techniques should be used, particularly
with the body coil and if slower scan times are utilized.
The staging features on MR imaging are similar to CT. However,
the spread of ovarian cancer into the uterus or adjacent organs
such as the sigmoid colon, bladder, and rectum may be better
appreciated on MRI than on CT (28). MRI is more limited in the
evaluation of intra-abdominal tumor spread, though peritoneal
deposits greater than 1 cm in diameter can probably be identified
with a similar sensitivity for both MRI and CT (112,113). Disease
within the mesentery or implants on the wall of the small and large
bowel are better detected by CT as are calcified deposits. An “omen-
tal tumor cake” can be identified as an infiltrating mass lying
beneath the abdominal wall and finger-like projections of tumor
may be seen spreading into the surrounding fat (Fig. 21.33). Omen-
tal disease also shows enhancement following injection of intrave-
nous contrast medium. Fat suppression sequences may also
increase the conspicuousness of enhancing peritoneal tumor
deposits and omental disease by suppressing the signal from hyper-
intense fat in the abdomen and pelvis (78). In MRI, delayed
enhancement at 3 to 10 minutes after gadolinium improves the
detection of peritoneal metastases (114). Although bowel opacifi-
cation is not routinely performed in most centers, the use of oral
contrast medium has been reported to be helpful in the detection
of peritoneal metastases (115,116). A negative contrast agent such
as supraparamagnetic iron oxide particles (e.g., Lumirem, Guerbet
Ltd.) or dilute barium sulfate (ReadiCat 2, E-Z-Em, Westbury, New
york) are preferable since the bowel contents then have a low signal
intensity on T1-weighting whereas enhancing tumor deposits have
a high signal intensity (114–116).
Despite these technical maneuvers, contrast-enhanced MRI has
a high false positive rate in the detection of peritoneal tumor
deposits due to enhancement of benign tissue such as granulation
tissue and postoperative adhesions, and also has a high false negative
rate due to the difficulty in identifying small volume disease.
420
Although MR imaging is well suited to examination of the
pelvis and characterization of pelvic mass lesion, as with CT, MR
imaging remains insensitive for detecting peritoneal, mesenteric,
and omental disease in ovarian malignancy. Currently, therefore,
the appropriate role of MRI is the characterizing of ovarian masses
rather than for abdomino-pelvic staging of proven ovarian cancer.
Key Points: MRI for Staging
■ Extra-ovarian spread of tumors into adjacent structures such
as the uterus is often better appreciated on MRI than CT
■ Contrast medium enhancement and fat suppression may
improve the detection of peritoneal nodules
■ Peritoneal deposits greater than 1 cm can probably be identified
with a similar sensitivity for both MRI and CT
■ Peritoneal deposits within the mesentery, bowel wall deposits as
well as calcified lesions are better appreciated on CT than MRI
Ultrasound
Although ultrasound is a valuable method of detecting and charac-
terizing ovarian masses, it is not widely used for staging ovarian
malignancy. Ultrasound is less accurate than CT and MRI for detect-
ing peritoneal disease or lymph node involvement (103). Ultrasound
may be used as a problem-solving tool, e.g., equivocal liver lesions.
Key Point: Ultrasound for Staging
■ Transabdominal ultrasound is unreliable for staging ovarian
cancer
Radionuclide Imaging
Positron Emission Tomography (PET)
FDG-PET is able to accurately identify the presence of advanced
disease. However, in staging ovarian cancer, FDG-PET has some
well-known limitations. The main one is its inability to accurately
detect disseminated carcinomatosis or locate small tumor deposits
less the 1 cm. False positive diagnoses may arise from benign
lesions with a significant inflammatory component. The differen-
tiation of physiologic colonic (bowel wall and lumen) and urine
activity from tumor uptake of FDG can be difficult. The advent of
combined PET CT imaging has largely circumvented the poor
localization of a disease (117,118). Nevertheless, for these reasons,
FDG PET is not routinely used in the staging of ovarian cancer.
Radioimmunoscintigraphy
Immunoscintigraphy has been investigated in ovarian cancer and
has an overall sensitivity of 63% to 92% in the detection of pri-
mary or recurrent ovarian malignancy (115,119). Currently, the
technique is not used in routine clinical practice as it is not widely
available and, even though small volume disease may be identified,
its sensitivity and specificity are still not sufficiently high.
Key Points: Radionuclide Imaging
■ FDG-PET lacks sensitivity in identifying peritoneal disease
■ Immunuscinitigraphy has a sensitivity of 63% to 92% in the
detection of primary or recurrent ovarian malignancies
 ovarian cancer

(A) (B)

(C) (D)

(E) (F)

Figure 21.29 The appearance of peritoneal deposits in six patients with ovarian carcinoma. (A) CT scan showing extensive ascites with typical small nodules on the
surface of the liver consistent with deposits (arrowed). Note too the omental “cake.” (B) Peritoneal deposits are readily seen in the presence of ascites (arrowed).
(C) Peritoneal thickening on the surface of the liver (arrow) due to diffuse peritoneal infiltration. Note the presence of left subphrenic lymph nodes and splenic deposits.
(D) Multiple small peritoneal nodules are seen (arrowed). There is also infiltration of the serosa of the small bowel (black arrow) and of the large bowel (arrowheads).
(E) A discrete mass is seen within the peritoneum in the right iliac fossa (arrowed) due to peritoneal infiltration. (F) Cystic peritoneal deposits demonstrated on
the lateral surface of the liver resulting in “scalloping” of the liver margin. Lymph node disease is also noted in relation to the liver, together with multiple small liver
deposits.

421
 primary tumor evaluation and staging
Plain Radiography and Intravenous Urography
Chest radiography is usually performed as part of the staging
procedure to identify pleural effusions in patients with advanced dis-
ease. Pulmonary metastases usually occur late in the natural history
of ovarian cancer. Intravenous urography (IVU) and barium studies
are no longer routinely performed as CT provides information on the
presence of hydronephrosis and ureteric dilatation (120).
ACCURACY OF STAGING
Surgery is the gold standard for staging ovarian cancer but, even
so, understaging due to inadequate exploration at surgery is
common, occurring in 30% to 40% of cases. A frequent reason
for understaging is that the preoperative diagnosis is of a benign
Figure 21.30 Calcification in carcinoma of the ovary. CT showing a large primary
carcinoma of the ovary lying centrally in the pelvis. The mass is of mixed density
containing fluid components, but also containing multiple, heavily calcified foci.
(A)
Figure 21.31 (A) Omental infiltration. A patient with carcinoma of the ovary. The initial scan showed loss of clarity of the normal omental fat with multiple small nod-
ules (arrows). (B) CT scan performed five months after the CT scan seen in (A) showing diffuse infiltration of the omental fat.
422
tumor resulting in an inappropriate abdominal incision, which
precludes the detection of upper abdominal disease (121–123). The
staging accuracy of CT ranges from 70% to 90% (52,124,125) and,
although CT cannot replace appropriate staging laparotomy, it is a
valuable procedure for postoperative staging in patients with irre-
sectable tumor or multiple sites of disease where optimum cytore-
duction cannot be achieved. Also CT may identify disease missed at
surgery, important sites being tumor deposits posteriorly in the
right lobe of the liver or in a subcapsular location, and involved
enlarged retroperitoneal and retrocrural lymph nodes (104,126).
Although transabdominal ultrasound and transvaginal ultra-
sound are useful techniques for preoperative characterization of
pelvic masses, these techniques have little role in tumor staging.
Transabdominal ultrasound may be helpful as an adjunct to CT or
further characterization of focal liver lesions.
According to the few studies where MRI and CT have been
compared, these techniques appear to be equal for staging
abdomino-pelvic disease, but the high cost and relatively long
examination times of MRI precludes its use in most patients.
Evaluation of disease within the pelvis is better demonstrated
with MRI but within the abdomen both techniques understage
seedling tumor implants (77). The detection of enlarged retro-
peritoneal lymph nodes is probably equal with CT and MRI
(127). Thus, at present, CT is the recommended imaging modality
of choice for staging ovarian cancer.
Key Points: Staging Methods
■ Although surgical staging remains essential, CT provides
additional useful information as a baseline investigation
■ CT is the recommended staging procedure of choice
■ The high cost and limited availability of MRI preclude its use
as a routine staging procedure
PREOPERATIVE PREDICTORS OR OPTIMAL
CYTOREDUCTION
Several studies have looked at laboratory or radiographic param-
eters that might indicate a low likelihood of achieving optimal
(B)
 ovarian cancer
Figure 21.32 A large omental “cake.” Post-contrast CT scan showing a large mass
infiltrating the omentum and mesentery. Diffuse infiltration of the small bowel is
also seen. Note the liver deposits (arrowed).
Figure 21.33 Peritoneal and omental disease on MR. Axial T1-weighted image
shows nodularity and thickening in the mesentery and a thick omental cake
anteriorly (arrows).
primary cytoreduction. Though serum CA-125 levels correlate
with volume of disease, the preoperative CA-125 level is not a
good indicator of the ability to predict surgical cytoreductive
outcome with accuracy rates of only 50% to 78% (20).
Many radiologic criteria have been evaluated for their ability to
predict suboptimal cytoreduction. In one study, a model with 13
radiographic features on CT and performance status had 93%
accuracy for predicting cytoreductive status (128). However, in
another study by Dowdy et al., only one radiographic feature on
CT—diffuse peritoneal thickening—independently predicted
suboptimal cytoreduction (129). In a recent multicenter reciprocal
validation study of CT predictors of suboptimal cytoreduction in
primary advanced ovarian cancer patients, Axtell et al. demon-
strated that these predictors could not be validated in a cohort of
patients from their own hospital reviewed retrospectively and,
furthermore, could not be applied to patient cohorts from the
other two centers (130). These results suggest that criteria for
non-resectable disease varies markedly from institution to institu-
tion and will depend on the aggressiveness of individual surgeons
(130). In general, however, optimal cytoreduction may not possi-
ble when the images show disease include tumor deposits larger
than 2 cm in the porta hepatis; disease in the intersegmental fis-
sure of the liver, on the diaphragm, in the lesser sac; gastrosplenic
ligament; presacral extraperitoneal disease and lymph node
enlargement at the level of the celiac axis or above (131,132). In
most centers multidisciplinary review of the imaging and clinical
factors is performed in selecting patient for cytoreduction.
ASSESSMENT OF TUMOR RESPONSE
CT is the most widely used technique to monitor response to
chemotherapy. As with other neoplasms when imaging, ovarian
cancer response assessment is based on size using the RECIST
criteria (133). However, response assessment in ovarian cancer
can be challenging because the peritoneal spread of disease limits
the application of RECIST. Often peritoneal disease cannot be
measured, particularly when nodules are less than 1 cm or there is
diffuse serosal disease of bowel and diffuse infiltration of the
abdominal viscera. In such situations subjective evaluation of
changes in peritoneal disease on imaging has to be made. For
epithelial ovarian cancer response assessment, the use of CA-125
measurement has also been suggested (134). Clinically, response
assessment is made using a combination of imaging and serum
tumor marker measurements.
Negative CT examination with normal clinical examination and
a normal CA-125 level constitutes complete remission.
Key Points: Response Assessment
■ On imaging RECIST criteria can be used for response assess-
ment in ovarian cancer. However, disease is often not mea-
surable, i.e., peritoneal nodules <1 cm or serosal involvement
of bowel loops
■ CA-125 is useful marker for response assessment in
epithelial ovarian cancer
RECURRENT DISEASE
Between 50% and 75% of patients with advanced disease at diag-
nosis will develop recurrent disease and undergo several courses
of treatment. CT is the imaging technique used to investigate sus-
pected relapse based on rising tumor marker or clinical features.
Serum CA-125 Levels
Serum CA-125 levels are useful monitors of disease status since an
elevated or rising CA-125 is an accurate predictor of residual or
recurrent disease (135). A rise in CA-125 often predates changes
detected on imaging. However, a normal CA-125 does not exclude
tumor recurrence and the level of CA-125 does not provide any
information about the location of the site of recurrence, even if
serum markers are elevated.
423
 primary tumor evaluation and staging

Computed Tomography ultrasound (TRUS) is superior to transabdominal ultrasound for

Computed tomography is frequently used to detect persistent or detecting recurrent pelvic disease and also appears to be superior
recurrent ovarian cancer (Figs. 21.34 and 21.35). Imaging findings to CT for detecting tumor recurrence in the region of the vaginal
in recurrent ovarian cancer may differ from those at initial staging, vault and bladder wall (142,143).
particularly in those patients that have under gone debulking sur-
gery and there is no greater omentum. Recurrent tumor may then
involve other peritoneal recesses and reflections, notably in the
supracolic compartment around the spleen and stomach. The
commonest patterns of relapse are with a pelvic mass, peritoneal
thickening, serosal disease on bowel, and enlarged lymphadenop-
athy, and less common sites of recurrence included recurrence in
the spleen, liver, and brain (136).
As in primary staging, meticulous CT technique is critically
important with thin sections and optimal bowel opacification
improving the detection of recurrent disease. Unopacified
bowel loops may be mistaken for tumor recurrence, interpreta-
tion being hampered by the presence of dilated bowel, adherent
bowel loops, and a generalized increased density within the
mesentery and peritoneum due to edema, inflammation, fibro-
sis, and tumor infiltration. Such appearances may result from
adhesions and a desmoplastic reaction to small tumor deposits,
and thus peritoneal recurrence is more difficult to detect in
treated patients than in previously untreated cases. It can be
useful to compare with previous CT studies to identify fixed
loops of bowel. Calcified deposits may be mistaken for bowel.
Pelvic recurrence of ovarian cancer may be central at the vagi-
nal vault (Fig. 21.36), associated with vaginal bleeding and dis- Figure 21.34 Recurrent carcinoma of the ovary detected on CT. The figure shows a
charge, or lateral involving the pelvic sidewall with venous thick-walled cystic lesion lying in close relation to the anterior aspect of the rectum
thrombosis or ureteric obstruction. Ascites may become locu- (arrowed). The mass can also be seen to be infiltrating the vaginal vault. The patient had
lated with displacement of adjacent organs; encysted lesser sac previously undergone a total abdominal hysterectomy and salpingo-oophorectomy.
ascites may compress the stomach leading to the squashed
stomach syndrome (137).

Magnetic Resonance Imaging

The MR imaging findings in recurrent ovarian cancer are similar
to those of CT; hence, similar difficulties are encountered. The
presence of ascites improves the detection of peritoneal disease
and, as in the assessment of pretreated disease, the use of oral bowel
contrast medium and intravenous contrast medium facilitates
tumor detection (135,138).

Positron Emission Tomography

FDG-PET may have a role in recurrent ovarian cancer. It may
be helpful in restaging suspected recurrent disease when CA-125
is rising and CT findings are negative or equivocal. FDG-PET
may be useful in detecting metastatic lesions intimately associ-
ated with bowel wall that might be difficult to distinguish on
CT or MRI. Similar limitations, as in primary staging, apply to
restaging with FDG-PET. Despite this the overall accuracy of
FDG-PET in diagnosis of recurrent ovarian cancer ranges from
79% to 93% (139).

Ultrasound
Ultrasound is useful for detecting recurrent tumor in the pelvis
where the technique has an accuracy of 90% (140,141). However,
in the abdomen, ultrasound is unreliable for detecting recurrence;
in the same way as it is for primary tumor staging. Transrectal
Figure 21.35 This figure shows the typical appearance of early recurrent carcinoma
of the ovary following total abdominal hysterectomy and bilateral salpingo-
oophorectomy. The CT scan shows multiple, thick-walled, well-defined cystic
lesions lying close in relation to the rectal wall, the left external iliac lymph nodes
and the pararectal region. Calcified hypogastric lymph nodes (also due to recurrent
disease) are seen on the right.

424
 ovarian cancer
(A)
(B)
Figure 21.36 Recurrent ovarian cancer at the vaginal vault. Axial (A) T1- and (B) T2- and (C) sagittal T2-weighted images showing recurrent nodule (arrow) at
vaginal vault.
Key Points: Recurrent Disease
■ CT is the imaging modality of choice for detecting the pres-
ence and extent of recurrent ovarian cancer in the abdomen
and pelvis
■ MRI is helpful in evaluating pelvic disease (Fig. 21.36)
■ FDG-PET has a high specificity for detecting recurrent
disease but a low sensitivity
CONCLUSION
Imaging is central to the multidisciplinary management of ovar-
ian cancer. Ultrasound is the primary imaging modality in the
detection and characterization of an ovarian mass. MRI should
be used for the characterization of masses in those patients where
the results of clinical, ultrasound and tumor marker assessment
are equivocal. Computed tomography (CT) is the major imaging
modality for patients with established ovarian cancer, both for
staging prior to treatment, and for evaluating therapeutic response
and in the detection of recurrence.
Summary
■ Ovarian cancer accounts for 4% of all female cancers and is the
most frequent cause of death from gynecological malignancy
■ Most patients with epithelial ovarian cancers present with
advanced disease (Stage III/Stage IV). They usually present
with abdominal pain and distension
(C)
■ Optimal tumor reduction is loosely defined as the largest
residual tumor deposit being less than 1 cm (preferably less
than 0.5 cm) in diameter
■ Ultrasound is the primary imaging modality for evaluating
pelvic adnexal mass lesions
■ For indeterminate masses on ultrasound contrast-enhanced
MR imaging is valuable in determining the nature of the lesion
and occasionally a definitive diagnosis may be made
■ CT remains the method of choice for staging intra-
abdominal and pelvic disease as well as for detecting recur-
rence, but MRI appears to be equally accurate to CT in the
staging evaluation of abdomino-pelvic disease
■ Non-invasive imaging has an important role in evaluating
tumor response and in the assessment of residual disease;
is useful for determining the need for secondary cytore-
ductive surgery and in the detection of recurrence
REFERENCES
1. Cancer Stats Incidence UK, 2008.
2. Cancer Facts and Figures. American Cancer Society, 2008.
3. Elmasry K, Gayther S. Epidemiology of ovarian cancer. In:
Reznek RH, ed. Cancer of the Ovary. Cambridge: Cambridge
University Press, 2007: 1–19.
4. Schildkraut JM, Thompson WD. Familial ovarian cancer: a
population-based case-control study. Am J Epidemiol 1988;
128: 456–66.
425
 primary tumor evaluation and staging
5. Claus EB, Schwartz PE. Familial ovarian cancer. Update and
clinical applications. [Review]. Cancer 1995; 76(Suppl 10):
1998–2003.
6. Lynch HT, Schuelke GS, Kimberling WJ, et al. Hereditary
nonpolyposis colorectal cancer (Lynch syndromes I and II).
Biomarker studies. Cancer 1985; 56: 939–51.
7. Crum C. Female genital tract. In: Kumar V, Abbas AK, Fausto N,
eds. Robbins and Cotran Pathologic Basis of Disease.
Philadelphia: Elsevier Saunders, 2005: 1092–105.
8. Wagner BJ, Buck JL, Seidman JD, McCabe KM. From
the archives of the AFIP. Ovarian epithelial neoplasms:
radiologic-pathologic correlation. Radiographics 1994;
14: 1351–76.
9. Lowe D. Pathological features of ovarian neoplasia. In:
Reznek RH, ed. Cancer of the Ovary. Cambridge: Cambridge
University Press, 2007: 20–46.
10. Link CJ Jr, Reed E, Sarosy G, Kohn EC. Borderline ovarian
tumors [Review]. Am J Med 1996; 101: 217–25.
11. Brown DL, Zou KH, Tempany CM, et al. Primary versus
secondary ovarian malignancy: imaging findings of adnexal
masses in the Radiology Diagnostic Oncology Group Study.
Radiology 2001; 219: 213–18.
12. Crawshaw J, Sohaib SA, Wotherspoon A, Shepherd JH.
Primary non-Hodgkin’s lymphoma of the ovaries: imaging
findings. Br J Radiol 2007; 80: e155–8.
13. Jacobs JJ, Bast RC Jr. CA-125 tumour associated antigen:
a review of the literature. Hum Reprod 1997; 1989:
1–12.
14. Forstner R. Radiological staging of ovarian cancer: imaging
findings and contribution of CT and MRI. Eur Radiol 2007;
17: 3223–35.
15. Bohm-Velez M, Mendelson E, Bree R, et al. Ovarian cancer
screening. American College of Radiology. ACR Appropriate-
ness Criteria. Radiology 2000; 215(Suppl): 861–71.
16. Buy JN, Moss AA, Ghossain MA, et al. Peritoneal implants
from ovarian tumors: CT findings. Radiology 1988; 169:
691–4.
17. Musumeci R, De Palo G, Kenda R, et al. Retroperitoneal
metastases from ovarian carcinoma: reassessment of 365
patients studied with lymphography. Am J Roentgenol 1980;
134: 449–52.
18. Pecorelli S, Benedet JL, Creasman WT, Shepherd JH. FIGO
staging of gynecologic cancer. 1994-1997 FIGO Committee on
Gynecologic Oncology. International Federation of Gynecology
and Obstetrics. Int J Gynaecol Obstet 1999; 65: 243–9.
19. Wittekind Ch, Greene FL, Hutter RV, Sobin LH, Klimpfinger M,
eds. TNM Atlas: Illustrated Guide to the TNM/pTNM
Classification of Malignant Tumours, 5th edn. Berlin:
Springer, 2005.
20. Fader AN, Rose PG. Role of surgery in ovarian carcinoma.
J Clin Oncol 2007; 25: 2873–83.
21. Lai CH, Chang TC, Hsueh S, et al. Outcome and prognostic
factors in ovarian germ cell malignancies. Gynecol Oncol
2005; 96: 784–91.
22. Murugaesu N, Schmid P, Dancey G, et al. Malignant ovarian
germ cell tumors: identification of novel prognostic markers
and long-term outcome after multimodality treatment.
J Clin Oncol 2006; 24: 4862–6.
426
23. Colombo N, Parma G, Zanagnolo V, Insinga A. Management
of ovarian stromal cell tumors. J Clin Oncol 2007; 25:
2944–51.
24. Piver MS, Lele SB, Marchetti DL, et al. The impact of aggres-
sive debulking surgery and cisplatin-based chemotherapy
on progression-free survival in stage III and IV ovarian
carcinoma. J Clin Oncol 1988; 6: 983–9.
25. Hacker NF, Berek JS, Lagasse LD, Nieberg RK, Elashoff RM.
Primary cytoreductive surgery for epithelial ovarian cancer.
Obstet Gynecol 1983; 61: 413–20.
26. Goodman HM, Harlow BL, Sheets EE, et al. The role of
cytoreductive surgery in the management of stage IV epithelial
ovarian carcinoma. Gynecol Oncol 1992; 46: 367–71.
27. Griffiths CT, Parker LM, Fuller AF Jr. Role of cytoreductive
surgical treatment in the management of advanced ovarian
cancer. Cancer Treat Rep 1979; 63: 235–40.
28. Potter ME, Partridge EE, Hatch KD, et al. Primary surgical
therapy of ovarian cancer: how much and when. Gynecol
Oncol 1991; 40: 195–200.
29. van der Burg ME, van Lent M, Buyse M, et al. The effect of
debulking surgery after induction chemotherapy on the
prognosis in advanced epithelial ovarian cancer. Gynecologi-
cal Cancer Cooperative Group of the European Organization
for Research and Treatment of Cancer. N Eng J Med 1995;
332: 629–34.
30. NIH consensus conference. Ovarian cancer. Screening,
treatment, and follow-up. NIH Consensus Development
Panel on Ovarian Cancer. JAMA 1995; 273: 491–7.
31. Winter-Roach B, Hooper L, Kitchener H. Systematic review
of adjuvant therapy for early stage (epithelial) ovarian
cancer. Int J Gynecol Cancer 2003; 13: 395–404.
32. McGuire WP, Hoskins WJ, Brady MF, et al. Cyclophosphamide
and cisplatin compared with paclitaxel and cisplatin in
patients with stage III and stage IV ovarian cancer. N Engl J
Med 1996; 334: 1–6.
33. Piccart MJ, Bertelsen K, James K, et al. Randomized
intergroup trial of cisplatin-paclitaxel versus cisplatin-
cyclophosphamide in women with advanced epithelial
ovarian cancer: three-year results. J Natl Cancer Inst 2000;
92: 699–708.
34. Paclitaxel plus carboplatin versus standard chemother-
apy with either single-agent carboplatin or cyclophosph-
amide, doxorubicin, and cisplatin in women with ovarian
cancer: the ICON3 randomised trial. Lancet 2002; 360:
505–15.
35. NICE. Guidance on the use of paclitaxel in the treatment of
ovarian cancer. In: Technology Appraisal Guidance No. 55,
2003.
36. Harries M, Gore M. Part II: chemotherapy for epithelial
ovarian cancer—treatment of recurrent disease. Lancet
Oncol 2002; 3: 537–45.
37. Parmar MK, Ledermann JA, Colombo N, et al. Paclitaxel plus
platinum-based chemotherapy versus conventional platinum-
based chemotherapy in women with relapsed ovarian
cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet 2003; 361:
2099–106.
38. Gershenson DM. Management of ovarian germ cell tumors.
J Clin Oncol 2007; 25: 2938–43.
 ovarian cancer
39. Bell R, Petticrew M, Sheldon T. The performance of screen-
ing tests for ovarian cancer: results of a systematic review.
Br J Obstet Gynaecol 1998; 105: 1136–47.
40. Taylor KJ, Schwartz PE. Screening for early ovarian cancer.
Radiology 1994; 192: 1–10.
41. Oram DH, Jeyarajah AR. The role of ultrasound and tumour
markers in the early detection of ovarian cancer. Br J Obstet
Gynaecol 1994; 101: 939–45.
42. Campbell S, Bhan V, Royston P, Whitehead MI, Collins WP.
Transabdominal ultrasound screening for early ovarian
cancer. BMJ 1989; 299: 1363–7.
43. Jacobs I, Stabile I, Bridges J, et al. Multimodal approach to
screening for ovarian cancer. Lancet 1988; 1: 268–71.
44. Menon U, Jacobs IJ. The current status of screening for
ovarian cancer. In: Jacobs IJ, Shepherd JH, Oram DH, et al.,
eds. Ovarian Cancer. Oxford: Oxford University Press, 2003:
171–8.
45. Jacobs I, Davies AP, Bridges J, et al. Prevalence screening
for ovarian cancer in postmenopausal women by CA 125
measurement and ultrasonography. BMJ 1993; 306: 1030–4.
46. Adonakis GL, Paraskevaidis E, Tsiga S, Seferiadis K, Lolis DE.
A combined approach for the early detection of ovarian
cancer in asymptomatic women. Eur J Obstet Gynecol
Reprod Biol 1996; 65: 221–5.
47. Gohagan JK, Prorok PC, Hayes RB, Kramer BS. The
Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer
Screening Trial of the National Cancer Institute: history,
organization, and status. Control Clin Trials 2000; 21(Suppl
6): 251S–72S.
48. Prorok PC, Andriole GL, Bresalier RS, et al. Design of
the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer
Screening Trial. Control Clin Trials 2000; 21(Suppl 6):
273S–309S.
49. Spencer JA, Forstner R, Hricak H. Investigating women
with suspected ovarian cancer. Gynecol Oncol 2008; 108:
262–4.
50. Kehoe S, Powell J, Wilson S, Woodman C. The influence of
the operating surgeon’s specialisation on patient survival in
ovarian carcinoma. Br J Cancer 1994; 70: 1014–17.
51. Junor EJ, Hole DJ, McNulty L, Mason M, Young J. Specialist
gynaecologists and survival outcome in ovarian cancer: a
Scottish national study of 1866 patients. Br J Obstet Gynaecol
1999; 106: 1130–6.
52. Fleischer AC. Transabdominal and transvaginal songraphy of
ovarian masses. Clin Obstet Gynaecol 1991; 34: 433.
53. Granberg S. Relationship of macroscopic appearance to the
histologic diagnosis of ovarian tumors. Clin Obstet Gynecol
1993; 36: 363–74.
54. Higgins RV, van NJ Jr, Donaldson ES, et al. Transvaginal
sonography as a screening method for ovarian cancer.
Gynecol Oncol 1989; 34: 402–6.
55. Podratz KC, Kinney WK. Second-look operation in ovarian
cancer. Cancer 1993; 71(Suppl 4): 1551–8.
56. McGuire WP. Primary treatment of epithelial ovarian
malignancies. Cancer 1993; 71(Suppl 4): 1541–50.
57. Hoskins WJ. Surgical staging and cytoreductive surgery of
epithelial ovarian cancer. Cancer 1993; 71(Suppl 4): 1534–40.
58. Conte M, Guariglia L, Benedetti Panici PL, et al. Ovarian
carcinoma: an ultrasound study. Eur J Gynaecol Oncol 1990;
11: 33–6.
59. Hata K, Hata T, Manabe A, Sugimura K, Kitao M. A critical
evaluation of transvaginal Doppler studies, transvaginal
sonography, magnetic resonance imaging, and CA 125 in
detecting ovarian cancer. Obstet Gynecol 1992; 80:
922–6.
60. Reles A, Wein U, Lichtenegger W. Transvaginal color Doppler
sonography and conventional sonography in the preopera-
tive assessment of adnexal masses. J Clin Ultrasound 1997;
25: 217–25.
61. Ferrazzi E, Zanetta G, Dordoni D, et al. Transvaginal ultra-
sonographic characterization of ovarian masses: comparison
of five scoring systems in a multicenter study. Ultrasound
Obstet Gynecol 1997; 10: 192–7.
62. Kurjak A, Predanic M. New scoring system for prediction of
ovarian malignancy based on transvaginal color Doppler
sonography. J Ultrasound Med 1992; 11: 631–8.
63. Jeong YY, Outwater EK, Kang HK. Imaging evaluation of
ovarian masses. Radiographics 2000; 20: 1445–70.
64. Hata T, Hata K, Senoh D, et al. Doppler ultrasound
assessment of tumor vascularity in gynecologic disorders.
J Ultrasound Med 1989; 8: 309–14.
65. Dock W, Grabenwoger F, Metz V, Eibenberger K, Farres MT.
Tumor vascularization: assessment with duplex sonography.
Radiology 1991; 181: 241–4.
66. Folkman J, Watson K, Ingber D, Hanahan D. Induction of
angiogenesis during the transition from hyperplasia to
neoplasia. Nature 1989; 339: 58–61.
67. Kurjak A, Salihagic A, Kupesic-Urek S, Predanic A. Clinical
value of the assessment of gynaecological tumour angiogen-
esis by transvaginal colour Doppler. Ann Med 1992; 24:
97–103.
68. Hamper UM, Sheth S, Abbas FM, et al. Transvaginal color
Doppler sonography of adnexal masses: differences in blood
flow impedance in benign and malignant lesions. Am J
Roentgenol 1993; 160: 1225–8.
69. Bromley B, Goodman H, Benacerraf BR. Comparison between
sonographic morphology and Doppler waveform for the
diagnosis of ovarian malignancy. Obstet Gynecol 1994; 83:
434–7.
70. Brown DL, Frates MC, Laing FC, et al. Ovarian masses:
can benign and malignant lesions be differentiated
with color and pulsed Doppler US? Radiology 1994; 190:
333–6.
71. Stein SM, Laifer-Narin S, Johnson MB, et al. Differentiation
of benign and malignant adnexal masses: relative value of
gray-scale, color Doppler, and spectral Doppler sonography.
Am J Roentgenol 1995; 164: 381–6.
72. Jain KA. Prospective evaluation of adnexal masses with
endovaginal gray-scale and duplex and color Doppler US: cor-
relation with pathologic findings [see comments]. Radiology
1994; 191: 63–7.
73. Timor-Tritsch LE, Lerner JP, Monteagudo A, Santos R. Trans-
vaginal ultrasonographic characterization of ovarian masses
by means of color flow-directed Doppler measurements and
427
 primary tumor evaluation and staging
a morphologic scoring system. Am J Obstet Gynecol 1993;
168(3 Pt 1): 909–13.
74. Schneider VL, Schneider A, Reed KL, Hatch KD. Comparison
of Doppler with two-dimensional sonography and CA 125
for prediction of malignancy of pelvic masses. Obstet Gynecol
1993; 81: 983–8.
75. Pellerito JS, Troiano RN, Quedens-Case C, Taylor KJ.
Common pitfalls of endovaginal color Doppler flow
imaging. Radiographics 1995; 15: 37–47.
76. Kinkel K, Hricak H, Lu Y, Tsuda K, Filly RA. US character-
ization of ovarian masses: a meta-analysis. Radiology 2000;
217: 803–11.
77. Forstner R, Hricak H, Occhipinti KA, et al. Ovarian cancer:
staging with CT and MR imaging. Radiology 1995; 197:
619–26.
78. Low RN, Sigeti JS. MR imaging of peritoneal disease. Am J
Roentgenol 1994; 163: 1131–40.
79. Ghossain MA, Buy JN, Ligneres C, et al. Epithelial tumors of
the ovary: comparison of MR and CT findings. Radiology
1991; 181: 863–70.
80. Thurnher S, Hodler J, Baer S, Marincek B, von Schulthess GK.
Gadolinium-DOTA enhanced MR imaging of adnexal
tumors. J Comput Assist Tomogr 1990; 14: 939–49.
81. Troiano RN, Lazzarini KM, Scoutt LM, et al. Fibroma and
fibrothecoma of the ovary: MR imaging findings. Radiology
1997; 204: 795–8.
82. Outwater EK, Siegelman ES, Talerman A, Dunton C. Ovarian
fibromas and cystadenofibromas: MRI features of the fibrous
component. J Magn Reson Imaging 1997; 7: 465–71.
83. Sohaib SA, Sahdev A, Van Trappen PO, Jacobs IJ, Reznek RH.
Characterization of adnexal mass lesions on MR imaging.
Am J Roentgenol 2003; 180: 1297–304.
84. Hricak H, Chen M, Coakley FV, et al. Complex adnexal
masses: detection and characterization with MR imaging −
multivariate analysis. Radiology 2000; 214: 39–46.
85. Yamashita Y, Torashima M, Hatanaka Y, et al. Adnexal masses:
accuracy of characterization with transvaginal US and
precontrast and postcontrast MR imaging. Radiology 1995;
194: 557–65.
86. Komatsu T, Konishi I, Mandai M, et al. Adnexal masses:
transvaginal US and gadolinium-enhanced MR imaging
assessment of intratumoral structure. Radiology 1996; 198:
109–15.
87. Rieber A, Nussle K, Stohr I, et al. Preoperative diagnosis
of ovarian tumors with MR imaging: comparison
with transvaginal sonography, positron emission tomo-
graphy, and histologic findings. Am J Roentgenol 2001;
177: 123–9.
88. Sohaib SA, Mills TD, Sahdev A, et al. The role of magnetic
resonance imaging and ultrasound in patients with adnexal
masses. Clin Radiol 2005; 60: 340–8.
89. Kinkel K, Lu Y, Mehdizade A, Pelte MF, Hricak H. Indeter-
minate ovarian mass at US: incremental value of second
imaging test for characterization – meta-analysis and
Bayesian analysis. Radiology 2005; 236: 85–94.
90. Walsh JW. CT of gynaecologic neoplasm. Radiol Clin North
Am 1992; 30: 826–30.
428
91. Buy JN, Ghossain MA, Sciot C, et al. Epithelial tumors of the
ovary: CT findings and correlation with US. Radiology 1991;
178: 811–18.
92. Van Trappen PO, Rufford BD, Mills TD, et al. Differential
diagnosis of adnexal masses: risk of malignancy index,
ultrasonography, magnetic resonance imaging, and radio-
immunoscintigraphy. Int J Gynecol Cancer 2007; 17:
61–7.
93. Hubner KF, McDonald TW, Niethammer JG, et al. Assess-
ment of primary and metastatic ovarian cancer by positron
emission tomography (PET) using 2-[18F]deoxyglucose
(2-[18F]FDG). Gynecol Oncol 1993; 51: 197–204.
94. Kalofonos HP, Karamouzis MV, Epenetos AA. Radioimmuno-
scintigraphy in patients with ovarian cancer. Acta Oncologica
2001; 40: 549–57.
95. Jacobs I, Oram D, Fairbanks J, et al. A risk of malignancy
index incorporating CA 125, ultrasound and menopausal
status for the accurate preoperative diagnosis of ovarian
cancer. Br J Obstet Gynaecol 1990; 97: 922–9.
96. Davies AP, Jacobs I, Woolas R, Fish A, Oram D. The adnexal
mass: benign or malignant? Evaluation of a risk of malig-
nancy index. Br J Obstet Gynaecol 1993; 100: 927–31.
97. Manjunath AP, Pratapkumar, Sujatha K, Vani R. Comparison
of three risk of malignancy indices in evaluation of pelvic
masses. Gynecol Oncol 2001; 81: 225–9.
98. Tingulstad S, Hagen B, Skjeldestad FE, et al. Evaluation of a
risk of malignancy index based on serum CA125, ultra-
sound findings and menopausal status in the pre-operative
diagnosis of pelvic masses. Br J Obstet Gynaecol 1996; 103:
826–31.
99. Spencer JA, Anderson K, Weston M, Wilkinson N, Hewitt M.
Image guided biopsy in the management of cancer of the
ovary. Cancer Imaging 2006; 6: 144–7.
100. Spencer JA. A multidisciplinary approach to ovarian cancer
at diagnosis. Br J Radiol 2005; 78 Spec No. 2: S94–102.
101. Hewitt MJ, Anderson K, Hall GD, et al. Women with perito-
neal carcinomatosis of unknown origin: Efficacy of image-
guided biopsy to determine site-specific diagnosis. BJOG
2007; 114: 46–50.
102. Pannu HK, Bristow RE, Montz FJ, Fishman EK. Multi-
detector CT of peritoneal carcinomatosis from ovarian
cancer. Radiographics 2003; 23: 687–701.
103. Tempany CM, Zou KH, Silverman SG, et al. Staging of
advanced ovarian cancer: comparison of imaging modalities –
report from the Radiological Diagnostic Oncology Group.
Radiology 2000; 215: 761–7.
104. Johnson RJ, Blackledge G, Eddleston B, Crowther D.
Abdomino-pelvic computed tomography in the manage-
ment of ovarian carcinoma. Radiology 1983; 146:
447–52.
105. Amendola MA, Walsh JW, Amendola BE, et al. Computed
tomography in the evaluation of carcinoma of the ovary.
J Comput Assist Tomogr 1981; 5: 179–86.
106. Megibow AJ, Bosniak MA, Ho AG, et al. Accuracy of CT in
the detection of persistent or recurrent ovarian carcinoma:
correlation with second-look laparotomy. Radiology 1988;
166: 341–5.
 ovarian cancer
107. Mitchell DG, Hill MC, Hill S, Zaloudek C. Serous carcinoma
of the ovary: CT identification of metastatic calcified
implants. Radiology 1986; 158: 649–52.
108. Low RN, Chen SC, Barone R. Distinguishing benign from
malignant bowel obstruction in patients with malignancy:
findings at MR imaging. Radiology 2003; 228: 157–65.
109. Halvorsen RA Jr, Panushka C, Oakley GJ, Letourneau JG,
Adcock LL. Intraperitoneal contrast material improves the
CT detection of peritoneal metastases. Am J Roentgenol
1991; 157: 37–40.
110. Coakley FV. Staging ovarian cancer: role of imaging. Radiol
Clin North Am 2002; 40: 609–36.
111. Coakley FV, Choi PH, Gougoutas CA, et al. Peritoneal
metastases: detection with spiral CT in patients with ovarian
cancer. Radiology 2002; 223: 495–9.
112. Stevens SK, Hricak H, Stern JL. Ovarian lesions: detection
and characterization with gadolinium-enhanced MR
imaging at 1.5 T. Radiology 1991; 181: 481–8.
113. Outwater EK, Dunton CJ. Imaging of the ovary and adnexa:
clinical issues and applications of MR imaging. Radiology
1995; 194: 1–18.
114. Low RN, Duggan B, Barone RM, Saleh F, Song SY. Treated
ovarian cancer: MR imaging, laparotomy reassessment, and
serum CA-125 values compared with clinical outcome at 1
year. Radiology 2005; 235: 918–26.
115. Low RN, Carter WD, Saleh F, Sigeti JS. Ovarian cancer:
comparison of findings with perfluorocarbon- enhanced
MR imaging, In-111-CYT-103 immunoscintigraphy, and CT.
Radiology 1995; 195: 391–400.
116. Prayer L, Stiglbauer R, Kramer J, et al. Superparamagnetic
particles as oral contrast medium in magnetic resonance
imaging of patients with treated ovarian cancer − comparison
with plain MRI. Br J Radiol 1993; 66: 415–19.
117. Karlan BY, Hawkins R, Hoh C, et al. Whole-body positron
emission tomography with 2-[18F]-fluoro-2-deoxy-D-
glucose can detect recurrent ovarian carcinoma. Gynecol
Oncol 1993; 51: 175–81.
118. Schaffler GJ, Groell R, Schoellnast H, et al. Digital image fusion
of CT and PET data sets—clinical value in abdominal/pelvic
malignancies. J Comput Assist Tomogr 2000; 24: 644–7.
119. Surwit EA, Childers JM, Krag DN, et al. Clinical
assessment of 111In-CYT-103 immunoscintigraphy in the
imaging of ovarian carcinoma. Gynecol Oncol 1993; 48:
285–92.
120. Hillman BJ, Clark RL, Babbitt G. Efficacy of the excretory
urogram in the staging of gynecologic malignancies. Am J
Roentgenol 1984; 143: 997–9.
121. Piver MS, Barlow JJ, Lele SB. Incidence of subclinical metas-
tasis in stage I and II ovarian carcinoma. Obstet Gynecol
1978; 52: 100–4.
122. Bagley CM Jr, Young RC, Schein PS, Chabner BA, DeVita VT.
Ovarian carcinoma metastatic to the diaphragm − frequently
undiagnosed at laparotomy. A preliminary report. Am J
Obstet Gynecol 1973; 116: 397–400.
123. Ozols RF, Fisher RI, Anderson T, Makuch R, Young RC. Peri-
toneoscopy in the management of ovarian cancer. Am J
Obstet Gynecol 1981; 140: 611–19.
124. Sanders RC, McNeil BJ, Finberg HJ, et al. A prospective
study of computed tomography and ultrasound in the
detection and staging of pelvic masses. Radiology 1983;
146: 439–42.
125. Shiels RA, Peel KR, MacDonald HN, Thorogood J, Robinson
PJ. A prospective trial of computed tomography in the
staging of ovarian malignancy. Br J Obstet Gynaecol 1985;
92: 407–12.
126. Blaquiere RM, Husband JE. Conventional radiology and
computed tomography in ovarian cancer: discussion paper.
J R Soc Med 1983; 76: 574–9.
127. Dooms GC, Hricak H, Crooks LE, Higgins B. Magnetic
resonance imaging of the lymph nodes: comparison with
CT. Radiology 1984; 153: 719–28.
128. Bristow RE, Duska LR, Lambrou NC, et al. A model for
predicting surgical outcome in patients with advanced
ovarian carcinoma using computed tomography. Cancer
2000; 89: 1532–40.
129. Dowdy SC, Mullany SA, Brandt KR, Huppert BJ, Cliby WA.
The utility of computed tomography scans in predicting
suboptimal cytoreductive surgery in women with advanced
ovarian carcinoma. Cancer 2004; 101: 346–52.
130. Axtell AE, Lee MH, Bristow RE, et al. Multi-institutional
reciprocal validation study of computed tomography pre-
dictors of suboptimal primary cytoreduction in patients
with advanced ovarian cancer. J Clin Oncol 2007; 25:
384–9.
131. Meyer JI, Kennedy AW, Friedman R, Ayoub A, Zepp RC.
Ovarian carcinoma: value of CT in predicting success of
debulking surgery. Am J Roentgenol 1995; 165: 875–8.
132. Nelson BE, Rosenfield AT, Schwartz PE. Preoperative
abdominopelvic computed tomographic prediction of
optimal cytoreduction in epithelial ovarian carcinoma. J Clin
Oncol 1993; 11: 166–72.
133. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines
to evaluate the response to treatment in solid tumors. Euro-
pean Organization for Research and Treatment of Cancer,
National Cancer Institute of the United States, National
Cancer Institute of Canada. J Natl Cancer Inst 2000; 92:
205–16.
134. Rustin GJ, Timmers P, Nelstrop A, et al. Comparison of
CA-125 and standard definitions of progression of ovarian
cancer in the intergroup trial of cisplatin and paclitaxel versus
cisplatin and cyclophosphamide. J Clin Oncol 2006; 24:
45–51.
135. Forstner R, Hricak H, Powell CB, et al. Ovarian cancer
recurrence: value of MR imaging. Radiology 1995; 196:
715–20.
136. Sahdev A, Hughes JH, Barwick T, et al. Computed tomogra-
phy features of recurrent ovarian carcinoma according to
time to relapse. Acta Radiol 2007; 48: 1038–44.
137. Spencer JA, Crosse BA, Mannion RA, et al. Gastroduodenal
obstruction from ovarian cancer: imaging features and
clinical outcome. Clin Radiol 2000; 55: 264–72.
138. Prayer L, Kainz C, Kramer J, et al. CT and MR accuracy in
the detection of tumor recurrence in patients treated for
ovarian cancer. J Comput Assist Tomogr 1993; 17: 626–32.
429
 primary tumor evaluation and staging
139. Avril N. PET and PET/CT in ovarian cancer. In: Reznek RH,
ed. Cancer of the Ovary. Cambridge: Cambridge University
Press, 2007: 156–72.
140. Murolo C, Costantini S, Foglia G, et al. Ultrasound exam-
ination in ovarian cancer patients. A comparison with sec-
ond look laparotomy. J Ultrasound Med 1989; 8: 441–3.
141. Lund B, Jacobsen K, Rasch L, et al. Correlation of abdominal
ultrasound and computed tomography scans with second-
430
or third-look laparotomy in patients with ovarian carcinoma.
Gynecol Oncol 1990; 37: 279–83.
142. Squillaci E, Salzani MC, Grandinetti ML, et al. Recurrence of
ovarian and uterine neoplasms: diagnosis with transrectal
US. Radiology 1988; 169: 355–8.
143. Meanwell CA, Rolfe EB, Blackledge G, et al. Recurrent female
pelvic cancer: assessment with transrectal ultrasonography.
Radiology 1987; 162(1 Pt 1): 278–81.
 22 Uterine and Cervical Tumors
Andrea G Rockall and Rodney H Reznek
INTRODUCTION
In recent years, the management of patients with carcinoma of the
cervix has changed substantially. At the same time, the incidence
of endometrial cancer has increased, particularly in older women
and often with co-morbidity. Both of these developments have
resulted in an increasing reliance on imaging in deciding on
appropriate treatment. Several imaging modalities play a role in
deciding on appropriate management at the time of presentation
as well as in detecting recurrent disease and dealing with compli-
cations both of the disease and treatment. Magnetic resonance
(MR) imaging has emerged as the most widely used technique in
evaluating patients with uterine and cervical cancer. For imaging
to be used effectively, however, it is important for the radiologist
to understand not only the treatment options that the multidisci-
plinary team and the patient with uterine cancer are faced with
but also the diagnostic performance, advantages, and limitations
of each of these imaging modalities. It is worthy of note that the
staging classifications for cervical, uterine and vulval carcinoma
have recently been changed by the International Federation of
Gynecology and Obstertrics (FIGO). Diagnostic performance
studies evaluating the different imaging modalities that were
published prior to 2009 will have been based on the earlier FIGO
staging classification.
CARCINOMA OF THE CERVIX
Imaging is widely used in the management of patients with cervical
carcinoma. It may be used in the pretreatment assessment of dis-
ease, as an adjunct to treatment planning (both surgical and non-
surgical), to predict prognosis, to monitor response to treatment,
and to detect recurrent disease.
Epidemiology
Cervix cancer is the third most common gynaecologic malignancy
in Western countries. In the UK, there were 2726 new cases in
2004; 2253 new cases in 2005 (8.8 per 100,000); and 949 deaths in
2006 (age-standardized mortality of 2.4 per 100,000). In the
United States, the incidence of new cases in 2004 was 11,892 (8.1
per 100,000) with 3850 deaths (age-standardized mortality of 2.4
per 100,000) (1). The peak incidence is between 30 and 50 years
(2,3). There has been a steady decrease in incidence in the United
Kingdom and the United States: a 15% decrease in incidence rate
was reported in the United Kingdom between 1996 and 2005 (2).
In the United States, almost all the decrease related to a reduction
in cases of squamous cell carcinoma (SCC) (3). The introduction
of screening programs, which detect pre-invasive disease on cervi-
cal smear, has resulted in a marked decrease in mortality rates (4).
However, the survival rates for patients who present with invasive
cervical cancer have not improved over the same period.
Cervix cancer remains one of the commonest cancers in women
in developing countries, including Central and South America, parts
of Africa, and South Central Asia (2). It is the second most common
cancer (after breast cancer) in women worldwide, and the third com-
monest cause of cancer death (behind lung and breast cancer) (5,6).
Marked differences in incidence are not only seen between countries
but also among different cultures and socio-economic groups within
the same country, due to differing exposure to risk factors and varia-
tions in the uptake and availability of screening programs.
The introduction of the vaccine against human papilloma virus
(HPV) 16 and 18 is likely to have a major impact on disease preven-
tion (7). This vaccine, made up of HPV virus-like particles, is highly
effective against HPV 16 and 18. Vaccination programs are cur-
rently being introduced in several countries. However, screening
programs remain essential as the vaccine is not active against the
other HPV types. In addition, there will be a long lag period during
which most of the population at risk will not be vaccinated.
Etiology
The dominant etiological factor in cervix cancer is exposure to
human papilloma virus (HPV). HPV DNA sequences can be
detected in over 99% of biopsies of invasive cervical cancer world-
wide (8). Pre-invasive disease (cervical intraepithelial neoplasia,
CIN) of any grade has been shown to be caused by infection with
HPV (9). Several factors have a causal relationship including
sexual activity and lack of barrier contraception. Although there
are 15 oncogenic HPV types, HPV 16 and 18 cause approximately
70% of cases of cervix cancer (7).
Key Points: Etiology and Epidemiology
■ The most important etiological factor is exposure to HPV,
particularly 16 and 18
■ The incidence of cervical cancer continues to decrease in
Western countries but it remains the second most common
cancer in women worldwide
Pathology
Two-thirds of all cervical carcinomas are of squamous cell carci-
noma (SCC) histology. There has been a gradual decrease in inci-
dence of SCC (3,10). SCCs arise at the squamo-columnar junction
in the region of the external os. In postmenopausal women, the
squamo-columnar junction tends to migrate and thus SCC may
arise within the endocervical canal, which may delay the diagnosis
due to false negative cervical smears and/or lack of significant
symptoms. The histology is categorized into pre-invasive disease
(cervical intraepithelial neoplasia, CIN) and invasive disease.
Adenocarcinomas and adenosquamous carcinomas previously
accounted for 10% of cases but the incidence of these subtypes
has increased and they now account for approximately 25% (3,11).
Adenocarcinoma arises in the glands which line the endocervical
431
 primary tumor evaluation and staging
canal and it is thought that conventional screening may not detect
cervical adenocarcinoma as efficiently as SCC, resulting in late
presentation (3). Neuroendocrine small cell tumors, sarcoma,
lymphoma, or malignant melanoma are rare (3).
Key Points: Pathology
■ Squamous cell carcinoma accounts for approximately
two-thirds of all cases and tend to arise at the external os
■ Adeno- and adenosquamous carcinomas account for 10–25%
of cases and in the United States have increased in frequency
Patterns of Tumor Spread
Cervical carcinoma grows in three main morphological patterns:
• The tumor may form an exophytic lesion protruding
from the ectocervix (Fig. 22.4)
• The tumor may remain predominantly within the
endocervical canal causing widening of the canal by
polypoid tumor growth (Fig. 22.5)
• The tumor may predominantly invade into the cervical
stroma, resulting in a “barrel-shaped” cervix (Fig. 22.8)
The lesion may be locally invasive and may infiltrate through the
cervical stroma into the vaginal fornices and into the parametrial
tissues lateral to the cervix. Tumor may track along the cervical
supporting ligaments including the uterosacral ligaments which
sweep posteriorly, merging with the mesorectal fascia, and the
cardinal ligaments which sweep laterally, extending to the pelvic
side-walls. The ureters may become involved, indicating pelvic
side-wall invasion. Tumor may infiltrate into the uterine myome-
trium superiorly. Where tumor infiltrates through the stroma
anteriorly, the bladder may become infiltrated, particularly below
the level of the peritoneal reflection, where there is a “bare-area” of
bladder. This differs to infiltration of the posterior structures,
where there is a deep peritoneal reflection, into the pouch of
Douglas and rectovaginal septum, which acts as a relative barrier
to penetration by tumor (Fig. 22.13).
Lymphovascular space invasion precedes lymph node metastases,
which include parametrial and paracervical nodes, followed by
obturator and external iliac, internal, and common iliac nodes.
Para-aortic and supraclavicular nodal metastases are seen in
advanced disease. Hematogenous metastases to the lungs, bone,
and liver may occur but are unusual in cervical squamous cell or
adenocarcinomas (12).
Clinical Features
In Western countries many patients are detected through screening
programs and are asymptomatic. Patients presenting with estab-
lished invasive cervical carcinoma may complain of abnormal
vaginal bleeding, which may be postcoital, intermenstrual, or
postmenopausal, or an abnormal vaginal discharge. Pelvic pain
may be present in advanced disease. The diagnosis is made at
colposcopy, during which the cervix is palpated and visually
inspected prior to colposcopic examination. Biopsy of suspicious
areas is undertaken to establish the diagnosis. Diagnostic imaging
for pretreatment evaluation is only appropriate once the diagnosis
of invasive disease has been established histologically.
432
Staging (Fig. 22.1 and Table 22.1)
The most widely used staging classification of cervical carcinoma is
that of the International Federation of Gynaecology and Obstetrics
(FIGO) (12A, 12B). In the case of cervix cancer, this is a clinical stag-
ing system which does not rely on surgico-pathological findings. This
allows uniformity of staging for all patients regardless of whether they
undergo surgical or non-surgical primary treatment. The staging
procedure includes examination of the cervix under anesthesia
(EUA), colposcopy, biopsy, cystoscopy, and sigmoidoscopy although
these procedures are optional (12B). Radiologic studies that can be
included are a chest radiograph, intravenous urography, and barium
enema. The use of CT and MRI are advocated in the revised FIGO
staging where available but are optional (12B). The clinical measure-
ment of the tumor size and the identification of parametrial invasion
are critical to the correct staging of the patient and thus the optimal
treatment (see below). There are difficulties with the clinical diagno-
sis of parametrial invasion due to confounding tumor-associated
inflammatory changes that may result in overdiagnosis of parametrial
disease. Thus, the FIGO committee recommends that a case should
only be classified as Stage IIB disease if the parametrium is nodular
out to the pelvic side wall (13).
It is recognized that clinical staging errors occur with reasonable
frequency. Staging errors occur in up to 25% of Stage I and Stage II
tumors; in 50–65% of Stage IIA to IIIB tumors; and in 67% of Stage
IVA tumors (14–16). Clinical staging underestimates the surgical
stage in 25–67% of cases and overestimates in 2% (16). A recent study
in 255 surgically staged patients reported that differentiation of Stage
I/IIA versus Stage IIB clinically had a specificity of 63%, accuracy of
75%, and sensitivity of 66% (17). Information derived from cross-
sectional imaging is not mandatory in the FIGO staging classification.
However, imaging is increasingly used, particularly in the assessment
of parametrial invasion. The detection of lymph node metastases
remains of relatively low sensitivity on CT and MR (see p. 444) but
has a high specificity and may alter treatment planning. In addition,
imaging provides a reproducible baseline for assessment of response
in those patients in whom non-surgical treatment is appropriate.
Key Points: Staging
■ The most widely used classification is the FIGO staging system
which is predominantly clinical
■ Although information derived from cross-sectional imaging
is not mandatory in the staging classification, it can be used
for treatment decisions
■ Clinical staging errors are frequent with accuracy of only
about 75%
Prognosis
The overall five-year relative survival rate for 1996–2004 from
17 SEER geographic areas was 71.2% (18). The prognosis for
cervix cancer is closely related to stage at presentation: five-year
survival rate in patients with disease confined to the cervix at
presentation is 91.7%; where there is local spread to the param-
etrium or regional lymph nodes, 55.9%; and where there was
distant spread of disease, 16.6% ( Table 22.2) (18). Tumor vol-
ume is also of prognostic significance in Stage IB/IIA tumors.
For example, patients with Stage IB and IIA tumors greater than
 uterine and cervical tumors

IA IB1 IB2

IB1 ≤ 4 cm

IA1 IA2

IB2 > 4 cm
≤4 cm >4 cm

IIA IIB

IIA1 ≤ 4 cm

IIA2 > 4 cm

IIIA IIIB

IVA IVB

(A)
Figure 22.1 Staging (A) cervical cancer. (Continued)

433
 primary tumor evaluation and staging

IA IA IB

II

IIIC2 - Positive
para-aortic
nodes

IIIB - Vaginal
or parametrial

IIIC1 - Positive
pelvic nodes
IIIA IIIB IIIC

IVA IVB
(B)

Figure 22.1 (Continued ) Staging (B) uterine cancer—primary tumor and metastases (FIGO).

434
 uterine and cervical tumors

Table 22.1 FIGO Staging of Carcinoma of the Cervix Treatment Options

(Revised 2009) The treatment of invasive cervical carcinoma depends upon the
Stage I Invasive carcinoma confined to the cervix
FIGO stage of the tumor at presentation as well as other factors
IA Diagnosed only by microscopy including lymph node status, tumor volume, and the fitness of the
IA1 Micro-invasive carcinoma with stromal invasion ≤3 mm in depth patient. The treatment options include radical surgery or platinum-
and ≤7 mm wide based chemoradiation (22). Treatment with radiotherapy or
IA2 Micro-invasive carcinoma not exceeding 5 mm in depth or 7 mm chemotherapy alone is limited to specific cases.
in width
Stage IB Clinically visible or microscopic lesion >1A2
IB1 Clinical lesions not exceeding 4 cm in diameter Surgical Treatment
IB2 Clinical lesions larger than 4 cm Radical surgery is the treatment of choice for young patients with
Stage II Extension beyond the cervix but not to the pelvic wall early stage disease. The survival outcomes following surgery or
IIA Without parametrial invasion chemo-radiotherapy are similar but surgery is usually preferred in
IIA1 Clinical lesion less not exceeding 4 cm in maximum dimension
young women in order to preserve ovarian function and to reduce the
IIA2 Clinical lesion larger than 4 cm maximum dimension
IIB Parametrial involvement not reaching the pelvic side wall morbidity from late radiation effects. Radical hysterectomy is per-
Stage III Extension to the pelvic wall or the lower third of the vagina. formed, which includes removal of a cuff of parametrial tissue and
Hydronephrosis or non-functioning kidney, unless due to a the vaginal fornices, as well as a pelvic lymphadenectomy, including
cause other than obstruction by tumor removal of the obturator, internal iliac, and common iliac nodes.
IIIA Involves the lower third of the vagina
Radical trachelectomy is a treatment option in patients who
IIIB Extension to the pelvic wall (includes hydronephrosis)
Stage IV Extension beyond the true pelvis or involving bladder or rectum wish to preserve their fertility. In this technique, the cervix is
IVA Involvement of the bladder or rectal mucosa resected from the uterus at the level of the internal os, together
IVB Spread outside the true pelvis or metastasis to distant organs with a cuff of parametrial tissue and the upper vaginal fornices.
The vagina is then anastomosed to the uterine isthmus and an
isthmic cerclage suture is inserted to ensure competency of the
Table 22.2 Stage Distribution at Presentation and Prognosis internal os on subsequent pregnancies (23). Thus the uterine cor-
in Cervical Cancer (SEER) (1) pus and ovaries are left in situ, allowing for future pregnancies.
At presentation (%) 5-yr survival rate (%) MR has been shown to be accurate in depicting the relationship
Tumor confined to cervix 51 91.7 between the proximal aspect of the primary tumor and the inter-
Involvement of parametria 35 55.9 nal os and in excluding the presence of myometrial involvement
or regional nodes (24). The most recent reports show that over 900 procedures have
Distant disease 10 16.6 been performed and published, with 195 live births, and a recur-
Extent of tumor 5 59.4
unknown
rence rate of 4% (23).

Radiotherapy and Chemotherapy

3 cm in diameter have a 40% chance of having lymph node
involvement (19). In patients being treated with radical radio-
therapy, the anterior-posterior dimension of the tumor has
prognostic value: if the tumor dimension exceeds 4 cm there
was a significant increased relative risk of death of 2.4 and there
was a clear correlation between AP dimension and lymph node
metastases (20).
There are conflicting reports about the impact of histology on
prognosis. Some studies have found no significant difference in
outcomes in patients with SCC and adenocarcinoma whilst others
have found a worse prognosis with adenocarcinoma (3). Analysis
of the records of 30,989 patients with histologically confirmed
carcinoma of the cervix between 1973 and 2002 showed histo-
logical type to be an important independent prognostic factor.
Poorest survival was associated with small cell carcinoma, mucinous
adenocarcinoma, and adenosquamous carcinoma (3).
Local recurrence occurs in about one-third of patients, usually
within 1–3 years of primary treatment, with 90% of recurrences
within five years of primary treatment (12,21).
Key Point: Prognosis
■ The stage of the disease, histological subtype, and the presence
or absence of nodal infiltration all influence the prognosis
Patients with bulky IB/IIA disease (tumors larger than 4 cm) or
locally advanced disease (Stages IIB and above) are treated non-
surgically. In the past, four-field radical radiotherapy was used,
comprising external beam and intracavitary treatment. However,
the maximum radiation dose was limited by the tolerance of
normal tissues. The recent development of intensity modulated
radiotherapy (IMRT) has allowed a relative sparing of the nor-
mal tissues with escalation of the dose to the primary tumor
(25). Concomitant treatment with platinum-based chemother-
apy and radical radiotherapy has been shown to reduce local and
distant recurrence and improve overall survival and this is the
current standard of care (22). Patients must be relatively fit with
adequate renal function in order to tolerate chemoradiation;
radiotherapy alone may be more appropriate in patients in poor
general health.
Key Points: Treatment
■ Radical surgery is the treatment of choice in young patients
with early stage disease
■ In patients wishing to preserve fertility, trachelectomy is
feasible if a small tumor lies distal to the internal os
■ Patients with bulky or locally advanced disease are usually
treated with concomitant chemoradiotherapy

435
 primary tumor evaluation and staging
IMAGING TECHNIQUES
Primary Tumor Staging
Ultrasound
Ultrasound is not widely used for the assessment of cervical car-
cinoma. Early stage tumors have been evaluated on both trans-
vaginal and transrectal ultrasound (26–28). Alterations in
vascularity have been detected in patients with a proven cervix
cancer, with a significantly lower resistive index, higher color
score, and higher vascularization index in tumor tissue compared
with normal controls. Intratumoral blood flow also correlates
with the presence of pelvic lymph node metastases (29).
The tumor size may be assessed and the extent of infiltration into
the parametrial tissues may be evaluated. Cervical cancer is seen as
a relatively hypoechoic (60%) or isoechoic (40%) mass within the
cervical stroma, with poorly defined margins (Fig. 22.2) (30). The
relatively high percentage of isoechoic tumors and relative lack of
contrast resolution precludes the identification of some tumors
(30). Parametrial extension is inferred when there is mass-like or
soft tissue stranding extending laterally into the paracervical tissues.
In a small study which compared several diagnostic modalities, the
staging accuracy in early tumors (Stage IIA or less) was 85% for
EUA, 75% for transrectal ultrasound, 65% for MR, and 50% for
spiral CT (30). For more advanced tumors (Stage IIB or greater),
MR had the best correlation with EUA findings. Ultrasound is lim-
ited by its inability to evaluate tumors which extend beyond its focal
range and for the assessment of lymph node metastases.
Computed Tomography
CT may play a role in staging clinically advanced cervical carci-
noma (Stages III–IV) in which error rates for clinical staging are
high (31–33).
In cases where CT is used for staging, for example if there is a
contraindication to MR, the technique should include careful
patient preparation, intravenous contrast administration, and
thin collimation. Ideally, the patient should have a moderately full
(A)
Figure 22.2 (A) Transrectal ultrasound of a patient with clinical Stage IB carcinoma of the cervix. There is smoothly marginated enlargement of the cervix by relatively hyporeflec-
tive tumor (arrows). Hyper-reflective cervical stroma (C) and hyporeflective parametria (P) are also demonstrated. (B) Magnetic resonance in the same patient as (A) demon-
strates tumor surrounded by an intact ring of low signal intensity cervical stroma (Stage IB). The parametria are of high signal intensity due to their vascular and fatty components.
436
bladder to elevate the uterus such that it lies in a relatively vertical
position. The patient is usually given oral water to drink according
to local preference. Using MDCT, a volume is included from the
diaphragm to the perineum in the portal-venous phase following
100 to 120 ml of iodinated contrast medium injected at 2 to 3 ml/
second with thin reconstructions (31). Thin sections allow sagittal
and coronal reformats, which help to delineate the extent of tumor.
Following injection of intravenous contrast medium, the uterus
enhances intensely, the cervical stroma only moderately. The
tumor is usually identifiable as a poorly enhancing mass, although
the intensity is variable.
CT features of parametrial invasion include:
• An irregular or ill-defined interface between the lateral
cervical margins and parametrium (subject to error in
the presence of parametritis)
• Soft tissue stranding extending into the parametrium
(subject to error in the presence of parametritis)
• Obliteration of the fat space around the ureter in
contiguity with the primary tumor
• A soft tissue mass extending into the parametrium in
contiguity with the primary tumor
Pelvic side wall extension is characterized by irregular soft tissue in
direct contiguity with the primary tumor extending to within 3 mm
of the obturator internus muscle and/or the piriformis muscle pos-
terolaterally. If there is frank invasion, these muscles may be enlarged
and demonstrate enhancing soft tissue mass within (31).
Computed tomography criteria for bladder or rectal involvement
are (34):
• Focal loss of the perivesical or perirectal fat plane
accompanied by asymmetric wall thickening
• Nodular indentations or serrations on the inner surface
of the bladder or rectal wall
• An intraluminal mass of tumor contiguous with the
primary mass
• Demonstration of a fistula
(B)
 uterine and cervical tumors

Partial volume averaging effects may cause problems in assessing to identify hydronephrosis or para-aortic lymph node enlargement.
possible spread to the bladder or rectum. Loss of the fat plane may Endoluminal (vaginal) coils have been shown to provide high spa-
be due to tumor abutting the viscus rather than infiltrating. tial resolution in small cervical cancers. However, the field of view
Lymph node metastases can be diagnosed with relatively high is inadequate to assess bulky or advanced disease and assessment of
specificity, particularly if necrosis is seen within a node. However, the extrauterine soft tissues is limited (38–42).
nodal staging suffers from a low sensitivity (see below). The pres-
ence of hydronephrosis or hydroureters should be commented on Sequences (Table 22.3)
as this indicates Stage IIIB disease. Liver and bone metastases are The sequences recommended by the authors are detailed in
rare at the time of presentation. The staging accuracy of CT is Table 22.3. Initially a large field-of-view axial T1-weighted acqui-
discussed later in the chapter, where it is compared to the staging sition is obtained from the level of the renal vessels down to the
accuracy of MR. perineum. This allows the detection of hydronephrosis, para-
The limitations of CT for staging cervical cancer are: aortic lymph node enlargement, and partial views of the liver and
bone marrow. This is followed by a smaller field-of-view axial
• Overstaging IB tumors by misinterpreting normal
acquisition of the pelvis, which gives an overview of the pelvic side-
parametrial structures or inflammation as tumor
walls, lymph nodes, and adnexal regions. A sagittal T2-weighted
• Understaging IIB–IIIB tumors due to microscopic tumor
acquisition is then planned, ideally along the line of the uterus,
spread
and extending to both pelvic side-walls. This provides important
• Difficulty in detection of bladder/rectal invasion
anatomical information concerning the tumor and its relationship
• Inability to identify metastases in normal-sized lymph
to the surrounding structures:
nodes
• The cranio-caudal extent of the tumor can be measured,
and the distance between the tumor and the internal os
Key Points: Cervical Cancer—TVUS and CT can be measured in those patients being considered for
trachelectomy
■ Transrectal ultrasound is a useful technique for measuring
tumor volume and distinguishing tumors confined to the • Invasion into the anterior or posterior fornices can be
assessed, although this is better evaluated at EUA
cervix from those with early parametrial spread
■ Transvaginal Doppler ultrasound is of limited value in
• Involvement of the posterior bladder wall and anterior
wall of the rectum can be assessed
staging carcinoma of the cervix
■ Although CT has limitations in staging carcinoma of the A high-resolution small field-of-view oblique axial acquisition,
cervix, it is accurate in advanced disease perpendicular to the line of the endocervical canal, is then obtained
(Fig. 22.5). This view is of critical importance for the assessment
of parametrial invasion (43). We believe that these sequences will
Magnetic Resonance suffice to answer all the relevant clinical questions. Additional
MR is now the most widely used imaging modality in the preop- sequences including STIR, T1, T1 plus fat saturation, and T1 plus
erative assessment of cervical cancer. The superior soft tissue fat saturation post-gadolinium have shown no advantage over the
delineation and the multiplanar capability are ideal for the delin- high-resolution T2 images (44–47).
eation of cervical tumors. Patient preparation is critical to ensure
high quality diagnostic images. The patient should be fasted for
four hours prior to the study in order to reduce bowel peristalsis. Table 22.3 Recommended Sequences for MR of the Uterus
An antiperistaltic agent may be given intramuscularly or intrave- and Cervix
nously to further reduce peristalsis, which can interfere signifi- Sequence Scan plane Parameters Rationale
cantly with image quality (35). It is helpful if the bladder is partially T1W Axial Large FOV Detect hydronephrosis and
full because if the bladder is too full the patient may become abdo and involvement of retroperi-
uncomfortable during the course of the scan. The patient is usu- pelvis toneal lymph nodes; bone
ally imaged supine. Prone positioning may be helpful if the patient marrow; liver
T2-FSE Axial Large FOV Overview of pelvis; assess
is claustrophobic. An anterior presaturation band is placed over
pelvis ovaries, lymph nodes;
the anterior abdominal wall to reduce breathing motion artifacts. pelvic side wall
Presaturation pulses above and below the imaged volume reduce T2-FSE Sagittal Small FOV Measure cranio-caudal size
intravascular signal from pelvic vessels. pelvis of tumor; position of
High tumor and distance from
resolution internal os; assess vaginal
Coils
fornices, bladder and
Most centers use a surface phased-array coil, which provides a rectum
higher signal-to-noise ratio than the integral body coil, and allows T2-FSE Oblique axial, Small FOV Measure transverse size of
better spatial resolution, and/or reduced imaging time (36,37). perpendicular cervix tumor; assess for
More recently, large surface coils have been developed that cover to endocervical High parametrial invasion,
canal resolution bladder and rectal
both the abdomen and pelvis. If the surface coil only covers the
involvement
pelvis, then the upper abdominal part of the scan can be performed
Abbreviations: FOV, field of view.
with the integral body coil as the image quality is usually adequate

437
 primary tumor evaluation and staging
Normal Uterine Appearances on MR
In a woman of reproductive age, the uterine corpus typically
has three distinctive zones on T2-weighted spin-echo sequences
(Fig. 22.3). Central high signal intensity corresponds to endo-
metrium and any fluid in the endometrial cavity. The endometrial
thickness varies between 5 and 10 mm depending on the phase of the
menstrual cycle. The junctional zone, a band of low signal intensity
between endometrium and outer myometrium, corresponds to the
inner third of the myometrium. Histological correlative studies have
indicated an increased nuclear-to-cytoplasmic ratio in the junctional
zone with a paucity of extracellular matrix around the constituent
smooth muscle fibers (48,49). The outer myometrium has signal
intensity intermediate between that of endometrium and junctional
zone on T2-weighted sequences. Variations in appearance in relation
to the stage of the menstrual cycle are recognized (50).
The stroma of the normal cervix usually has lower signal inten-
sity than the myometrium, reflecting a high proportion of fibrous
connective tissue. However, in women of reproductive age, there
may be three signal intensity layers in the cervix with a “junctional
zone” extending from the myometrium into the cervix, seen dis-
tinctly from the cervical stroma, and the endocervical mucosa,
lined with the plica palmatae (Fig. 22.3).
Women using the oral contraceptive pill develop a swollen, glob-
ular uterus with higher than normal myometrial signal intensity
possibly due to edema (50). The junctional zone is narrow and there
is endometrial atrophy (width <3 mm) with little variation during
the cycle (51). Women taking gonadotrophin-releasing hormone
for treatment of uterine leiomyomata exhibit myometrial and endo-
metrial atrophy and a reduction in myometrial signal intensity.
The uterus in premenarchal and postmenopausal females is
small and featureless on MR, with indistinct zonal anatomy, and
Figure 22.3 Normal uterine anatomy. Sagittal T2-weighted MRI in a pre-
menopausal woman. The three layers of the uterus are clearly delineated. The
endometrial lining is of high signal intensity (*), the junctional zone (the inner
part of the myometrium) is of low signal intensity (short white arrow) and the
myometrium is of intermediate signal intensity (long white arrow). The plica
palmatae of the endocervix may be seen (black arrow).
438
atrophic endometrium less than 2 to 3 mm wide. The corpus and
cervix uteri are of approximately equal length. Myometrial signal
intensity is lower than in women of reproductive age. Patients
who have undergone pelvic radiotherapy also have a very low
signal intensity myometrium. Women taking hormone replacement
therapy have a uterine appearance similar to that of women of
reproductive age.
Key Points: Normal Appearance of the Uterus on MR
■ Women using the oral contraceptive pill have a swollen,
globular, or hyperintense uterus with a narrow junctional zone
■ In postmenopausal women, the uterus is small and featureless
■ Following radiotherapy, the myometrium has a very low
signal intensity
Staging of Cervical Carcinoma on MR (Fig. 22.1A)
MR is of value as an aid to treatment planning in patients with
cervical carcinoma. Firstly, the findings may improve the distinc-
tion between early stage disease (Stage I to IIA) which may be
treated with radical surgery, from advanced disease (Stage IIB and
above) which should be treated with chemoradiotherapy. Secondly,
in those patients who will be treated with chemoradiotherapy, the
findings may contribute to the delineation of the radiotherapy
treatment field.
Stage I
In early stage disease, particularly in screen-detected tumors, there
may be no residual visible disease at the time of the MR staging.
Often the shape of the cervix is distorted due to previous cone
biopsy. A tumor mass which is visible but confined to the cervix is
staged as FIGO IB. The signal intensity of the tumor is typically
mildly hyperintense relative to the low signal intensity of the cer-
vical stroma on T2-weighted images (Figs. 22.4–22.6) (52,53). An
intact low signal intensity ring of cervical stroma, separating the
tumor from the hyperintense parametrium on the oblique axial
images, is consistent with IB disease (Fig. 22.5B) (54). If the mass
is less than 4 cm in greatest dimension it is staged as IB1 and if it is
over 4 cm in greatest dimension then it is IB2 (Fig. 22.6). In
patients in whom trachelectomy is planned, particular attention
must be paid to the distance from the proximal aspect of the
tumor to the internal os. This can be assessed with a high sensitiv-
ity (100%) and specificity (96%) (24). In addition, the length of
the endocervical canal and the length of the uterine cavity to the
fundus should be measured. These measurements, which can be
made with high accuracy, will not only determine whether the
patient is a suitable candidate for trachelectomy but will help the
surgeon accurately resect the cervix (23,24).
Stage II
In Stage IIA disease, there is involvement of the upper two-thirds
of the vaginal fornices. On MR, this is detected as loss of the low
signal intensity of the normal vaginal wall, in contiguity with the
tumor mass (Fig. 22.7). It can be difficult to determine early vagi-
nal infiltration in the fornices in cases where tumor closely abuts
the vaginal wall. The recent FIGO revision has divided IIA into
tumors less than or equal to 4cm (IIA1) and those greater than
 uterine and cervical tumors

(A) (B)
Figure 22.4 Exophytic cervical cancer, FIGO stage IB1. (A) Sagittal and (B) oblique axial T2-weighted images demonstrate a tumor of intermediate signal intensity aris-
ing from the anterior lip of cervix (white arrows). The tumor mass is almost completely exophytic in this case. The posterior lip of cervix is intact (black arrow) and there
is no parametrial invasion.

(A) (B)
Figure 22.5 Endophytic cervical carcinoma stage IB1. (A) Sagittal T2-weighted image demonstrates an intermediate signal intensity mass within the endocervical
canal (white arrow), between the internal os (short black arrow) and external os (black arrow). (B) Oblique axial T2-weighted image perpendicular to endocervical canal
demonstrates distension of the canal by tumor (white arrow) and an intact ring of cervical stroma (black arrow).

4 cm in greatest dimension (IIA2) (12a, 12b). In some centers
ultrasound gel may be instilled into the vagina to better delineate
the vaginal fornices. As the fornices are assessed at EUA, in most
centers jointly by the surgeon and the clinical oncologist, gel is not
widely used to make this evaluation. In Stage IIB disease there is
extension of tumor beyond the cervical stroma and into the
parametrial tissues (Figs. 22.8 and 22.9). The radiological sign for
parametrial invasion is breach of the low signal intensity ring of
cervical stroma, as seen on the oblique axial high resolution images
(54). There may be a spiculated interface between the tumor and
the parametrial tissues, overt soft tissue extending into the param-
etria and along the cardinal or uterosacral ligaments, and in some
cases the cervix may be pulled over to the side with parametrial
invasion.

439
 primary tumor evaluation and staging
Stage III
Stage IIIA is diagnosed if tumor extends down to the lower third
of the vaginal wall. Where tumor has extended into the deep
parametrium, resulting in obstruction of one or both ureters, or
if tumor reaches the level of the vessels along the pelvic side-wall,
the tumor has extended into the “surgical” pelvic side-wall,
consistent with Stage IIIB disease (Figs. 22.10 and 22.14B).
Figure 22.6 Cervical carcinoma FIGO stage 1B2. Sagittal T2-weighted image dem-
onstrates a mass in the endocervical canal and posterior lip of cervix, extending
into the lower uterine segment. The mass is greater than 4 cm in diameter (arrows).
There was no parametrial invasion.
(A)
Figure 22.7 Cervical cancer FIGO stage IIA2. (A) Sagittal and (B) oblique axial T2-weighted images demonstrate a mass greater than 4 cm in maximum dimension in the anterior
lip of cervix (white arrow) which extends into the upper aspect of the anterior vaginal fornix (short black arrows). The posterior vaginal fornix is intact (long black arrow).
440
Stage IV
FIGO Stage IVA disease indicates tumor invasion into the mucosa
of the bladder or rectum that is visible at cystoscopy or sigmoidos-
copy (Figs. 22.11 and 22.12). Stage IVA disease is seen most com-
monly due to bladder invasion, below the level of the peritoneal
reflection, where there is a relative “bare area” of bladder posteri-
orly. There is a relative barrier to invasion posteriorly due to the
deep peritoneal reflection and rectovaginal septum (Fig. 22.13).
Contiguous extension of tumor from the cervix to the wall of
bladder or rectum, with loss of the intervening fat plane, may
indicate serosal involvement. If in addition there is interruption of
the normal low signal intensity muscular layer, this indicates mus-
cle invasion. Both of these findings may not be appreciated at cys-
toscopy, although bullous oedema may be appreciated both on
MR and cystoscopy in many of these cases. Mucosal invasion is
seen as overt tumor nodules within the mucosa of the bladder or
rectum, and this equates to clinical FIGO Stage IVA disease. FIGO
Stage IVA disease can be excluded with a very high negative pre-
dictive value on MR if a low threshold for reporting involvement
of the bladder wall is adopted (55). The high negative predictive
value of MR for Stage IVA disease may obviate the need for inva-
sive cystoscopy and sigmoidoscopy in the majority of patients and
indeed these invasive staging techniques are now used in less than
10% of patients undergoing surgical treatment (56).
Stage IVB indicates distant metastatic disease outside the true
pelvis. The detection of lymph node metastases is paramount and
will be discussed separately below.
Nodal Metastases
The presence of lymph node metastases does not alter the FIGO
stage but significantly affects the prognosis of the patient. Nodal
drainage patterns have been assessed using sentinel node tech-
niques, which identify the first draining node using patent blue
injection with or without lymphoscintigraphy (57,58). The majority
(B)
 uterine and cervical tumors

(A) (B)

(C)
Figure 22.8 Barrel-shaped cervical cancer FIGO stage 2B. (A) Sagittal and (B) oblique axial T2-weighted images demonstrate a large tumor which diffusely infiltrates the whole
cervix, circumferentially (white arrows). Tumor breaches through the low signal intensity ring of the cervical stroma, into the right parametrium (black arrow). (C) Large field
of view images of the pelvis demonstrate the tumor (white arrow) extending into the right parametrium (short black arrow) as well as a parametrial node (long black arrow).

(A) (B)

Figure 22.9 Diffusely infiltrating tumor in the anterior lip of cervix stage IIB. (A) Sagittal T2W MRI demonstrates the intermediate signal intensity of the tumor (arrows)
which has invaded the anterior vaginal fornix. (B) Oblique axial T2W image demonstrates extension of the tumor beyond the cervical stroma, into the parametria bilat-
erally (white arrows), extending along the transverse cervical ligaments (black arrows).

441
 primary tumor evaluation and staging

(A) (B)

(C) (D)
Figure 22.10 Cervical carcinoma FIGO stage IIIB. (A) Sagittal T2W image demonstrates a large mass which engulfs the cervix (white arrow), invades the uterine corpus
and extends anteriorly to touch the bladder wall (black arrow). (B) Oblique axial T2W image demonstrates a small area of residual cervical stroma (short white arrow)
with extensive breach into the parametria bilaterally (long white arrow). The right ureter was involved (black arrow), resulting in obstruction. (C) Following radiother-
apy, most of the cervix returned a low signal intensity (black arrow) but there was residual intermediate signal intensity in the right parametrium (white arrow). (D) This
was the only site of activity on the FDG-PET/CT (white arrow) and the patient was considered suitable for exenteration.

of sentinel nodes lie in the medial external iliac, inter-iliac, and
obturator groups, although other sites include common iliac and
parametrial groups (Fig. 22.14). This correlates well with the site
of the first radiologically visible nodal metastases (59). When stag-
ing more advanced disease, MR may demonstrate para-aortic
lymph node metastases, typically located in the left para-aortic
region (Fig. 22.15). The main criterion used to diagnose a nodal
metastasis is the axial short axis diameter of the node and the
most widely quoted threshold above which the node is considered
malignant is 10 mm short axis. However, MR lacks sensitivity for
the detection of metastases in “normal” sized nodes (between
8–10 mm short axis). If a node is round in shape, with a short axis
to long axis diameter ratio of >0.8, then detection may improve
(60). Nodal metastases may be diagnosed with high specificity if
the axial short axis diameter of the node is greater than 10 mm or
if there is visible necrosis, seen as pockets of high T2 signal intensity,
within the node (Fig. 22.14) (59,61). Other morphological fea-
tures of invasion include soft tissue of the same signal intensity of

442
 uterine and cervical tumors
the tumor within the node and extracapsular extension of tumor
(62). Conversely, a large fatty hilum or a long thin shape are in
favor of a benign node. The diagnostic performance of MR for
nodal metastases is discussed below.
Figure 22.11 Cervical carcinoma FIGO stage IVA with bladder invasion. Sagittal
T2-weighted image demonstrates a large tumor mass in the cervix which invades
the full width of the posterior bladder wall (black arrow). Bullous edema is seen
along the superior bladder wall (white arrow).
(A) (B)
Figure 22.12 Cervical cancer FIGO stage IVA with rectal invasion. (A) Sagittal and (B) oblique axial T2-weighted images demonstrate a large tumor mass (white arrow)
which extends through the fat plane between the cervix and rectum. The rectum and mesorectum are extensively involved (black arrows).
Accuracy of MR Staging
The key criteria for treatment planning include the size of the
tumor, paramatrial invasion, and nodal metastases. The diagnos-
tic performance of MR in these areas will now be considered.
Tumor Size
MR is highly accurate in the assessment of the tumor size. In a
study of 71 surgically confirmed cases, tumor size was accurately
measured on MR with a correlation coefficient of 0.93, with 93%
of cases within 5 mm of the resected size(32). In a retrospective
study of 151 surgically staged patients, the mean difference in size
between MR and histology was –0.9 mm (63). These results are
better than the reported results of clinical assessment of tumor size
(14–16).
Parametrial Invasion
The diagnosis of parametrial invasion relies on the disruption of
the low signal intensity ring of the cervix by the tumor on high-
resolution axial oblique T2-weighted sequences. Preservation of
the low-signal intensity ring has a high negative predictive value
for parametrial invasion of 94% to 100% (45,54,63). The accu-
racy for the detection of parametrial invasion on MR ranges
from 88% to 97%, sensitivity ranges from 44% to 100%, and
specificity ranges from 80 to 97% (32,45,63–66). It is the high
negative predictive value of MR which is useful clinically, by
helping to confidently identify those patients suitable for radical
surgery.
Understaging on MR occurs in the presence of microscopic
tumor extension into the parametrium and overstaging due to
difficulties in differentiating tumor from edema in the tissues sur-
rounding the cervix, particularly in large tumors (54,67).
443
 primary tumor evaluation and staging

Accuracy of MR in Diagnosing Lymph

Node Metastases
Unfortunately, when using standard size criteria to define nor-
mality, the sensitivity for detecting lymph node metastases on
both CT and MR is disappointing. The sensitivities on MR range
from 29% to 86% (17,32,59,66). The diagnostic performance
will depend on the size criteria adopted: if the short axis diameter
of 10 mm is used as the threshold above which the node is con-
sidered malignant, a low sensitivity results with a very high speci-
ficity (>95%). If the threshold is lowered to 8 mm, the sensitivity
for detection of metastases increases, but with a loss of specificity
(59). The presence of necrosis within the node on T2-weighted
MR has a positive predictive value of 100% for nodal involvement,
but this is an infrequent finding and is predominantly found in
nodes which are overtly enlarged (61).
New techniques are being developed to improve the assessment
of lymph node involvement. Lymph node-specific iron oxide
nanoparticle contrast agents have been shown to increase the
sensitivity for detection of nodal metastases with no loss of
specificity, and imaging with FDG-PET/CT may also prove to be
useful (59).

Figure 22.13 Cervical carcinoma with bladder invasion. Sagittal T2-weighted
image demonstrates a rather ill-defined cervical tumor invading anteriorly
into the bladder wall. The peritoneal reflections are well demonstrated in this
case due to a small volume of ascites. The peritoneal reflection between the
bladder and uterus is relatively high (short black arrow), leaving a “bare area”
between the cervix and bladder wall. The peritoneal reflection in the Pouch of
Douglas is deeper (long black arrow), providing a relative barrier to invasion
of the rectum.
Overall Staging Accuracy: CT Compared to MR
The overall staging accuracy of MR has been reported as 77% to
90% (32,53,65,68–70).
In single institution studies, MR performs better than CT in
the depiction of parametrial invasion and overall staging accu-
racy (68,70–72). Studies in which CT and MR were directly com-
pared demonstrated staging accuracies on CT of 53% to 69%

(A) (B)
Figure 22.14 Pelvic lymphadenopathy. (A) Bilateral enlarged nodes are demonstrated along the external iliac vessels and the obturator fossae (arrows). The nodes are of
similar signal intensity to the primary tumor, a sign of involvement. There is extra-capsular extension of tumor from one of the nodes (white arrow), a recognized sign
of involvement. (B) There is extensive necrosis in the bilateral pelvic nodes, indicated by the very high signal intensity (black arrows). The large primary cervical tumor
extends to invade the pelvic side-wall on the right (white arrow).

444
 uterine and cervical tumors
(A)
Figure 22.15 Para-aortic nodal disease. (A) Sagittal T2-weighted image demonstrates a very aggressive cervical carcinoma which diffusely invades the uterus (black
arrows). (B) A lymph node measuring 11 mm in short axis is seen in the left para-aortic region (white arrow). This is highly likely to be involved.
compared with staging accuracies on MR of 77% to 90%
(32,68,73). A meta-analysis of 57 single-institution studies found
that MR was more sensitive than CT in determining the presence
of parametrial invasion (CT was 76–80% accurate, MR was
87–94% accurate) and MR was better at correctly selecting candi-
dates for operative management (70). CT and MR were equiva-
lent for the detection of lymph node metastases.
More recently, in a 25-center prospective study undertaken by
the American College of Radiology Imaging Network (ACRIN)
and the Gynecologic Oncology Group (GOG), MR and CT were
compared in over 170 women with early cervical cancer. The
sensitivity for the detection of advanced disease was relatively
poor for clinical FIGO staging (29%), CT (42%), and MR (53%).
Specificity for detecting advanced disease on clinical FIGO stag-
ing was 99%, CT was 82%, and for MR was 85%. In this study,
CT and MR performed equally for detection of Stage IIB or
higher disease, but staging accuracies were lower than in previ-
ous single institution studies (74). The visualization of the pri-
mary tumor and detection of parametrial invasion and extension
into the uterine body were significantly better on MR than on
CT (33).
Not all authors agree with the use of pre-treatment MR (66). In
one recent study of 255 surgically staged patients, the benefit of
MR was questioned. In this report, patients were categorized as
Stage IIA or less or Stage IIB or more. The accuracy, sensitivity,
and specificity were 75%, 66%, and 81% for clinical staging; 59%,
43%, and 71% for CT; and 58%, 52%, and 63% for MR, respec-
tively. The authors questioned the value of pre-treatment MR
(17). Nevertheless, in most institutions, where available, MR is
regarded as an important adjunct to planning treatment, in early
stage disease in determining suitability for radical surgery or fer-
tility-preserving radical trachelectomy, and in advanced disease
for planning conformal radiotherapy.
(B)
Key Point: CT and MR in Staging Cervix Cancer
■ Although contrast-enhanced MDCT and MR have similar
diagnostic performances in staging early cervix cancer, MR is
far superior in showing the tumor; important for planning
surgery and radiotherapy
MR in Radiotherapy Planning
Conformal radiotherapy treatment planning in carcinoma of the
cervix, endometrium, or vagina uses CT, and increasingly MR, to
guide treatment planning (75). Computed tomography and MR
imaging simulation of radiotherapy planning has shown that when
treatment fields are planned using bony landmarks alone, there is a
significant incidence of geographic tumor misses, particularly in
the anterior and posterior extent of the lateral fields (76). Patient
position and the degree of distension of bladder and bowel can also
affect the position of the pelvic organs (77). With the advent of
sophisticated radiotherapy field design, such as intensity-modu-
lated pelvic radiotherapy, the need to precisely delineate the tumor
[gross tumor volume (GTV)] and surrounding normal tissues at
the time of treatment delivery becomes even more crucial (78). CT
is the standard imaging method, but has inferior soft tissue con-
trast to MR imaging and requires the administration of oral, intra-
venous, and rectal contrast. The GTV measured on CT has been
shown to be substantially larger than that measured on MR (33,79).
Furthermore, MR can define tumor extent without contrast media,
but it has the disadvantage of lack of information about tissue elec-
tron density needed for dosimetry, and is also susceptible to geo-
metric distortion. Work is being done to combine MR imaging and
CT images with radiotherapy planning systems to improve cover-
age of the primary tumor and lymph nodes, whilst reducing dose
to organs at risk, such as the bowel and bladder (80,81).
445
 primary tumor evaluation and staging
NUCLEAR MEDICINE TECHNIQUES IN STAGING,
PROGNOSIS, AND TREATMENT PLANNING
FDG-PET/CT and sentinel node scintigraphy are used in the
assessment of cervical carcinoma.
Sentinel Node Scintigraphy
Sentinel node scintigraphy is a technique which aims to detect the
first draining lymph node from the cervical cancer, using a radio-
nuclide-labeled tracer and patent blue dye. Technetium 99m-labeled
nanocolloid can be injected into the cervix the day before radical
hysterectomy and the draining lymph nodes subsequently identi-
fied intraoperatively using a gamma probe, and removed for histo-
logical examination. Preliminary results show that the technique is
feasible, but the clinical value of sentinel node examination to
exclude metastases and replace formal lymphadenectomy in cervi-
cal cancer remains to be fully evaluated (57,58).
18
FDG-PET/CT
The use of 18FDG-PET imaging is now well established in cervical
cancer as most cervical tumors are FDG-avid. Mucinous adeno-
carcionomas, which usually have low FDG uptake, are an excep-
tion (82). Evaluation of the pelvis can be challenging due to
occasional intense uptake in the rectum or sigmoid, or FDG
activity within the ureters and bladder, and the patient should be
asked to empty her bladder before the study. However, the devel-
opment of PET/CT has allowed better anatomical delineation in
the pelvis. FDG-PET/CT may be used at the time of presentation
in staging and prognosis, to monitor response, to detect recurrent
disease, and to plan radiotherapy.
Primary Tumor Staging
The extent of local tumor invasion within the cervix or the
presence of parametrial invasion cannot be reliably assessed on
PET/CT (82–84). In the context of staging disease at presentation,
PET/CT plays a definite role in the evaluation of metastatic dis-
ease, particularly lymph node metastases. There are two main
clinical situations where PET/CT could potentially play an
important role (85):
• To rule out pelvic lymph node metastases in patients
with early stage disease, in order to select patients for
radical surgery
• To detect para-aortic lymph node metastases in patients
with advanced disease, in order to plan radiotherapy fields
Nodal Staging in Early-Stage Disease
Several studies have investigated the performance of FDG-PET or
FDG-PET/CT in detecting lymph node metastases in patients
with Stage I or II disease, with mixed results (83). When compared
with MR, one retrospective study reported a sensitivity of 91% with
FDG-PET compared to 73% on MR, and specificities of 100% with
FDG-PET compared to 83% on MR (86). The positive predictive
value of FDG-PET was higher than that of MR (0.90 for PET
versus 0.64 for MR, p < 0.05) (86). However, most other authors
report lower sensitivities in early stage disease, ranging from 25% to
73% (84,87–89). In a prospective study of 60 patients who were
446
considered operable, with Stages IA–IIA disease, less than 4 cm in
diameter with no enlarged nodes on MR, only one of 10 positive
pelvic nodes was detected on FDG-PET, although the single positive
para-aortic node was detected (87). This research group has con-
cluded that PET/CT has a limited role in the evaluation of early
stage disease and lymph node dissection remains the gold standard
for the detection of lymph node metastases (87). The sensitivity is
influenced by the nodal size: nodes less than 5 mm short axis cannot
be reliably detected, whereas nodes with increasing diameter were
detected with increasing sensitivity (85,88).
Nodal Staging in Advanced Disease
Nodal metastases are frequent in patients with advanced disease
and FDG-PET has been shown to have a high specificity for the
detection of nodes in this group of patients (83). Prospective stud-
ies have found sensitivities of 75% to 100% and specificities of
87% to 100% (90–93). FDG-PET also improves initial staging in
cases of advanced disease by demonstrating unexpected sites of
disease beyond the pelvis or retroperitioneum, such as supra-
clavicular nodal metastases (83). In patients with advanced disease
at presentation, PET or PET/CT has been found to alter manage-
ment in a significant number of patients (94).
Determining Prognosis and Treatment Response
The extent of metabolic activity [the standardized uptake value
(SUVmax)] in the primary tumor is under investigation as a pos-
sible tool to predict prognosis. Three distinct prognostic groups
were identified in one study of 287 patients with Stage IA2 to IVB
cervix cancer (95). Overall five-year survival rates were 95% for an
SUVmax ≤5.2, 70% for an SUVmax between 5.2 and 13.3, and
44% for an SUVmax >13.3. In this study there was no correlation
between tumor size and SUVmax. The higher the SUVmax pre-
treatment, the greater the likelihood of persistent FDG-uptake
after radical radiotherapy. This study suggests that SUVmax may
be used to predict prognosis in addition to being a potential bio-
marker for response to treatment. FDG-avid para-aortic lymph
nodes have also been found to predict prognosis: para-aortic
nodal disease with an SUVmax of >3.3 was associated with
reduced overall survival (96).
The findings on FDG-PET or PET/CT following treatment with
radiotherapy are highly predictive of prognosis: in one study , in cases
where there was no residual FDG activity, the five-year cause-specific
survival estimate was 80%. In cases where there was residual activity
in the primary tumor or nodes, the survival was 32%. In patients in
whom new anatomic sites of disease were demonstrated, none were
alive at 5 years. The authors concluded that persistent or new FDG
activity following radiotherapy may be predictive of tumor recur-
rence or death but that further prospective validation is needed (97).
In another study, the two-year survival rate in patients with
suspected recurrence clinically was 85% in those patients that
had a negative PET study compared to 10.7% if there was a site of
FDG uptake (98).
Optimization of Treatment
PET/CT may be used to determine the extent of the radiotherapy
field in patients being planned for chemoradiation therapy. Sev-
eral studies have demonstrated that adding PET or PET/CT to the
 uterine and cervical tumors

standard staging techniques resulted in an alteration of treatment

plan in 18% to 45% of patients, either by “downstaging” the
patient, identifying new sites of potentially curable disease, or in
other cases by changing the patient from radical to palliative treat-
ment due to unexpected sites of metastatic disease beyond the
planned treatment field (94,99). FDG-avid para-aortic nodes
could obviate the need for surgico-pathological confirmation and
patients with evidence of para-aortic nodal disease on PET should
be offered extended field radiotherapy (83).
PET/CT may also contribute to radiotherapy treatment plan-
ning by improving the delineation of the gross tumor volume. The
demonstration of the biologically active tissue on PET/CT has
been shown to have a significant impact on radiotherapy plan in
several other tumor types.

DETECTION OF RECURRENT DISEASE

Approximately 30% of women treated for invasive cervical carci-

noma die of residual or recurrent disease. Pelvic recurrence is
often central, arising in the uterus or cervix after radiotherapy, or
in the uterine bed or vagina after surgery (12). Recurrence may be
asymptomatic, detected at clinical examination or on surveillance
cross-sectional imaging. Tumor extension to involve the bladder
or rectum may be complicated by fistula formation. Recurrence
on the pelvic side-wall, due to direct spread or nodal metastases, Figure 22.16 Post-trachelectomy appearance. Sagittal T2-weighted image following
may result in hydronephrosis or symptoms of pain or lower limb fertility preserving surgery for early stage cervical carcinoma. The cervix has been
swelling. Patients treated with pelvic radiotherapy may relapse in removed with a cuff of vaginal fornix and parametrium. The lower uterine segment
extrapelvic sites such as the liver and lungs, despite successful local has been anastomosed onto the upper vagina (white arrow).
control (12).

CT and MR in Detection of Recurrence

Both CT and MR have an important role in the detection of recur-
rent cervical cancer (12,31,100). The accuracy of CT for demon-
strating local recurrence after surgery and/or radiotherapy is 85%
(100). The major difficulty when using CT is the differentiation of
radiation fibrosis and postsurgical change from recurrent disease
(31,100). Vesico-vaginal and recto-vaginal fistulae may also be
difficult to delineate on CT.
MR is an accurate method for detecting recurrent disease in the
pelvis, and is more appropriate than CT in patients treated with
chemoradiotherapy and in surveillance of patients following tra-
chelectomy (Fig. 22.16) (101,102). Following radiotherapy, tumor
recurrence usually manifests as a mass of relatively high signal
intensity within the low signal intensity of the irradiated cervix, in
the uterine bed or on the pelvic side wall (Figs. 22.10 and 22.17).
Established fibrosis usually has low signal intensity on T2-weighted
MR imaging sequences. However, areas of high signal intensity
may also represent inflammation, which is the most likely cause of
a false positive diagnosis of recurrent disease, particularly in the
first 6 months after radiotherapy (102,103). In general, the use of
IV contrast medium has not been shown to improve the ability of
MR to detect tumor recurrence following radiotherapy as both Figure 22.17 Recurrent cervical carcinoma. Axial T2-weighted image demonstrates
a soft tissue mass encasing the vessels of the right pelvic side-wall (white arrow).
recurrent tumor and irradiated tissue enhance, but quantitative
dynamic scanning with analysis of signal intensity-time curves
may allow separation between these distinct entities to be made PET/CT in the Detection of Recurrence
(104,105). MR is also preferable to CT for demonstrating fistulae In patients with suspected recurrence clinically, PET/CT has
(Fig. 22.18). been reported to be accurate in confirming the presence or

447
 primary tumor evaluation and staging
absence of recurrent disease with sensitivities of 90.3% to 92.7%
and specificity of 81% to 100% on a patient basis (Fig. 22.19)
(98,106). This is a higher sensitivity than CT and MR for detect-
ing recurrent disease However, as yet, there is no evidence that
routine surveillance of asymptomatic patients for recurrence
improves survival.
Figure 22.18 Recurrent cervical carcinoma. Sagittal T2-weighted mass invades the
vagina and extends into the urethra, forming a fistula (white arrow). Urine and air
are seen within the lower vagina.
(A) (B)
Figure 22.19 Recurrent cervical carcinoma. (A) Sagittal T2-weighted MRI demonstrates a mass of intermediate soft tissue intensity (black arrow) following completion of treat-
ment with radiotherapy. (B) The mass is FDG-avid on PET/CT (short white arrow). In addition, para-aortic and mediastinal nodal disease is demonstrated (long white arrows).
448
Key Points: Cervical Cancer—Tumor Recurrence
■ Approximately 30% of patients treated for invasive cervical
cancer die of residual/recurrent disease
■ MR and CT are equally accurate in demonstrating recurrence,
but MR is preferable to CT following radiotherapy and in
demonstrating fistulae
■ 18FDG-PET has a higher sensitivity than CT or MR for detecting
cervical carcinoma
ENDOMETRIAL CARCINOMA
Incidence
Endometrial carcinoma is the most prevalent gynaecologic malig-
nancy in the United States and the United Kingdom, and the inci-
dence of endometrial cancer in the United Kingdom has recently
surpassed that of ovarian cancer (2,18). In the United Kingdom,
the incidence of new cases in 2005 was 6891 (21 per 100,000), with
1651 deaths in 2006 (2). The incidence rate rose by 27% between
1996 and 2005 whilst the mortality rate fell by 27% between 1971
and 2005 (2). The age-standardized mortality rate in the United
Kingdom is 3.5 per 100,000 (2).
In the United States in 2004 there were 36,900 new cases of
endometrial cancer (25.3 per 100,000, nearly twice the incidence
of ovarian cancer) and 6900 deaths (1). The age-standardized
mortality rate in the United States is 4.1 per 100,000.
Thus, despite a relatively high incidence, endometrial carcinoma
is not a common cause of cancer death, with a 10-year survival
rate of 75%. The five-year survival rate is 85% for Stage I tumors
and 25% for Stage IV tumors (2).
 uterine and cervical tumors
Etiology
There are several risk factors for endometrial carcinoma. Condi-
tions which result in prolonged unopposed estrogen stimulation of
the endometrial lining predispose to endometrial neoplasia. Excess
estrogen may be exogeneous (unopposed estrogen therapy) or
endogenous, such as in patients with obesity, ovarian malfunction
due to polycystic ovarian syndrome, or estrogen-secreting tumors
such as granulosa-cell and theca-cell tumors of the ovary (107).
Nulliparity also increases the risk (108). Other factors previously
thought to increase the risk are diabetes mellitus and hypertension
but, more recently, Epplein et al. found no association between
endometrial cancer and diabetes mellitus or hypertension (108).
Tamoxifen, a selective estrogen-receptor modulator used in the
treatment of breast cancer, has an estrogenic effect on the endo-
metrium and increases the risk of endometrial carcinoma and
uterine sarcoma (109–111). The risk of developing endometrial
cancer due to tamoxifen increases if, in addition, there is obesity
or if there has been previous use of estrogen replacement therapy
during the menopause. The risk is also dependent on the duration
of treatment (111,112). In patients with breast cancer, the relative
risk for developing endometrial carcinoma in those treated with
tamoxifen is 6.4 to 7.5, compared with those patients not treated
with tamoxifen (107).
Endometrial cancer may occur as part of a hereditary disease,
including hereditary non-polyposis colorectal cancer (HNPCC),
also known as Lynch syndrome II (110). In patients with HNPCC,
screening for endometrial carcinoma may be effective and some
authors advocate prophylactic surgery from the age of 40 years
(113). Early onset of endometrial carcinoma may be the sentinel
cancer event in a family with unrecognized HNPCC (114). Here-
ditary risk evaluation may be appropriate in these families (115).
Key Points: Incidence and Etiology
of Endometrial Cancer
■ The incidence of endometrial cancer has risen in the United
Kingdom and United States over the past decade.
■ Risk factors for endometrial cancer include obesity, nulliparity,
external sources of oestrogen, tamoxifen, HNPCC.
Clinical Features and Diagnosis
Endometrial carcinoma typically presents in postmenopausal
women, with a peak incidence between 55 and 69 years (116).
Postmenopausal bleeding is the most common presenting
complaint and as this usually occurs early in the course of the
disease, most patients have disease limited to the uterus at the
time of presentation (Table 22.4). Premenopausal patients may
present with intermenstrual or abnormal menstrual bleeding, or
occasionally as part of the investigation of infertility.
Following presentation, the initial investigation is usually
ultrasound of the pelvis, including a careful assessment of the
endometrial thickness (see section on Ultrasound). If the endo-
metrium is thickened or if abnormal vaginal bleeding persists,
sampling of the endometrial lining is undertaken. This is com-
monly done as an outpatient procedure using a pipelle biopsy
sampling technique, but may be done in theatre as a hysteroscopy
with dilatation and curettage.
Table 22.4 Stage at Presentation and Prognosis in Endometrial
Cancer (2,3)
FIGO stage Stage at presentation (%) 5-yr survival rate (%)
Stage I 81 83–85
Stage II 11 68–75
Stage III 6 45–52
Stage IV 2 25–52
Pathology
The interpretation of endometrial tissue that is obtained at pipelle
sampling can be challenging and on occasion only a small amount
of endometrial tissue is available (117). Clinical information is
necessary as the menopausal status of the patient as well as the use
of any exogenous hormonal treatments, such as the contraceptive
pill, HRT or tamoxifen, will alter the histologic appearance of the
endometrium.
Endometrial carcinomas fall into two major histological catego-
ries: Type 1 tumors which are well or moderately differentiated,
estrogen-dependent and tend to have a good prognosis; and Type
2 which are aggressive, non-estrogen-dependent tumors such as
clear cell or serous subtypes. Ninety percent of endometrial carci-
nomas are endometriod adenocarcinomas and are divided into
three grades from Grade 1 (well differentiated) to Grade 3 (poorly
differentiated, included in the Type 2 tumors) (118). Less com-
mon histological subtypes, accounting for approximately 7% of
cases, include clear cell carcinoma, and papillary serous carcinoma
(119). The latter two histological subtypes and Grade 3 adenocar-
cinoma carry a worse prognosis. It is recognized that in some cases
an initial diagnosis of Grade 1 histology may be upgraded once
the hysterectomy specimen is assessed (120).
Rare tumors of mesenchymal origin account for approximately
3% of cases. These include endometrial sarcomas, malignant mixed
Mullerian tumors (MMMT), adenosarcomas, and leiomyosarco-
mas. Gestational trophoblastic tumors are very rare and arise from
abnormal proliferation of trophoblastic elements in the fertilized
ovum. These tumors are described later in the chapter.
Prognosis
Histopathology Sub-type; Age; Lymphovascular Space Invasion
The five-year survival rate for patients with endometrial cancer over-
all is relatively high compared with other gynaecologic malignancies,
with a five-year survival rate of 83% in most cases (Table 22.4) (18).
This is in part due to the disease being at an earlier stage at the time
of presentation (121). However, outcomes are affected by the age of
the patient and stage of disease at presentation (Table 22.4) as well as
the histological subtype (2). High-grade endometriod carcinoma,
papillary serous adenocarcinoma, clear cell, or sarcomatous have an
increased rate of recurrence and a poorer prognosis (122). The latter
two histological subtypes in particular carry a worse prognosis (119).
Other poor prognostic factors include deep myometrial invasion,
cervical invasion, lymph node involvement, and a high FIGO stage
of disease (123,124). The depth of myometrial invasion is one of the
most important prognostic factors due to an association with nodal
metastases: in one study, in Grade 3 tumors there was a 9% incidence
of nodal metastases if superficial myometrial invasion was present
(involving the inner third), rising to 34% if deep myometrial inva-
sion was present (involving the outer third) (124). In patients with
449
 primary tumor evaluation and staging
no myometrial invasion and low-grade histology, the five-year sur-
vival rate is 95% whereas in patients with tumor invasion extending
into the outer half of myometrium and high grade histology, the
five-year survival rate is 42% (125).
Significant predictors of poor outcome in patients with recurrent
disease are multiple sites of recurrence, hematogenous, peritoneal
and nodal disease, increasing age at primary surgery, high tumor
grade, and early relapse (126).
Key Points: Endometrial Cancer—Histopathology
and Prognosis
■ Ninety-seven percent are endometriod, clear cell, and papillary
serous adenocarcinomas
■ Prognosis is affected by the age of the patient, stage of the
disease, the grade of the tumor, and certain histological
subtypes such as papillary serous or clear cell
■ Deep myometrial and cervical invasion also carry a poorer
prognosis
Patterns of Tumor Growth
Endometrial cancer arises in the glandular component of the uter-
ine epithelium. The tumor grows either as a polypoid mass within
the uterine cavity or a more diffuse thickening of the endometrial
lining. Invasion of the myometrium occurs by direct spread
through the superficial and deep layers through to the serosal sur-
face. Tumors that penetrate the uterine serosa may directly invade
adjacent organs and may also produce seedling metastases within
the peritoneal cavity. Specific histological subtypes, clear cell, and
papillary serous carcinomas, are particularly prone to peritoneal
spread. Tumor can also extend down the endocervical canal, and
may invade the cervical glandular epithelium or stroma (124). The
uterus has a rich blood supply as well as a rich lymphatic network,
and in advanced disease both lymph node metastases and blood-
borne deposits may occur. Tumors in the upper part of the uterine
body metastasize to the common iliac and para-aortic lymph
nodes. The mid and lower body and the cervix drain to parame-
trial, paracervical, and obturator lymph nodes, and then via the
iliac chains to paraaortic lymph nodes. Inguinal nodes may be
involved by spread along the round ligament or by metastasis from
tumor involvement of the lower vagina.
In patients with recurrent disease, the most frequently observed
sites of relapse are lymph nodes, vagina, peritoneum, and lung
(126). Metastases also occur in the liver, bones, and brain.
Staging and Treatment (Table 22.5)
Clinical evaluation of endometrial cancer by bimanual evaluation
and examination under anesthesia is inaccurate (124,127). The
important staging criteria cannot be adequately assessed as the
depth of myometrial invasion cannot be determined and the pre-
diction of cervical invasion is poor. For example, in one study only
24% of patients thought to have Stage II disease on clinical exam-
ination actually had a true surgical Stage II cancer (127).
As a result, the FIGO staging of endometrial cancer was reclas-
sified in 1988 as a surgico-pathological staging (128). Surgical
staging is retained in the revised FIGO staging for endometrial
(12A, 128A) In order for full FIGO staging to be performed the
450
Table 22.5 FIGO Staging of Carcinoma of the Uterine Corpus
(Revised 2009)
Stage Ia Tumor confined to the corpus uteri
IA Tumor extending to <50% of myometrial depth
IB Tumor extending to >50% of myometrial depth
Stage IIa Tumor invades cervical stroma, but does not extend beyond
the uterus
Stage IIIa Local and/or regional spread of the tumor
IIIA Tumor invades the serosa of the corpus uteri and/or adnexae
IIIB Vaginal and/or parametrial involvement
IIIC Metastases to pelvic and/or para-aortic lymph nodes
IIIC1 Positive pelvic nodes
IIIC2 Positive para-aortic lymph nodes with or without positive pelvic
lymph nodes
Stage IVa Tumor invades bladder and/or bowel mucosa, and/or distant
metastases
IVA Tumor invasion of bladder and/or bowel mucosa
IVB Distant metastases, including intra-abdominal metastases and/or
inguinal lymph nodes
a
Positive cytology obtained at peritoneal washings should be recorded but does
not alter any stage.
patient should undergo total abdominal hysterectomy (TAH),
bilateral salpingo-ophrectomy (BSO), peritoneal washings, and
assessment and sampling of pelvic and para-aortic lymph nodes.
This gives the most accurate staging (129). Imaging is not included
in the standard FIGO classification.
The standard of care for the treatment of endometrial carcinoma
is defined by the surgical staging procedure and TAH/BSO with
peritoneal washings is performed in most patients. Although
lymphadenectomy is part of FIGO staging, the rate of lymph node
involvement in endometrial cancer is low (5–8%) and lymph-
adenectomy has a significant complication rate of 17% to 19%
(122,130). This complication rate is particularly marked in patients
who are at high surgical risk, such as those who are obese, have dia-
betes or ischaemic heart disease (131). Recent reports have also
demonstrated no benefit in overall or disease free survival following
lymphadenectomy (131A,131B). Overall, only approximately 30%
of patients undergo lymph node dissection in the United States
(132). This rate rises to 48.3% in specialized cancer centers (132).
In practice, patients are usually triaged into categories depending
on the extent of poor prognostic factors. Patients at low risk of extra-
uterine spread (Grade 1 or 2 histology, new FIGO Stage <1B) may be
treated with total abdominal hysterectomy and bilateral salpingo-
oopherectomy. In these cases, where there is a low risk of nodal
metastases, formal lymphadenectomy is not always undertaken,
although if a node appears suspicious at the time of surgery, this will
be removed. In patients at high risk of extrauterine spread (Grade
>2, new FIGO Stage >1A), full surgical staging will be performed,
including lymphadenectomy, in most specialist centers. In women
with early stage disease, laparoscopic lymph node dissection and
vaginal hysterectomy offers a minimally invasive technique with a
reduced hospital stay, less pain, and a more rapid return to normal
activities without any difference in complication rate (131,133,134).
The ability to select patients for lymphadenectomy prior to
surgery may therefore be of value. Nodal metastases are related
to histologic grade of tumor, depth of myometrial invasion and
cervical invasion (124). The incidence of pelvic lymph node
 uterine and cervical tumors

involvement has been shown to increase from 3% to 9% with

superficial myometrial invasion (less than one third) to up to 34%
with deep myometrial invasion (invasion of the outer third).
Another factor is cervical stromal invasion: there is a three-fold
greater risk of lymph node involvement in Stage II disease than
Stage I disease (124). Preoperative imaging may help to make this
selection by demonstrating the depth of myometrial invasion by
the tumor and the presence or absence of cervical invasion.
A further important risk factor is the histological grade of the
tumor: the overall risk of lymph node metastases is less than 10% in
those with Stage I disease, except in Grade 3 tumors when the risk is
18% (124,129). However, it is worth noting that following surgical
resection it is found that the pathological grade from the preopera-
tive biopsy sample is inaccurate in up to 15% to 30% of cases (120).

Adjuvant Therapy
The use of adjuvant therapy in endometrial carcinoma remains
controversial and there is no consensus (135). The options avail-
able include external beam radiotherapy (EBRT) and vaginal vault
brachytherapy. Intensity modulated radiotherapy (IMRT) is
becoming more widely available. The role for chemotherapy is yet
to be determined. EBRT has been shown to decrease the risk of
pelvic recurrence but it is uncertain whether it increases patient
survival. Vaginal vault brachytherapy in low-risk endometrial can-
cer results in virtually complete disease-free survival at 5 years. The
roles for EBRT and brachytherapy are currently being investigated
in patients with intermediate risk disease in large trials. Chemo-
therapy may be used (with or with radiotherapy) in selected
patients with aggressive histological subtypes, either in the context
of a clinical trial (PORTEC 3) or as a palliative measure (135).
Key Points: Staging and Treatment
■ Full surgical staging requires lymphadenectomy but this
procedure is associated with morbidity
■ The likelihood of lymph node infiltration is substantially
increased in the presence of deep myometrial invasion, cervical
stromal infiltration, and more aggressive histological subtypes
■ The role of adjuvant therapies in intermediate and high-risk
endometrial cancer is currently under investigation
IMAGING
Ultrasound
Following presentation with abnormal uterine bleeding, transvagi-
nal ultrasound (TVUS) is the first-line imaging test (Fig. 22.20).
This is because TVUS is highly accurate in measuring the endo-
metrial thickness and, in postmenopausal women, endometrial
cancer can be ruled out with a very high probability when the
endometrial thickness is less than or equal to 4 mm (136). A meta-
analysis of TVUS findings in studies involving 5892 women with
postmenopausal bleeding concluded that given a pretest probabil-
ity of endometrial cancer of 10%, an endometrial thickness on
ultrasound of 5 mm or less reduced the post-test probability of
cancer to 1% (137). Ultrasound has a 90% to 96% sensitivity for
detecting endometrial cancer when the threshold of endometrial
thickness of 5 mm or greater is used (136–138).
Figure 22.20 Endometrial carcinoma on transvaginal ultrasound. The endome-
trial stripe (between the white arrows) is distended to 15 mm by a hyperechoic soft
tissue mass, in a woman with post-menopausal bleeding.
The presence of endometrial thickening or an endometrial mass
does not necessarily indicate a malignant lesion: it is not possible
to confidently differentiate endometrial hyperplasia or a benign
endometrial polyp from a cancer (139). Consequently, if the endo-
metrium is found to be thickened, the patient must proceed to
sampling of the endometrium. Endometrial sampling should also
be undertaken in women with a normal ultrasound if abnormal
bleeding persists.
At TVUS, endometrial cancer is seen as thickening of the endo-
metrial stripe by a heterogeneous mass with an irregular, poorly
defined contour. Myometrial invasion is suggested if there is loss
of the subendometrial halo or if the myometrium is heterogenous
with areas of increased echogenicity. The sensitivity for the detec-
tion of deep myometrial invasion on ultrasound has been reported
to be 88% to 93%, with diagnostic accuracies for myometrial inva-
sion of 68% to 81% (140–143). Some authors advocate the use of
Doppler imaging and report that an intratumoral resistive index of
<0.4 is correlated with a high risk of lymph node metastases (144).
However, when TVUS was directly compared with gadolinium-
enhanced MR, the assessment of myometrial invasion was shown
to be superior on MR (143,145).
Computed Tomography
CT is not sensitive or specific enough to assess the depth of
myometrial invasion or cervical involvement (146). The tumor is
usually slightly lower in attenuation than the myometrium and
may be difficult to clearly delineate (147). CT does have a role in
identifying extra-uterine spread (Stage I/II vs. III/IV) and performs
as well as MR in identifying nodal pathology. It may be used in
assessing the extent of metastatic disease in patients with high
grade or sarcomatous pathology, although FDG-PET/CT has been
shown to perform better than CT alone (148). It is also used in
patients in whom disease recurrence is suspected.

451
 primary tumor evaluation and staging
Magnetic Resonance
Once a histological diagnosis of endometrial cancer is made, MR
may be used to assess the extent of disease prior to planning surgi-
cal management (149,150). MR is probably of greatest value in
assessing tumors that may be at risk of extrauterine spread, where
a large tumor mass is seen at ultrasound and the histology is Grade
2 or 3. The use of MR for pretreatment assessment of small endo-
metrial lesions with Grade 1 histology is controversial and MR has
no role in the primary diagnosis of endometrial cancer.
Technique
The protocol is similar to that used for cervical carcinoma, although
gadolinium contrast medium is routinely used. Good technique is
essential: the patient is asked to fast and antiperistaltic agents may
be used to minimize movement artifact from the bowel (35,151).
The patient is also asked to empty her bladder before the examina-
tion to limit artifact (151,152). High resolution T2-weighted images
of the pelvis are obtained in the sagittal plane and in an oblique
axial plane (with a small field-of-view), perpendicular to the endo-
metrial cavity, to assess depth of tumor invasion into the myome-
trium and cervical invasion. Dynamic post-contrast T1-weighted
images are often helpful in this assessment. Ideally, post contrast
images should be acquired in both the sagittal plane and the oblique
axial plane. Optimal tumor-to-myometrial contrast usually occurs
at 50 to 120 seconds after injection of contrast medium (152,153).
Wide field-of-view images of the upper abdomen are obtained to
look for para-aortic lymph node enlargement, metastases and any
complications, such as hydronephrosis (149).
Tumor Appearance
On non-contrast T1-weighted MR images, the zonal anatomy of the
uterus cannot be distinguished, nor can the tumor be clearly visualized.
(A)
Figure 22.21 Endometrial carcinoma FIGO 1A. (A) Sagittal and (B) oblique axial T2-weighted MRI. There is a small volume of intermediate T2 signal intensity soft
tissue within the endometrium (arrows). No breach of the junctional zone is visible and the interface between the tumor and junctional zone is well-defined. This patient
was in her thirties and presented for investigation of infertility.
452
T2-weighted MR images are used to stage the tumor. As discussed
earlier in the chapter, the normal endometrium is of high signal
intensity, having a smooth border with the low signal intensity junc-
tional zone; the myometrium is usually of intermediate signal inten-
sity (Fig. 22.3) (48–50). Endometrial carcinoma is usually mildly
hypointense to endometrium on T2-weighted images; (149,154) usu-
ally hyperintense to the myometrium on T2-weighted sequences, but
may be heterogenous or even of low signal intensity (149,151). On
T1-weighted post-contrast images the tumor typically enhances less
than the normal myometrium, and the contrast between tumor and
myometrium increases to a maximum at approximately 50 to 120 sec-
onds after injection, whereas delayed images at 4 to 5 minutes post-
injection have been found to improve detection of cervical stromal
invasion (147,151,152). Occasionally, high grade tumors may be very
vascular and enhance to the same extent as the myometrium.
Preoperative Staging on MR
The criteria used in the TNM or the FIGO staging system may
be applied to pre-operative MR ( Table 22.5, Fig. 22.1B). In situ
(Stage 0) has recently been removed from the FIGO staging
classification (12A).
Stage I
Stage I tumors, which are confined to the uterine corpus, account
for over 80% of cases. The new FIGO staging classification has
merged the previous stages IA (no myometrial invasion) and IB
(myometrial invasion of less than 50% of myometrial thickness)
into stage IA. In Stage IA disease, the endometrial width is usually
widened, either focally or diffusely, by soft tissue which is of lower
signal intensity that the endometrium. In cases where there is no
invasion interface between the endometrium and the junctional
zone is intact and smooth with no evidence of invasion into the
(B)
 uterine and cervical tumors

junctional zone (Fig. 22.21) (155,156). T1-weighted post-contrast
images help to differentiate viable tumor from debris within the
cavity and to demonstrate the intact band of endometrial enhance-
ment (143,156,157).
Myometrial invasion may be diagnosed when the intermediate
signal of the tumor is seen breeching the junctional zone and
extending into the myometrium on T2-weighted images (Fig. 22.22).
There may be a subtle irregularity between the margin of the
tumor and the junctional zone in cases of early invasion. If tumor
is seen to extend into the deep myometrium that is over 50% of
the myometrial depth, this indicates Stage IB disease (Fig. 22.23).
The delineation of the depth of invasion may be improved
following intravenous injection of gadolinium, which may also
confirm preservation of an intact rim of normal myometrium
(149,156,157). The poorly enhancing tumor is seen within the
avidly enhancing myometrium; following contrast medium injec-
tion; enhancement has been found to be particularly useful in
post-menopausal women (152). The degree of invasion should be
assessed on both the T2-weighted images in the sagittal and
oblique axial views as well as on the post-contrast images.
Pitfalls to interpreting the depth of invasion include:
• Where there is extensive disruption of the myometrium
by tumor, and it is not clear whether the myometrium
is stretched and thinned, or deeply invaded by a large
polypoidal tumor
• Where the myometrium is distrorted by fibroids or
adenomyosis (Figs. 22.24 and 22.25)

(A) (B)

(C)
Figure 22.22 Endometrial carcinoma FIGO stage IA. (A) Sagittal (B) oblique axial (C) Sagittal dynamic post contrast images. There is a polypoid tumor arising from the
anterior myometrium (arrows). There is invasion of the myometrium, extending to <50% of the myometrial thickness. The tumor is typically of intermediate signal
intensity on T2 images. The oblique axial image demonstrates blurring of the interface between tumor and junctional zone. The post-contrast image demonstrates the
typical bright enhancement of the myometrium with intermediate enhancement of the tumor.

453
 primary tumor evaluation and staging
(A)
Figure 22.23 Endometrial carcinoma FIGO 1B in a post-menopausal woman. (A) The tumor (arrow) is poorly defined on the T2-weighted image, in this case. Depth of
myometrial invasion is difficult to assess. (B) Dynamic post contrast image clearly defines the brightly enhancing myometrium from the tumor. The posterior myome-
trium (long black arrow) demonstrates the true depth of myometrium and this can be used to assess the depth of invasion anteriorly (short black arrow), which is greater
than 50% of the myometrial thickness.
Figure 22.24 Fibroid uterus with multi-focal endometrial carcinoma. The presence
of the fibroids distorts the myometrium and can make assessment of depth of
invasion very difficult. The tumor mass in the fundus (long arrow) extends to
the serosal surface. The tumor mass in the lower uterine segment appears to be
confined to the endometrium (short arrow).
• Where the zonal anatomy is poorly defined in a small
atrophic postmenopausal uterus
• Where the tumor extends into the cornu (151,155,156,
158,159)
454
(B)
Errors in the assessment of the depth of invasion may also occur when
the depth is close to 50%, as the exact depth of the myometrium
estimated by the radiologist and the pathologist may vary
slightly.
MR has been shown to be highly sensitive at detecting invasion
but non-specific in differentiating no invasion from early invasion
(155). The reported sensitivities and specificities for the diagnosis
of depth of invasion range from 50% to 100%, but most studies
report sensitivities of between 70% and 95%, and specificities
between 80% and 95% (149,151). It is important to note that deep
invasion can be ruled out with a very high negative predictive
value of 90% (155). This is critical for the triage of patients into a
lower risk category.
Overall, T1-weighted post-contrast sequences have been shown
on meta-analysis to improve the accuracy of detecting deep myo-
metrial invasion when compared to T2-weighted sequences (153).
As a result, it is our practice to routinely include contrast-enhanced
sequences when staging endometrial cancer in order to select
patients for treatment at the specialist cancer center rather than at
the cancer unit.
Stage II
Stage II disease is present if there is invasion of the cervical stroma
(Figs. 22.26 and 22.27). When using the previous FIGO stage II
(which included both endocervical invasion, IIA, or stromal inva-
sion, IIB) this occured in only 7% of endometrial cancer but its
identification is important as 50% to 67% of patients with cervical
invasion have lymph node metastases or other sites of extrauter-
ine disease (127,155,160). Normal cervical stroma is low in signal
intensity on T2-weighted images, and this sequence is good for
assessing invasion by the intermediate signal intensity tumor, in
the sagittal and oblique axial planes. This assessment may be
 uterine and cervical tumors

(A) (B)
Figure 22.25 Endometrial carcinoma in a patient with adenomyosis , stage IA. (A) Sagittal and (B) oblique axial images demonstrate marked thickening of the junctional
zone, consistent with adenomyosis. There is a tumor of intermediate signal intensity filling the endometrial cavity. There appears to be invasion of the inner half of the
myometrium (arrows). Assessment of depth of invasion in the presence of adenomyosis can be difficult as multiple small pockets of high T2 signal intensity within the
myometrium may be due to the adenomyosis rather than the tumor.

(A) (B)
Figure 22.26 Endometrial carcinoma extending into the endocervical canal. (A) Sagittal and (B) oblique axial T2-weighted images demonstrate an intermediate signal
intensity mass (black arrow). This lesion was thought to be confined to the endocervical canal but on histology there was minimal invasion of tumor into the cervical
stroma (FIGO II). In retrospect, there is some thinning of the low signal intensity cervical stroma (white arrow). Minimal invasion of the stroma is difficult to report
confidently and remains a potential pitfall.

improved on late dynamic post-contrast T1-weighted imaging,
which can help to distinguish between true invasion and a poly-
poid tumor protruding into the endocervical canal but not invad-
ing the stroma (147).
Stage II disease is seen as tumor extending into and widening
the internal os and endocervical canal with disruption of the nor-
mal low signal intensity fibrocervical stroma by high signal tumor
on T2-weighted images indicating stromal invasion. Both
T2-weighted and T1-weighted post-contrast images have a high
negative predictive value for cervical invasion of at least 90%
(155).
Overall, the accuracy of MR in cervical involvement is reported
as 90% to 92% with sensitivities of 75% to 80% and specificities of
94% to 96% (52,161,162).

455
 primary tumor evaluation and staging

(A) (B)
Figure 22.27 Endometrial carcinoma FIGO stage II. (A) Sagittal T2-weighted image demonstrates a multifocal tumor within the endometrial cavity, which invades the
outer half of the myometrium (black arrow). There is a non-contiguous tumor nodule in the cervical stroma (white arrow). (B) Oblique axial T2-weighted image clearly
demonstrates invasion of the cervical stroma (white arrow). Non-contigous sites of disease are a potential staging pitfall.

Stage III
Stage IIIA disease encompasses invasion of the uterine serosa or
the adnexae. In the revised FIGO staging, positive peritoneal
cytology from peritoneal washings does not alter the stage of dis-
ease. On T2-weighted images, tumor may be seen in contiguity
extending beyond the outer margin of the uterus. On contrast-
enhanced images, there is loss of the normal rim of brightly
enhancing myometrium. Tumor deposits may be identified in the
ovaries, even in the absence of serosal invasion and particularly in
high grade or serous papillary tumors (Fig. 22.28).
Invasion of the vagina or parametria, either by direct extension
or as metastatic disease, indicates Stage IIIB disease. Vaginal inva-
sion is seen as intermediate signal intensity tumor invading
through the low signal intensity of the vaginal wall on T2-weighted
images.
Stage IIIC disease indicates regional nodal involvement.
Stage IIIC1 indicates positive pelvic nodes whereas IIIC2 indi-
cates positive para-aortic nodes, whether or not the pelvic
nodes are positive. Lymph nodes are seen as low signal inten-
sity within the high signal fat on T1-weighted images or inter-
mediate signal intensity on T2-weighted images (59). Nodal
metastases are distributed along the external iliac and common
iliac vessels (160). Whilst identification of lymph nodes is rela-
tively straightforward, the diagnosis of lymph node metastases
on MR remains unsatisfactory. Nodal diagnosis is discussed
earlier in the chapter.
Stage IV
Stage IVA disease indicates direct infiltration of the bladder or
bowel mucosa, which is seen as a loss of the low signal intensity
wall of the bladder or rectum on T2-weighted images and tumor
nodules in the mucosa of the invaded organ. Distant metastatic
deposits, peritoneal deposits and/or positive inguinal nodes indi-
cate Stage IVB disease (Fig. 22.1B, Table 22.5). Peritoneal deposits
may be seen outlined by ascites and are best seen on delayed
dynamic contrast-enhanced images, but deposits of less than 1 cm
may not be well seen by any imaging modality (147,151).
Key Points: Imaging and Staging
■ MR is more accurate than US or CT in assessing myometrial
and cervical invasion
■ MR is accurate at differentiating superficial from deep
myometrial invasion (FIGO IA from IB)
■ Overall, MR is highly sensitive and specific in identifying
cervical invasion
■ Both CT and MR lack sensitivity in identifying nodal
infiltration
PET/CT and Staging
The main role for FDG-PET/CT in endometrial cancer is not for
the assessment of the primary disease, but for the detection of
extrauterine disease. PET/CT has been compared with MR and
surgico-pathological staging in a group of 53 women with endo-
metrial cancer. MR and PET/CT detected the primary tumor
with equal diagnostic performance. The sensitivity for detection
of lymph node metastases was 46% on MR and although PET/CT
sensitivity was higher, this was not statistically significant. There
was a high negative predictive value for nodal metastases
(94–96%) on both modalities. PET/CT did, however, detect distant

456
 uterine and cervical tumors

(A) (B)

(C) (D)
Figure 22.28 Endometrial carcinoma stage IIIA. (A) and (B) Sagittal T2-weighted images demonstrate the tumor within the endometrial cavity (white arrow). To the left
of midline, there is a tumor deposit lying along the peritoneal reflection between uterus and bladder (black arrow). (C) Oblique axial T2-weighted image demonstrates
the peritoneal mass (black arrow) as well as a mass in the right ovary (white arrow). (D) Axial T1-weighted image following administration of gadolinium demonstrates
enhancement of the right ovarian metastatic deposit.

metastatic disease with a sensitivity of 100% and specificity of
94% (163). These findings have been corroborated by Kitajima
et al., where PET/CT had sensitivity for the detection of nodal
metastases of 50% and specificity of 86% on a per patient basis.
On a node by node basis, metastatic nodes 4 mm or less were
detected with 17% sensitivity; those between 5 mm and 9 mm,
67% sensitivity; and if 10 mm or above, detected with sensitivity
of 93% (148).
Most authors conclude that PET/CT is not sensitive enough to
obviate the need for lymph node dissection.

457
 primary tumor evaluation and staging
RECURRENCE
Follow-up and Imaging
Endometrial cancer has a low locoregional recurrence rate of 4% to
9% (164,165). Factors that predict relapse include age over 60 years,
high-grade histology, lymphovascular space invasion, and stage at
presentation (164,166). Distant relapse is associated with high
FIGO stage, high tumor grade, histological subtype (higher risk of
recurrence with papillary/papillary-serous/clear cell subtypes),
and local disease control (165). In patients with poor prognostic
factors, radiotherapy has been shown to reduce local recurrence,
but had no impact on survival (164). Following primary surgery,
64% of recurrences occur within two years and 87% within three
years (126). The commonest locations for a single site of recur-
rence are lymph nodes (48%) and the vaginal vault (42%) although
recurrent disease may be seen in the peritoneum, liver, lung, or
bones (Fig. 22.29) (126). Early detection of recurrence in asymp-
tomatic patients can have a significant impact on survival but rou-
tine follow-up has a poor yield in asymptomatic patients (167).
The identification of patients at increased risk of recurrence,
together with knowledge of the likely time scale to relapse, can
inform and direct an appropriate strategy for follow-up imaging.
18
FDG-PET has been shown to be very helpful in the assessment
of patients with suspected recurrence (167). The sensitivity, speci-
ficity, diagnostic accuracy, and positive and negative predictive val-
ues of FDG PET imaging in the post-therapy surveillance of
endometrial carcinomas were 96%, 78%, 90%, 89%, and 91%,
respectively. PET findings significantly altered the treatment choice
in nine of 26 patients due to the detection of unsuspected distant
metastatses. In patients clinically suspected of recurrence, PET/CT
is very effective in identifying or excluding recurrent disease (167).
False positive results may occur if the surgery or radiotherapy was
recent. It is our policy to restrict the routine use of MR in surveil-
lance to those patients in whom risk factors increase the likelihood
of recurrence.
(A)
Figure 22.29 Recurrent endometrial carcinoma. (A) CT demonstrates a recurrent mass at the vaginal cuff (arrow) which invades the posterior bladder and the utero-
sacral ligaments. The vaginal cuff is the most frequent site of recurrent disease in endometrial carcinoma. (B) In a different patient, there is a recurrent mass in the
peritoneum (black arrow) and in a left obturator node (white arrow).
458
Key Points: Recurrent Endometrial Cancer
■ Following surgery, 64% of recurrences occur within 2 years
and 87% within 3 years
■ Early detection of recurrence has a significant impact on
survival
■ PET/CT is likely to be substantially more accurate than CT
or MR in detecting recurrent disease
RARE TUMORS OF THE UTERUS
Sarcomas
Sarcomas account for less than 5% of uterine malignancies (107).
Traditionally, uterine sarcomas have been divided into three main
categories:
• Malignant mixed Müllerian tumors (MMMT), often
called carcinosarcoma
• Endometrial stromal sarcomas
• Leiomyosarcomas
Rhabdomyosarcomas are extremely rare. Treatment should be
undertaken in a specialist gynaeoncology center. Surgical removal
of the primary mass and surgical staging is the standard of care.
Depending on the histology, adjuvant chemotherapy may be
considered (168,169).
Endometrial Stromal Cell Sarcomas (Fig. 22.30)
Endometrial stromal sarcomas (ESS) account for 15% to 20% of all
uterine sarcomas and typically occur in premenopausal women.
Depending on the mitotic rate they are classified as low grade or high
grade. Lesions usually originate in the endometrium but invariably
infiltrate the myometrium (170). Rarely, the lesion may originate
within the myometrium due to the presence of endometrial tissue
within the myometrium in adenomyosis (171).
(B)
 uterine and cervical tumors

(A) (B)
Figure 22.30 Endometrial stromal sarcoma on CT in a 50-year-old patient presenting with pelvic pain. (A) Coronal and (B) sagittal reformats demonstrate a large mass
within the myometrium (arrows) and distension of the endometrial cavity. The enhancement of the mass is of similar attenuation to the myometrium.

Low-grade stromal sarcomas may present clinically as a pelvic

mass and suspected leiomyoma, but with an unusual extent of
vaginal bleeding (171,172).
On ultrasound, the tumor may appear as a complex uterine
mass with cystic and nodular solid components (171). On CT, the
tumor appears as a heterogeneous uterine mass with marked
irregular enhancement and curvilinear calcifications (171,173).
On MR, tumors appear either as a polypoid uterine mass or
endometrial thickening with diffuse myometrial infiltration,
which may be sharply demarcated or diffusely infiltrative (170).
The tumor signal intensity is low on T1 and high on T2. Bands of
low signal intensity may be observed within the areas of myome-
trial infiltration on T2, corresponding to bands of preserved
normal myometrium running through the tumor tissue. Tumor
extension along the adjacent vessels, ligaments, or fallopian tubes
may also be seen (170,171,174).

Malignant Mixed Müllerian Tumor

Malignant mixed Müllerian tumors (MMMT), also known as car-
cinosarcomas, are the most frequent form of uterine sarcoma.
Histologically, there are both epithelial and mesenchymal ele-
ments within the tumor. There is increasing evidence that these
tumors represent very poorly differentiated epithelial carcinomas.
These tumors are usually aggressive and tend to spread via the
lymphatics. The initial stage at presentation is the strongest pre-
dictor of survival, with a 60% five-year survival rate in Stage I,
34% in Stage II, and 0% in Stages III and IV disease (175). The
median survival is 30 months (176).
On MR imaging, these tumors are typically large heteroge-
neous endometrial masses with deep myometrial invasion
(Figs. 22.31 and 22.32) (177). Intraperitoneal, ovarian, and lymph
node metastatic disease may be seen. The appearance may be indis-
tinguishable from an endometrial adenocarinoma (177,178).
Figure 22.31 Malignant mixed Mullerian Tumor. Sagittal T1-weighted image with
fat saturation following dynamic enhancment with intravenous gadolinium. The
polypoid tumor mass (arrow) enhances to the same extent as the brightly enhancing
myometrium. When seen in endometrial masses, this radiological sign may alert
the radiologist to an unusual underlying histology or high grade tumor.
Leiomyosarcoma
Leiomyosarcomas are rare tumors, accounting for approximately
1% of uterine malignancies. These tumors may arise from
an underlying fibroid but most are thought to arise de novo.
The behavior varies from indolent to aggressive. In the aggressive
subgroup, metastatic sites are seen early in the course of disease,
with a lower incidence of pelvic lymph nodes compared with

459
 primary tumor evaluation and staging
(A)
Figure 22.32 Malignant mixed Mullerian Tumor, in an 87-year-old patient with post-menopausal bleeding. (A) Sagittal and (B) axial T2-weighted images demonstrate
a heterogeneous tumor mass distending the endometrium and invading the deep myometrium and cervix (black arrows). A non-contiguous mass (white arrow) was
thought to be an unusual fibroid at the time of reporting, but was confirmed to be a further tumor mass at histology.
carcinosarcoma. Spread tends to be hematogenous, with metastases
to the lungs, liver, bones or muscles (179). The indolent subgroup
of tumors tends to be estrogen and progesterone receptor-positive.
In these cases, there may be a delayed pattern of recurrence.
On MR, difficulty may arise in distinguishing these sarcomas
from benign fibroids which are undergoing degeneration, as both
may have a variable appearance with heterogeneous foci of high
T2 signal intensity. It is not possible to distinguish these benign
changes confidently from the appearance of a leiomyosarcoma.
However, although there are only few reports of the MR appear-
ances, certain characteristics should raise the possibility of sar-
comatous change. In one series, nine of 12 lesions had more than
50% high signal intensity areas as well as some small areas of high
T1 signal intensity. There were small high T2 signal intensity
pocket-like areas which were well demarcated and non-enhancing
(178,180). The presence of small cystic pockets of high T2 signal
intensity and enhancement of solid components has been
described in a further study (178).
Key Points: Sarcomas
■ The commonest uterine sarcomas include carcinosarcomas
(MMMT), endometrial stromal cell sarcomas, and
leiomyosarcomas
■ Endometrial stromal cell sarcomas originate in the endome-
trium, infiltrate the myometrium, and occur predominantly
in premenopausal women
■ MMMTs account for <5% of uterine malignancies and
typically are large heterogeneous endometrial masses with
deep myometrial invasion
■ Leiomyosarcomas can be difficult to distinguish from degen-
erating benign fibroids
460
(B)
Gestational Trophoblastic Tumors
Gestational trophoblastic neoplasias are a wide spectrum of placen-
tal tumors that include premalignant hydatidiform mole (complete
and partial), the malignant invasive mole, choriocarcinoma, and
rare placental site trophoblastic tumor (PSTT). It results from
abnormal proliferation of trophoblastic elements in the fertilized
ovum. Clinically, patients present during pregnancy with abnormal
vaginal bleeding, high blood pressure, vomiting, and inappropri-
ately elevated beta-HCG levels. The uterus may be large for dates.
Complete hydatidiform mole is the commonest type, accounting
for 80% of cases. The chromosomally abnormal embryo dies but
does not abort normally and the uterine cavity becomes distended
by a grape-like proliferation of chorionic villi. In partial hydatidi-
form mole, fetal parts are present. Ultrasound is the first-line
imaging investigation and demonstrates a complex multicystic/
solid mass filling the endometrial cavity, with anechoic spaces rep-
resenting hydropic swelling of the villi. Treatment by dilatation
and curettage is usually curative, but there may be persistent or
recurrent disease in 15% to 20%, with persistent elevation of beta-
hCG levels. Penetration of the uterine muscle by trophoblastic
elements indicates an invasive mole.
Choriocarcinoma is carcinoma of the chorionic epithelium sec-
ondary to invasive growth of trophoblast and erosion of blood
vessels. Pulmonary metastases are frequent, due to embolization
of tumor particles into the venous outflow of the uterus, and the
patient may have symptoms of pulmonary embolic disease. Meta-
stases also commonly occur to the vagina as well as other blood-
borne sites. Ultrasound is usually the initial imaging investigation
and demonstrates a uterine mass which is indistinguishable from
a hydatidiform mole (181). However, MR has the advantage of
demonstrating the deep extent of the tumor and the relations
with the other pelvic structures. CT is used for the detection of
metastatic disease (181).
 uterine and cervical tumors
VAGINAL CANCER
Primary vaginal cancer is rare, accounting for only 1% to 2% of
gynaecologic malignancies. There were only 246 new cases
reported in the United Kingdom in 2004, with 103 deaths in 2006
(age-standardized mortality of 0.2 per 100,000) (2). The peak age
incidence is >85 years. In the United States in 2004, there were
1130 new cases and 416 deaths (age-standardized mortality of
0.2 per 100,000) (1).
Etiology, Pathology, and Clinical Features
Approximately 40% of primary vaginal cancers are attributable to
HPV infection (6). Vaginal intraepithelial neoplasia (VAIN),
which is linked to HPV infection, may precede the development of
carcinoma. Most vaginal cancers are squamous cell carcinomas
(85%). There is an association with previous carcinoma of the
cervix and up to 10% of patients have a previous history of
radiotherapy for cervix cancer (182). About 5% to 10% of vaginal
cancers are adenocarcinomas, which typically develop in post-
menopausal women. A subset of women, exposed to diethylstil-
boestriol in utero in the 1950s, are at high risk of developing clear
cell adenocarcinoma at a young age (183). About 2% to 3% of
vaginal cancers are sarcomas, usually leiomyosarcoma, and 2% to
3% are malignant melanoma.
Patients usually present with abnormal vaginal bleeding
(65–80%) or discharge (30%) but many also complain of uri-
nary symptoms, pelvic pain, or a feeling of a mass in the vagina
(184). Diagnosis is made by smear testing or colposcopy and
biopsy.
Primary vaginal carcinomas are defined as arising solely from
the vagina with no involvement of the external os superiorly or
the vulva inferiorly. The tumor usually arises from the upper
posterior vaginal fornix (185,186). Secondary involvement of the
vaginal from an adjacent primary is much more common, including
direct extension, metastasis, or recurrence from a cervical, vulval,
or endometrial cancer.
The staging classification of primary vaginal cancer is by FIGO
( Table 22.6) and is based on findings at clinical examination.
Early stage carcinoma of the vaginal vault may be treated by
vaginectomy and pelvic lymphadenectomy. Inguinal lymph-
adenectomy is performed in tumors of the lower third of the
vagina. Advanced stage tumors are treated by radiotherapy.
Prognosis is stage-dependent, with a five-year survival of about
80% in Stages I–II disease, falling to 20% in Stage III–IV
disease.
Table 22.6 FIGO Staging of Carcinoma of the Vagina
Stage 0 Carcinoma in situ, cervical intraepithelial neoplasia
Stage I Invasive carcinoma confined to the vagina
Stage IA Tumor is <2 cm wide and <1 mm depth of invasion
Stage IB Tumor is >2 cm wide and >1 mm depth of invasion
Stage II Tumor invades paravaginal tissues but not to the pelvic wall
Stage III Extension to the pelvic wall
Stage IVA Extension beyond the true pelvis or invasion of bladder or rectum
Stage IVB Pelvic or inguinal lymphadenopathy, or distant metastases
Imaging
Although imaging is not part of the FIGO staging procedure, it
can provide important information which may help in treat-
ment planning, including the exact location, size and extent of
the tumor, the demonstration of parametrial invasion, extension
to the bladder or rectum, and lymph node metastases (187,188).
CT is used for radiotherapy treatment planning.
MR using a phased-array surface coil is the preferred imaging
modality. The recommended sequences include a T1- and
T2- weighted axial acquisition from the aortic bifurcation to
below the level of the vulva, allowing an overview of the
pelvis and lymph nodes; a sagittal T2-weighted acquisi-
tion extending to both pelvic side-walls, allowing assessment
of the uterus, cervix, bladder, and rectum; and a high resolu-
tion oblique axial acquisition, perpendicular to the long axis of
the vagina. The oblique axial view of the vagina provides the
optimal imaging plane for assessment of extension of the
tumor into the surrounding tissues. Coronal T2-weighted
acquisition may be added to the standard sequences, when a
large tumor is identified, in order to assess involvement of the
pelvic floor.
Primary vaginal tumors are best demonstrated on T2-weighted
images and are seen as an intermediate to high signal intensity
mass arising from the low signal intensity of the vaginal wall.
The vagina may be distended by the mass (Fig. 22.33). The
tumor may appear either as an infiltrating, ulcerative mass,
well-defined and lobulated mass, or result in an annular con-
striction (186). Tumor necrosis, typically seen in high-grade
histological subtypes, may be seen as pockets of very high
T2 signal intensity (186). In Stage I disease, the vaginal muscu-
lar wall appears intact. If there is disruption of the low signal
intensity of the vaginal wall, with tumor extending into the par-
avaginal tissues, this correlates with Stage II disease. Extension
of the mass to the pelvic side-walls or the pelvic floor indicates
Stage III disease. Invasion of the mass into the bladder or rec-
tum indicates Stage IVA disease. Pelvic or inguinal lymph node
enlargement >1 cm short axis indicates Stage IVB disease.
Although lymph nodes in the groin may be assessed clinically,
ultrasound and fine needle aspiration may provide more accu-
rate nodal staging.
Key Points: Vaginal Carcinoma
■ Accounts for only 1% to 2% of all gynecological malignancy
and has a peak incidence at >85 years
■ Most are squamous cell carcinomas
■ On MR, the tumor appears as a mass that can be ulcerative
and infiltrating, well defined and lobulated, or annular
contricting
VULVAL CANCER
Epidemiology
Vulval cancer is rare, accounting for 3% to 5% of gynecological
malignancy (189,190). There were only 1022 new cases reported
461
 primary tumor evaluation and staging

(A) (B)
Figure 22.33 Vaginal carcinoma. (A) Sagittal and (B) oblique axial T2-weighted images demonstrate a well defined intermediate signal intensity mass arising from the
anterior wall of the vagina (arrow). On the oblique axial image, the low signal intensity of the normal posterior vaginal wall can be seen but the anterior muscular wall
is irregular and disrupted.The patient had previously undergone a TAH for benign disease.

in the United Kingdom in 2004, with 350 deaths in 2006 (age-
standardized mortality of 0.6 per 100,000) (2). The peak age inci-
dence is 69 to 85 years (18). In the United States in 2004, there
were 3631 new cases and 806 deaths (age-standardized mortality
of 0.5 per 100,000) (1,18).
Between 1996 and 2004, 61% of cases presented with localized
disease, 29% with involvement of local lymph nodes or direct
extension beyond the primary site and 4% presented with distant
metastases. The overall five-year survival rate was 76.9%, with a
five-year survival rate of 91.5% for localized disease, 56.1% for
regional spread, and 15.9% for distant spread of disease.
The most important prognostic factor is the presence or absence
of lymph node metastases (189).
Most cases are squamous cell carcinoma (190). Rarely, other
tumor types may occur in the vulva, including angiomyxoma
and malignant melanoma.
Staging is according to the FIGO classification, which was recently
revised (12a,190a) (Table 22.7). Tumor spreads locally to the
regional lymph nodes in a stepwise manner: first to the superficial,
then deep inguinal nodes, followed by the pelvic nodes (191).
On MR, small primary tumors and plaque-like tumors may not
be seen. In cases where the tumor is visible, the lesion is usually
isointense to muscle on T1 and intermediate to high in signal
intensity on T2-weighted images, which is the best sequence for
demonstration of the tumor (Fig. 22.34). The role of MR in the
preoperative assessment of vulval cancer has not been fully
defined. The primary tumor may be staged with an accuracy of
70% (192). MR may be of help in delineating the deep extent of
large vulval tumors.
Table 22.7 FIGO Staging of Vulval Cancer (Revised 2009)
Stage I Tumor confined to the vulva
IA Lesions ≤2 cm in size, confined to the vulva or perineum and with
stromal invasion ≤1.0 mm, no nodal metastasis
IB Lesions >2 cm in size or with stromal invasion >1.0 mm, confined
to the vulva or perineum, with negative nodes
Stage II Tumor of any size with extension to adjacent perineal structures
(1/3 lower urethra, 1/3 lower vagina, anus) with negative nodes
Stage III Tumor of any size with or without extension to adjacent perineal
structures (1/3 lower urethra, 1/3 lower vagina, anus) with
positive inguino-femoral lymph nodes
IIIA (i) With one lymph node metastasis (≥5 mm), or
(ii) one to two lymph node metastasis(es) (<5 mm)
IIIB (i) With two or more lymph node metastases (≥5 mm), or
(ii) three or more lymph node metastases (<5 mm)
IIIC With positive nodes with extracapsular spread
Stage IV Tumor invades other regional (2/3 upper urethra, 2/3 upper
vagina) or distant structures
IVA Tumor invades any of the following:
(i) upper urethral and/or vaginal mucosa, bladder mucosa, rectal
mucosa, or fixed to pelvic bone, or
(ii) fixed or ulcerated inguino-femoral lymph nodes
IVB Any distant metastasis including pelvic lymph nodes
Lymph node staging is of critical importance in managing
patients with vulval cancer. Groin surgery is the gold standard
for detection of nodal metastases, but this procedure carries a
high morbidity. A technique which could accurately rule out the
presence of lymph node metastases would allow the avoidance

462
 uterine and cervical tumors

(A) (B)

(C)
Figure 22.34 Vulval cancer. (A) Axial T2-weighted, (B) axial STIR through the vulva demonstrate an intermediate signal intensity mass in the midline (arrows). There is
some high T2 signal intensity, suggesting possible necrosis within the tumor. (C) Axial T2-weighted image at a more cranial position demonstrates an enlarged and
necrotic node in the left inguinal region (black arrow). In addition, the patient has an incidentally detected rectal cancer (white arrow).

of groin surgery in node negative patients. Ultrasound together node biopsy, however, is a promising technique which needs
with fine needle aspiration may be used to evaluate the inguinal further evaluation (196).
nodes (191).
Lymph node staging has been attempted using cross-sectional
imaging techniques and the reported sensitivities for detection Key Points: Vulval Cancer
of nodal metastases range from 40% to 89% (192–195). How-
■ Accounts for only 3% to 5% of gynecological malignancy,
ever, in a review of the literature, it has been suggested that no
majority being squamous carcinoma
non-invasive technique can predict nodal metastases with a
■ Identification of lymph node metastases is of critical clinical,
high enough negative predictive value to accurately select
imaging and prognostic importance
patients to avoid groin surgery. Minimally invasive sentinel

463
 primary tumor evaluation and staging
Summary
■ In patients with endometrial cancer, full surgical staging
requires lymphadenectomy but the procedure results in
morbidity and so risk factors for increased risk of lymph
node metastases including myometrial, cervical invasion,
certain histological subtypes
■ In patients with histologically proven endometrial carcinoma,
imaging is directed toward identifying the presence of deep
myometrial and cervical invasion
■ Endometrial sarcomas are unusual but their presence often
can be suggested on the appearance at MR
■ In patients with cervical cancer, MR is used in conjuction
with examination under anesthesia to direct patient manage-
ment into either surgical treatment or chemoradiotherapy.
Identifying the presence of parametrial invasion is of para-
mount importance
■ In patients with either cervical or endometrial cancer, the
detection of pelvic and para-aortic nodal metastases on MR
and CT is currently based on size criteria, which are highly
specific if the nodal short axis is greater than 10 mm, but
have a low sensitivity for detecting small metastases in nodes
less than 10 mm
■ MR and PET/CT may be used to monitor response to
chemoradiotherapy and to identify recurrent disease
■ In patients with vulval cancer, imaging is predominantly used
to evaluate the inguinal nodes. MR and/or ultrasound with fine
needle aspiration may be used to detect nodal metastases
REFERENCES
1. US Cancer Statistics Working Group. United States Cancer
Statistics: 2004 Incidence and Mortality (US Department of
Health and Human Services, Centers for Disease Control
and Prevention, Atlanta and National Cancer Institute)
2007. [Available from: http://apps.nccd.cdc.gov/uscs].
2. Cancer Research UK. Cancer Stats, 2009. [Available from:
http://info.cancerresearchuk.org/cancerstats].
3. Vinh-Hung V, Bourgain C, Vlastos G, et al. Prognostic value
of histopathology and trends in cervical cancer: a SEER
population study. BMC Cancer 2007; 7: 164.
4. Sigurdsson K. Effect of organized screening on the risk of
cervical cancer. Evaluation of screening activity in Iceland,
1964–1991. Int J Cancer 1993; 54: 563–70.
5. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statis-
tics, 2002. CA Cancer J Clin 2005; 55: 74–108.
6. Parkin DM, Bray F. Chapter 2: The burden of HPV-related
cancers. Vaccine 2006; 24(Suppl 3): S3/11–25.
7. Stanley M. Human papillomavirus vaccines versus cervical
cancer screening. Clin Oncol (R Coll Radiol) 2008; 20: 388–94.
8. Walboomers JM, Jacobs MV, Manos MM, et al. Human
papillomavirus is a necessary cause of invasive cervical can-
cer worldwide. J Pathol 1999; 189: 12–19.
9. Koutsky LA, Holmes KK, Critchlow CW, et al. A cohort
study of the risk of cervical intraepithelial neoplasia grade
2 or 3 in relation to papillomavirus infection. N Engl J Med
1992; 327: 1272–8.
464
10. Vizcaino AP, Moreno V, Bosch FX, et al. International trends
in incidence of cervical cancer: II. Squamous-cell carci-
noma. Int J Cancer 2000; 86: 429–35.
11. Vizcaino AP, Moreno V, Bosch FX, et al. International trends
in the incidence of cervical cancer: I. Adenocarcinoma and
adenosquamous cell carcinomas. Int J Cancer 1998; 75:
536–45.
12. Babar S, Rockall A, Goode A, Shepherd J, Reznek R. Magnetic
resonance imaging appearances of recurrent cervical carci-
noma. Int J Gynecol Cancer 2007; 17: 637–45.
12A. Pecorelli S. Revised FIGO staging for carcinoma of the
vulva, cervix, and endometrium. Int J Gynaecol Obstet
2009; 105: 103–4.
12B. Pecorelli S, Zigliani L, Odicino F. Revised FIGO staging
for carcinoma of the cervix. Int J Gynaecol Obstet 2009;
105: 107–8.
13. Creasman WT. New gynecologic cancer staging. Gynecol
Oncol 1995; 58: 157–8.
14. Van Nagell J Jr, Roddick JW Jr, Lowin DM. The staging of
cervical cancer: inevitable discrepancies between clinical
staging and pathologic findinges. Am J Obstet Gynecol
1971; 110: 973–8.
15. Averette HE, Ford JH Jr, Dudan RC, et al. Staging of cervical
cancer. Clin Obstet Gynecol 1975; 18: 215–32.
16. Lagasse LD, Creasman WT, Shingleton HM, Ford JH,
Blessing JA. Results and complications of operative staging
in cervical cancer: experience of the Gynecologic Oncology
Group. Gynecol Oncol 1980; 9: 90–8.
17. Hancke K, Heilmann V, Straka P, Kreienberg R, Kurzeder C.
Pretreatment staging of cervical cancer: is imaging better
than palpation? Role of CT and MRI in preoperative stag-
ing of cervical cancer: single institution results for
255 patients. Ann Surg Oncol 2008; 15: 2856–61.
18. National Cancer Institute. Surveillance Epidemiology and End
Results. Cancer Statistics. U S National Institues of Health,
2009. [Available from:http://seer.cancer.gov/statistics].
19. Blake P. Cervix. In: Price P, Sikora K, eds. Treatment of
Cancer. London: Chapman and Hall, 1995: 697–719.
20. Shepherd SF, Collins CD, Fryatt IJ, Parsons CA, Blake PR.
Computerized axial tomographic scan measurements as
prognostic indicators in patients with cervical carcinoma.
Br J Radiol 1995; 68: 600–3.
21. Halpin TF, Frick HC, Munnell EW. Critical points of failure
in the therapy of cancer of the cervix: a reappraisal. Am J
Obstet Gynecol 1972; 114: 755–64.
22. Tierney JF, Vale C, Symonds P. Concomitant and neoadju-
vant chemotherapy for cervical cancer. Clin Oncol (R Coll
Radiol) 2008; 20: 401–16.
23. Shepherd JH, Milliken DA. Conservative surgery for carci-
noma of the cervix. Clin Oncol (R Coll Radiol) 2008; 20:
395–400.
24. Peppercorn PD, Jeyarajah AR, Woolas R, et al. Role of MR
imaging in the selection of patients with early cervical car-
cinoma for fertility-preserving surgery: initial experience.
Radiology 1999; 212: 395–9.
25. Taylor A, Powell ME. Conformal and intensity-modulated
radiotherapy for cervical cancer. Clin Oncol (R Coll Radiol)
2008; 20: 417–25.
 uterine and cervical tumors
26. Hsu KF, Su JM, Huang SC, et al. Three-dimensional power
Doppler imaging of early-stage cervical cancer. Ultrasound
Obstet Gynecol 2004; 24: 664–71.
27. Testa AC, Ferrandina G, Distefano M, et al. Color Doppler
velocimetry and three-dimensional color power angiogra-
phy of cervical carcinoma. Ultrasound Obstet Gynecol
2004; 24: 445–52.
28. Tepper R, Zalel Y, Altaras M, Ben Baruch G, Beyth Y.
Transvaginal color Doppler ultrasound in the assessment of
invasive cervical carcinoma. Gynecol Oncol 1996; 60: 26–9.
29. Hsieh CY, Wu CC, Chen TM, et al. Clinical significance of
intratumoral blood flow in cervical carcinoma assessed by
color Doppler ultrasound. Cancer 1995; 75: 2518–22.
30. Yang WT, Walkden SB, Ho S, et al. Transrectal ultrasound in
the evaluation of cervical carcinoma and comparison with
spiral computed tomography and magnetic resonance
imaging. Br J Radiol 1996; 69: 610–16.
31. Pannu HK, Corl FM, Fishman EK. CT evaluation of cervi-
cal cancer: spectrum of disease. Radiographics 2001; 21:
1155–68.
32. Subak LL, Hricak H, Powell CB, Azizi L, Stern JL. Cervical
carcinoma: computed tomography and magnetic resonance
imaging for preoperative staging. Obstet Gynecol 1995; 86:
43–50.
33. Hricak H, Gatsonis C, Coakley FV, et al. Early invasive cervi-
cal cancer: CT and MR imaging in preoperative evaluation—
ACRIN/GOG comparative study of diagnostic performance
and interobserver variability. Radiology 2007; 245: 491–8.
34. Walsh JW. Computed tomography of gynecologic neo-
plasms. Radiol Clin North Am 1992; 30: 817–30.
35. Johnson W, Taylor MB, Carrington BM, Bonington SC,
Swindell R. The value of hyoscine butylbromide in pelvic
MRI. Clin Radiol 2007; 62: 1087–93.
36. Yu KK, Hricak H, Subak LL, Zaloudek CJ, Powell CB. Pre-
operative staging of cervical carcinoma: phased array coil
fast spin-echo versus body coil spin-echo T2-weighted MR
imaging. Am J Roentgenol 1998; 171: 707–11.
37. Hawighorst H, Schoenberg SO, Knapstein PG, et al. Staging
of invasive cervical carcinoma and of pelvic lymph nodes
by high resolution MRI with a phased-array coil in com-
parison with pathological findings. J Comput Assist Tomogr
1998; 22: 75–81.
38. Milestone BN, Schnall MD, Lenkinski RE, Kressel HY. Cer-
vical carcinoma: MR imaging with an endorectal surface
coil. Radiology 1991; 180: 91–5.
39. Kaji Y, Sugimura K, Kitao M, Ishida T. Histopathology
of uterine cervical carcinoma: diagnostic comparison of
endorectal surface coil and standard body coil MRI. J Com-
put Assist Tomogr 1994; 18: 785–92.
40. DeSouza NM, Whittle M, Williams AD, et al. Magnetic
resonance imaging of the primary site in stage I cervical
carcinoma: a comparison of endovaginal coil with exter-
nal phased array coil techniques at 0.5T. J Magn Reson
Imaging 2000; 12: 1020–6.
41. DeSouza NM, Dina R, McIndoe GA, Soutter WP. Cervical
cancer: value of an endovaginal coil magnetic resonance imag-
ing technique in detecting small volume disease and assessing
parametrial extension. Gynecol Oncol 2006; 102: 80–5.
42. Wang LJ, Wong YC, Chen CJ, Huang KG, Hsueh S. Cervical
carcinoma: MR imaging with integrated endorectal/phased-
array coils: a pilot study. Eur Radiol 2001; 11: 1822–7.
43. Shiraiwa M, Joja I, Asakawa T, et al. Cervical carcinoma:
efficacy of thin-section oblique axial T2-weighted images
for evaluating parametrial invasion. Abdom Imaging
1999; 24: 514–19.
44. Scheidler J, Heuck AF, Steinborn M, Kimmig R, Reiser MF.
Parametrial invasion in cervical carcinoma: evaluation of
detection at MR imaging with fat suppression. Radiology
1998; 206: 125–9.
45. Lam WW, So NM, Yang WT, Metreweli C. Detection of
parametrial invasion in cervical carcinoma: role of short tau
inversion recovery sequence. Clin Radiol 2000; 55: 702–7.
46. Iwata S, Joja I, Okuno K, et al. Cervical carcinoma with full-
thickness stromal invasion: efficacy of dynamic MR imag-
ing in the assessment of parametrial involvement. Radiat
Med 2002; 20: 247–55.
47. Van Vierzen PB, Massuger LF, Ruys SH, Barentsz JO. Fast
dynamic contrast enhanced MR imaging of cervical carci-
noma. Clin Radiol 1998; 53: 183–92.
48. Scoutt LM, McCauley TR, Flynn SD, Luthringer DJ,
McCarthy SM. Zonal anatomy of the cervix: correlation of
MR imaging and histologic examination of hysterectomy
specimens. Radiology 1993; 186: 159–62.
49. Brown HK, Stoll BS, Nicosia SV, et al. Uterine junctional
zone: correlation between histologic findings and MR imag-
ing. Radiology 1991; 179: 409–13.
50. McCarthy S, Tauber C, Gore J. Female pelvic anatomy:
MR assessment of variations during the menstrual cycle and
with use of oral contraceptives. Radiology 1986; 160: 119–23.
51. Demas BE, Hricak H, Jaffe RB. Uterine MR imaging: effects
of hormonal stimulation. Radiology 1986; 159: 123–6.
52. Seki H, Azumi R, Kimura M, Sakai K. Stromal invasion
by carcinoma of the cervix: assessment with dynamic MR
imaging. Am J Roentgenol 1997; 168: 1579–85.
53. Hricak H, Lacey CG, Sandles LG, et al. Invasive cervical
carcinoma: comparison of MR imaging and surgical find-
ings. Radiology 1988; 166: 623–31.
54. Kaur H, Silverman PM, Iyer RB, et al. Diagnosis, staging,
and surveillance of cervical carcinoma. Am J Roentgenol
2003; 180: 1621–31.
55. Rockall AG, Ghosh S, Alexander-Sefre F, et al. Can MRI rule
out bladder and rectal invasion in cervical cancer to help select
patients for limited EUA? Gynecol Oncol 2006; 101: 244–9.
56. Amendola MA, Hricak H, Mitchell DG, et al. Utilization of
diagnostic studies in the pretreatment evaluation of inva-
sive cervical cancer in the United States: results of inter-
group protocol ACRIN 6651/GOG 183. J Clin Oncol 2005;
23: 7454–9.
57. Barranger E, Grahek D, Cortez A, et al. Laparoscopic senti-
nel lymph node procedure using a combination of patent
blue and radioisotope in women with cervical carcinoma.
Cancer 2003; 97: 3003–9.
58. Chung YA, Kim SH, Sohn HS, et al. Usefulness of lympho-
scintigraphy and intraoperative gamma probe detection in
the identification of sentinel nodes in cervical cancer. Eur J
Nucl Med Mol Imaging 2003; 30: 1014–17.
465
 primary tumor evaluation and staging
59. Rockall AG, Sohaib SA, Harisinghani MG, et al. Diagnostic
performance of nanoparticle-enhanced magnetic resonance
imaging in the diagnosis of lymph node metastases in
patients with endometrial and cervical cancer. J Clin Oncol
2005; 23: 2813–21.
60. Jager GJ, Barentsz JO, Oosterhof GO, Witjes JA, Ruijs SJ.
Pelvic adenopathy in prostatic and urinary bladder carci-
noma: MR imaging with a three-dimensional TI-weighted
magnetization-prepared-rapid gradient-echo sequence.
Am J Roentgenol 1996; 167: 1503–7.
61. Yang WT, Lam WW, Yu MY, Cheung TH, Metreweli C.
Comparison of dynamic helical CT and dynamic MR imag-
ing in the evaluation of pelvic lymph nodes in cervical car-
cinoma. Am J Roentgenol 2000; 175: 759–66.
62. Barentsz JO, Jager GJ, van Vierzen PB, et al. Staging urinary
bladder cancer after transurethral biopsy: value of fast
dynamic contrast-enhanced MR imaging. Radiology 1996;
201: 185–93.
63. Sahdev A, Sohaib SA, Wenaden AE, Shepherd JH, Reznek
RH. The performance of magnetic resonance imaging in
early cervical carcinoma: a long-term experience. Int J
Gynecol Cancer 2007; 17: 629–36.
64. Sironi S, Belloni C, Taccagni GL, DelMaschio A. Carcinoma
of the cervix: value of MR imaging in detecting parametrial
involvement. Am J Roentgenol 1991; 156: 753–6.
65. Sheu MH, Chang CY, Wang JH, Yen MS. Preoperative stag-
ing of cervical carcinoma with MR imaging: a reappraisal of
diagnostic accuracy and pitfalls. Eur Radiol 2001; 11:
1828–33.
66. Chung HH, Kang SB, Cho JY, et al. Can preoperative MRI
accurately evaluate nodal and parametrial invasion in early
stage cervical cancer? Jpn J Clin Oncol 2007; 37: 370–5.
67. Sheu M, Chang C, Wang J, Yen M. MR staging of clinical
stage I and IIa cervical carcinoma: a reappraisal of efficacy
and pitfalls. Eur J Radiol 2001; 38: 225–31.
68. Kim SH, Choi BI, Han JK, et al. Preoperative staging of
uterine cervical carcinoma: comparison of CT and MRI
in 99 patients. J Comput Assist Tomogr 1993; 17:
633–40.
69. Cobby M, Browning J, Jones A, Whipp E, Goddard P.
Magnetic resonance imaging, computed tomography and
endosonography in the local staging of carcinoma of the
cervix. Br J Radiol 1990; 63: 673–9.
70. Bipat S, Glas AS, van der Velden J, et al. Computed tomog-
raphy and magnetic resonance imaging in staging of uter-
ine cervical carcinoma: a systematic review. Gynecol Oncol
2003; 91: 59–66.
71. Kim SH, Choi BI, Lee HP, et al. Uterine cervical carcinoma:
comparison of CT and MR findings. Radiology 1990; 175:
45–51.
72. Hricak H, Powell CB, Yu KK, et al. Invasive cervical carci-
noma: role of MR imaging in pretreatment work-up—cost
minimization and diagnostic efficacy analysis. Radiology
1996; 198: 403–9.
73. Ozsarlak O, Tjalma W, Schepens E, et al. The correlation of
preoperative CT, MR imaging, and clinical staging (FIGO)
with histopathology findings in primary cervical carci-
noma. Eur Radiol 2003; 13: 2338–45.
466
74. Hricak H, Gatsonis C, Chi DS, et al. Role of imaging in pre-
treatment evaluation of early invasive cervical cancer:
results of the intergroup study American College of Radiol-
ogy Imaging Network 6651-Gynecologic Oncology Group
183. J Clin Oncol 2005; 23: 9329–37.
75. Taylor A, Rockall AG, Powell ME. An atlas of the pelvic
lymph node regions to aid radiotherapy target volume def-
inition. Clin Oncol (R Coll Radiol) 2007; 19: 542–50.
76. Thomas L, Chacon B, Kind M, et al. Magnetic resonance
imaging in the treatment planning of radiation therapy in
carcinoma of the cervix treated with the four-field pelvic
technique. Int J Radiat Oncol Biol Phys 1997; 37: 827–32.
77. Taylor A, Powell ME. An assessment of interfractional uter-
ine and cervical motion: implications for radiotherapy tar-
get volume definition in gynaecological cancer. Radiother
Oncol 2008; 88: 250–7.
78. Roeske JC, Lujan A, Rotmensch J, et al. Intensity-modulated
whole pelvic radiation therapy in patients with gynecologic
malignancies. Int J Radiat Oncol Biol Phys 2000; 48:
1613–21.
79. Mitchell DG, Snyder B, Coakley F, et al. Early invasive cervi-
cal cancer: tumor delineation by magnetic resonance imag-
ing, computed tomography, and clinical examination,
verified by pathologic results, in the ACRIN 6651/GOG 183
Intergroup Study. J Clin Oncol 2006; 24: 5687–94.
80. Viswanathan AN, Dimopoulos J, Kirisits C, Berger D, Potter
R. Computed tomography versus magnetic resonance
imaging-based contouring in cervical cancer brachytherapy:
results of a prospective trial and preliminary guidelines for
standardized contours. Int J Radiat Oncol Biol Phys 2007;
68: 491–8.
81. Taylor A, Rockall AG, Reznek RH, Powell ME. Mapping
pelvic lymph nodes: guidelines for delineation in inten-
sity-modulated radiotherapy. Int J Radiat Oncol Biol
Phys 2005; 63: 1604–12.
82. Iyer RB, Balachandran A, Devine CE. PET/CT and cross
sectional imaging of gynecologic malignancy. Cancer Imag-
ing 2007; 7 Spec No A: S130–S138.
83. Magné N, Chargari C, Vicenzi L, et al. New trends in the
evaluation and treatment of cervix cancer: the role of FDG-
PET. Cancer Treat Rev 2008; 34: 671–81.
84. Park W, Park YJ, Huh SJ, et al. The usefulness of MRI and
PET imaging for the detection of parametrial involvement
and lymph node metastasis in patients with cervical cancer.
Jpn J Clin Oncol 2005; 35: 260–4.
85. Narayan K, Hicks RJ, Jobling T, Bernshaw D, McKenzie AF.
A comparison of MRI and PET scanning in surgically
staged loco-regionally advanced cervical cancer: potential
impact on treatment. Int J Gynecol Cancer 2001; 11:
263–71.
86. Reinhardt MJ, Ehritt-Braun C, Vogelgesang DM, et al.
Metastatic lymph nodes in patients with cervical cancer:
detection with MR imaging and FDG PET. Radiology 2001;
218: 776–82.
87. Chou HH, Chang TC, Yen TC, et al. Low value of [18F]-flu-
oro-2-deoxy-D-glucose positron emission tomography in
primary staging of early-stage cervical cancer before radical
hysterectomy. J Clin Oncol 2006; 24: 123–8.
 uterine and cervical tumors
88. Sironi S, Buda A, Picchio M, et al. Lymph node metastasis in
patients with clinical early-stage cervical cancer: detection
with integrated FDG PET/CT. Radiology 2006; 238: 272–9.
89. Wright JD, Dehdashti F, Herzog TJ, et al. Preoperative
lymph node staging of early-stage cervical carcinoma by
[18F]-fluoro-2-deoxy-D-glucose-positron emission tomog-
raphy. Cancer 2005; 104: 2484–91.
90. Rose PG, Adler LP, Rodriguez M, et al. Positron emission
tomography for evaluating para-aortic nodal metastasis in
locally advanced cervical cancer before surgical staging: a
surgicopathologic study. J Clin Oncol 1999; 17: 41–5.
91. Sugawara Y, Eisbruch A, Kosuda S, et al. Evaluation of FDG
PET in patients with cervical cancer. J Nucl Med 1999; 40:
1125–31.
92. Lin WC, Hung YC, Yeh LS, et al. Usefulness of (18)F-fluoro-
deoxyglucose positron emission tomography to detect
para-aortic lymph nodal metastasis in advanced cervical
cancer with negative computed tomography findings. Gyne-
col Oncol 2003; 89: 73–6.
93. Loft A, Berthelsen AK, Roed H, et al. The diagnostic value
of PET/CT scanning in patients with cervical cancer: a pro-
spective study. Gynecol Oncol 2007; 106: 29–34.
94. Chao A, Ho KC, Wang CC, et al. Positron emission tomog-
raphy in evaluating the feasibility of curative intent in cer-
vical cancer patients with limited distant lymph node
metastases. Gynecol Oncol 2008; 110: 172–8.
95. Kidd EA, Siegel BA, Dehdashti F, Grigsby PW. The stan-
dardized uptake value for F-18 fluorodeoxyglucose is a sen-
sitive predictive biomarker for cervical cancer treatment
response and survival. Cancer 2007; 110: 1738–44.
96. Yen TC, See LC, Lai CH, et al. Standardized uptake value in
para-aortic lymph nodes is a significant prognostic factor
in patients with primary advanced squamous cervical can-
cer. Eur J Nucl Med Mol Imaging 2008; 35: 493–501.
97. Grigsby PW, Siegel BA, Dehdashti F, Rader J, Zoberi I. Post-
therapy [18F] fluorodeoxyglucose positron emission tomo-
graphy in carcinoma of the cervix: response and outcome.
J Clin Oncol 2004; 22: 2167–71.
98. Chung HH, Jo H, Kang WJ, et al. Clinical impact of inte-
grated PET/CT on the management of suspected cervical
cancer recurrence. Gynecol Oncol 2007; 104: 529–34.
99. Yildirim Y, Sehirali S, Avci ME, et al. Integrated PET/CT for
the evaluation of para-aortic nodal metastasis in locally
advanced cervical cancer patients with negative conven-
tional CT findings. Gynecol Oncol 2008; 108: 154–9.
100. Heron CW, Husband JE, Williams MP, Dobbs HJ, Cosgrove
DO. The value of CT in the diagnosis of recurrent carci-
noma of the cervix. Clin Radiol 1988; 39: 496–501.
101. Weber TM, Sostman HD, Spritzer CE, et al. Cervical car-
cinoma: determination of recurrent tumor extent versus
radiation changes with MR imaging. Radiology 1995;
194: 135–9.
102. Williams MP, Husband JE, Heron CW, Cherryman GR,
Koslin DB. Magnetic resonance imaging in recurrent carci-
noma of the cervix. Br J Radiol 1989; 62: 544–50.
103. Hricak H, Swift PS, Campos Z, et al. Irradiation of the cer-
vix uteri: value of unenhanced and contrast-enhanced MR
imaging. Radiology 1993; 189: 381–8.
104. Yamashita Y, Harada M, Torashima M, et al. Dynamic MR
imaging of recurrent postoperative cervical cancer. J Magn
Reson Imaging 1996; 6: 167–71.
105. Kinkel K, Ariche M, Tardivon AA, et al. Differentiation
between recurrent tumor and benign conditions after treat-
ment of gynecologic pelvic carcinoma: value of dynamic
contrast-enhanced subtraction MR imaging. Radiology
1997; 204: 55–63.
106. Sironi S, Picchio M, Landoni C, et al. Post-therapy surveil-
lance of patients with uterine cancers: value of integrated
FDG PET/CT in the detection of recurrence. Eur J Nucl
Med Mol Imaging 2007; 34: 472–9.
107. Rose PG. Endometrial carcinoma. N Engl J Med 1996; 335:
640–9.
108. Epplein M, Reed SD, Voigt LF, et al. Risk of complex and
atypical endometrial hyperplasia in relation to anthropo-
metric measures and reproductive history. Am J Epide-
miol 2008; 168: 563–70.
109. Polin SA, Ascher SM. The effect of tamoxifen on the genital
tract. Cancer Imaging 2008; 8: 135–45.
110. Lavie O, Barnett-Griness O, Narod SA, Rennert G. The risk
of developing uterine sarcoma after tamoxifen use. Int J
Gynecol Cancer 2008; 18: 352–6.
111. Swerdlow AJ, Jones ME. Tamoxifen treatment for breast
cancer and risk of endometrial cancer: a case-control study.
J Natl Cancer Inst 2005; 97: 375–84.
112. Bernstein L, Deapen D, Cerhan JR, et al. Tamoxifen therapy
for breast cancer and endometrial cancer risk. J Natl Cancer
Inst 1999; 91: 1654–62.
113. Kwon JS, Sun CC, Peterson SK, et al. Cost-effectiveness
analysis of prevention strategies for gynecologic cancers in
Lynch syndrome. Cancer 2008; 113: 326–35.
114. Lu KH, Schorge JO, Rodabaugh KJ, et al. Prospective deter-
mination of prevalence of lynch syndrome in young women
with endometrial cancer. J Clin Oncol 2007; 25: 5158–64.
115. Lancaster JM, Powell CB, Kauff ND, et al. Society of Gyne-
cologic Oncologists Education Committee statement on
risk assessment for inherited gynecologic cancer predispo-
sitions. Gynecol Oncol 2007; 107: 159–62.
116. Office for National Statistics. Cancer Statistics Registrations
Series MB1 No. 37, 2006. [Available from: http://www.statis-
tics.gov.uk].
117. McCluggage WG. My approach to the interpretation of endo-
metrial biopsies and curettings. J Clin Pathol 2006; 59:
801–12.
118. Clement PB, Young RH. Endometrioid carcinoma of the
uterine corpus: a review of its pathology with emphasis on
recent advances and problematic aspects. Adv Anat Pathol
2002; 9: 145–84.
119. Clement PB, Young RH. Non-endometrioid carcinomas of
the uterine corpus: a review of their pathology with empha-
sis on recent advances and problematic aspects. Adv Anat
Pathol 2004; 11: 117–42.
120. Ben Shachar I, Pavelka J, Cohn DE, et al. Surgical staging for
patients presenting with grade 1 endometrial carcinoma.
Obstet Gynecol 2005; 105: 487–93.
121. Abeler VM, Kjorstad KE. Endometrial adenocarcinoma in Nor-
way. A study of a total population. Cancer 1991; 67: 3093–103.
467
 primary tumor evaluation and staging
122. Morrow CP, Bundy BN, Kurman RJ, et al. Relationship
between surgical-pathological risk factors and outcome in
clinical stage I and II carcinoma of the endometrium: a
Gynecologic Oncology Group study. Gynecol Oncol 1991;
40: 55–65.
123. Kosary CL. FIGO stage, histology, histologic grade, age and
race as prognostic factors in determining survival for can-
cers of the female gynecological system: an analysis of
1973–87. SEER cases of cancers of the endometrium, cer-
vix, ovary, vulva, and vagina. Semin Surg Oncol 1994; 10:
31–46.
124. Creasman WT, Morrow CP, Bundy BN, et al. Surgical patho-
logic spread patterns of endometrial cancer. A Gynecologic
Oncology Group Study. Cancer 1987; 60(Suppl 8):
2035–41.
125. Amant F, Moerman P, Neven P, et al. Endometrial cancer.
Lancet 2005; 366: 491–505.
126. Sohaib SA, Houghton SL, Meroni R, et al. Recurrent endo-
metrial cancer: patterns of recurrent disease and assessment
of prognosis. Clin Radiol 2007; 62: 28–34.
127. Creasman WT, DeGeest K, Disaia PJ, Zaino RJ. Significance
of true surgical pathologic staging: a Gynecologic Oncol-
ogy Group Study. Am J Obstet Gynecol 1999; 181: 31–4.
128. Shepherd JH. Revised FIGO staging for gynaecological
cancer. Br J Obstet Gynaecol 1989; 96: 889–92.
128A. Creasman W. Revised FIGO staging for carcinoma of the
endometrium. Int J Gynaecol Obstet 2009; 105: 109.
129. Boronow RC, Morrow CP, Creasman WT, et al. Surgical
staging in endometrial cancer: clinical-pathologic findings
of a prospective study. Obstet Gynecol 1984; 63: 825–32.
130. McMeekin DS, Lashbrook D, Gold M, et al. Nodal distribu-
tion and its significance in FIGO stage IIIc endometrial
cancer. Gynecol Oncol 2001; 82: 375–9.
131. Tozzi R, Malur S, Koehler C, Schneider A. Analysis of morbid-
ity in patients with endometrial cancer: is there a commit-
ment to offer laparoscopy? Gynecol Oncol 2005; 97: 4–9.
131A. Kitchener H, Swart AM, Qian Q, Amos C, Parmar MK.
Efficacy of systematic pelvic lymphadenectomy in endo-
metrial cancer (MRC ASTEC trial): a randomised study.
Lancet 2009; 373: 125–36.
131B. Benedetti Panici P, Basile S, Maneschi F, et al. Systematic
pelvic lymphadenectomy vs. no lymphadenectomy in
early-stage endometrial carcinoma: randomized clinical
trial. J Natl Cancer Inst 2008; 100: 1707–16.
132. Partridge EE, Shingleton HM, Menck HR. The National
Cancer Data Base report on endometrial cancer. J Surg
Oncol 1996; 61: 111–23.
133. Eltabbakh GH, Shamonki MI, Moody JM, Garafano LL.
Laparoscopy as the primary modality for the treatment of
women with endometrial carcinoma. Cancer 2001; 91:
378–87.
134. Fagotti A, Ferrandina G, Longo R, Mancuso S, Scambia G.
Minilaparotomy in early stage endometrial cancer: an alter-
native to standard and laparoscopic treatment. Gynecol
Oncol 2002; 86: 177–83.
135. Kong A, Powell M, Blake P. The role of postoperative
radiotherapy in carcinoma of the endometrium. Clin Oncol
(R Coll Radiol) 2008; 20: 457–62.
468
136. Karlsson B, Granberg S, Wikland M, et al. Transvaginal
ultrasonography of the endometrium in women with post-
menopausal bleeding—a Nordic multicenter study. Am J
Obstet Gynecol 1995; 172: 1488–94.
137. Smith-Bindman R, Kerlikowske K, Feldstein VA, et al.
Endovaginal ultrasound to exclude endometrial cancer
and other endometrial abnormalities. JAMA 1998; 280:
1510–17.
138. Tsikouras P, Liberis V, Galazios G, et al. TV sonographic
assessment in postmenopausal women with bleeding. Eur J
Gynaecol Oncol 2008; 29: 67–71.
139. Davidson KG, Dubinsky TJ. Ultrasonographic evaluation
of the endometrium in postmenopausal vaginal bleeding.
Radiol Clin North Am 2003; 41: 769–80.
140. DelMaschio A, Vanzulli A, Sironi S, et al. Estimating the
depth of myometrial involvement by endometrial carci-
noma: efficacy of transvaginal sonography vs MR imaging.
Am J Roentgenol 1993; 160: 533–8.
141. Prömpeler HJ, Madjar H, du Bois A, et al. Transvaginal
sonography of myometrial invasion depth in endometrial
cancer. Acta Obstet Gynecol Scand 1994; 73: 343–6.
142. Fishman A, Altaras M, Bernheim J, et al. The value of trans-
vaginal sonography in the preoperative assessment of myo-
metrial invasion in high and low grade endometrial cancer
and in comparison to frozen section in grade 1 disease. Eur
J Gynaecol Oncol 2000; 21: 128–30.
143. Yamashita Y, Mizutani H, Torashima M, et al. Assessment of
myometrial invasion by endometrial carcinoma: transvagi-
nal sonography vs contrast-enhanced MR imaging. Am J
Roentgenol 1993; 161: 595–9.
144. Cheng WF, Chen CA, Lee CN, et al. Preoperative ultrasound
study in predicting lymph node metastasis for endometrial
cancer patients. Gynecol Oncol 1998; 71: 424–7.
145. Kim SH, Kim HD, Song YS, Kang SB, Lee HP. Detection of
deep myometrial invasion in endometrial carcinoma: com-
parison of transvaginal ultrasound, CT, and MRI. J Com-
put Assist Tomogr 1995; 19: 766–72.
146. Hardesty LA, Sumkin JH, Hakim C, Johns C, Nath M. The
ability of helical CT to preoperatively stage endometrial
carcinoma. Am J Roentgenol 2001; 176: 603–6.
147. Ascher SM, Reinhold C. Imaging of cancer of the endo-
metrium. Radiol Clin North Am 2002; 40: 563–76.
148. Kitajima K, Murakami K, Yamasaki E, et al. Accuracy of
18F-FDG PET/CT in detecting pelvic and paraaortic lymph
node metastasis in patients with endometrial cancer. Am J
Roentgenol 2008; 190: 1652–8.
149. Barwick TD, Rockall AG, Barton DP, Sohaib SA. Imaging
of endometrial adenocarcinoma. Clin Radiol 2006; 61:
545–5.
150. Hricak H, Stern JL, Fisher MR, et al. Endometrial carci-
noma staging by MR imaging. Radiology 1987; 162:
297–305.
151. Sala E, Wakely S, Senior E, Lomas D. MRI of malignant
neoplasms of the uterine corpus and cervix. Am J Roent-
genol 2007; 188: 1577–87.
152. Joja I, Asakawa M, Asakawa T, et al. Endometrial carcinoma:
dynamic MRI with turbo-FLASH technique. J Comput
Assist Tomogr 1996; 20: 878–87.
 uterine and cervical tumors
153. Frei KA, Kinkel K, Bonel HM, et al. Prediction of deep myo-
metrial invasion in patients with endometrial cancer: clini-
cal utility of contrast-enhanced MR imaging-a
meta-analysis and Bayesian analysis. Radiology 2000; 216:
444–9.
154. Manfredi R, Gui B, Maresca G, Fanfani F, Bonomo L.
Endometrial cancer: magnetic resonance imaging. Abdom
Imaging 2005; 30: 626–36.
155. Rockall AG, Meroni R, Sohaib SA, et al. Evaluation of endo-
metrial carcinoma on magnetic resonance imaging. Int J
Gynecol Cancer 2007; 17: 188–96.
156. Sironi S, Colombo E, Villa G, et al. Myometrial invasion by
endometrial carcinoma: assessment with plain and gado-
linium-enhanced MR imaging. Radiology 1992; 185:
207–12.
157. Ito K, Matsumoto T, Nakada T, et al. Assessing myometrial
invasion by endometrial carcinoma with dynamic MRI.
J Comput Assist Tomogr 1994; 18: 77–86.
158. Yamashita Y, Harada M, Sawada T, et al. Normal uterus
and FIGO stage I endometrial carcinoma: dynamic gado-
linium-enhanced MR imaging. Radiology 1993; 186:
495–501.
159. Kinkel K. Pitfalls in staging uterine neoplasm with imaging:
a review. Abdom Imaging 2006; 31: 164–73.
160. Mariani A, Webb MJ, Keeney GL, Podratz KC. Routes of
lymphatic spread: a study of 112 consecutive patients with
endometrial cancer. Gynecol Oncol 2001; 81: 100–4.
161. Manfredi R, Mirk P, Maresca G, et al. Local-regional staging
of endometrial carcinoma: role of MR imaging in surgical
planning. Radiology 2004; 231: 372–8.
162. Toki T, Oka K, Nakayama K, Oguchi O, Fujii S. A compara-
tive study of pre-operative procedures to assess cervical
invasion by endometrial carcinoma. Br J Obstet Gynaecol
1998; 105: 512–16.
163. Park JY, Kim EN, Kim DY, et al. Comparison of the validity
of magnetic resonance imaging and positron emission
tomography/computed tomography in the preoperative
evaluation of patients with uterine corpus cancer. Gynecol
Oncol 2008; 108: 486–92.
164. Creutzberg CL, van Putten WL, Koper PC, et al. Surgery
and postoperative radiotherapy versus surgery alone for
patients with stage-1 endometrial carcinoma: multicentre
randomised trial. PORTEC Study Group. Post operative
radiation therapy in endometrial carcinoma. Lancet 2000;
355: 1404–11.
165. Corn BW, Lanciano RM, D’agostino R, et al. The relation-
ship of local and distant failure from endometrial cancer:
defining a clinical paradigm. Gynecol Oncol 1997; 66:
411–16.
166. Creutzberg CL, van Putten WL, Warlam-Rodenhuis CC,
et al. Outcome of high-risk stage IC, grade 3, compared
with stage I endometrial carcinoma patients: the postoper-
ative radiation therapy in endometrial carcinoma trial. J
Clin Oncol 2004; 22: 1234–41.
167. Belhocine T, De Barsy C, Hustinx R, Willems-Foidart J.
Usefulness of (18)F-FDG PET in the post-therapy surveillance
of endometrial carcinoma. Eur J Nucl Med Mol Imaging
2002; 29: 1132–9.
168. Reed NS. The management of uterine sarcomas. Clin Oncol
(R Coll Radiol) 2008; 20: 470–8.
169. Reed NS, Mangioni C, Malmstrom H, et al. Phase III
randomised study to evaluate the role of adjuvant pelvic
radiotherapy in the treatment of uterine sarcomas stages I
and II: an European Organisation for Research and Treat-
ment of Cancer Gynaecological Cancer Group Study (pro-
tocol 55874). Eur J Cancer 2008; 44: 808–18.
170. Koyama T, Togashi K, Konishi I, et al. MR imaging of endo-
metrial stromal sarcoma: correlation with pathologic find-
ings. Am J Roentgenol 1999; 173: 767–72.
171. Toprak U, Pasaoglu E, Karademir MA, Gulbay M. Sono-
graphic, CT, and MRI findings of endometrial stromal sar-
coma located in the myometrium and associated with
peritoneal inclusion cyst. Am J Roentgenol 2004; 182:
1531–3.
172. Chien JC, Hsieh SC, Lee RC, et al. Endometrial stromal sar-
coma mimicking submucosal myoma protruding to the
vagina: MRI findings. Eur J Gynaecol Oncol 2005; 26:
657–60.
173. Pekindil G, Tuncyurek O, Orguc S, et al. A case of endome-
trial stromal sarcoma with curvilinear calcification. Gyne-
col Oncol 2005; 98: 318–21.
174. Koyama T, Tamai K, Togashi K. Staging of carcinoma of the
uterine cervix and endometrium. Eur Radiol 2007; 17:
2009–19.
175. Ivy JJ, Unger JB. Malignant mixed mullerian sarcomas of
the uterus—the LSUHSC Shreveport experience. J La State
Med Soc 2004; 156: 324–6.
176. Inthasorn P, Carter J, Valmadre S, et al. Analysis of clinico-
pathologic factors in malignant mixed Mullerian tumors of
the uterine corpus. Int J Gynecol Cancer 2002; 12: 348–53.
177. Shapeero LG, Hricak H. Mixed mullerian sarcoma of the
uterus: MR imaging findings. Am J Roentgenol 1989; 153:
317–19.
178. Sahdev A, Sohaib SA, Jacobs I, et al. MR imaging of uterine
sarcomas. Am J Roentgenol 2001; 177: 1307–11.
179. O’Brien JM, Brennan DD, Taylor DH, et al. Skeletal muscle
metastasis from uterine leiomyosarcoma. Skeletal Radiol
2004; 33: 655–9.
180. Tanaka YO, Nishida M, Tsunoda H, Okamoto Y, Yoshikawa
H. Smooth muscle tumors of uncertain malignant poten-
tial and leiomyosarcomas of the uterus: MR findings. J
Magn Reson Imaging 2004; 20: 998–1007.
181. Allen SD, Lim AK, Seckl MJ, Blunt DM, Mitchell AW. Radi-
ology of gestational trophoblastic neoplasia. Clin Radiol
2006; 61: 301–13.
182. Merino MJ. Vaginal cancer: the role of infectious and
environmental factors. Am J Obstet Gynecol 1991; 165(4 Pt
2): 1255–62.
183. Rubin MM. Antenatal exposure to DES: lessons learned…
future concerns. Obstet Gynecol Surv 2007; 62: 548–55.
184. Dixit S, Singhal S, Baboo HA. Squamous cell carcinoma of
the vagina: a review of 70 cases. Gynecol Oncol 1993; 48:
80–7.
185. Al Kurdi M, Monaghan JM. Thirty-two years experience in
management of primary tumors of the vagina. Br J Obstet
Gynaecol 1981; 88: 1145–50.
469
 primary tumor evaluation and staging
186. Parikh JH, Barton DP, Ind TE, Sohaib SA. MR imaging fea-
tures of vaginal malignancies. Radiographics 2008; 28: 49–63.
187. Chang SD. Imaging of the vagina and vulva. Radiol Clin
North Am 2002; 40: 637–58.
188. Siegelman ES, Outwater EK, Banner MP, et al. High-
resolution MR imaging of the vagina. Radiographics 1997;
17: 1183–203.
189. Homesley HD. Management of vulvar cancer. Cancer 1995;
76(Suppl 10): 2159–70.
190. Joura EA, Losch A, Haider-Angeler MG, Breitenecker G,
Leodolter S. Trends in vulvar neoplasia. Increasing incidence
of vulvar intraepithelial neoplasia and squamous cell carci-
noma of the vulva in young women. J Reprod Med 2000; 45:
613–15.
190A. Hacker NF. Revised FIGO staging for carcinoma of the
vulva. Int J Gynaecol Obstet 2009; 105: 105–6.
191. Sohaib SA, Moskovic EC. Imaging in vulval cancer. Best
Pract Res Clin Obstet Gynaecol 2003; 17: 543–56.
470
192. Sohaib SA, Richards PS, Ind T, et al. MR imaging of car-
cinoma of the vulva. Am J Roentgenol 2002; 178:
373–7.
193. Bipat S, Fransen GA, Spijkerboer AM, et al. Is there a role
for magnetic resonance imaging in the evaluation of
inguinal lymph node metastases in patients with vulva
carcinoma? Gynecol Oncol 2006; 103: 1001–6.
194. Singh K, Orakwue CO, Honest H, et al. Accuracy of
magnetic resonance imaging of inguinofemoral lymph
nodes in vulval cancer. Int J Gynecol Cancer 2006; 16:
1179–83.
195. Hawnaur JM, Reynolds K, Wilson G, Hillier V, Kitchener
HC. Identification of inguinal lymph node metastases from
vulval carcinoma by magnetic resonance imaging: an initial
report. Clin Radiol 2002; 57: 995–1000.
196. Oonk MH, Hollema H, de Hullu JA, van der Zee AG. Pre-
diction of lymph node metastases in vulvar cancer: a review.
Int J Gynecol Cancer 2006; 16: 963–71.
 23 Primary Retroperitoneal Tumors
Isaac R Francis, Richard H Cohan, Datla GK Varma, and Sandra Wong
INTRODUCTION
Primary tumors originating in the retroperitoneum are extremely
uncommon. However, when they occur, the vast majority of these
primary retroperitoneal neoplasms are malignant. Primary retro-
peritoneal tumors can be divided into (i) those arising from the
mesenchyme (soft tissue sarcomas); (ii) those arising from germ
cells (extragonadal germ cell tumors); (iii) those arising from
hematopoietic tissue—lymph nodes (lymphoma).
RETROPERITONEAL SARCOMAS
Incidence and Pathology
Retroperitoneal soft tissue sarcomas are rare tumors, accounting
for only approximately 0.1% of malignancies in the United States.
It is estimated that soft tissue sarcomas account for approximately
1% of all solid tumors with approximately 10,000 new cases being
diagnosed per year in the United States (1). Of these, only about
10% to 15% (1000–1500 cases) occur in the retroperitoneum. The
peak incidence is in the fifth decade of life, although they can
occur in any age group.
Retroperitoneal soft tissue sarcomas are derived from mesen-
chymal tissues: skeletal muscle, fibrous tissue, fat, peripheral
nerves, and blood vessels. They are classified histologically accord-
ing to the mature tissue that they most resemble.
The most commonly diagnosed types of retroperitoneal soft
tissue sarcomas in adults vary from study to study. However, in
most studies the most frequently encountered cell types have been
liposarcomas, leiomyosarcomas, and malignant fibrous histiocy-
tomas (pleomorphic undifferentiated sarcomas, as they are now
referred to) (2–4). In the pediatric age group, rhabdomyosarcomas
are the most common soft issue sarcoma.
Soft tissue sarcomas arising in the large potential spaces of the
retroperitoneum can grow very large without producing symptoms
(5,6). Moreover, when symptoms do occur, they are non-specific,
such as abdominal pain and fullness, and are easily dismissed as
being caused by other less serious processes (7). These factors
frequently result in a delay in diagnosis and, as a result, these
tumors are usually very large at the time of presentation.
Tumor Staging
Accurate staging is important as it facilitates determination of
appropriate surgery, establishes prognosis, and provides a guide
for adjunctive therapy.
The American Joint Committee Staging System of soft tissue
sarcomas, which is based on the TNM classification, is most com-
monly used for most retroperitoneal soft tissue sarcomas (with the
major exceptions being rhabdomyosarcoma, desmoid tumor, Kaposi
sarcoma, angiosarcoma, and dermatofibrosarcoma protuberans),
although it is better suited for extremity sarcomas (8). This staging
system takes into consideration histological grade, tumor size, and
depth relative to the superficial muscular fascia, presence or absence
of lymph node involvement, and the presence or absence of distant
metastases [Table 23.1 (9)]. There are several limitations to the stag-
ing system when it is used for primary retroperitoneal soft tissue
sarcomas compared with extremity sarcomas. While Stage T1 and
Stage T2 tumors are distinguished merely based upon tumor size
(with tumors measuring <5 cm being Stage I neoplasms and those
measuring >5 cm being Stage II neoplasms), this distinction is not
useful in the retroperitoneum, since nearly all retroperitoneal sarco-
mas exceed 5 cm in size at the time of diagnosis and are, therefore, at
least Stage II tumors. Also, by definition, all retroperitoneal sarcomas
are deep to the superficial fascia. Thus, retroperitoneal sarcomas are
nearly always classified as Stage IIB (large, low-grade, and deep) or
Stage III (large, high-grade, and deep) neoplasms, with the distinc-
tion between these two alternatives made purely on the basis of his-
tologic grade. Consequently, staging of retroperitoneal soft tissue
sarcomas is essentially only affected by tumor grade. Additionally,
high-grade tumors are much more likely to have metastasized to the
lungs or liver at the time of diagnosis than are low-grade tumors.
Key Points: Staging of Retroperitoneal Soft
Tissue Sarcoma
■ Using the American Joint Committee Staging System of soft
tissue sarcomas, localized retroperitoneal sarcomas are nearly
always classified as Stage IIB or III as they are large, deeply
invasive, and low-grade or high-grade
■ Staging of retroperitoneal soft tissue sarcomas is affected
more by grade and histology than anatomical extent
Tumor Types
Most retroperitoneal sarcomas have similar clinical behavior and
radiologic appearance. Nevertheless, there are some specific
clinical and imaging characteristics that may help to distinguish
different histologic types from one another and their related
benign counterparts. While imaging distinction of primary ret-
roperitoneal soft tissue sarcomas from other malignancies or
benign conditions is extremely important, differentiation among
histologic subtypes of primary retroperitoneal soft tissue sarcomas
is usually not important, as this has little impact on subsequent
treatment and prognosis.
LIPOMATOUS TUMORS
Liposarcomas
Clinicopathological Features
In many series, liposarcomas are the most common histological
type of retroperitoneal sarcomas. These tumors are the second-
most common soft tissue sarcoma overall, accounting for 16% to
471
 primary tumor evaluation and staging

Table 23.1 American Joint Committee on Cancer GTNM can vary in degrees of aggressiveness, while the pleomorphic and
Classification and Stage Grouping of Soft Tissue Sarcomas dedifferentiated types are high-grade sarcomas (13). Dedifferenti-
ated liposarcomas account for about 10% of liposarcomas (14,15).
Stage Description
These are high-grade, predominantly fatty neoplasms, which have
Tumor grade areas of fibrous fibrous, vascular, osteoid, or skeletal and smooth
GX Grade cannot be assessed muscle elements.
G1 Well differentiated
In some instances it may be difficult to differentiate liposarcoma
G2 Moderately differentiated
from the normal fat invariably present in the retroperitoneum, a
G3 Poorly differentiated
feature that may lead to incomplete resection. This may also be
G4 Undifferentiated
Primary tumor
true for local recurrences after initial resection which occur in
TX Primary tumor cannot be assessed over two-thirds of patients regardless of grade (16,17). This can
T0 No evidence of a primary tumor lead to difficulties in detecting recurrence on imaging studies.
T1 Tumor <5 cm in greatest diameter In contrast, development of distant metastatic disease is related
T1a Superficial tumor to the degree of histological differentiation, being much more
T1b Deep tumor common in high-grade liposarcomas and is virtually exclusively
T2 Tumor <5 cm in greatest diameter hematogenous in nature. Interestingly, myxoid/round cell liposar-
T2a Superficial tumor comas have a unique metastatic pattern among sarcomas, with a
T2b Deep tumor tendency to metastasize to the serosal and pleural surfaces as well
Lymph node involvement
as to soft tissues, particularly the paraspinous soft tissues and the
NX Regional lymph nodes cannot be assessed
spine (15,17,18).
N0 No known metastases to lymph nodes
N1 Verified metastases to lymph nodes
Distant metastasis Imaging Features
MX Presence of distant metastasis cannot be On CT and MRI, liposarcomas present as large heterogeneous
assessed masses with fatty and soft tissue components (Fig. 23.1) (19–28).
M0 No known distant metastasis The imaging appearance does depend somewhat on the histo-
M1 Known distant metastasis logical type with the well-differentiated tumors appearing as a
Stage grouping predominantly fatty mass with some linear or nodular septa
Stage I G1-2, T1a, N0, M0 (Fig. 23.2) (22,25,26,28). The myxoid/round cell and pleomorhic
G1-2, T1b, N0, M0 types of liposarcoma do not contain large amounts of fat and, in
G1-2, T2a, N0, M0
fact, only about 50% demonstrate any fat radiographically
G1-2, T2b, N0, M0
(Fig. 23.3) (16,20,23,27). The fat, when present, is lacy, linear, or
Stage II G3-4, T1a, N0, M0
G3-4, T1b, N0, M0
amorphous in nature. The pleomorphic and myxoid/round cell
G3-4, T2a, N0, M0 types are more heterogeneous. On imaging, a well-defined pre-
Stage III G3-4, T2b, N0, M0 dominantly fatty component juxtaposed with a well-defined
Stage IV Any G, any T, N1, M0 non-lipomatous component is suggestive of a dedifferentiated
Any G, any T, N0, M1 liposarcoma (29–32).
Source: Modified from the American Joint Committee on Cancer. AJCC Cancer
Staging Manual, 6th edn., 2002. Key Points: Liposarcoma
■ Many series show this to be the most common retroperitoneal
18% of all malignant soft tissue tumors, and usually present sarcoma
between the fifth and sixth decades of life (10). Liposarcomas occur ■ On CT/MRI, the appearance depends on the histological type:
most commonly in the thigh and retroperitoneum. In a large series many well-differentiated tumors appear as predominantly
of 1755 tumors, 50% occurred in the lower extremities, and 33% fatty masses; myxoid/round cell, pleomorphic, and round cell
occurred in the trunk, including the retroperitoneum (11). types do not contain large amounts of fat and sometimes do
Four histological variants or subtypes of liposarcomas have not contain any recognizable fat on imaging studies
been recognized: well-differentiated, myxoid/round cell, pleomor- ■ Liposarcomas commonly recur following surgery
phic, and dedifferentiated (12). Most retroperitoneal liposarcomas
are of the well-differentiated (54%) or pleomorphic types (31%)
as reported in a study of 1755 tumors (11). The well-differentiated MUSCLE TUMORS
type is inherently a low-grade tumor and is further subdivided
into: (i) lipoma-like, (ii) inflammatory, and (iii) sclerosing sub- Leiomyosarcomas
types. All of these different subtypes can coexist within large Clinicopathological Features
well-differentiated liposarcomas and, as described later, well- Leiomyosarcomas account for about 29% of all soft tissue sarcomas,
differentiated liposarcomas can also undergo focal dedifferentiation and in many series are the second most common retroperitoneal
into higher-grade sarcomas. sarcoma (13). In a study of 118 leiomyosarcomas from the MD
The myxoid and round cell types (referred to as myxoid/round Anderson Cancer Center, 20% arose from the retroperitoneum
cell in this chapter) are often mixed in the same tumor and hence (33). The majority of patients with leiomyosarcomas are in the fifth

472
 primary retroperitoneal tumors

(A) (B)
Figure 23.1 Moderately well-differentiated liposarcoma. (A) Axial T1-weighted SE image demonstrates a predominantly high signal intensity retroperitoneal mass with
a small focus of low signal intensity (arrow). (B) Axial fat-suppressed T2-weighted image demonstrates that majority of the mass suppresses with fat suppression except
for a small focus of tumor (arrow).

Figure 23.2 Well-differentiated liposarcoma. Contrast-enhanced axial CT in 47-year- Figure 23.3 Pleomorphic liposarcoma. Contrast-enhanced axial CT in 68-year-
old female shows a predominantly fatty retroperitoneal tumor with fine septations old male with a pleomorphic high-grade liposarcoma. Note paucity of fat in
(arrow). this tumor.

or sixth decades of life, with tumors in children being uncommon
(34,35). Retroperitoneal leiomyosarcomas are more commonly
seen in women with a female-to-male ratio of 2–7:1 being
reported. In contrast, leiomyosarcomas arising from the soft tissue
and large veins are more common in males.
Retroperitoneal leiomyosarcomas may arise in association with or
from the walls of vessels (veins and arteries). In a review of the
literature, Kervorkian and Cento reported that large veins were four
times more frequently involved as compared to arteries (36). The
most common location for these tumors is the inferior vena cava
(IVC), which accounts for 50% of reported cases. Tumor growth in
inferior vena caval tumors may be extraluminal, intraluminal, or a
combination of both (37). When the tumor growth is predominantly
intraluminal, symptoms of IVC obstruction can develop (34,36).
When distant metastases occur they most commonly involve the
lung, with the liver being the next most common site (35).
Imaging Features
On CT and MRI, leiomyosarcomas are seen as large heterogeneous
primarily soft tissue density/signal intensity tumors with cystic
areas of internal degeneration, hemorrhage, and necrosis
(Fig. 23.4) (33,34,37–41). The presence of a large heterogeneous
mass arising in contiguity with the IVC (Fig. 23.5) without or with
the presence of an intraluminal tumor thrombus (Fig. 23.6)
should suggest the diagnosis of leiomyosarcoma arising from the
IVC (34,36,38–42).

473
 primary tumor evaluation and staging

Key Points: Retroperitoneal Leiomyosarcoma

■ Arise more frequently from the veins than the arteries
■ On CT/MRI, the diagnosis may be suggested by the presence
of a large heterogeneous predominantly soft tissue density/
signal intensity mass arising in continuity with the IVC

Rhabdomyosarcomas (See also Chap. 39)

Figure 23.4 Retroperitoneal leiomyosarcoma. Contrast-enhanced axial CT
demonstrates a large predominantly heterogeneous retroperitoneal mass, which
displaces the descending colon anteriorly.
Clinicopathological Features
This is the most common soft tissue malignancy of childhood and
accounts for about 19% of all childhood soft tissue sarcomas (43).
Rhabdomyosarcomas are divided into three types: (i) embryonal
(most common, 55–70%), (ii) alveolar (18–45%), and (iii) pleo-
morphic. The last type is the most common in adults.
Rhabdomyosarcomas occur more frequently in males and only
about 5% of these tumors occur in the retroperitoneum (44,45).
When these tumors metastasize, they most commonly spread to
the lungs and pleura, but the liver, bone, bone marrow, and lymph
nodes are also occasionally involved (42).

(A) (B)

Figure 23.5 Leiomyosarcoma involving the IVC. (A) Contrast-enhanced axial CT demonstrates a small homogeneous mass posterior to and contiguous with the IVC
(arrow). (B) T2-weighted fast spin-echo (FSE) image demonstrates a homogeneous high signal intensity mass abutting the IVC (arrow).

(A) (B)
Figure 23.6 Inferior vena caval leiomyosarcoma with intraluminal extension. (A) Contrast-enhanced axial CT image demonstrates a large heterogeneous retroperitoneal
mass, contiguous with the IVC. (B) Note intraluminal component extending (arrow) within the inferior vena caval lumen.

474
 primary retroperitoneal tumors
Imaging Features
On CT and MRI, the imaging appearance is non-specific in nature.
These are usually seen as large heterogeneous soft tissue density/
signal intensity masses. Intralesional hemorrhage and marked
enhancement following intravenous administration of contrast
material may be seen (44–46).
FIBROUS TUMORS
Fibrosarcomas
Clinicopathological Features
Fibrosarcomas account for only about 5% of soft tissue sarcomas
and are seen primarily in adults, with 60% of patients being
between the ages of 40 and 70 years (47,48). The rate of local
recurrence after resection is high, and the probability of metastases
is greater than 60% (49).
Imaging Features
The imaging appearance is non-specific and overlaps that of many
of the other malignant soft tissue sarcomas. Once again, these
neoplasms are usually large, heterogeneous, and primarily of soft
tissue density (Fig. 23.7).
FIBROHISTIOCYTIC TUMORS
Malignant Fibrous Histiocytomas
Clinicopathological Features
Malignant fibrous histiocytoma (MFH) is a pleomorphic sar-
coma composed of histiocyte and fibroblast-like elements, and its
distinction from fibrosarcoma is based on its relatively variable
histological appearance and the presence of giant cells (the latter
being absent in fibrosarcoma (50).
MFH has been the most common soft tissue sarcoma occurring
in late adult life, accounting for 20% to 30% of all soft tissue sar-
comas (13,50). Men are affected twice as frequently as women.
The most common location is the extremities, which account for
nearly 75% of all tumors, with only 15% of tumors occurring in
the retroperitoneum. More recently, with the emergence of new
immunohistochemistry staining techniques, some pathologists
(A)
Figure 23.7 Fibrosarcoma. (A) Contrast-enhanced axial CT in 62-year-old male demonstrates a heterogeneously enhancing mass, which invades the liver and the right
kidney. (B) Inferiorly, the tumor also involves the right colon (arrow).
have suggested that many neoplasms previously diagnosed as
MFH, actually represent dedifferentiated liposarcomas or even
other nonsarcomatous malignancies (2–4). This has led to many
fewer diagnoses of MFH because of the changing tumor classifica-
tions.
Apart from the sporadically occurring tumors, MFH can also
occur as a long-term complication of radiation therapy (51). In fact,
it is the most common radiation-induced sarcoma. In a study by
Laskin et al., malignant fibrous histiocytoma represented more
than two-thirds of the 52 cases encountered (51).
The pathological subtypes of MFH are: (i) storiform/pleomorphic,
(ii) myxoid, (iii) giant cell, (iv) inflammatory, and (v) angioma-
toid. The storiform or pleomorphic type, which can occur in the
retroperitoneum, is the most common type of MFH, accounting
for 50% to 60% of all MFHs (50–52). The myxoid type is the next
most common type, while the inflammatory subtype of MFH
accounts for fewer than 10% of these tumors.
The storiform and pleomorphic tumors are more likely to
metastasize, with the commonest site of distant metastases being
the lungs. In contrast, the myxoid/round cell type of MFH does
not usually metastasize.
Imaging Features
Malignant fibrous histiocytomas also present as large heteroge-
neous, predominantly soft tissue density masses producing
marked extrinsic compression on the adjacent organs in the abdo-
men and pelvis (53–61). They often contain areas of hemorrhage
and/or necrosis (54–61). Calcification has been seen in 10% to
25% of tumors (Fig. 23.8) (52). The imaging appearance of MFH
overlaps that seen in both leiomyosarcomas and certain subtypes
of liposarcoma.
Key Points: Malignant Fibrohistocytoma
■ The most common type of radiation-induced sarcoma in the
retroperitoneum
■ The most common histological subtype (storiform/plexiform)
frequently metastasizes to the lung and lymph nodes; the
myxoid type do not usually metastasize
(B)
475
 primary tumor evaluation and staging
Figure 23.8 Malignant fibrous histiocytoma. Contrast-enhanced axial CT in 61-year-
old male demonstrates a large right retroperitoneal mass with areas of low density
due to necrosis and cystic degeneration as well as areas of calcification (arrows).
NEUROGENIC TUMORS
Peripheral Nerve Sheath Tumors
Clinicopathological Features
These tumors are usually encountered in patients between the
ages of 20 and 50, and have an equal prevalence in women and
men (62). They frequently involve the major nerves and nerve
trunks, and are associated with pain and neurologic symptoms.
These tumors can also be radiation-induced. This subtype
accounts for about 11% of these tumors (63,64).
These are high-grade sarcomas. Local recurrence after resection
is common and seen in about 40% of patients. Metastases are seen
in about 65% of patients, with the most common sites being lung,
bone, and pleura (65).
Imaging Features
Although differentiation of benign from malignant neurogenic
tumors is very difficult, in general, malignant neurogenic tumors
are large (>5 cm), lack an identifiable capsule, are more heteroge-
neous, and tend to demonstrate more vascularity (Fig. 23.9).
Larger lesions are also more likely to undergo hemorrhage and
demonstrate fluid–fluid levels on imaging (65). In contrast, some
benign lesions (neurofibromas) tend to be homogeneous and
of relatively low (near but above water) density on CT (due to
abundant intracellular lipid).
Paragangliomas (See also Chap. 16)
Clinicopathological Features
These are uncommon tumors and arise from neural crest cells
associated with autonomic ganglia; they can be located anywhere
from the skull base to the pelvis (66). These can be functional or
non-functional in nature. Those arising from the adrenal medulla
are called “pheochromocytomas.”
476
Figure 23.9 Malignant peripheral nerve sheath tumor. Contrast-enhanced axial
image demonstrates a large heterogeneously enhancing mass in the right iliac fossa.
Extra-adrenal paragangliomas, which may arise in the retro-
peritoneum, are functional in 25% to 60% of patients (67–69).
Over 90% of extra-adrenal paragangliomas are benign. Malignant
neoplasms can metastasize, with the common sites of metastases
being regional lymph nodes, bones, liver, and lung (66).
Imaging Features
On MRI, the lesions are of intermediate to very high signal intensity
on T2-weighted images (Fig. 23.10). Although in initial reports
there was enthusiasm that the high signal intensity on T2-weighted
images may be specific for paragangliomas, subsequent studies have
shown that T2-weighted appearances of these tumors overlap with
those of other neoplasms (68–71). After contrast material adminis-
tration, paragangliomas can show very brisk enhancement on CT
or MRI (68,69,72,73). A minority of these neoplasms will contain
calcifications that can be visualized on CT (72). In a study of
400 patients, iodine-labelled MIBG scintigraphy has been shown to
have a sensitivity rate of 87% for the detection and localization of
paragangliomas, although other tumors of the amine precursor and
decarboxylase (APUD) system also take up the tracer (66,70,71).
Neuroblastomas/Ganglioneuromas/
Ganglioneuroblastomas
Clinicopathological Features
These tumors arise from the neural crest cells that occur along the
sympathetic ganglia. The majority of neuroblastomas, which are
the least differentiated of this group of tumors, tend to produce
catecholamines, in contrast to ganglioneuromas, which rarely
secrete these hormones (74). Neuroblastomas are the most common
solid neoplasms in children and infants arising outside the central
nervous system (CNS). Most neuroblastomas (90%) are seen in
children under the age of five, in contrast to ganglioneuromas,
which are usually seen after the age of 10.
While most neuroblastomas originate in the adrenal glands,
occasionally they may develop at other locations. Extra-adrenal
neuroblastomas are most commonly seen in the abdomen (18%),
and most of these occur in the retroperitoneum (75,76).
Metastatic disease is common in neuroblastoma at the time of
presentation with common sites of involvement being bone,
lymph nodes, and liver (76).
 primary retroperitoneal tumors
(A)
(B)
Figure 23.10 Paraganglioma. (A) Axial T1-weighted image demonstrates a low sig-
nal intensity mass contiguous with the superior mesenteric artery. (B) Axial fast
spin-echo T2-weighted image shows very high signal intensity and heterogeneity
within the mass.
Imaging Features
On imaging studies, calcification is seen in about 50% of retro-
peritoneal neuroblastomas and in about 30% of ganglioneuromas
(Figs. 23.11 and 23.12) (75,77). While both CT and MRI have
been used to image these tumors, MRI appears to be favored at
most large centers, as it is superior for detecting tumor extension
into the spinal canal and for detection of bony metastases, which
occur commonly. The MRI findings are non-specific, however,
with the tumor exhibiting low to intermediate signal intensity in
comparison to skeletal muscle on T1-weighted images and mod-
erate to high signal intensity on T2-weighted images (Fig. 23.13)
(78–81). Iodine-labelled MIBG scintigraphy has also been used to
detect the primary tumor as well as sites of metastases (81).
VASCULAR TUMORS/MALIGNANT VASCULAR TUMORS
These rare tumors comprise about 2% of all retroperitoneal sarco-
mas and usually present in the fifth decade of life (82). There are
two types of malignant vascular tumors: hemangiopericytomas
and angiosarcomas.
Figure 23.11 Ganglioneuroma. Contrast-enhanced axial CT in four-year-old
female demonstrates a large low-density retroperitoneal mass with calcification
(arrow) but no adjacent organ invasion.
Hemangiopericytomas
Clinicopathological Features
The term “hemangiopericytoma” is now being abandoned, and
hemangiopericytomas are now thought to represent solitary
fibrous tumors. This tumor most often affects middle-aged
individuals and about 25% of these tumors arise from a retro-
peritoneal location (82). It is difficult to determine the prognosis
of this tumor although mitotic activity, necrosis, and other patho-
logical features have been used to predict malignant behavior (83).
Associated hypoglycemia may co-exist with these neoplasms
(82–86). This tumor generally has a favorable prognosis, although
local recurrence is common, and metastases occur in about 10%
to 25% of patients (82).
Imaging Features
On MRI, these tumors demonstrate high signal-intensity on
T2-weighted images. Serpentine vessels accounting for the vascu-
lar nature of these tumors and fluid levels due to hemorrhage
may also be seen (84–88). These tumors typically show marked
enhancement following intravenous administration of iodinated
or gadolinium based contrast material for CT or MRI, respectively
(Fig. 23.14) (84–88).
Angiosarcomas
Clinicopathological Features
These tumors have a poor prognosis and have a tendency to
metastasize early to the lungs, bones, and lymph nodes (87,88).
Imaging Features
These are very uncommon, aggressive vascular tumors that have a
very non-specific appearance on imaging (Fig. 23.15) (87,88).
Key Points: Vascular Tumors
■ There are two types of vascular tumors: hemangioperiocytomas
and angiosarcomas
■ Hemangioperiocytomas generally have a favorable prognosis
and metastases occur in 10% to 25% of patients: angiosarcomas
have a poor prognosis and tend to metastasize early.
477
 primary tumor evaluation and staging

(A) (B)
Figure 23.12 Extra-adrenal neuroblastoma. (A) Contrast-enhanced axial CT in a two-year-old female shows a large low-density mass, which encases the celiac axis.
(B) Note small punctate calcifications within the tumor (arrows).

(A) (B)

(C)
Figure 23.13 Extra-adrenal neuroblastoma. (A) Coronal T1-weighted MR image demonstrates low signal intensity within a left retroperitoneal mass. (B) Following
intravenous injection of gadolinium a coronal T1-weighted image demonstrates heterogeneous enhancement within the mass. (C) Axial T2-weighted fast spin-echo
(FSE) image demonstrates heterogeneity within the mass. Note obstruction of the left kidney (arrow).

478
 primary retroperitoneal tumors

instances does not improve patient prognosis (6,89–98). As

TREATMENT OF RETROPERITONEAL SARCOMAS
The definitive treatment of primary retroperitoneal sarcomas is
surgical resection (88). Chemotherapy and radiotherapy without
surgical debulking have rarely been beneficial when used alone or
in combination (6). Pre-, intra-, or postoperative radiotherapy,
however, has been of benefit in some patients, but in most
these tumors are locally invasive, extensive, and aggressive, local
resection of the tumor and adjacent organs and structures
should be performed at the time of presentation, as this is the
most definitive form of therapy. Resection of the tumor en-bloc
with adjacent adrenals, kidneys, small bowel, and colon is often
required as these tumors can often encase these structures or
their vascular supply (99–101).
Complete resection (with negative tumor margins) is possible
in less than 70% of cases, even when aggressive surgery is per-
formed (12,99–105). Wide resection is often not possible, given
the anatomic confines of retroperitoneal tumors (99). Even with
complete resection, local recurrence occurs in approximately half
the patients. Median survival was improved after complete resec-
tion for recurrent disease (106). When complete resection is not
possible, aggressive surgical debulking may be performed, though
incomplete gross resection does not improve survival.

EXTRAGONADAL GERM CELL TUMORS

Figure 23.14 Hemangiopericytoma. Contrast-enhanced axial CT in 46-year-old
male demonstrates a homogeneously enhancing left pelvic mass (arrows).
Clinicopathological Features
Almost all retroperitoneal germ cell tumors will eventually
prove to represent metastatic disease from testicular primaries.
For this reason, a thorough and careful survey of the pelvis and
scrotum should be performed to exclude a primary testicular

(A) (B)

(C) (D)
Figure 23.15 Angiosarcoma. (A) Contrast-enhanced axial CT image in a 29-year-old male shows a predominantly cystic mass with a solid component (arrow) in the left
paravertebral region. (B) Axial T1-weighted image demonstrates predominantly high signal intensity within the cystic mass. (C) and (D) Axial gadolinium-enhanced
T1-weighted image, and axial fast-spin-echo (FSE) T2-weighted image. The latter shows a heterogeneous mass with cystic and solid (arrow) areas.

479
 primary tumor evaluation and staging
Figure 23.16 Primary extra-gonadal germ cell tumor. Contrast-enhanced axial CT
in 33-year-old male demonstrates a large low-density right-sided retroperitoneal
mass posterior to the IVC. No testicular mass was found.
neoplasm in any patient in whom a retroperitoneal germ cell
tumor is diagnosed.
Only about 1% to 10% of germ cell tumors originate in an
extragonadal location, with the majority arising in the mediasti-
num. Primary extragonadal germ cell tumors are very rare in the
retroperitoneum, accounting for less than 10% of retroperitoneal
neoplasms. As with germ cell tumors that originate in the testes,
primary retroperitoneal germ cell neoplasms can be of various
histological subtypes, including seminoma, embryonal carcinoma,
choriocarcinoma, teratoma, and yolk sac tumor.
Primary extragonadal germ cell tumors are usually large at pre-
sentation, and the majority of non-seminomatous tumors present
with elevated levels of human chorionic gonadotrophin (HCG) and
alpha-fetoprotein (AFP) (107). Seminomatous tumors are usually
treated with surgery and/or radiation, with the latter being utilized
because this cell type is very radiation-sensitive. In contrast, the
much less radiosensitive non-seminomatous tumors are usually
treated with a combination of surgery and chemotherapy (107).
Imaging Features
On imaging, depending on their histology, retroperitoneal
extragonadal germ cell tumors can often have a varying appear-
ance (Fig. 23.16), with seminomas presenting as homogeneous
or heterogeneous soft tissue density masses; teratomas often
demonstrating fat, calcification, and bone formation; and with
choriocarcinomas often being highly vascular and hemorrhagic
(108–110).
Key Points: Extragonadal Germ Cell Tumors
■ Almost all retroperitoneal germ cell tumors will prove to be
metastases from testicular primaries
■ The majority of primary extragonadal germ cell tumors are
large at presentation and are in the mediastinum
480
ROLE OF IMAGING IN RETROPERITONEAL MALIGNANT
TUMORS—AN OVERVIEW
Preoperative Imaging
As previously stated, most retroperitoneal sarcomas have a non-
specific appearance on imaging, which limits the ability to make a
tissue-specific diagnosis. Since the treatment and prognosis of the
majority of retroperitoneal soft tissue sarcomas does not vary with
differences in cell type, failure to distinguish one tumor type from
another is usually not crucial (111). On rare occasions, it may be
possible to identify the nature of a large retroperitoneal mass more
specifically when imaging it, without performing a biopsy. As pre-
viously mentioned, many liposarcomas contain macroscopic fat.
While occasionally paragangliomas may demonstrate increased
vascularity and may contain calcification, or may develop in
patients in whom there is concern for a functional neoplasm,
many paragangliomas are indistinguishable from other primary
retroperitoneal neoplasms and present in an unhelpful clinical
setting (since many are not functional) (72).
The goals of imaging of any retroperitoneal tumor are to depict
tumor size, relationship to and involvement of adjacent organs and
structures, vascular invasion, and the detection of distant spread.
As other neoplastic processes that are treated differently may
mimic retroperitoneal sarcomas, tissue diagnosis is of paramount
importance. For this reason, image-guided biopsies have a rela-
tively greater role to play in the diagnosis of retroperitoneal sar-
comas than is the case for sarcomas elsewhere in the body
(112–115). For example, while diffuse retroperitoneal lymph
node enlargement almost always indicates lymphoma or meta-
static cancer, lymphoma also can present as a solitary mass of
matted lymph nodes or extranodal tumor. In this case, image-
guided biopsies can usually establish the diagnosis and direct
management appropriately.
Also, it is not always possible to be certain prior to biopsy that a
tumor in the retroperitoneum is actually arising from the retro-
peritoneum, rather than from retroperitoneal or intra-abdominal
viscera. Confusion seems particularly frequent in the upper retro-
peritoneum, where retroperitoneal sarcomas are often misinter-
preted as arising from the liver, kidneys, adrenal glands, or
pancreas. Treatment options are obviously quite different for
different neoplasms, so careful assessment of the relationship of
the tumor to adjacent structures is important. Gastrointestinal
stromal tumors (GIST) occasionally may appear similar to retro-
peritoneal sarcomas, both on imaging and on histology, but the
treatment is very different, so differentiation here is also of major
clinical significance.
Once a diagnosis is made, the surgical team needs to determine
if the retroperitoneal sarcoma is localized, and, if so, whether it is
resectable. Therefore, one of the first determinations to be made is
whether there is evidence of intra- or extra-abdominal spread of
tumor. Important adjunct imaging includes CT of the thorax to
evaluate for pulmonary metastases.
Prior to attempting removal of soft tissue sarcomas that appear
to be resectable on imaging studies, the imaging should be reviewed
with the surgical team so that an appropriate operative approach
can be planned. The location and size of the tumor, its relation-
ship to adjacent organs, presence or absence of local extension,
 primary retroperitoneal tumors
relationship to and/or involvement of major vascular structures,
as well as the presence of normal anatomic variants and anomalies
of major abdominal arteries and veins, are all crucial pieces of
information that need to be provided. Since resection of one kidney
is not uncommon, any radiographic evidence of unilateral renal
dysfunction should be relayed to the surgical team. In evaluating
preoperative imaging studies, the radiologist should be cognizant
of two facts: (i) up to 75% of retroperitoneal sarcoma resections
involve concomitant resection of at least one adjoining intra-
abdominal visceral organ (commonly large or small bowel or
kidney); and (ii) the most common types of vascular involve-
ment precluding resection are involvement of the proximal
superior mesenteric vessels or involvement of bilateral renal vessels.
Accordingly, the mesenteric and renal vessels should be carefully
examined and their relationship to mid or upper retroperitoneal
tumors described.
Although MRI is the imaging tool of choice for tumors of the
musculoskeletal system, CT is the most commonly used modality
for identification, localization, and staging of retroperitoneal
tumors, as it provides a comprehensive examination by providing
a survey of the chest, abdomen, and pelvis (5,8,116–119). The use
of MRI is generally reserved for selected problem-solving, such as
addressing questions regarding vascular invasion, and evaluating
problematic indeterminate liver lesions (Fig. 23.17).
18
FDG PET imaging has not been used extensively for evaluat-
ing retroperitoneal sarcomas. There are, however, a few recent
studies which have assessed the role of FDG-PET in patients with
these tumors (120–124). In a study by Johnson et al., FDG-PET
was superior to CT in detecting local recurrences and distant
metastases (Fig. 23.18). In this series FDG-PET detected all
22 such cases, while CT identified only 18. The difference was
most pronounced in patients with prior extensive surgical and
(A)
Figure 23.17 Coronal (A) pre- and (B) post-contrast MR images show the relationship of a myxofibrosarcoma (arrows) to the IVC.
radiation treatment (123). In another study of both seminomatous
and non-seminomatous germ cell tumors, the accuracy, sensitivity,
and negative predictive values of FDG-PET scanning for detection
of the primary tumor and metastases were slightly superior to
CT (125). Now that combined FDG-PET CT scanners are in use
in most hospitals, it is possible that in the future this modality will
play an increasing role in the staging of retroperitoneal sarcomas
at the time of presentation and for follow-up imaging.
Prognosis
Tumor grade and resectability are the only features that affect sur-
vival (102,104,111,114,115). In general, imaging is of limited value
in predicting tumor grade. The only exception to this may be with
liposarcomas, where identification of a predominantly fatty mass
with little or no soft-tissue component would most likely repre-
sent a well-differentiated liposarcoma (126,127). Because of the
limited value of imaging in predicting tumor grade, tissue diagnosis
by open surgical or percutaneous biopsy is essential.
Imaging Follow-Up After Resection
After tumor resection, surveillance imaging is routinely per-
formed to assess for tumor recurrence. Follow-up imaging is
usually performed with CT or MR imaging, with the frequency
of follow-up being often dictated by the completeness of the
repeat resection, tumor type, and grade (99,102). Tumor recur-
rence is common, even in patients in whom a curative resection
was thought to have been achieved (7,99,102). This is especially
true in patients with high-grade or de-differentiated neoplasms.
Most of these recurrences occur within two years of initial surgi-
cal resection (7,99). Since subsequent prognosis is affected by the
ability to completely resect local recurrences, early detection of
the recurrence is essential. As most recurrences are local, careful
(B)
481
 primary tumor evaluation and staging

(A) (B)
Figure 23.18 (A, B) PET/CT images show recurrent tumor (arrows) in a patient with recurrent diaphragmatic fibrosarcoma at the surgical bed.

Figure 23.19 Axial contrast-enhanced CT (image on left) shows subtle tumor recurrence (arrow) which went undetected. A follow-up exam three months later (image
on right) shows enlarging recurrent tumor (arrow) in the surgical bed.

scrutiny of the surgical bed for subtle changes on follow-up imag-
ing should be made (127).
In the immediate postoperative period, postoperative changes
complicate the radiographic evaluation of the retroperitoneum.
For upper retroperitoneal tumors, peripancreatic fluid collections
(“pseudocysts”) are common findings that may persist for many
months after surgery and can be difficult to discriminate from
recurrence.
Detection of small local recurrences after the initial postop-
erative period also can occasionally be difficult. Soft-tissue
attenuation recurrences may not be easily distinguished
from postoperative fibrosis in the surgical bed ( Fig. 23.19 ).
Also, when small, early local recurrent liposarcomas can be
difficult to distinguish from normal retroperitoneal fat on CT
and MRI examinations (127,128). Occasionally, closer scru-
tiny may show that the fat in a recurrent liposarcoma is of
slightly higher density when compared to normal retroperito-
neal fat (Fig. 23.20). Also, at times, recurrent liposarcomas
can have different imaging characteristics than that of the
primary tumor. In one CT study of predominantly fat-containing
liposarcomas, four of the eight recurrent tumors did not contain
any visible fat (127).
Regional metastases are also frequent and a thorough search of
peritoneal surfaces and liver should be made prior to evaluation
for distant metastases on follow-up studies. As recurrent tumors
are often treated with repeat surgical resection, all tumor-bearing
sites should be identified to enable optimal and complete re-
resection (127,129).
Key Points: Imaging Follow-up
■ Most recurrences are local, occur within two years after
surgery and prognosis is improved by early detection
■ The frequency of follow-up imaging is determined by the
tumor type and grade, and completeness of the resection

482
 primary retroperitoneal tumors

(A) (B)

(C)
Figure 23.20 Recurrent liposarcoma. (A) Contrast-enhanced axial CT in 60-year-old female demonstrates an intermediate grade liposarcoma with both fatty and soft
tissue components. (B) Follow-up contrast-enhanced axial CT performed 10 months following resection of the tumor, shows subtle early tumor recurrence which is
of slightly higher density than that of retroperitoneal fat (arrow). (C) Follow-up contrast-enhanced axial CT performed 18 months following initial tumor resection
shows progression of tumor recurrence with solid and fatty components (arrows).

Summary
■ Approximately 90% of all retroperitoneal masses are sarcomas
■ Most common cell types are liposarcoma, leiomyosarcoma
and malignant fibrous histiocytoma
■ Local recurrence is common
■ Common sites of metastases are lung, and liver.
■ Imaging is helpful to guide biopsy and stage the extent of
tumor
■ Well-differentiated liposarcomas can be diagnosed with
great accuracy, but with almost all other sarcomas defini-
tive diagnosis is not possible due to overlap of imaging
appearances
■ MRI is helpful in assessing vascular involvement
■ Tumor grade and resectability are the only factors that affect
prognosis. CT and MRI have a limited role in predicting
tumor grade
■ Despite advances in chemotherapy and radiotherapy, the defin-
itive treatment continues to be surgical resection
■ Imaging follow-up is crucial to detect early recurrence
REFERENCES
1. Jemal A, Siegel R, Ward E, et al. Cancer Statistics 2008. CA
Cancer J Clin 2008; 58: 71–96.
2. Borden EC, Baker LH, Bell RS, et al. Soft tissue sarcomas of
adults: State of the translational science. Clin Cancer Res 2003;
9: 1941–56.
3. Coindre JM, Mariani O, Chibon E, et al. Most malignant
fibrous histiocytomas developed in the retroperitoneum are
dedifferentiated liposarcomas: a review of 25 cases initially
diagnosed as malignant fibrous histiocytomas. Modern
Pathology 2003; 16: 256–62.
4. Daugaard S. Current soft-tissue sarcoma classifications. Eur J
Cancer 2004; 40: 543–8.
5. Papanicolaou N, Yoder IC, Lee MJ. Primary retroperitoneal
neoplasms: how close can we come in making the correct
diagnosis? Urol Radiol 1992; 14: 221–8.
6. Singer S, Corson JM, Demetri GD, et al. Prognostic factors
predictive of survival for truncal and retroperitoneal soft
tissue sarcoma. Ann Surg 1995; 221: 185–95.

483
 primary tumor evaluation and staging
7. van Dalen T, van Geel AN, van Coevorden F, et al. Dutch soft
tissue sarcoma group. Soft tissue carcinoma in the retroperi-
toneum: an often-neglected diagnosis. Eur J Surg Oncol
2001; 27: 74–9.
8. Russell WO, Cohen J, Edmonson JH, et al. Staging system for
soft tissue sarcoma. Semin Oncol 1981; 8: 156–9.
9. Green FL, Page DL, Fleming ID, et al., eds. The AJCC Cancer
Staging Manual, 6th edn. Philadelphia: Lippincott Raven,
1997.
10. Enzinger FM, Weiss SW, eds. Liposarcoma. In: Soft Tissue
Tumors, 3rd edn. St. Louis: CV Mosby Company, 1995:
381–466.
11. Kransdorf MJ, Murphey MD. Lipomatous tumors. In:
Imaging of Soft Tissue Tumors. Philadelphia: WB Saunders,
1997: 57–101.
12. Singer S, Anotonescu CR, Riedel E, Brennan MR. Histologic
subtype and margin of resection predict patter of recurrence
and survival for retroperitoneal sarcoma. Ann Surg 2003;
238: 358–71.
13. Kransdorf MJ, Murphey MD. Soft tissue tumors in a large
referral population: prevalence and distribution of diagnoses
by age, sex and location. In: Imaging Soft Tissue Tumors.
Philadelphia: WB Saunders, 1997: 3–35.
14. Azumia N, Curtis J, Kempson RL, Hendrickson MR. Atypical
and malignant neoplasms showing lipomatous differentia-
tion. A study of 111 cases. Am J Surg Pathol 1987; 11:
161–83.
15. Evans HL. Liposarcomas and atypical lipomatous tumors.
A study of 66 tumors followed for a minimum of 10 years.
Surg Pathol 1988; 1: 41–54.
16. Reszel PA, Soule EH, Coventry MB. Liposarcoma of the extrem-
ities and limb girdles. A study of two hundred twenty-two cases.
J Bone Joint Surg 1966; 48: 229–44.
17. Evans HL. Liposarcoma. A study of 55 cases with reassessment
of its classification. Am J Surg Pathol 1979; 3: 507–23.
18. Enzinger FM, Winslow DJ. Liposarcoma: a study of 103 cases.
Virchows Arch (Pathol Anat) 1962; 335: 367–88.
19. Lindahl S, Markhede G, Berlin O. Computed tomography of
lipomatous and myxoid tumors. Acta Radiol Diagn (Fasc 6)
1985; 26: 709–13.
20. Jelinek JS, Kransdorf MJ, Shmookler BM, Aboulafia AJ,
Malawer MM. Liposarcoma of the extremities: MR and CT
findings in the histologic subtypes. Radiology 1993; 186:
455–9.
21. Kim T, Murakami T, Oi H, et al. CT and MR imaging
of abdominal liposarcoma. Am J Roentgenol 1996; 166:
829–33.
22. Munk PL, Lee MJ, Janzen DL, et al. Lipoma and liposarcoma:
evaluation using CT and MR imaging. Am J Roentgenol
1997; 169: 589–94.
23. Sundaram M, Baran G, Merenda G, McDonald DJ. Myxoid
liposarcoma: magnetic resonance imaging appearances with
clinical and histological correlation. Skel Radiol 1990; 19:
359–62.
24. Hosono M, Kobayashi H, Fujimoto R, et al. Septum-like
structures in lipoma and liposarcoma: MR imaging and
pathologic correlation. Skel Radiol 1997; 26: 150–4.
484
25. Einarsdottir H, Söderlund V, Larson O, Jenner G, Bauer HC.
MR imaging of lipoma and liposarcoma. Acta Radiol 1999;
40: 64–8.
26. Matsumoto K, Takada M, Okabe H, Ishizawa M. Foci of
signal intensities different from fat in well-differentiated
liposarcoma and lipoma: correlation between MR and histo-
logical findings. Clin Imaging 2000; 24: 38–43.
27. Sung MS, Kang HS, Suh JS, et al. Myxoid liposarcoma:
appearance at MR imaging with histologic correlation.
Radiographics 2000; 20: 1007–19.
28. Kransdorf MJ, Bancroft LW, Peterson JJ, et al. Imaging of
fatty tumors: distinction of lipoma and well-differentiated
liposarcoma. Radiology 2002; 224: 99–104.
29. Lucas DR, Nascimento AG, Sanjay BK, Rock MG. Well-
differentiated liposarcoma: The Mayo Clinic experience with
58 cases. Am J Clin Pathol 1994; 102: 677–83.
30. Meis JM. “Dedifferentiation” in bone and soft-tissue tumors:
a histologic indicator of tumor progression. In: Rosen PP,
Feckner RE, eds. Pathology Annual. Norwalk, CT: Appleton
and Lange, 1991: 37–62.
31. Kransdorf MJ, Meis JM, Jelinek JS. Dedifferentiated liposar-
coma of the extremities: imaging findings in four patients.
Am J Roentgenol 1993; 161: 127–30.
32. Weiss SW, Rao VK. Well-differentiated liposarcoma (atypical
lipoma) of deep soft tissues of the extremities, retroperito-
neum, and miscellaneous sites: a follow-up study of 92 cases
with analysis of the incidence of “dedifferentiation.” Am J
Surg Pathol 1992; 16: 1051–8.
33. McLeod AJ, Zornoza J, Shirkhoda A. Leiomyosarcoma:
computed tomographic findings. Radiology 1984; 152:
133–6.
34. Hartman DS, Hayes WS, Choyke PL, Tibbetts GP. From the
archives of the AFIP. Leiomyosarcoma of the retroperitoneum
and inferior vena cava: radiologic-pathologic correlation.
Radiographics 1992; 12: 1203–20.
35. Schmookler BM, Lauer DH. Retroperitoneal leiomyosarcoma.
A clinicopathologic analysis of 36 cases. Am J Surg Pathol
1983; 7: 269–80.
36. Kervorkian J, Cento DP. Leiomyosarcoma of large arteries
and veins. Surgery 1973; 73: 390–400.
37. Roy C, Beaujeux R, Mutter D. Leiomyosarcoma of the
femoral vein: imaging findings. Am J Roentgenol 1993;
160: 1125–6.
38. Blum U, Wildanger G, Windfuhr M, et al. Preoperative CT
and MR imaging of inferior vena cava leiomyosarcoma.
Eur J Radiol 1995; 20: 23–7.
39. Young R, Friedman AC, Hartman DS. Computed tomography
of leiomyosarcoma of the inferior vena cava. Radiology 1982;
145: 99–103.
40. Hemant D, Krantikumar R, Amita J, Chawla A, Ranjeet N.
Primary leiomyosarcoma of inferior vena cava, a rare entity:
imaging features. Australas Radiol 2001; 45: 448–51.
41. Thapar PM, Mathur SK, Saksena DS, Shah HK. Leiomyosar-
coma of inferior vena cava presenting as acute Budd-Chiari
syndrome. Indian J Gastroenterol 2001; 20: 33–5.
42. Hines OJ, Nelson S, Quinones-Baldrich WJ, Eilber FR.
Leiomyosarcoma of the inferior vena cava: prognosis and
 primary retroperitoneal tumors
comparison with leiomyosarcoma of other anatomic sites.
Cancer 1999; 85: 1077–83.
43. Agamanolis DP, Dasu S, Krill CE. Tumors of skeletal muscle.
Hum Pathol 1996; 17: 778–95.
44. Tannous WN, Azouz EM, Kiruluta HG, Grattan-Smith D. CT
and ultrasound imaging of pelvic rhabdomyosarcoma in
children. Pediatr Radiol 1989; 19: 530–4.
45. Dillon E, Parkin GJ. The role of diagnostic radiology in the
diagnosis and management of rhabdomyosarcoma in young
persons. Clin Radiol 1978; 29: 53–9.
46. Judmaier W, Birbamer G, Buchberger W, et al. MR imaging
of late onset orbital rhabdomyosarcoma with intracranial
extension. Magn Reson Imaging 1993; 11: 285–8.
47. Pritchard DJ, Sim FH, Ivins JC, Soule EH, Dahlin DC. Fibro-
sarcoma of bone and soft tissues of the trunk and extremities.
Orthop Clin North Am 1977; 8: 869–81.
48. Pritchard DJ, Soule EH, Taylor WF, Ivins JC. Fibrosarcoma—
a clinicopathologic and statistical study of 199 tumors of the
soft tissues of the extremities and trunk. Cancer 1974; 33:
888–97.
49. Scott SM, Reiman HM, Pritchard DJ, Ilstrup DM. Soft tissue
fibrosarcoma. A clinicopathologic study of 132 cases. Cancer
1989; 64: 925–31.
50. Enzinger FM, Weiss SW. Malignant fibrous histiocytoma. In:
Enzinger FM, Weiss SW, eds. Soft Tissue Tumours, 3rd edn.
St Louis: Mosby, 1988: 351–80.
51. Laskin WB, Silverman TA, Enzinger FM. Postirradiation
soft tissue sarcomas. An analysis of 52 cases. Cancer 1988;
62: 2330–40.
52. Kransdorf MJ, Murphey MD. Fibrohistiocytic tumors. In:
Imaging of Soft Tissue Tumors. Philadelphia: WB Saunders
Company, 1997: 187–215.
53. Murphey MD, Gross TM, Rosenthal HG. Musculoskeletal
malignant fibrous histiocytoma: Radiologic–pathologic
correlation. Radiographics 1994; 14: 807–26.
54. Mahajan H, Kim EE, Wallace S, et al. Magnetic resonance
imaging of malignant fibrous histiocytoma. Magn Reson
Imaging 1989; 7: 283–8.
55. Panicek DM, Casper ES, Brennan MF, Hajdu SI, Heelan RT.
Hemorrhage simulation tumor growth in malignant
fibrous histiocytoma at MR imaging. Radiology 1991; 181:
398–400.
56. Miller TT, Hermann G, Abdelwahab IF, et al. MRI of
malignant fibrous histiocytoma of soft tissue: analysis of 13
cases with pathologic correlation. Skeletal Radiol 1994; 23:
271–5.
57. Peterson KK, Renfrew DL, Feddersen RM, Buckwalter JA,
el-Khoury GY. Magnetic resonance imaging of myxoid
containing tumors. Skeletal Radiol 1991; 209: 245–50.
58. Ros PR, Viamonte M, Rywin AM. Malignant fibrous histio-
cytoma: mesenchymal tumor of ubiquitous origin. Am J
Roentgenol 1984; 142: 753–9.
59. Fignon A, Marret H, Body G, et al. [Retroperitoneal malig-
nant fibrous histiocytoma]. (Article in French). Ann Chir
1997; 51: 1023–7.
60. Tsai JC, Dalinka MK, Fallon MD, Zlatkin MB, Kressel HY.
Fluid-fluid level: a nonspecific finding in tumors of bone and
soft tissue. Radiology 1990; 175: 779–82.
61. Goldman SM, Hartman DS, Weiss SW. The varied radio-
graphic manifestations of retroperitoneal malignant fibrous
histiocytoma revealed though 27 cases. J Urol 1986; 135:
33–8.
62. Kransdorf MJ, Murphey MD. Neurogenic tumors. In: Imag-
ing of Soft Tissue Tumors. Philadelphia: WB Saunders, 1997:
235–69.
63. Enzinger FM, Weiss SW. Malignant tumors of the peripheral
nerves. In: Soft Tissue Tumors, 3rd edn. St. Louis: CV Mosby,
1995: 889–928.
64. Ducatman BS, Scheithauer BW, Piepgras DG, Reiman HM,
Ilstrup DM. Malignant peripheral nerve sheath tumors. A
clinicopathologic study of 120 cases. Cancer 1986; 57:
2006–21.
65. Murphey MD, Smith WS, Smith SE, Kransdorf MJ, Temple HT.
From the archives of the AFIP. Imaging of musculo-
skeletal neurogenic tumors: radiologic-pathologic correla-
tion. Radiographics 1999; 19: 1252–80.
66. Enzinger FM, Weiss SW. Paraganglioma. In: Soft Tissue
Tumors, 3rd edn. St Louis: CV Mosby, 1995: 965–90.
67. Schmedtje JF Jr, Sax S, Pool JL, Goldfarb RA, Nelson EB.
Localization of ectopic pheochromocytomas by magnetic
resonance imaging. Am J Med 1987; 83: 770–2.
68. Falke TH, van Gils AP, van Seters AP, Sandler MP. Magnetic
resonance imaging of functioning paragangliomas. Magn
Reson Q 1990; 6: 35–64.
69. Velchik M, Alavi A, Kressel HY, Engelman K. Localization of
pheochromocytoma: MIBG, CT and MRI correlation. J Nucl
Med 1989; 30: 328–36.
70. Van Gils AP, Falke TH, van Erkel AR, et al. MR imaging and
MIBG-scintigraphy of pheochromocytomas and extraadre-
nal functioning paragangliomas. Radiographics 1991; 11:
37–57.
71. Quint LE, Glazer GM, Francis IR, Shapiro B, Chenevert TL.
Pheochromocytoma and paraganglioma: comparison of MR
imaging with CT and I-131 MIBG scintigraphy. Radiology
1987; 165: 89–93.
72. Hayes WS, Davidson AJ, Grimley PM, Hartman DS. Extraad-
renal retroperitoneal paraganglioma: clinical, pathologic,
and CT findings. Am J Roentgenol 1990; 155: 1247–50.
73. Pui MH, Liu MJ, Guo Y, Chen YM. Computed tomography
of retroperitoneal paragangliomas. Australasian Radiology
1999; 43: 303–6.
74. Stout AP. Ganglioneuroma of the sympathetic nervous system.
Surg Gynecol Obstet 1947; 84: 101–10.
75. David R, Lamki N, Fan S, et al. The many faces of neuro-
blastoma. Radiographics 1989; 9: 859–82.
76. Page D, DeLellis R, Hough A. Tumors of the adrenal.
In: Hartmann WH, Sobin LH, eds., Atlas of Tumor
Pathology. Washington, DC: Armed Forces Institute of
Pathology, 1985: 219–46.
77. Armstrong EA, Harwood-Nash DC, Ritz CR, et al. CT of
neuroblastomas and ganglioneuromas in children. Am J
Roentgenol 1982; 139: 571–6.
78. Dietrich RB, Kangarloo H, Lenarsky C, Feig SA. Neuroblastoma:
the role of MR imaging. Am J Roentgenol 1987; 148: 937–42.
79. Stark DD, Moss AA, Brasch RC, et al. Neuroblastoma: diag-
nostic imaging and staging. Radiology 1983; 148: 101–5.
485
 primary tumor evaluation and staging
80. Evans AE. Staging and treatment of neuroblastoma. Cancer
1980; 45: 1799–1802.
81. Munkner T. (131)I-meta-iodobenzylguanidine scintigraphy of
neuroblastomas. Semin Nucl Med 1985; 15: 154–60.
82. Enzinger FM, Weiss SW. Perivascular tumors. In: Soft Tissue
Tumors, 3rd edn. St. Louis: CV Mosby, 1995: 701–33.
83. Enzinger FM, Smith BH. Hemangiopericytoma. An analysis
of 106 cases. Hum Pathol 1976; 7: 61–82.
84. Goldman SM, Davidson AJ, Neal J. Retroperitoneal and pelvic
hemangiopericytomas: clinical, radiologic and pathologic
correlations. Radiology 1988; 168: 13–7.
85. Lorigan JG, David CL, Evans HL, Wallace S. The clinical and
radiologic manifestations of hemangiopericytoma. Am J
Roentgenol 1989; 153: 345–9.
86. Alpern MB, Thorsen MK, Kellman GM, Pojunas K, Lawson TL.
CT appearance of hemangiopericytoma. J Comput Assist
Tomgr 1986; 10: 264–7.
87. Murphey MD, Fairbairn KJ, Parman LM, et al. From the
archives of the AFIP. Musculoskeletal angiomatous lesions:
radiologic-pathologic correlation. Radiographics 1995; 15:
893–917.
88. Kransdorf MJ, Murphey MD. Vascular and lymphatic tumors.
In: Kransdorf MJ, Murphy MD, eds. Imaging of Soft Tissue
Tumors. Philadelphia: WB Saunders, 1997: 103–41.
89. Stoeckle E, Coindre JM, Bonvalot S, et al. French Federation
of Cancer Centers Sarcoma Group. Prognostic factors in
retroperitoneal sarcoma: a multivariate analysis of a series of
165 patients of the French Cancer Center Federation Sarcoma
Group. Cancer 2001; 92: 359–68.
90. Catton CN, O’Sullivan B, Kotwall C, et al. Outcome and
prognosis in retroperitoneal soft tissue sarcoma. Int J Radiat
Oncol Biol Phys 1994; 29: 1005–10.
91. Lewis JJ, Leung D, Woodruff JM, Brennan MF. Retroperitoneal
soft-tissue sarcoma. Analysis of 500 patients treated and
followed at a single institution. Ann Surg 1998; 228: 355–65.
92. Sondak VK, Robertson JM, Sussman JJ, et al. Preoperative
idoxuridine and radiation for large soft tissue sarcomas:
clinical results with five-year follow-up. Ann Surg Oncol
1998; 5: 106–12.
93. McGinn CJ. The role of radiation therapy in resectable
retroperitoneal sarcomas. Surg Oncol 2000; 9: 61–5.
94. Alektiar KM, Hu K, Anderson L, Brennan MF, Harrison LB.
High-dose-rate intraoperative radiation therapy (HDR-IORT)
for retroperitoneal sarcomas. Int J Radiat Oncol Biol Phys
2000; 47: 157–63.
95. Makela J, Kiviniemi H, Laitinen S. Prognostic factors pre-
dicting survival in the treatment of retroperitoneal sarcoma.
Eur J Surg Oncol 2000; 26: 552–5.
96. Goss G, Demetri G. Medical management of unresectable,
recurrent low-grade retroperitoneal liposarcoma: integration
of cytotoxic and non-cytotoxic therapies into multimodality
care. Surg Oncol 2000; 9: 53–9.
97. Mahajan A. The contemporary role of the use of radiation
therapy in the management of sarcoma. Surg Oncol Clin N
Am 2000; 9: 503–24.
98. Pisters PW, Ballo MT, Patel SR. Preoperative chemoradiation
treatment strategies for localized sarcoma. Ann Surg Oncol
2002; 9: 535–42.
486
99. Marinello P, Montresor E, Iacono C, et al. Long-term
results of aggressive surgical treatment of primary and
recurrent retroperitoneal liposarcomas. Chir Ital 2001; 52:
149–57.
100. Karakousis CP, Gerstenbluth R, Kontzoglous K, Driscoll DL.
Retroperitoneal sarcomas and their management. Arch Surg
1995; 130: 1104–9.
101. Sindelar WF, Kinsella TJ, Chen PW, et al. Intraoperative
radiotherapy in retroperitoneal sarcomas. Final results of a
prospective, randomized, clinical trial. Arch Surg 1993; 128:
402–10.
102. Ferrario T, Karakousis CP. Retroperitoneal sarcomas: grade
and survival. Arch Surg 2003; 138: 248–51.
103. Feig BW. Retroperitoneal sarcomas. Surg Oncol Clin N Am
2003; 12: 369–77.
104. Mendenhall WM, Zlotecki RA, Hochwald SN, et al.
Retroperitoneal soft tissue sarcoma. Cancer 2005; 104: 669–75.
105. Lewis JJ, Leung D, Woodruff JM, Brennan MF. Retroperito-
neal soft-tissue sarcoma: analysis of 500 patients treated
and followed at a single institution. Ann Surg 1998; 228:
355–65.
106. Shibata D, Lewis JJ, Leung DH, Brennan MF. Is there a role
for incomplete resection in the management of retroperitoneal
liposarcomas? J Am Coll Surg 2001; 193: 373–9.
107. Choyke PL, Hayes WS, Sesterhenn IA. Primary extragonadal
germ cell tumors of the retroperitoneum: differentiation of
primary and secondary tumors. Radiographics 1993; 13:
1365–78.
108. Delgado FG, Tjulandin SA, Garin AM. Long term results of
treatment in patients with extragonadal germ cell tumours.
Eur J Cancer 1993; 29: 1002–5.
109. Nichols CR, Fox EP. Extragonadal and pediatric germ cell
tumors. Hematol Oncol Clin N Am 1991; 5: 1189–209.
110. Blomlie V, Lien HH, Fossa SD, Jacobsen AB, Stenwig AE. CT
in primary malignant germ cell tumors of the retroperitoneum.
Acta Radiologica 1991; 32: 155–8.
111. Bautista N, Su W, O’Connell TX. Retroperitoneal soft tissue
sarcomas: prognosis and treatment of primary and recurrent
disease. Am Surg 2000; 66: 832–6.
112. Arca MJ, Sondak VK, Chang AE. Diagnostic procedures and
pretreatment evaluation of soft tissue sarcomas. Semin Surg
Oncol 1994; 10: 323–31.
113. Karakousis CP, Kontzoglou K, Driscoll DL. Resectability of
retroperitoneal sarcomas: a matter of surgical technique? Eur
J Surg Oncol 1995; 21: 617–22.
114. Storm FK, Mahvi DM. Diagnosis and management of retro-
peritoneal soft-tissue sarcoma. Ann Surg 1991; 214: 2–10.
115. Heslin MJ, Lewis JJ, Nadler E, et al. Prognostic factors associ-
ated with long-term survival for retroperitoneal sarcoma:
implications for management. J Clin Oncol 1997;15: 2832–9.
116. Eilber FC, Eilber KS, Eilber FR. Retroperitoneal sarcomas.
Curr Treat Options Oncol 2000; 1: 274–8.
117. Heslin MJ, Smith JK. Imaging of soft tissue sarcomas. Surg
Oncol Clin N Am 1999; 8: 91–107.
118. Varma DG. Optimal radiologic imaging of soft tissue sarcomas.
Semin Surg Oncol 1999; 17: 2–10.
119. Varma DG. Imaging of soft-tissue sarcomas. Curr Oncol Rep
2000; 2: 487–90.
 primary retroperitoneal tumors
120. Folpe AL, Lyles RH, Sprouse JT, Conrad EU 3rd, Eary JF.
(F-18) fluorodeoxyglucose positron emission tomography as
a predictor of pathologic grade and other prognostic vari-
ables in bone and soft tissue sarcoma. Clin Cancer Res 2000;
6: 1279–87.
121. Messa C, Landoni C, Pozzato C, Fazio F. Is there a role for
FDG PET in the diagnosis of musculoskeletal neoplasms?
J Nucl Med 2000; 41: 1702–3.
122. Schwarzbach MH, Dimitrakopoulou-Strauss A, Willeke F,
et al. Clinical value of [18-F] fluorodexoyglucose positron
emission tomography imaging in soft tissue sarcomas. Ann
Surg 2000; 231: 380–6.
123. Johnson GR, Zhuang H, Khan J, Chiang SB, Alavi A.
Roles of positron emission tomography with flourine-18-
deoxyglucose in the detection of local recurrent and
distant metastatic sarcoma. Clin Nucl Med 2003: 28:
815–20.
124. Arush MW, Israel O, Postovsky S, et al. Positron emission
tomography/computed tomography with 18fluoro-deoxyg-
lucose in the detection of local recurrence and distant
metastases of pediatric sarcoma. Pediatr Blood Cancer 2007;
49: 901–5.
125. Tsatalpas P, Beuthien-Baumann B, Kropp J, et al. Diagnostic
value of 18F-FDG positron emission tomography for detection
and treatment control of malignant germ cell tumors. Urol
Int 2002; 68: 157–63.
126. Cohan RH, Baker ME, Cooper C, et al. Computed tomography
of primary retroperitoneal malignancies. J Comput Assist
Tomogr 1988; 12: 804–10.
127. Gupta AK, Cohan RH, Francis IR, Sondak VK, Korobkin M.
CT of recurrent retroperitoneal sarcomas. Am J Roentgenol
2000; 174: 1025–30.
128. Varma DG, Jackson EF, Pollock RE, Benjamin RS. Soft-tissue
sarcoma of the extremities: MR appearance of post-treatment
changes and local recurrences. Magn Reson Imaging Clin N
Am 1995; 3: 695–711.
129. Fotiadis C, Zografos GN, Karatzas G, Papachristodoulou A,
Sechas MN. Recurrent liposarcomas of the abdomen and
retroperitoneum: three case reports. Anticancer Res 2000;
20: 579–83.
487
 24 Primary Bone Tumors
Steven LJ James, Murali Sundaram, and A Mark Davies

INTRODUCTION CLINICAL DIAGNOSIS AND DETECTION

Primary malignant tumors of bone are rare and encompass a broad Patient age is perhaps the most important consideration when diag-
spectrum of diagnoses as outlined by the World Health Organization nosing a primary bone tumor. Certain lesions tend to have a particu-
(WHO) in 2002 (1). It is important to recognize that whilst this pro- lar predilection for specific age groups, each of which have been
vides a seemingly clear demarcation between pathological processes summarized in Table 24.1. Primary bone tumors as a group are
no system is all encompassing. When considering a potentially neo- bimodal, the first peak occurring during the second decade of life
plastic lesion of bone one needs to consider other conditions which and the second peak in patients older than 60 years. It should be
can present clinically and resemble radiologically a primary bone stressed, however, that it is much more common over 40 years of age
malignancy. This will on occasion include traumatic or stress related for a bone lesion to be secondary to metastases, myeloma, or lym-
injury, reactive and infective lesions (2,3). A logical approach is there- phoma than a primary bone sarcoma. Furthermore, certain tumors
fore required and can aid greatly in the formulation of a differential tend to occur in particular locations whether this is in the metaphy-
diagnosis that allows recommendations for further imaging and sis, diaphysis, or epiphysis of long bones as summarized in Table 24.2.
biopsy to be made (4). In some instances, certain imaging character-
istics are sufficiently diagnostic for a benign or non-neoplastic lesion Table 24.1 Typical Age of Presentation of Malignant Bone Lesions
that radiographs suffice and further more complex imaging is not
indicated. Often however, both radiological and histological exami- Age Diagnosis
nation is required and it is vital that both assessments are performed Under 20 yr Ewing sarcoma
Osteosarcoma (conventional, periosteal, telangiectatic, small cell,
in conjunction rather than taken in isolation. This is best achieved by
low grade central, high grade surface)
close co-operation between the oncology surgeon, radiologist, and 20−40 yr Chondrosaroma (mesenchymal, clear cell)
histopathologist in order to provide a complete evaluation. Osteosarcoma (parosteal)
In this chapter we aim to provide a framework for the assessment, Fibrosarcoma
characterization, staging, and follow-up of primary malignant Chordoma
Angiosarcoma
tumors of bone. Clearly there are a number of imaging modalities
Over 40 yr Chondrosarcoma (conventional, dedifferentiated)
available to the radiologist when investigating any lesion; however, Malignant fibrous histiocytoma
radiographs still provide the mainstay in diagnosis and are manda- Secondary osteosarcoma (Paget’s disease, radiation)
tory in all cases (5). The role and relative value of computed tomog- Fibrosarcoma
raphy (CT), magnetic resonance (MR) imaging, bone scintigraphy, Plasma cell myeloma
Lymphoma
and positron emission tomography (PET) in both diagnosis and
Angiosarcoma
staging is discussed. The classification of primary bone tumors as set Leiomyosarcoma
out by the WHO is reviewed (1). This provides the basic categories
Lesions that are included in more than one age range have a fairly uniform age
into which primary bone malignancies can be placed. The epidemi- of presentation across those age ranges.
ology of the common lesions is discussed including relative
incidence and importantly, age at presentation. The age-specific
frequencies and incidence rates of bone sarcomas aid significantly in Table 24.2 Typical Location of Malignant Bone Tumors
narrowing potential diagnoses. The imaging features of the common Site of origin Lesion
tumors and variants are then reviewed. Bone biopsy and the role of Metaphyseal
imaging in the assessment of treatment and follow-up are discussed. Medullary Conventional osteosarcoma
Benign and non-neoplastic lesions, myeloma, and lymphoma are Chondrosarcoma
Myeloma
outside the remit of this chapter though the latter two diagnoses are
Fibrosarcoma
incorporated into some of the Tables for the sake of completeness. Angiosarcoma
Lymphoma
Key Points: General Juxtacortical Periosteal osteosarcoma
Parosteal osteosarcoma
■ Primary malignant tumors of bone are rare High grade surface osteosarcoma
■ A logical approach aids greatly in the assessment of bone Juxtacortical chondrosarcoma
lesions and differentiating malignant lesions from benign or Epiphyseal Clear cell chondrosarcoma
Diaphyseal
non-neoplastic reactive lesions Medullary Ewing sarcoma
■ Assessment of primary bone sarcomas is best performed by close Lymphoma
cooperation between the oncology surgeon, histopathologist, Myeloma
and radiologist Angiosarcoma

488
 primary bone tumors

(A) (B) (C)

Figure 24.1 Osteosarcoma. (A) AP radiograph demonstrating an osteosarcoma of the proximal fibula. A sclerotic metaphyseal lesion is demonstrated which shows the
amorphous appearance of malignant osteoid. (B) AP radiograph demonstrating a purely lytic osteosarcoma of the proximal humerus. The lesion is ill defined and shows
a moth-eaten/permeative pattern, particularly at the distal margin. (C) AP radiograph demonstrating an osteosarcoma of the proximal tibia. This demonstrates a mixed
pattern of sclerosis and lysis.

Both the age of peak incidence and location act as a guide and should
be taken into account with the radiographic features described below
to reach a differential diagnosis.
In general, the clinical presentation of patients with primary
bone tumors is rather non-specific. The most common symptom
is pain, which typically is of insidious onset unless the presenta-
tion is with a pathological fracture. There may be local swelling
and limitation of movement especially if the lesion is located close to
a joint. Finally, there may be systemic symptoms including general
malaise, fever, lethargy, and weight loss (6).

Key Points: Diagnosis and Detection

■ Patient age is of critical importance when considering the
diagnosis of a primary bone sarcoma
■ Primary bone tumors have a bimodal age distribution
■ Over 40 years of age, metastases, myeloma, and lymphoma
are more common than primary bone sarcomas

ROLE OF IMAGING IN DIAGNOSIS AND STAGING

Radiographs
Radiographs continue to be of utmost importance in the diagnosis
of primary bone tumors. Imaging analysis consists of assessment of
certain radiographic features to establish a differential diagnosis
based both on these and the patient’s age, clinical presentation, and
tumor location. The matrix mineralization, presence and type of
periosteal reaction, zone of transition, cortical destruction, and soft
tissue extension all need to be considered (4). Each of these will be
reviewed in turn to aid the observer in understanding how to analyze
the radiographic appearances to reach a differential diagnosis.
Tumor Matrix
The degree of opacity of a primary bone lesion on radiographs may
be described as being predominantly sclerotic, lytic, or may show a
mixed pattern (Fig. 24.1). The tumor matrix refers to the tissue make
Figure 24.2 AP radiograph of the proximal femur demonstrating a well-differentiated
chondrosarcoma. The classic chondroid matrix consisting of punctate, ring, and arc
like areas of calcification is identified.
up of that lesion whether it is osteoid, cartilaginous, fibrous, or adi-
pose tissue in origin. The pattern of calcification or ossification of
this matrix is referred to as the matrix mineralization and can provide
a clue as to the predominant matrix type of the tumor. Characteristi-
cally, chondroid calcification for example has a dot and comma,
punctate or arc-like pattern (Fig. 24.2) whereas mineralized osteoid
has a more amorphous cloud-like or fluffy appearance (Fig. 24.1A).

489
 primary tumor evaluation and staging

(A) (B) (C)

Figure 24.3 (A) AP radiograph of the proximal femur. A multi-lamellated “onion skin” periosteal reaction is identified in this patient with Ewing sarcoma. (B) AP radiograph
of the elbow demonstrating a Ewing sarcoma of the distal humerus. On the ulna border of the humerus there is a multi-lamellated periosteal reaction. A more aggressive
spiculate reaction is seen distal to it. (C) AP radiograph of the proximal tibia demonstrating a mixed lytic and sclerotic osteosarcoma. A Codman triangle is identified at
the distal margin of the lesion secondary to periosteal elevation. The soft tissue extension of the tumor can be readily appreciated.

Periosteal Reaction
The host bone may react in different fashions to the insult of a pri-
mary lesion. This allows further characterization of the potential
behavior of that lesion to be evaluated. The response of the perios-
teum may vary from the most innocuous or benign appearance of a
continuous uninterrupted reaction, through to a multi-lamellated
“onion skin” appearance (Fig. 24.3A) to the most aggressive sun-
burst or spiculate form (Fig. 24.3B). A localized interrupted trian-
gular elevation of the periosteum is frequently termed a “Codman’s
triangle.” This occurs at the margin of an aggressive lesion and is
most commonly associated with osteosarcoma (Fig. 24.3C) (7).

Zone of Transition and Lesion Margin

Both of these radiographic features serve to provide information
regarding the relative aggressiveness of a particular lesion. This
can therefore be used to provide an indication of the rate of growth
of a tumor. Malignant lesions tend to have a wide zone of transi-
tion with indistinct margins (Fig. 24.1B). Identifying where a
lesion starts and stops is often difficult to define particularly in a
predominantly lytic process. This pattern is often described as
moth-eaten or permeative (Fig. 24.1B).

Cortical Destruction and Soft Tissue Extension
Soft tissue extension is relatively poorly appreciated on radiographs
and if visualized often gives an indication that there may be exten-
sive soft tissue involvement. There may be loss of definition of fat
planes adjacent to bone and this may be extremely subtle. However,
cortical destruction with soft tissue extension is highly suggestive of
a malignant lesion be it primary or secondary (Fig. 24.4).
Computed Tomography
CT has a limited role in the local staging of primary bone tumors
because of the inherently better soft tissue characterization of MR
Figure 24.4 AP radiograph illustrating a large osteosarcoma of the proximal
humerus with cortical destruction and soft tissue extension.
imaging. It is the preferred technique in those situations where
characterization of a lesion by radiography may be incomplete
or difficult because of inadequate visualization of the matrix of
a lesion (e.g., the flat bones such as the pelvis, scapula, or poste-
rior elements of the vertebrae) (Fig. 24.5) (8). The role of CT
in these circumstances is to characterize the lesion and deter-
mine whether it is potentially malignant or not, and often the

490
 primary bone tumors

Figure 24.5 Axial CT image demonstrating the typical pattern of chondroid calcifi-
cation in a peripheral pelvic chondrosarcoma.
(A) (B)
Figure 24.6 (A) AP radiograph of the proximal femur shows an area of lamellated
periosteal reaction in a Ewing sarcoma. It is impossible to appreciate the true
extent of the lesion. (B) Coronal STIR MR sequence demonstrates the true
cranio-caudal extent of intraosseous involvement.

obtained CT images may suffice for local staging. CT remains

the examination of choice for evaluation of the thorax for
metastatic disease (9).

Magnetic Resonance Imaging

Local staging and characterization of all potentially malignant
tumors in bone is most accurately achieved by MR imaging,
which should be performed prior to biopsy (10,11). Axial
imaging complemented by either coronal or sagittal imaging
planes using T1-weighted spin-echo sequences augmented by
fat-suppressed T2-weighted spin-echo sequences is required
(12). Short tau inversion recovery (STIR) sequences may over-
estimate the degree of tumor involvement. The intraosseous
extent of the lesion should be assessed in the longitudinal plane
either on coronal or sagittal images with the maximum dimen-
sion of the tumor being measured prior to treatment (Fig.
24.6). The entire length of the affected bone must be included
in at least one sequence for the assessment of skip lesions (Fig.
24.7). Of those cases seen at tertiary referral centers treating
primary bone sarcomas, it is the omission of this which unfor-
tunately all too often necessitates repeat imaging (13). The
opposite side of the joint should also be included so that the
presence of transarticular skip lesions can be excluded (14).
Axial imaging enables the relationship of the extraosseous
component of the tumor to be assessed including its proximity
to the neurovascular bundle. Intraarticular spread of tumor
also needs to be identified for lesions arising close to the joint
margins (Fig. 24.8) (15).
The use of static gadolinium enhancement is not routinely Figure 24.7 Sagittal T1-weighted MR image demonstrating two skip lesions
required for staging and has a limited role in tumor assessment (16). proximal to a distal femoral osteosarcoma.

491
 primary tumor evaluation and staging

(A)

Figure 24.8 Sagittal STIR MR sequence of the knee showing intra-articular invasion
from a proximal tibial osteosarcoma. Tumor can be identified extending into
Hoffa’s fat pad (arrow) and along the anterior cruciate ligament.

Post-contrast imaging can be used to distinguish between solid

and cystic lesions and can aid in planning biopsy of the solid
component (Fig. 24.9) (16). Dynamic contrast-enhanced MR
imaging may be used in an attempt to differentiate benign from
malignant tumors. Malignant lesions tend to take up contrast
more rapidly and to a greater degree than benign lesions (17).
There is, unfortunately, overlap but high grade malignant
lesions can be excluded effectively if a very slowly enhancing
mass is demonstrated. This technique can also be applied in an
attempt to better differentiate the margin of a lesion relative to
its reactive zone of tumor related edema. Tumor related edema (B)
can be distinguished by an enhancement curve with a slope
Figure 24.9 Telangiectatic osteosarcoma. (A) Axial T2-weighted fat suppressed
20% or less than the tumor (18). Finally, the degree of tumor MR image demonstrating a heterogeneous mass in the proximal tibia. There are
response to chemotherapy and differentiation of tumor from cystic areas posteriorly with several fluid-fluid levels. (B) Axial T1-weighted fat
post chemotherapy inflammatory changes may be improved by suppressed MR sequences following gadolinium administration demonstrates the
using dynamic contrast-enhanced MR imaging (19,20). cystic nature of the lesion posteriorly and the solid areas of enhancing tumor ante-
riorly which can be targeted for biopsy.

Bone Scintigraphy
Technetium scintigraphy is the technique of choice for evaluation
of the entire skeleton to determine the presence of metastatic dis-
ease although in the future it may be superseded by whole-body
MR imaging (21,22). In osteosarcoma, non osseous metastases
may show radionuclide uptake and so pulmonary metastases may
simulate rib deposits to the unwary (Fig. 24.10).
Positron Emission Tomography
Elevated 18-fluoro-2-deoxyglucose (18FDG) accumulation has been
demonstrated in a variety of malignant tissues, including sarcomas,
and this information can be used to augment conventional imaging
techniques such as CT and MR imaging (23,24). PET has a limited
role in the local staging of bone sarcomas. Although the spatial reso-
lution of PET imaging is higher than that of other scintigraphic
techniques, it is not sufficiently accurate to delineate tumor margins
and anatomic boundaries, and information regarding local disease
extent is better assessed by CT or MR imaging (25). There is limited
evidence supporting the use of FDG PET in the identification of
metastases from some primary bone sarcomas (26,27). 18FDG
PET has been found to be superior to conventional skeletal scintig-
raphy for detection of osseous metastases from Ewing sarcoma

492
 primary bone tumors

(A) (B)
Figure 24.10 Primary osteosarcoma. (A) Whole body bone scintigraphy (posterior view) demonstrates multiple areas of abnormal uptake projected over the right
hemithorax. A further large abnormal area of uptake is identified in the pelvis. (B) Axial CT of the chest demonstrates the lesions identified on bone scintigraphy to
represent ossified pulmonary metastases.

(Fig. 24.11), but inferior for detection of osseous metastases from
osteosarcoma (28). Although 18FDG PET has been found to be
accurate in the detection of nodal, pulmonary, and osseous metas-
tases in patients with soft tissue sarcomas (29,30), the results for
osseous tumors are much less promising. Although pulmonary
metastases from osteogenic sarcoma can be detected with 18FDG
PET (31), CT has been found to be superior for detection and delin-
eation of pulmonary metastases (32) and a negative PET scan does
not exclude the presence of metastases. PET may also play a role in
restaging primary osseous lesions and their response to therapy.
This will be covered in a later section in this chapter where assess-
ment of treatment and follow-up is discussed.
EPIDEMIOLOGY AND CLASSIFICATION
Primary bone sarcomas account for approximately 0.2% of all
neoplasms (33). The incidence of newly diagnosed bone sarcomas
in North America and Europe is 0.8/100,000 population per
year (1). In the United Kingdom primary bone and connective
tissue tumors account for less than 1% of all cancers with an inci-
dence of 3.3 per 100,000 population (34). The WHO classification
of bone tumors is based on both histological and genetic criteria
and incorporates both benign and malignant bone tumors (1).
Table 24.3 summarizes the classification of malignant bone lesions
according to this system.

Key Points: Role of Imaging in Diagnosis and Staging

■ Radiographs remain paramount in the identification of
Osteosarcoma
Osteosarcoma is the most common non-hematological primary
potential bone tumors
bone tumor and accounts for approximately 35% of all primary
■ The matrix mineralization, presence and type of periosteal
bone sarcomas (1). It is a tumor of mesenchymal origin which is
reaction, zone of transition, cortical destruction, and soft tissue
characterized by tumor cells which produce osteoid. The classic or
extension all need to be considered
typical tumor is referred to as a conventional osteosarcoma
■ CT allows better identification of the tumor matrix if this is
(approximately 85%). However, there are a number of variants
difficult to appreciate on radiographs and is the modality of
which include telangiectatic osteosarcoma (<4%); small cell oste-
choice for imaging the thorax for metastatic disease
osarcoma (1.5%); low grade central osteosarcoma (<1%);
■ MR imaging most accurately establishes the intraosseous
parosteal osteosarcoma (4%); periosteal osteosarcoma (<2%);
and extraosseous extent of the tumor and should include the
high grade surface osteosarcoma (<1%); and those which may be
whole affected bone to identify skip metastases
associated with pre-existing conditions such as Paget’s disease or
■ Bone scintigraphy remains the current preferred technique for
following radiotherapy (4%) (1). Furthermore, sub classification
the identification of bone metastases
can be performed on the basis of histology according to the dom-
■ The role of PET continues to evolve with some limited evidence
inant tissue type—osteoblastic, fibroblastic, chondroblastic.
supporting the use of FDG PET in the identification of metastases
It predominantly occurs in individuals younger than age 20
from some primary bone sarcomas
though the age at presentation is bimodal: 10 to 25 years and 60 to

493
 primary tumor evaluation and staging

Figure 24.11 PET-CT in a patient with metastatic Ewing sarcoma demonstrating metastases in the L3 vertebra, right acetabulum, and both proximal femora.

Table 24.3 WHO Classification of Malignant Bone Tumors

Cartilage tumors Fibrogenic tumors
Chondrosarcoma Fibrosarcoma
Central, primary, and secondary
Fibrohistiocytic tumors
Peripheral
Malignant fibrous histiocytoma
Dedifferentiated
Mesenchymal Ewing sarcoma/primitive neuroectodermal tumor
Clear cell Ewing sarcoma
Osteogenic tumors Hematopoietic tumors
Osteosarcoma Plasma cell myeloma
Conventional Malignant lymphoma
Chondroblastic
Notochordal tumors
Fibroblastic
Chordoma
Osteoblastic
Telangiectatic Vascular tumors
Small cell Angiosarcoma
Low grade central
Smooth muscle tumors
Secondary
Leiomyosarcoma
Parosteal
Periosteal Lipogenic tumors
High grade surface Liposarcoma

494
 primary bone tumors
80 years. Males are more frequently affected than females, which
may relate to their longer growth period. The tumor may involve
any bone; however, approximately 90% will occur in the meta-
physis of long tubular bones with the knee being the commonest
site (45%) (35). The predilection for the appendicular skeleton
tends to decrease with age, and in patients older than 50 years,
osteosarcoma accounts for 50% of extremity lesions (1). Parosteal
and periosteal osteosarcoma tend to present in a slightly older
age group.
Conventional osteosarcoma may show considerable variation
in the radiographic appearance. The most commonly identified
appearance is a mixed lytic/sclerotic lesion; however, a purely
lytic or dense sclerotic pattern may be observed (Fig. 24.1). Areas
of cloud-like amorphous opacification corresponding to malig-
nant osteoid production are evident (Fig. 24.1A). The lesion is
metaphyseal in origin (Fig. 24.12A) but may extend into the epi-
physis in up to 88% of cases (35). There is typically an indistinct
margin, wide zone of transition, soft tissue mass, and disorga-
nized periosteal reaction (Fig. 24.4), either sunburst/spiculated
reaction or the classic “Codman triangle” being secondary to
periosteal elevation (Fig. 24.3C). The variants of osteosarcoma
have a number of imaging patterns which can aid in differentia-
tion. Telangiectatic osteosarcoma typically has an aggressive lytic
appearance and is characterized by rapid bone destruction. Occa-
sionally, oblique or vertical lytic striations may be evident parallel
to the shaft of a long bone thought to be secondary to intraosseous
venous hypertrophy (36). This variant most frequently affects the
(A) (B)
Figure 24.12 Sclerotic osteosarcoma. (A) AP radiograph of the knee demonstrates a typical metaphyseal sclerotic osteosarcoma. (B) Sagittal T1-weighted MR image
shows areas of intermediate and low signal intensity. (C) Sagittal STIR MR image demonstrates the heterogeneous signal pattern with quite prominent areas of low signal
consistent with malignant osteoid production.
metaphysis of long bones with the knee being most common
(Fig. 24.13A) (35). Parosteal osteosarcoma demonstrates a lobu-
lated ossified mass along the surface of bone in the metaphysis
(Fig. 24.14A). There is typically thickening of the adjacent cortex
and occasionally intramedullary extension (10%). Higher grade
parosteal osteosarcoma may undergo dedifferentiation most
commonly to a high grade surface osteosarcoma. Periosteal oste-
osarcoma again involves the surface of bone but is often less
densely mineralized than a parosteal osteosarcoma and more fre-
quently occurs in the diaphysis (Fig. 24.15A). There is often a
large soft tissue component to this tumor and scalloping of the
cortex may be evident (35).
On MR imaging, conventional osteosarcoma typically demon-
strates a mixed signal pattern predominantly of intermediate
signal intensity on T1-weighting and intermediate to increased
intensity on STIR/T2-weighted sequences; however, the signal
pattern is determined by the degree of tumor matrix mineraliza-
tion (Fig. 24.12B and C) (37). The entire involved bone needs to
be covered as the incidence of skip metastases in osteosarcoma is
approximately 6.5% (Fig. 24.7) (38). Low signal intensity regions
on all pulse sequences are common and correspond to areas of
malignant osteoid when correlated with radiographs (Fig. 24.12B
and C). Extension of tumor into the diaphyseal and epiphyseal
region is frequent as is soft tissue extension (35). Pathological frac-
ture may be a presenting feature and there may be areas of increased
signal intensity on T1-weighted sequences corresponding with
areas of subacute hemorrhage. If a fracture is present there is often
(C)
495
 primary tumor evaluation and staging

(A) (B)
Figure 24.13 Telangiectatic osteosarcoma. (A) AP radiograph illustrates an ill-defined lytic lesion in the proximal fibula with periosteal elevation inferiorly. (B) Axial
T2-weighted fat suppressed MR image demonstrating multiple fluid-fluid levels.

(A) (B)
Figure 24.14 Parosteal osteosarcoma. (A) Lateral radiograph demonstrates a lobulated ossified mass arising from the posterior aspect of the distal femur. (B) Sagittal
T1-weighted MR image of the distal femur demonstrates a lobular low signal intensity mass lesion without intramedullary extension.

marked soft tissue edema and inflammatory change on the fat
suppressed T2/STIR sequences which is not usually a feature in the
absence of a fracture. Telangiectatic osteosarcoma characteristi-
cally shows multiple fluid-fluid levels secondary to the blood filled
cavities which are evident on pathological examination (Fig.
24.13B). In light of the degree of hemorrhage shown by these
lesions there are frequently areas of increased signal intensity on
both T1- and T2-weighted sequences (39). On MR imaging, the
presence of multiple fluid-fluid levels may mimic an aneurysmal
bone cyst. Parosteal osteosarcoma shows predominantly low signal
intensity on pulse sequences due to the presence of marked mineral-
ization. This has a characteristic lobular appearance and MR imag-
ing is of value in demonstrating the presence of intramedullary
involvement (Fig. 24.14B) (40). Periosteal osteosarcoma demon-
strates a mass arising from the cortex with soft tissue extension and
cortical scalloping/erosion. The lesion is of intermediate signal
intensity on T1-weighted and intermediate to high signal on
T2-weighted sequences (Fig. 24.15B). A chondroid matrix may

496
 primary bone tumors
(A)
Figure 24.15 Periosteal osteosarcoma. (A) AP radiograph of the femur shows a diaphyseal lesion which has a less densely mineralized pattern than is evident in a parosteal
tumor (see Fig. 24.13A for comparison). (B) Sagittal STIR shows predominantly high signal with internal areas of lower signal intensity consistent with the areas of
mineralization identified on radiographs.
be identified and there is sparring of the medullary cavity (41).
High grade surface osteosarcoma may show similar imaging fea-
tures to periosteal osteosarcoma but is associated with a higher inci-
dence of marrow invasion.
Key Points: Osteosarcoma
■ Osteosarcoma is the most common non-hematological
primary bone tumor
■ Most cases arise de novo but osteosarcoma may arise in
pre-existing lesions, typically in older patients
■ Osteosarcoma most commonly involves the metaphysis of
long tubular bones
■ Conventional osteosarcoma demonstrates a variable radio-
graphic appearance. Features include amorphous areas of
cloud-like malignant osteoid production, an indistinct
margin, wide zone of transition, soft tissue mass, and disor-
ganized periosteal reaction
■ MR imaging allows assessment for local staging and
may allow further characterization of some subtypes of
osteosarcoma
Chondrosarcoma
This is a malignant tumor with pure hyaline cartilage differen-
tiation which may contain areas of myxoid change, calcification,
(B)
or ossification (1). Chondrosarcoma is the third most common
primary bone tumor and accounts for approximately 20% of
cases (42). Chondrosarcomas show a gradual increase in inci-
dence rates up to the age of 50 with the peak incidence in the
fifth to seventh decades. Half of chondrosarcomas occur in the
long bones; other major sites are the pelvis and ribs. Chondro-
sarcomas can be subdivided into primary, which accounts for
approximately one-third of lesions, and secondary. Secondary
lesions may arise for pre-existing lesions such as enchondroma,
osteochondroma, and periosteal chondroma or from bone which
has been previously irradiated or is affected by Paget’s disease
(43). The risk of chondrosarcoma is increased in patients with
Ollier and Mafucci disease (25–30%) (44). Primary lesions can
then be further subclassified into conventional, periosteal,
mesenchymal, clear cell, and de-differentiated.
Conventional chondrosarcoma can again be subclassified into
central and peripheral. Histologically, differing grades of
malignancy are identified (low, intermediate, and high grade).
Dedifferentiated chondrosarcoma represents a separate entity
and is composed of two distinct components: a well-differentiated
cartilage tumor and high-grade non-cartilaginous sarcoma
(45). Mesenchymal chondrosarcoma has a peak incidence in the
second and third decades with the most common sites of
involvement including the craniofacial bones, ribs, ilium, and
vertebrae (46). Clear cell chondrosaracoma is a rare subarticular
497
 primary tumor evaluation and staging

(A) (B) (C)

Figure 24.16 Chondrosarcoma. (A) Lateral radiograph of the humerus demonstrates an ill-defined chondrosarcoma in the diaphysis with endosteal scalloping. (B) Axial
T2-weighted fat-suppressed MR image shows an anterior cortical breach in the humerus with some soft tissue extension. (C) Coronal T1-weighted MR image shows the
longitudinal extent of the chondrosarcoma with small low signal areas of signal void from the areas of calcification.

lesion which most commonly involves the humeral or femoral
head (47).
Conventional chondrosarcoma can vary from a well-differen-
tiated, relatively slow growing tumor to a more aggressive
poorly-differentiated form. Radiographs show a predominantly
lytic pattern in a medullary location (Fig. 24.16A). The margins
of the lesion vary from well-defined to indistinct. The classic
chondroid matrix consists of punctate, arc or dot, and comma
like calcifications (Fig. 24.2) (48). The slow growth pattern of
central chondrosarcomas may lead to areas of endosteal scal-
loping (Fig. 24.16A). Periosteal reaction and soft tissue exten-
sion are frequent findings in higher grade lesions (Fig. 24.16B).
MR imaging demonstrates a lobular mass with the non-calci-
fied areas showing increased signal intensity on T2-weighted
sequences. The calcified areas demonstrate signal voids on MR
imaging being of low signal on all pulse sequences (Fig. 24.16C)
(48). Periosteal chondrosarcoma involves the cortex and
demonstrates indistinct margins and is primarily lytic with
areas of punctate calcification. There may be variable erosion of the
cortical bone (49).
Dedifferentiated chondorsarcoma typically demonstrates a
bimorphic pattern, one related to the underlying chondroid lesion
and a separate lytic lesion often with cortical destruction and soft
tissue extension (Fig. 24.17) (45). Mesenchymal chondrosarcoma
is primarily lytic, expansile, and destructive on radiographs and is
indistinguishable from conventional chondrosarcoma on imag-
ing. Clear cell chondrosarcoma demonstrates a well-defined sub-
articular lesion with a thin sclerotic border and is difficult
radiographically to differentiate from a chondroblastoma; however,
age at presentation aids in differentiating these two entities
(Fig. 24.18) (47).
Key Points: Chondrosarcoma
■ Chondrosarcoma may be primary or secondary to a pre-existing
lesion such as an osteochondroma, enchondroma, or periosteal
chondroma
■ The risk of chondrosarcoma is increased in patients with
Ollier and Mafucci disease
■ Conventional chondrosarcoma can show a wide range of
appearances according to tumor grade from relatively indolent
to an aggressive pattern
■ The classic chondroid matrix consists of punctate, arc or dot,
and comma like calcifications
Malignant Fibrous Histiocytoma
Malignant fibrous histiocytoma represents the commonest malig-
nant fibrous tumor of bone and accounts for less than 2% of all
primary malignant bone lesions (1). These tumors may present
over a broad age range though there is a slightly higher incidence
over the age of 40 years. This lesion may arise de novo or can arise
in a pre-existing lesion such as within an area of Paget’s disease,
irradiated bone, or an area of osteonecrosis. The typical site of
involvement is in a long bone metaphysis (90%) and the femur is
the most commonly affected bone (30–45%) (50). Histologically
this lesion is composed of fibroblasts and pleomorphic cells with
a prominent storiform pattern.

498
 primary bone tumors

(A) (B) (C)

Figure 24.17 Dedifferentiated chondrosarcoma. (A) AP view of the proximal femur demonstrates a chondroid lesion with areas of ill-defined lucency and an associated
pathological fracture. (B) Coronal STIR MR image shows the typical lobular high signal intensity pattern distally with more intermediate weighted signal intensity
proximally in a dedifferentiated chondrosarcoma of the proximal femur. (C) Coronal T1-weighted MR demonstrates the cortical breach of the medial wall on the femur.

(A) (B)
Figure 24.18 Clear cell chondrosarcoma. (A) AP radiograph of the proximal femur demonstrates a well-defined lucency in the epiphysis extending into the femoral neck
in this patient with a clear cell chondrosarcoma. (B) Coronal T1-weighted MR image showing the intraosseous extent and involvement of the epiphysis.

Radiographs demonstrate a predominantly lytic metaphyseal
lesion which may extend into the epiphysis. There is a wide zone
of transition with ill-defined margins and soft tissue extension
is frequent (Fig. 24.19). Cortical destruction is a common fea-
ture and a periosteal reaction is infrequent (51). Particularly in
older patients, the features are non-specific and often cannot be
differentiated from metastases, myeloma, or lymphoma.
Approximately 20% of patients will present with a pathological
fracture. The MR imaging appearances are rather non-specific
being of intermediate signal intensity on T1 and hyperintense
on fat-suppressed T2/STIR relative to muscle (51). It will show
a rather inhomogeneous locally destructive lesion with soft tissue
extension. The main role of imaging is showing the true intra
and extraosseous extent of disease.
Fibrosarcoma
This is a rare spindle cell neoplasm which is characterized by the
presence of tumor cells organized in a fascicular or herringbone
pattern (1). It is less frequently encountered than malignant
fibrous histiocytoma though there is some overlap in terms of

499
 primary tumor evaluation and staging
(A) (B)
Figure 24.19 Malignant fibrous histiocytoma. (A) AP and (B) lateral radiographs
of the distal femur showing a lytic metaphyseal lesion.
histological classification making it difficult to estimate the true
incidence. This lesion most commonly occurs between the second
and sixth decades. The long bones are most commonly affected
with an intramedullary metaphyseal position the most common.
The femur is the most commonly involved bone (52). A signifi-
cant proportion (up to one-third) of these tumors may arise in
pre-existing lesions.
Radiographs demonstrate an aggressive destructive lesion
with a wide zone of transition and ill-defined margins. There
may be expansion of the involved bone and pathological frac-
tures are relatively frequent (53). Periosteal reaction including
the presence of a Codman’s triangle is often seen as is the pres-
ence of a soft tissue mass (52). MR imaging may demonstrate
areas of low signal intensity on both T1- and T2-weighted
sequences though frequently the MR imaging appearances are
non-specific and indistinguishable on imaging from malignant
fibrous histiocytoma.
Key Points: Malignant Fibrous Histiocytoma
and Fibrosarcoma
■ Both lesions are rare tumors which may arise de novo or in
pre-existing lesions
■ Both most commonly affect a long bone metaphysis,
frequently the femur
■ Radiographs demonstrate an ill-defined, lytic lesion with a
non-specific MR signal intensity pattern
Ewing Sarcoma and Primitive Neuroectodermal
Tumor (PNET)
Both these conditions were originally thought to represent
discrete clinicopathologic entities; however, it has become evident
500
that they form part of a spectrum of disease. This is in the light of
recent evidence from immunohistochemical, cytogenetic, and
molecular genetic studies that supports a common neuroectoder-
mal origin. Ewing sarcoma is a highly aggressive malignant tumor
of childhood and adolescence. It is characterized by the presence
of small round cells of uncertain origin which do not produce a
tumor matrix (1). Ewing sarcoma can occur in any bone but most
commonly occurs in the proximal metadiaphyseal region of long
bones. The pelvis is also a common site of involvement in approx-
imately 30% of cases (54). Involvement of the ribs (6%) and
spine (5%) is not infrequent. It typically presents between 5 and
30 years of age and is the second most common malignant pri-
mary bone tumor of childhood and adolescence. Approximately
80% of cases occur before the age of 20 years (1). It accounts for
approximately 6% to 8% of primary malignant bone tumors.
Males are more frequently affected than females (2:1), 95% are of
white ethnic origin.
Ewing sarcoma typically demonstrates ill-defined bone destruc-
tion with a permeative, moth-eaten pattern and a wide zone of
transition (Fig. 24.3). Most lesions demonstrate a mixed sclerotic/
lytic pattern (75%) with a purely lytic form also occurring (25%)
(54). Long bones are most frequently involved in the metadiaphy-
seal region though it may be purely diaphyseal. The femur and
humerus are most commonly involved but lesions involving the
pelvic bones and ribs are not infrequent. A periosteal reaction is
frequently present which typically has an interrupted lamellated
pattern. The classic “onion skin” or “sunburst” pattern may also
occur and the Codman triangle is also commonly observed (27%)
(Fig. 24.3) (54). There is frequently a large soft tissue mass which
may cause scalloping or saucerization of the cortex. Occasionally,
Ewing sarcoma may have a predominantly sclerotic pattern;
however this is more common in the flat bones. MR imaging
demonstrates an area of marrow infiltration of intermediate sig-
nal intensity on T1 and intermediate/high signal on T2/STIR
sequences (Fig. 24.6) (54). Skip metastasis may be identified
(14%) so imaging of the whole bone is again vital (54). A circum-
ferential soft tissue mass and multilaminated periosteal reaction is
often identified. Saucerization of the cortex is well-demonstrated
representing subperiosteal tumor spread. Very rarely a periosteal
Ewing sarcoma occurs, most often in adolescent males. The imag-
ing features are of a soft tissue mass arising from the surface of
bone without extension into the medullary cavity.
Key Points: Ewing Sarcoma
■ Aggressive small round cell tumor often involving the metadia-
physeal region of a long bone but not infrequently involving
the pelvis and ribs
■ The majority occur in the white population
■ Imaging demonstrates ill-defined bone destruction with a
permeative, moth-eaten pattern and a wide zone of transi-
tion, periosteal reaction, cortical scalloping, and soft tissue
extension
Chordoma
Chordoma arises from remnants of the notochord and therefore
occurs in the midline and has a predilection for the sacrum and
 primary bone tumors
clivus. They account for 1% to 4% of all primary malignant bone
tumors and should be considered a low to intermediate grade
malignancy, but despite this there is a high local recurrence rate
following treatment (1). The most common site is the sacrococ-
cygeal junction (50–60%) followed by the speno-occipital region
(25–40%) with the remainder occurring in the midline in the cer-
vical, lumbar, and thoracic spine in descending order of frequency
(1,42). This presents most frequently after the third decade and
the peak incidence is in the sixth decade. Males are more com-
monly affected than women (2:1).
In the sacral region, radiographs demonstrate a lytic midline
lesion (Fig. 24.20A). There is usually an associated pre-sacral soft
tissue mass; however, this can be hard to appreciate on radio-
graphs. This displaces rather than invades the posterior rectal wall.
Small areas of internal calcification may be identified on radio-
graphs (50–60%); however, this is better appreciated on CT (55).
MR imaging again demonstrates the midline location of the lesion
and more accurately defines both intra and extraosseous extent of
disease (Fig. 24.20B and C). A lobulated pattern with expansion is
frequently encountered. The tumor is of low to intermediate sig-
nal intensity on T1 and high signal on fat suppressed T2/STIR
images (55). In the cervical region, chordoma typically presents
with a parapharyngeal mass or symptoms relating to nerve root
compression.
Benign notochordal cell tumors (also termed giant noto-
chordal rest and notochordal hamartoma) have recently been
described and may mimic chordoma. It has been postulated that
this benign intraosseous lesion may be a precursor lesion to chor-
doma. They present in identical location but are usually small with
no bone destruction or soft tissue extension on cross-sectional
imaging (56).
Key Points: Chordoma
■ Low grade malignant tumor which arises from the notochord
with a propensity for local recurrence
■ Sacrococcygeal region is the most common site
■ MR imaging provides the best imaging assessment demon-
strating a midline mass typically of high signal on T2-weighted
sequences
LT
(A) (B)
Figure 24.20 Chordoma. (A) AP radiograph of the pelvis shows extensive areas of lysis in the sacrum secondary to a chordoma. (B) Sagittal STIR MR image shows a
lobulated mass of high signal arising in the sacrum extending proximally behind the S1 segment to the level of the lumbosacral disc space. This has displaced the rectum
anteriorly. (C) Axial fat suppressed T2-weighted MR image shows a midline mass of high signal with a lobular outline.
BIOPSY
Over the past 20 years, percutaneous biopsy under image guid-
ance has become the standard procedure for obtaining tissue from
bone neoplasms for histological diagnosis. The satisfactory results
obtained by this technique have, in many centers, supplanted the
open incisional biopsy as the primary interventional approach.
This is primarily due to improved cost-effectiveness of percutane-
ous biopsy compared with that of open biopsy, lower complica-
tion rate, a smaller limited biopsy tract, and the ability to begin
more rapidly neoadjuvant chemotherapy and/or radiation ther-
apy. With a definitive diagnosis, neoadjuvant chemotherapy or
radiation therapy can be started soon after core-needle biopsy. A
surgical approach often results in a delay of 10 days to three weeks
to allow wound healing (57).
A multidisciplinary approach including an orthopedic oncolo-
gist and orthopedic pathologist is essential. The presence of a
cytopathologist to assess the quality and adequacy of the fine-
needle aspirate to ensure that viable tumor cells are obtained
improves the quality of the tissue samples and accurate histologi-
cal diagnostic yield (58). In addition to the co-operative team
effort, radiologists performing this procedure need to have a clear
understanding of compartmental anatomy (59,60). This is a cru-
cial part of staging and must be done with an appropriate tech-
nique and a clear view of the eventual surgical treatment. The
placement of the biopsy must be carefully planned to allow for an
eventual en-bloc resection of a malignant neoplasm together with
the entire biopsy tract. The hazards and ensuing complications of
improperly carried out open biopsies have been addressed twice,
14 years apart by some of the same authors, who surprisingly
found that neither errors in the approach to biopsies nor compli-
cations had decreased since the first publication (61,62). The
biopsy of the tumor completes the staging process.
Key Points: Biopsy
■ Percutaneous biopsy is the method of choice to provide tissue
for histological diagnosis
■ Appropriate planning according to anatomic boundaries and
planned surgical approach is required
(C)
501
 primary tumor evaluation and staging

chemotherapy. Depending on location and extent of disease, radi-

PATHOLOGICAL STAGING
ation therapy may be added in the treatment of Ewing sarcoma.
The TNM staging system is not commonly used for sarcomas of Neoadjuvant therapy is ineffective in the treatment of chondro-
bone because of the rarity with which they metastasize to lymph sarcoma but may be used in the treatment of de-differentiated
nodes. Two staging systems are in current use: the Musculoskeletal chondrosarcoma. The goal of surgery is to resect the tumor with a
Tumor Society system (MSTS) (Table 24.4) and the American wide margin and reconstruct the limb. The combination of neo-
Joint Committee on Cancer (AJCC) system (Table 24.5) (63,64). adjuvant therapy and limb-salvage surgery has reduced mortality
The staging system adopted by the Musculoskeletal Tumor Society and morbidity in comparison with patient outcome prior to the
for the staging of bone tumors built on the work of Enneking et al. introduction of these treatment techniques. Critical to outcome is
(65). This stages malignant lesions according to the local extent the accurate depiction of local disease by MR imaging and sys-
(T), the grade (G), and the presence or absence of regional or temic disease by CT. It is imperative that MR imaging be per-
distant metastases (M). In this system, neoplasms are divided into formed after neoadjuvant therapy and prior to definitive surgery
two grades: low (G1) and high (G2). The anatomic extent (T) is (re-staging), and ideally in planes and pulse sequences compara-
divided according to whether the lesion is intracompartmental (A) ble to the initial staging examination. MR imaging remains criti-
or extracompartmental (B). The presence or absence of metastasis cal for recognizing tumor response, tumor necrosis, and evaluating
(M) is the final component of this staging system. The system extent (Fig. 24.21). Radiologists in referring institutions, who are
adopted by the American Joint Committee on Cancer is similar to likely to be primarily responsible for imaging and interpretation
that devised by Enneking; however, there have been a number of of patient examination following definitive surgery, need to be
modifications. These include the replacement of intraosseous or aware of some of the findings of tumor recurrence, infection,
extraosseous extent of tumor with tumor size, which is thought to pseudotumor, and rickets, which may be encountered (67–69).
be of more prognostic importance, location of metastases and Most osseous malignancies are treated with chemotherapy and
whether they involve lung only or involve other locations including in some instances combined with radiotherapy, followed by sur-
bone and skip metastases in the same bone (66). gery. The effectiveness of pre-surgical treatment regimens can be
assessed preoperatively by MR imaging and postoperatively by
quantification of histological necrosis within the tumor. Anatom-
Key point: Pathological Staging ical imaging techniques such as CT and MR imaging rely on phys-
ical properties of the tumor, such as macroscopic necrosis and
■ Two staging systems are in current use: the Musculoskeletal reduction in tumor dimension. A good response on MR imaging
Tumor Society system (MSTS) and the American Joint to Ewing sarcoma for example would include:
Committee on Cancer (AJCC) system
• Disappearance of the soft tissue element of the tumor
• Encirclement of the bone by a heterogeneous well-defined
ASSESSMENT OF TREATMENT AND FOLLOW-UP cuff of tissue (70)
Osteosarcoma, however, is somewhat different and these features
Osteosarcoma (excluding parosteal and low-grade intraosseous cannot be relied upon when assessing response. There are no
osteosarcoma) and Ewing sarcoma are treated with neoadjuvant effective criteria for reliable early identification of good respond-
ers on MR imaging; however, an increase in tumor volume and
increase in signal intensity of the extra-osseous tumor both pre-
Table 24.4 The Musculoskeletal Tumor Society Staging System dict a poor response (71). Dynamic contrast-enhanced MR imag-
Stage Grade Local extent Metastases ing enhancement characteristics have also been investigated.
Erlemann and co-workers (72) reported accuracy of 86% for
I-A Low Intracompartmental None identification of malignancy using this technique and in another
I-B Low Extracompartmental None
II-A High Intracompartmental None
study, responders with less than 3% viable tumor remaining could
II-B High Extracompartmental None be distinguished reliably from non-responders (73).
III Any Any Present PET has been evaluated in restaging of osteosarcoma and Ewing
sarcoma and has been shown to be accurate in demonstrating
both local and distant recurrence (74). The intensity of 18FDG
uptake by tumor is a measure of tumor metabolism and viability.
Table 24.5 The American Joint Committee on Cancer Staging PET therefore potentially provides a non-invasive means of assess-
System ing metabolic changes in the tumor prior to surgery. In patients
Stage Grade Local extent Metastases with both osteosarcoma and Ewing sarcoma, findings of 18FDG
PET have been found to be predictive of therapeutic response. In
I-A Low ≤8 cm None
I-B Low >8 cm None
one study of 15 patients with either osteogenic sarcoma or Ewing
II-A High ≤8 cm None sarcoma, PET was performed prior to initiation of therapy and
II-B High >8 cm None again after completion of therapy. PET scans were scored based on
III Any Any Skip metastases tumor to non-tumor FDG uptake ratios (T/NT), and tumor
IV-A Any Any Pulmonary metastases response to therapy was judged by postsurgical histological evalu-
IV-B Any Any Other metastases
ation. A decrease in T/NT ratio of greater than 30% on PET was

502
 primary bone tumors

(A) (B)
Figure 24.21 Ewing sarcoma. (A) Axial fat suppressed T2-weighted MR image prior to chemotherapy showing a large soft tissue mass. (B) Axial fat suppressed T2-weighted
MR image shows significant reduction in the size of the soft tissue mass following chemotherapy indicating a good response.

found to be associated with a good histological response, whereas

an increase in the T/NT ratio or a decrease of less than 30% was
found to be associated with a poor histological response (75). In a
second study of 33 patients with osteosarcoma or Ewing sarcoma,
the ratio of pre-therapy/post-therapy standardized uptake values
(SUVs) significantly correlated with histological outcome of neo-
adjuvant therapy (76). Ultimately, 18FDG PET may provide the
means to assess effectiveness of therapy early after initiation, and
therefore direct changes in treatment regimens in order to achieve
optimal pre-surgical necrosis.
There is wide variation among individual centers treating both
primary bone tumors and soft tissue sarcomas in their follow-up
strategies. Our preferred protocol is to perform three-monthly
chest radiographs for the first two years, six-monthly for the next
five years and then annual follow-up. The rational behind this is
that with time the risk of developing both local recurrence and
metastatic disease reduces. Chest CT is reserved for those patients
where chest radiographs are equivocal or in patients with suspected
pulmonary metastases to establish the extent of disease. The site of
surgery is monitored with serial radiographs again three-monthly
for two years, six-monthly for five years, and then annually. How-
ever, this is predominantly to assess either the allograft or prosthe-
sis mechanics rather than to identify local recurrence (Fig. 24.22).
If the patient presents with a clinical recurrence then full staging is
required to include radiographs, MR imaging, bone scintigraphy,
CT chest, and confirmatory biopsy.

Key Points: Assessment of Treatment and Follow up

■ MR imaging is the modality of choice for the assessment of
local disease recurrence
■ 18FDG PET may allow early prediction of tumor response
following initiation of therapy
Figure 24.22 Recurrent osteosarcoma. Lateral radiograph shows recurrent osteo-
sarcoma arising from the anterior border of the distal femur during follow-up
imaging of the prosthesis.

503
 primary tumor evaluation and staging
Summary
■ Primary bone tumors are rare, accounting for less than 0.2%
of all tumors
■ Conventional radiographs provide the mainstay for diagnosis
of primary bone tumors
■ Age-specific frequencies and incidence rates of bone sarco-
mas are important considerations in reaching a definitive
diagnosis
■ MR imaging is the modality of choice for characterization
and staging of bone tumors
■ Contrast medium has a limited role in the assessment of
primary bone tumors
■ 18FDG PET has a limited role in the investigation of primary
bone tumors but may be used to identify bone metastases
■ Osteosarcoma is the most common primary bone tumor
accounting for 35% of all primary bone tumors
■ Chondrosarcoma has a peak incidence in the fifth to
seventh decades and may be primary or secondary
■ Ewing sarcoma is the second most common primary bone
tumor of childhood and most commonly involves the meta-
physeal regions of long bones
■ Neoadjuvant chemotherapy, with or without radiotherapy,
followed by surgical resection is the main approach to
management for most primary bone tumors
■ MR imaging has an important place in follow-up of
primary bone tumors
■ 18FDG PET may have a useful role in assessing the efficacy of
chemotherapy early in the course of treatment
REFERENCES
1. Fletcher DM, Krishnan Unni K, Mertens F. World Health
Organisation Classification of Tumours. Pathology and
Genetics of Tumours of Soft Tissue and Bone. Lyon: IARC
Press, 2002.
2. Fottner A, Baur-Melnyk A, Birkenmaier C, Jansson V, Dürr
HR. Stress fractures presenting as tumours: a retrospective
analysis of 22 cases. Int Orthop 2009; 33: 489–92.
3. Lalam RK, Cassar-Pullicino VN, Tins BJ. Magnetic resonance
imaging of appendicular musculoskeletal infection. Top Magn
Reson Imaging 2007; 18: 177–91.
4. Miller TT. Bone tumors and tumorlike conditions: analysis
with conventional radiography. Radiology 2008; 246:
662–74.
5. Priolo F, Cerase A. The current role of radiography in the
assessment of skeletal tumors and like-like lesions. Eur J Radiol
1998; 27(Suppl 1): S77–85.
6. Simpson PM, Reid R, Porter D. Ewing’s sarcoma of the upper
extremity: presenting symptoms, diagnostic delay and outcome.
Sarcoma. 2005; 9: 15–20.
7. Wenaden AET, Szyszko TA, Saifuddin A. Imaging of periosteal
reactions associated with focal lesions of bone. Clin Radiol
2005; 60: 439–56.
8. Masciocchi C, Sparvoli L, Barile A. Diagnostic imaging of
malignant cartilage tumors. Eur J Radiol 1998; 27(Suppl 1):
S86–90.
504
9. Franzius C, Daldrup-Link HE, Sciuk J, et al. FDG-PET for
detection of pulmonary metastases from malignant primary
bone tumors: comparison with spiral CT. Ann Oncol 2001; 12:
479–86.
10. Saifuddin A. The accuracy of imaging in the local staging of
appendicular osteosarcoma. Skeletal Radiol 2002; 31: 191–201.
11. Alyas F, James SL, Davies AM, Saifuddin A. The role of MR
imaging in the diagnostic characterisation of appendicular
bone tumours and tumour-like conditions. Eur Radiol 2007;
17: 2675–86.
12. Vanel D, Verstraete KL, Shapeero LG. Primary tumors of the
musculoskeletal system. Radiol Clin North Am 1997; 35: 213–37.
13. Saifuddin A, Twinn P, Emanuel R, Cannon SR. An audit of
MRI for bone and soft-tissue tumours performed at referral
centres. Clin Radiol 2000; 55: 537–41.
14. Kager L, Zoubek A, Kastner U, et al. Cooperative Osteosar-
coma Study Group. Skip metastases in osteosarcoma: experience
of the Cooperative Osteosarcoma Study Group. J Clin Oncol
2006; 24: 1535–41.
15. Schima W, Amann G, Stiglbauer R, et al. Preoperative staging
of osteosarcoma: efficacy of MR imaging in detecting joint
involvement. AJR Am J Roentgenol 1994; 163: 1171–5.
16. May DA, Good RB, Smith DK, Parsons TW. MR imaging of
musculoskeletal tumors and tumour mimickers with intravenous
gadolinium: experience with 242 patients. Skeletal Radiol
1997; 26: 2–15.
17. Verstraete KL, De Deene Y, Roels H, et al. Benign and malig-
nant musculoskeletal lesions: dynamic contrast-enhanced MR
imaging—parametric “first-pass” images depict tissue vascu-
larization and perfusion. Radiology 1994; 192: 835–43.
18. Lang P, Honda G, Roberts T, et al. Musculoskeletal neoplasm-
perineoplastic edema versus tumour on dynamic postcontrast
MR-images with spatial-mapping of instantaneous enhancement
rates. Radiology 1995; 197: 831–9.
19. Shapeero LG, Vanel D. Imaging evaluation of the response of
high-grade osteosarcoma and Ewing sarcoma to chemotherapy
with emphasis on dynamic contrast-enhanced magnetic reso-
nance imaging. Semin Musculoskelet Radiol 2000; 4: 137–46.
20. Verstraete KL, Dierick A, De Deene Y, et al. First-pass images
of musculoskeletal lesions: a new and useful diagnostic applica-
tion of dynamic contrast-enhanced MRI. Magn Reson Imaging
1994; 12: 687–702.
21. Thomson V, Pialat JB, Gay F, et al. Whole-body MRI for metas-
tases screening: a preliminary study using 3D VIBE sequences
with automatic subtraction between non contrast and contrast
enhanced images. Am J Clin Oncol 2008; 31: 285–92.
22. Brauck K, Zenge MO, Vogt FM, et al. Feasibility of whole-body
MR with T2- and T1-weighted real-time steady-state free preces-
sion sequences during continuous table movement to depict
metastases. Radiology 2008; 246: 910–16.
23. Bastiannnet E, Groen H, Jager PL, et al. The value of FDG-PET
in the detection, grading, and response to therapy of soft tissue
and bone sarcomas; a systematic review and meta-analysis.
Cancer Treat Rev 2004; 30: 83–101.
24. Peterson JJ. F-18 FDG-PET for detection of osseous metastatic
disease and staging, restaging, and monitoring response to
therapy of musculoskeletal tumors. Semin Musculoskelet
Radiol 2007; 11: 246–60.
 primary bone tumors
25. Ho YY. Review of non-positron emission tomography func-
tional imaging of primary musculoskeletal tumours: beyond
the humble bone scan. Australas Radiol 2005; 49: 445–59.
26. McCarville MB, Christie R, Daw NC, Spunt SL, Kaste SC.
PET/CT in the evaluation of childhood sarcomas. AJR Am J
Roentgenol 2005; 184: 1293–304.
27. Völker T, Denecke T, Steffen I, et al. Positron emission
tomography for staging of pediatric sarcoma patients:
results of a prospective multicenter trial. J Clin Oncol 2007;
25: 5435–41.
28. Franzius C, Sciuk J, Daldrup-Link HE, Jurgens H, Schober O.
FDG-PET for detection of osseous metastases from malignant
primary bone tumours: comparison with bone scintigraphy.
Eur J Nucl Med 2000; 27: 1305–11.
29. Lucas JD, O’Doherty MJ, Wong JC, et al. Evaluation of fluo-
rodeoxyglucose positron emission tomography in the man-
agement of soft-tissue sarcomas. J Bone Joint Surg 1998; 80B:
441–7.
30. Lucas JD, O’Doherty MJ, Cronin BF, et al. Prospective evaluation
of soft tissue masses and sarcomas using fluorodeoxyglucose
positron emission tomography. Br J Surg 1999; 86: 550–6.
31. Tse N, Hoh C, Hawkins R, Phelps M, Glaspy J. Positron emission
tomography diagnosis of pulmonary metastases in osteogenic
sarcoma. Am J Clin Oncol 1994; 17: 22–5.
32. Franzius C, Daldrup-Link HE, Sciuk J, et al. FDG-PET for
detection of pulmonary metastases from malignant primary
bone tumors: comparison with spiral CT. Ann Oncol 2001; 12:
479–86.
33. Ries LAG, Kosary CL, Hankey BF, et al. SEER Cancer Statistics
Review 1999: 1973–1996. Bethesda, MD: National Cancer
Institute, 1999.
34. UK bone cancer incidence statistics. Cancer Research UK, 2008.
[Available from: http://info.cancerresearchuk.org/cancerstats/
types/bone/incidence/]
35. Suresh S, Saifuddin A. Radiological appearances of appendicular
osteosarcoma: a comprehensive pictorial review. Clin Radiol
2007; 62: 314–23.
36. Vanel D, Tcheng S, Contesso G, et al. The radiological appear-
ances of telangiectatic osteosarcoma. A study of 14 cases.
Skeletal Radiol 1987; 16: 196–200.
37. O’Flanagan SJ, Stack JP, McGee HM, et al. Imaging of intra-
medullary tumour spread in osteosarcoma. A comparison of
techniques. J Bone Joint Surg Br 1991; 73: 998–1001.
38. Sajadi KR, Heck RK, Neel MD, et al. The incidence and prog-
nosis of osteosarcoma skip metastases. Clin Orthop Relat Res
2004; (426): 92–6.
39. Murphey MD, wan Jaovisidha S, Temple HT, et al. Telangiectatic
osteosarcoma: radiologic-pathologic comparison. Radiology
2003; 229: 545–53.
40. Jelinek JS, Murphey MD, Kransdorf MJ, et al. Parosteal osteo-
sarcoma: value of MR imaging and CT in the prediction of
histologic grade. Radiology 1996; 201: 837–42.
41. Murphey MD, Jelinek JS, Temple HT, Flemming DJ, Gannon FH.
Imaging of periosteal osteosarcoma: radiologic-pathologic
comparison. Radiology 2004; 233: 129–38.
42. Unni KK. Chordoma. In: Unni KK, ed. Dahlin’s Bone Tumors:
General Aspects and Data on 11,087 Cases, 5th edn. Philadelphia:
Lippincott-Raven, 1996: 291–305.
43. Brandolini F, Bacchini P, Moscato M, Bertoni F. Chondrosar-
coma as a complicating factor in Paget’s disease of bone.
Skeletal Radiol 1997; 26: 497–500.
44. Schwartz HS, Zimmerman NB, Simon MA, et al. The malig-
nant potential of enchondromatosis. J Bone Joint Surg Am
1987; 69: 269–74.
45. Staals EL, Bacchini P, Bertoni F. Dedifferentiated central
chondrosarcoma. Cancer 2006; 106: 2682–91.
46. Koeller KK. Mesenchymal chondrosarcoma and simulating
lesions of the orbit.Radiol Clin North Am 1999; 37: 203–17.
47. Collins MS, Koyama T, Swee RG, Inwards CY. Clear cell
chondrosarcoma: radiographic, computed tomographic, and
magnetic resonance findings in 34 patients with pathologic
correlation. Skeletal Radiol 2003; 32: 687–94.
48. Murphey MD, Walker EA, Wilson AJ, et al. From the
archives of the AFIP: imaging of primary chondrosarcoma:
radiologic-pathologic correlation.Radiographics 2003; 23:
1245–78.
49. Vanel D, De Paolis M, Monti C, Mercuri M, Picci P. Radiological
features of 24 periosteal chondrosarcomas. Skeletal Radiol
2001; 30: 208–12.
50. Bielack SS, Schroeders A, Fuchs N, et al. Malignant fibrous
histiocytoma of bone: a retrospective EMSOS study of 125 cases.
Acta Orthop Scand 1999; 70: 353–60.
51. Link TM, Haeussler MD, Poppek S, et al. Malignant fibrous
histiocytoma of bone: conventional x-ray and MR imaging
features. Skeletal Radiol 1998; 27: 552–8.
52. Taconis WK, Mulder JD. Fibrosarcoma and malignant fibrous
histiocytoma of long bones: radiographic features and grading.
Skeletal Radiol 1984; 11: 237–45.
53. Larsson SE, Lorentzon R, Boquist L. Fibrosarcoma of bone.
A demographic, clinical and histopathological study of all
cases recorded in the Swedish cancer registry from 1958 to
1968. J Bone Joint Surg Br 1976; 58-B: 412–17.
54. Peersman B, Vanhoenacker FM, Heyman S, et al. Ewing’s sar-
coma: imaging features. JBR-BTR 2007; 90: 368–76.
55. Gerber S, Ollivier L, Leclère J, et al. Imaging of sacral tumours.
Skeletal Radiol 2008; 37: 277–89.
56. Yamaguchi T, Iwata J, Sugihara S, et al. Distinguishing benign
notochordal cell tumors from vertebral Chordoma. Skeletal
Radiol 2008; 37: 291–9.
57. Jelinek JS, Murphey MD, Welker JA, et al. Diagnosis of primary
bone tumors with image-guided percutaneous biopsy: experience
with 110 tumors. Radiology 2002; 223: 731–7.
58. Hau MA, Kim JI, Kattapuram S, et al. Accuracy of CT-guided
biopsies in 359 patients with musculoskeletal lesions. Skeletal
Radiol 2002; 31: 349–53.
59. Anderson MW, Temple HT, Dussault RG, Kaplan PA. Compart-
mental anatomy: relevance to staging and biopsy of musculosk-
eletal tumors. AJR Am J Roentgenol 1999; 173: 1663–71.
60. Liu PT, Valadez SD, Chivers FS, et al. Anatomically based
guidelines for core needle biopsy of bone tumors: implications
for limb-sparing surgery. Radiographics 2007; 27: 189–205.
61. Mankin HJ, Lange TA, Spanier SS. The hazards of biopsy in
patients with malignant primary bone and soft tissue tumors.
J Bone Joint Surg Am 1982: 64: 1121–7.
62. Mankin HJ, Mankin CJ, Simon MA. The hazards of biopsy,
revisited. J Bone Joint Surg Am 1996; 78: 656–63.
505
 primary tumor evaluation and staging
63. Stacy GS, Mahal RS, Peabody TD. Staging of bone tumors: a
review with illustrative examples. AJR Am J Roentgenol 2006;
186: 967–76.
64. Heck RK Jr, Stacy GS, Flaherty MJ, et al. A comparison study
of staging systems for bone sarcomas. Clin Orthop Relat Res
2003; 64–71.
65. Enneking WF, Spanier SS, Goodman MA. A system for the
surgical staging of musculoskeletal sarcoma. Clin Orthop
1980; 153: 106–20.
66. Greene FL, Page DL, Fleming ID, et al. AJCC Cancer Staging
Manual, 6th edn. New York: Springer-Verlag, 2002.
67. Fletcher BD, Wall JE, Hanna SL. Effect of hematopoietic
growth factors on MR images of bone marrow in children
undergoing chemotherapy. Radiology 1993; 189: 745–51.
68. Ryan SP, Weinberger E, White KS, et al. MR imaging of bone
marrow in children with osteosarcoma: effect of granulocyte
colony-stimulating factor. AJR Am J Roentgenol 1995; 165:
915–20.
69. Silberzweig JE, Haller JO, Miller S. Ifosfamide: a new cause of
rickets. AJR Am J Roentgenol 1992; 158: 823–4.
70. Van der Woude HJ, Bloem JL, Holscher HC, et al. Monitoring
the effect of chemotherapy in Ewing’s sarcoma of bone with
MR imaging. Skeletal Radiol 1994; 23: 493–500.
506
71. Holscher HC, Bloem JL, Van der Woude HJ, et al. Can MRI
predict the histopathological response in patients with
osteosarcoma after the first cycle of chemotherapy? Clin Radiol
1995; 50: 384–90.
72. Erlemann R, Reiser MF, Peters PE, et al. Musculo-skeletal
neoplasms: static and dynamic Gd-DTPA-enhanced MR
imaging. Radiology 1989; 171: 767–73.
73. de Baere T, Vanel D, Shapeero LG, et al. Osteosarcoma after
chemotherapy: evaluation with contrast material-enhanced
subtraction MR imaging. Radiology 1992; 185: 587–92.
74. Franzius C, Daldrup-Link HE, Wagner-Bohn A, et al. FDG-PET
for detection of recurrences from malignant primary bone
tumors: comparison with conventional imaging. Ann Oncol
2002; 13: 157–60.
75. Franzius C, Sciuk J, Brinkschmidt C, et al. Evaluation of che-
motherapy response in primary bone tumors with F-18
FDG positron emission tomography compared with histo-
logically assessed tumor necrosis. Clin Nucl Med 2000; 25:
874–81.
76. Hawkins DS, Rajendran JG, Conrad EU, et al. Evaluation of
chemotherapy response in pediatric bone sarcomas by [F-18]-
fluorodeoxy-D-glucose positron emission tomography. Cancer
2002; 94: 3277–84.
 25 Soft Tissue Sarcomas
Eleanor Moskovic
INTRODUCTION
Soft tissue sarcomas (STSs) are a rare but heterogeneous group of
malignant tumors that are often highly aggressive. Originating
from connective tissue other than bone, they arise from tendon,
cartilage, fibrous, adipose, neural, or vascular tissue and can
develop anywhere within the body.
Soft tissue sarcomas are very rare, accounting for about 1% of
adult cancers and 6% of childhood malignancy; approximately
10,000 new cases arise annually in the United States and 2000 in
the United Kingdom (1,2). The etiology in the vast majority of
cases is unknown, but genetic factors are responsible for a few
(e.g., neurofibromatosis, basal cell nevus, and Li Fraumeni syn-
dromes) and an association with therapeutic doses of ionizing
radiation is also well established (3).
The rarity and diversity of STSs frequently hinder their correct
diagnosis, because most non-specialized units are seldom exposed
to a case of STS. The prognosis of STSs depends predominantly on
the histological grade of the tumor and surgical resectability;
50% of those with high-grade tumors develop metastases despite
adequate primary treatment, and this situation is almost invariably
fatal, with less than 10% of patients surviving beyond two years
(4–6). The key to survival in this disease is prompt management
by a specialized multidisciplinary team incorporating surgeons,
radiologists, pathologists, radiotherapists, and oncologists.
The role of the radiologist in STSs has burgeoned with the
advent of both computed tomography (CT) and magnetic reso-
nance (MR) imaging over the last two decades. This has coincided
with a trend away from radical ablative surgery and amputation
towards limb-conservation techniques, which demand more accu-
rate pre-operative staging about the tumor anatomy and its rela-
tionship to neurovascular and other vital structures. Preoperative
or postoperative radiotherapy is now employed routinely (7).
Post-radiotherapy assessment demands knowledge of the appear-
ances of radiation change on imaging as well as those of superim-
posed tumor recurrence. Knowledge of tumor behavior and the
pattern of spread are required to detect metastatic disease. This
chapter considers the role of imaging in the management of STSs
at all stages of the disease spectrum.
PATHOLOGY
Soft tissue sarcomas originate from connective tissue other than
bone arising from:
• Tendon
• Cartilage
• Fibrous tissue
• Adipose tissue
• Neural tissue
• Vascular tissue
Soft tissue sarcomas have a predilection for certain anatomical
sites:
• Lower extremities, 40%
• Trunk and retroperitoneum, 30%
• Upper extremities, 20%
• Head and neck, 10%
Arising from elements of the mesenchyme, STSs are classified
according to the adult tissue they most resemble histologically
rather than the anatomical tissue of origin. For example a lipo-
sarcoma, an angiosarcoma, and a synovial sarcoma do not arise
from fat, blood vessel, or synovium, respectively, but their cellular
morphology is most similar to these tissues. Hence, bone-forming
tumors may arise at extraskeletal sites, and neurogenic tumors
may occur distantly from the neural network. Although there are
numerous histologically distinct sarcomas, around 15% of STSs
are too poorly differentiated to be classified, lacking any distinc-
tive pathological morphology or immunohistochemical features.
From the radiologists’ viewpoint, some STSs have characteristic
features that may point to the correct diagnosis (e.g., liposar-
coma), but many will have the non-specific appearances of a soft
tissue mass, whatever imaging modality is used. In the largest
series of STSs to date, Kransdorf (8) reviewed over 12,000 malig-
nant soft tissue tumors occurring at all ages and showed that more
than 80% fell into the following pathological diagnoses:
• Pleomorphic malignant fibrous histiocytoma (MFH),
otherwise known as undifferentiated pleomorphic
sarcoma, 24%
• Liposarcoma, 14%
• Leiomyosarcoma, 8%
• Malignant peripheral nerve sheath tumor (MPNST), 6%
• Dermatofibrosarcoma protuberans, 6%
• Synovial sarcoma, 5%
• Fibrosarcoma, 5%
• Rhabdomyosarcoma (the most common pediatric
tumor), 1.9%
Kransdorf (8) has combined the pathological data with epidemio-
logical data about these tumors, such as patient age and tumor loca-
tion, and has produced a useful referral database for projecting the
most likely diagnosis of an STS. Thus the majority of STSs fall into a
few well-defined diagnostic categories that allows the radiologist to
be more circumspect when considering the differential diagnosis.
The tumor grade describes the degree of malignancy and reflects
several histological features, namely:
• Degree of cellularity
• Cellular pleomorphism anaplasia
• Mitotic activity
• Degree of necrosis
• Infiltrative growth
507
 primary tumor evaluation and staging
The most important of these criteria in grading STSs are mitotic
activity and degree of necrosis; sarcomas are thus categorized as
low, intermediate, or high grade. The vast majority of STSs are
high-grade tumors. These include pleomorphic MFH, synovial
sarcoma, pleomorphic and round cell liposarcomas, neuroblas-
toma, rhabdomyosarcomas, extra skeletal Ewing’s, and MPNSTs.
The few STSs that are of low or intermediate grade include well-
differentiated and myxoid liposarcomas and the subcutaneous
STS dermatofibrosarcoma protuberans (3,9,10).
Key Points: General Features
■ Soft tissue sarcomas are very rare, accounting for 1% of adult
malignancy
■ Prognosis depends on histological grade and surgical
resectability
■ Fifty percent of patients with high-grade tumors develop
metastases despite adequate primary treatment
■ Fifteen percent of STSs are too poorly differentiated to be
classified
■ Pleomorphic MFH is the commonest histological type
BIOLOGICAL BEHAVIOR OF SOFT TISSUE SARCOMAS
It is important to understand the biological behavior and natural
history of STSs. Arising from a single focus, sarcomas of the muscu-
loskeletal system enlarge in a centrifugal fashion, forming a “pseudo-
capsule” at the periphery. This capsule is formed as a host reaction
to the neoplasm by compression and layering of normal tissue cells
at the expanding border of the growing tumor. A reactive zone at
the periphery of the pseudocapsule contains microscopic exten-
sions or pseudopods of the tumor that extend continuously into the
normal surrounding soft tissue, forming microscopic malignant
satellite nodules. These may be found at some distance from the
primary mass within the same muscle compartment. Except in
advanced cases or in those tumors disrupted by previous surgery,
extremity STSs respect fascial borders and extend typically in a lon-
gitudinal fashion within the barriers of well-defined anatomical
compartments. Major fascial septae, cortical bone, articular carti-
lage, joint capsule, and neurovascular sheaths are not generally
transgressed, and broaching these barriers only occurs generally as
a late phenomenon or in very aggressive, high-grade lesions. The
growth pattern of STSs thus dictates the approach to limb-conserv-
ing surgery; excision of the whole muscle compartment is manda-
tory to avoid local recurrence (11). Even so, a report from the MD
Anderson Cancer Centre revealed that patients referred to a special-
ist centre after apparent macroscopic resection of their tumor had a
high incidence of residual tumor and benefited from re-resection,
even if radiotherapy had been given previously (12).
Key Points: Patterns of Tumor Growth
■ Soft tissue sarcomas grow from a single focus, forming a
pseudocapsule at the periphery
■ Microscopic extensions through the pseudocapsule account
for foci of tumor distant to the primary mass
■ Excision of the whole muscle compartment is mandatory to
avoid local recurrence
508
CLINICAL DIAGNOSIS
The extremities are the predominant site of origin for STSs and
most patients present with a palpable painless mass, often clini-
cally indistinguishable from benign soft tissue tumors, which are
around 100 times commoner than their malignant counterparts
(13,14). Many sarcomas are very large at presentation, that is,
>10 cm, in contrast to benign soft tissue tumors, of which only 5%
exceed 5 cm in diameter (9). If retroperitoneal in origin, STS may
weigh several kilograms at diagnosis yet cause few, if any, symp-
toms (15). A correct histological diagnosis is essential before any
treatment can be considered, and the recommended biopsy tech-
nique for a palpable mass is that of multiple 14-gauge percutane-
ous core-cut biopsies, usually undertaken in the outpatient clinic
under local anesthesia. This approach provides adequate tissue for
accurate diagnosis without compromising subsequent surgery by
an inappropriately sited incisional biopsy (4,6,16). For deep-
seated extremity tumors or retroperitoneal masses, the same tech-
nique is employed using CT or ultrasound guidance. Fine-needle
aspiration cytology (FNAC) is inadequate for sarcoma diagnosis
since the material cannot provide information about histological
type and grade. It is useful in the diagnosis of local or distant
recurrence, since the aspirate can then be compared with the
previous histology.
RADIOLOGICAL DIAGNOSIS OF SOFT TISSUE SARCOMA
Methods of Imaging
The radiological evaluation of a soft tissue tumor should begin
with a plain radiograph, although this is usually unremarkable
(9,17). Primarily this is taken to identify any calcifications that
may be suggestive of the histological diagnosis such as phlebo-
liths in a hemangioma or malignant tumoral calcification in a
synovial sarcoma (Figs. 25.1 and 25.2). A plain film also may
reveal an underlying skeletal deformity such as an exostosis,
which may mimic a soft tissue mass. In addition, a radiograph
will show subtle or overt bone destruction by the tumor, or a
periosteal reaction. Many primary bone tumors present with a
soft tissue mass, and the radiologist may need to decide whether
a tumor is arising from bone and invading the soft tissues or vice
versa. This decision is particularly relevant in cases of Ewing’s
and osteogenic sarcomas, both of which contain distinctive
calcifications, commonly arise from bone, and may arise purely
from the soft tissues, in which instance treatment is different
(11,18).
It is now universally accepted that MR imaging has many
advantages over CT in the diagnosis of both benign and malig-
nant soft tissue masses and MR imaging has become the imag-
ing method of choice in evaluation of these tumors (9). The
merits of MR imaging however relate not to specificity of diag-
nosis but to improved soft tissue contrast and multiplanar image
acquisition, which allow more accurate anatomical delineation
of the lesion and its relationship to neurovascular structures.
These features improve the radiologist’s confidence in predict-
ing resectability. Other advantages of MR imaging are the lack
of ionizing radiation or need for iodinated contrast medium
and its associated risks.
 soft tissue sarcomas

(A) (B)

(C)
Figure 25.1 (A) Conventional radiograph of the shoulder in adult male showing multiple phleboliths within a hemangioma (AVM). (B) Coronal T1-weighted MR image
of same patient showing mass containing fat and signal voids indicating an AVM. (C) Axial T2-weighted MR image as above.

(A) (B)

Figure 25.2 Synovial sarcoma. (A) Plain radiograph of shoulder in 29-year-old female, showing calcification in the soft tissues of the axilla (arrow). (B) MR image of
same patient showing large axillary soft tissue mass; the calcification lies within the areas of low signal intensity centrally.

Although in general MR imaging has replaced CT in the evaluation can make the diagnosis immediately obvious (Fig. 25.3). Although
of STSs, there are still certain areas where CT can add complementary soft tissue calcification is important in the diagnosis of benign soft
information. These areas include the detection of: tissue masses (9,18) there are a number of STSs in which the
presence of calcification may point towards the diagnosis. These
• Soft tissue calcification include:
• Subtle cortical bone destruction
• Presence of soft tissue gas (9,17) • Synovial sarcoma
• Extraskeletal osteogenic sarcoma
Inability to detect soft tissue calcification renders a mass non- • Extraskeletal Ewing’s sarcoma
specific on MR imaging, whereas a plain radiograph or CT scan • Extraskeletal chondrosarcoma

509
 primary tumor evaluation and staging
(A)
Figure 25.3 (A) MRI of pelvis showing large heterogeneous soft tissue mass originally thought to be a STS. (B) CT of the same patient showing the mass to contain
extensive calcification and to involve the superior pubic ramus (arrow). Diagnosis: chondrosarcoma arising from the bony pelvis.
and less commonly:
• Pleomorphic MFH
• Liposarcomas (Fig. 25.21A)
Involvement of adjacent cortical bone by STSs is not infrequent
in MFH and synovial sarcoma, and requires pre-operative detec-
tion for adequate surgery. Although early comparison suggested
that CT was superior to MR imaging in detection of the destruc-
tion of cortical bone, more recent studies suggest that CT and
MR imaging are comparable in this regard. Overall, CT delinea-
tion of fine osseous detail remains superior to MR imaging (9).
Other drawbacks of MR imaging in relation to STSs include the
limited access for guided biopsy, for which CT is clearly still more
practical, and, for staging purposes, the inability to image the
lungs adequately. The lung is the commonest site of first metastasis
(>70%) in STSs, and 10% to 20% of patients have pulmonary
deposits at primary diagnosis (10,17,19). Knowledge of the pres-
ence of pulmonary metastases is critical to optimum treatment
planning (Fig. 25.4).
Soft tissue sarcomas rarely metastasise to bone and therefore
nuclear medicine techniques, including PET-CT, do not play a
major role in their early diagnosis or work-up, unless major ablative
limb surgery involving amputation is considered necessary at the
outset.
However, it has been suggested recently that FDG PET may be
able to detect malignant transformation in von Recklinghausen
neuro fibromatosis 1 (NF1), where increased glucose metabolism
may indicate sarcomatous change. If substantiated by further
studies, 18FDG PET could provide a non-invasive screening tool
for this high-risk group (20).
Ultrasound is an invaluable method of evaluating soft tissue
masses, benign and malignant. It is widely available, non-invasive,
and relatively cheap. Due to its high spatial resolution it is par-
ticularly useful for assessing tumors of the hand, foot, wrist, and
ankle, as well as the head and neck. Tumor vascularity, necrosis,
myxoid consistency, and the relationship of the tumor to tendons
and vessels can readily be examined. Furthermore, it readily
lends itself to guided biopsy and may be utilized for monitoring
response to therapy. The availability of color Doppler, and in
510
(B)
particular Power Doppler, is extremely helpful for assessing intra-
tumoral blood flow. The presence of subtle vascularity may raise
the possibility of malignancy and there are particular character-
istics which suggest a benign vascular malformation or heman-
gioma (9).
Radiological Features of Soft Tissue Sarcomas
It is beyond the scope of this text to describe the radiological fea-
tures of individual sarcomas in detail; there are many descriptive
texts on this subject (9). In general, the primary mass and its
pseudocapsule will be easily recognized on MR imaging or CT
and the role of the radiologist is to:
• Identify the muscular compartment involved
• Delineate the mass and assess its relationship to neuro-
vascular structures
• Determine involvement of bone
• Detect the presence of distant disease
Using MR imaging, lesions should be imaged in at least two orthog-
onal planes using conventional T1-weighted and T2-weighted
spin-echo pulse sequences in at least one of these. Radiologists are
generally most familiar with interpretation of anatomy in the axial
plane, and selection of additional planes varies with the particu-
lar location of the tumor being imaged. STIR imaging has a lower
signal-to-noise ratio than standard spin-echo sequences but
produces fat suppression, which is helpful in identifying fat-
containing tumors; however, STIR sequences should always be
used with standard spin-echo sequences because STIR overes-
timates tumor size (21). Intravenous contrast material gadolini-
um-diethylenetriamine penta-acetic acid (Gd-DTPA) is useful for
enhancing many tumors using T1-weighted spin-echo images; in
some cases enhancement increases the demarcation between
tumor, muscle and edematous tissue; it also provides information
about tumor vascularity and tissue perfusion. In general, although
malignant lesions show greater enhancement and greater rates of
enhancement than benign lesions, there is overlap and the use of
intravenous contrast medium has not been shown to advance the
specificity of diagnosis of malignant masses (9,22–24).
 soft tissue sarcomas

(A) (B)

(C)
Figure 25.4 Seventy-five-year-old male. (A) T2-weighted coronal MR image of the right thigh showing large heterogeneous MFH. (B) T1-weighted fat suppressed axial
MR image post intravenous contrast medium. (C) CT of the chest showing numerous concomitant pulmonary metastases.

Overall, the diagnosis of an STS should be considered when
• a lesion is large (greater than 5 cm), usually deep, dem-
onstrates a fibrous “pseudocapsule,”
• shows high signal intensity on T2-weighted MR images and
heterogeneous signal intensity on T1-weighted images,
• displays central necrosis and irregular peripheral
enhancement following IV contrast, and
• involves the local neurovascular structures, and more
rarely the underlying bone (9)
Despite huge advances in imaging technology, the majority of
STSs cannot be characterized precisely either with MR imaging
(or CT), and the correct histological diagnosis is only reached
on the basis of imaging in around 25% to 35% of cases (9,25).
The anatomical location and age of the patient may allow pre-
diction of histology (3), but the final diagnosis in most cases
rests on biopsy. There are however a few instances in which
imaging can point to the correct diagnosis in STSs. These
include:
• MFH
• Liposarcoma
• Synovial sarcoma
• MPNST
• Gastrointestinal stromal tumor (GIST)
Pleomorphic Sarcoma/Malignant Fibrous Histiocytoma
Pleomorphic sarcoma or malignant fibrous histiocytoma (MFH)
is the commonest STS of late adult life, accounting for 20% to
30% of all adult sarcomas, occurring most often in the fifth
decade, and with a male/female predominance of 2:1 (26). The
vast majority occur in the extremities (75%), usually the lower
extremity. The lesions are deep, intramuscular masses that may
be large (>10 cm). Malignant fibrous histiocytomas are generally

511
 primary tumor evaluation and staging

(A) (B)

(C)
Figure 25.5 MFH of the right thigh. (A) T1-weighted axial MR image showing a large soft tissue mass arising from the vasti muscles. (B) T1-weighted image
following intravenous contrast medium showing irregular peripheral enhancement. (C) T2-weighted image showing heterogeneity and increased signal intensity.

high-grade tumors and they are also the commonest post-irradiation
sarcoma, accounting for more than 70%. The storiform or
pleomorphic variant is the commonest (60%) with myxoid,
giant cell, inflammatory, and angiomatoid variants representing
the remainder. Radiologically, MFH contains faint calcification
in less than 20%, and may erode bone if arising adjacent to the
bony diaphysis (27).
The standard appearance of malignant fibrous histiocytoma on
MR imaging is that of a large lobulated soft tissue mass of inter-
mediate intensity on T1 weighting and high signal intensity on
T2 weighting (Figs. 25.4 and 25.5). MR imaging sequences often
show heterogeneity on all pulse sequences, reflecting the variable
pattern seen histologically, and there is generally enhancement of
solid components after administration of intravenous contrast
material. Hemorrhagic areas are common as areas of high signal
intensity on T1- and T2-weighted images (Fig. 25.6). On CT,
MFH appears as a large intramuscular mass of similar attenua-
tion to muscle, demonstrating peripheral enhancement following
IV contrast and areas of central necrosis. Calcification and bone
erosion may sometimes be evident (26,27).
Key Points: Pleomorphic Sarcoma/Malignant
Fibrous Histiocytoma
■ MFH is the commonest STS of late adult life
■ Seventy-five percent occur in the extremities and most in the
lower limbs
■ On MR imaging these tumors appear as intermediate and
heterogeneous signal intensity (SI) masses on T1-weighting and
high SI on T2-weighting
Liposarcoma
Liposarcomas can be easily characterized by the presence of fat,
providing they contain well-differentiated adipose elements. After
MFH, liposarcoma is the second commonest adult STS accounting

512
 soft tissue sarcomas

(A) (B)
Figure 25.6 MFH of the arm. (A) T1-weighted sagittal MR image of the upper arm showing a mass arising from the biceps muscle with areas of increased signal intensity consistent
with hemorrhage. (B) Axial T2-weighted image shows the large mass destroying the entire biceps muscle. Heterogeneity within the mass indicates necrosis and internal hemorrhage.

(A) (B)
Figure 25.7 Well-differentiated liposarcoma of the left shoulder musculature. (A) Axial T1-weighted MR image showing a fatty mass containing internal septations and
nodularity arising deep to deltoid muscle. (B) Contrast-enhanced fat suppressed T1-weighted MR image showing enhancement of septations within the mass.

for just under 20% of all sarcomas. Approximately 40% of these scattered but pathognomonic lipoblasts that confer malignancy. The
arise in the thigh and a further 40% in the retroperitoneum. There myxoid variant is the commonest liposarcoma and contains abundant
are five histological subtypes: gelatinous material comprising non-sulfated glycosaminoglycans. This
produces a deceptively benign cystic appearance on both MR imaging
• Well-differentiated
and CT and an early tumor may be confused with a benign myxoma.
• Myxoid
The well-differentiated and myxoid liposarcomas are both considered
• Round cell
to be low-grade tumors and individuals with those arising in the limb
• Pleomorphic
have a five-year survival rate of 85% (Fig. 25.7).
• Dedifferentiated
The other varieties do not contain gross fat or any other specific
The well-differentiated variety is often confused both radiologically radiological feature and are inseparable from other STS; they are
and histologically with its benign counterpart, the lipoma and variants, also high-grade tumors, with generally poor prognoses (28–30).
and a sampling biopsy must be large enough to contain the often Liposarcomas arising in the retroperitoneum may achieve very large

513
 primary tumor evaluation and staging

sizes before diagnosis, particularly if they are of low grade. In addi-
tion, these large liposarcomas may contain areas of poorly differen-
tiated MFH (known as dedifferentiated liposarcoma) and along
with pleomorphic liposarcoma are the most aggressive of these
tumors. When arising in the perirenal area, liposarcomas displace
the kidney forward and medially, and those arising in the pelvis often
extend through the inguinal canal or obturator foramen into the
thigh or through the sacro-sciatic notch into the buttock. Tumors of
the retroperitoneum, although sometimes of low grade, are usually
unresectable because of their relationship to crucial structures; they
have a poorer prognosis than their extremity counterparts, with
overall five-year survival rates of less than 40% (28).
Plain radiographs may demonstrate calcification (<10%) or
even ossification. The hallmark of the well-differentiated liposar-
coma variant is the presence of fat. On both CT and MR imaging
this tumor appears as a predominantly fatty mass with irregularly
thickened linear or nodular septae which are of decreased signal
on T1-weighted images and increased signal intensity on
T2-weighted images (Fig. 25.8) (31). The fat component suppresses
on appropriate sequences. Areas of dedifferentiation appear more
solid and heterogeneous. The myxoid, pleomorphic, and round
cell liposarcomas do not generally contain substantial amounts of
fat, and only 50% of masses demonstrate fat radiologically. The
myxoid variant is typically more homogeneous and may appear
deceptively benign on both MR imaging and CT, with a cystic
appearance (Fig. 25.9).
Key Points: Liposarcomas
■ Well-differentiated liposarcomas are often confused
radiologically and histologically with benign lipomas
■ Well-differentiated and myxoid liposarcomas have a five-year
survival rate of 85%
■ Pleomorphic liposarcomas are the most aggressive of these
tumors
Synovial Sarcoma
This is the fifth commonest STS (after MFH, liposarcoma,
leiomyosarcoma, and (jointly) MPNST and dermatofibrosarcoma
protuberans) accounting for up to 10% of all STSs; typically it

(A) (B)
Figure 25.8 Retroperitoneal liposarcoma. (A) CT showing huge abdominal mass with displacement of the left kidney into the midline. The mass almost completely fills
the abdominal cavity and contains abnormal fat with soft tissue septations (small arrow). There is also a large solid component of de-differentiated tumor (large arrow).
(B) CT showing that much of the abdominal cavity is replaced by abnormal fat with internal septations.

(A) (B)
Figure 25.9 Myxoid liposarcoma of the left thigh. (A) T1-weighted axial MR image showing an oval mass in left rectus femoris muscle. The lesion has areas of high signal
intensity within it, suggesting traces of fat or hemorrhage. (B) T2-weighted MR image showing that the mass has a smooth margin and minor internal heterogeneity.
This lesion was initially considered in error to be benign.

514
 soft tissue sarcomas

affects young adults (15–40 years). Although these tumors tend to
arise adjacent to a joint, bursa, or tendon sheath, as discussed, the
tissue of origin is not synovium but undifferentiated mesenchyme;
it simply most resembles adult synovium microscopically.
The tumor typically presents as a deep-seated mass that is
often painful and is situated around a joint in the lower limb.
This is seen in 60% to 70% of cases. Radiologically there are
various features which point to the diagnosis. However, synovial
sarcoma has also been designated as the STS most likely to be
mistaken for a benign lesion; this error may have fatal conse-
quences since it is a high-grade tumor that carries a median
survival rate from diagnosis of 33 months and five-year survival
rates of less than 50% (25,32,33). Of all synovial sarcomas, 30%
contain calcification which is visible on a plain radiograph and
CT but not MR imaging. The presence of calcification denotes a
more favorable prognosis (Fig. 25.2) (33,34).
MR imaging may not reveal involvement of the underlying
bone. This occurs in 20% of cases, with features including periosteal
reaction, bone remodelling, and direct invasion. MR imaging
findings are generally those of a non-specific heterogeneous
mass; however, many display smooth well-defined margins with
cystic contents leading to an erroneous diagnosis of a benign
ganglion or myxoma (Fig. 25.10) (25,34). Changes compatible
with hemorrhage are seen in 40% of cases and fluid-fluid levels

(A) (B)

(C)

Figure 25.10 Twenty-two-year-old male. Synovial sarcoma of the right ankle. (A) Proton density sequence with fat saturation showing a lobulated mass encasing the
peroneal tendons around the lateral malleolus. (B) T1-weighted coronal image showing interposition of the tumor between talus and calcaneum. (C) Contrast-enhanced
T1-weighted MR image showing homogeneous tumor enhancement.

515
 primary tumor evaluation and staging

are seen in around 20% of lesions. The so-called “triple-signal” with

areas of hyperintensity, isointensity and hyperintensity to fat on
T2-weighted images has been noted in 35% of cases, representing
a mixture of cystic and solid areas with hemorrhage and fibrous
tissue (Fig. 25.11) (35). As with other STSs the lung is the main
site of metastasis in synovial sarcoma. Lung metastases occur in
over 50% of patients and as many as 25% present with metastatic
disease. Of note, synovial sarcoma is one of the few STSs which
commonly spread to regional lymph nodes, occurring in up to
20% of cases; this should be borne in mind when imaging the
tumor so that the regional lymph nodes are included in the area
scanned (Fig. 25.12) (10,33,34).
Key Points: Synovial Sarcoma
■ Thirty percent of synovial sarcomas contain calcification
■ Over 50% develop lung metastases
■ Twenty-five percent present with metastatic disease
■ Regional lymph node spread is seen in up to 20% of patients
at the time of diagnosis
Malignant Peripheral Nerve Sheath Tumor
Malignant peripheral nerve sheath tumors account for 5% to
10% of all STSs, with 20% to 70% arising in association with
von Recklinghausen neurofibromatosis 1 (NF1) and occurring

(A) (B)

(C)

Figure 25.11 Synovial sarcoma of the arm. (A) T1-weighted axial MR image showing a mass arising from distal biceps muscle containing areas of high signal intensity,
indicating hemorrhage. (B) Axial STIR MR image showing internal heterogeneity. (C) Sagittal T2-weighted MR image.

516
 soft tissue sarcomas

(A)

(C)

(B)

Figure 25.12 Advanced synovial sarcoma. (A) Axial MR images (proton density) showing a large mass of high signal intensity in the medial left thigh transgressing
muscular compartments. (B) Axial MR images of the pelvis showing a metastatic nodal mass in the left external iliac region (arrow). (C) Coronal STIR image showing
the primary tumor in the left thigh with metastatic nodal disease in the left groin.

at a younger age in this population. Large masses (>5 cm) or
rapid growth of a pre-existing neurofibroma or sudden onset
of deep truncal or sciatic pain in a patient with NF1 should be
regarded as suspicious of malignant transformation, justify-
ing biopsy (36). Malignant transformation occurs in around
20% of those affected; the risk increases with age. Most of
these tumors originate from major nerve trunks such as the
sciatic nerve, brachial plexus, and sacral plexus so that masses
generally occur around the shoulder girdle, hip, or thigh.
Pathologically the MPNST appears as an eccentric fusiform
mass associated with a major nerve; they are usually large
(>5 cm) and contain prominent areas of hemorrhage and
necrosis.
MPNSTs are locally aggressive high-grade sarcomas which fre-
quently metastasise (65%) and despite adequate local treatment,
they often recur locally (40%); the five-year survival rate is
around 50% (36,37). The plain radiograph may demonstrate the
osseous manifestations of NF1 and in addition, the tumor itself
may be faintly calcified or even contain more mature areas of
osteoid or chondroid. These tumors rarely invade bone. On CT
or MRI, MPNSTs are generally extremely vascular and can
usually be seen directly related to the neurovascular bundle; the
nerve may be seen to directly enter and exit the mass as a tubular
structure. Long-axis MR imaging is particularly appropriate for
imaging MPNSTs and the additional presence of multiple
neurofibromata, such as dumbbell spinal lesions, will frequently
be evident in NF1.
Benign neurofibromata are typically well circumscribed, of
low attenuation on CT. This is due to their content of lipid-rich
Schwann cells in myelin and perineural adipose tissue and
also due to cystic necrosis and infarction. Differentiation of
benign from malignant nerve sheath tumors can be difficult.
Malignant change results in increased attenuation on CT and
there is an increase in the vascularity of the lesion. On MR
imaging, the characteristic “target” sign of benign neurofi-
broma, that is, low signal intensity centrally on T2-weighted
images and high signal intensity peripherally, is lost and
replaced by a more irregular highly vascular mass that lacks
encapsulation. Lesions adjacent to bone may cause bony
destruction (Figs. 25.13–25.15).
Key Points: Malignant Peripheral Nerve Sheath Tumor
■ MPNST is associated with NF1 in 20% to 70% of cases
■ The majority arise from major nerve trunks, for example,
sciatic nerve
■ It is invariably a high-grade tumor with metastases
occurring in 65%
■ The five-year survival rate is around 50%
Malignant Gastrointestinal Stromal Tumor
Malignant gastrointestinal stromal tumors (GIST) are rare tumors
of the GI tract mesentery and omentum, ranging from indolent
tumors curable with surgery alone to aggressive cancers. Formerly
considered to be GI leiomyomas and leiomyosarcomas, the term
GIST has been introduced during the past two decades due to
clearer histological diagnostic criteria.

517
 primary tumor evaluation and staging
Figure 25.13 NFI with MPNST of the chest wall. Contrast-enhanced CT showing
heterogeneous mass arising from the right chest wall and compressing the liver
capsule. Multiple cutaneous neurofibromata are evident (arrow).
Figure 25.14 NF1 with MPNST arising from a lumbar neural foramina. Contrast-
enhanced CT shows a large right retroperitoneal mass displacing the right kidney
and invading the vertebra with extension into the spinal canal. Contralateral
neurofibroma noted (arrow).
Malignant GIST is the commonest sarcoma of the GI tract and
accounts for around 5% of all sarcomas (38). GISTs characteristi-
cally express the KIT protein, a transmembrane tyrosine kinase
receptor for stem cell factor (detected clinically by immunohis-
tochemical assays for CD117 antigen). Since the year 2000, this
finding has led to the development of molecularly targeted therapy
for GISTs with the KIT-receptor tyrosine-kinase inhibitor imatinib
mesylate. This novel oral therapy has produced significant clinical
responses that are durable and therefore radiological recognition
of these tumors has become important (39).
Malignant gastrointestinal stromal tumors occur mainly in the fifth
and sixth decades, with a slight male predominance. They are com-
518
Figure 25.15 NF1 with MPNST arising from the path of the right sciatic nerve above
the knee. CT of the lower legs shows an invasive tumor mass arising from a low atten-
uation neurofibroma in the right popliteal fossa (arrow). The tumor is invading the
femoral condyles anteriorly and the subcutaneous tissues and skin posteriorly. Low
attenuation neurofibromata are also seen in the left popliteal fossa (small arrows).
Figure 25.16 Advanced GIST at presentation. Contrast-enhanced CT showing a large
upper abdominal mass relating to the greater curve of the stomach and invading the
spleen. A peritoneal deposit is seen in the epigastrium and there is a liver metastasis.
monly found in the stomach (40–70%) but can occur anywhere else in
the gastrointestinal tract with 20% to 40% in the small bowel, 5% to
15% in the colon and rectum, <5% in the esophagus, and <5% in the
omentum and retroperitoneum. Lesions typically grow in an endo-
phytic fashion parallel to the bowel lumen, commonly with mucosal
ulceration and necrosis which varies in size from a few millimeters to
40 cm in diameter. Large lesions may invade directly into surrounding
organs and frequently cause anemia from tumor hemorrhage.
Gastrointestinal stromal tumors commonly metastasise with
15% to 50% having spread, commonly to the liver and/or perito-
neum, at the time of diagnosis (Fig. 25.16). A frequent presenta-
tion is bowel perforation and intra-abdominal blood loss. On CT
 soft tissue sarcomas

(A) (B)
Figure 25.17 Gastric GIST. (A) CT showing a large heterogeneous lobulated mass arising from the gastric body anteriorly and invading the left hepatic lobe. (B) CT
following therapy with imatinib shows considerable shrinkage of the tumor and the left lobe of the liver is more clearly demarcated.

these tumors are generally large, centrally necrotic, and are related Table 25.1 AJC Cancer Staging of Soft Tissue Sarcoma
intimately to bowel, often with intraluminal extension or fistula
Classification
formation locally. Typically the tumor shows peripheral enhance-
ment with central necrosis and may contain eccentric air if T stage
Tx Primary tumor can not be treated
communicating with bowel loops. Hepatic metastases are typically T0 No evidence of primary tumor
target-type lesions and are usually multiple. T1 Tumor ≤5 cm
Following appropriate chemotherapy the primary tumor and T1a superficial tumors
metastases may shrink dramatically (Fig. 25.17), often disappearing T1b deep tumors
completely; the liver lesions may become cystic (39). Radiologically T2 Tumor >5 cm
T2a superficial tumors
the diagnosis should be suspected in a patient with a large upper
T2b deep tumors
gastrointestinal mass. The differential diagnosis includes extranodal
N stage
lymphoma (see chap. 34). N0 No regional lymph node metastases
N1 Regional lymph node metastases
M stage
Key Points: Malignant Gastrointestinal Stromal M0 No distant metastases
Tumor (GIST) M1 Distant metastases
Histological stage
■ Previously mis-classified as GI leiomyosarcomas G1 Well differentiated
■ Forty to seventy percent occur in the stomach or upper GI tract G2 Moderately differentiated
■ Often large masses with lobulated contour, central necrosis G3 Poorly differentiated
■ Liver and peritoneal metastases most common G4 Undifferentiated
Stage groupings
Stage I T1a, 1b, 2a, 2b N0 M0 G1-2
Stage II T1a, 1b, 2a N0 M0 G3-4
STAGING OF SOFT TISSUE SARCOMAS
Stage III T2b N0 M0 G3-4
Stage IV Any T N1 M0 Any G
Various staging systems for STSs have been used in an attempt to Any T N0 M1 Any G
predict patient outcome using specific prognostic factors and
therefore to help select patients with poor prognosis disease for
adjuvant therapy. However, unfortunately no universally accepted
which is TNM based, and a second system developed by Enneking,
staging system exists, due to:
which is surgically based and subdivides stage with respect to whether
• Rarity of sarcomas the tumor is intra- or extra-compartmental (4,9,10,13,40,41). These
• Diverse biological behavior of STSs staging systems differ in the way tumors are grouped and assigned
• Disagreement amongst pathologists regarding histogenesis relative to prognostic significance; however, the individual prognostic
and grading factors are the same. The key prognostic variables relating to STS are:
• Lack of consensus regarding the value of various
• Grade of tumor
prognostic factors
• Size
There are currently two major staging systems for adult sarcomas— • Extent
one devised by the American Joint Committee on Cancer (Table 25.1) • Presence or absence of metastases

519
 primary tumor evaluation and staging
The principles underlying the staging of STSs are described in
relation to prognostic factors with emphasis on the role of
imaging. Radiologically it is not possible to judge tumor grade
with any certainty, other than the well-differentiated liposarco-
mas. Although 18FDG PET has shown some ability to differen-
tiate low-grade and high-grade sarcomas, it is of limited value
in the assessment of the primary tumor because the vast major-
ity of STSs are high grade. In addition the technique is inade-
quate for distinguishing low grade from benign lesions (42,43).
The location, size, and extent of tumor are readily assessed using
MR imaging, and for the abdomen and retroperitoneum, either
MR imaging or CT. Whichever technique is used the key role of
cross-sectional imaging in staging STSs is in determining:
• Surgical resectability
• Accurate anatomical relationships to neurovascular
structures and involvement of bone
• Proximity to other vital organs
Accurate assessment of these parameters is required for preopera-
tive planning and for defining treatment fields for postoperative
radiotherapy. For example, although head and neck STSs are smaller
at presentation than STSs at other sites, the survival at five years
(50%) is intermediate between that of extremity STS (70%) and ret-
roperitoneal STSs (20%). The commonest cause of death in patients
with head and neck STS is local recurrence rather than distant
metastasis (Fig. 25.18) (13,44,45). This relates directly to incomplete
excision of STSs involving the skull base, or root of the neck and/or
brachial plexus, and difficulty in delivering adequate radiotherapy
due to proximity to the spinal cord and brachial plexus (44,45).
Tumors lying solely within the neck may be compartmentalized and
therefore can be widely excised. There is a higher local recurrence
rate for STS of the head and neck than in other sites. In the extremity
tumor size is highly relevant; extremity STSs >5 cm at diagnosis have
a substantially poorer prognosis than those <5 cm and tumors >10 cm
have an even worse outcome (13,15).
Figure 25.18 Liposarcoma of the right neck. Contrast-enhanced CT showing right
supraclavicular mass with fatty and de-differentiated components. Although
clearly separated from the neurovascular bundle, the mass passed into the root of
the neck and lung apex. Surgically a marginal resection only was achieved and
despite radiotherapy, the patient relapsed within one year of treatment.
520
The concept of compartmental staging is not easily applied to
tumors of the retroperitoneum because they usually present at a
late stage when complete resection may be impossible. In these
patients imaging is useful for determining the size and anatomical
relationships of the mass, thereby directly influencing surgical
choice between a debulking procedure and resection. Locally
involved organs or viscera are sacrificed as appropriate (15).
Regional lymph node metastases are rare at presentation, occur-
ring in fewer than 5% of cases. Nodal disease is more frequent in
certain histological types, namely:
• Synovial sarcoma
• Rhabdomyosarcoma
• Epithelioid sarcoma
• Clear cell sarcoma
The presence of nodal disease at presentation upstages the tumor
and worsens the prognosis. Screening for metastases at presentation
of a STS is generally limited to the search for pulmonary deposits
which occur in more than 50% of patients whether local control is
achieved or not (4,10,15). Only 10% to 20% of patients present
with pulmonary metastases, rendering the patient effectively incur-
able. However, “curative” surgery of the primary tumor is still rec-
ommended to achieve local control (4). A high resolution CT scan
of thorax is the optimal technique for staging the lungs, although in
low-grade peripheral STS the plain CXR is adequate (46,47).
TREATMENT OF SOFT TISSUE SARCOMAS
Patients with STSs fare best in specialist units that deliver multi-
disciplinary therapy by diagnosticians and clinicians experienced
in the field. Because most adult STSs are chemoresistant with
overall response rates of <25%, chemotherapy does not generally
play a role in the primary management of STS outside clinical
trials and any chance of cure relies directly on surgery and radio-
therapy. The standard treatment of extremity STSs now involves
limb-conserving surgery with adjuvant radiotherapy to the tumor
bed and achieves local control rates of 80% to 90% at two to five
years, that is, the local recurrence rate is between 10% and 20%
compared with amputation alone which has a recurrence rate in
the stump of 7% (4,6). Amputation is reserved for cases where
the tumor is genuinely unresectable, where there is insufficient
skin and soft tissue for primary wound closure despite recon-
structive techniques, or in locally recurrent disease when initial
radical surgery and radiotherapy has rendered further conserving
surgery impossible (Figs. 25.19 and 25.20) (14,48,49).
The success of primary surgery (and hence long-term survival)
in STSs depends on the margins of tumor excision. As well as
viable tumor being present in the pseudocapsule, up to 20% of
high-grade STSs also have “skip metastases” within normal tissue
elsewhere within the compartment that cannot be identified pre-
operatively on imaging (9,13,15). Ideally, a “radical compartmen-
tectomy” is undertaken, which involves removal of the entire
anatomical musculo-fascial compartment involved by the tumor
as well as the potential skip lesions; this approach, combined with
postsurgical radiotherapy brings the local recurrence rate down
to 10% to 20% (4,16,50). Often the final operation is a compromise
between a wide and a radical resection depending on the size and
anatomical location of the mass; if the tumor is abutting bone it
 soft tissue sarcomas

(A) (B)
Figure 25.19 Dermato fibrosarcoma protuberans (DFSP) of the abdominal wall. (A) Contrast-enhanced CT showing large ulcerating soft tissue mass arising from the
lower abdominal wall. (B) T1-weighted MR image showing vascular enhancement and separation from underlying musculature and vessels. Despite extensive cutaneous
involvement, satisfactory excision with good margins was achieved using plastic surgery techniques with free tissue transfer.

(A) (B)
Figure 25.20 Inoperable STS. Fibromyxoid sarcoma of the lower leg. (A) T1-weighted MR image and (B) T2-weighted MR image showing circumferential tumor encasing
entire anterior compartment of the calf with subcutaneous involvement. Amputation is the only surgical option.

is resected with the adjacent periosteum and tumors adjacent to
arteries and nerves can be resected with adventitia and perineu-
rium, respectively.
Retroperitoneal sarcomas have the lowest cure rates (well under
20% at five years) because it is generally impossible to achieve
complete excision due to the large size of these tumors at presen-
tation and involvement of multiple organs. Even with resection of
bowel, kidneys, and major vessels, local recurrence occurs in over
80% of cases at five years. Some survival advantage is obtained
from debulking surgery, albeit temporarily, and this is generally
advocated, particularly in low-grade liposarcomas. The role of
radiotherapy in the retroperitoneum is limited or even contrain-
dicated by the tolerance of surrounding tissue such as bowel,
spinal cord, liver, and kidney (4,6,50).
Recently, there has been interest in preoperative or “neoadju-
vant” radiotherapy in selected cases of STSs (19). This approach
is generally indicated for bulky tumors in order to downstage
the tumor prior to surgery thereby making subsequent surgery
less invasive. Although, in general, adult STSs are relatively
chemo-resistant, preoperative (neoadjuvant) chemotherapy is
indicated in certain tumors including Ewing’s sarcoma, primi-
tive neuroectodermal tumor (PNET), and rhabdomyosarcoma
(51,52).
Key Points: Treatment
■ Local control using surgery and radiotherapy can be achieved
in 80% to 90% of limb and limb-girdle tumors
■ Twenty percent of high-grade STSs have skip metastases
within the muscle compartment
■ Adult STSs are relatively chemo-resistant

521
 primary tumor evaluation and staging

change and fluid collections on the basis of signal intensity in the

FOLLOW-UP OF SOFT TISSUE SARCOMAS
majority of cases (8,54,57). Thus areas of low or intermediate sig-
nal intensity on T1 weighting and T2 weighting without a mass
Local Recurrence suggest postoperative change only (Figs. 25.23 and 25.24) (9,54,57).
The local recurrence rate for STSs depends on the adequacy of
Correlation with the primary tumor histology is important; myx-
primary surgery, that is, resectability and ability to deliver adequate
oid liposarcomas and synovial sarcomas contain cystic, gelatinous,
radiotherapy. For these reasons local recurrence rarely occurs in
or myxoid material that can mimic cyst formation giving a high
extremity tumors (10–20%), more frequently in head and neck
signal intensity on T2-weighted images. In general recurrent tumor
tumors (50%) and almost invariably in retroperitoneal tumors.
is characterized by the presence of a discrete nodule or mass with
In all cases relapse occurs generally within two years of primary
signal characteristics that usually mimic those of the original tumor
surgery (4,6,15,45,53–56). Detection of local recurrence is usually
and MR imaging sequences such as an unenhanced T1-weighted
clinically evident in the extremities but there are often situations
fat suppressed examination may help to differentiate posttreat-
where postoperative and postradiation change may obscure the
ment hemorrhage from tumor (58). For example the CT findings
presence of relapse or be confused with it. Both CT and MR imag-
of recurrent liposarcoma are similar to those of the initial tumor
ing are useful for detecting local sarcoma recurrence which is char-
and recurrence often demonstrates rapid growth, with a mean
acterized by the presence of a mass (Fig. 25.21). On MR imaging
tumor volume doubling time of approximately 100 days (59).
tumor recurrence has a low signal intensity on T1-weighted images
The appearances may be equally confusing on CT and ultra-
and an intermediate/high signal intensity on T2-weighted images
sound examination with guided biopsy or aspiration cytology is
(Fig. 25.22). The administration of intravenous contrast medium
the best method of resolving the issue (Figs. 25.25 and 25.26).
may be useful. Recurrence can be distinguished from postoperative
Ultrasound is also used to monitor response to therapy. Similar to

(A) (B) (C)

Figure 25.21 Liposarcoma of the right retroperitoneum. (A) CT showing mixed histological elements with solid high-grade tumor, abnormal fat, and coarse calcification.
(B) Postoperative CT showing complete tumor resection and a right nephrectomy. (C) CT one year postoperatively showing recurrence of a solid high-grade sarcoma in
the retroperitoneum applied to the aorta and inferior vena cava.

(A) (B) (C)

Figure 25.22 (A) T1-weighted coronal MR image of a recurrent fibroblastic sarcoma of the right forefoot. There is a lobulated tumor mass under the previous surgical
flap applied to the tarsal bones (arrows). (B) Coronal and (C) axial MR images showing diffuse tumoral enhancement.

522
 soft tissue sarcomas

(A) (B)
Figure 25.23 Myxoid liposarcoma of the thigh. (A) Preoperative CT showing adductor compartment tumor containing fatty and solid components. (B) Postsurgery and
radiotherapy. A mass was suspected at the resection site. CT shows an encysted fluid collection/seroma in the excision bed (arrow) with surrounding edema of the soft
tissues following irradiation. There is no evidence of tumor recurrence.

(A) (B)

Figure 25.24 (A) Postoperative adductor compartmentectomy following radiotherapy. Coronal T1-weighted MR image showing large cavity containing hemorrhagic
fluid (arrow). No sign of tumor recurrence. (B) Axial T2-weighted MR image.

Figure 25.26 Recurrent myxoid liposarcoma in abdominal cavity. Ultrasound

Figure 25.25 Recurrent sarcoma. Ultrasound guided core-cut biopsy. shows solid mass within peritoneum; guided biopsy confirmed sarcoma.

523
 primary tumor evaluation and staging
(A)
Figure 25.27 (A) PET scan in asymptomatic patient during follow-up after surgery for previous liposarcoma of left shoulder. Incidental finding of a metastasis in the left
inferior pubic ramus (black arrow). (B) CT scan on the same patient confirms the presence of a lytic bone metastasis (white arrow).
MR imaging and CT, ultrasound is unable to characterize tumors
accurately (60,61).
Once CT findings of local recurrence has been confirmed
treatment depends on the site and grade of tumor, but also on the
adequacy of initial excision, which may limit further conservative
surgery. After initial radical surgery an extremity recurrence is
more likely to involve or be adjacent to nerve, artery, or bone;
furthermore surgery is made more difficult by previous radio-
therapy which impairs wound healing. However, limb-salvage
surgery should still be possible for the vast majority of patients
using major reconstructive procedures such as myocutaneous or
free flaps to provide vascularized skin and soft tissue cover for
defects, and to promote healing. Arterial and venous reconstruc-
tion may be necessary if recurrent tumor is encasing vessels. The
success of surgery in recurrent extremity STSs is reflected in sur-
vival data; around 50% of patients are alive at five years following
repeat surgery (6,62).
At the time of diagnosis of local recurrence careful re-staging
for metastatic disease is required, especially if amputation is to be
considered. This will include a CT scan of the thorax since the
lung is the first and sole site of metastasis in up to 70% of patients
and is usually asymptomatic (4,5,62). 18FDG PET can provide
unique information (63) (Fig. 25.27) as high grade malignancies
tend to have higher rates of glycolysis and FDG uptake than low-
grade malignancies and in general sarcomas tend to be FDG-avid,
as do their metastases (9).
Recently 18FDG PET has been investigated as a method of mon-
itoring response to chemotherapy in patients with metastatic dis-
ease; the results in small groups of patients have shown that the
524
(B)
amount of FDG uptake strongly correlates with response to therapy.
Clearly this will be an avenue for further evaluation (64–66).
Key Points: Local Recurrence
■ Local recurrence rates depend upon the site of the primary
tumor
■ Recurrence occurs in 10% to 20% of extremity tumors,
50% of head and neck tumors, and is almost invariable in
retroperitoneal tumors
■ On MR imaging, tumor recurrence has a low signal intensity
on T1 weighting and an intermediate or high signal intensity
on T2 weighting
■ Low/intermediate signal intensity on T1 weighting and T2
weighting on MR imaging without a mass suggests postoperative
change
Metastatic Disease
Metastases develop in 50% to 60% of patients with high-grade
sarcomas despite adequate primary therapy and without treat-
ment they are invariably fatal. Local or systemic recurrence occurs
within two years of primary treatment in 80% of those destined to
relapse; the lung is the commonest site of spread in 80% and also
the sole site of disease in 70% of patients (5,6,15,62). Spread to the
regional lymph nodes occurs in less than 20% of cases and liver
and CNS involvement is also rare, usually denoting widespread
disease. Common practice for follow-up after initial surgery and
radiotherapy for extremity STSs is three-monthly clinic visits with
six-monthly chest radiographs for the first two years. The majority
 soft tissue sarcomas
(A)
Figure 25.28 Metastatic STS. (A) Routine follow-up chest radiograph in an asymptomatic patient one year after resection of a limb sarcoma. A solitary mass lies behind
the aortic knuckle (arrow). (B) CT shows a pleurally based metastasis in the left paravertebral region.
of patients with lung metastases are asymptomatic at discovery, even
in those with large “cannonball” deposits; increasing breathlessness
may be due to a pleural effusion, pericardial effusion, or pneu-
mothorax (62). If a chest radiograph is abnormal or equivocal a
CT scan of chest may provide further information (Fig. 25.28). At
this stage, pulmonary metastasectomy may be considered but
selection of candidates for thoracotomy is controversial.
Criteria for metastasectomy include:
• Controlled disease at the primary site
• No extrapulmonary deposits
• Complete operability of all lung metastases, leaving
adequate residual lung following resection
• Few deposits per lung
• A long disease-free interval (>1 year) since initial surgery
for the primary tumor (4–6,15)
Although there has been no controlled prospective clinical trial
specifically addressing pulmonary metastasectomy in STS, avail-
able data have shown a benefit from this procedure in certain
cases, with a 20% to 40% survival at five years (67). It is probable
that younger, fit patients with a long disease-free interval and
completely resected lung metastases are most likely to remain dis-
ease free. Some patients go on to repeat metastasectomy which
again is of uncertain benefit (4,6,68–70).
There is a growing body of evidence that FDG PET has an
important role in detecting occult metastatic disease, either at
staging or following local relapse, and work-up for patients
being considered for metastasectomy includes a full-body CT
and/or CT-PET because visceral metastases may occur simulta-
neously in some STSs and render the patient ineligible for
thoracic surgery. It is well documented that the number of pul-
monary metastases detected preoperatively commonly underes-
timates the true number of deposits by up to 33%; the number
of patients described as having unilateral disease preoperatively
on CT but with bilateral disease at surgery has also been reported
as high as 43% (5,70–72).
(B)
The role of chemotherapy in metastatic sarcoma is limited to
palliation and experimental drugs. There is some evidence that
Ifosfamide and Doxorubicin have some efficacy in symptom
control but there is no regime which currently confers any overall
survival benefit (51).
Summary
■ Soft tissue sarcomas are a rare heterogeneous group of
tumors that are frequently highly malignant
■ Soft tissue sarcomas are generally surrounded by a pseudocapsule,
which often contains microscopic tumor
■ A conventional radiograph may show calcification, providing
vital information in the initial diagnosis
■ The majority of STSs cannot be adequately classified using
CT or MR imaging, although imaging may suggest the
correct diagnosis in liposarcoma, synovial sarcoma, MPNST,
and GIST
■ MR imaging provides accurate anatomical delineation of
the tumor and its relationship to nerves and vessels
■ Ultrasound is valuable for biopsy guidance, which should be
done using a core-cut needle
■ The primary treatment for STS is surgical excision with as
wide as margin as possible
■ Local recurrence is related to adequacy of primary surgery. Eighty
percent of recurrences occur with two years of initial excision
■ Repeat surgery is the treatment of choice for local recurrence
■ The first site of metastasis is the lung in the majority of cases
■ Pulmonary metastasectomy is considered in selected cases
■ Most STSs are chemoresistant and chemotherapy is usually
used for palliation of metastatic disease outside clinical trials
■ 18FDG PET has an evolving role in STS and may be useful for
detection of local recurrence and metastases as well as for
monitoring response to therapy. It is advised for staging prior
to metastasectomy or amputation
525
 primary tumor evaluation and staging
REFERENCES
1. Cancer Facts & Figures 2008. American Cancer Society, 2008.
2. Risks and causes of soft tissue sarcomas. Cancer Help,
Cancer Research UK, June 2008. [Available from: www.
cancerresearchuk.org]
3. Weiss SW, Goldblum JR. General considerations. In: Enzinger
FM, Weiss SW, eds. Soft Tissue Tumors, 4th edn. St. Louis:
Mosby, 2001: 1–17.
4. Robinson MH. The management of adult soft tissue sarcomas.
Clin Oncol 1994; 6: 183–92.
5. Gardner TE, Daly JM. Diagnosis and management of distant
recurrence in soft tissue sarcomas. Semin Oncol 1993; 20:
456–61.
6. Thomas JM. Soft tissue sarcomas. Curr Pract Surg 1996; 8:
59–63.
7. O’Sullivan B, Ward I, Catton C. Recent advances in radiotherapy
for soft-tissue sarcoma. Curr Oncol Rep 2003; 5: 274–81.
8. Kransdorf MJ. Malignant soft tissue tumors in a large referral
population: prevalence and distribution of diagnoses by
age, sex and location. AJR Am J Roentgenol 1995; 164:
129–34.
9. Kransdorf MJ, Murphey MD. Chapter 3, Imaging of Soft
Tissue Tumors. In: Imaging of Soft Tissue Tumors, 2nd
edn. Philadelphia: Lippincott Williams & Wilkins, 2005:
38–79.
10. Peabody TD, Simon MA. Principles of staging of soft tissue
sarcomas. Clin Orthop Related Res 1993; 289: 19–31.
11. Simon MA, Enneking WF. The management of soft tissue sar-
comas of the extremities. J Bone Joint Surg Am 1976; 58:
317–27.
12. Zagars GK, Ballo MT, Pisters PW, et al. Preoperative vs. post-
operative radiation therapy for soft tissue sarcoma: a retro-
spective comparative evaluation of disease outcome. Int J
Radiat Oncol Biol Phys 2003; 56: 482–8.
13. Moreau G, Bush CH, Scarborough MT, Enneking WF. Surgical
considerations in a diagnostic imaging evaluation of muscu-
loskeletal masses. Magn Reson Imaging Clin N Am 1995; 3:
577–90.
14. McGee JO’D, Isaacson PG, Wright NA. Pathology of Systems:
Soft tissue tumors. In: Oxford Textbook of Pathology, Vol. 2b.
Oxford: Oxford University Press, 1992: 2106–8.
15. Chang AE, Sondak VE. Clinical evaluation and treatment of
soft tissue tumors. In: Enzinger FM, Weiss SW, eds. Soft Tissue
Tumors, 4th edn. St. Louis: Mosby, 2001: Chapter 2.
16. Pitcher ME, Fish S, Thomas JM. Management of soft tissue
sarcoma. Br J Surg 1994; 81: 1136–9.
17. Hodler J, Yu JS, Steinert HC, Resnick D. MR imaging versus
alternative imaging techniques. Magn Reson Imaging Clin N
Am 1995; 3: 591–608.
18. Weiss SW, Goldblum JR. Osseous soft tissue tumors. In:
Enzinger FM, Weiss SW, eds. Soft Tissue Tumors, 4th edn. St.
Louis: Mosby, 2001: Chapter 35.
19. Singer S, Demetri GD, Baldini EH, Fletcher CD. Management
of soft tissue sarcomas: an overview and update. Lancet Oncol
2000; 1: 75–85.
20. Solomon SB, Semih Dogan A, Nicol TL, Campbell JN, Pomper
MG. Positron emission tomography in the detection and
526
management of sarcomatous transformation in neurofibro-
matosis. Clin Nucl Med 2001; 26: 525–8.
21. Shuman WP, Patten RM, Baron RL, et al. Comparison of STIR and
spin-echo MR imaging at 1.5T in 4 suspected extremity tumors:
lesion conspicuity and extent. Radiology 1991; 179: 247–52.
22. Crim JR, Seeger LL, Yao L, Chandnani V, Eckardt JJ. Diagnosis of
soft tissue masses with MR imaging; can benign masses be
differentiated from malignant ones? Radiology 1992; 185: 581–6.
23. Benedikt RA, Jelinek JS, Kransdorf MJ, Moser RP, Berrey BH.
MR imaging of soft tissue masses: role of gadopentetate dime-
glumine. J Magn Reson Imaging 1994; 4: 485–90.
24. Valenzuela RF, Kim EE, Seo JG, Patel S, Yasko AW. A revisit of MRI
analysis for synovial sarcoma. Clin Imaging 2000; 24: 231–5.
25. Berquist TH, Ehman RL, King BF, Hodgman CG, Ilstrup DM.
Value of MR imaging in differentiating benign from malignant
soft tissue masses: study of 95 lesions. AJR Am J Roentgenol
1990; 155: 1251–5.
26. Weiss SW, Goldblum JR. Malignant fibrohistiocytic tumors.
In: Enzinger FM, Weiss SW, eds. Soft Tissue Tumors, 4th edn.
St. Louis: Mosby, 2001: Chapter 15.
27. Kransdorf MJ, Murphey MD. Chapter 7, Malignant fibrous and
fibrohistiocytic tumors. In: Imaging of Soft Tissue Tumors, 2nd
edn. Philadelphia: Lippincott Williams & Wilkins 2005: 257–97.
28. Weiss SW, Goldblum JR. Liposarcoma. In: Enzinger FM, Weiss
SW, eds. Soft Tissue Tumors, 4th edn. St. Louis: Mosby, 2001:
Chapter 17.
29. Hanna SL, Fletcher BD. MR imaging of malignant soft tissue
tumors. Magn Reson Imaging Clin N Am 1995; 3: 629–50.
30. Kransdorf MJ, Murphey MD. Chapter 4, Lipomatous tumors.
In: Imaging of Soft Tissue Tumors, 2nd edn. Philadelphia:
Lippincott Williams & Wilkins, 2005: 80–149.
31. Kransdorf MJ, Bancroft LW, Peterson JJ, et al. Imaging of fatty
tumors: distinction of lipoma and well-differentiated liposar-
coma. Radiology 2002; 224: 99–104.
32. Van Slyke MA, Moser RP Jr, Madewell JE. MR imaging of peri-
articular soft tissue lesions. Magn Reson Imaging Clin N Am
1995; 3: 651–67.
33. Weiss SW, Goldblum JR. Malignant tumors of uncertain type.
In: Enzinger FM, Weiss SW, eds. Soft Tissue Tumors, 4th edn.
Mosby, 2001: Chapter 37.
34. Kransdorf MJ, Murphey MD. Chapter 10, Synovial tumors.
In: Imaging of Soft Tissue Tumors, 2nd edn. Philadelphia:
Lippincott Williams & Wilkins, 2005: 381–436.
35. Jones BC, Sundaram M, Kransdorf MJ. Synovial sarcoma: MR
imaging findings in 34 patients. AJR Am J Roentgenol 1993;
161: 827–30.
36. Kransdorf MJ, Murphey MD. Chapter 9, Neurogenic tumors.
In: Imaging of Soft Tissue Tumors, 2nd edn. Philadelphia:
Lippincott Williams & Wilkins 2005: 328–80.
37. Weiss SW, Goldblum JR. Malignant tumors of the peripheral
nerves. In: Enzinger FM, Weiss SW, eds. Soft Tissue Tumors,
4th edn. St. Louis: Mosby, 2001: Chapter 31.
38. Joensuu H, Fletcher C, Dimitrijevic S, et al. Management of
malignant gastrointestinal stromal tumors. Lancet Oncol
2002; 3: 655–64.
39. Burkill GJ, Badran M, Al-Muderis O, et al. Malignant gastroin-
testinal stromal tumor: distribution, imaging features and
pattern of metastatic spread. Radiology 2003; 226: 527–32.
 soft tissue sarcomas
40. Wolf RE, Enneking WF. The staging and surgical management
of musculoskeletal neoplasms. Orthop Clin North Am 1996;
27: 473–81.
41. Panicek DM, Gatsonis C, Rosenthal DI, et al. CT and MR
imaging in the local staging of primary malignant musculosk-
eletal neoplasms: Report of the Radiology Diagnostic Oncology
Group. Radiology 1997; 202: 237–46.
42. Dimitrakopoulou-Strauss A, Strauss LG, Schwarzbach M,
et al. Dynamic PET 18F-FDG studies in patients with primary
and recurrent soft-tissue sarcomas: impact on diagnosis and
correlation with grading. J Nucl Med 2001; 42: 713–20.
43. Ioannidis JP, Lau J. 18F-FDG-PET for the diagnosis and grad-
ing of soft-tissue sarcoma: a meta-analysis. J Nucl Med 2003;
44: 717–24.
44. Thomas JM. Surgical management of truncal and head
and neck soft tissue tumors. In: Bamberg M, Hoffman W,
Hossfeld DK, eds. Recent Results in Cancer Research: Soft
Tissue Sarcomas in Adults. New York: Springer-Verlag,
1994: 41–5.
45. Eeles RA, Fisher C, A’Hern RP, et al. Head and neck sarcomas:
prognostic factors and implications for treatment. Br J Cancer
1993; 68: 201–7.
46. Fleming JB, Cantor SB, Varma DG, et al. Utility of chest com-
puted tomography for staging patients with T1 extremity soft
tissue sarcomas. Cancer 2001; 92: 863–8.
47. Beitler AL, Virgo KS, Johnson FE, Gibbs JF, Kraybill WG. Cur-
rent follow-up strategies after potentially curative resection
of extremity sarcomas: results of a survey of the members of
the society of surgical oncology. Cancer 2000; 88: 777–85.
48. Williard WC, Collin C, Casper ES, Hajdu SI, Brennan MF. The
changing role of amputation for soft tissue sarcoma of the
extremity in adults. Surg Gynecol Obstet 1992; 175: 389–96.
49. Sadoski C, Suit HD, Rosenberg A, Mankin H, Efird J. Preop-
erative radiation, surgical margins and local control of extremity
sarcomas of soft tissues. J Surg Oncol 1993; 52: 223–30.
50. Lindberg RD, Martin RG, Romsdahl MM, Barkley HT Jr.
Conservative surgery and post-operative radiotherapy in 300
adults with soft tissue sarcomas. Cancer 1981; 47: 2391–7.
51. Ottaiano A, De Chiara A, Fazioli F, et al. Neoadjuvant chemo-
therapy for intermediate/high-grade soft tissue sarcomas: five-
year results with epirubicin and ifosfamide. Anticancer Res
2002; 22: 3555–9.
52. McHugh K, Boothroyd AE. The role of radiology in childhood
rhabdomyosarcoma. Clin Radiol 1999; 54: 2–10.
53. Alvarenga JC, Ball AB, Fisher C, et al. Limitations of surgery in the
treatment of retroperitoneal sarcoma. Br J Surg 1991; 78: 912–16.
54. Reuther G, Mutschler W. Detection of local recurrent disease
in musculoskeletal tumors: magnetic resonance imaging versus
computed tomography. Skeletal Radiol 1990; 19: 85–90.
55. Bradley JC, Caplan R. Giant retroperitoneal sarcoma: a case
report and review of the management of retroperitoneal
sarcomas. Am Surg 2002; 68: 52–56.
56. Gupta AK, Cohan RH, Francis IR, Sondak VK, Korobkin M.
CT of recurrent retroperitoneal sarcomas. AJR Am J Roentgenol
2000; 174: 1025–30.
57. Vanel D, Shapeero LG, De Baere T, et al. MR imaging in the
follow-up of malignant and aggressive soft tissue tumors:
results of 511 examinations. Radiology 1994; 190: 263–8.
58. Garner HW, Kransdorf MJ, Bancroft LW, et al. Benign and
malignant soft tissue tumors: posttreatment MR imaging.
Radiographics 2009; 29: 119–34.
59. Kim EY, Kim SJ, Choi D. Recurrence of retroperitoneal lipos-
arcoma: imaging findings and growth rates at follow-up CT.
AJR Am J Roentgenol 2008; 191: 1841–6.
60. Pathria MN, Zlatkin M, Sartoris DJ, Scheible W, Resnick D.
Ultrasonography of the popliteal fossa and lower extremities.
Radiol Clin North Am 1988; 26: 77–85.
61. Choi H, Varma DG, Fornage BD, Kim EE, Johnston DA. Soft
tissue sarcoma: MR imaging vs sonography for detection of
local recurrence after surgery. AJR Am J Roentgenol 1991; 157:
353–8.
62. Sauter ER, Hoffman JP, Eisenberg BL. Diagnosis and surgical
management of locally recurrent soft tissue sarcomas of the
extremity. Semin Oncol 1993; 20: 451–5.
63. Schwarzback MH, Mitrakopoulou-Strauss A, Willeke F, et al.
Clinical value of (18F) fluorodeoxyglucose positron emission
tomography imaging in soft tissue sarcomas. Ann Surg 2000;
231: 380–6.
64. Stokkel MP, Draisma A, Pauwels EK. Positron emission tomog-
raphy with 2-(18-F)-fluoro-2-deoxy-glucose in oncology. Part
IIIb: therapy response monitoring colorectal and lung tumors,
head and neck cancer, hepatocellular carcinoma and sarcoma.
J Cancer Res Clin Oncol 2001; 127: 278–85.
65. Vernon CB, Eary JF, Rubin BP, Conrad EU 3rd, Schuetze S.
FDG PET imaging guided re-evaluation of histopathologic
response in a patient with high-grade sarcoma. Skeletal Radiol
2003; 32: 139–42.
66. Bredella MA, Caputo GR, Steinbach LS. Value of FDG positron
emission tomography in conjunction with MR imaging for
evaluating therapy response in patients with musculoskeletal
sarcomas. AJR Am J Roentgenol 2002; 179: 1145–50.
67. Rusch VW. Pulmonary metastasectomy. Current indications.
Chest 1995; 107(Suppl 6): 322S–31S.
68. Robinson MH, Sheppard M, Moskovic E, Fisher C. Lung
metastasectomy in patients with soft tissue sarcoma. Br J
Radiol 1994; 67: 129–35.
69. Barr LC, Skene AI, Thomas JM. Metastasectomy. Br J Surg
1992; 79: 1268–74.
70. Pogrebniak HW, Roth JA, Steinberg SM, Rosenberg SA,
Pass HI. Reoperative pulmonary resection in patients with
metastatic soft tissue sarcoma. Ann Thorac Surg 1991; 52:
197–203.
71. Franzius C, Daldrup-Link HE, Sciuk J, et al. FDG-PET for
detection of pulmonary metastases from malignant primary
bone tumors: comparison with spiral CT. Ann Oncol 2001; 12:
479–86.
72. Roth JA, Pass HI, Wesley MN, et al. Comparison of median
sternotomy and thoracotomy for resection of pulmonary
metastases in patients with soft tissue sarcomas. Ann Thorac
Surg 1986; 42: 134–8.
527
 26 Breast Cancer
David MacVicar
INTRODUCTION
Breast cancer is the commonest malignancy found in women in
Europe and the United States, and the incidence continues to
rise slowly. In 2004, there were 44,000 new incident cases of
breast cancer diagnosed in the United Kingdom. Breast cancer
accounts for 31% of cancer diagnoses in the female population,
compared with colorectal (12%), lung (11%), and ovarian car-
cinoma (5%). In 2005, breast cancer accounted for 17% of cancer
deaths, slightly fewer than lung cancer which accounted for
19% of cancer deaths. In the United States, over 180,000 new
cases of invasive breast cancer are diagnosed each year (1,2).
The incidence rate in Western Europe and North America is
approximately 50 to 60 per 100,000 women, and the mortality
rate is of the order of 15 to 25 per 100,000 women, that is 30%
to 40% of the incidence rate. There are marked geographical
variations in incidence. The highest rates have been observed in
Hawaii, California, and British Columbia. Slightly lower rates
are seen in western Europe. Indian, African, and Chinese women
have intermediate incidence rates of the disease, while the low
incidence rates previously reported in Japan are now increasing.
Within Europe, incidence rates decrease from north to south
and from west to east. Within each country breast cancer inci-
dence correlates with the per capita income of the population in
various districts. Studies conducted on migrant populations
have shown that the incidence rate converges with that of the
indigenous population within two generations, confirming the
importance of environmental factors (3).
Recent data from the United States underlines the complexity of
the situation. Between 1980 and 1987, breast cancer incidence
rates increased rapidly among women of all races, at a time when
there was increasing use of screening mammography. This increase
continued between 1987 and 2002, since which time the incidence
appears to be decreasing for African American women under the
age of 50 years but continuing to increase slowly in white women
aged 50 years and older. Incidence rates in white women under
50 years and African American women over 50 years are reported
to be stable (4). Attempts have been made to link fluctuations in
breast cancer incidence with exposure to hormone replacement
therapy and screening mammography in certain groups within
the community (5,6).
Key Points: Incidence
■ Breast cancer is the most frequent female cancer detected in
the Western world
■ There are over 180,000 new cases of breast cancer in the
United States per annum and approximately 44,000 in the
United Kingdom
528
ETIOLOGY
Genetic factors affect incidence and an increase in the risk of breast
cancer among first-degree relatives of patients has been recognized
for over 60 years (7,8). Recent interest has focused on specific genetic
defects. For example, an inherited mutation in the p53 tumor-
suppressor gene on the short arm of chromosome 17 underlies the
high cancer risk in the extremely rare Li-Fraumeni syndrome, which
predisposes to several malignancies including breast cancer. In 1990,
Hall et al. identified a gene on the long arm of chromosome 17, now
known as BRCA1 (9). The carrier frequency of BRCA1 mutations
in Britain is estimated at 1 in 883. About 2% of breast and 3% of
ovarian cancers are linked to BRCA1, rising to 8% of all breast can-
cers diagnosed in women under 30 years of age (10). BRCA2 was
described in 1994 (11). After almost two decades of investigation, it
appears that there are three reasonably well-defined classes of
genetic alleles which increase breast cancer susceptibility. There are
rare high-penetrance alleles, rare moderate-penetrance alleles, and
common low-penetrance alleles. The contribution of each of these
to breast cancer predisposition is still under investigation, as are the
biological and phenotypic characteristics of the cancers associated
with each of them (12). Knowledge of such genes raises questions of
ethics and economics, and a period of careful evaluation of their
impact on clinical practice is necessary, before genetic testing comes
into general oncological practice (13).
A number of environmental risk factors can be identified, the
most obvious of which is age; the older the woman, the higher the
risk. Reproductive and hormonal factors are also linked to risk. Late
menarche and early menopause reduce the risk. Nulliparity and ini-
tial childbearing after the age of 30 approximately doubles the risk
compared with a woman who has her first child before the age of
20 years. The link between exogenous hormones (oral contracep-
tion and hormone replacement therapy) and increased breast can-
cer risk remains under evaluation (14). The effect of dietary factors
on breast cancer risk is still unclear. High-fat diets have been linked
to an increased risk, but there are difficulties in measuring fat intake
in humans. It appears that high birth weight, and excessive maternal
weight gain during pregnancy increase breast cancer risk in the
offspring, yet high birth weight during pre-pubertal childhood can
have an opposite effect (15). Vitamin D may reduce the risk of
several cancers including breast cancer (16). Breast cancer is one of
the few malignancies that has a higher incidence in upper socio-
economic groups in Britain (17). Ionizing radiation in large doses
increases cancer risk, but only if the exposure was prior to the age of
30 years (18,19). Few data are available to support the hypothetical
risk of repeated mammography as a significant carcinogen.
The presence of benign breast disease carries only a marginally
increased risk of malignancy, although certain types of benign dis-
ease such as diffuse papillomatosis and atypical ductal hyperplasia
increase the risk approximately fourfold.
 breast cancer
In summary, several factors are related to an increased risk of
breast cancer and include:
• Genetic factors
• Age
• Reproductive and hormonal factors
• Diet and environmental factors
• Socio-economic factors
• Some types of benign breast disease
PATHOLOGY
Histopathogenesis
The malignant transformation occurs mainly in the terminal duc-
tal/lobular unit of the breast. Logically, the earliest malignant trans-
formation must occur in situ, but it is not possible to elucidate how
long the proliferation remains in situ before infiltrating. The fact
that cancer foci of <1 mm are frequently seen with invasive features
suggests that invasion can develop very early in the process.
Marked heterogeneity of malignant cells has been noted in
human breast cancer. Many authorities accept the dogma of mono-
clonal origin of malignant cells (i.e., they arise from a single trans-
formed cell), but it is possible that a carcinogenic stimulus causes
several normal cells to undergo simultaneous neoplastic transfor-
mation, resulting in a polyclonal tumor. A clinical indication of the
heterogeneity of breast carcinomas is the frequent observation of
mixed responses to systemic treatment in disseminated disease (in
approximately 10–20% of patients).
Breast cancer may have a multicentric origin. Multicentric
primary carcinomas are described, and clinically occult breast
cancers may be found in surgical specimens following resection
for a presumed solitary primary (20).
Histopathology
Breast carcinomas are classified as ductal or lobular (Table 26.1),
corresponding to the ducts and lobules of the normal breast. There
is evidence that most tumors arise in the terminal duct section of
the breast regardless of the pathological type (21). Tumors arising
from the epithelium which are confined within the lumen of ducts
or lobules are referred to as carcinoma in situ. Depending on the
cytological features and growth pattern, tumors are designated duc-
tal carcinoma in situ (DCIS) or lobular carcinoma in situ (LCIS).
When the basement membrane is breached, tumors are designated
invasive or infiltrating. Histopathological classification of breast
cancer is shown in Table 26.1.
Invasive ductal carcinomas that have no special histological
features are designated NOS (not otherwise specified), and these
account for approximately 70% of breast cancers. Various degrees
of fibrotic response and associated DCIS are present. The prognosis
of NOS tumors is worse than other ductal tumor types.
Medullary carcinomas demonstrate low-grade infiltrative prop-
erties and are usually well circumscribed, although they can
become large. They constitute approximately 5% of breast cancers
and are associated with a relatively favorable prognosis. A tumor
in which tubule formation is conspicuous is designated a tubular
carcinoma. Another ductal type is the mucinous or colloid carci-
noma, comprising about 3% of all breast cancers. Rare types of
ductal carcinoma include papillary, apocrine, secretory, squamous,
Table 26.1 Tumor Types: Classification of Breast Carcinoma
Classification of breast carcinoma:
Ductal carcinoma
Ductal carcinoma in situ (DCIS)
Invasive ductal carcinoma
Medullary carcinoma
Mucinous (colloid) carcinoma
Papillary carcinoma
Apocrine carcinoma
Squamous carcinoma
Carcinosarcoma
Lobular carcinoma
Lobular carcinoma in situ (LCIS)
Invasive lobular carcinoma
Inflammatory carcinoma
and carcinosarcoma; ductal carcinoma NOS may contain small
areas of these rare cell types.
Infiltrating lobular carcinoma is relatively uncommon, account-
ing for approximately 10% of breast tumors. The clinical presen-
tation may be with ill-defined thickening rather than the discrete
lump characteristic of ductal carcinoma. The clinical and imaging
features make it one of the more difficult subtypes to diagnose
with confidence. Lobular carcinoma is generally agreed to be mul-
ticentric, and microscopically it is typified by small cells in a linear
arrangement (Indian filing).
Inflammatory breast carcinoma is an aggressive disease with a
poor prognosis, characterized clinically by skin edema and indu-
ration of breast tissues, although a discrete mass is frequently not
palpable. The skin is red and appears to be inflamed. Pathological
proof of the diagnosis can be made by skin biopsy, which shows
involvement of skin lymphatics by cancer cells although fine nee-
dle aspiration and core biopsy are usually employed. True inflam-
matory cells are not usually seen, and the name given refers to the
clinical presentation.
Key Points: Histopathogenesis and Histopathology
■ Breast carcinomas are classified as ductal or lobular
■ Most tumors arise in the terminal duct section of the breast
■ Carcinoma in situ arises from the epithelium and is confined
within the lumen of ducts or lobules
■ Invasive or infiltrating cancers breach the basement membrane
■ Seventy percent of breast cancers are invasive ductal
carcinomas that have no special histological features and
are designated NOS
SCREENING FOR BREAST CANCER
Routine screening for breast cancer is now generally accepted as a
valuable tool for decreasing mortality from breast cancer, and
screening programs exist in many developed nations. Mammog-
raphy is the preferred radiological technique, and evidence for its
benefit derives from several large randomized, controlled trials
conducted in North America and Europe, starting in the 1960s
(22–27). These studies varied in design, using different screening
529
 primary tumor evaluation and staging
intervals and mammographic techniques. The age of patients
within the studies also varied, but a meta-analysis of the results
from these studies showed a statistically significant reduction
in mortality from breast cancer of around 25% to 30% among
screened groups compared with controls (28).
As well as decreasing mortality from breast cancer, screening
mammography results in diagnosis of smaller tumors with a lower
incidence of nodal involvement (29). However, the statistical
analyses are complex and there are some dissenting voices. The
debate over the efficacy of screening mammography was re-opened
by Gotzsche and Olsen, who consider that all-cause mortality among
screened women was no different from that in the control group,
suggesting that, while there may be fewer deaths from breast cancer
in the screened group, lives were not saved overall. They also
questioned the methodology used in several trials (30,31). There
has been further heated debate over the age at which screening
programs should start. A recent report by Tabar et al. of mam-
mography screening and mortality in breast cancer patients from
Sweden has shown deaths from breast cancer fell significantly in
those screened who were in the 40 to 49 year age group as well as
in the 40 to 69 year age group (32). Screening in younger women
may not be as effective as in the older population, due to the fact
that breast density is generally greater in younger women, and this
may obscure breast cancer. Tumors in younger women may have
more aggressive biology and faster growth rates (33). Early detec-
tion of such tumors may not lead to decreased mortality. Also, in
younger women, a greater proportion of screen-detected lesions
are DCIS (34), a phenomenon that can be argued as an advantage
or disadvantage of screening younger women. The age at which
screening should cease is also debatable. The incidence of breast
cancer rises with age, but at some point the potential benefit to the
elderly will be outweighed by disadvantages of cost, inconven-
ience, and morbidity associated with investigation (35). There is
no consensus on the optimum screening interval. In the United
Kingdom, screening mammography is undertaken every three
years, in the Netherlands every two years, and in Japan annually.
Screening of high-risk patients raises further controversy.
Patients with a strong family history of breast cancer, those who
have mutations of BRCA1 or BRCA2 genes and patients with a
history of Hodgkin’s lymphoma treated with radiation may all be
considered high risk. Some success has been reported of screening
mammography in high-risk women under the age of 50, but
numbers are small, and the women studied were mostly in their
40s (36,37). Despite rather scanty supporting data, recommenda-
tions have been made that mammographic screening of women
with BRCA1 and BRCA2 mutations should begin at the age of 25
to 35 years (38). The possibility of an increased radiation risk in
women with these genetic mutations because of impaired DNA
repair capabilities has been raised (39).
False negative and false positive interpretations of screening
mammography are inevitable. A frequently cited criticism of screen-
ing mammography is that it gives false reassurance to women,
encouraging them to ignore clinical symptoms, thus delaying diag-
nosis. Such false negative interpretations may be caused in a number
of ways. Carcinoma can be truly invisible if it is non-calcified, not
causing parenchymal distortion and is overlain by dense paren-
chyma. Poor mammographic technique may also conceal tumors,
and abnormalities may be wrongly classified as benign or simply
530
missed. Some of these are avoidable, and screening centers must
strive to maintain optimal mammographic technique. Double read-
ing is routine and in future computer-aided detection may be
utilized. False positive interpretations can also be disruptive to the
patient, although counseling and education of the patient can reduce
the anxiety produced by recalls (40). There will always be a trade-off
between maintaining a high sensitivity for detection of cancer and
the generation of false positives (41). Despite the difficulties and
controversies in screening mammography, it is difficult to imagine
the screening programs being dismantled. More work is needed to
determine the optimum strategies in the general population and in
high-risk women. A certain level of observer variability and false
negative and false positive interpretations are inherent to the process.
These can be kept to a minimum by ongoing audit, which is under-
taken in the U.K. screening program. One of the greatest challenges
at the time of writing is in recruitment and retention of sufficient
numbers of suitable radiologists to screening centers.
Until the present time all national screening programs have used
mammography as the principal imaging technique, but the next
phase of the debate will undoubtedly bring in other imaging modal-
ities such as magnetic resonance (MR) imaging. The efficacy of MR
imaging compared with mammography has been studied in a pro-
spective multi-center cohort study involving 649 women aged 35 to
49 years with a strong family history of breast cancer, or a high
probability of a BRCA1, BRCA2, or TP53 mutation. This high-risk
population was recruited from 22 centers in the United Kingdom,
and women were offered annual screening with contrast-enhanced
MR imaging and mammography for a period varying between two
and seven years. Within the group, 35 cancers were diagnosed, 19 by
contrast-enhanced MR imaging only, six by mammography only,
and eight by both, with two interval cancers. Sensitivity was signifi-
cantly higher for contrast-enhanced MR imaging (77%) compared
with mammography (40%). Sensitivity was 94% when both meth-
ods were used. Specificity was 93% for mammography, 81% for
contrast-enhanced MR imaging, and 77% with both methods used.
The difference between sensitivity for contrast-enhanced MR imag-
ing and mammography appeared to be particularly pronounced in
BRCA1 carriers. In this group 13 cancers were diagnosed, 92% of
which were diagnosed on MR imaging compared with 23% on
mammography. From this study it appears that contrast-enhanced
MR imaging has an increased sensitivity for cancer detection than
mammography in this selected screening population, and that spec-
ificity for both procedures is acceptable. There was a high propor-
tion of cancers with Grade 3 malignancy but tumors were small and
there was a low percentage of women with node positivity (42). The
study group further observed that the incremental cost per cancer
detected with MR imaging and mammography combined was
approximately £28,000, but that it may be a cost-effective screening
modality for women, particularly those with BRCA1 and BRCA2,
and further work was needed to assess the impact of such screening
on mortality and health-related quality of life (43). In the United
Kingdom, the National Institute for Health and Clinical Excellence
(“NICE”) offered a new guideline suggesting that women who are
known to have a genetic mutation should be offered annual MR
imaging surveillance if they carried BRCA1 or BRCA2 and are aged
30 to 49 years; in addition TP53 mutation carriers should be
screened if aged 20 years or older. Further guidelines were offered
suggesting that women aged 30 to 39 years should be offered MR
 breast cancer

imaging screening if their 10-year risk is considered greater than The significance of calcification as a mammographic sign of
8%, and to women to 40 to 49 years if their 10-year risk is greater breast cancer was first recognized around 50 years ago, and the fea-
than 20% (44). It was not made clear how clinical expertise and tures such as clustering, multiplicity, and polymorphism, which
financial support for implementation of the guideline could be pro- indicate a likely malignant condition, are well established (Fig. 26.1).
vided, but the guidance went on to suggest that genetic testing is Benign calcifications are usually larger and are more likely to be
appropriate only for a small proportion of women who are from round or crescentic, uniform in density and size, and randomly
high-risk families. distributed throughout the breasts. However, many calcifications
are seen which are classified as indeterminate (Fig. 26.2) and warrant
further investigation with fine-needle aspiration, core biopsy, or
Key Points: Screening excision biopsy. A full discussion of the diagnostic criteria for
■ A statistically significant reduction in mortality from radiographic and ultrasonic diagnosis of breast cancer is beyond
breast cancer of around 25% to 30% among mammo- the scope of this chapter, and the reader is referred to some of the
graphically screened groups compared with controls has classic articles on the subject available in the literature (45,46).
been demonstrated
■ Screening mammography results in diagnosis of smaller
New Techniques in Breast Cancer Diagnosis
A number of novel imaging techniques have made an impact
tumors with a lower incidence of nodal involvement
recently on radiological diagnosis of breast cancer. Digital mam-
■ Tumors in younger women may have faster growth rates and
mography systems were initially used to aid localization and biopsy
screening may not improve outcome in this group
of focal abnormalities, but now most analogue systems in the
■ The age at which screening should commence and cease is
United States, United Kingdom, and mainland Europe are being
debatable
replaced by full-field digital mammographic systems (Fig. 26.3).
■ There is no consensus on the optimum screening interval
Clinical trials have compared digital mammography with screen
■ Screening with contrast-enhanced MR imaging in high-risk
film mammography. Lewin et al. (47,48) found the techniques are
populations has been shown to have higher sensitivity for
approximately equal in cancer detection, and digital mammo-
cancer detection than mammography
graphy (DM) had a lower recall rate. The improvement in recall
rate may have been related to the ability to manipulate images on
RADIOLOGICAL DIAGNOSIS OF PRIMARY BREAST soft copy display. The patients in these studies underwent both DM
and screen film mammography and where there was discordance
CANCER
between the results it appeared to be due to visibility differences,
Detection of primary breast cancer is one of the most challenging
areas of radiology. A variety of techniques have been utilized, of
which X-ray mammography and ultrasound are pre-eminent,
although rapid progress is being made in magnetic resonance
imaging. Breast masses and calcification require evaluation by an
experienced observer, and the goal of imaging is to detect breast
cancer at the earliest stage while keeping unnecessary surgery to a
minimum.
The characteristic mammographic stigma of an invasive carci-
noma is a stellate mass. Other pathologies that are less common
may mimic invasive carcinoma such as:
• Fat necrosis
• Radial scar
• Sclerosing adenosis
• Fibromatosis
Poorly defined irregular masses may also be seen in association with
invasive carcinomas and inflammatory conditions. Well-defined
mammographic masses are likely to represent:
• Fibroadenoma
• Cyst
• Intramammary lymph nodes
• Lipid cysts
Figure 26.1 Craniocaudal mammogram of left breast showing very extensive
• Galactoceles malignant type calcifications. Clinically, a palpable mass was measured at 2 × 2 cm.
However, circumscribed carcinomas such as colloid and medullary The patient went forward to mastectomy, which revealed invasive carcinoma
throughout the upper outer and lower outer quadrants with extension into the
carcinomas occasionally mimic benign conditions. Ultrasound is upper medial quadrant and to within 2 cm of the nipple. The presence of such
frequently helpful in clarifying indeterminate mammographic extensive mammographic microcalcification is a clear pointer to disease which is
masses. more extensive than clinically apparent.

531
 primary tumor evaluation and staging
Figure 26.2 Indeterminate calcification on mammography (arrow) which was
excised after wire localization and proved to be a 9 mm Grade 3 invasive ductal
carcinoma with surrounding DCIS.
Figure 26.3 Mediolateral oblique digital mammogram demonstrating three areas
of increased density (arrows) within the breast parenchyma which represented
multifocal carcinoma.
most commonly caused by differences in positioning and not
related to technical properties of the machinery being used. A fur-
ther study of interpretation between DM and screen film mam-
mography found only a 4% difference in interpretation that
532
affected management in the clinical setting of symptomatic
patients (49). It is likely that DM will prove at least as useful as
screen film mammography in diagnosis. Currently, one of the
limitations of DM is high cost of new equipment, but in time
filmless reporting may prove cost effective.
A potential refinement of DM is computer-aided detection
(CAD), which aims to reduce the false negative rate, particularly
for screening mammography by marking an electronically per-
ceived abnormality and directing the interpreting radiologist
towards it. The greatest interest in CAD has been in the setting of
screening mammography. Double-reading (DR) is routinely used
within the United Kingdom NHS Breast Screening Program
(NHSBSP). CAD could potentially fulfil the role of a “second
reader.” Analysis of both methods is incomplete as no randomized
controlled trial (RCT) has been completed to assess whether a
survival advantage is gained when using these techniques com-
pared with single reading. CAD and DR have shown improvement
in sensitivity, but specificity has often been decreased. How CAD
is used depends on attitudes towards the balance of sensitivity and
specificity, which is influenced by cultural factors, risk of litiga-
tion, healthcare policy, cost, and patient preference. CAD systems
use software programs to analyze digitized analogue or digital
mammography by placing a mark at the site of findings associated
with breast cancer. It is intended that CAD acts as a second reader.
If a radiologist reviews CAD results before seeing the mammo-
gram, CAD acts as a first reader, while the radiologist acts as a
second “expert” reader. Two retrospective analyses indicated that
CAD could potentially have reduced the false-negative rate in
patients who subsequently developed cancer (50,51). In a pro-
spective study involving 12,860 patients, a 19% improvement in
mammographic cancer detection was noted. Of the incremental
cancers detected, 87% were microcalcifications and 75% of incre-
mental detections proved to be DCIS. This left a 5% improvement
in detection of invasive cancer. Recall rates increased by 18%. On
the other hand, CAD failed to detect 33% of invasive cancers
showing as mass lesions on mammography which were found by
the reporting radiologist (52). Although it is intuitive that CAD
should help performance by detecting overlooked findings, the
clinical impact of these systems requires careful analysis because
of the complex psychosocial effect on reporting behavior, and
cognitive and decision-making processes may change when reading
with CAD systems. Using an experimental dataset of 60 cases
which included 30 cancers, Alberdi et al. presented mammo-
graphic examinations to 39 doctors. By decreasing the perfor-
mance of a CAD system and presenting cases to radiologists with
CAD annotations, average reader sensitivity with CAD reduced
to 61%, compared with 73% without CAD. One explanation for-
warded was “automation bias” in which radiologists faced with a
negative CAD decreased their interpretation vigilance and
ignored lesions they would otherwise have made a note of (53).
CAD remains a work in progress, and computer software is devel-
oping rapidly. The burgeoning literature already includes a num-
ber of detailed reviews (54). Further developments of the digital
platform include attempts to use contrast enhancement with
mammography, and breast tomosynthesis. Contrast-enhanced
digital mammography with sequential temporal acquisition has
been described by Jong et al. (55). Imaging was conducted in the
cranio-caudal projection using light compression. A mask image
 breast cancer
was obtained initially, and multiple post-contrast images were
obtained from which subtraction images were generated. A group
of 22 patients including 10 malignant and 12 benign lesions were
studied. The investigators observed that there was sufficient over-
lap in the kinetic analysis of contrast uptake that benign lesions
could not be distinguizhed from malignant, a phenomenon
which is also observed with other contrast-enhanced imaging
methods such as MRI. Breast tomosynthesis is a technique in
which the digital mammography platform is modified to allow
the X-ray tube to travel through an arc of excursion, acquiring a
fixed number of images while the breast remains in compression.
Individual projection images are low in dose, and the composite
dose should be comparable to a single view mammogram. The
theoretical concept is to avoid overlap of dense parenchymal
structures which result in summation densities. Rafferty et al.
evaluated radiologists’ ability to identify suspicious lesions (47
lesions in 40 patients). Detectability of masses and areas of architec-
tural distortion was reported to be superior on tomosynthesis in
89% of cases. Within the group, seven clinically palpable lesions
were included, and six of these seven lesions were detected using
tomosynthesis while remaining occult on routine mammography
(56). However, calcifications do not appear to be better demon-
strated by tomosynthesis.
Interest in nuclear medicine techniques for the diagnosis of
breast cancer has waxed and waned over the years. 2-[F-18]fluoro-
2-deoxy-D-glucose positron emission tomography (18FDG PET)
has been used recently, and initial reports have demonstrated that
increased uptake of 18FDG could be detected in primary breast car-
cinoma. However, there is considerable variation in reported sensi-
tivity and specificity, reflecting differences in the patient population,
criteria for image interpretation, and image acquisition protocols.
Avril et al. (57) evaluated the diagnostic accuracy of 18FDG PET
imaging in 144 patients with masses suggestive of breast cancer on
mammography. Relatively low sensitivity (64%) was reported, and
for small breast carcinomas (up to 1 cm at pathology) the detection
rate was poor. 99mTc-sestamibi has been used for breast scinti-
graphy. This technique shares with 18FDG PET limited sensitivity
for lesions <1 cm. Although both of these techniques have been
used to help in characterization of indeterminate mammographic
lesions, a wide range of specificities is reported and neither
technique has a major role in breast cancer diagnosis currently (58).
The diagnostic potential of breast MR imaging has received
considerable attention in the literature recently. MR imaging has a
high sensitivity for breast cancer detection that relies on the tendency
of malignant tumors to generate neovascularity. Administration
of an intravenous extracellular contrast agent such as gadolinium-
DTPA causes enhancement of the tumor on T1-weighted images.
Malignant angiogenesis is associated with leaky capillaries that
allow the contrast agent to show the high-intensity peak with
rapid wash-out that is seen in most, but not all, malignancies. False
negative examinations have been reported with well-differentiated
ductal carcinomas and lobular carcinoma (59). Although sensitiv-
ity is high for invasive carcinoma, DCIS is more difficult to detect,
with a sensitivity as low as 40% (60–62). Breast MR imaging is
best used as an adjunct to conventional imaging, complementing
mammography, and ultrasound. False positive breast MR imaging
is not infrequent, and fibroadenomas, atypical ductal hyperplasia,
lobular carcinoma in situ, papilloma, fibrocystic changes, and a
variety of benign breast conditions may result in abnormal focal
enhancement. Some benign lesions have characteristic morphol-
ogy allowing confident diagnosis, but many perceived abnor-
malities are difficult to diagnose. If MR imaging is to become a
mainstream investigation, greater availability of machine time
and biopsy devices will be required. The relatively low specificity
is likely to be the greatest impediment to an increase in clinical
utility for MR imaging. There is still variation between institu-
tions in the MR imaging protocols used, and efforts are being
made to standardize imaging techniques, terminology, and report-
ing practice (63). Although controversy still exists, consensus is
developing that MR imaging is useful in the search for occult
breast primaries, in staging local tumor spread and assessment of
multifocal disease in selected patients, in assessment of potential
tumor recurrence at lumpectomy sites and where doubt exists
after inconclusive mammography, and ultrasound (64).
Key Points: New Techniques
■ Digital mammography is at least as useful as screen film
mammography in diagnosis of breast cancer
■ Computer-aided detection may increase sensitivity for cancer
detection; how CAD is best used is a complex issue
■ 18FDG PET and other isotope techniques can detect primary
breast cancers but with a low sensitivity, especially for lesions
<1 cm in diameter
■ Isotope studies and new techniques such as dynamic digital
mammography and breast tomosynthesis have not reached
mainstream practice
■ The sensitivity of MR imaging is high for invasive carcinoma
but DCIS is more difficult to detect, with sensitivities as low
as 40%
■ Breast MR imaging is best used as an adjunct to conventional
imaging, complementing mammography, and ultrasound
STAGING CLASSIFICATION
In order to compare results in clinical research and to identify the
most appropriate treatment choices, a system of staging according
to the extent of disease spread is needed. The tumor nodes metas-
tases (TNM) system is used by the Union Internationale Contre
Le Cancer (UICC) and the American Joint Committee on Cancer
(AJCC). The current TNM staging classification is shown in
Table 26.2 and Figure 26.4 (65).
The TNM classification is largely clinical, but imaging tech-
niques are being increasingly used to assist in delineating the
extent of tumor. Nodal metastases can be demonstrated by ultra-
sound, CT, and MR imaging, particularly if there is a question of
metastasis to the internal mammary or other mediastinal nodes.
Radiological techniques are an integral part of assessment for
distant metastases when clinically indicated.
The pTN pathological classification requires the examination of
a resected primary carcinoma with no gross tumor at the margins
of resection. Pathological staging of the nodes requires resection
and examination of axillary and internal mammary lymph nodes.
The pTN classification is given in Table 26.3. Stage grouping is
also practiced (Table 26.4).
533
 primary tumor evaluation and staging

Table 26.2 TNM Classification of Breast Cancer

T Primary tumor NX Regional lymph nodes cannot be assessed
TX Primary tumor cannot be assessed (e.g., previously removed)
T0 No evidence of primary tumor N0 No regional lymph node metastasis
Tis Carcinoma in situ N1 Metastasis in movable ipsilateral axillary node(s)
Tis(DCIS) Ductal carcinoma in situ N2 Metastasis in fixed ipsilateral axillary node(s) or in clinically apparent
Tis(LCIS) Lobular carcinoma in situ ipsilateral internal mammary lymph node(s) in the absence of
Tis(Paget) Paget disease of the nipple with no tumor clinically evident axillary lymph node metastasis
T1 Tumor <2 cm in greatest dimension N2a Metastasis in axillary lymph node(s) fixed to one another or to
T1mic Microinvasion <0.1 cm in greatest dimension other structures
T1a >0.1 cm but not >0.5 cm in greatest dimension N2b Metastasis only in clinically apparent internal mammary lymph
T1b >0.5 cm but not >1 cm in greatest dimension node(s) and in the absence of clinically evident axillary lymph
T1c >1 cm but not >2 cm in greatest dimension node metastasis
T2 Tumor >2 cm but <5 cm in greatest dimension N3 Metastasis in ipsilateral infraclavicular lymph node(s) with or without
T3 Tumor >5 cm in greatest dimension axillary lymph node involvement; or in clinically apparent ipsilateral
T4 Tumor of any size with direct extension to chest wall or skin internal mammary lymph node(s) in the presence of clinically
only as described in T4a to T4d (Chest wall includes ribs, evident axillary lymph node metastasis; or metastasis in ipsilateral
intercostal muscles, and serratus anterior muscle, but not supraclavicular lymph node(s) with or without axillary or internal
pectoral muscle) mammary lymph node involvement
T4a Extension to chest wall N3a Metastasis in infraclavicular lymph node(s)
T4b edema (including peau d’orange), or ulceration of N3b Metastasis in internal mammary and axillary lymph nodes
skin of the breast, or satellite skin nodules confined N3c Metastasis in supraclavicular lymph node(s)
to the same breast M Distant metastasis
T4c Both 4a and 4b above MX Distant metastasis cannot be assessed
T4d Inflammatory carcinoma M0 No distant metastasis
N Regional lymph nodes M1 Distant metastasis

T1 T2 T3

>1–2 cm (Tlc) >2–5 cm

>0.5–1 cm (Tlb)
>0.1–0.5 cm (Tla)
NI
>5 cm

T4a T4b T4c T4d

e
S a t ll i t e
nodule

N2 (a,b)

T4b
Inflammatory
carcinoma

N3 (a,b,c)
(A) (B)
Figure 26.4 Staging diagrams (A) and (B) (See also Table 26.2).

534
 breast cancer

Table 26.3 pTN Pathological Classification Table 26.4 Stage Grouping

pT Primary tumor Stage 0 Tis N0 M0
The pathological classification requires the examination of the Stage I T1a N0 M0
primary carcinoma with no gross tumor at the margins of Stage IIA T0 N1 M0
resection. A case can be classified pT if there is only microscopic T1a N1 M0
tumor in a margin. The pT categories correspond to the T T2 N0 M0
categories. Stage IIB T2 N1 M0
pN Regional lymph nodes T3 N0 M0
The pathological classification requires the resection and examina- Stage IIIA T0 N2 M0
tion of at least the low axillary lymph nodes (level 1). Such a T1a N2 M0
resection will ordinarily include 6 or more lymph nodes. If the T2 N2 M0
lymph nodes are negative, but the number ordinarily examined is T3 N1, N2 M0
not met, classify as pN0. Stage IIIB` T4 N0, N1, N2 M0
Examination of one or more sentinel lymph nodes may be used for Stage IIIC Any T N3 M0
pathological classification. If classification is based solely on sentinel Stage IV Any T Any N M1
node biopsy without subsequent axillary lymph node dissection it a
T1 includes T1mic.
should be designated (sn) for sentinel node, eg., PN1(sn).
pNX Regional lymph nodes cannot be assessed (not removed for study or
previously removed)
pN0 No regional lymph node metastasis to treat undetectable micro-metastases, which are presumed to be
pN1mi Micrometastasis (>0.2 mm, but none >2 mm in greatest dimension
pN1 Metastasis in 1–3 ipsilateral axillary lymph node(s), and/or in
the cause of later distant relapse. Since the move away from radical
ipsilateral internal mammary nodes with microscopic metastasis operations, a variety of surgical approaches have been used. Simple
detected by sentinel lymph node dissection but not clinically excision (lumpectomy) of the primary tumor without radiother-
apparent apy is associated with a high incidence of local recurrence, rates
pN1a Metastasis in 1–3 axillary lymph node(s), including at varying from 15% to 40% (66,67). Postoperative radiotherapy
least one >2 mm in greatest dimension
pN1b Internal mammary lymph nodes with microscopic
results in considerable reduction of the local recurrence rate
metastasis detected by sentinel lymph node dissection (67,68). The Uppsala Örebro study demonstrated that in unifocal
but not clinically apparent tumors up to 2 cm in diameter treated by excision of the tumor,
pN1c Metastasis in 1–3 axillary lymph nodes and internal mam- pectoral fascia and axillary node dissection had lower rates of local
mary lymph nodes with microscopic metastases recurrence after a three year follow-up period. The local recur-
detected by sentinel lymph node dissection but not
clinically apparent
rence rate was 2.9% with the use of radiotherapy and 7.6% with-
pN2 Metastasis in 4–9 ipsilateral axillary lymph nodes, or in clinically out (68). With the demonstration that a wider excision technique
apparent ipsilateral internal mammary lymph node(s) in the reduces local recurrence, the procedure of quadrantectomy has
absence of axillary lymph node metastasis gained popularity. Quadrantectomy aims for a 2 to 3 cm clearance
pN2a Metastasis in 4–9 axillary lymph nodes, including at least by resection of the quadrant of the breast centered on the tumor.
one >2 mm
pN2b Metastasis in clinically apparent internal mammary
The procedure known as wide local excision aims for a 1 cm margin.
lymph node(s), in the absence of axillary lymph node Veronesi et al. have studied groups of patients treated by wide
metastasis local excision and quadrantectomy (both followed by radiotherapy)
pN3 Metastasis in 10 or more ipsilateral axillary lymph nodes; or in and found that wide local excision yields a recurrence rate of 7%
ipsilateral infraclavicular lymph nodes; or in clinically apparent at five years, while quadrantectomy leads to a 2% local recurrence
ipsilateral internal mammary lymph nodes in the presence of one or
more positive axillary lymph nodes; or in more than 3 axillary lymph
rate. Veronesi also studied local recurrence rates in women treated
nodes with clinically negative, microscopic metastasis in internal by quadrantectomy, axillary dissection, and radiotherapy (QUART)
mammary lymph nodes; or in ipsilateral supraclavicular lymph nodes for tumors <2 cm diameter, and found a local recurrence rate of
pN3a Metastasis in 10 or more axillary lymph nodes (at least one 3% at 10 years, and demonstrated no significant difference in
>2 mm) or metastasis in infraclavicular lymph nodes outcome between patients treated with the QUART regimen and
pN3b Metastasis in clinical apparent internal mammary lymph
radical mastectomy (69,70).
node(s) in the presence of positive axillary lymph
node(s); or metastasis in more than 3 axillary lymph However, mastectomy still has a role in the treatment of breast
nodes and in internal mammary lymph nodes with cancer, namely as the treatment of multifocal tumors, in tumors
microscopic metastasis detected by sentinel lymph node that are centrally situated (within 2 cm of the nipple), tumors that
dissection but not clinically apparent are large relative to breast size or where there is an adjacent exten-
pN3c Metastasis in supraclavicular lymph node(s)
sive in situ component. The move towards less radical surgery
pM Distant metastasis
The pM categories correspond to the M categories places a responsibility on the radiologist to define the size of
tumor, the site (particularly in relation to the nipple), the presence
of adjacent DCIS, and the presence or absence of multifocal/
Treatment Options multicentric disease (Figs. 26.1 and 26.3).
The treatment for early invasive breast cancer has moved towards
a multidisciplinary approach based on a combination of chemo- Staging the Primary Tumor
therapy, radiotherapy, and surgery. The prime role of surgery now The optimal staging technique for a primary breast carcinoma
is to provide optimal tumor control in the breast and axilla while remains controversial. Fornage et al. investigated the accuracy of
systemic adjuvant chemotherapy and hormone therapy are given ultrasound in assessing the size of mass lesions of invasive ductal

535
 primary tumor evaluation and staging
carcinoma, and found that ultrasound compared favorably with
mammography and clinical palpation in predicting the size of the
mass at pathological examination (71). Other series have reported
a lesser degree of correlation, with ultrasound tending to under-
estimate tumor size while mammography tends to overestimate
(72). There would appear to be practical problems in assessing
tumor size with mammography. The breast is compressed, and the
stellate distortion of tissues surrounding the mass often extends
well beyond the apparent primary. Despite this, Flanagan et al. (73)
describe a technique of mammographic measurement of the prin-
cipal tumor density, not including surrounding spiculation and
calcification, for which they claim an almost exact 1:1 relationship
with the gross pathological tumor size in the resected specimen.
Ultrasound has the theoretical advantage that the breast is rela-
tively undistorted, but some carcinomas are well circumscribed on
ultrasound while others are sufficiently irregular and poorly defined
to make accurate measurement difficult (Figs. 26.5 and 26.6).
Figure 26.5 Well-circumscribed carcinoma. There is inhomogeneity of the echo
pattern within the mass and the borders are clearly defined, resulting in little
difficulty in obtaining accurate measurements. Although some features suggest
a benign lesion, the histology was Grade 3 invasive ductal carcinoma.
Figure 26.6 Ultrasound demonstrates a poorly defined carcinoma with posterior
acoustic shadowing and some increased vascularity on color Doppler. Measurement
is prone to observer variability.
536
MR imaging has also been advocated as the most accurate technique
for tumor measurement (74).
The difficulty of any measuring technique is underlined by
consideration of the work of Holland et al. (75) who performed
5 mm sections of a series of 399 mastectomy specimens following
surgery for invasive cancer. Each 5 mm section was radiographed,
and any radiologically suspicious area was examined histologically
(Table 26.5). Tumor beyond the apparent primary focus was
detected in 63% of patients. In 43% this was more than 2 cm from
the primary (27% DCIS and 16% invasive carcinoma).
In a further paper, Holland et al. have drawn attention to the
presence of an extensive intraductal component (EIC) associated
with some primary tumors (76). The demonstration of these
satellite lesions and the presence of an EIC helps to explain the
increased local recurrence rate after breast-conserving surgery. The
radiologist must consider how to demonstrate such lesions and
thus advise on the suitability of limited surgery. Once again, MR
imaging appears to have great potential (Figs. 26.7 and 26.8). A
variety of methods have been described, mostly involving adminis-
tration of intravenous contrast medium (gadolinium-DTPA) with
or without subtraction and fat suppression techniques, and there is
now little doubt that gadolinium-enhanced MR imaging is the
most sensitive modality for detection of multicentric and multifo-
cal disease. Breast MR imaging can also give helpful information in
assessing tumor size as well as chest wall and muscle invasion.
Several investigators have shown that MR imaging is able to detect
additional foci of disease in up to one-third of patients (77,78).
MR imaging information may result in treatment changes, includ-
ing preoperative planning for single-stage resection of breast can-
cers (79,80). It should be remembered that breast-conserving
surgery, in conjunction with radiotherapy and chemotherapy,
results in recurrence rates of under 10%, and randomized con-
trolled trials of various treatment regimens have been based on
clinical and mammographic examination. Physicians and surgeons
have accepted the possibility of recurrence in an important but
relatively small number of patients. More recently, MR imaging,
with its increased sensitivity, detects multiple lesions which are too
small to feel or detect with mammography or ultrasound. This
leads to controversy because the treatment of local breast cancer is
apparently satisfactory, and the extra information from MR
imaging is not necessarily welcome and has not been proven in a
randomized controlled trial setting to be of clinical importance.
One of the results of incorporating breast MR imaging into the
evaluation might be to unnecessarily increase the mastectomy rate,
as some of the enhancing lesions detected may be assumed to be
invasive cancer whereas they are DCIS or an entirely benign lesion.
At one extreme, it could be said that all patients being submitted to
breast surgery need preoperative MR imaging; at the other end of
the spectrum it can be stated that preoperative MR imaging has
Table 26.5 Histological Examination of Mastectomy
Specimens (75)
Focus of tumor around primary tumor Specimens (%)
Nil 37
Within 2 cm 20
Beyond 2 cm 43 (27 in situ; 16 invasive)
 breast cancer

(A) (B)
Figure 26.7 (A) Mediolateral oblique mammogram showing a spiculated density in the left upper outer quadrant at the site of a poorly defined palpable mass (arrow). (B)
MR images following gadolinium (3-dimensional acquisition with fat suppression, reconstructed in coronal plane). There is very extensive abnormal enhancement
throughout the lateral half of the breast, more extensive than would have been predicted from clinical and mammographic examination. Multiple trucut biopsies through-
out the lateral left breast revealed invasive ductal carcinoma. The patient went forward to neoadjuvant chemotherapy. The right breast is normal.

(A) (B)
Figure 26.8 (A) Mediolateral oblique mammogram shows no gross abnormality. (B) In presence of a palpable mass and focal lesion with possible satellite nodules on
ultrasound, MRI was performed. Fat-saturated gadolinium-enhanced T1W sequence demonstrates an enhancing mass centrally with multiple small enhancing lesions
indicating multifocal carcinoma. An enhancing node is also present in the axilla. Mastectomy confirmed multifocal carcinoma.

not been shown to prevent local recurrence or increase five-year
survival. Used judiciously, preoperative breast MR imaging should
help to decrease positive margin rates, re-operation, and local
recurrence in patients with newly diagnosed breast cancer. It should
be able to identify those patients in whom mastectomy as first-line
therapy would be of benefit.
Where it has been used, the ability of breast MR imaging to
detect breast wall invasion and multicentric or multifocal disease
has clearly influenced patient management, but it is not yet a routine
procedure in all centers (81–86).
Current practice in the Uinted Kingdom relies heavily on
clinical assessment, although in specialist centers, both mam-
mography and ultrasound are widely used and have been shown
to correlate accurately with tumor size measured at pathology
(73,87). It seems likely that ultrasound must be relatively insen-
sitive in detection of an extensive intraductal component or

537
 primary tumor evaluation and staging
multifocal disease at a microscopic level. On the basis of
increased sensitivity, mammography and MR imaging are more
likely to detect EIC and multifocal disease. The choice of staging
technique for the primary tumor in an individual center remains
likely to be influenced by availability of both equipment and
radiological expertise.
Key Points: Staging and Treatment Options
■ TNM staging utilizes largely clinical and pathological
information but imaging is increasing in importance
■ Multimodality treatment of early breast cancer, including
chemotherapy and radiotherapy, has coincided with a move
away from more radical surgical techniques
■ Pathological data indicates that tumor is frequently more
extensive than initially suspected
■ MR imaging appears to be the most sensitive technique for
detection of multifocal/multicentric disease and overall extent
of disease
ASSESSMENT OF TUMOR RESPONSE TO
CHEMO-ENDOCRINE THERAPY BEFORE SURGERY
It has been shown that drug treatment with either cytotoxic
chemotherapy or tamoxifen can reduce the risk of relapse and
mortality when given as adjuvant systemic therapy following
surgery for primary breast cancer (88). Systemic chemoendo-
crine therapy is also used as primary medical (or neoadjuvant)
treatment before surgical removal of the tumor. Most tumors
will show some response to treatment, and for locally advanced
(A)
Figure 26.9 Mammogram before and after neoadjuvant chemoendocrine therapy. (A) Mediolateral oblique mammogram shows a large mass in the right upper outer
quadrant. (B) Following neoadjuvant therapy, the mass resolved clinically and at mammography. Source: From Ref. 90.
538
and inflammatory carcinoma, neoadjuvant chemoendocrine
therapy has become routine. Potential benefits include:
• Downstaging the primary tumor
• Reduction in the need for mastectomy
• Reduction in dissemination of tumor cells at surgery
• Destruction of micro-metastases
• Potential survival benefit
Powles et al. in a randomized trial have demonstrated that neoad-
juvant chemoendocrine therapy benefits the patient with operable
breast cancer by reducing the T stage and diminishing the require-
ment for mastectomy (89). A further theoretical advantage of
neoadjuvant chemotherapy is a reduction of the risk of dissemi-
nation of tumor cells at the time of surgery as a result of inactiva-
tion by pre treatment; also any response of the primary tumor
may be indicative of the efficacy of systemic drug treatment on
micro-metastases, thereby allowing optimization of treatment.
The advantages of neoadjuvant therapy have to be balanced
against the drawback of not having a full initial pathological assess-
ment (diagnoses are made by fine-needle aspiration cytology
[FNAC] and/or core biopsy), especially the grade of malignancy,
assessment of ductal and microvascular invasion, and metastatic
status of axillary nodes. Vinnicombe et al. showed a variety of
changes are clearly demonstrable on mammography. Masses reduce
in size and density, calcifications become more closely clustered
(largely as a result of reduction in the overall size of the lesion) but
do not disappear, and in 8% of patients mammographic abnormal-
ities resolve completely (Figs. 26.9 and 26.10). Unfortunately, some
patients with complete resolution of mammographic change have
residual invasive cancer, and conversely, some patients with clearly
discernible mammographic abnormalities have no residual malig-
nant cells (90). While mammography demonstrated some change
(B)
 breast cancer
(A)
Figure 26.10 Mammogram before and after chemoendocrine therapy. (A) Mediolateral oblique mammogram revealing a mass in the upper outer quadrant of the left
breast which is associated with extensive polymorphic calcification. (B) Following neoadjuvant therapy the mass has reduced in density and size, and the malignant
microcalcifications have been drawn together as the mass shrinks. Source: From Ref. 90.
in over 80% of patients, partial response (PR) was often not demon-
strable. (PR = reduction by greater than 50% bidimensionally of
measurable area or 30% unidimensional measurement (91,92)).
A viable alternative is the use of ultrasound. In the series of
Powles et al., an objective reduction in tumor size was detected by
ultrasound in 88% of measurable tumors, and a reduction in
blood flow through the tumor, assessed by color Doppler signal
intensity measurement, was observed in 36% (89). Further small
series have also demonstrated the utility of ultrasound as a
useful tool in monitoring response to neoadjuvant therapy (93).
However, neither ultrasound nor mammography will rule out the
presence of residual invasive cancer, even in the presence of
complete imaging remission.
Magnetic resonance imaging has recently been used in the evalu-
ation of response to neoadjuvant therapy in locally advanced breast
cancer. Abraham et al. (94) consider that it assesses response to
neoadjuvant therapy better than traditional methods of physical
examination or mammography. Using rotating delivery of excita-
tion off resonance (RODEO) with gadolinium enhancement they
demonstrate that MR imaging accurately predicts the pathological
determination of residual disease in 97% of patients (30 out of 31
cases). Changes in vascularity of tumors are demonstrable early in
the course of chemotherapy, which may help to predict response
(95). Such techniques are not widely available and currently may
be considered to be experimental. However, several interesting
observations have already been made, notably that enhancing tis-
sue disappears from tumor masses in a piecemeal fashion, raising
the possibility that destruction of tumor cells is patchy throughout
the tumor mass rather than uniform, which may have implications
for planning of surgical intervention (94).
18
FDG PET may emerge as a useful tool for predicting the likely
response to chemotherapy at an early stage during treatment.
Some authors have found that quantifying the reduction in tumor
uptake of FDG between a pre-treatment study and a subsequent
(B)
scan obtained after the first course of chemotherapy will predict
histological response with high sensitivity and specificity (96,97).
However, Burcombe et al. (98), in a small series of patients, per-
formed 18FDG PET immediately prior to surgery, and no abnor-
mal uptake of FDG was found but 9 of their 10 patients had
residual invasive carcinoma at operation, ranging from 2 to 22 mm
in maximum dimension. It is possible that 18FDG PET will develop
a clinical role in guiding changes in neoadjuvant chemotherapy,
but it does not appear to be useful in excluding the presence of
residual invasive carcinoma following treatment.
Key Points: Assessment of Chemo-Endocrine
Therapy Response Before Surgery
■ Most tumors show some response to neoadjuvant therapy
■ Mammography, ultrasound, and MR imaging are all useful
tools for evaluating treatment response
■ FDG PET may prove to be useful for predicting response
prior to commencement of therapy
■ All imaging techniques are unreliable in prediction of residual
tumor after neoadjuvant therapy and residual abnormalities
may not represent active cancer
REGIONAL NODAL INVOLVEMENT
The most common sites of regional lymph node involvement in
breast cancer are:
• Axillary nodes
• Internal mammary nodes
• Supraclavicular nodes
The axillary nodes are the principal site of regional metastases,
with approximately 40% of patients having evidence of spread at
539
 primary tumor evaluation and staging
(A)
Figure 26.11 (A) A small, well-circumscribed hypo-echoic mass representing a carcinoma, 1 cm in maximum dimension. (B) Axillary nodal mass of similar echogenicity
to primary tumor, and normal nodal architecture has been lost.
the time of diagnosis. The likelihood of axillary node involvement
appears to be related directly to the size of the primary tumor (99).
Detection of axillary involvement by physical examination has
high false-positive and false-negative rates. If axillary nodes are:
• Palpable, histological evidence of metastatic disease is
found in approximately 75%
• Not palpable, histological involvement is found in
approximately 30%
There are few data evaluating the accuracy of radiological assess-
ment of axillary nodal disease. Ultrasound is widely used, and
involved nodes are characteristically hypoechoic, round rather
than ovoid, and >1 cm in maximum diameter (Fig. 26.11). The
nodes may be fixed to each other and demonstrate increased vas-
cularity. However, there is no doubt that ultrasound sometimes
fails to identify involved nodes, particularly in the apex of the
axilla. 18FDG PET also suffers from a lack of sensitivity in detect-
ing axillary lymph node metastases. Guller et al. (100) concluded
that selective axillary surgery in breast cancer patients based on
PET findings is not yet possible, and that detection of small lymph
metastases is limited by the currently achievable spatial resolution
of PET imaging. Attempts have been made to demonstrate tumor
involvement of nodes by MR imaging. Features such as irregular
contours, abnormal cortex, high signal intensity on T2-weighted
imaging, and enhancement following gadolinium are associated
with axillary nodal involvement by breast cancer (101). Although
the technique is not widely used, useful information on axillary
anatomy may be available if MR imaging is being undertaken for
indications such as detection of multifocal breast carcinoma. Most
surgeons currently practice nodal dissection, in part because of
the high correlation of histological involvement of axillary nodes
with prognosis. Patients with negative nodes have a distinctly
540
(B)
greater likelihood of survival and the prognosis is inversely related
to the number of involved nodes.
For the purposes of analysis, the axilla is commonly divided into
three levels:
• Proximal (level one), which is inferior and lateral to the
lower border of the pectoralis minor muscle
• Middle (level two), which is beneath the pectoralis minor
muscle
• Distal (level three), referring to nodes superior to the
upper border of the pectoralis minor muscle
Involvement of the nodes at level three carries a poor prognosis,
but whether the prognosis relates directly to the level of involvement
or the number of nodes involved remains a moot point (102).
Involvement of axillary nodes is usually sequential (103). Involve-
ment of levels two and three without involvement of level one is
seen in approximately 2% of patients, so many surgeons practice
dissection of the lower levels to determine nodal involvement
while leaving some of the higher nodes to reduce the incidence of
lymphedema following surgery. A dissection of level one nodes is
an effective method of determining nodal involvement, but may
occasionally underestimate the total extent.
The second major site of regional metastases is the internal
mammary lymph node chain, which lies parasternally in the ante-
rior mediastinum. Involvement of these nodes is most frequently
seen in association with inner quadrant or central tumors, but
even in patients with inner and central tumors, axillary nodal
involvement is more common (104,105). CT is an effective way of
demonstrating internal mammary node involvement, but this is
rarely undertaken at the time of diagnosis. 18FDG PET appears to
be slightly more sensitive than CT, and FDG PET may uncover
 breast cancer
disease in nodal regions that may escape detection by other imaging
methods (106). It is not standard practice to treat the internal
mammary chain by surgery or radiotherapy as part of primary
treatment, so this region remains a potential site for relapse.
Supraclavicular node involvement represents a late stage of
axillary node involvement and carries a poor prognosis. Clinical
examination, ultrasound, and fine-needle aspiration are all useful
techniques in establishing supraclavicular node involvement.
SENTINEL NODE DETECTION
The sentinel node concept has been applied to a number of tumor
types, particularly melanoma. The prognosis of breast cancer is
significantly influenced by axillary lymph node status. Axillary
lymph node dissection (ALND) surgery carries some morbidity,
with lymphedema, pain, numbness, and limited shoulder move-
ment among the potential hazards (107). The sentinel node is the
first draining node on the lymphatic drainage pathway from the
primary tumor site. The principle is that the sentinel node will
show metastatic disease if any lymphatic spread has occurred.
Sentinel lymph node biopsy (SLNB) is a less invasive alternative to
ALND. If the sentinel node is positive for tumor, there is a 40%
risk that nodes further up the drainage pathway will be involved
with metastatic disease (108). Absence of metastatic disease in the
sentinel node in patients with breast cancer has been reported to
have a negative predictive value of 98% (109). Although no results
are yet available from randomized trials in SLNB, excellent clinical
outcomes using a variety of protocols have been reported in a
large number of patients (108). SLNB is usually performed in
patients with T1 and T2 tumors (<5 cm diameter) as the incidence
of nodal deposits in T3 and T4 tumors is frequently considered
sufficiently high to warrant ALND as the preferred procedure.
The challenge is to identify the sentinel node, and this is usually
attempted with a combination of dyes and radiopharmaceuticals.
The sentinel node is more successfully identified with radiopharma-
ceuticals than with dyes, but a combined technique using both will
maximize the potential of the procedure (110). A radiopharmaceuti-
cal is made by applying a tracer such as 99mTechnetium to a suitably
sized particle. The colloid employed should be of a size where it is
likely to be retained within the sentinel node. The highest counts
found in recovered sentinel nodes have been from albumen colloid
particles of 110 to 200 nm (111). Filtered 99mTechnetium sulphur
colloid (diameter approximately 100 nm) has a fast transport rate
to regional nodes, and is therefore more suitable if surgery is to be
performed within two hours of injection. Another technical issue
surrounds the issue of preoperative lymphoscintigraphy. This adds
time and expense to the procedure, and some breast centers consider
that the surgical decision-making can be performed intraoperatively
with visualization of blue dyes and utilization of a hand-held gamma
probe. However, preoperative lymphoscintigraphy may enable faster
location of nodes, and a combined approach can result in identifica-
tion and harvesting of more nodes (112). It appears that there
may be more than one sentinel node, and using dual agents and
all available imaging techniques will result in a better chance of iden-
tifying all sentinel nodes. In a prospective study of 1436 patients,
a false negative rate of 14.3% was reported if a single sentinel
node was removed, compared with 4.3% if multiple sentinel nodes
were removed (113). The preferred site for injection of dye and
radiopharmaceuticals has been controversial. Peritumoural,
intratumoural, subtumoural, periareolar, subareolar, intradermal,
and subdermal sites have all been suggested. One of the factors
dictating choice is whether the intention is to locate internal
mammary nodes in addition to axillary nodes. Some authors
indicate that the internal mammary sentinel node is more frequently
detected by peritumoral injection (114), whereas other groups have
claimed technical advances for intradermal injection techniques
using sulphur colloid and blue dye (115). There is some reluctance to
use intratumoral injection due to concerns over tumor seeding and
the possibility of higher intratumoral interstitial pressure, making
injection difficult and drainage less reliable. The tumor itself lacks
lymphatics, and therefore intuitively the intratumoral injection site
is less attractive. Overall, the identification rate, accuracy, and pre-
dictive value of sentinel node biopsy seem to be relatively unaffected
by the site of injection. Likewise, there has been debate over whether
radioisotope should be injected on the day of surgery or the day
before, but no clear advantage has been identified for either
technique (116). The dose of radioactivity to operating theatre staff
is low (radiation dose to the hands of a surgeon performing 30 SLNB
procedures following administration of a radiopharmaceutical is
equivalent to one-year’s background radiation), and exposure to
pathology staff is negligible due to radioactive decay of technetium
during fixation in formalin. No additional procedures are required
for protection of staff, and SLNB can be performed safely during
pregnancy as fetal dose is very low (117).
Concentration on the sentinel node by the pathologist, using
multisectioning and immunohistochemical staining techniques, has
been reported to result in an increased detection of micrometastases
compared to conventional axillary node dissection. A micrometas-
tasis is defined as a tumor deposit in a node ranging from 0.2 to
2 mm. A cluster of cells of <0.2 mm is designated isolated tumor
cells (118). It is not yet clear whether the presence of additional
micrometastases carries the same prognostic significance as nodal
deposits found on conventional axillary surgery. There is some
evidence to suggest that micrometastases are of similar prognostic
significance to macrometastases (119), and a wide literature review
concludes that the presence of micrometastases confers a worse
prognosis than is associated with no axillary involvement (120).
The correlation between sentinel node findings and the status of
the remaining axillary lymph nodes is so good that some investiga-
tors in both Europe and North America argue that sentinel node
biopsy should be the standard method of managing the axilla in
early breast cancer (121,122). However, some argue that the con-
cept of a sentinel node is too simplistic and at variance with mod-
ern views on the biology of breast cancer where distant metastases
may be present at the time of diagnosis (123). In addition, the good
correlation between sentinel node and axillary basin findings may
be partly due to the fact that the sentinel node is looked at more
thoroughly (with step sections, immunostaining, and polymerase
chain reaction enhancement) than the remaining nodes. It is also
not clear what should be done if the sentinel node is at level two of
the axillary nodes, skipping level one, as has been described in
some series (122), or if the sentinel node appears to be in the inter-
nal mammary chain. Avoidance of unnecessary axillary lymph
node dissection is a worthwhile objective and sentinel node biopsy
may provide a way of achieving this. However, some authorities
541
 primary tumor evaluation and staging
consider that the technique is unproven in breast cancer (123).
Nevertheless, SLNB has moved rapidly into mainstream clinical
practice, and is being performed mostly outside clinical trials.
Patient choice has been driven to some extent by non-medical
media. At the time of writing, the results from three multicenter
trials sponsored by the National Cancer Institute are eagerly
awaited, and may resolve some of the remaining controversies.
Key Points: Nodal Metastases
■ Approximately 40% of patients have spread to axillary lymph
nodes at the time of diagnosis
■ The chance of axillary nodal spread is related to the size of
the primary tumor
■ Prognosis is inversely proportional to the number of lymph
nodes involved
■ Internal mammary nodes are more frequently involved in
inner quadrant or central tumors
■ Absence of metastatic disease in a sentinel node has been
reported to have a negative predictive value of 98%
■ Sentinel lymph node biopsy has now become mainstream
clinical practice
IMAGING OF DISTANT METASTATIC DISEASE
Staging of Metastatic Disease at the Time
of Primary Diagnosis
Staging investigations that may be used include:
• Chest radiography
• Plain skeletal radiographs
• Computed tomography
• Liver ultrasound
• Magnetic resonance imaging
• Skeletal scintigraphy
• Positron emission tomography
Metastatic spread from carcinoma of the breast can involve virtu-
ally any organ. However, distant metastatic disease demonstrable
by imaging at the time of diagnosis of primary breast cancer is
distinctly unusual. For this reason, radiological evaluation for
distant metastases should be limited at the time of diagnosis. It
should be noted that bilateral mammography, performed as part
of the diagnostic work-up, may reveal a contralateral tumor, and
the rate of synchronous contralateral breast carcinoma detected
by mammography is as high as 2.4% in some series (124).
In recent years, with increasing sophistication of cross-sectional
imaging techniques, oncologists have drifted towards an attitude
that all new cancer patients must be “staged.” This is justifiable when
a cross-sectional technique can demonstrate locoregional spread of
the primary tumor and involvement of nodes (for example, lung
and esophageal cancer). However, detection of locoregional disease
in breast cancer is not best achieved by a whole body technique such
as CT, and there is little evidence to suggest that investigation for
metastatic disease at the time of diagnosis is of clinical benefit.
Schneider et al. (125) described 488 consecutive patients who
underwent surgery for primary operable breast cancer. These
542
patients were investigated for distant metastases with chest radio-
graph, liver ultrasound, and isotope bone scan. Distant metastases
were found in 19 patients (3.9%). Bone metastases were detected in
2.7%, liver metastases in 1%, and pulmonary metastases in 0.4%.
Among patients with breast tumors less than 1 cm at pathology, no
metastatic deposits were found. In patients with locally advanced
tumors (pathologically T4, including patients with extension to
chest wall, skin edema and satellite nodules, and inflammatory
carcinoma), the incidence of metastasis was 18%. The message that
locally advanced tumors are more likely to have metastasized at the
time of diagnosis is unsurprising, but the absence of metastases
with small tumors led Schneider et al. to conclude that imaging
can be omitted from the work-up in patients with small breast
tumors (T1 and T2) presenting with symptoms of local disease
only. This reflects other contributions to the literature, which have
found that patients with T1 and T2 tumors (i.e., <5 cm in diame-
ter) had positive isotope bone scans in only 2% (126). Yeh et al.
have gone as far as describing routine isotope bone scan in patients
with T1 and T2 breast carcinoma as a waste of money (127). In this
study, a number of false positive investigations were identified. Of
316 women with early stage breast cancer, 63 had isotope bone
scans which precipitated further investigations. A total of seven
patients were found to have skeletal metastases, six of whom had
unequivocal clinical stigmata of disseminated disease.
The question of whether it is worthwhile detecting metastatic
disease at an asymptomatic stage was addressed by two multi-
center randomized trials conducted in Italy. Roselli del Turco
(128) randomized a group of 1243 consecutive patients with no
symptoms of metastatic disease at the time of breast cancer diag-
nosis into two groups. One group had physical examination and
mammography at six-month intervals, whereas patients in the
“intensive follow-up” group were investigated with chest radio-
graphy and isotope bone scans every six months. Vital status at five
years was the main outcome measure. A total of 393 recurrences
(104 local and 289 distant) were observed. Increased detection of
isolated bone deposits and lung metastases was evident in the
intensive follow-up group compared with the clinical follow-up
group. No difference in incidence was observed for metastases at
other sites or for local and regional recurrences. There was no dif-
ference in five-year overall mortality, but relapse-free survival rate
was significantly higher in the group on clinical follow-up only.
Patients in the intensive follow-up group showed earlier detection
of recurrence. The group was followed up with 10-year statistics,
and once again, no difference in survival was detectable (129). The
GIVIO investigators (130) randomized 1320 patients into two
groups. One was assessed with clinical examination and annual
mammography, the other group was assessed with isotope bone
scan and liver ultrasound at yearly intervals, chest radiograph
twice-yearly and laboratory blood tests every three months.
Median follow-up was 71 months, and there was no overall differ-
ence in survival noted. The study also measured health-related
quality of life, including emotional well-being, quality of life
perception, social function, body image, and satisfaction with care
and symptoms. No difference in quality of life was reported, so
symptom relief cannot be used as a justification for attempts to
detect metastatic disease early. Both trials came to the conclusion
that routine use of imaging investigations for asymptomatic
patients does not affect survival and has no useful function.
 breast cancer
Despite the good evidence discouraging this approach, the
Faculty of Clinical Oncology of the Royal College of Radiologists
recommended that chest radiography should be performed on
women undergoing conservation surgery for T1 and T2 breast
carcinoma, while chest radiograph, isotope bone scan and cross-
sectional imaging of the liver should be performed on women
undergoing mastectomy (131). A brisk response from radiologists
practicing in the field of breast cancer pointed out that it is illogi-
cal to use the type of surgery proposed as a prognostic indicator,
as a patient with a small low-grade invasive tumor with extensive
surrounding ductal carcinoma in situ (DCIS) would be treated
with a mastectomy, but is at low risk of developing metastases,
while a patient undergoing conservation surgery for a small high-
grade invasive cancer may well have micrometastases which
declare in future years (132). It was reiterated that there is no
survival benefit derived from early detection of metastatic disease,
and attention was drawn to the possibility of false positive results
generating anxiety and consuming resources unnecessarily.
Prognostic indicators based on adverse pathological features are
the primary indicators influencing decisions on appropriate adju-
vant therapy. Advice from the Royal College of Radiologists was
subsequently amended to the effect that, prior to mastectomy, if
there is any suspicion that patients may have clinically apparent
metastatic disease, isotope bone scan and cross-sectional imaging
of the liver should be employed. In the response (133), attention
was drawn to the problems faced by oncologists treating patients
that there is no reliable way of identifying patients with early meta-
static disease, and therefore it is difficult to assess the effect on the
natural history of metastatic disease of expensive modern cytotoxic
drugs, bisphosphonates, and emerging novel biological agents such
as trastuzumab (Herceptin®). It is legitimate to subject patients to
cross-sectional imaging within clinical trials of these agents, but
only if the patient is appropriately consented to the effect that there
is no proven clinical benefit derived from imaging investigations
which may detect asymptomatic metastatic disease.
The pressure towards use of more imaging investigation regu-
larly demonstrates the capability of modern imaging techniques
of producing a multitude of false positive findings. Even in a
patient with an established diagnosis of cancer, the majority of
radiological lesions will prove to be benign entities such as liver
cysts or pulmonary granulomas. Since the diagnosis of metastatic
disease renders a patient “incurable” the diagnosis should be
made with some circumspection and only when it is unequivocal.
Imaging studies performed with the intention of reassuring the
patient frequently do the opposite, and the time to image a patient
is when symptoms present which may benefit from systemic or
local treatment.
Key Points: Staging for Metastatic Disease
at Diagnosis
■ Distant metastatic disease, detectable by imaging is very
unusual at the time of diagnosis
■ Patients with T1and T2 tumors have bone metastases on
bone scan at diagnosis in only 2%
■ Two large clinical trials have concluded that imaging investiga-
tions for asymptomatic patients do not have a useful function
Imaging of Symptomatic Metastatic Disease
at Follow-up
Autopsy studies demonstrate that breast carcinoma is capable of
metastasizing to any organ. To quote Lee (134), “breast cancer is
known to metastasize to all organs of the human body and its
manifestations are protean. It is almost impossible to predict which
organ system will be invaded.” Lee summarized seven autopsy stud-
ies from the American literature, from 1950 to 1982. Two thousand
one hundred and forty-seven patients were included in these series,
and despite variable methods, similarities between the series were
more pronounced than differences. The commonest sites of metas-
tasis are presented in Table 26.6. Rare sites in these series included
esophagus, gallbladder, rectum, vagina, urinary bladder, and eye.
Some of the statistics are surprising, notably that central nervous
system (CNS) metastases seem under-represented by today’s stan-
dards. The pattern of metastatic disease has been demonstrated to
be dependent to an extent upon the age of the patient, previous
treatment, and tumor type. Viadana et al. showed that patients
below 50 years of age had a median of nine sites involved by metas-
tasis at autopsy, while patients over 50 years of age had a median of
seven involved sites (135). Amer compared patterns of metastatic
disease in patients who had received chemotherapy with those who
had not. One of the interesting statistics to emerge was that those
patients who had not received chemotherapy had an overall inci-
dence of CNS metastasis of 35%, compared with an incidence of
62% in patients who had received chemotherapy (136). It is possible
to postulate that younger patients survive longer and develop more
sites of metastases; also that patients pre-treated with chemotherapy
survive long enough to develop more CNS metastases. Appropriate
timing and choice of investigations for symptomatic metastatic dis-
ease is controversial. The majority of breast cancer recurrences are
between two and five years after presentation. Initial investigations
when metastasis is clinically suspected should be directed at the
symptomatic area, but given the propensity of the disease to involve
multiple sites, whole body imaging techniques may be employed.
However, while metastatic breast cancer is considered incurable, it is
far from untreatable and control of symptoms can result in pro-
longed survival with good quality of life. Specific palliative mea-
sures may be guided by investigations tailored to the clinical history,
Table 26.6 Site of Metastasis in Breast Cancer (134)
Site of metastasis % of patients affected (median)
Lung 71
Bone 71
Nodes 67
Liver 62
Pleura 51
Adrenal 41
Brain 26
Peritoneum 21
Ovary 20
Dura 18
Leptomeninges 16
Spleen 15
Pancreas 14
Kidney 14
Thyroid 12
Pituitary 9
Spinal cord 8
543
 primary tumor evaluation and staging
and a balance needs to be struck between specific symptom diagno-
sis and a broader “trawling” technique.
Key Points: Imaging Symptomatic
Metastatic Disease
■ Breast cancer can metastasize to any organ
■ The pattern of metastatic disease is dependent on the age of
the patient, nature of previous treatment, and tumor type
■ Younger patients (<50 years) tend to have more sites of
demonstrable metastases
■ Most recurrences occur between two and five years after
presentation
Nodal Metastatic Disease
In the current version of the TNM staging system, metastatic dis-
ease to the supraclavicular fossa nodes is characterized as N3,
although in previous versions it has been designated N1. Cervical
nodal disease is considered metastatic. Most nodal metastases to the
(A)
(B)
Figure 26.12 (A) MR imaging performed for symptomatic brachial plexopathy
three years after treatment for localized breast cancer shows poorly defined soft
tissue in the infraclavicular region (arrows), lying anterior and posterior to subcla-
vian vessels and brachial plexus. (B) Ultrasound shows small confluent soft tissue
lesions (arrows) presumed to be nodal, anterior to the subclavian artery (A) and
vein (V). Fine needle aspiration guided by ultrasound confirmed malignant cytol-
ogy consistent with recurrent breast cancer.
544
neck and axilla are diagnosed by clinical examination. However CT
and ultrasound can be used for confirmation in clinically equivocal
cases. Nodal recurrence may take the form of discrete rounded
nodes, but may also take a diffuse and infiltrative form which is
assumed to originate in nodes. Ultrasound can be particularly
useful in superficial sites as cytological confirmation of disease
recurrence can be obtained by fine needle aspiration (Fig. 26.12).
Intrathoracic Metastases
Symptoms related to the respiratory system should initially be inves-
tigated by chest radiography. A baseline study from the time of diag-
nosis is frequently available, but it has been shown that regular chest
radiography in follow-up contributes little to patient management
(137). Metastatic deposits from breast carcinoma can vary from large
and well defined to small and poorly defined. Typically they are
irregular rather than of “cannon ball” type associated with some
tumors (Fig. 26.13). Lymphangitic spread is well described and is
demonstrable by high-resolution CT (HRCT) of the lungs in the
presence of equivocal findings on plain radiography. Chest CT is also
a useful method of confirming mediastinal lymphadenopathy, which
is not unusual and may be the initial site of metastatic disease (Fig.
26.14). An infiltrative form of mediastinal disease, manifested on CT
by alteration of attenuation of fat within the mediastinum or diffuse
poorly defined enhancing mass lesions may also be seen (Figs. 26.15
and 26.16). Pleural effusion as a result of pleural involvement is com-
mon, but pleural mass lesions are not frequently apparent.
Bone Metastases
In oncological practice, the clinical context of musculoskeletal pain
is of paramount importance. Back pain in a patient with a previous
history of breast cancer is an example of how clinical background
fundamentally influences selection and interpretation of imaging
investigation. For example, a patient aged 70 diagnosed 15 years pre-
viously with a 1 cm Grade 1 carcinoma of breast with no axillary
nodes involved, complaining of back pain following digging the gar-
den, is unlikely to have recurrent disease, and a conservative approach
to investigation is indicated. However, a patient aged 40 years
presenting with back pain at rest three years after resection of a 5 cm
Grade 3 carcinoma with involved nodes has a high chance of recur-
rence, and should proceed directly to investigative imaging. Isotope
Figure 26.13 Pulmonary metastases from breast cancer, showing typical irregular
shape and poorly defined outline.
 breast cancer

Figure 26.14 Mediastinal and contralateral axillary lymphadenopathy. CT shows

abnormal nodes in the prevascular space and retrocaval nodes (arrows). There is
also an abnormal node in the left axilla (arrowhead). Note the abnormality of the
right breast. The patient had previously received radiation therapy to breast, right
axillary and right supraclavicular nodes, and went on to develop pulmonary and
pleural metastatic disease.
Figure 26.16 CT of chest shows a mass lesion in the anterior mediastinum which
demonstrates inhomogeneous enhancement. The appearance represents diffuse
mediastinal infiltration by metastatic breast carcinoma which subsequently
responded to systemic chemotherapy.

Figure 26.15 CT showing poorly defined infiltrative mass lesion in prevascular

space. Biopsy confirmed metastatic adenocarcinoma with pathological features
consistent with the previously excised breast primary.

bone scanning is an appropriate initial study and is clearly superior

to skeletal radiographs as a means of early detection (138). Its advan-
tages are sensitivity, and the ease of inclusion of the entire skeleton at
a single investigation. False-positive findings frequently need further
investigation, particularly in the elderly population. There is also a
small but important false-negative rate, which may be attributed to
deposits that are confined to the bone marrow, and therefore have
little effect on osteoblastic activity. If clinical symptomatology (e.g., (A) (B)
back pain) is highly suggestive of metastatic disease, MR imaging is
Figure 26.17 (A) Isotope bone scan, appearance within normal limits. (B) MR image
a suitable method of further evaluation (see chap. 43) (139). On of spine (sagittal T1-weighted spin-echo sequence). Owing to continued back pain
T1-weighted spin-echo sequences, focal deposits of breast carcinoma and a high clinical suspicion of metastatic disease, the patient had this MRI study five
contrast well with normal fatty bone marrow (Fig. 26.17). Further days after the isotope bone scan. Extensive bony metastatic disease is present.

545
 primary tumor evaluation and staging
sequences, including fat suppression techniques such as STIR
(short tau inversion recovery) and T2-weighted spin-echo as well as
gradient echo techniques are advocated (140,141).
Lytic deposits return a low signal on T1-weighted sequences
and high signal on T2-weighted sequences, while sclerotic depo-
sits return comparatively low signal on all pulse sequences. These
sequences are discussed in more detail in chapter 43.
Liver
Statistically, liver deposits are slightly less common than bone and
pulmonary deposits. Hepatomegaly, right upper quadrant pain or
disturbance of liver function are the usual precipitants of hepatic
imaging. Initial investigation with ultrasound will usually make
Figure 26.18 There are poorly defined low attenuation lesions scattered through-
out the liver. Some of these show rim enhancement, and there is confluent disease
in places. Individual lesions are difficult to measure. The appearance is not entirely
specific, but is typical of breast carcinoma metastatic to the liver.
(A)
Figure 26.19 “Pseudocirrhosis” in a patient three years after diagnosis of breast cancer. (A) Contrast-enhanced CT demonstrates a non-enlarged liver with mixed attenu-
ation nodules, irregular outline and ascites. (B) Ultrasound reveals a diffuse echogenic pattern without obvious discrete masses. The appearance was stable on imaging
over an eight-month interval, at which time the clinician insisted on a biopsy which revealed metastatic breast cancer. Source: From Ref. (144).
546
the diagnosis, breast deposits are typically hypoechoic and some-
times demonstrate a “target” lesion appearance. On CT breast
metastases are usually of low attenuation during portal venous
phase dominant imaging (Fig. 26.18). They may demonstrate an
irregular outline with peripheral enhancement. Metastases may be
small and become confluent and diffuse resulting in an appear-
ance which can be confused with cirrhosis (Fig. 26.19). Borja et al.
(142) writing over 30 years ago drew attention to the phenomenon
of metastatic breast carcinoma to the liver mimicking cirrhosis,
and noted a histological feature of diffuse fibrosis of the liver
parenchyma initiated by metastatic scirrhous carcinoma. Perivas-
cular tumor infiltration had resulted in portal hypertension. At
that time, they found six reported cases including their own in the
literature. Subsequent reports in the imaging literature indicate
that the appearance of “pseudocirrhosis” caused by metastatic
breast cancer is not rare (143,144). MR imaging is not routinely
used in the evaluation of hepatic metastatic disease but has a
useful problem-solving role, particularly in the evaluation of
indeterminate focal lesions.
Brain
Brain metastases in breast cancer are not uncommon and most
frequently present with headache or convulsions. Localizing signs
such as hemiplegia or ataxia may be present. Magnetic resonance
imaging is established as the most sensitive method of detecting
intracranial mass lesions, although in the presence of a suggestive
clinical history, CT is usually adequate for diagnostic purposes.
There is said to be an association between the development of pri-
mary breast carcinoma and meningioma. Both conditions are
seen most frequently in middle aged women, and are not uncom-
mon. There is also a tendency for breast cancer to result in meta-
static lesions at the periphery of the brain (Fig. 26.20). Both
meningioma and breast metastases may enhance homogeneously
and cause enhancement of adjacent meninges, and may cause
parenchymal brain edema to varying degrees. If a solitary cerebral
deposit is identified, it is always tempting to suggest a diagnosis of
meningioma, but in the author’s experience, a solitary deposit is
(B)
 breast cancer
Figure 26.20 Gadolinium-enhanced T1W MR imaging shows a solitary peripheral
lesion in the right hemisphere. The location raises the possibility of a meningioma
but in the clinical context of a patient with previous breast cancer, it is likely to be
a metastasis. Subsequent whole body CT showed pulmonary metastases.
more frequent than an incidental meningioma. A pragmatic
approach favors an early follow-up investigation to assess growth
rate rather than immediate craniotomy. Cranial irradiation is an
effective method of symptom control for metastatic disease and
has the advantage of treating micro-metastases, which may not be
apparent on imaging at the time of demonstration of brain
involvement. In the autopsy series of Lee (134), CNS metastases
were found in 26% of patients. If autopsy studies were performed
regularly on patients with breast cancer today, it is difficult to
imagine that the incidence would be this low. Amer (136) observed
that patients treated with chemotherapy generated more CNS
metastases, indicating that it may be a sanctuary site. Some sys-
temic chemotherapy regimens have incomplete penetration of the
blood-brain barrier. For example, trastuzumab (Herceptin®) is a
large molecule which does not easily pass the blood-brain barrier.
There is an unsubstantiated theoretical risk that successful treat-
ment of metastatic disease at other sites with trastuzumab may
alter the natural history of the disease to allow development of
symptomatic CNS disease in some patients.
Meningeal and Spinal Cord Metastases
The meninges and spinal cord may also be involved by metastases,
and this can result in a variety of clinical presentations including
isolated and multiple cranial neuropathies, mixed peripheral root
lesions, and localizing signs related to the spinal cord. Investiga-
tion for intra-axial spinal deposits and meningeal deposits relies
heavily on MR imaging using gadolinium-enhanced T1-weighted
Figure 26.21 The spleen is enlarged and contains numerous ill-defined metastases,
which have similar characteristics to those within the liver. Source: From Ref. (144).
sequences and is discussed in chapter 45. The technique differs
from that used for patients with classical signs of cord compres-
sion due to bony metastasis, so the clinical features must be care-
fully considered in all patients with neurological presentation in
order to tailor the MR imaging examination appropriately.
Abdominal Metastases
Lee’s autopsy series (134) indicated that metastatic disease to the
abdominal cavity is far from unusual, with metastatic disease
being observed to the peritoneum in 21% of patients, GI tract
(16%), spleen (15%), pancreas (14%), as well as the more com-
mon sites of liver and adrenal gland. Splenic deposits are generally
hypoechoic on ultrasound and low attenuation on CT, compara-
ble to liver metastases (Fig. 26.21). Metastatic infiltration of the
adrenals is suggested by loss of the normal shape of the gland and
by increase in size. Metastases to the adrenal tend to be asymp-
tomatic, although hypoadrenalism occasionally occurs, and adre-
nal deposits may be seen incidentally during investigation of
metastases in other organs.
Retroperitoneal nodal deposits may present as mass lesions or
more poorly-defined infiltration. Peritoneal deposits from any
tumor are notoriously difficult to identify, and breast carcinoma
is no exception. However, the typical appearance is of diffuse
ill-defined nodularity (Fig. 26.22). Transcoelomic spread to the
peritoneum can cause development of malignant ascites, and
the Pouch of Douglas is a frequent site of metastasis (Fig. 26.23).
A clinical problem which may arise is the possibility of co-
existent incidental ovarian carcinoma, particularly if BRCA1
gene mutation is present. Tumor markers such as CA125 in
blood and ascitic fluid may be helpful, but peritoneal disease of
any sort may elevate the CA125. In patients with suspected
metastatic breast cancer in the pelvis, surgery is sometimes
undertaken with curative intent. An interesting observation is
547
 primary tumor evaluation and staging

that metastasis from invasive lobular carcinoma has a higher rate

of involvement of unusual sites, for example, gut, retroperito-
neum, and peritoneum (145,146).

Whole-Body Positron Emission Tomography Imaging

in the Detection of Metastases
Whole-body PET scanners may allow staging of tumors by detect-
ing disease in soft tissue, bone, and central nervous system during
a single investigation (147). Increased glycolytic activity is present
in most tumor tissue, which enables its differentiation from
normal or scar tissue by using 18FDG. Alternatively, increased
amino acid incorporation into tumor tissue may be shown using
methionine or leucine labelled with a positron-emitting isotope
of carbon (11C-methionine, 11C-leucine). Initial studies with
18
FDG PET were encouraging, with claims that the technique can
distinguish benign from malignant primary breast lesions (148),
and that the axilla can be assessed for metastases with a sensitivity
of 90% and specificity of 100% (149). High sensitivity has also
been reported in detection of tumor deposits in the contralateral
breast, bone, and elsewhere (150,151). Most PET is now PET-CT
and the technique is clearly a sensitive and useful method of
detecting metastasis but at the time of writing is a relatively scarce,
expensive, and time-consuming investigation.

Key Points: Metastases

Figure 26.22 Diffuse, ill-defined nodularity and stranding is seen within the
omental fat (arrows), a characteristic appearance of peritoneal deposits. Source:
From Ref. 144.
Figure 26.23 A 4.5 cm adnexal mass, an ovarian deposit from breast cancer, with
an irregular convex anterior border is seen to indent the posterior aspect of the
bladder. There are no specific features to discriminate from a primary ovarian
carcinoma, but metastatic deposits rarely have a cystic component. Source: From
Ref. 144.
■ Nodal disease to the supraclavicular fossa is now denoted as
metastatic disease in the TNM staging classification
■ Ultrasound is useful for assessing superficial sites and can be
readily used for guiding fine needle aspiration
■ Regular chest radiography during follow-up contributes
little to patient management
■ Lung metastases vary from large well-defined deposits to
small ill-defined lesions
■ Chest CT is useful for confirming mediastinal
lymphadenopathy
■ Isotope bone scanning continues to be an important first
investigation in the detection of metastatic bone disease
■ MR imaging is the investigation of choice in patients with a
high clinical suspicion of bone metastases and normal isotope
study
■ Liver metastases from breast cancer are typically small
hypoechoic lesions on ultrasound
■ Liver metastases may become confluent and diffuse, giving
an appearance described as “pseudocirrhosis”
■ MR imaging is the most sensitive technique for detecting
brain metastases
■ A solitary peripheral brain metastasis may have similar
appearances as meningioma
■ Suspected spinal cord and meningeal deposits should be
imaged with contrast enhanced MR imaging
■ Metastases to the peritoneum, gastrointestinal tract, and
spleen are not uncommon
■ 18FDG PET-CT has a useful and growing role in the detection
of metastatic breast disease
■ Use of alternative tracers (11C methionine and 11C leucine)
are also being explored

548
 breast cancer

relatively low, although semi-quantitative assessments of rate of

INVESTIGATION FOR LOCOREGIONAL
increase of signal intensity following contrast enhancement show
RECURRENT DISEASE promise in improving specificity. However, when abnormal
enhancement is apparent, cytological or histological confirmation
The move away from radical mastectomy has precipitated the
of recurrence should be achieved before re-operation. Magnetic
problem of how best to investigate for suspected locally recurrent
resonance imaging shares with ultrasound the ability to detect
disease. Recurrence rates following lumpectomy alone have been
fluid collections, and neither technique is hindered by the presence
sufficiently high that most clinicians opt for wide local excision or
of a reconstructive prosthesis.
quadrantectomy followed by radiotherapy. Surgical scarring and
radiation changes vary between individuals, and the feasibility of
Investigation of Neurological Symptoms and Edema
imaging depends on factors such as:
of the Arm
• Breast size Arm swelling and neurological symptoms in the arm are not
• Degree of architectural distortion unusual following treatment for breast cancer. The surgeon under-
• Parenchymal pattern taking nodal dissection of the axilla usually leaves some apical
• Time elapsed since completion of treatment nodes to prevent arm swelling. However, this approach does not
Recommendations abound on how frequently to re-investigate always work, and when arm swelling develops, it can be difficult to
patients following treatment of primary breast cancer; the Royal determine whether swelling is due to recurrent tumor in level 3
College of Radiologists in the United Kingdom has recommended nodes or simply as a result of surgery. The assessment is even more
that mammography should be repeated annually for five years fol- difficult when radiotherapy has been used in treatment. The cru-
lowing completion of treatment, and every two years thereafter. cial discrimination in any patient with symptoms referable to the
Duration is not specified, but it is noted that 80% of recurrences arm is between a recurrent mass or radiation fibrosis, both of
occur within 10 years (152). The British Association of Surgical which may present clinically as brachial plexopathy. Computed
Oncology makes similar recommendations but practice is far tomography and MR imaging can both demonstrate tumor masses
from uniform (153). Local recurrence is estimated to occur at a in the chest wall, apex of the axilla, infraclavicular, and supra-
rate of approximately 1% per year (154). Mammography is the clavicular regions (Figs. 26.24–26.27).
mainstay of follow-up imaging after surgery and radiotherapy. Computed tomography is established as a reliable method of
The breast may initially enlarge after radiotherapy but in most demonstrating axillary nodal masses (161,162), but more recently
cases it will subsequently shrink. Clinical examination is difficult MR imaging has been suggested as the investigation of choice
since induration and masses may result from: (163,164). 18FDG PET has been investigated, and appears to be a
useful investigation, particularly when combined with a cross-
• Inflammation
sectional technique such as CT or MR imaging (165,166). This
• Fat necrosis
role of PET is likely to be further enhanced by the introduction of
• Scar formation
PET-CT.
• Neoplastic recurrence
A baseline mammogram is helpful 6 to 12 months after comple-
tion of treatment. Scarring will develop by one year. Edema and
skin thickening may be present for months after radiation treat-
ment but will resolve within two years. New calcifications occur
frequently following radiotherapy, but are usually benign (155),
dense, and dystrophic in character. However, typical malignant-
type microcalcification occurs in almost a half of mammographi-
cally detected recurrences, and must be distinguished from the
radiation-induced calcification (156). Any increase in the extent
of abnormality following the baseline should be viewed with sus-
picion on mammography, which can be expected to detect about
two-thirds of recurrences (157). Ultrasound may be helpful and
Doppler signal is important to assess the vascularity of the area of
suspicion. Scar tissue should be relatively avascular, and fat necrosis
may contain areas of cystic change.
As in other aspects of breast imaging, advances are being made
in the use of MR imaging in the detection of locally recurrent dis-
ease (158). Most authors recommend the use of gadolinium-
enhanced techniques usually involving fat suppression, since large
amounts of fat within the breast may obscure enhancing lesions.
Subtraction techniques have also been recommended (159,160).
The major advantage of MR imaging is its high sensitivity. If no
abnormal enhancement is present, it is extremely unlikely that the Figure 26.24 Contrast-enhanced CT demonstrating small volume nodal recur-
tumor has recurred. Most authors agree that specificity remains rence (clinically impalpable) in left axilla (arrow).

549
 primary tumor evaluation and staging
Figure 26.25 CT demonstrating recurrent mass in apex of left axilla (arrow). Note
the poorly defined margins. The patient had been treated with wide local excision
and nodal dissection followed by radiotherapy, and presented three years later with
symptoms of brachial plexopathy.
Figure 26.26 MR imaging (coronal T1-weighted spin-echo sequence) demonstrat-
ing bulky recurrent tumor in the apex of the axilla, involving the brachial plexus.
The mass surrounds the subclavian/axillary artery. At this level, the mass will
involve the cords of the brachial plexus, resulting in clinical brachial plexopathy.
The patient had previously received radiation therapy to the axilla and left supra-
clavicular fossa region, and, remarkably, the lesion was not palpable due to
induration of tissues.
Brachial Plexus
The brachial plexus provides sensory and motor innervation, and
forms in the posterior triangle of the neck by union of the nerve
roots of the fifth to eighth cervical and first thoracic spinal segments.
The exiting roots pass between the anterior and middle scalene
muscles forming the upper, middle, and lower trunks just lateral to
the border of the anterior scalene. The trunks each divide into ante-
rior and posterior divisions just superior to the subclavian artery.
550
(A)
(B)
Figure 26.27 (A) Sagittal T1-weighted MR images using a flexible local coil dem-
onstrating the normal brachial plexus in relationship to the subclavian vessels. The
subclavian artery (a) and vein (v) lie inferior to the clavicle. The individual cords
of the brachial plexus are identifiable forming an arcade superior and posterior to
the subclavian vessels and individual nerves are beginning to leave the plexus at
this site (arrow). (B) Sagittal T1-weighted sequence using a flexible local coil. The
subclavian artery can be discerned in the infraclavicular region. There is a mass
lesion surrounding it and obliterating the anatomy of the cords of the brachial
plexus which should be visible at this site. Recurrent tumor encases the vessels and
brachial plexus (arrow).
These divisions unite to form three cords that come to surround the
axillary artery, forming the posterior, medial, and lateral cords named
according to their relationship with the artery (Fig. 26.28). Pathology
at any level of the brachial plexus can result in symptoms and signs.
It is therefore important to image the entire structure from cervical
spine to distal axilla.
Using MR imaging, sagittal and axial images should be
obtained through the lower cervical and upper thoracic spine,
which should demonstrate bony or soft tissue deposits imping-
ing on the exiting nerve roots as they run anteriorly between the
scalene muscles. Sequences should then be performed in the
coronal plane using a suitable coil to demonstrate the lower
neck, upper mediastinum, and both axillae to show the relation-
ship of the large vessels to the brachial plexus as it moves towards
 breast cancer

Anterior scalene seen following surgery or radiation. Both radiation fibrosis and
infiltrative tumor may enhance, and under these circumstances
Middle scalene follow-up imaging is recommended. However, a study from the
C3 Royal Marsden Hospital showed that MR imaging had a sensitiv-
4
ity of 93%, a specificity of 95%, a positive predictive value (PPV)
Upper trunk C4 of 93%, and a negative predictive value (NPV) of 95% in the
5
Middle trunk detection of recurrent tumor involving the brachial plexus in a
Lower trunk C5
6 series of 50 patients (167). Recurrent tumor should not be diag-
7 C6 nosed in the absence of clear morphological demonstration of a
mass lesion which has appropriate signal intensity characteristics
Clavicle 8 C7 for a malignant tumor. Presentation with brachial plexopathy is
common following treatment of breast cancer, and clinical col-
T1 leagues may have difficulty in examining the area, as is evidenced
by the finding of some remarkably large recurrent masses that
Humerus are impalpable due to induration and fibrosis of subcutaneous
Clavicle tissues (Fig. 26.26).

Manubrium
ROLE OF IMAGING IN BREAST CANCER
Radial Subclavian artery Breast cancer remains a common and important challenge for the
Median Subclavian vein radiologist. Its high incidence means that diagnosis and staging of
Ulnar the primary tumor cannot remain the domain of the specialist,
Lateral cord
and many general radiologists are called upon to investigate
Posterior cord possible local or distant recurrence. Strategies of surgical and
Medial cord radiation therapy are subject to almost constant reappraisal, and
Figure 26.28 Diagram of brachial plexus. Roots from C5 to T1 pass between ante- the radiological literature bulges with information on the relative
rior and middle scalene muscles, and near the lateral margin of the muscles form merits of new diagnostic imaging techniques. The next few years
upper, middle and lower trunks that travel posterior and superior to the subclavian will almost certainly see an increase in the use of MR imaging and
vessels, towards the supraclavicular fossa. The trunks separate into three anterior
PET-CT in diagnosis and follow-up, but it remains to be seen to
and three posterior divisions, which recombine at the lateral border of the first rib
to form medial, lateral, and posterior cords, named according to their relationship what extent the newer techniques will replace those currently
with the artery. The terminal branches form at the lateral border of the pectoralis established in radiological practice.
minor.

Key Points: Investigation of Locoregional Recurrence

the axilla. The whole plexus is rarely imaged on a single slice, but
4 to 5 mm slices through the entire structure bilaterally are
extremely helpful in localizing suspicious areas. A flexible local
coil may be used for detailed imaging of the trunks, divisions,
and cords of the brachial plexus (Fig. 26.27). Ideally, axial, coronal,
and sagittal planes are obtained. Sequences may include
T1-weighted imaging before and after gadolinium enhancement.
Subtraction and fat suppression techniques such as STIR may
also be useful, but protocols will be influenced by availability of
sequences as well as imaging time, and contrast enhancement is
not mandatory. In patients with breast cancer, brachial plexopathy
is most likely to be due to:
• Lymphadenopathy
• Infiltrative tumor
• Radiation fibrosis
Lymphadenopathy as the cause of brachial plexopathy is demon-
strable as a mass lesion. Involved nodes are isointense with mus-
cle on T1-weighted sequences, hyperintense on T2-weighted
images, and enhance following gadolinium-DTPA. Infiltrative
tumor may be more difficult to detect and may be confused with
thickening of nerves, which is a non-specific finding that may be
■ Recurrence rates have been reduced by giving radiotherapy
after wide local excision or quadrantectomy
■ Typical malignant-type microcalcification occurs in almost
50% of mammographically detected recurrences
■ Doppler ultrasound may distinguish highly vascular recurrent
tumor lesions, discriminating recurrence from scar tissue that
is relatively avascular
■ Gadolinium-enhanced MR imaging is highly sensitive for
detecting recurrence but has a relatively low specificity
■ MR imaging has a high sensitivity and specificity in the
detection of recurrent tumor involving the brachial plexus
Summary
■ Breast cancer is the commonest female malignancy in the
Western world
■ Genetic factors have a strong causal relationship in breast
cancer, and specific oncogenes have been identified
■ Epidemiological studies confirm that environmental
factors also have a strong influence on development of
breast cancer

551
 primary tumor evaluation and staging
■ Breast cancer pathology is broadly split into ductal and lobular
types
■ Mammography is the mainstay of breast cancer diagnosis
■ Ultrasound, MR imaging, and a variety of new techniques
contribute to diagnosis in both screening and symptomatic
clinical settings
■ Treatment of early breast cancer has moved towards a multi-
disciplinary approach using chemotherapy, radiotherapy,
and surgery, and surgical procedures have been refined to
allow a less radical approach
■ Establishing the extent of primary tumor relies on a combi-
nation of mammography, ultrasound, and MR imaging
■ Evaluation of response to chemotherapy utilizes ultrasound
and mammography, but MR imaging and PET are developing
a role
■ There is no imaging method which reliably excludes residual
tumor following local treatment with chemotherapy
■ Metastasis from breast cancer may go to any organ
■ There is some evidence that successful treatment of local and
metastatic breast cancer is altering the natural history of the
disease
■ There is evidence that attempts to demonstrate metastatic
disease at an asymptomatic stage will not prolong survival
■ Metastatic disease at the time of presentation of early breast
cancer is very unusual
■ Surveillance protocols for detection of locoregional recurrence
of breast cancer vary, but mammography is the mainstay in
detection of local recurrence
■ MR imaging is a useful adjunct in the detection of local
recurrence
REFERENCES
1. Cancer Research UK. UK Cancer incidence statistics
for females, February 2008. [Available from: http://info.
cancerresearchuk.org].
2. Cancer Facts & Figures 2008. American Cancer Society Inc.,
2008.
3. Boyd NF. The epidemiology of breast cancer. In: Souhami
RL, Tannock I, Hohenberger P, Horiot J-C, eds. Oxford Text-
book of Oncology, 2nd edn. Oxford: Oxford University Press,
2002;1683–96.
4. Smigal C, Jemal A, Ward E, et al. Trends in breast cancer by
race and ethnicity: update 2006. CA Cancer J Clin 2006; 56:
168–83.
5. Glass AG, Lacey JV Jr, Carreon JD, Hoover RN. Breast cancer
incidence, 1980–2006: combined roles of menopausal hormone
therapy, screening mammography, and estrogen receptor
status. J Natl Cancer Inst 2007; 99: 1152–61.
6. Jemal A, Ward E, Thun MJ. Recent trends in breast cancer
incidence rates by age and tumour characteristics among
U.S. women. Breast Cancer Res 2007; 9: R28.
7. Wassink WF. Cancer et Hérédité. Genitika 1935; 17: 103–44.
8. Smithers DW. Family histories of 459 patients with cancer of
the breast. Br J Cancer 1948; 2: 163–7.
552
9. Hall JM, Lee MK, Newman B, et al. Linkage of early-onset
familial breast cancer to chromosome 17q21. Science 1990;
250: 1684–9.
10. Eeles R. Testing for the breast cancer predisposition gene,
BRCA1. Br Med J 1996; 313: 572–3.
11. Wooster R, Neuhausen SL, Mangion J, et al. Localization of a
breast cancer susceptibility gene, BRCA2, to chromosome
13q12-13. Science 1994; 265: 2089–90.
12. Stratton MR, Rahman N. The emerging landscape of breast
cancer susceptibility. Nat Genet 2008; 40: 17–22.
13. Begg CB, Haile RW, Borg A, et al. Variation of breast cancer
risk among BRCA1/2 carriers. JAMA 2008; 299: 194–201.
14. Collaborative Group on Hormonal Factors in Breast Cancer.
Breast cancer and hormonal contraceptives: collaborative
analysis of individual data on 53,297 women with breast can-
cer and 100,239 without breast cancer from 54 epidemio-
logical studies. Lancet 1996; 347: 1713–27.
15. De Assis S, Hilakivi-Clarke L. Timing of dietary estrogenic
exposures and breast cancer risk. Ann N Y Acad Sci 2006;
1089: 14–35.
16. John EM, Schwartz GG, Koo J, Wang W, Ingles SA. Sun expo-
sure, vitamin D receptor gene polymorphisms, and breast
cancer risk in a multiethnic population. Am J Epidemiol
2007; 166: 1409–19.
17. Yorkshire Cancer Organisation. Cancer in Yorkshire. Cancer
Registry Reports, Series 3. Breast Cancer, YCO 1995.
18. Tokunaga M. Breast cancer among atomic bomb survivors. In:
Boice JD Jr, Fraumeni JF Jr, eds. Radiation Carcinogenesis—
Epidemiology and Biological Significance. New York: Raven
Press, 1984: 45–6.
19. Miller AB, Howe GR, Sherman GJ, et al. Mortality from breast
cancer after irradiation during fluoroscopic examinations in
patients being treated for tuberculosis. N Engl J Med 1989;
321: 1285–9.
20. Schwartz GF, Patchefsky AS, Feig SA, Shaber GS, Schwartz
AB. Multicentricity of non-palpable breast cancer. Cancer
1980; 45: 2913–16.
21. Wellings SR, Jensen HM. On the origin and progression of
ductal carcinoma in the human breast. J Natl Cancer Inst
1973; 50: 1111–18.
22. Schapiro S, Venet W, Strax P, Venet L, Roeser R. Ten to four-
teen year effect of screening on breast cancer mortality. J Natl
Cancer Inst 1982; 69: 349–55.
23. Nystrom L, Rutqvist LE, Wall S, et al. Breast cancer screening
with mammography: overview of Swedish randomised trials.
Lancet 1993; 341: 973–8.
24. Roberts MM, Alexander FE, Anderson TJ, et al. Edinburgh
trial of screening for breast cancer: mortality at seven years.
Lancet 1990; 335: 241–6.
25. Miller AB, Baines CJ, To T, Wall C. Canadian National Breast
Screening Study: 1. Breast cancer detection and death rates
among women aged 40–49 years. Can Med Assoc J 1992; 147:
1459–76.
26. Miller AB, Baines CJ, To T, Wall C. Canadian National Breast
Screening Study: 2. Breast cancer detection and death rates
among women aged 50–59 years. Can Med Assoc J 1992; 147:
1477–88.
 breast cancer
27. Otto SJ, Fracheboud J, Looman CW, et al. Initiation of popu-
lation-based mammography screening in Dutch municipali-
ties and effect on breast-cancer mortality: a systematic review.
Lancet 2003; 361: 1411–17.
28. Kerlikowske K, Grady D, Rubin SM, Sandrock C, Ernster VL.
Efficacy of the screening mammography. A meta-analysis.
JAMA 1995; 273: 149–54.
29. Nystrom L, Anderson L, Bjurstam N, et al. Long-term effects
of mammography screening: updated overview of the Swedish
randomised trials. Lancet 2002; 359: 909–19.
30. Gotzsche PC, Olsen O. Is screening for breast cancer with
mammography justifiable? Lancet 2000; 355: 129–34.
31. Olsen O, Gotzsche PC. Cochrane review on screening
for breast cancer with mammography. Lancet 2001; 358:
1340–2.
32. Tabar L, Yen MF, Vitak B, et al. Mammography service screen-
ing and mortality in breast cancer patients: 20-year follow-
up before and after introduction of screening. Lancet 2003;
361: 1405–10.
33. Moskowitz M. Breast cancer: age specific growth rates and
screening strategies. Radiology 1986; 161: 37–41.
34. Evans WP 3rd, Starr AL, Bennos ES. Comparison of the
relative incidence of impalpable invasive breast carcinoma
and ductal carcinoma in situ in cancers detected in patients
older and younger than 50 years of age. Radiology 1997;
204: 489–91.
35. Nattinger AB. Older women, mammography and mortality
from breast cancer. Am J Med 2000; 108: 174–5.
36. Chart PL, Franssen E. Management of women at increased
risk for breast cancer: preliminary results from a new
programme. Can Med Assoc J 1997; 157: 1235–42.
37. Lalloo F, Boggis CR, Evans DG, et al. Screening by mammo-
graphy in women with a family history of breast cancer.
Eur J Cancer 1998; 34: 937–40.
38. Burke W, Daly M, Garber J, et al. Recommendations for
follow-up care of individuals with an inherited predis-
position to cancer. II. BRCA1 and BRCA2. Cancer Genetics
Studies Consortium. JAMA 1997; 277: 997–1003.
39. Gilson E. Benefits and risk of screening mammography in
women with BRCA1 and BRCA2 mutations. (Letter) JAMA
1997; 278: 289–90.
40. Gilbert FJ, Cordiner CM, Affleck IR, et al. Breast screening:
the psychological sequelae of false positive recall in women
with and without a family history of breast cancer. Eur J
Cancer 1998; 34: 2010–14.
41. Elmore JG, Barton MB, Moceri VM, et al. Ten year risk of
false positive screening mammograms and clinical breast
examinations. N Engl J Med 1998; 338: 1089–96.
42. Leach MO, Boggis CR, Dixon AK, et al. Screening with magnetic
resonance imaging and mammography of a UK population at
high familial risk of breast cancer: a prospective multicentre
cohort study (MARIBS). Lancet 2005; 365: 1769–78.
43. Griebsch I, Brown J, Boggis C, et al. Cost-effectiveness of
screening with contrast enhanced magnetic resonance imag-
ing vs X-ray mammography of women at a high familial risk
of breast cancer. Br J Cancer. 2006; 95: 801–10.
44. NICE guideline. [Available from: www.nice.org.uk/cg041].
45. Feig SA. Breast masses. Mammographic and sonographic
evaluation. Radiol Clin North Am 1992; 30: 67–92.
46. Bassett LW. Mammographic analysis of calcifications. Radiol
Clin North Am 1992; 30: 93–105.
47. Lewin JM, Hendrick RE, D’Orsi CJ, et al. Comparison of full-
field digital mammography with screen-film mammography
for cancer detection: results of 4,945 paired examinations.
Radiology 2001; 218: 873–80.
48. Lewin JM, D’Orsi CJ, Hendrick RE, et al. Clinical compari-
son of full-field digital mammography and screen-film
mammography for detection of breast cancer. AJR Am J
Roentgenol 2002; 179: 671–7.
49. Venta LA, Hendrick RE, Adler YT, et al. Rates and causes of
disagreement in interpretation of full-field digital mammog-
raphy and film-screen mammography in a diagnostic setting.
AJR Am J Roentgenol 2001; 176: 1241–8.
50. Warren Burhenne LJ, Wood SA, D’Orsi CJ, et al. Potential
contribution of computer-aided detection to the sensitiv-
ity of screening mammography. Radiology 2000; 215:
554–62.
51. Ikeda DM, Birdwell RL, O’Shaughnessy KF, et al. Computer-
aided detection output on 172 subtle findings on normal
mammograms previously obtained in women with breast
cancer detected at follow-up screening mammography.
Radiology 2004; 230: 811–19.
52. Freer TW, Ulissey MJ. Screening mammography with com-
puter-aided detection: prospective study of 12,860 patients
in a community breast center. Radiology 2000; 220: 781–6.
53. Alberdi E, Povyakalo AA, Strigini L, et al. Use of computer-
aided detection (CAD) tools in screening mammography:
a multidisciplinary investigation. Br J Radiol 2005; 78:
S31–40.
54. Helvie M. Improving mammographic interpretation: double
reading and computer-aided diagnosis. Radiol Clin North
Am 2007; 45: 801–11.
55. Jong RA, Yaffe MJ, Skarpathiotakis M, et al. Contrast-
enhanced digital mammography: initial clinical experience.
Radiology 2003; 228: 842–50.
56. Rafferty EA, Kopans DB, Georgian-Smith D, et al. Compari-
son of full-field digital tomosynthesis and conventional two
view film screen mammography in lesion detection and
assessment of lesion conspicuity. Abstract in: abstracts of
103rd Meeting of American Roentgen Ray Society, San Diego,
California, 2003.
57. Avril N, Rose CA, Schelling M, et al. Breast imaging with
positron emission tomography and fluorine-18-fluorode-
oxyglucose: use and limitations. J Clin Oncol 2000; 18:
3495–502.
58. Gopalan D, Bomanji JB, Costa DC, Ell PJ. Nuclear medicine
in primary breast cancer imaging. Clin Radiol 2002; 57:
565–74.
59. Boetes C, Strijk SP, Holland R, et al. False-negative MR
imaging of malignant breast tumours. Eur Radiol 1997; 7:
1231–4.
60. Soderstrom CE, Harms SE, Copit DS, et al. Three-dimensional
RODEO breast MR imaging of lesions containing ductal
carcinoma in situ. Radiology 1996; 201: 427–32.
553
 primary tumor evaluation and staging
61. Orel SG, Mendonca MH, Reynolds C, et al. MR imaging of
ductal carcinoma in situ. Radiology 1997; 202: 413–20.
62. Gilles R, Zafrani B, Guinebretière JM, et al. Ductal carcinoma
in situ. MR imaging-histopathologic correlation. Radiology
1995; 196: 415–19.
63. Ikeda DM, Baker DR, Daniel BL. Magnetic resonance
imaging of breast cancer: clinical indications and breast
MRI reporting system. J Magn Reson Imaging 2000; 12:
975–83.
64. Morris EA. Diagnostic breast MR imaging: current status
and future directions. Radiol Clin North Am 2007; 45:
863–80.
65. Greene FL, Page DL, Fleming ID, et al. AJCC Cancer Staging
Handbook. TNM Classification of Malignant Tumours, 6th
edn. New York: Springer-Verlag, 2002.
66. Greening WP, Montgomery AC, Gordon AB, Gowing NF.
Quadrantic excision and axillary node dissection without
radiotherapy: the long-term results of a selective policy in
the treatment of Stage I breast cancer. Eur J Surg Oncol 1988;
14: 221–5.
67. Fisher B, Redmond C, Poisson R, et al. Eight-year results of a
randomised clinical trial comparing total mastectomy and
lumpectomy with or without irradiation in the treatment of
breast cancer. N Engl J Med 1989; 320: 822–8.
68. Uppsala-Örebro Breast Cancer Study Group. Sector resec-
tion with or without post-operative radiotherapy for Stage I
breast cancer. A randomised trial. J Natl Cancer Inst 1990; 82:
277–82.
69. Veronesi U, Banfi A, Salvadori B, et al. Breast conservation
is the treatment of choice in small breast cancer: long-term
results of a randomised trial. Eur J Cancer 1990; 26:
668–70.
70. Veronesi U, Volterrani F, Luini A, et al. Quadrantectomy ver-
sus lumpectomy for small size breast cancer. Eur J Cancer
1990; 26: 671–3.
71. Fornage BD, Toubas O, Morel M. Clinical, mammographic,
and sonographic determination of preoperative breast can-
cer size. Cancer 1987; 60: 765–71.
72. Pain JA, Ebbs SR, Hern RP, Lowe S, Bradbeer JW. Assessment
of breast cancer size: a comparison of methods. Eur J Surg
Oncol 1992; 18: 44–8.
73. Flanagan FL, McDermott MB, Barton PT, et al. Invasive
breast cancer: mammographic measurement. Radiology
1996; 199: 819–23.
74. Davis PL, McCarty KS Jr. Technologic considerations for
breast tumour size assessment. Magn Reson Imaging Clin N
Am 1994; 2: 623–31.
75. Holland R, Veling SH, Mravunac M, Hendriks JH. Histologic
multifocality of Tis, T1-2 breast carcinomas. Implications for
clinical trials of breast conserving surgery. Cancer 1985; 56:
979–90.
76. Holland R, Connolly JL, Gelman R, et al. The presence of an
extensive intraductal component following a limited exci-
sion correlates with prominent residual disease in the remain-
der of the breast. J Clin Oncol 1990; 8: 113–18.
77. Harms SE, Flamig DP, Hesley KL, et al. MR imaging of the
breast with rotating delivery of excitation off resonance:
554
clinical experience with pathologic correlation. Radiology
1993; 187: 493–501.
78. Orel SG, Schnall MD, Powell CM, et al. Staging of suspected
breast cancer: effect of MR imaging and MR-guided biopsy.
Radiology 1995; 196: 115–22.
79. Fischer U, Kopka L, Grabbe E. Breast carcinoma: effect of
preoperative contrast-enhanced MR imaging on the thera-
peutic approach. Radiology 1999; 213: 881–8.
80. Esserman L, Hylton NM, Yassa L, et al. Utility of magnetic
resonance imaging in the management of breast cancer: evi-
dence for improved preoperative staging. J Clin Oncol 1999;
17: 110–19.
81. Stelling CB. Breast cancer staging with contrast material-
enhanced MR imaging: should it change patient treatment?
Radiology 1995; 196: 16–18.
82. Morris EA, Schwartz LH, Drotman MB, et al. Evaluation of
pectoralis major muscle in patients with posterior breast
tumours on breast MR images: early experience. Radiology
2000; 214: 67–72.
83. Bedrosian I, Mick R, Orel SG, et al. Changes in the surgical
management of patients with breast carcinoma based on
preoperative magnetic resonance imaging. Cancer 2003; 98:
468–73.
84. Bluemke DA, Gatsonis CA, Chen MH, et al. Magnetic reso-
nance imaging of the breast prior to biopsy. JAMA 2004; 292:
2735–42.
85. Morrow M. Magnetic resonance imaging in breast cancer:
one step forward, two steps back? JAMA 2004; 292:
2779–80.
86. Bilimoria KY, Cambic A, Hansen NM, Kethke KP. Evaluating
the impact of preoperative breast magnetic resonance imag-
ing on the surgical management of newly diagnosed breast
cancers. Arch Surg 2007; 142: 441–5.
87. Fourouhi P, Walsh JS, Anderson TJ, Chetty U. Ultrasonogra-
phy as a method of measuring breast tumour size and moni-
toring response to primary systemic treatment. Br J Surg
1994; 81: 223–5.
88. Early Breast Cancer Trialists Collaborative Group: Systemic
treatment of early breast cancer by hormonal, cytotoxic or
immune therapy: 133 randomised trials involving 31,000
recurrences and 24,000 deaths among 75,000 women. Lancet
1992; 339: 1–15, 71–85.
89. Powles TJ, Hickish TF, Makris A, et al. Randomised trial of
chemoendocrine therapy started before or after surgery for
treatment of primary breast cancer. J Clin Oncol 1995; 13:
547–52.
90. Vinnicombe SJ, MacVicar AD, Guy RL, et al. Primary breast
cancer: mammographic changes after neoadjuvant chemo-
therapy with pathologic correlation. Radiology 1996; 198:
333–40.
91. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting
results of cancer treatment. Cancer 1981; 47: 207–14.
92. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines
to evaluate the response to treatment in solid tumours. J Natl
Cancer Inst 2000; 92: 205–16.
93. Gawne-Cain ML, Smith E, Darby M, Given-Wilson R.
The use of ultrasound for monitoring breast tumour
 breast cancer
response to pro-adjuvant therapy. Clin Radiol 1995; 50:
681–6.
94. Abraham DC, Jones RC, Jones SE, et al. Evaluation of neoad-
juvant chemotherapeutic response of locally advanced breast
cancer by magnetic resonance imaging. Cancer 1996; 78:
91–100.
95. Padhani AR, Hayes C, Assersohn L, et al. Prediction of clini-
copathologic response of breast cancer to primary chemo-
therapy at contrast-enhanced MR imaging: initial clinical
results. Radiology 2006; 239: 361–74.
96. Smith IC, Welch AE, Hutcheon AW, et al. Positron emission
tomography using [(18)F]fluorodeoxy-D-glucose to predict
the pathologic response of breast cancer to primary chemo-
therapy. J Clin Oncol 2000; 18: 1676–88.
97. Schelling M, Avril N, Nahrig J, et al. Positron emission tomog-
raphy using [(18)F]Fluorodeoxyglucose for monitoring pri-
mary chemotherapy in breast cancer. J Clin Oncol 2000; 18:
1689–95.
98. Burcombe RJ, Makris A, Pittam M, et al. Evaluation of good
clinical response to neoadjuvant chemotherapy in primary
breast cancer using [18F]-fluorodeoxyglucose positron emission
tomography. Eur J Cancer 2002; 38: 375–9.
99. Carter CL, Allen C, Henson DE. Relation of tumour size,
lymph node status and survival in 24,740 breast cancer cases.
Cancer 1989; 63: 181–7.
100. Guller U, Nitzsche EU, Schirp U. Selective axillary surgery in
breast cancer patients based on positron emission tomogra-
phy with 18F-fluoro-2-deoxy-D-glucose: not yet! Breast
Cancer Res Treat 2002; 71: 171–3.
101. Rahmouni A, Luciani A, Dao DH. Imaging axillary lymph
nodes: role of MR imaging. Cancer Imaging 2002; 3: 7–9.
102. Nemoto T, Vana J, Bedwani RN, et al. Management and
survival of female breast cancer: results of a survey by the
American College of Surgeons. Cancer 1980; 45: 2917–24.
103. Veronesi U, Rilke F, Luini A. Distribution of axillary node
metastases by level of invasion. An analysis of 539 cases.
Cancer 1987; 59: 682–7.
104. Handley RS. Carcinoma of the breast. Ann R Coll Surg Engl
1975; 57: 59–66.
105. Veronesi U, Cascinelli N, Greco M. Prognosis of breast cancer
patients after mastectomy and dissection of internal mam-
mary nodes. Ann Surg 1985; 202: 702–7.
106. Eubank WB, Mankoff DA, Takasugi J, et al. 18-fluorode-
oxyglucose positron emission tomography to detect medi-
astinal or internal mammary metastases in breast cancer.
J Clin Oncol 2001; 19: 3516–23.
107. Warmuth MA, Bowen G, Prosnitz LR, et al. Complications
of axillary lymph node dissection for carcinoma of the
breast: a report based on a patient survey. Cancer 1988; 83:
1362–8.
108. Jakub JW, Cox CE, Pippas AW, et al. Controversial topics in
breast lymphatic mapping. Semin Oncol 2004; 31: 324–32.
109. Turner RR, Ollila DW, Krasne DL, Giuliano AE. Histopatho-
logic validation of sentinel lymph node hypothesis for breast
carcinoma. Ann Surg 1997; 226: 271–8.
110. Styblo T, Aarsvold JN, Grant SF, et al. Sentinel lymph nodes;
optimising success. Semin Roentgenol 2001; 36: 261–9.
111. Edreira MM, Colombo LL, Perez JH, Sajaroff EO, de Castiglia
SG. In vivo evaluation of three different 99mTc-labelled
radiopharmaceuticals for sentinel lymph node identification.
Nucl Med Commun 2001; 22: 499–504.
112. Motomura K, Noguchi A, Hashizume T, et al. Usefulness of
a solid-state gamma camera for sentinel node identification
in patients with breast cancer. J Surg Oncol 2005; 89:
12–17.
113. Wong SL, Edwards MJ, Chao C, et al. Sentinel lymph node
biopsy for breast cancer: impact of the number of sentinel
nodes removed on the false negative rate. J Am Coll Surg
2001; 192: 684–9.
114. Park C, Seid P, Morita E, et al. Internal mammary sentinel
lymph node mapping for invasive breast cancer: implications
for staging and treatment. Breast J 2005; 11: 29–33.
115. Lin KM, Patel TH, Ray A, et al. Intradermal radioisotope is
superior to peritumoral blue dye or radioisotope in identify-
ing breast cancer sentinel nodes. J Am Coll Surg 2004; 199:
561–6.
116. Babiera GV, Delpassand ES, Breslin TM, et al. Lymphatic
drainage patterns on early versus delayed breast lymphoscin-
tigraphy performed after injection of filtered Tc-99m sulfur
colloid in breast cancer patients undergoing sentinel lymph
node biopsy. Clin Nucl Med 2005; 30: 11–15.
117. Collins CD. The sentinel node in breast cancer: an update.
Cancer Imaging 2005; 5: S3–S9.
118. Hermanek P, Hutter RV, Sobin LH, Wittekind C. International
Union Against Cancer. Classification of isolated tumor cells
and micrometastasis. Cancer 1999; 86: 2668–73.
119. Gerber B, Krause A, Reimer T. Immunohistochemically
detected lymph node micrometastases in breast cancer and
their correlation with prognostic factors. Breast J 1997; 3:
106–11.
120. Sakorafas GH, Geraghty J, Pavlakis G. The clinical signifi-
cance of axillary lymph node micrometastases in breast cancer.
Eur J Surg Oncol 2004; 30: 807–16.
121. Veronesi U, Paganelli G, Galimberti V, et al. Sentinel-node
biopsy to avoid axillary dissection in breast cancer with clinical
negative lymph-nodes. Lancet 1997; 349: 1864–7.
122. Albertini JI, Lyman GH, Cox C, et al. Lymphatic mapping
and sentinel node biopsy in the patient with breast cancer.
JAMA 1996; 276: 1818–22.
123. Querci della Rovere G, Bird PA. Sentinel lymph node biopsy
in breast cancer. Lancet 1998; 352: 421–2.
124. Chaudary MA, Millis RR, Hoskins EO. Bilateral primary
breast cancer: a prospective study of disease incidence. Br J
Surg 1984; 71: 711–14.
125. Schneider C, Fehr MK, Steiner RA, et al. Frequency and
distribution pattern of distant metastases in breast cancer
patients at the time of primary presentation. Arch Gynaecol
Obstet 2003; 269: 9–12.
126. Khansur T, Haick A, Patel B, et al. Evaluation of bone scan as
a screening work up in primary and loco-regional recurrence
of breast cancer. Am J Clin Oncol 1987; 10: 167–70.
127. Yeh KA, Fortunato L, Ridge JA, et al. Routine bone scanning
in patients with T1 and T2 breast cancer: a waste of money.
Ann Surg Oncol 1995; 2: 319–24.
555
 primary tumor evaluation and staging
128. Roselli del Turco M, Palli D, Cariddi A, et al. Intensive
diagnostic follow-up after treatment of primary breast
cancer. A randomized trial. National Research Council
Project on Breast Cancer follow-up. JAMA 1994; 271:
1593–7.
129. Palli D, Russo A, Saieva C, et al. Intensive vs clinical follow-up
after treatment of primary breast cancer: 10-year update of a
randomized trial. National Research Council Project on
Breast Cancer Follow-up. JAMA 1999; 281: 1586.
130. GIVIO Investigators. Impact of follow-up testing on survival
and health-related quality of life in breast cancer patients. A
multicenter randomized controlled trial. JAMA 1994: 271:
1587–92.
131. Imaging for Oncologists. Collaboration between clinical
radiologists and clinical oncologists in diagnosis, staging and
radiotherapy planning. Board of the Faculty of Clinical
Oncology, Royal College of Radiologists, London, 2004; RCR
Ref: BFCO(04)2. [Available from: www.rcr.ac.uk].
132. Evans AJ, Wilson R, Britton P, et al. Staging imaging in
women with primary operable breast cancer. Clin Rad
2005; 60: 520.
133. Hunter R. Re: Staging imaging in women with primary
operable breast cancer—response. Clin Rad 2005; 60:
520–1.
134. Lee YT. Breast carcinoma: pattern of metastasis at autopsy.
J Surg Oncol 1983; 23: 175–80.
135. Viadana E, Cotter R, Pickren JW, Bross ID. An autopsy study
of metastatic sites of breast cancer. Cancer Res 1973; 33:
179–81.
136. Amer MH. Chemotherapy and pattern of metastases in
breast cancer patients. J Surg Oncol 1982; 19: 101–5.
137. Moskovic E, Parsons C, Baum M. Chest radiography in the
management of breast cancer. Br J Radiol 1992; 65: 30–2.
138. O’Mara RE. Skeletal scanning in neoplastic disease. Cancer
1976; 37: 480–6.
139. Jones AL, Williams MP, Powles TJ, et al. Magnetic resonance
imaging in the detection of skeletal metastases in patients
with breast cancer. Br J Cancer 1990; 62: 296–8.
140. Altehoefer C, Ghanem N, Hogerle S, Moser E, Langer M.
Comparative detectability of bone metastases and impact on
therapy of magnetic resonance imaging and bone scintigra-
phy in patients with breast cancer. Eur J Radiol 2001; 40:
16–23.
141. Walker R, Kessar P, Blanchard R, et al. Turbo STIR magnetic
resonance imaging as a whole-body screening tool for metas-
tases in patients with breast carcinoma: preliminary clinical
experience. J Magn Reson Imaging 2000; 11: 343–50.
142. Borja ER, Hori JM, Pugh RP. Metastatic carcinomatosis of
the liver mimicking cirrhosis: case report and review of the
literature. Cancer 1975; 35: 445–9.
143. Young ST, Paulson EK, Washington K, et al. CT of the liver in
patients with metastatic breast carcinoma treated by chemo-
therapy: findings simulating cirrhosis. AJR Am J Roentgenol
1994; 163: 1385–8.
144. Brookes M, MacVicar D, Husband J. Metastatic carcinoma of
the breast: the appearance of metastatic spread to the abdo-
men and pelvis as demonstrated by CT. Br J Radiol 2007; 80:
284–92.
556
145. Lamovec J, Bracko M. Metastatic pattern of infiltrating lobu-
lar carcinoma of the breast: an autopsy study. J Surg Oncol
1991; 48: 28–33.
146. Borst MJ, Ingold JA. Metastatic patterns of invasive lobular
versus invasive ductal carcinoma of the breast. Surgery 1993;
144: 637–41.
147. Dahlbom M, Hoffman EJ, Hoh CK, et al. Whole-body posi-
tron emission tomography: part I. Methods and performance
characteristics. J Nucl Med 1992; 33: 1191–9.
148. Crowe JP, Adler LP, Shenk R, Sunshine J. Positron emission
tomography and breast masses: comparison with clinical,
mammographic, and pathological findings. Ann Surg Oncol
1994; 1: 132–40.
149. Adler LP, Crowe JP, al-Kaisi NK, Sunshine JL. Evaluation of
breast masses and axillary lymph nodes with [F-18]
2-deoxy-2-fluoro-D-glucose PET. Radiology 1993; 187:
743–50.
150. Nieweg OE, Kim EE, Wong WH, et al. Positron emission
tomography with fluorine-18-deoxyglucose in the detec-
tion and staging of breast cancer. Cancer 1993; 71:
3920–5.
151. Rostom AY, Powe J, Kandil A, et al. Positron emission tomog-
raphy in breast cancer: a clinico-pathological correlation of
results. Br J Radiol 1999; 72: 1064–8.
152. Guidance on screening and symptomatic breast imaging,
2nd edn. Board of the Faculty of Clinical Radiology, Royal
College of Radiologists, London, 2003; RCR Ref No BFCR(03)2.
[Available from: www.rcr.ac.uk].
153. Guidelines for the management of symptomatic breast dis-
ease. The Association of Breast Surgery @ BASO, Royal
College of Surgeons of England. Eur J Surg Oncol 2005; 31:
S1–21.
154. Kurtz JM, Amalric R, Brandone H, et al. Local recurrence
after breast conserving surgery and radiotherapy. Fre-
quency, time course and prognosis. Cancer 1989; 63:
1912–17.
155. Libshitz HI, Montague ED, Paulus DD. Calcifications and the
therapeutically irradiated breast. AJR Am J Roentgenol 1977;
128: 1021–5.
156. Stomper PC, Recht A, Berenberg AL, Jochelson MS,
Harris JR. Mammographic detection of recurrent cancer in
the irradiated breast. AJR Am J Roentgenol 1987; 148:
39–43.
157. Dershaw DD. Mammography in patients with breast
cancer treated by breast conservation (lumpectomy with
or without radiotherapy). AJR Am J Roentgenol 1995;
164: 309–16.
158. Whitehouse GH, Moore NR. MR imaging of the breast after
surgery for breast cancer. Magn Reson Imaging Clin N Am
1994; 2: 591–603.
159. Heywang-Koebrunner SH, Schlegel A, Beck R, et al.
Contrast-enhanced MRI of the breast after limited surgery
and radiation therapy. J Comput Assist Tomogr 1993; 17:
891–900.
160. Gilles R, Guinebretiere JM, Shapeero LG, et al. Assessment of
breast cancer recurrence with contrast-enhanced subtraction
MR imaging: preliminary results in 26 patients. Radiology
1993; 188: 473–8.
 breast cancer
161. Cooke J, Cooke D, Parsons C. The anatomy and pathology of
the brachial plexus as demonstrated on computed tomogra-
phy. Clin Radiol 1988; 39: 595–601.
162. Olliff JF, Cherryman GR. The role of computed tomography
in the investigation of recurrent axillary disease in patients
with carcinoma of the breast. Clin Radiol 1990; 41: 31–3.
163. Moore NR, Dixon AK, Wheeler TK, et al. Axillary fibrosis or
recurrent tumour. An MRI study in breast cancer. Clin Radiol
1990; 42: 42–6.
164. Iyer RB, Fenstermacher MJ, Libshitz HI. MR imaging of the
treated brachial plexus. AJR Am J Roentgenol 1996; 167:
225–9.
165. Ahmad A, Barrington S, Maisey M, Rubens RD. Use of
positron emission tomography in the evaluation of bra-
chial plexopathy in breast cancer patients. Br J Cancer
1999; 79: 478–82.
166. Hathaway PB, Mankoff DA, Maravilla KR. Value of combined
FDG-PET and MR imaging in the evaluation of suspected
recurrent locoregional breast cancer: preliminary experience.
Radiology 1999; 210: 807–14.
167. Qayyum A, MacVicar AD, Padhani AR, Revell P, Husband
JE. Symptomatic brachial plexopathy following treatment
for breast cancer: utility of MR imaging with surface coil
techniques. Radiology 2000; 214: 837–42.
557
 27 Paranasal Sinus Neoplasms
Sheila Rankin
INTRODUCTION
Malignant tumors of the paranasal sinuses and nasal cavity are rare.
They are often clinically silent or present with non-specific com-
plaints such as nasal obstruction (69.9%), nasal discharge (69.3%),
cheek pain (47.8%), and cheek swelling (79.1%) or present with
infection. Consequently, they are usually diagnosed late with advanced
disease that limits the surgical and chemo/radiotherapeutic options.
There is usually a six-month delay between the onset of symptoms
and diagnosis in both antral and ethmoid tumors. Pain indicates
advanced disease with possible perineural invasion, this being espe-
cially common with adenoid cystic carcinoma. Overall survival
remains poor, even with new surgical and radiotherapy techniques.
Antral tumors usually present with epiphora, orbital pain, propto-
sis, trigeminal- or sphenopalatine nerve-related deficits, or swelling
of the cheek. Ethmoid tumors usually present with nasal stuffiness
and headaches. Frontal sinus tumors may present with facial defor-
mity and symptoms of intracranial spread, whereas sphenoid tumors
extend into the nasopharynx, orbit, or intracranially.
INCIDENCE
Malignant sinonasal tumors represent 3% of all head and neck
tumors, and 0.2% to 0.8% of all malignant tumors (1). The inci-
dence in the United States is 0.75 per 100,000 individuals, but
these tumors occur more frequently in other regions of the world,
including Japan and South Africa. Lesions of the maxillary antrum
are twice as frequent as those of the nasal cavity. Cancers of the
ethmoid and sphenoid sinuses are the least frequently observed.
The disease occurs more frequently in males than females (2:1),
usually in their sixth decade of life.
PATHOLOGY
Sinonasal tumors can be classified as epithelial or mesenchymal in
origin. Epithelial tumors may arise from the ectodermally derived
lining of the nasal and sinus cavities (schneiderian mucosa) and
include squamous cell carcinomas and intestinal adenocarcinomas,
from salivary tissue giving rise to benign and malignant salivary
tumors, from neuroendocrine tissue (neuroendocrine carcinomas),
and from the olfactory mucosa (olfactory neuroblastoma). Mesen-
chymal malignancies arise from bone, cartilage, fibroblasts, smooth
muscle, and lymphoid tissue (Table 27.1). Cross-sectional imaging
is rarely diagnostic and immunohistochemistry is necessary to dif-
ferentiate between sinonasal undifferentiated carcinoma, sinonasal
neuroendocrine tumor, lymphoma, olfactory neuroblastoma, and
amelanotic melanoma.
Schneiderian Mucosa (Ectodermally-Derived)
Inverted Papilloma
Inverted papillomas are benign epithelial neoplasms character-
ized by invaginating growth into the underlying stroma. They
558
usually arise from the lateral wall of the nasal cavity and spread
into adjacent sinuses involving the maxillary sinus in 69%, the
ethmoid sinus in 50% to 90%, the sphenoid sinus in 10% to 20%,
and the frontal sinus in 10% to 15%. They are associated with
squamous cell carcinoma (SCC) in 1.5% to 15% of cases, more
commonly synchronously than metachronously (2). They are
treated by lateral rhinotomy and medial maxillectomy, although
now many are resected endoscopcally. Recurrence is common if
they are incompletely excised.
They are suspected on CT if a solitary polypoid lesion is seen
containing calcification and showing inhomogeneous enhance-
ment following intravenous contrast medium injection. The
point of attachment is identified by focal hyperostosis on the wall
of the sinus. On MR they have a septated, striated appearance of
the epithelium which is hypointense on T2-weighted imaging
and the underlying stroma which is hyperintense. The epithelium
does enhance but less than the adjacent stroma. On FDG-PET,
inverted papillomas have a high SUV (>3) and those associated
with malignancy have an even higher SUV (3).
Squamous Cell Carcinoma
More than 70% of sinonasal tumors are squamous cell carcino-
mas, arise from the mucosal surface of the paranasal sinuses and
nasal cavity, and spread along mucosal and deep planes, with 25%
to 58% arising in the maxillary antrum, 25% to 35% in the nasal
cavity, 10% in the ethmoids, and 1% in the sphenoid and frontal
sinuses (4). Secondary extension of tumor into the maxillary
antrum is common, occurring in 80% of cases. There is an
increased risk with inverted papillomas, which develop squamous
cell cancer either concurrently or subsequently in 3% to 24% of
patients. Metachronous or synchronous tumors occur in 15% of
patients, with 40% of these arising in the head and neck, and 60%
occurring below the clavicles.
Antral carcinomas are twice as common in men as in women
and 95% occur in individuals over the age of 40 years. At pre-
sentation 40% to 60% will have facial asymmetry, with tumor
bulging into the oral cavity or extension into the nasal cavity
(Fig. 27.1).
Frontal sinus carcinoma is rare, usually presenting as sinusitis.
Bone erosion is common and few patients survive more than two
years. Sphenoid cancer is also very rare with a very poor prognosis
and intracranial extension is common.
Adenocarcinoma
Approximately 10% of all sinonasal tumors are of glandular origin
and are either minor salivary glandular tumors (adenoid cystic,
mucoepidermoid, or acinic cell carcinomas), intestinal-type
adenocarcinoma, or sinonasal neuroendocrine tumors.
Most intestinal-type adenocarcinomas (75–90%) occur in men
55 to 60 years of age. Papillary tumors are low grade with a good
prognosis. Signet cell tumors are high grade and similar to colonic
 paranasal sinus neoplasms

Table 27.1 Sinonasal Tumors and gastric cancer. Many tumors are advanced at presentation
with cribriform plate erosion in 50% and dural invasion is not
Primary
Schneiderian mucosa:
uncommon. Rarely, adenocarcinoma or spindle cell carcinoma is
Papillomas–inverted associated with inverted papillomas.
Squamous cell carcinoma
Adenocarcinoma
Minor salivary gland tumors: Minor Salivary Gland Tumors
Adenoid cystic carcinoma Most of these tumors arise from the salivary tissue in the palate
Adenocarcinoma and extend into the sino-nasal cavity
Benign and malignant pleomorphic adenomas
Muco-epidermoid carcinoma
Acinic cell carcinoma Adenoid Cystic Carcinoma
Olfactory mucosa:
These represent 35% of the adenocarcinomas arising from sali-
Olfactory neuroblastoma (esthesioneuroblastoma)
Mesenchymal: vary tissue and occur in a younger age group (30–60 years). Three
Lymphoma different architectural patterns are seen: tubular, cribriform, and
Plasmacytoma solid. Tubular adenoid cystic carcinoma is considered to be well
Melanoma differentiated, whereas the solid type is poorly differentiated and
Osteosarcoma
carries a worse prognosis. Perineural invasion is common with
Chondrosarcoma
Rhabdomyosarcoma skip lesions occurring; consequently, negative surgical margins do
Hemangiopericytoma not indicate the prognosis. Fifty percent arise in the maxillary
Angiofibroma antrum (Fig. 27.2), 3% in the nasal cavity, and 7% in the ethmoid
Metastases sinus. Local recurrences are common in up to 75% of patients
Renal within five years. Approximately 50% of patients will have distant
Breast metastases to the lung and less commonly to bone. Staging of the
Lung
chest using CT is indicated.

(A) (B) (C)

(D) (E)
Figure 27.1 Squamous cell carcinoma of the maxillary antrum. (A) Axial contrast-enhanced CT scan. There is destruction of the medial and lateral wall of the antrum. (B)
Coronal CT scan shows tumor extending through the hard palate. (C) Sagittal reconstruction. Tumor extends through the posterior wall. (D) Axial CT. Tumor extending
into the pterygo-palatine fossa (arrow). (E) Axial PET/CT demonstrating an FDG-avid tumor. The anatomic detail is less than that demonstrated on the CT.

559
 primary tumor evaluation and staging

(A) (B) (C)

(D) (E) (F)

Figure 27.2 Adenoid cystic carcinoma of the antrum. (A) Axial contrast-enhanced CT. The tumor is seen to involve the posterior wall (arrow) but is quite difficult to separate
from secretions. (B) Axial T2-weighed MR. The tumor is clearly separated from the high signal secretions. (C) Axial CT shows the tumor extending into the pterygo-palatine
fossa with widening of the fossa (white arrow). (D, E) Axial T1-weighted MR pre- and post-contrast medium. Enhancing tumor is easily identified within the PPF and
extending into the sphenopalatine fossa (arrows). (F) Coronal CT (bone windows). Enlargement of the foramen rotundum (arrow) due to perineural spread of tumor.

Mucoepidermoid Carcinoma Mesenchymal Tumors

These carcinomas arise in the maxillary antrum and nasal cavity, are
of high or intermediate grade, and are similar to adenocarcinomas in
activity. They are treated by surgery with radiotherapy if the resection
margins are positive.
Olfactory Mucosa
Olfactory Neuroblastoma (Esthesioneuroblastoma)
This is a neural crest neoplasm that arises from the olfactory mucosa
in the superior nasal fossa, representing 2% of all malignant nasal
tumors. It has a bimodal distribution, occurring in the second and
sixth decades of life, and represents 16.8% and 22.8% of sinonasal
tumors in those age groups, respectively. Involvement of the cribri-
form plate and intracranial extension is common (Fig. 27.3). It is
graded into four groups based on histology (Hyams grading system)
with Grade 1 being the most differentiated. Immunohistochemistry
is required for the differentiation of high-grade tumors. They are
polypoid masses when small and dumbbell-shaped when large with
the upper portion extending into the anterior cranial fossa (Fig.
27.3). Bone remodeling causes enlargement of the nasal cavity and
destruction of the cribriform plate is common. On CT there is an
enhancing mass and on MR the tumor is hypointense on T1 with
areas of hyperintense hemorrhage and intermediate to hyperintense
on T2W. Nodal metastases occur in 20% of patients at presentation.
Melanoma
Melanocytes migrate from the neural crest to the mucosa of the
sinonasal cavity and 4% of melanomas arise within the sinonasal
complex, the majority within the nasal cavity, especially the ante-
rior septa, lateral nasal wall, and the inferior turbinates. Within the
sinuses the maxillary antrum is the site of origin in 80% of cases
and 10% to 30% are amelanotic. On CT they appear as lobulated
enhancing masses and on MR they are high signal on T1 if melan-
otic and intermediate signal if amelanotic. They are hypointense
on T2W and enhance avidly following contrast medium adminis-
tration, although this may be difficult to appreciate if high signal
pre-contrast. The treatment is by wide local excision with or with-
out radiotherapy, but the prognosis is poor with a mean survival of
two years. Nodal metastases are present at presentation in 40% of
affected individuals and 60% will develop local recurrence or
metastases in the first year.
Non Hodgkin’s Lymphoma (See Chap. 33 “Lymphoma”)
This represents less than 1% of all head and neck cancers. Eight
percent of head and neck NHL is extranodal with 44% of this occur-
ring in the sinonasal cavities. It is commonest in the nasal cavity,
followed by the maxillary antrum and then the ethmoid sinuses. On
CT it presents as a bulky soft tissue mass with remodeling, rather

560
 paranasal sinus neoplasms
(A) (B)
Figure 27.3 Olfactory neuroblastoma. (A) Axial T1-weighted image pre and (B) post gadolinium. Enhancing tumor in nasal cavity extending into the left maxillary antrum.
(C) Coronal STIR sequence—tumor immediately adjacent to the medial rectus muscle with obliteration of the fat (arrow), but no evidence of involvement at surgery.
than erosion of bone, and enhances homogeneously. On MR the
signal intensity is similar to muscle on T1W and is of homogeneous
intermediate signal on T2W but less than that of the mucosa. On
FDG-PET they demonstrate moderate uptake.
Patterns of Spread
This may be by direct extension into adjacent structures or by
perineural spread. Maxillary antral tumors that arise in the supe-
rior antrum spread into the orbit and ethmoids, and tumor-free
surgical margins are unlikely. Tumors in the posterior antrum
extend into the pterygoid plates and the pterygo-palatine fossa
(PPF), and then by perineural spread into the masticator space or
intracranially. Tumors arising medially and inferiorly extend into
the nasal cavity and alveolus respectively, can usually be removed
by en-bloc excision, and have a better prognosis.
Ethmoid tumors extend to involve the cribriform plate and, if
there is intracranial spread, craniofacial resection is required. If
they extend laterally into the lamina papyracea then spread is
into the orbit and orbital exenteration is required. Sphenoid
sinus tumors, because of their central position, are difficult to
resect completely and extend into the cavernous sinus, posterior
ethmoids, and nasopharynx.
EPIDEMIOLOGY
Occupational exposure is a recognized etiological factor with nickel
workers (5) having a 40 to 250 times greater incidence than the nor-
mal population for nasal and antral squamous cell carcinoma; a
latent period of up to 30 years is not unusual. In wood workers (6),
there is a 20-fold increase in the incidence of squamous cell carci-
noma and a 900-fold increase in the incidence of adenocarcinoma
compared to the normal population. Other occupations associated
with a high incidence of nasal cavity cancers include those in the
textile, boot, and shoe industries (7). Tumors resulting from expo-
sure tend to arise in the nasal cavity and ethmoids, whereas sporadic
(C)
tumors are commoner in the maxillary antrum. Occupational malig-
nancy is diagnosed late with a consequent poorer prognosis. Other
etiological agents include exposure to chromium, mustard gas,
radium, and isopropyl alcohol. Tobacco use is also associated with
squamous cell cancer but not adenocarcinoma (8). Although 15% to
20% of patients will have concomitant chronic sinusitis, no causative
effect has been proven between tumors and chronic inflammation.
Key Points: Pathology and Epidemiology
■ Eighty to ninety percent of tumors are squamous in origin;
the majority arise in the maxillary antrum
■ Antral carcinomas are twice as common in men as women,
and 95% occur in those over the age of 40 years
■ Ten percent of all sinonasal tumors are of glandular origin
■ Occupational exposure to nickel, textiles, furniture, boot,
and shoemakers are all important etiological factors
■ Spread of tumors is either directly into adjacent structures or by
perineural invasion; orbital invasion carries a poor prognosis
STAGING (TABLE 27.2, FIG. 27.4)
Staging is based on the size and location of the tumor (T stage),
nodal involvement (N stage), and the presence of distant metasta-
ses (M stage), using the TNM system developed by the American
Joint Committee on Cancer (9). However, in sinonasal tumors only
maxillary antral and ethmoid tumors are formally staged. Some
changes have been made in the most recent classification published
in 2002 (Table 27.2). The nasoethmoid complex is described as a
second site with two regions within it (nasal cavity and ethmoid
sinus). The nasal cavity is divided into four subsites: septum, floor,
lateral wall, and vestibule. The ethmoid sinus is divided into two
subsites: right and left. The T stage for ethmoid tumors has been
revised and for maxillary antral tumors T4 lesions have been
divided into T4a (resectable) and T4b (non-resectable).
561
 primary tumor evaluation and staging

Table 27.2 Staging of Maxillary Antral and Ethmoid Sinus Tumors (9)
Primary tumor (T)
Tx Primary tumor cannot be assessed
T0 No evidence of primary tumor
Tis Carcinoma in situ
Maxillary sinus
T1 Tumor limited to the antral mucosa, no bony erosion or destruction
T2 Tumor with bony erosion or destruction including extension into the hard palate and/or middle nasal meatus. Not involving posterior wall
of sinus or pterygoid plates
T3 Tumor invades any of the following: posterior maxillary wall, floor or medial wall of the orbit, pterygoid fossa, ethmoid sinuses, or
subcutaneous tissues
T4a Tumor invades anterior orbital contents, pterygoid plates, infratemporal fossa, cribriform plate, sphenoid or frontal sinuses, skin of cheek
T4b Tumor invades any of the following: orbital apex, dura, brain, middle cranial fossa, cranial nerves [except maxillary division of the
trigeminal nerve (V2)], nasopharynx, or clivus
Nasal cavity and ethmoid sinus
T1 Tumor restricted to one site, with or without bone invasion
T2 Tumor invading two subsites in a single region or involving an adjacent region within the nasoethmoidal complex, with or without bony
invasion
T3 Tumor extends to invade medial wall or floor of orbit, maxillary sinus, palate, or cribriform plate
T4a Tumor invades any of the following: anterior orbit, skin of nose or cheek, minimal extension into anterior cranial fossa, pterygoid plates,
sphenoid or frontal sinuses
T4b Tumor invades any of the following: orbital apex, dura, brain, middle cranial fossa, cranial nerves (except V2), nasopharynx, or clivus
Regional lymph nodes (N)
Nx Regional lymph nodes cannot be assessed
N0 No nodal metastasis
N1 Metastasis in a single ipsilateral lymph node, ≤3 cm in greatest dimension
N2 Metastasis in a single ipsilateral lymph node, >3 cm but <6 cm in greatest dimension, or in multiple ipsilateral lymph nodes, none >6 cm in
greatest dimension, or in bilateral or contralateral lymph nodes, none >6 cm in greatest dimension
N2a Metastasis in a single ipsilateral lymph node, >3 cm but <6 cm in greatest dimension
N2b Metastasis in multiple ipsilateral lymph nodes, none >6 cm in greatest dimension
N2c Metastasis in bilateral or contralateral lymph nodes, none >6 cm in greatest dimension
N3 Metastasis in a lymph node >6 cm in greatest dimension
Distant metastases (M)
MX Distant metastases cannot be assessed
M0 No distant metastasis
M1 Distant metastasis
Stage grouping
Stage 0 Tis N0 M0 T4a N1 M0
Stage I T1 N0 M0 T1 N2 M0
Stage II T2 N0 M0 T2 N2 M0
Stage III T3 N0 M0 T3 N2 M0
T1 N1 M0 T4a N2 M0
T2 N1 M0 Stage IVB T4b Any N M0
T3 N1 M0 Any T N3 M0
Stage IVA T4a N0 M0 Stage IVC Any T Any N M1

T Stage
The site of origin of maxillary antral tumors influences the prog-
nosis. Tumors limited to the anterior portion of the sinus have a
better prognosis and can be treated by partial or total maxillec-
tomy, whereas tumors involving the postero-superior portion
usually require a total maxillectomy and orbital exenteration. If
tumor extends beyond the bony margins, they are T3 or T4
tumors, and are treated with surgery and radiotherapy, or chemo/
radiotherapy. Sixty percent of patients will have T3 or T4 tumors
at presentation. In ethmoid sinus disease, if the tumor extends
into the nasal cavity it is classified as T2, and with intracranial
extension it is T4 disease.
the skin, alveolar buccal sulcus, or the pterygoid muscles, and are
associated with a poor prognosis. The nodes primarily involved are
the retropharyngeal nodes but these may be obliterated with child-
hood infections, and the next group of nodes to be involved are
levels I and II (upper internal jugular and submandibular) nodes.
Node-positive patients are treated aggressively. There is a debate
about the treatment of node-negative patients with some centers
advocating prophylactic radiotherapy whereas others only do so
only for advanced cases. The ultimate failure in N0 disease is 19%
and recurrence within the neck carries a poor prognosis, so prophy-
lactic treatment may be of value in T3 and T4 tumors, particularly
SCC and adenocarcinoma (10), but not in earlier stage disease (11).

N Stage M Stage
Nodal metastases in sinonasal tumors are uncommon, occurring Distant metastases are associated with nodal metastases and found
in 4% to 16% of patients at presentation, and indicate that there is in 34% of autopsies (12), but identified in only 10% of patients at
tumor spread outside the sinonasal cavity with tumor extension to presentation, except in adenoid cystic tumors where the incidence

562
 paranasal sinus neoplasms

T1 T2

Coronal view Coronal view

T3 T3

Sagittal view Coronal view

T4a T4a
Ethmoid
sinus
Orbit

Sphenoid sinus

Coronal view Sagittal view

Invades anterior orbital contents, skin of cheek, pterygoid plates, infratemporal fossa, cribiform plate,
sphenoid, or frontal sinuses

T4b T4b T4b

Invades any of the following: orbital apex, dura, brain, middle cranial fossa, cranial nerves other than
maxillary division of trigeminal nerve, nasopharynx, or clivus
Figure 27.4 Staging diagram.

of metastatic disease is 50%. Whether chest computed tomography PROGNOSIS

(CT) should routinely be included in staging is more contentious.
Chest CT is not routinely undertaken for sinonasal tumors, but
should be performed if the patient has three or more lymph node
metastases, bilateral nodal metastases, nodes >6 cm, or low jugular
lymph node metastases (13).
The staging guidelines apply to all cancers but not to non-
epithelial tumors, for example, lymphoid, soft tissue, bone, or car-
tilage. For olfactory neuroblastoma the Kadish staging system,
which is based on clinical findings, can be used. Stage A tumors
are confined to the nasal cavity and have a 75% five-year survival
rate; Stage B lesions involve the nasal cavity and one or more
sinuses; and Stage C disease extends beyond the nasal cavity and
sinuses, and has a 41% five-year survival rate.
Overall the five-year survival of all sinonasal tumors after combi-
nation surgery and radiotherapy in patients without nodal involve-
ment is 30% to 50%, wherever the primary is sited. Multimodality
chemo/radiotherapy has resulted in an overall improvement in
survival of up to 50%, with better results for some tumors. The
most frequent site of treatment failure is local recurrence which
occurs in 30% of cases. Isolated regional recurrence and distant
metastases are unusual if the primary is controlled, occurring in
only 5% of cases. Overall the five-year local control is 70%, with
better results for surgery plus chemo/radiotherapy (56%) than for
radiotherapy alone (33%) (14). However, if there is a single ipsilat-
eral involved node this decreases survival by 50%. Patients with

563
 primary tumor evaluation and staging
bilateral metastatic nodes have a survival rate 25% of that expected,
and extracapsular spread of tumor decreases this by a further 50%
(15). The site, stage, and form of treatment modality are all impor-
tant prognostic factors (16). Tumor limited to the maxillary antrum
has a good prognosis and can be treated with total maxillectomy,
whereas involvement of the central skull base or pterygo-palatine
fossa implies a poor prognosis and is treated by radical maxillec-
tomy and adjuvant radiotherapy. In a recent study (17) the two-
year disease-free survival rate was 75% for both total and radical
maxillectomy, and the local recurrence rates were 8.3% and 18.7%,
respectively. All recurrences occurred at the posterior resection
margin of the maxillectomy. The risk of local recurrence overall is
40% but the risk is higher if the pterygoid muscle (69%), pterygoid
plates (70%), or base of skull is involved (66%). Most recurrences
occur within 12 months (18). Positive nodes at presentation, which
occur most frequently with T2 tumors involving the floor of the
antrum are a poor prognostic factor with a five-year survival of
50.6% if node-negative, but only 16.8% if N1 disease.
In ethmoid sinus tumors the prognosis is dependent on T stage
and histology (19). Local recurrence is common at five years and
although nodal disease is rare at presentation (1.6%) it carries a
very poor prognosis with a five-year survival of 0% if node-positive
compared to 45% if node-negative (20). Carcinomas of the nasal
cavity are low grade and treated by surgery with or without adju-
vant radiotherapy. Local recurrence occurs in 20% to 50% and
most of these (80%) develop in the first year, with a five-year
survival rate of 62% (14,21).
The type of histology is also an important prognostic factor.
Squamous cell carcinoma has the worst prognosis with a five-year
survival rate between 20% and 40%; however, it does depend on
the stage, ranging from 54% for Stage I to less than 29% for Stage IV
tumors with local recurrence occurring in 25% to 35% within one
year. However, aggressive multimodality therapy has increased the
five-year survival rate of T4 tumors to 60% (22). Non-squamous
cell carcinomas have a better prognosis compared to similar stage
squamous cell carcinoma. Adenoid cystic carcinomas are treated by
wide local excision and postoperative radiotherapy but late recur-
rences may occur, usually locally (73%) (23). Patients treated by
combined surgery and radiotherapy have lower recurrence rates
(40%) than those treated with surgery alone, with distant metasta-
ses occurring in 32% and nodal failure in 4.6%. Treatment failures
may occur late after five years with the overall survival and disease-
free survival rates at 10 years of 37.6% to 55% and 13.6% to 15%
(10,24) (Fig. 27.5). The significant prognostic factors influencing
10-year survival are the pathological finding of perineural invasion
and the initial mode of treatment.
The prognosis for olfactory neuroblastoma is better than for the
other sinonasal tumors, with treatment by craniofacial resection,
which is curative in 90% of patients as microscopic disease in the
cribriform plate and olfactory bulb, which cannot be identified
on preoperative imaging, will be removed en bloc. If more lim-
ited surgery is undertaken, then the recurrence rate is high, up to
50% after extended lateral rhinectomy, in patients with Stage A
and B tumors. The five-year survival for all patients is 69%; more
recent reports suggest an improved survival of 80%. If survival is
stratified for grade, it is 40% for high-grade and 80% for low-
grade tumors. Locoregional nodes are found in 6% to 17% of
affected persons at presentation with distant metastases found in
564
38% at relapse, which may occur after many years. Poor prognostic
factors include:
• Females
• Age over 50
• High-grade or Stage C at presentation (25,26)
Key Points: Staging and Prognosis
■ Sixty percent of tumors are Stage T3 or T4 at presentation
■ There is a five-year survival in SCC of 30% to 40% following
surgery and radiotherapy irrespective of the primary site
■ Chemotherapy increases five-year survival to 60%
■ Ipsilateral nodal involvement decreases survival by 50%
■ Bilateral nodal involvement decreases survival by 75%
TREATMENT DECISIONS AND PLANNING
Surgery
Sinonasal tumors are treated by surgery and radiotherapy. Surgery is
undertaken with curative intent and, if only the inferior structures of
the sinonasal cavity are involved, local excision with clear margins is
possible. The main cause for treatment failure is local recurrence; if
the tumor extends superiorly or posteriorly, or if there is vascular or
perineural invasion, then radiotherapy is required. The overall sur-
vival rates are similar whether the radiotherapy is given before or
after the surgery, but there are fewer complications if it is given post-
surgery. Palliative surgery may be undertaken to debulk tumors prior
to radiotherapy, for decompression, or for pain control.
Craniofacial resection is performed for tumors of the frontal,
ethmoid, and sphenoid sinuses (27,28). A transfacial approach is
used for the nasal cavity and maxillary antrum, but for more
central tumors extending through the floor of the anterior cranial
fossa, transcranial resection may be more suitable (29). Orbital
exenteration will be performed as necessary. Using this approach,
a five-year cancer-specific survival rate of 69% with an overall
survival rate of 61% at five years and 48% at 10 years has been
reported for Stages III and IVa tumors, and an aggressive policy of
resection and radiotherapy gives survival results that are compa-
rable to less advanced tumors (30).
In a large series by Howard et al. (31) reviewing the results in a
single institution over 25 years, the overall five-year survival was
59%, with the 10-year survival 40%, and the 15-year survival 33%.
This compared to the results of an earlier study from the same group
published in 1998 (32) when the five-year survival was 44% and the
10-year survival 32%. The most significant prognostic factors were
intracranial extension, type of malignancy, and orbital involvement.
Involvement of the brain carries a very poor prognosis irrespective
of the tumor type. The most sustained improvement in survival has
been in patients with esthesioneuroblastoma (74% five-year survival
compared with 65%) and chondrosarcoma (94% compared with
79%). SCC also showed some improvement but still carries a poor
prognosis (53% at five years decreasing to 32% at 10 years). Orbital
involvement is important when deciding between orbital clearance
and periosteal excision. Periosteal resection with orbital preservation
is undertaken if the full thickness of orbital periosteum has not been
breached with a consequent functional improvement and no
 paranasal sinus neoplasms

(A) (B)

(C)
Figure 27.5 Adenoid cystic carcinoma. (A) T2-weighted sequence. The low signal intensity tumor is easily differentiated from the adjacent high signal secretions (arrow).
(B) Axial CT undertaken two years later shows extensive local recurrence with bony destruction and (C) involved lymph nodes (arrow).

reported prognostic disadvantage. Most recurrences are local and
may be amenable to further therapy. Distant metastases are rare and
this group did not perform routine neck dissection. No significant
difference in outcome was found in this study in patients who
received combination therapy, whether the radiotherapy was given
before or after surgery. Recently, complete endoscopic resection has
been advocated as the most appropriate surgical approach in selected
cases with few postoperative complications and a reported 88% five-
year survival but no long-term follow-up is yet available (33,34).
In another large study of sinonasal tumors reported by Guntinas-
Lichius et al. (35), 32% had surgery only, 47% underwent multi-
modal therapy including surgery, and 20% had no surgery. The stage
and type of therapy were independent prognostic factors with an
overall five-year survival of 41%, disease-specific survival (DSS) of
51%, and local control in 64%. Patients with early stage disease
(Stage I and II) treated by surgery alone had an overall five-year
survival of 52% and DSS of 63%, whereas late stage disease treated
with radiotherapy with or without chemotherapy had a very poor
five-year survival (13%) with a DSS of 21%. Chen et al. (36) in a
study of patients with T3 or T4 sinonasal undifferentiated carcinoma
treated with multimodality therapy obtained overall local control in
56% at five years with local control of 74% in those who had total
resection compared to only 24% in those with subtotal resection.
Criteria for non-resectability include:
• Distant metastases
• Extensive intracerebral involvement
• Invasion of the optic chiasm
• Bilateral cavernous sinus invasion
• Poor patient performance status
Radiotherapy/Chemotherapy
Surgery is the initial treatment but a combined modality approach
with radiotherapy is used. Although the outcome is poor, there
have been improvements over the years with advances in surgery
and radiotherapy techniques. Most tumors are locally advanced
at the time of presentation and their proximity to critical struc-
tures including the orbit, optic pathways, and anterior cranial
fossa makes management difficult. Radiotherapy is used both as
part of multimodal therapy combined with surgery and as pri-
mary treatment. The results are related to the stage of disease;
one group achieved 10-year control of disease in 86% of Stage I,

565
 primary tumor evaluation and staging
65% of Stage II, and 34% of Stage III tumors (11). In this group
of patients, 27% developed unilateral blindness secondary to
radiation retinopathy as orbital involvement required very high
doses for control.
In a review of radiotherapy techniques over the last four decades
including conventional 3D conformal radiotherapy and intensity-
modulated radiotherapy (IMRT), Chen et al. (37) found the five-
year estimates of overall survival, local control, and disease-free
survival were 52%, 62%, and 54%, respectively. Although the
radiotherapy technique did not alter any of these end-points,
more advanced cases were being treated and there was a signifi-
cant decrease in complications with severe (Grades 3 and 4) toxic-
ity decreasing from 53% in the 1960s to 16% in the 2000s,
particularly with IMRT (38,39). Patients who have gross tumor
resection prior to RT have a more favorable outcome. Adjuvant
radiotherapy in olfactory neuroblastoma will allow 92% of
patients to be disease-free at five years (25,40). The role of chemo-
therapy is unclear; however, in a small study of maxillary tumors
using primary chemotherapy followed by craniofacial resection
and postoperative radiotherapy a three-year survival of 69% was
reported, whereas other authors have found neoadjuvant chemo-
therapy offers no therapeutic advantage (41,42). Using intra-arte-
rial cisplatin with concurrent radiotherapy followed by surgery
gave an overall survival of 76% to 80%, and in T4 tumors gave
100% local control with a five-year survival of 87% (43–45).
Key Points: Treatment
■ Surgery offers the best chance for cure, but only in Stage I to
III disease
■ Preoperative chemotherapy may avoid orbital exenteration
■ Chemo/radiotherapy will increase the disease-free interval in
Stage IV tumors
■ New radiotherapy techniques have decreased the rate of
complications
(A)
Figure 27.6 Radiation necrosis. (A) Coronal T1-weighted scans pre and (B) post gadolinium. Following cranio-facial resection and radiotherapy for an ethmoid carcinoma
there is an enhancing lesion in the frontal lobe but no evidence of local recurrence (arrow). This was radiation necrosis on biopsy.
566
Complications of Treatment
Radiation Necrosis
This occurs in 3% to 10% of patients, the site depending on the
radiation field. The necrosis most commonly affects the temporal
or frontal lobes, is often asymptomatic and may occur within three
to four months following radiotherapy. On MRI it appears as hyper-
intensity on T2-weighted sequences due to edema and demyelina-
tion, which is often reversible. Later injury, months or even years
following radiotherapy, is due to vascular injury, demyelination,
and inflammation with hyperintensity seen on T2-weighted images
with mass effect and ring-like or solid enhancement (Fig. 27.6). In
“burnt out” cases this leads to temporal lobe encephalomalacia. The
differential diagnosis includes metastases, but these are unlikely in
sinonasal tumors. Radiation may also cause a vasculitis, leading to
ischemia of the basal ganglia, thalami, and deep white matter, caus-
ing confusion, seizures, or focal neurology (46). Radiation osteone-
crosis is also a long-term complication with cortical interruption,
fragmentation, and soft tissue thickening identified on CT and
marrow signal alterations on MRI.
Cranial Neuropathies
These are unusual, with the optic and hypoglossal nerves most
commonly affected, leading to optic neuritis with enlargement of
the optic tracts, and neovascular glaucoma or denervation of the
tongue with ispilateral edema and fatty infiltration.
Radiation Induced Tumors
These occur within the radiation field with a latency period of
longer than five years. The commonest histologies are meningioma,
sarcomas, squamous cell carcinomas, and thyroid cancer.
PURPOSE OF IMAGING
Although plain radiographs are still used to screen for sinonasal
malignancy and in 70% to 90% of cases bone destruction will
(B)
 paranasal sinus neoplasms

be identified, cross-sectional imaging is used to provide both from 0.5 to 2 mm. Scans should be obtained following intravenous
tumor-mapping and to identify disease in critical areas that will contrast medium timed to visualize the vascular tree. Scanning
influence surgical or radiotherapy planning. This includes 100 seconds after the contrast has started will allow visualization of
tumors involving the floor of the anterior and middle cranial the arteries and veins and enhancement of the tumor. The first and
fossa, the pterygopalatine fossa, the orbit, and hard palate. second order draining nodes (levels 1 and 11) should be included.
Endoscopy demonstrates the superficial extent of sinonasal The final data set should consist of axial and coronal images viewed
tumors and guides biopsy. Neither CT nor MR can completely dis- as 2 to 3 mm slices viewed on soft tissue and bone windows.
criminate between benign and malignant tumors but are both used Sagittal images may be helpful in some circumstances.
to map out the deep extent, particularly in areas than cannot be
assessed endoscopically such as the anterior cranial fossa, orbit, and T Stage
the pterygo-palatine fossa. MRI is particularly suited for this as it On CT most sinonasal tumors are soft tissue masses that enhance
can differentiate secretions from tumor based on T2-weighted mildly after contrast with margins that are difficult to discern and
images, can identify perineural and perivascular spread, orbital, and separate from adjacent secretions. Thin-section, high-definition
dural invasion. CT is better for defining cortical bone, particularly CT is very good for identifying early bone erosion, but it is difficult
subtle erosions. CT is also faster, cheaper, and more readily available to differentiate tumor invasion from tumor abutment and to diag-
than MRI. For assessment of lymph node involvement, ultrasound nose early intracranial extension. The extent of local tumor spread
is increasingly being used in addition to CT and MR. Computed can be defined with an accuracy approaching 98%, although dural
tomography and/or MR should be performed as pre-therapy and periosteal invasion still may require biopsy (47).
staging and also repeated after surgery to act as a baseline for the Most tumors are not diagnosed when they are small and curable,
evaluation of recurrent disease. Functional imaging with FDG apart from when they are large enough to affect adjacent bone. The
PET-CT can be used for both staging and follow up of patients. pattern of bony involvement may be helpful in the differential
diagnosis. In squamous cell carcinoma there is aggressive bony
destruction with only small fragments remaining; this pattern is
Key Points: Purpose of Imaging
also seen in lymphoma, metastases, and sarcomas, whereas bone
■ Identify intracranial extension and thereby determine those remodelling is seen in inverted papillomas, minor salivary gland
patients not suitable for surgery tumors, olfactory neuroblastomas, hemangiopericytomas (Fig. 27.7),
■ Identify tumor margins and differentiate tumor from and in most sarcomas. Sclerotic bony changes are not normally
secretions seen with tumors but are seen with inflammation, fungal, or gran-
■ Identify nodal involvement ulomatous disease, and may occur in nasopharyngeal carcinoma,
■ Plan radiotherapy portals osteosarcoma, and prostatic metastases. Tumoral calcification is
■ Act as a baseline for assessment of disease recurrence uncommon and also suggests chronic infection, but may occur
with osteoblastic chondrosarcoma, olfactory neuroblastoma, and
osteosarcoma (Fig. 27.8).
IMAGING TECHNIQUES (TABLE 27.3) Sinonasal tumors are increasingly being diagnosed on imaging
performed prior to endoscopic surgery. The bony destruction is
Computed Tomography well shown but the low-dose technique employed is unsuitable for
Multidetector CT provides thin-section high-resolution scans that evaluation of the soft tissue component (Fig. 27.9).
can be reformatted in any plane with no loss of resolution. The
slice thickness depends on the number of detectors and varies Orbital Invasion
The detection of orbital invasion is extremely important as it
greatly influences surgical planning. The orbit can be preserved
Table 27.3 Comparison of Techniques even if the orbital wall is destroyed as long as the periorbita is not
invaded. Displacement and distortion of the orbital wall occurs
Technique Advantages Disadvantages frequently, making it difficult to assess on CT; thus, although
CT Fast acquisition Poor at differentiating tumor osseous destruction and orbital fat involvement indicates orbital
Sensitive for bony destruction from secretions invasion, the converse is not true and the absence of abnormal fat
Nodal architecture better Poor for determining extent
on imaging does not exclude invasion. Tumor adjacent to the
defined of tumor
Readily available Poor for perineural tumor periorbita is the most sensitive predictor of orbital invasion (90%
and intracranial extension CT and MR) but has low specificity (29–44%). On MR, if a thin
MRI No dental amalgam artifact MRI contraindications and smooth arc of signal hypointensity is seen on a T2-weighted
Multiplanar capability Slower sequence between the orbital fat and the tumor, then the perior-
Differentiates tumor from Limited availability
bita is considered to be intact. However, no criterion is more than
secretions
Intracranial and perineural 79% accurate and, if there is any doubt, frozen section at the time
extension of surgery is required (48).
PET/CT Functional imaging Limited availability
Distant metastases Expensive N Stage
Response to treatment Poor spatial resolution
Size is used to define normal nodes on both CT and MR if the
Recurrence
nodes are homogeneous and clearly demarcated. Nodes >1 cm,

567
 primary tumor evaluation and staging
(A) (B)
Figure 27.7 Hemangiopericytoma. (A) Axial post-contrast medium CT shows an enhancing lesion in nasal cavity which on (B) coronal image on bone windows shows
remodelling of bone (arrow).
Figure 27.8 Olfactory neuroblastoma. Axial CT post-contrast medium shows an
enhancing lesion in the nasal vault containing fragments of bone (arrow).
except the jugulo-diagastric nodes, which may be up to 1.5 cm in
length, are considered abnormal. Groups of smaller nodes are
also suspicious, with numerous nodes measuring 8 to 15 mm in
length or 8 to 9 mm in axial diameter suggestive of malignancy.
Clinical palpation is a good method for the staging of lymph
nodes; however, deep nodes may not be palpable. In a meta-
analysis of CT versus physical examination, CT is more sensi-
tive, specific, and accurate than physical examination (PE)
alone but not significantly so. The sensitivity of CT was 83%
(PE 74%), specificity 83% (PE 81%), and accuracy 83% (PE
77%) (9). Although the soft tissue resolution of MRI is supe-
rior to CT, it is no better than CT for the assessment of lymph
nodes (50).
The most reliable indicator of malignancy and nodal infiltra-
tion on CT is “central necrosis,” where the node has a low attenu-
ation centre and is irrespective of nodal size. Central necrosis
occurs in 74% of involved nodes and is thus also reasonably
568
sensitive. However, in small involved lymph nodes, central necro-
sis is much less common. Contrast-enhanced CT can identify
enlarged or necrotic nodes, but cannot differentiate minimally
enlarged or normal-sized nodes containing micrometastases
from reactive nodes unless there is extracapsular spread of tumor
or necrosis (51).
Extracapsular nodal spread of tumor indicates a poor prognosis
with a reduction in overall survival of 50% and a tenfold increase
in the risk of neck recurrence compared to patients without extra-
capsular spread. On CT this is seen as an enhancing rim that is
irregular and thickened with infiltration into the adjacent fat. This
represents macroscopic spread, which is found in 40% of nodes
<2 cm, in 50% of nodes between 2 and 3 cm, and rises to 75% in
nodes >3 cm in diameter.
Key Points: CT and Staging
■ Computed tomography is accurate in assessing bone
destruction
■ Using size criteria and necrosis, CT accurately assesses nodal
involvement
■ Computed tomography is poor at defining the extent of
tumor and differentiation from secretions
■ Computed tomography is relatively poor at detecting early
intracranial extension
■ In extracapsular nodal tumors the risk of neck recurrence is
increased tenfold
Ultrasound in N Staging
Using high-frequency ultrasound, nodal metastases are usually
hyperechoic but may be inhomogeneously echogenic with loss of
the echogenic hilus. In the presence of extranodal spread the out-
lines become indistinct and liquid areas within the node indicate
central necrosis. The sensitivity of ultrasound in the diagnosis of
nodal metastases varies from 75% to 92%, with a specificity of
63% to 91%. The use of ultrasound-guided fine-needle aspiration
increases specificity up to 100% (52–55).
 paranasal sinus neoplasms

(A) (B)

(C)

(D)

Figure 27.9 Squamous cell carcinoma of the ethmoid sinus. (A) Coronal CT scan on bone windows performed prior to endoscopic surgery shows destruction of the
cribriform plate (arrow). (B) Coronal T2-weighted image and (C) coronal T1-weighted image post-gadolinium shows an enhancing tumor in the ethmoid sinus.
(D) Sagittal image. Tumor can be seen adjacent to the dura, but no evidence of intracranial extension at surgery.

Magnetic Resonance Imaging
Suggested technique for MRI includes:
• Four millimeter coronal and axial T1-weighted images
• Axial T2-weighted images
• Post-gadolinium T1-weighted axial and coronal images
with fat saturation
• Sagittal images post-gadolinium may be helpful to assess
perineural, intracranial, orbital, or extradural extension
• Diffusion-weighted imaging may be useful
T Stage
Most sinonasal tumors are highly cellular and are of homogeneous
intermediate signal intensity on T1- and slightly higher signal
intensity on T2-weighted images with homogeneous enhancement
following IV injection of contrast medium (Fig. 27.10). If the
tumors are large, they are non-homogeneous because of necrosis
and hemorrhage. Adenoid cystic tumors have variable T1 and
T2 intensity, and melanoma is hyperintense on T1- and variable on
T2-weighted images. If subacute hemorrhage has occurred there
may be focal areas of high signal intensity on T1- and T2-weighted
images. Areas of necrosis are of low to intermediate signal intensity
on T1- and high signal intensity on T2-weighted sequences (46).
Differentiation of tumor from secretions, and hence the extent
of tumor, is better with MR than CT. Secretions have a high
water content, so are of low signal intensity on T1-weighted
sequences, high signal intensity on T2-weighted sequences (Fig.
27.5A), and show peripheral enhancement. As the protein con-
tent of the secretions increases they become more hyperintense
on T1-weighted images. When the protein content reaches 25%
secretions are hyperintense on T1- and T2-weighted images, and
if the protein content is >25% they are hyperintense on
T1-weighted and hypointense on T2-weighted images. Finally,
with a protein content >28% secretions are hypointense on both
T1- and T2-weighted sequences (56). Tumors are highly cellular
and are of intermediate to low signal intensity on T2-weighted
sequences, with more solid nodular enhancement. Small tumors
may not be detected as the MR characteristics seen in this

569
 primary tumor evaluation and staging
(A)
(C)
Figure 27.10 Squamous cell carcinoma of the maxillary antrum. (A) T1-weighted scan with low signal antral tumor extending into the nasal cavity. (B) T1-weighted image
post-gadolinium. There is some enhancement following gadolinium. (C) T2-weighted sequence. Tumor is of increased signal intensity compared to the T1-weighted sequence.
instance may be similar to those seen when inflammation is
present. Diffusion-weighted imaging can be used to differentiate
necrotic from viable areas of tumor, with a reported sensitivity
of 92.9%, specificity of 93%, and accuracy of 94.6% (57).
Intracranial and Dural Invasion
Contrast-enhanced T1-weighted MR with sagittal and coronal
views (Fig. 27.9D) is the best investigation to assess the optic
canal, cavernous sinus, and perineural spread at the skull base.
These sequences are also used to differentiate dural and paren-
chymal brain invasion (58,59) as the distinction between extra-
axial tumor and brain invasion has surgical implications. Smooth
dural enhancement may be seen in either malignant or reactive
changes. Discontinuous enhancement with thickening or nodular-
ity of >5 mm with high signal on T2-weighted sequences in the
adjacent brain is seen in malignant infiltration (Fig. 27.11).
Although CT identifies skull base destruction better than MR,
MR is more sensitive for skull base invasion, marrow infiltration,
and the extent of dural involvement (60). On contrast-enhanced
sagittal and coronal T1-weighted or gadolinium-enhanced fat
saturation sequences, three layers can be identified (periostium,
dura, and CSF). If tumor abuts the cribriform plate but does
not interrupt its hypointense signal, it is extracranial. Effacement
of the hypointense layer implies bone-periosteal penetration.
570
(B)
If thickened but uninterrupted enhancing dura is seen, the tumor
is intracranial but extradural, and if focal or diffuse replacement
of the dura is seen this indicates intracranial intradural invasion
(Fig. 27.10). Patients with limited brain invasion treated by cran-
iofacial resection will have decreased survival compared to those
with dural invasion only. The normal marrow in the skull base is
hyperintense on T1-weighting, and tumor is seen as hypointense
on T1-weighted sequences. However, this may also be seen with
marrow edema and T1-weighted sequences pre- and post-contrast
medium, and T2-weighted sequences may be required to differen-
tiate tumor from non-malignant change (61).
Pterygopalatine Fossa (PPF). Detection of posterior spread into
the PPF is important for treatment planning. On MR, invasion is
suspected if the fat content of the fossa is replaced or effaced by
tumor. This can also be identified on CT (Figs. 27.1D and 27.2D).
The pterygoid canal and nerve, foramen rotundum, and maxillary
nerve are all well demonstrated on MR.
Perineural Spread. This term includes involvement of the
perineurium and also of all compartments of the neural sheath.
Tumor increases the permeability of the perineural capillaries and
causes disruption of the blood-nerve barrier. Segmental nerve
enhancement indicates perineural spread. This is best shown on
MR using contrast-enhanced, high-resolution, fat-suppressed
sequences. False positives will occur in other conditions that
 paranasal sinus neoplasms
(A) (B)
Figure 27.11 Adenocarcinoma of the ethmoid sinus with extensive intracranial involvement, seen on the axial T1-weighted sequences (A) pre and (B) post gadolinium.
(C) Intracranial extension is well shown on the coronal view.
disrupt the blood/nerve barrier including inflammation, isch-
emia, trauma, axial degeneration, and demyelination. Growth of
tumor along the nerve will cause thickening of the nerve that can
be identified on either CT or MR. Perineural extension may erode
bony fissures or enlarge foramina and can be seen on CT (Fig.
27.2). Involved nerves may be of normal caliber within the canal
but enlarge again when outside the boney confines. Tumor may
spread via V2 and V3 into Meckel’s cave and into the cavernous
sinus with replacement of the normal fluid signal in Meckel’s cave
by soft tissue and enlargement of the cavernous sinus. Magnetic
resonance imaging has a higher sensitivity (100%) and specificity
(85%) than CT (sensitivity 88%, specificity 89%) in detecting
perineural spread along the base of the skull (62).
N Stage
Using MR, normal nodes are of similar signal intensity to muscle
on T1-weighting and slightly higher signal than muscle on
T2-weighted sequences. They enhance slightly more than muscle
following injection of IV contrast medium. The central low
attenuation seen in malignant nodes is best shown using
T1-weighted, contrast-enhanced sequences where there is cen-
tral low signal with peripheral enhancement. Fat-suppressed
sequences allow better assessment of this enhancement and also
improve the visualization of extracapsular spread of tumor.
Using size criteria, the false-negative and false-positive rate for
MR for detecting nodal infiltration is between 10% and 20%. If
size criteria and internal architecture are combined, there is an
improved diagnostic accuracy with a negative predictive value for
CT and MR of 84% and 79%, respectively, and a positive predictive
value for CT and MR of 59% and 52%, respectively (63).
Recently, however, the use of superparamagnetic iron oxide
particles (SPIOs) as lymphangiographic agents has been devel-
oped and does offer potential for improvement. The small iron
oxide particles are injected intravenously and are taken up by the
reticuloendothelial system in normal or inflamed lymph nodes.
(C)
These nodes show signal drop on T2* sequences, whereas meta-
static nodes do not show this effect. A recent study using this
technique found a sensitivity of 86% and a specificity of 100% for
metastatic nodes, but micrometastases may be missed (64,65).
The incidence of micrometastases in patients with head and neck
cancer is high (59%) and in 25% of patients only micrometastases
may be present (66). So, although the use of MR with SPIOs may
help in altering the extent of surgery, it is unlikely that it can be
used to substitute for a neck dissection.
Diffusion-weighted imaging appears to be useful in differen-
tiating benign from malignant nodes with the mean apparent
diffusion coefficient (ADC) significantly lower for malignant
nodes with a reported sensitivity of 98%, specificity 88%, PPV
98.5%, and NPV of 83.7% for malignant nodes, with the smallest
node identified as 9 mm (67). However, these results have still to
be substantiated.
Key Points: Magnetic Resonance Imaging and Staging
■ Magnetic resonance imaging accurately assesses intra-cranial
and perineural extension, accurately differentiates secretions
from tumor, and readily detects recurrent disease
■ Superior soft tissue contrast and multiplanar imaging provide
MR with an advantage over CT in staging
Computed Tomography Versus Magnetic Resonance
Imaging in Staging
Magnetic resonance imaging is not as sensitive as CT in the detection
of early bone erosion but will certainly identify tumor extent and
marrow involvement. MR is better than CT at identifying intracra-
nial extension including dural, cavernous sinus, or carotid artery
invasion (68,69). Some authors have found MR less accurate than
CT for the assessment of nodal necrosis (MR accuracy 86%, CT
accuracy 91–96%) and for diagnosing extracapsular nodal spread.
571
 primary tumor evaluation and staging
Overall the accuracy of CT compared to surgery in T-staging
sinonasal tumors is 78% to 85% with difficulty in assessing orbital
invasion and differentiating encroachment from invasion, whereas
MR is 94% accurate, increasing to 98% if post-contrast images are
included (47). As the accuracy for the detection of nodal metastases
is similar, MR has become the investigation of choice, although
many centers still use CT as it is less expensive and more readily
available.
Positron Emission Tomography
Positron emission tomography (PET) is an imaging technique that
can map functional and metabolic activity before structural
changes have taken place. PET scanning using either 2-18fluoro-2-
deoxy-D-glucose (18FDG) or 11C-methionine can differentiate
malignant from normal tissue based on enhanced glycolysis or
amino acid metabolism by tumor cells and can thus identify tumor
in normal-sized lymph nodes, differentiate sinus malignancy from
secretions, and fibrosis from tumor (70). The development of PET/
CT has improved the anatomic registration and decreased overall
scanning time and is of benefit over PET alone. In sinonasal tumors
the role of PET/CT is probably not in staging, as distant metastases
are rare at presentation, but in planning radiation fields and is
assessing recurrent disease.
Staging
PET-CT appears to add no additional information is assessing the
extent of the primary tumor compared to CT and MR (71) (Fig.
27.1). Positron emission tomography utilizes activity rather than
size and has a reported sensitivity for nodal detection is 80% to
96% with specificity of 90% to 94%. In a recent study, FDG-PET
was superior to CT for the detection of cervical nodal metastases
with the sensitivity for FDG-PET 85% (CT 80%, MR 93%), speci-
ficity 98% (CT 93%, MR 95%), and with an overall accuracy of
96% (CT 92%, MR 94%) (72). PET does not negate the need for
neck dissection. In a study of N0 nodes on CT and MR, PET-CT
did identify positive nodes with a sensitivity of 67% but did not
identify micrometastases (73). Other tracers have been used
including 18F-3-fluoro-3-deoxy-thymidine (18F-FLT), which is a
pyrimidine analogue that reflects the activity of the S phase of
DNA synthesis requiring thymidine kinase-1 and is a surrogate
marker for cell proliferation. In a small study comparing F-FLT
and FDG-PET for nodal involvement, uptake was seen with F-FLT
in both reactive and metastatic nodes with a sensitivity of 100%
but a specificity of 16.7%; hence, it is unsuitable for staging nodal
disease and may be of limited use in assessing response (74).
Comparing all the modalities for detecting nodal infiltration,
ultrasound has the highest specificity when compared to CT, MR,
and PET, with a maximum accuracy of only 76% for all studies
(75,76). Thus, neck dissection cannot be avoided in those head
and neck tumors with a high incidence of nodal metastases. FDG-
PET is a whole-body imaging system and so can identify distant
metastases, a second primary malignancy, and will identify more
metastases than CT or MR, providing additional information over
CT and altering management in 11% to 31% (77,78) of patients
with head and neck cancer. This may have less impact in sinonasal
malignancy where distant metastases are unusual at presentation.
The degree of uptake in the primary tumor may relate to the
outcome following therapy so that tumors with a higher initial
572
SUV are more likely to fail treatment with poorer local control
and disease-free survival (79). Dobert et al. (80) found the initial
SUV did not correlate with the risk of recurrence but did appear
to be a prognostic factor for response to intra-arterial chemotherapy
with tumors with a lower SUV responding better.
Radiotherapy Planning
In head and neck tumors FDG-PET may provide more accurate
information on the extent of tumor than MR or CT and allow a
decrease in the gross tumor volume (GTV). The addition of PET-CT
is useful in delineating the GTV for intensity-modulated radiother-
apy (IMRT) leading to a change in volume in 14% to 57% of
patients when compared to CT alone (81,82) and, in addition, may
identify distant metastases (83). Early work with fluorine-18-
labeled fluoromisonidazole [(18)F-FMISO] PET-CT, which images
hypoxia, suggests it can be combined with IMRT to maximally
escalate the dose to radioresistant hypoxic tissues (84).
FDG-PET appears to be the best imaging method for assessing
recurrent tumor, although there are problems with false positives
due to inflammation (85). It is also possible to quantify uptake in
absolute units, a factor that may increase sensitivity when moni-
toring metabolic changes after treatment, with a reduction in
uptake correlating with tumor regression and a high initial uptake
predicting a poorer outcome (86).
Response to Therapy
PET-CT may become a powerful tool for following response to
therapy. Reduction in FDG uptake appears to correlate with a
decline in the number of viable cells and a metabolic response
may precede changes in tumor volume. There are some limita-
tions to using FDG-PET in this manner. The timing of the scan is
very important. Surgery causes an inflammatory reaction and
may cause false positive results; conversely, immediately following
chemotherapy there may be false negative results and at least three
weeks should elapse after chemotherapy. However, FDG-PET does
not appear to be sufficiently sensitive (40–75%) or specific
(25–64%) to identify the presence of residual disease in cervical
nodes after completion of chemotherapy (87,88) and to predict
the need for post-treatment neck dissection, although Ong et al.
(89) studied PET-CT post-chemo/radiotherapy and found there
was a high NPV for both nodal disease and the primary tumor.
These authors thought that potentially a negative 18F-FDG PET-
CT may become the only, or at least most decisive, criterion in the
management of the patient’s neck after chemo/radiotherapy.
The timing after radiotherapy (RT) is also important: scans
which are positive after four weeks indicate residual disease, but
a negative scan is unreliable with a NPV of 14% (90). However,
a scan at four months may more accurately reflect disease with a
negative predictive value of 100%, suggesting that no biopsy will
be needed for at least one year if the PET is negative (91). Greven
et al. (92) found FDG-PET useful for the initial imaging of head
and neck cancer, but the initial SUV did not predict response to
RT, and the one month post-RT scan was inaccurate (35% false
negative) with the four-month post-RT scan a better predictor
for the presence of residual tumor. Goerres et al. (93) found
FDG-PET performed at six weeks after completion of chemo-
radiotherapy will provide both sensitive (91%) and specific
(93%) information about residual disease, and will also provide
 paranasal sinus neoplasms

information about distant metastases or second primary tumors.
Our policy is to wait for at least three months following radio-
therapy before performing the scan.
Imaging for Follow-up
The distortion following neck dissection and the inflammatory
reaction and loss of fat planes following radiotherapy makes iden-
tification of residual tumor very difficult using either CT or MR.
This is a particular problem with base of skull tumors where post-
therapy bone or cartilage necrosis and soft tissue desmoplastic
changes may mimic malignancy. Serial imaging showing stability
or a decrease in size of a lesion indicates fibrosis, whereas growth
indicates tumor. However, this may lead to a delay in diagnosis or
unnecessary biopsy as radiotherapy effects may lead to an increase
in the size of a mass. In addition, it may be difficult to know which
part of the lesion to biopsy, making sampling errors common. If
the surgery is recent, there is active inflammation with edema and
hemorrhage. Months or years post-surgery mature granulation
tissue or vascularized scarring may form. Bony sclerosis may occur
and radiation osteitis produces sclerotic fragmentation of bone.
Plain films do not allow adequate assessment of soft tissue
recurrence; CT or MR must be used. In assessing the postsurgical
patient MR is superior to CT. On CT, secretions are of lower
attenuation than tumor on unenhanced scans. After contrast,
inflammation enhances more than tumor and fibrosis does not
enhance. Vascularized scar cannot be reliably differentiated from
inflammation or tumor.
On MR, granulation tissue, scar tissue, and fibrosis show vari-
able enhancement. Early scar and granulation tissue are of
increased signal on T2-weighting and enhance following injec-
tion of contrast medium, making differentiation from tumor
difficult (Fig. 27.12). A baseline study post-treatment is helpful
as an increase in mass effect often indicates recurrence and con-
traction suggests scar tissue. Mature scar has little or no mass
effect, is hypointense on T2-weighting, and does not enhance
following injection of contrast medium. Following maxillec-
tomy the sinus cavity is lined with a split-skin graft, which should
be smooth and moderately thin, six to eight weeks after surgery. If
the cavity is nodular, biopsy should be performed, as tumor is
present until proved otherwise (Fig. 27.13). Following craniofacial

(A) (B)
Figure 27.12 Adenoid cystic carcinoma of the maxillary antrum. Recurrence following surgery. (A) Axial T1-weighted image pre and (B) post gadolinium. There is
nodular enhancement of the surgical margin (arrows). Biopsy showed recurrent tumor.

(A) (B)
Figure 27.13 Squamous cell carcinoma of the ethmoid sinus. Axial T1-weighted sequences (A) pre and (B) post gadolinium. There is smooth enhancement of vascularized
scar on the right (arrow) with thick nodular enhancement of recurrent tumor on the left (broken arrow).

573
 primary tumor evaluation and staging

resection the anterior dura adjacent to the craniotomy is thickened
and enhances. The musculofacial flap is often shown on coronal
images and initially the flap is of intermediate signal intensity on
T1-weighted images and high signal intensity on T2-weighted
images, but as fibrosis occurs it becomes low signal intensity on
both T1- and T2-weighted images. Nodularity on the cranial or
nasal margin of the graft, near the suture line or in the sinonasal
cavity, or progressive thickening of the graft should be biopsied to
confirm the presence of tumor (94).
FDG-PET, which depends on cellular activity and is not influ-
enced by anatomical distortion, is very helpful in these cases. Gen-
erally, recurrent neoplasms show significant uptake on FDG-PET
(Fig. 27.14), whereas scar tissue does not, although radiation
necrosis may show some uptake (95).
The timing of FDG-PET is important as initially there may be
uptake in treated areas, and following radiotherapy the scans at
four months more accurately reflect disease status than scans at
one month (92), whereas following chemo/radiotherapy, FDG-
PET may be useful to monitor response after one course (96,97).
Following chemo-radiotherapy FDG-PET was more sensitive
and specific (88% and 81%, respectively) than CT/MR (75% and
30%, respectively) and, more importantly, FDG-PET has a high
negative predictive value of 91%, so a negative PET may preclude
further invasive procedures (98) (Fig. 27.15).

Figure 27.14 Adenoid cystic carcinoma post surgery. Axial FDG-PET/CT showing uptake in recurrence which involves the anterior wall.

(A) (B) (C)

(D) (E)
Figure 27.15 SCC right maxilla resected. Now left sided facial pain. (A) Axial post-contrast CT shows soft tissue mass involving the right pterygoid muscle suggesting
recurrence. (B) Axial contrast-enhanced CT shows mass in the left retropharyngeal space. (C) Axial PET/CT. No evidence of recurrence on the right. (D) Axial PET/CT
confirms malignancy in the left retropharyngeal space. (E) Coronal PET/CT identifies multiple bone metastases (arrows), not seen on the CT scan.

574
 paranasal sinus neoplasms
In the postsurgical patient it is possible to differentiate inflam-
matory change or fibrosis from tumor recurrence using FDG-PET,
which has a high NPV and therefore may in some cases obviate
the need for biopsy. Diffusion-weighted MR may be more specific
than FDG-PET (99).
Summary
■ Sinonasal tumors require cross-sectional imaging for staging
prior to treatment and following initial therapy to act as a
baseline for assessment of recurrent tumor
■ MRI is better for assessing the extent of tumor, and intracranial
and perineural involvement
■ Computed tomography is better for demonstrating fine bone
detail
■ Computed tomography and MRI are of similar accuracy in
staging lymph node involvement. US-guided FNAC is the
most specific method
■ Positron emission tomography is useful to identify involved
normal-sized lymph nodes and to monitor response to
therapy and identify recurrent disease
■ Magnetic resonance imaging should be performed as a
baseline study after initial therapy and used to identify
recurrent disease
■ If only one imaging modality is to be used for staging, it
should be MRI, including diffusion-weighted imaging
REFERENCES
1. Boring CC, Squires TS, Tong T. Cancer Statistics CA 1992; 42:
19–38.
2. Von Buchwald C, Bradley PJ. Risks of malignancy in inverted
papilloma of the nose and paranasal sinuses. Curr Opin Oto-
laryngol Head Neck Surg 2007; 15: 95–8.
3. Shojaku H, Fujisaka M, Yasumura S, et al. Positron emission
tomography for predicting malignancy of sinonasal inverted
papilloma. Clin Nuc Med. 2007; 32: 275–8.
4. Som PM, Branwein MS. Tumours and tumour-like condi-
tions. In: Head and Neck Imaging, 4th edn. St Louis: Mosby,
2003: 261–373.
5. Barton RT. Nickel carcinogenesis of the respiratory tract.
J Otolaryngol 1977; 6: 412–22.
6. van den Oever R. Occupational exposure to dust and sinona-
sal cancer. An analysis of 386 cases reported to the NCCSF
cancer registry. Acta Oto-Rhino-Laryngologica Belgica 1996;
50: 19–24.
7. Acheson ED, Cowdell RH, Jolles B. Nasal cancer in the
Northamptonshire boot and shoe industry. Br Med J 1970; 1:
385–93.
8. Hayes RB, Kardaun JW, de Bruyn A. Tobacco use and
sinonasal cancer: a case–control study. Br J Cancer 1987;
56: 843–6.
9. AJCC. Cancer Staging Manual, 6th edn. New York: Springer-
Verlag, 2002.
10. Kim GE, Park HC, Keum KC, et al. Adenoid cystic carcinoma
of the maxillary antrum. Am J Otolaryngol 1999; 20: 77–84.
11. Katz TS, Mendenhall WM, Morris CG, et al. Malignant tumors
of the nasal cavity and paranasal sinuses. Head Neck 2002; 24:
821–9.
12. Nishijima W, Takooda S, Tokita N, Takayama S, Sakura M.
Analysis of distant metastases in squamous cell carcinoma
of the head and neck and lesions above the clavicles at
autopsy. Arch Otolaryngol Head Neck Surg 1993; 119:
65–8.
13. de Bree R, Deurloo EE, Snow GB, Leemans CR. Screening
for distant metastases in patients with head and neck cancer.
Laryngoscope 2000; 110: 397–401.
14. Dulguerov P, Jacobsen MS, Allal AS, Lehmann W, Calcaterra T.
Nasal and paranasal sinus carcinoma: are we making progress?
A series of 220 patients and a systematic review. Cancer 2001;
92: 3012–29.
15. Som PM. Detection of metastasis in cervical lymph nodes: CT
and MR criteria and differential diagnosis. Am J Roentgenol
1992; 158: 961–9.
16. Hicsonmez A, Andrieu MN, Karaca M, Kurtman C. Treatment
outcome of nasal and paranasal sinus carcinoma. J Otolaryn-
gol 2005; 34: 379–83.
17. Choi EC, Choi YS, Kim CH, et al. Surgical outcome of radical
maxillectomy in advanced maxillary sinus cancers. Yonsei Med
J 2004; 45: 621–8.
18. Khan MH, Haque S, Yagi K, et al. Pattern of local relapse of
maxillary sinus carcinoma. Mymensingh Med J 2006; 15:
188–91.
19. Bhattacharyya N. Factors predicting survival for cancer of the
ethmoid sinus. Am J Rhinol 2002; 16: 281–6.
20. Cantu G, Bimbi G, Miceli R, et al. Lymph node metastases in
malignant tumors of the paranasal sinuses: prognostic value
and treatment. Arch Otolaryngol Head Neck Surg 2008; 134:
170–7.
21. Spiro JD, Soo KC, Spiro RH. Squamous carcinoma of the
nasal cavity and paranasal sinuses. Am J Surg 1989; 158:
328–32.
22. Nibu K, Sugasawa M, Asai M, et al. Results of multimodality
therapy for squamous cell carcinoma of maxillary sinus. Can-
cer 2002; 94: 1476–82.
23. Bhattacharyya N. Survival and staging characteristics for non-
squamous cell malignancies of the maxillary sinus. Arch Oto-
laryngol Head Neck Surg 2003; 129: 334–7.
24. Tran L, Sidrys J, Horton D, Sadeghi A, Parker RG. Malignant
salivary gland tumors of the paranasal sinuses and nasal
cavity. The UCLA experience. Am J Clin Oncol 1989; 12:
387–92.
25. Levine P, Gallagher R, Cantrell R. Esthesioneuroblastoma:
reflections of a 21-year experience. Laryngoscopy 1999; 109:
1539–43.
26. Jethanamest D, Morris LG, Sikora AG, Kutler DI. Esthesioneu-
roblastoma: a population-based analysis of survival and prog-
nostic factors. Arch Otolaryngol Head Neck Surg 2007; 133:
276–80.
27. Som PM, Lawson W, Biller HF. Ethmoid sinus disease:
CT evaluation in 400 cases. Part III. Craniofacial resection.
Radiology 1986; 159: 605–9.
28. Wax MK, Yun KJ, Wetmore S, Lu X, Kaufman HH. Adenocar-
cinoma of the ethmoid sinuses. Head Neck 1995; 17: 303–11.
575
 primary tumor evaluation and staging
29. McCutcheon IE, Blacklock JB, Weber RS, et al. Anterior tran-
scranial (craniofacial) resection of tumors of the paranasal
sinuses: surgical technique and results. Neurosurgery 1996; 38:
471–9.
30. Bridger GP, Kwok B, Baldwin M, Williams JR, Smee RI. Cran-
iofacial resection for paranasal sinus cancers. Head Neck 2000;
22: 772–80.
31. Howard DJ, Lund V, Wei WI. Craniofacial resection for tumors
of the nasal cavity and paranasal sinuses: a 25-year experience.
Head Neck 2006; 28: 867–73.
32. Lund V, Howard DJ, Wei WI, Cheesman AD. Craniofacial
resection for tumors of the nasal cavity and paranasal sinuses—a
17-year experience. Head Neck 1998; 20: 97–105.
33. Lund V, Howard DJ, Wei WI. Endoscopic resection of malig-
nant tumors of the nose and sinuses. Am J Rhinol 2007; 21:
89–94.
34. Podboj J, Smid L. Endoscopic surgery with curative intent for
malignant tumors of the nose and paranasal sinuses. Eur J
Surg Oncol 2007; 33: 1081–6.
35. Guntinas-Lichius O, Kreppel MP, Stuetzer H, et al. Single
modality and multimodality treatment of nasal and paranasal
sinuses cancer: a single institution experience of 229 patients.
Eur J Surg Oncol 2007; 33: 222–8.
36. Chen AM, Daly ME, El-Sayed I, et al. Patterns of failure
after combined-modality approaches incorporating radio-
therapy for sinonasal undifferentiated carcinoma of the
head and neck. Int J Radiat Oncol Biol Phys 2008; 70:
338–43.
37. Chen AM, Daly ME, Bucci MK, et al. Carcinomas of the para-
nasal sinuses and nasal cavity treated with radiotherapy at a
single institution over five decades: are we making improve-
ment? Int J Radiat Oncol Biol Phys 2007; 69: 141–7.
38. Daly ME, Chen AM, Bucci MK, et al. Intensity-modulated
radiation therapy for malignancies of the nasal cavity and
paranasal sinuses. Int J Radiat Oncol Biol Phys 2007; 67:
151–7.
39. Dirix P, Nuyts S, Vanstraelen B, et al. Post-operative intensity-
modulated radiotherapy for malignancies of the nasal cavity
and paranasal sinuses. Radiother Oncol 2007; 85: 385–91.
40. Choi KN, Rotman M, Aziz H, et al. Locally advanced paranasal
sinus and nasopharynx tumors treated with hyperfractionated
radiation and concomitant infusion cisplatin. Cancer 1991;
67: 2748–52.
41. Licitra L, Locati LD, Cavina R, et al. Primary chemotherapy
followed by anterior craniofacial resection and radiotherapy
for paranasal cancer. Ann Oncol 2003; 14: 367–72.
42. Kim GE, Chang SK, Lee SW, et al Neoadjuvant chemotherapy
and radiation for inoperable carcinoma of the maxillary
antrum: a matched-control study. Am J Clin Oncol 2000; 23:
301–8.
43. Nashino H, Miyata M, Morita M, et al. Combined therapy
with conservative surgery, radiotherapy, and regional chemo-
therapy for maxillary sinus carcinoma. Cancer 2000; 89:
1925–32.
44. Madison ML 2nd, Soreenson JM, Samant S, Robertson JH.
The treatment of advanced sinonasal malignancies with pre-
operative intra-arterial cisplatin and concurrent radiation.
J Neurooncol 2005; 72: 67–75.
576
45. Shiga K, Yokoyama J, Hashimoto S, et al. Combined therapy
after superselective arterial cisplatin infusion to treat maxil-
lary squamous cell carcinoma. Otolaryngol Head Neck Surg
2007; 136: 1003–9.
46. Loever LA, Sonners AI. Imaging of neoplasms of the paranasal
sinuses. MRI Clin North Am 2002; 10: 467–93.
47. Lloyd G, Lund VJ, Howard D, Savy L. Optimal imaging
for sinonasal malignancy. J Laryngol Otol 2000; 114:
557–62.
48. Eisen MD, Yousem DM, Loevner LA, et al. Preoperative imag-
ing to predict orbital invasion by tumor. Head Neck 2000;
22: 456–62.
49. Merritt RM, Williams MF, James TH, Porubsky ES. Detection
of cervical metastasis. A meta-analysis comparing computed
tomography with physical examination. Arch Otolaryngol
Head Neck Surg 1997; 123: 149–52.
50. Hao SP, Ng SH. Magnetic resonance imaging versus clinical
palpation in evaluating cervical metastasis from head and
neck cancer. Otolaryngology Head Neck Surg 2000; 123:
324–7.
51. Van den Brekel MW, Castelijns JA, Snow GB. Detection of
lymph node metastases in the neck: radiologic criteria. Radi-
ology 1994; 192: 617–18.
52. Di Martino E, Nowak B, Hassan HA, et al. Diagnosis and stag-
ing of head and neck cancer: a comparison of modern imag-
ing modalities (positron emission tomography, computed
tomography, color-coded duplex sonography) with panendo-
scopic and histopathologic findings. Arch Otolaryngol Head
Neck Surg 2000; 126: 1457–61.
53. Yusa H, Yoshida H, Ueno E. Ultrasonographic criteria for
diagnosis of cervical lymph node metastasis of squamous cell
carcinoma in the oral and maxillofacial region. J Oral Maxillo-
facial Surg 1999; 57: 41–8.
54. Takes RP, Knegt P, Manni JJ, et al. Regional metastasis in head
and neck squamous cell carcinoma: revised value of US with
US-guided FNAB. Radiology 1996; 198: 819–23.
55. Righi PD, Kopecky KK, Caldemeyer KS, et al. Comparison of
ultrasound-fine needle aspiration and computed tomography
in patients undergoing elective neck dissection. Head Neck
1997; 19: 604–10.
56. Som PM, Dillon WP, Fullerton GD, et al. Chronically
obstructed sinonasal secretions: observations on T1 and
T2 shortening. Radiology 1989; 172: 515–20.
57. Razek AA, Megahed AS, Denewer A, et al. Role of diffusion-
weighted magnetic resonance imaging in differentiation
between the viable and necrotic parts of head and neck tumors.
Acta Radiol 2008; 49: 364–70.
58. Eisen MD, Yousem DM, Montone KT, et al. Use of preopera-
tive MR to predict dural, perineural, and venous sinus
invasion of skull base tumors. Am J Neuroradiol 1996; 7:
1937–45.
59. Chong VF, Fan YF, Khoo JB. Nasopharyngeal carcinoma with
intracranial spread: CT and MR characteristics. J Comput
Assist Tomogr 1996; 20: 563–48.
60. Ishida H, Mohri M, Amatsu M. Invasion of the skull base by
carcinomas: histopathologically evidenced findings with
CT and MRI. Eur Arch Otorhinolaryngol 2002; 259:
535–9.
 paranasal sinus neoplasms
61. Loevner LA, Tobey JD, Yousem DM, Sonners AI, Hsu WC.
MR imaging characteristics of cranial bone marrow in adult
patients with underlying systemic disorders compared with
healthy control subjects. Am J Neuroradiol 2002; 23:
248–54.
62. Hanna E, Vural E, Prokopakis E, et al. The sensitivity and spec-
ificity of high-resolution imaging in evaluating perineural
spread of adenoid cystic carcinoma to the skull base. Arch
Otolaryngol Head Neck Surg 2007; 133: 541–5.
63. Curtin HD, Ishwaran H, Mancuso AA, et al. Comparison of
CT and MR imaging in staging of neck metastases. Radiology
1998; 207: 123–30.
64. Mack MG, Balzer J , Straub R, Eichler K, Vogl TJ. Superpara-
magnetic iron oxide-enhanced MR imaging of head and neck
lymph nodes. Radiology 2002; 222: 239–44.
65. Sigal R, Vogl T, Casselman J, et al. Lymph node metastases
from head and neck squamous cell carcinoma: MR imaging
with ultrasmall superparamagnetic iron oxide particles
(Sinerem MR) – results of a phase-III multicenter clinical trial
(comment). Eur Radiol 2002; 12: 1104–13.
66. van den Brekel MW, van der Waal I, Meijer CJ, et al. The
incidence of micrometastases in neck dissection specimens
obtained from elective neck dissections. Laryngoscope 1996;
106: 987–91.
67. Abdel Razek AA, Soliman NY, Elkhamary S, Alsharaway MK,
Tawfik A. Role of diffusion-weighted MR imaging in cervical
lymphadenopathy. Eur Radiol 2006; 16: 1468–77.
68. Kraus DH, Lanzieri CF, Wanamaker JR, Little JR, Lavertu P.
Complementary use of computed tomography and magnetic
resonance imaging in assessing skull base lesions. Laryngo-
scope 1992; 102: 623–9.
69. Som PM, Dillon WP, Sze G, et al. Benign and malignant sinon-
asal lesions with intracranial extension: differentiation with
MR imaging. Radiology 1989; 172: 763–6.
70. Greven KM, Williams DW 3rd, Keyes JW Jr, et al. Positron
emission tomography of patients with head and neck carci-
noma before and after high dose irradiation. Cancer 1994; 74:
1355–9.
71. Wild D, Eyrich GK, Ciernik IF, et al. In-line (18)F-fluorode-
oxyglucose positron emission tomography with computed
tomography (PET/CT) in patients with carcinoma of the sinus/
nasal area and orbit.J Craniomaxillofac Surg 2006; 34: 9–16.
72. Dammann F, Horger M, Mueller-Berg M, et al. Rational diag-
nosis of squamous cell carcinoma of the head and neck region:
comparative evaluation of CT, MRI, and 18FDG PET. Am J
Roentgenol 2005; 184: 1326–31.
73. Schoder H, Carlson DL, Kraus DH, et al. 18F-FDG PET/CT
for detecting nodal metastases in patients with oral cancer
staged N0 by clinical examination and CT/MRI. J Nucl Med
2006; 47: 755–62.
74. Troost EG, Vogel WV, Merkx MA, et al. 18F-FLT PET does not
discriminate between reactive and metastatic lymph nodes in
primary head and neck cancer patients. J Nucl Med 2007; 48:
726–35.
75. Adams S, Baum RP, Stuckensen T, et al. Prospective compari-
son of 18F-FDG-PET with conventional imaging modalities
(CT, MRI, US) in lymph node staging of head and neck cancer.
Eur J Nucl Med 1998; 25: 1255–60.
76. Stuckensen T, Kovacs AF, Adams S, Baum RP. Staging of the
neck in patients with oral cavity squamous cell carcinomas: a
prospective comparison of PET, ultrasound, CT and MRI.
J Craniomaxillofac Surg 2000; 28: 319–24.
77. Sigg MB, Steinert H, Gratz K, et al. Staging of head and neck
tumours:[18F]fluorodeoxyglucose positron emission tomo-
graphy compared with physical examination and imaging
modalities. J Oral Maxillofac Surg 2003; 61: 1022–9.
78. Fleming AJ Jr, Smith SP Jr, Paul CM, et al. Impact of [18F]-2-
fluorodeoxyglucose-positron emission tomography/computed
tomography on previously untreated head and neck cancer
patients. Laryngoscope 2007; 117: 1173–9.
79. Allal AS, Slosman DO, Kebdani T, et al. Prediction of outcome
in head-and-neck cancer patients using the standardized
uptake value of 2-[18F]fluoro-2-deoxy-D-glucose. Int J Radiat
Oncol Biol Phys 2004; 59: 1295–300.
80. Dobert N, Kovacs AF, Menzel C, et al. The prognostic value of
FDG PET in head and neck cancer. Correlation with histopa-
thology. Q J Nucl Med Mol Imaging 2005; 49: 253–7.
81. Koshy M, Paulino AC, Howell R, et al. F-18 FDG PET-CT
fusion in radiotherapy treatment planning for head and neck
cancer. Head Neck 2005; 27: 494–502.
82. Wang D, Schultz CJ, Jursinic PA, et al. Initial experience of
FDG-PET/CT guided IMRT of head-and-neck carcinoma. Int
J Radiat Oncol Biol Phys 2006; 65: 143–51.
83. Ciernik IF, Dizendorf E, Baumert BG, et al. Radiation treat-
ment planning with an integrated positron emission and com-
puter tomography (PET/CT): a feasibility study. Int J Radiat
Oncol Biol Phys 2003; 57: 853–63.
84. Lee NY, Mechalakos JG, Nehmeh S, et al. Fluorine-18-
labeled fluoromisonidazole positron emission and computed
tomography-guided intensity-modulated radiotherapy for
head and neck cancer: a feasibility study. Int J Radiat Oncol
Biol Phys 2008; 70: 2–13.
85. Kresnik E, Mikosch P, Gallowitsch HJ, et al. Evaluation of head
and neck cancer with 18F-FDG-PET: a comparison with con-
ventional methods. Eur J Nucl Med 2001; 28: 816–21.
86. Halfpenny W, Hain S F, Biassoni L, et al. FDG-PET. A possible
prognostic factor in head and neck cancer. Br J Cancer 2002;
86: 512–16.
87. Brkovich VS, Miller FR, Karnad AB, et al. The role of positron
emission tomography scans in the management of the N-
positive neck in head and neck squamous cell carcinoma after
chemotherapy. Laryngoscope 2006; 116: 855–8.
88. Gourin CG, Williams HT, Seabolt WN, et al. Utility of posi-
tron emission tomography-computed tomography in identifi-
cation of residual nodal disease after chemoradiation for
advanced head and neck cancer. Laryngoscope 2006; 116:
705–10.
89. Ong SC, Schöder H, Lee NY, et al. Clinical utility of 18F-FDG
PET/CT in assessing the neck after concurrent chemoradio-
therapy for Locoregional advanced head and neck cancer.
J Nucl Med 2008; 49: 532–40.
90. Rogers J, Greven KM, McGuirt WE, et al. Can post-RT neck
dissection be omitted for patients with head-and-neck
cancer who have a negative PET scan after definitive radia-
tion therapy? Int J Radiat Oncol Biol Phys 2004; 58:
694–7.
577
 primary tumor evaluation and staging
91. Conessa C, Herve S, Foehrenbach H, Poncet JL. FDG-PET scan
in local follow-up of irradiated head and neck squamous cell
carcinomas. Ann Otol Rhinol Laryngol 2004; 113: 628–35.
92. Greven KM, Williams DW 3rd, McGuirt WF Sr, et al. Serial
positron emission tomography scans following radiation ther-
apy of patients with head and neck cancer. Head Neck 2001;
23: 942–6.
93. Goerres GW, Schmid DT, Bandhauer F, et al. positron emission
tomography in the early follow-up of advanced head and neck
cancer. Arch Otolaryngol Head Neck Surg 2004; 130: 105–9.
94. Tomura N, Watanabe O, Hirano Y, et al. MR imaging of recurrent
head and neck tumours following flap reconstructive surgery.
Clin Radiol 2002; 57: 109–13.
95. Fischman AJ, Thornton AF, Frosch MP, et al. FDG hyperme-
tabolism associated with inflammatory necrotic changes
578
following radiation of meningioma. J Nucl Med 1997; 38:
1027–9.
96. Rege S, Safa AA, Chaiken L, et al. Positron emission tomo-
graphy: an independent indicator of radiocurability in
head and neck carcinomas. Am J Clin Oncol 2000; 23:
164–9.
97. Haberkorn U, Strauss LG, Dimitrakopoulou A, et al. Fluoro-
deoxyglucose imaging of advanced head and neck cancer after
chemotherapy. J Nucl Med 1993; 34: 12–17.
98. Kubota K, Yokoyama J, Yamaguchi K, et al. FDG-PET delayed
imaging for the detection of head and neck cancer recurrence
after radio-chemotherapy: comparison with MRI/CT. Eur J
Nucl Med Mol Imaging 2004; 31: 590–5.
99. Hermans R. Posttreatment imaging in head and neck cancer.
Eur J Radiol 2008; 66: 501–11.
 28 Tumors of the Pharynx, Tongue, and Mouth
Robert Hermans
INTRODUCTION
Computed tomography (CT) or magnetic resonance imaging
(MRI) of the head and neck is frequently performed to evaluate
tumors. Most primary head and neck cancers are mucosal lesions,
and their mucosal extent can far better be evaluated by the clini-
cian than with even sophisticated imaging methods such as CT or
MRI. Indeed, imaging plays little role in the initial detection and
characterization of head and neck malignancies. However, these
tumors do have a tendency to spread submucosally. This exten-
sion into the deeply lying tissue planes is not always easy, and
sometimes impossible, to detect by clinical examination. Some
regions, such as the base of the skull, pterygopalatine and infratem-
poral fossa, orbits, and brain are beyond clinical evaluation, but
critical management decisions have to be made based on involve-
ment of these structures; imaging findings are of the utmost
importance in such cases. Perineural and/or perivascular spread,
eventually leading to tumor progression or recurrences at a dis-
tance from the primary tumor, can be detected by imaging. Bone
involvement, or cartilage invasion or destruction can be visualized
using CT or MRI. Metastatic adenopathies can be identified,
sometimes still in a subclinical stage or at places not accessible to
clinical examination, such as in the retropharyngeal or paratra-
cheal lymph nodes. All these findings can profoundly influence
the staging and management of the patient with head and neck
cancer. Finally, imaging may be used to monitor tumor response
and to try to detect recurrent or persistent disease before it
becomes clinically evident, possibly with a better chance for
successful salvage.
NORMAL ANATOMY
The pharynx is divided in three sections: the nasopharynx lies behind
the nasal cavity, the oropharynx lies behind the oral cavity, and the
hypopharynx lies behind the larynx, merging with the proximal
oesophagus at the lower level of the cricoid bone (Fig. 28.1).
The pharyngeal constrictor muscles compose the posterior and
lateral wall of the pharynx. They all insert into a midline localized
fibrous raphe. This posterolateral wall of the pharynx is a continu-
ous structure, without markings to allow separation into a naso-,
oro-, or hypopharyngeal level. The pharyngeal constrictor muscle
does not reach the skull base: cranially, it is continuous with a
fascial layer known as the pharyngobasilar fascia.
The nasopharynx is in direct communication with the middle
ear cavities via the Eustachian tubes. Each Eustachian tube has a
bony portion, in the temporal bone, and a cartilaginous portion,
ending in the nasopharynx. To reach the lumen of the nasophar-
ynx, this cartilaginous portion must perforate the pharyngobasi-
lar fascia. The natural defect in this fascia is known as the sinus
of Morgagni; this is a point of low resistance allowing spread of
cancer outside the nasopharynx.
The cartilaginous portion of the Eustachian tube forms a prom-
inent structure in the posterolateral nasopharyngeal wall known
as torus tubarius. Just posterior to the torus is a recess in the
posterolateral nasopharyngeal wall known as the lateral pharyn-
geal recess or fossa of Rosenmüller. This fossa is a common site of
origin of nasopharyngeal cancer. The actual opening of the Eustachian
tube is located just in front of the torus tubarius. Just above the
fossa of Rosenmüller is the foramen lacerum, also a point of lesser
resistance, and a potential pathway for nasopharyngeal cancer to
spread intracranially, directly into the cavernous sinus.
The soft palate separates the nasopharynx from the oropharynx.
On imaging studies, a line drawn through the hard and soft palate
is often used as a demarcation line on the lateral and posterior
wall; an alternative is to use a horizontal line through the C1 to C2
articulation (1).
The oropharynx is separated from the hypopharynx by the
pharyngo-epiglottic folds (Fig. 28.1). The border between the
oropharynx and oral cavity is more complex, being ring-like and
composed of several structures. The upper part of this ring is
formed by the junction between the hard and soft palate: the hard
palate is therefore a structure belonging to the oral cavity, while the
soft palate is an oropharyngeal structure (actually only its under-
surface—the upper surface belongs to the nasopharynx). A mucosal
fold, known as the anterior tonsillar pillars forms the lateral parts
of the ring. These mucosal folds mark the anterior border of the
tonsillar fossa. The lower part of the ring is formed by a row of
small structures on the back of the tongue, the circumvallate papillae.
These papillae are on a V-shaped line, with the tip of the V pointing
posteriorly. By definition, the posterior third or base of the tongue
is part of the oropharynx, and not of the oral cavity (2).
The soft palate is a complex structure made up of muscles, some
fat, and lymphoid tissue. Two muscles arising from the skull base
take part in the formation of the soft palate. The more medial one is
known as the levator veli palatini, the more lateral one as the tensor
veli palatini. These muscles have an important role during degluti-
tion and phonation. They also form a functional unit with the
Eustachian tube: their action opens the Eustachian tube fissure dur-
ing swallowing and yawning. Dysfunction of the Eustachian tube
causes serous otitis, a common finding in nasopharyngeal cancer.
The anterior and posterior tonsillar pillars define the triangular
tonsillar fossa. Both are mucosal folds produced by underlying
muscular structures. The anterior one is the palatoglossal muscle,
connecting the soft palate with the tongue base. Oropharyngeal
cancers commonly arise on the anterior tonsillar pillar, using this
muscle and the overlying mucosa as a pathway to spread into the
soft palate and tongue base. The posterior muscle is the palato-
pharyngeal muscle, which takes part in the formation of the mus-
cular pharyngeal wall. The tonsillar fossa harbors the palatine
tonsil, consisting of encapsulated lymphoid tissue; it is one of the
major tonsils in the lymphoid ring of Waldeyer, together with
the lingual tonsil in the tongue base and the pharyngeal tonsil
in the roof of the nasopharynx.
579
 primary tumor evaluation and staging
N
OC OP
HP
L HP
(A)
Figure 28.1 Normal upper aerodigestive tract. Sagittal (A) and coronal (B) drawing of the upper aerodigestive tract illustrates its major subdivisions: the nasopharynx
(N), oropharynx (OP), oral cavity (OC), hypopharynx (HP), and larynx (L).
Between the tongue base and the free edge of the epiglottis a pit
is formed, divided by a median mucosal fold running from the
base of the tongue to the epiglottis, known as the glosso-epiglottic
fold. These pits are called the valleculae and are part of the
oropharynx. For staging purposes, the free edge of the epiglottis,
including its lingual surface, is considered to belong to the larynx.
Underneath the bottom of the valleculae a laryngeal fat plane is
present, known as the pre-epiglottic fat plane; this fat tissue is
sometimes used by oropharyngeal tumors to extend into the larynx,
an extension which is occult to the examining clinician.
The largest part of the tongue base is made up of muscles, both
intrinsic and extrinsic muscles. On axial imaging these intrinsic
muscular fibers give the tongue base a symmetric higher density
appearance, and this should not be confused with a mass lesion.
The lymphoid tissue within the ring of Waldeyer can appear
prominent in younger subjects, prolapsing into the pharyngeal
lumen. The amount of the lymphoid tissue decreases with age.
Patients older than 40 years are not expected to have a significant
amount of residual lymphatic tissue, but small tags of tissue may
persist. The volume of the tonsils may increase due to an upper
respiratory tract infection, but also due to extranodal lymphoma
localization. A persistent or asymmetric-appearing lingual tonsil
can cause problems, as differentiation with a malignant tumor is
not always possible. Clues, which may help to differentiate, are air-
filled crypts and the presence of small calcifications within the
lymphatic tissue. Lymphatic tissue does not invade the deeper
structures. It is important to be prudent, and in the case of doubt,
biopsies are warranted.
Oral Cavity
The oral part of the tongue and the floor of the mouth have an
intimate relationship with the oropharynx. An important structure
580
Nasal septum
Soft palate
N Lateral wall:
includes fossa of
Rosenmüller
Uvula
OP
Pharyngoepiglottic
fold
Aryepiglottic fold
Piriform sinus
Posterior
pharyngeal wall
Postcricoid area
(B)
in the floor of the mouth is the mylohyoid muscle. Underneath
the mylohyoid muscle there are two paired muscles, which are the
anterior bellies of the digastric muscle. Above the mylohyoid mus-
cle there are two other pairs of muscles, the geniohyoid, attaching
to the hyoid, and the genioglossal muscles. A midline fatty space
known as the lingual septum is found in between these muscles.
The geniohyoid and genioglossal muscles are sometimes called
the root of the tongue.
The mylohyoid muscle separates two spaces: below the
mylohyoid muscle the submandibular space and above it the sub-
lingual space. The submandibular space contains lymph nodes
and the submandibular salivary gland. The sublingual space lying
between the mylohyoid muscle and the geniohyoid and genioglos-
sal muscles contains the sublingual salivary gland, some extrinsic
tongue muscle fibers and a number of vessels and nerves, such
as the lingual artery and nerve, and the hypoglossal and
glossopharyngeal nerve.
The posterior edge of the mylohyoid muscle is free-ending;
therefore, at this point the submandibular and sublingual spaces
are in continuity. The submandibular gland, lying relatively poste-
rior in the submandibular space, turns around the posterior edge
of the mylohyoid muscle, and has a small, deep component lying
in the posterior part of the sublingual space. At this point, this
gland forms its excretory duct (Wharton’s duct), which runs ante-
riorly in the sublingual space to pierce the mucosa of the floor of
the mouth anteriorly in the oral cavity.
Parapharyngeal Space and Related Spaces
The parapharyngeal space runs from the skull base to the sub-
mandibular salivary glands. It essentially consists of fat and is
bordered medially by the pharyngeal walls and laterally by
the infratemporal space (containing the masticatory muscles).
 tumors of the pharynx, tongue, and mouth
Cartilaginous
Eustachian tube
Levator palati
muscle
Lateral pharyneal
recess
Prevertebral
muscle
Retropharyngeal
node
Figure 28.2 Axial diagrammatic image through the mid-nasopharynx, demonstrating the regional anatomy and the anatomy of the parapharyngeal space.
Its function is to allow movement of the pharyngeal walls during
deglutition and of the masticatory muscles during mastication.
The parapharyngeal space is lined by the fascial margins of the
surrounding spaces. It is also bordered by the deep lobe of the
parotid gland. Posterior to this space is the carotid space contain-
ing the internal carotid artery, internal jugular vein, and the ninth
to eleventh cranial nerves (Fig. 28.2). Inferiorly it is not separated
from the submandibular space by a fascial barrier; pathology of
the parapharyngeal space can present itself as a submandibular
mass. Contrary to the superficial tissues of the oropharynx, which
may appear somewhat asymmetric, this deeper lying parapharyngeal
space should always appear symmetric and any asymmetry should
be treated with extreme caution (3).
Some authors limit the parapharyngeal space to the fatty space
anterior to the carotid space, while others consider the suprahyoid
part of the carotid space as a part of the parapharyngeal space.
Another approach is to divide the parapharyngeal space into two
compartments using the tensor veli-vascular-styloid fascia as a
separating layer. This fascial layer runs between the tensor veli
palatini muscle, styloid process, and styloid musculature; the pre-
styloid compartment is anterolateral, the retrostyloid compart-
ment is posteromedial to this fascial layer and includes the carotid
space (Fig. 28.2) (4).
The parapharyngeal space has a small anterior extension between
the oropharyngeal wall and the medial pterygoid muscle; this nar-
row space is known as the pterygomandibular space, reaching the
mandible; it contains the lingual nerve, a branch of the third por-
tion of the trigeminal nerve. This small pterygomandibular space
is actually a crossroads of several structures belonging to different
Lateral pterygoid muscle
Medial pterygoid muscle
Tensor palati muscle
Tensor veli-vascular-styloid fascia
Internal carotid artery
Styloid process
Internal jugular vein
Parotid gland
spaces. The anterior tonsillar pillar, connecting the soft palate to
the tongue base and using the pterygomandibular space as access
to the parapharyngeal space, is very close. There is also the retro-
molar trigonum of the mandible, a small triangular bony space,
located just behind the third lower molar. Its mucosal surface cov-
ers the fibrous pterygomandibular raphe on which posteriorly a
part of the pharyngeal constrictor muscle originates; anteriorly
from this raphe, the buccinator muscle takes its origin, forming
the muscular substrate of the cheek.
Key Points: Normal Anatomy
■ After the age of 40 years, no significant amount of lymphatic
tissue is expected to be present in the ring of Waldeyer
■ Slight asymmetry of the superficial oropharyngeal tissues
may be normal; correlation with clinical findings is essential
to rule out pathology
■ The deeper neck spaces, such as the parapharyngeal spaces,
should normally appear symmetric
IMAGING MODALITIES
Conventional Radiography
The role of conventional radiography in the detection and delin-
eation of these tumors is very limited. In oral cavity malignancies,
panoramic radiography may reveal erosion of the alveolar ridge in
an early stage, but is hampered by poor visualization of the lingual
and buccal mandibular surface. Mandibular films are useful to
581
 primary tumor evaluation and staging
determine the dental condition of the patient and to judge the
amount of mandibular bone available, in case a mandibular rim
resection is considered; edentulous patients may have pronounced
atrophy of the mandibular alveolar process, interfering with such
procedures.
Conventional skull films are inadequate for detecting skull base
invasion by nasopharyngeal malignancies.
A barium swallow may accurately show the mucosal extent of
hypopharyngeal cancer in patients being evaluated for dysphagia,
but this technique fails to depict the submucosal extent, impor-
tant to know for proper tumor staging.
In advanced, unresectable head and neck cancer, angiography
has a role in new treatment strategies where local supradose intra-
arterial chemotherapy is combined with radiotherapy (5).
Computed Tomography
In the evaluation of head and neck cancer there is no scientific
evidence to establish whether CT or MRI is superior. They should
be regarded as complementary tools, each with its advantages and
disadvantages.
With sufficient attention to technical detail, multidetector CT
provides very reliable and reproducible results. Important are the
use of thin slices (usually 2–3 mm), a field-of-view adapted to the
region of interest, and an adequate injection protocol of contrast
agent to obtain a good tumor to normal tissue contrast (6). Over-
all, CT is recommended as the first imaging investigation for eval-
uation of laryngeal or hypopharyngeal cancer, or when an imaging
evaluation of the entire neck is needed (e.g., staging of neck ade-
nopathies, the search for unknown primary tumors). Owing to
the short acquisition time, supplementary dynamic images can be
acquired using CT. For example, during the modified Valsalva
manoeuvre (having the patient blowing against closed lips), the
hypopharynx becomes distended; this may allow a more reliable
assessment of the extent of hypopharyngeal tumors. From the
volumetric data set obtained by multidetector CT, high-quality
multiplanar or three-dimensional images can be reformatted,
useful for treatment planning in selected cases.
CT is a reliable tool to evaluate bony structures. Thin slices
reconstructed in a high-resolution algorithm for optimal bone
detail should be obtained. High-quality MRI also provides ade-
quate information on bony structures with a sufficient thick corti-
cal margin. Although MRI is of value in detecting tumor spread
within the bone marrow, it is uncommon to see such spread
beyond the limits of bone destruction observed on CT.
Concerning suprahyoid pathology, CT and MRI yield more or
less equivalent results, but the use of MRI is usually more appro-
priate around the skull base. This is mainly related to the higher
contrast resolution obtained with MRI, very useful in the more
complex anatomical environment of the upper neck and skull
base. In oral cavity pathology, the presence of artefacts originating
from dental amalgam may limit the diagnostic yield of CT studies;
depending on the exact composition of the amalgam, MR studies
are less disturbed by these materials.
Magnetic Resonance Technique
Similar to CT, close attention to technical detail is required to
obtain MR studies of high diagnostic quality. A neck coil is used
for imaging of the infrahyoid neck, the head coil for imaging of
582
the suprahyoid neck; a combined head-neck coil, if available,
allows a uniform image quality throughout the entire head
and neck area. T2-weighted, plain, and gadolinium-enhanced
T1-weighted images are needed. Spin-echo or turbo spin-echo
sequences are used most often and are usually sufficient. Fat satu-
ration may be useful, although the use of this technique may cause
artifacts. Image thickness should not exceed 4 mm, a high-resolution
matrix (5122), and a field of view as small as feasible (taking the
signal-to-noise ratio into consideration) should be selected.
Proper magnification of the images for display is needed. Full
advantage of the multiplanar capabilities of MRI should be taken.
The main disadvantages of MRI are, apart from its higher cost and
more limited availability compared to CT, motion artefacts, espe-
cially in the region of the lower neck (swallowing, coughing, pul-
sating carotid arteries) and oral cavity (swallowing, tongue
movements). By proper patient instruction, most of these artifacts
can be reduced; however, consistent avoidance of motion-induced
artefacts is not possible as these patients tend to swallow, cough,
or scrape their throat frequently, due to symptoms caused by the
examined pathology.
Diffusion-weighted (DW) MRI is an imaging technique show-
ing molecular diffusion. Cell size, cell density, and cell integrity
influence the signal intensity seen on DW images. Recent research
suggests this technique may have an important complementary
value to standard MR-sequences, particularly in nodal staging of
squamous cell carcinoma.
Ultrasound
Although ultrasound is commonly used in the examination of the
cervical region, its value in the evaluation of primary oral cavity
and pharyngeal malignancies is limited due to bone and air inter-
faces. However, this technique has proven to be valuable in the
staging of metastatic neck adenopathies, particularly when com-
bined with ultrasound-guided fine-needle aspiration cytology
(FNAC) (7,8).
Nuclear Imaging
The diagnostic accuracy of CT and MRI is limited as these tech-
niques depend on the morphological characteristics of the tumor.
Nuclear imaging techniques allow imaging based on tissue
metabolism. The data provided by these techniques are indepen-
dent from associated structural changes; biochemical distur-
bances, preceding anatomical changes, can be detected and
monitored.
Positron emission tomography (PET) is the most sensitive and
specific technique for in vivo imaging of metabolic pathways and
receptor ligand interactions in human tissues (9). Different radio-
isotopes of natural elements can be used. The most commonly
used tracer is fluorine-18-labeled 2-fluoro-2-deoxy-D-glucose
(FDG). The use of FDG for in vivo cancer imaging is based upon
the higher rate of glucose metabolism in cancer cells.
FDG is not a specific cancer tracer, also accumulating in other non-
neoplastic hypermetabolic cells (10). This may increase the diagnos-
tic sensitivity of FDG PET, as a large part of a tumor consists of viable
non-neoplastic cells. However, it may also cause underestimation of
treatment effectiveness, due to inflammatory, immune and scaveng-
ing reactions after successful treatment, increasing the overall FDG
uptake (11). Furthermore, false-positive findings may occur, such as
 tumors of the pharynx, tongue, and mouth
non-neoplastic inflammatory changes (e.g., in radiation-induced
necrosis) accumulate FDG (12).
The clinical applications of FDG PET can be assigned to three
domains: staging disease at initial diagnosis, staging recurrent dis-
ease, and assessment of treatment response. In general, the added
value of metabolic imaging lies mainly in the exclusion of meta-
static disease, and in the follow-up of patients, rather than in the
initial, pre-treatment locoregional tumor staging (13).
Key Points: Imaging Techniques
■ The role of conventional radiography in the evaluation of
head and neck malignancies is very limited
■ Adequate locoregional staging of head and neck tumors
requires high-quality CT or MRI
■ Computed tomography and MRI are complementary imaging
tools
■ Thin slices, an adapted field of view, and a high resolution
matrix are essential both in CT and MRI
■ In CT, sufficient attention should be given to the contrast
agent injection protocol
TUMOR TYPES
Squamous Cell Carcinoma
Squamous cell carcinoma (SCC) is, apart from basocellular skin
carcinoma, the most common head and neck malignancy. These
tumors originate from the mucosa and as such are visible superfi-
cially; rarely, they arise from the duct of a minor salivary gland or
from glandular folds as in the tonsils, and develop beneath an intact-
appearing mucosa. Squamous cell carcinomas can be preceded by a
premalignant state in which the epithelial cells lose their normal
appearance and resemble malignant cells; however, infiltration of
surrounding tissues is lacking. Premalignant disease can manifest
itself as leukoplakia or erythroplakia, a white, or red mucosal lesion.
Infiltration or invasion occurs when the basal membrane of the
epithelium is disrupted. Initially only the subepithelial fibrous tis-
sue is infiltrated; the type of tissue invaded in later stages depends
on the localization of the tumor. Muscle invasion is a common fea-
ture. These tumors are usually diverted by bone or cartilaginous
structures to easier pathways of spread; bone and/or cartilage inva-
sion is mostly a late phenomenon. Perineural and/or perivascular
spread can be encountered in all head and neck localizations.
Locoregional extension of SCC of the head and neck is often due
to invasion of capillary lymphatics, with subsequently metastatic
deposits in neck lymph nodes. Some primary tumor locations are
associated with a high incidence of metastatic lymph nodes (e.g.,
nasopharyngeal carcinoma), while others rarely show such spread
(such as glottic carcinoma). Distant spread is relatively rare.
Apart from the “classic” SCC, some other types are encountered
in the head and neck region. Verrucous carcinoma is a well-
differentiated papillomatous tumor, in the oral region often asso-
ciated with other premalignant or malignant epithelial lesions.
Lymphoepithelioma (also known as undifferentiated carcinoma) is
a carcinoma with a lymphoid stroma, occurring at sites that have
lymphoid aggregates in the submucosa, namely in the ring of
Waldeyer; it predominantly occurs in the nasopharynx. Other
carcinomas resemble sarcomas, showing a squamous cell carci-
noma component; they are known as spindle cell carcinoma and
by other names.
Other Carcinomas
Adenocarcinoma is a malignant neoplasm of epithelial cells, grow-
ing in a glandular or gland-like pattern. Many have mucoserous
characteristics and are readily recognized as being of major or
minor salivary gland origin; these can be classified to standard
categories, such as adenoid cystic carcinoma and mucoepider-
moid carcinoma. Others have histological patterns that resemble
adenocarcinoma of the colon (intestinal-type adenocarcinoma);
these nearly exclusively occur in the sinonasal tract.
Minor salivary glands are found everywhere in the mucosa of
the oral and upper respiratory tract, but are concentrated in the
buccal, labial, lingual, and palatal region. Although varying figures
are reported in literature, about 50% of tumors originating from
the minor salivary glands are malignant.
About 25% to 35% of minor salivary gland tumors are adenoid
cystic carcinomas. These tumors are mainly seen in the fourth, fifth,
and sixth decades of life. The patient may present with a slow-growing
mass, concealing its true malignant nature. Sometimes a dull pain
and/or paralysis of a cranial nerve are present, related to the marked
tendency of this tumor to invade nerves. Invasion of nerves is almost
invariably a microscopic finding, and definitely more often seen
with this neoplasm than with any other head and neck cancer. Skip
lesions within nerves occur; negative surgical margins therefore
have little significance. The long-term outcome for patients with
this tumor is poor (about 75% survival rate at five years, but only
about 15% at 20 years). The relatively high recurrence rate may be
due to incomplete primary surgical treatment, related to unrecog-
nized perineural tumor extension. Distant metastatic deposits occur
late in the disease, often in the lungs; tumor progression is slow and
patients may live a long time with metastatic disease.
Mucoepidermoid carcinoma is a neoplasm apparently arising
from the ducts of major or minor salivary glands. Its incidence is
highest in the palate. It occurs at all ages, and is the most frequent
malignant salivary gland tumor in children. Mucoepidermoid car-
cinoma is often classified as low grade, intermediate, or high grade.
Low-grade tumors grow slowly, recur rather frequently, and may
rarely metastasize; high-grade tumors display an aggressive clinical
course, with a high rate of local recurrence and distant metastases.
Lymphoma (See Chap. 33)
Non-Hodgkin’s lymphoma is a heterogeneous group of neoplasms
originating from lymphocytes or their derivatives. It is a disease of
the middle-aged and elderly, with only few cases occurring before
the age of 40 years. It represents about 5% of head and neck malig-
nancies. About 11% of non-Hodgkin’s lymphomas present with
pathology in this region, and about 50% of patients with head and
neck disease have systemic disease.
Non-Hodgkin’s lymphoma can involve virtually any site in the
extracranial head and neck. Nodal involvement is common, but in
several studies extranodal localizations are reported to occur more
frequently than nodal enlargement. In the head and neck, two
distinct extranodal sites are recognized: extranodal lymphatic
localizations or involvement of Waldeyer’s ring, and extranodal
extralymphatic localizations (14).
583
 primary tumor evaluation and staging
Hodgkin’s lymphoma is less commonly seen in the head and
neck region. Unlike non-Hodgkin’s lymphoma, primary extran-
odal localizations are rare in Hodgkin’s lymphoma, especially
without involvement of lymph nodes. Extranodal spread usually
occurs when the tumor breaks through the nodal capsule and
grows into the neighboring tissues. Involvement of Waldeyer’s
ring by Hodgkin’s lymphoma is very rare (15).
Sarcoma
Rhabdomyosarcoma is a malignant tumor of skeletal muscle. This
tumor mainly occurs in children. Apart from lymphoma, it is the
most common malignant tumor of the head and neck in child-
hood. Rhabdomyosarcoma is divided into four histological sub-
types: embryonal, botryoid, alveolar, and pleomorphic; the
embryonal and botryoid subtype account for about 90% of pri-
mary head and neck lesions. Head and neck rhabdomyosarcoma
has three sites of predilection: the orbit, the nasopharynx and
paranasal cavities, and the temporal bone. Patients with a naso-
pharyngeal, paranasal, or temporal bone rhabdomyosarcoma are
at risk of developing meningeal extension, followed by brain
involvement and eventually subarachnoidal dissemination to the
entire neural axis. Lymphatic spread is rarely seen. Distant metas-
tasis, mainly to the lungs, is detected in about 10% to 15% of
patients presenting with head and neck rhabdomyosarcoma.
Osteosarcoma is a malignant tumor arising from bone-forming
cells. About 6% of the osteosarcomas originate in the maxillo-
facial skeleton, the mandible being the most frequent site. There is
a wider age distribution in maxillofacial osteosarcoma than in
skeletal osteosarcoma.
EPIDEMIOLOGY OF ORAL CAVITY AND PHARYNGEAL
SQUAMOUS CELL CARCINOMA
Malignant tumors of the head and neck region are found infre-
quently. The age-adjusted incidence is between 0.4 and
1.4:100,000/year for men; the age-adjusted incidence for women
is lower. Generally, these tumors start to be seen in middle-aged
persons, with a rising incidence up to the age of 70 to 80 years.
Some malignancies, including nasopharyngeal cancer, may be
seen in younger individuals.
Some head and neck tumors are found very frequently in some
parts of the world, such as oral cancer in India and nasopharyn-
geal cancer along the southeastern coast of China.
In west Europe, about one quarter of head and neck tumors
arises in the larynx, one-forth in the oral cavity, and one-forth in
the pharynx; about 12% arises in the thyroid gland and about 7%
in the salivary glands. Overall, these tumors belong to the malig-
nancies with a relatively good prognosis after appropriate therapy,
with a five-year survival rate of about 67%.
The incidence of these tumors is clearly affected by environmen-
tal factors. Cigarette smoking can therefore increase the relative
risk up to 20 times. High alcohol consumption has a synergistic
effect together with smoking. The relation with alcohol abuse and
cigarette smoking has been demonstrated for tumors of the oral
cavity, oro- and hypopharynx, and larynx. These factors explain
the higher incidence in men; changing habits over the past decades
have led to a higher frequency of these tumors in women (16).
584
There seems to be an association between nasopharyngeal
carcinoma and infection with the Epstein–Barr virus; a causal
relation has not been proven.
Smoking and alcohol abuse irritate the entire mucosa of the
respiratory tract, inducing premalignant and malignant lesions.
This has led to the concept of “field cancerization” or “condemned
mucosa.” A second primary malignant tumor can be detected dur-
ing the diagnostic work-up of the first malignant tumor (“index
tumor”); a new malignant tumor can also be detected during
follow-up of the index tumor. The reported frequency of such a
second malignant tumor ranges from 10% to 35%.
Key Points: Tumor Types and Epidemiology
■ Squamous cell carcinoma is the most common head and
neck malignancy, commonly invades muscle, and shows
perineural and perivascular spread
■ Adenocarcinoma can be classified as adenoid cystic, mucoepi-
dermoid, or intestinal type (which occur mainly exclusively
in the sinonasal tract)
■ Other malignancies include lymphoma and sarcoma
(rhabdo- and osteosarcoma)
■ The age-adjusted incidence for men of head and neck tumors
is 0.4 to 1.4/100,000; less for women; incidence is related to
cigarette smoking and alcohol consumption
ORAL CAVITY TUMORS
Clinical Presentation
Roughly 25% of all head and neck malignancies originate in the
oral cavity. Most of them are SCC. The natural behavior and symp-
toms of the cancer vary according to the site of origin within the
oral cavity. Although tumors in this region may present at an ear-
lier stage than elsewhere due to easy inspection, some may present
in a locally advanced stage. The distribution of cancer, according
the WHO-defined oral cavity regions, is shown in Table 28.1 (17).
A small minority originates from minor salivary glands; these
are most commonly seen in the palate. Adenoid cystic carcinoma
may present with neurological symptoms, such as facial pain,
without a tumor mass being visible.
Staging and Radiological Features
The T-staging is based on tumor size and whether adjacent struc-
tures are involved (Table 28.2).
Lip
Nearly all lip cancers are located in the under lip (90%) and are
detected in an early stage. Upper lip cancers behave more
Table 28.1 Distribution of Oral Cancer According
to WHO-Defined Regions
Lip 40%
Cheek (including gingiva and retromolar trigone) 20%
Oral tongue 20%
Floor of the mouth 15%
Hard palate 5%
Source : From Ref. 36.
 tumors of the pharynx, tongue, and mouth
Table 28.2 T-Staging of Lip and Oral Cavity Carcinoma (24)
Tis Carcinoma in situ
T1 Tumor <2 cm in greatest dimension
T2 Tumor >2 cm but <4 cm in greatest dimension
T3 Tumor >4 cm in greatest dimension
T4a Lip: Tumor invades through cortical bone, inferior alveolar nerve, floor
of mouth, or skin of face (chin or nose)
Oral cavity : Tumor invades through cortical bone into deep/extrinsic
muscle of tongue (genioglossus, hyoglossus, palatoglossus, and
styloglossus), maxillary sinus, skin of face
T4b Lip and oral cavity: Tumor invades masticator space, pterygoid plates,
skull base or encases internal carotid artery
Source : From Ref. 64.
Figure 28.3 Coronal gadolinium-enhanced T1-weighted spin-echo image in a
patient with an upper gingivobuccal sulcus cancer (white asterisk). The lesion
extends into the buccinator space (black arrowheads) and erodes the alveolar
process of the maxilla (white arrowhead); the maxillary sinus is also invaded (black
asterisks).
aggressively and are more difficult to treat. Advanced cases of
lip cancer may erode bone and grow perineurally. Lymphatic
spread is first to lymph nodes at levels I and II.
Most lip cancers do not require imaging. Only advanced or
recurrent lesions are referred for imaging. This may be done either
by CT or MRI. Early mandibular or maxillary bone invasion may
be easier to detect using CT, but MRI may be preferred in cases
suspect for perineural tumor spread.
Cheek, Including Gingiva and Retromolar Trigone
Most cancers of the cheek mucosa originate at the level of the teeth
occlusion line; although easily visible or palpable at that level they
often present in an advanced stage, growing in the buccinator muscle
and space, possibly extending into the infratemporal fossa.
Most gingival cancers originate from the lower buccogingival
sulcus. In many cases the mandible is involved at presentation.
Lesions originating from the upper buccogingival sulcus may
invade the maxillary bone and sinus (Fig. 28.3).
Cancer originating in the retromolar trigone rapidly spreads to
neighboring structures, such as medial to the anterior tonsillar
pillar in the oropharynx, anteriorly to the buccinator space, pos-
teromedial to the parapharyngeal space via the pterygomandibu-
lar space, inferior to the floor of the mouth, and superior to the
nasopharynx and maxillary tuberosity (Fig. 28.4). As the retromo-
lar trigone overlies the mandible, early bone invasion may occur.
Much of the tumor spread may occur subclinically but is visual-
ized with dedicated CT or MRI. The retromolar trigone is fairly
commonly involved by lateral spread of oropharyngeal cancer.
Oral Tongue
Most tongue cancers originate in the oral part of the tongue.
Tumors arising from the most anterior part are usually seen in an
early stage as a superficial lesion. More posteriorly located lesions
may be deeply infiltrating at presentation; there is no barrier within
the tongue to restrict their spread. Posterior spread to the orophar-
ynx (along the anterior tonsillar pillar) and further inferior spread
to the sublingual space and remainder of the floor of the mouth is
possible. The first-order lymph nodes are the submandibular and
high parajugular groups (levels I and II). CT or MRI is very useful
for studying the deep spread of these cancers (Fig. 28.5).
Floor of Mouth
Cancer arising in the anterior floor of the mouth commonly spreads
into the sublingual space; such spread may obstruct Wharton’s duct,
and cause retro-obstructive submandibular sialadenitis; an enlarged
and inflamed submandibular salivary gland may clinically be
mistaken for a metastatic submandibular adenopathy.
The tumor may grow medially and cross the midline. Lateral
extension to the mandible is seen in bulky tumors. Laterally
spreading tumor is diverted superiorly by the strong mandibular
periosteum; neoplastic invasion of the mandible usually occurs
via the dental sockets. Superior extension into the oral tongue
may occur and is often subclinical. Posterior extension into the
deep neck spaces can be seen. Inferior spread through the
mylohyoid muscle may be encountered in very advanced cases.
Pathology arising from the sublingual gland is rare. However,
sublingual gland neoplasms are predominantly malignant and
thus important to recognize; most patients present with a submu-
cosal mass under the tongue, causing discomfort.
Palatal Tumors
Unlike tumors at other oral cavity sites, those that arise at the level
of the hard palate are more commonly of salivary gland histology
than squamous cell tumors as the palate has the highest concen-
tration of minor salivary glands of any site in the upper aerodiges-
tive tract (18).
Upper buccogingival sulcus cancers are difficult to differentiate
from primary hard palate cancer. Advanced palatal cancers are
also difficult to differentiate from primary sinonasal cancer,
extending to the hard palate.
Palatal cancer commonly ulcerates and invades the palatal bone;
more advanced lesions spread to the nasal cavity and maxillary
sinus.
585
 primary tumor evaluation and staging

(A) (B)

(C)

Figure 28.4 Axial CT images in a patient with an extensive cancer, centered on the right retromolar trigonum. (A) From the region of the retromolar trigonum (black
asterisk), the soft tissue mass extends towards the medial pterygoid muscle and anterior tonsillar pillar (black arrows). Extension towards the base of the tongue and floor
of the mouth (white arrowhead) is seen. The lesion causes mandibular osteolysis and grows massively in the soft tissue of the cheek (white arrowheads). (B) The soft
tissue lesion is growing more cranially along the anterior margin of the mandibular ramus and into the soft palate (asterisks; medial tumor border in soft palate indicated
by black arrowhead); superior extension is also seen underneath the buccinator muscle (white arrowheads). (C) The lesion reaches lateral to the maxillary alveolar
process (white arrowheads) and maxillary tuber (black arrow); also at this level, tumor involvement of the palate is recognized (white arrows).

Perineural spread along palatine branches of the maxillary nerve
may occur to reach the pterygopalatine fossa; from there it may
spread intracranially to reach the cavernous sinus. Such perineu-
ral spread may be discontinuous, with skip areas (17). As palatal
tumors of minor salivary gland origin are often submucosal, they
may be asymptomatic, only becoming diagnosed when perineural
tumor spread occurs. Dedicated imaging is of great importance in
such cases (Fig. 28.6) (19).
Differential Diagnosis
Sublingual pathology is often associated with sialolithiasis, but
this has a different clinical and radiographic presentation.
A ranula is an epithelial-lined cyst in the sublingual space, origi-
nating from the sublingual salivary gland and caused by obstruction
of its duct(s). It is a mucous retention cyst. A simple ranula is limited
to the floor of the mouth, superior to the mylohyoid muscle. After
rupture, a ranula may dissect through the mylohyoid muscle, appear-
ing in the submandibular space; it is then termed a plunging ranula.
Aggressive fibromatosis is a very rare, locally invasive prolifera-
tion of fibrous tissue, with a musculo-aponeurotic origin, typi-
cally occurring in children and young adults. It may occur in the
oral cavity and submandibular space. On CT it appears as a mass
lesion with variable enhancement; the signal characteristics on
MRI are also variable.
The most common tumoral pathologies of the mandible are
odontogenic cysts and, more rarely, odontogenic tumors; nearly
always, these lesions show features very different from cancer,
both on clinical and radiographic examination.

586
 tumors of the pharynx, tongue, and mouth

(A) (B)

Figure 28.5 (A) Axial gadolinium-enhanced T1-weighted spin-echo image. Enhancing soft tissue mass in the right side of the oral tongue, extending over the midline
(arrowheads). Posterior extension into the tongue base (arrow). (B) Coronal gadolinium-enhanced T1-weighted spin-echo image. Inferiorly, the lesion is bordering the
sublingual gland (asterisk). Medially, the lesion is again seen to extend slightly over the midline, invading the superior portion of the lingual septum (arrow). Squamous
cell carcinoma was diagnosed.

Several non-odontogenic tumors may affect the mandible.
Apart from SCC invading the mandible, malignant tumors include
osteosarcoma (seen in a younger population than cancer patients),
mandibular metastasis (rare), multiple myeloma (associated with
other bone lesions), and non-Hodgkin’s lymphoma (rare, usually
associated with nodal and possibly other extranodal localizations,
often with no risk factors for cancer).
Treatment
The treatment of oral cavity cancer depends on its location and
extent at presentation. Small lesions can often be cured by wide
resection and subsequent surgical reconstruction, or by brachyther-
apy. Larger lesions are treated by radiotherapy, concomittant chemo-
radiotherapy, or a combined therapy. When a cancer lesion is close to
or involving the mandible, mandibular rim resection or partial man-
dibulectomy may be necessary. The treatment choice is also influ-
enced by the presence and extent of metastatic neck adenopathy.
Key Points: Oral Cavity Tumors
■ Submucosal spread of oral cavity cancer is common
■ Deep spread must be precisely determined by imaging
techniques
■ Perineural spread may occur, particularly in adenoid cystic
carcinoma
OROPHARYNGEAL TUMORS
Clinical Presentation
Squamous cell carcinoma is the most frequent malignant tumor
of the oropharynx (90%). Most patients complain of a sore throat,
otalgia, or dysphagia; more advanced, invasive tumors may cause
severe pain and trismus.
Staging and Radiological Features
The T-staging is based on tumor size and whether adjacent
structures are involved ( Table 28.3 and Fig. 28.7)
Tongue base cancer tends to grow silently and deeply, and is
often larger than suspected at clinical examination. Peripheral
tumors may spread to the anterior tonsillar pillar, but this is less
frequently seen than spread of tonsillar cancer to the tongue base.
Anterior spread into the floor of the mouth and/or tongue body
may occur (Fig. 28.8). Spread to the valleculae and piriform
sinuses, and into the pre-epiglottic space may be seen.
Extension of a tongue base cancer across the midline usually pre-
cludes surgical cure as one lingual neurovascular pedicle needs to be
conserved for sufficient functional recovery to allow safe swallowing.
Nearly all tonsillar cancers originate from the anterior tonsillar
pillar. These cancers spread antero-inferiorly to the tongue base, and
superomedially to the soft palate, both along the palatoglossal mus-
cle. Anterolateral spread, along the pharyngeal constrictor muscle to
the retromolar trigone, is also commonly seen (Fig. 28.9). Advanced
lesions may invade the mandible and spread along the pharyngeal
wall to the nasopharynx, or through the pharyngeal wall into the
parapharyngeal space and muscles of mastication (Fig. 28.10).
Soft palate cancer may spread laterally along the tonsillar pillars.
Superior spread to the nasopharynx occurs in advanced disease.
Carcinoma of the soft palate may occasionally spread perineurally
along palatine branches of the maxillary nerve (18).
Lesions of the posterior oropharyngeal wall are rare; they may
spread (sub)mucosally both to the hypopharynx and nasopharynx.
Lymphatic spread usually occurs in a predictable way, from
superior to inferior, the upper parajugular lymph nodes (level II)

587
 primary tumor evaluation and staging

(A) (B)

(C)

Figure 28.6 Patient presenting with right-sided unilateral facial headache and anaesthesia of the palate. Clinically, there was no evidence for a tumoral lesion. Axial plain
T1-weighted spin-echo image (A) shows a soft tissue mass lesion in the right pterygopalatine fossa (asterisk), extending anterolaterally along the wall of the maxillary
sinus (double arrowhead), laterally in the infratemporal fossa (arrow), and posteriorly in the pterygoid canal (single arrowhead). Section somewhat lower (B) shows soft
tissue thickening in the region of the greater palatine canal (containing the greater palatine nerve, large arrow), and along the posterolateral wall of the maxillary sinus
(arrowheads); there is signal loss in the right bony pterygoid process (small arrows). At the level of the maxillary alveolar process (C), soft tissue thickening is seen at its
palatal side (arrow) and vestibular side (arrowheads); the bone itself also shows signal loss (asterisk). These findings are highly suggestive of a malignant neoplasm, arising
at the level of the palate, with extensive perineural tumoral spread. Deep biopsy revealed adenoid cystic carcinoma.

Table 28.3 T-Staging of Oropharyngeal Carcinoma (24) Imaging is performed to evaluate the tumor extent as described
earlier.
Tis Carcinoma in situ
T1 Tumor <2 cm in greatest dimension
T2 Tumor >2 cm but <4 cm in greatest dimension Differential Diagnosis
T3 Tumor measures >4 cm in greatest dimension The lateral oropharyngeal walls sometimes appear somewhat
T4a Tumor invades any of the following: larynx, deep/extrinsic muscle of
the tongue (genioglossus, hyoglossus, palatoglossus, and styloglos-
asymmetric on imaging studies; this can be due to asymmetric
sus), medial pterygoid, hard palate, and mandible chronic inflammation of the palatine tonsils, a condition regularly
T4b Tumor invades any of the following: lateral pterygoid muscle, seen in the patient population at risk for tumor pathology of this
pterygoid plates, lateral nasopharynx, skull base, or encases the region, often smokers and drinkers. Slight asymmetry in the thick-
carotid artery ness of the lateral oropharyngeal walls should therefore not be
Source : From Ref. 64. considered as evidence of a tumor, although it should be regarded
with suspicion, making sure no other signs of tumor involvement
being the first at risk for lymphatic spread from an oropharyngeal are present (2). Small calcifications are frequently seen in this
cancer. Retropharyngeal adenopathy may occur (Figs. 28.9 and 28.10). region; these are probably due to calcium precipitation in areas of
Bilateral adenopathies are commonly seen in soft palate cancer as previous or chronic inflammation. Small retention cysts can also
well as in cancer of the base of the tongue. be seen in this region.

588
 tumors of the pharynx, tongue, and mouth
T1 T2
≤2 cm
2–4 cm
T4a
Tumor invades the larynx, deep/extrinsic muscle
of tongue, medial pterygoid, hard palate, or mandible
Figure 28.7 Oropharyngeal staging diagram.
Owing to the abundant lymphoid tissue in the oropharynx
(lingual and palatine tonsils), non-Hodgkin’s lymphoma occurs
in this region (8%). These tumors frequently appear large and
homogeneous on imaging studies; adenopathies may be present at
sites unusual for an untreated carcinoma, or the oropharyngeal
lesion may be associated with another extranodal neck lymphoma
location (14). Such findings occurring in patients without the
classical risk factors for head and neck carcinoma are suggestive of
lymphoma.
Minor salivary gland tumors are also seen (2%); in the soft pal-
ate, these are usually benign pleomorphic adenomas, but in other
oropharyngeal sites, mucoepidermoid and adenoid cystic carci-
noma predominate (Fig. 28.11) (20).
Treatment
Oropharyngeal cancer is treated with curative intent by radiother-
apy, surgery, or a combination of both modalities. Advanced
T3
>4 cm
T4b
Tumor invades lateral pterygoid muscle, pterygoid plates,
lateral nasopharynx or skull base or encases carotid artery
lesions can be treated by concomittant chemoradiotherapy. The
benefit of improving the survival of the patients must be weighed
against the toxicity inherent to the combined use of chemotherapy
and radiotherapy (21).
Key Points: Tumors of the Oropharynx
■ Many oropharyngeal SCCs arise from the anterior tonsillar
pillar
■ Submucosal tumor extension within the oropharynx is
common
■ In tumors of the tongue base, extension across the midline
usually precludes surgical cure
■ Spread to the prestyloid and/or poststyloid parapharyngeal
space, and infratemporal space may occur
■ The tonsillar fossa is a prime site for lymphoma
589
 primary tumor evaluation and staging
Figure 28.8 Axial plain T1-weighted spin-echo image in a patient with a left-sided
tongue base cancer. The soft tissue mass (asterisk) grows over the midline (black
arrowheads), involves the left sublingual space (arrow) and genioglossus/geniohyoid
muscle (white arrowhead).
NASOPHARYNGEAL CARCINOMA
Clinical Presentation
The most common nasopharyngeal malignancy is SCC. The most
common presenting symptom is a neck mass (caused by neck
adenopathies). Nasal obstruction is also common; epistaxis may
be present. Hearing loss secondary to dysfunction of the eusta-
chian tube may also be the first symptom; unilateral serous otitis
media in an adult patient should always raise the possibility of a
nasopharyngeal tumor. With disease progression, other symptoms
may arise, such as those caused by skull base invasion (resulting in
cranial nerve dysfunction in 15% to 20% of cases at presentation)
or by orbital invasion.
Staging and Radiological Features
(Table 28.4, Fig. 28.12)
Imaging is required for both staging and treatment planning. MRI
is the preferred imaging modality as it shows early invasion of the
pharyngobasilar fascia, allowing earlier identification of spread to
surrounding soft tissue structures, such as the parapharyngeal
space. Detection of such tumor invasion is required by the T-staging
system (22). Complementary CT may be useful for detection of
early cortical bone invasion at the level of the skull base; however,
MRI is more reliable in detecting bone marrow infiltration (23).
In contrast to the primary tumor, cervical lymphadenopathy is
more accurately evaluated using CT (24). Therefore, comprehensive
evaluation of locoregional tumor extent in nasopharyngeal cancer
590
may require both imaging modalities. Taking cost into consider-
ation, staging the primary tumor and cervical adenopathies ini-
tially with CT may be recommended, with MRI as a complementary
tool if a diagnostic problem has not been resolved with CT (25).
An alternative approach may be to use MRI to stage the primary
tumor and retropharyngeal lymph nodes, and to apply ultrasound
for evaluation of neck disease.
The T-staging is determined by the anatomical extent of the
primary lesion (Table 28.4 and Fig. 28.15) (26).
Many of these tumors arise in Rosenmüller’s fossa. Lateral
spread through the foramen of Morgagni provides access to the
parapharyngeal space, and is commonly seen (Fig. 28.13). Such
spread leads to involvement of the levator veli palatini, resulting in
serous otitis media. Further posterolateral spread may cause
involvement of the carotid space and even the jugular foramen
(Fig. 28.14), which may result in cranial nerve palsies.
From the parapharyngeal space, the mass may spread to the
skull base and/or progress towards the masticator space.
Direct superior extension in or through the skull base is seen in
about 25% to 35% of patients (27). Skull base invasion may occur
at the level of the foramen lacerum and/or petroclinoid fissure
(Fig. 28.15). Intracranial invasion is detected in 3% to 12% of
patients. If the lesion spreads to the masticator space, superior
extension along the mandibular nerve (through the foramen
ovale) may be observed (Fig. 28.14).
Anterior spread to the nasal cavity is also commonly observed;
this may progress to involvement of the pterygopalatine fossa via
the sphenopalatine foramen. Destruction of the pterygoid process
and posterolateral wall of the maxillary sinus may be seen. From
the pterygopalatine fossa, retrograde perineural extension along
the maxillary nerve may be seen, possibly reaching the cavernous
sinus and even the cisternal portion of the trigeminal nerve.
Posterior spread may cause involvement of the prevertebral
muscles (Fig. 28.14); very advanced cases may show involvement
of vertebral bodies and spinal canal.
Inferior extension along the pharyngeal walls may be observed.
Nasopharyngeal cancer may spread to all lymph node levels in
the head and neck, but the primary draining lymph nodes are the
retropharyngeal lymph nodes. Medial and lateral retropharyngeal
lymph nodes are distinguished, the lateral ones being the most
frequently seen. These adenopathies are seen to occur medial to
the internal carotid artery and only exist above the level of the
hyoid bone. In nasopharyngeal cancer, they may be difficult to
recognize, as they often blend with the primary tumor.
Differential Diagnosis
Radiological differentiation between SCC and non-Hodgkin’s lym-
phoma of the ring of Waldeyer (including the pharyngeal tonsil) may
be difficult, especially when there is extension outside the tonsils.
Findings that suggest the correct diagnosis are multiple non-contiguous
sites of disease (rarely seen in SCC) and an association with large,
non-necrotic lymph nodes, especially when they are bilateral and in
unusual draining routes for SCC. The diagnosis of non-Hodgkin’s
lymphoma is strongly suggested if there is an association between a
lesion in the ring of Waldeyer and an extralymphatic lesion.
Apart from lymphoma, rhabdomyosarcoma should be consid-
ered in children. These tumors are usually large at presentation
 tumors of the pharynx, tongue, and mouth

(A) (B)

(C)

Figure 28.9 Axial contrast-enhanced CT images in a patient with right-sided oropharyngeal cancer. (A) A soft tissue mass is visible in the tongue base (arrows). (B) At a
slightly higher level, the lesion (arrows) is seen to extend across the glossotonsillar sulcus (black arrow) into the anterior tonsillar pillar; there may also be some slight soft
tissue thickening and increased enhancement on the soft palate (arrowhead). (C) Retropharyngeal adenopathy on the right, and a questionable retropharyngeal lymph
node on the left (arrows).

and nearly always invade neighboring structures; lymphadenopa-
thies are rarely seen.
Juvenile angiofibroma is an uncommon, highly vascular, locally
invasive benign tumor that originates almost exclusively in the
posterior nasal cavity of adolescent males. Symptoms include
nasal obstruction and recurrent severe epistaxis. The tumor
appears clinically as a deep red mass with increased vascularity of
the overlying mucosa. Biopsy is seldom required and dangerous
to perform. On CT and MRI, the tumor appears as a strongly
contrast-enhancing mass lesion in the posterior nasal cavity and
nasopharynx, with intratumoral flow voids present on MR
images. The mass lesion is typically centered on the sphenopala-
tine foramen and very often extends into the pterygopalatine
fossa, resulting in widening of this fossa with anterior bowing of
the posterior maxillary wall. Invasion of the neighboring skull
base structures is often seen; orbital and infratemporal spread are
not uncommon. In large tumors, even intracranial extension may
be seen.
Treatment
Nasopharyngeal carcinoma is treated, depending on its stage, by
radiotherapy or chemoradiotherapy. The radiation fields are indi-
vidualized based on disease extent; imaging findings play an impor-
tant role in this regard.
The control rates after radiotherapy are higher for nasopharyn-
geal lymphoepithelioma compared to squamous cell carcinoma at
other head and neck sites.
Surgery may be considered in resectable local recurrences.

591
 primary tumor evaluation and staging

(A) (B)
Figure 28.10 (A) Axial T2-weighted and (B) plain T1-weighted spin-echo image in a patient with an oropharyngeal cancer on the left side. The soft tissue mass involves
the palatine tonsil, grows through the pharyngeal constrictor muscle into the parapharyngeal space (thick arrows), reaches the retromolar trigone (thin arrow), and
compresses slightly the tongue base (thin arrowheads). Retropharyngeal adenopathy (white asterisk). Normal pharyngeal constrictor muscle on right side (thick arrowheads);
normal right parapharyngeal space (black asterisk).

Key Points: Tumors of the Nasopharynx

■ Most nasopharyngeal cancers arise in the fossa of
Rosenmüller
■ Spread into the surrounding structures, including the skull
base, is common
■ The incidence of distant metastatic disease is higher in
nasopharyngeal cancer compared with other head and neck
cancers
■ Imaging plays an important role in planning radiotherapy

HYPOPHARYNGEAL CANCER

Clinical Presentation
The lesions may remain asymptomatic for a long period; at pre-
sentation, the disease is often advanced. The characteristic symptoms
are sore throat, referred otalgia, and dysphagia, but frequently a
neck mass (due to metastatic neck adenopathies) is the presenting
symptom.

Staging and Radiological Features

Figure 28.11 Axial T2-weighted spin-echo image. Well demarcated hyperintense
soft tissue mass (arrow) posterolaterally in the tongue base. Mucoepidermoid
The T-staging is determined by tumor size, extent and presence of
carcinoma was diagnosed. hemilaryngeal fixation (Table 28.5 and Fig. 28.16) (26).
Early piriform sinus tumors may be very subtle; images
Table 28.4 T-Staging of Nasopharyngeal Carcinoma (26) obtained during a modified Valsalva manoeuvre (while letting
the patient blow against closed lips) may be helpful (Fig.
Tis Carcinoma in situ
T1 Tumor confined to nasopharynx
28.17). Larger cancers appear as soft tissue masses, often
T2 Tumor extends to oropharynx and/or nasal fossa involving the anterior, lateral, and posterior wall of the piri-
T2a—without parapharyngeal extension form sinus. Piriform sinus cancers have the tendency to grow
T2b—with parapharyngeal extension anteriorly in the laryngeal paraglottic space. Anterolateral
T3 Tumor invades bony structures and/or paranasal sinuses spread often results in invasion of the thyroid cartilage
T4 Tumor with intracranial extension and/or involvement of cranial
(Fig. 28.18). Soft tissue thickening or obliteration of the deep
nerves, infratemporal fossa, hypopharynx, orbit or masticator space
fat planes behind the level of the true vocal cord signifies
Source : From Ref. 64.
involvement of the piriform sinus apex. Inferior extension

592
 tumors of the pharynx, tongue, and mouth

T1

T2a T2b

T3

T4

T4

Intracranial extension and/or involvement of cranial nerves, infratemporal fossa, hypopharynx, orbit or masticator space
Figure 28.12 Nasopharyngeal staging.

into the postcricoid area may occur submucosally and there-
fore be endoscopically undetectable (Fig. 28.19). Lateral exten-
sion may result in extrapharyngeal spread into the neck; the
large neck vessels are then at risk of becoming involved by the
primary tumor.
Cancer of the posterior hypopharyngeal wall commonly appears
as a flat but often widespread mass lesion, which may extend into
the lower oropharynx.
Cancer originating in the postcricoid area is rare. Besides superior
spread within the hypopharynx and extrapharyngeal spread,
involvement of the proximal oesophagus may also be seen.
These cancers may invade the prevertebral muscles; CT and
MRI have a high true-negative but also high false-positive rate in
diagnosing such posterior tumoral spread.
At least 60% of patients with hypopharyngeal cancer present
with clinically positive nodal metastases. In a small minority of

593
 primary tumor evaluation and staging

patients, the primary cancer may at that stage be clinically occult,
and may be detected by imaging. At least 75% will have neck ade-
nopathies at some time during the course of disease (20).
Differential Diagnosis
Nearly all malignant tumors of the hypopharynx are SCC. Rarely,
a sarcoma, minor salivary gland neoplasms or plasmocytoma may
occur. These entities show non-specific imaging findings; they are
dealt with in a similar way to SCC.
Treatment
Most posterior hypopharyngeal wall lesions are treated by radio-
therapy or, depending on their stage, by chemoradiotherapy. Post-
cricoid cancer is treated by total laryngopharyngectomy and
reconstruction, usually with a pectoralis major myocutaneous
flap. If the tumor extends to the oesophagus, an oesophagectomy
is also required. In cancer confined to the piriform sinus or with
minimal extension beyond it, a partial laryngopharyngectomy is
feasible; in larger lesions, growing beyond the borders of the piri-
form sinus, total laryngopharyngectomy may be necessary.
Low-volume hypopharyngeal cancer can be effectively treated
by radiation therapy. As in laryngeal cancer (28,29), CT (or
MRI) is helpful in selecting patients into a favorable group for
radiation treatment, by providing an estimate of tumor vol-
ume. It appears that patients with bulky disease at the piriform
apex on imaging have a less favorable local outcome after
radiotherapy (30).

Key Points: Tumors of the Hypopharynx

Figure 28.13 Gadolinium-enhanced T1-weighted spin-echo image through the
nasopharynx. Tumor mass in the nasopharyngeal lumen (asterisk). On the left
side, the levator veli palatini muscle (white arrowhead), tensor veli palatini muscle
(white arrow) and pharyngobasilar fascia (black arrowhead) are recognized. On
the right side, the levator veli palatini muscle is not visible any more; the tumor
grows focally through the pharyngobasilar fascia (black arrow), showing early
infiltration of the parapharyngeal space.
■ Hypopharyngeal cancer is nearly always SCC
■ Commonly present with neck nodal disease; the primary
tumor may be clinically occult
■ The primary tumor is often in an advanced stage at presentation
■ Subclinical submucosal cancer spread is common, to be
detected by CT/MRI
■ Computed tomography or MRI is helpful in selecting a
favorable group of patients for radiotherapy by providing an
estimate of tumor volume

(A) (B)
Figure 28.14 Gadolinium-enhanced T1-weighted spin-echo images through the nasopharynx. (A) Axial image showing tumor mass extensively invading the parapha-
ryngeal space, involving both the prestyloid (white asterisks) and retrostyloid compartment (black arrow). The tumor mass lies close to the lateral pterygoid muscle
(black asterisk). The right-sided masticatory muscles (black asterisk and black arrowheads) show slight volume loss and somewhat higher intensity compared to the left,
suggestive of denervation atrophy and indicating involvement of the mandibular nerve. The prevertebral muscles are invaded (white arrow). (B) Coronal image shows
lateral spread of the tumor (asterisk), extending through the foramen ovale into the cavernous sinus (arrowhead).

594
 tumors of the pharynx, tongue, and mouth

(A) (B)

Figure 28.15 Gadolinium-enhanced T1-weighted spin-echo images through the nasopharynx. (A) Axial image showing a large soft tissue mass, centered on the right
fossa of Rosenmüller (normal left fossa of Rosenmüller, arrow). The lesion extends in the right parapharyngeal space, displacing the tensor veli palatini muscle
(arrowheads). (B) Coronal image showing spread through the skull base, at the level of the foramen lacerum, into the cavernous sinus (arrow); the cavernous portion of
the internal carotid artery is displaced by the tumor mass. Tumoral spread is seen through the lateral wall of the right sphenoid sinus, also containing more hypointense
inflammatory material.

Table 28.5 T-Staging of Hypopharyngeal Carcinoma (26)
Tis Carcinoma in situ
T1 Tumor limited to one subsite of hypopharynx and <2 cm in greatest
dimension
T2 Tumor invades more than one subsite of hypopharynx or an adjacent
site, or measures >2 cm but <4 cm in greatest dimension, without
fixation of hemilarynx
T3 Tumor measures >4 cm in greatest dimension, or with fixation of
hemilarynx
T4a Tumor invades any of the following: thyroid/cricoid cartilage, hyoid
bone, thyroid gland, oesophagus, central compartment soft tissue
T4b Tumor invades prevertebral fascia, encases carotid artery, or invades
mediastinal structures
Source: From Ref. 64.
NECK LYMPH NODE STAGING
Clinical evaluation of neck lymph nodes is not very precise, with
false-negative and false-positive rates of 15% to 25% and 30% to
50%, respectively, being reported.
The radiological criteria used to diagnose neck lymphadenopa-
thy on CT and MR studies are size and internal structure. A mini-
mum axial diameter of >10 mm or the presence of central
hypodensity, indicating necrosis, are generally accepted criteria of
abnormality. The size criterion is a compromise between sensitiv-
ity and specificity. Using such criteria, the sensitivity of CT is
about 90%, and the specificity about 73%. The results with CT
are generally slightly better than with MRI (24).
The impact of imaging on patient management is high when
lymphadenopathy, previously undetected clinically or at places
beyond the planned treatment field, is seen. In SCC, CT, or MRI
shows lympadenopathy in 7.5% to 19% of clinical “N0 necks”
(necks where no lymphadenopathy can be palpated). Imaging
may detect lymphadenopathy in the retropharyngeal or paratra-
cheal spaces, and in sites that are not accessible or that cannot be
reached without difficulty by clinical examination alone.
None of the currently available anatomical imaging methods
can reliably depict small tumor deposits within non-enlarged
lymph nodes, or differentiate reactively enlarged lymph nodes
from metastatic lymphadenopathy. This can be overcome by com-
bining ultrasonography with fine-needle aspiration cytology (US
FNAC). In N0 necks, a sensitivity of 73% and specificity of 100%
have been reported with this technique, significantly better than
can be obtained with CT or MRI (7,8). The reliability of US FNAC
is dependent on the experience of the examiner.
Efforts have been made to increase the diagnostic accuracy of
MRI by injecting special contrast agents, such as ultrasmall super-
paramagnetic iron oxide particles. These particles are captured
by macrophages of normal lymph nodes. Because of the T2 and
susceptibility effect of iron oxide, signal intensity reduction will
be observed in tissue in which the contrast agent accumulates,
potentially allowing a better distinction between benign and
malignant lymph nodes. Aside from the added cost, the reported
results for neck nodal staging using this contrast agent have been
variable (31,32). Also, at the time being, this contrast agent is not
yet commercially available.
An alternative approach to improve the accuracy of MRI for
neck nodal staging is to combine conventional sequences with
diffusion-weighted (DW) MRI. Non-necrotic metastatic adenop-
athies show diffusion restriction compared to normal lymph
nodes, while inflammatory lymph nodes show increased diffusion
(33,34). This technique seems to be able to significantly improve
nodal staging (Fig. 28.20). Further studies are required to confirm
these data.

595
 primary tumor evaluation and staging

T1 T1 T1

≤2 cm
≤2 cm
≤2 cm

Limited to the piriform sinus Limited to the posterior wall Limited to the postcricoid area

T2 T2 T2

2–4 cm 2–4 cm 2–4 cm

Invasion of the piriform sinus Invasion of the piriform sinus Invasion of the piriform sinus
and the aryepiglottic fold and the posterior wall and the postcricoid area
T3 T3 T3

>4 cm

>4 cm >4 cm

Invasion of piriform sinus and Invasion of piriform sinus and Invasion of piriform sinus and
aryepiglottic fold or with posterior wall or with postcricoid area or with
fixation of the hemilarynx fixation of the hemilarynx fixation of the hemilarynx
T4a T4b

Invasion of thyroid/cricoid cartilage, hyoid bone, Invasion of prevertebral fascia, encases carotid artery,
thyroid gland, esophagus, or central compartment soft tissue or involves mediastinal structures

Figure 28.16 Hypopharyngeal staging.

Malignant lymphadenopathy may spread through the lymph
node capsule; such extracapsular spread implies a worse prognosis.
Radiological criteria for capsular penetration are an irregular nodal
margin, without clear distinction between the node and the sur-
rounding fat, and thickening of surrounding fibroadipose tissue or
muscles. Only major extranodal spread can be detected by imaging.
It is important to detect invasion of the carotid artery
as resectability may become impossible. Carotid wall involve-
ment can be suggested if the artery is surrounded by more
than 270° by the tumor (35). However, sometimes the
surgeon can peel the tumor off the vessel even if this sign is
positive.

596
 tumors of the pharynx, tongue, and mouth

(A) (B)
Figure 28.17 Contrast-enhanced CT images. (A) Axial image during quiet breathing shows subtle soft tissue thickening in the apex of the right piriform sinus (arrow;
compare to opposite side). There is subtle infiltration or displacement of the paraglottic space fat (arrowhead). (B) Axial image obtained during modified Valsalva
manoeuvre. The right piriform sinus expands somewhat less than the opposite side; the soft tissue irregularity produced by the cancer is now more visible (arrowheads).
Squamous cell carcinoma was diagnosed.

The N-staging criteria, excluding nasopharyngeal cancer, are

given in Table 28.7.
Concerning nodal staging, there are a number of differences
between nasopharyngeal cancer and other sites of head and
neck cancer ( Table 28.8) as the distribution of nodal metastasis
and associated prognosis is different (26). In nasopharyngeal
cancer, the 3 cm criterion is not used; only size < or > 6 cm
matters, separating N2 from N3. Contralateral adenopathies
do not upstage a patient to N2c, but remain N1, as long as they
are <6 cm; the reason for this is that the nasopharynx is consid-
ered to be a midline structure. Also, the level of involvement,
not taken into account in other head and neck cancers, does
matter in nasopharyngeal cancer, as this is associated with an
increased risk of systemic metastasis: involvement of the supr-
aclavicular fossa upstages the patient to N3b. Three points
define the supraclavicular fossa: the superior margin of the
sternal end and the lateral end of the clavicle, and the point
where the neck meets the shoulder.

Figure 28.18 Contrast-enhanced CT image. Squamous cell cancer originating from

the right piriform sinus, growing anteriorly in the paraglottic space, anterolaterally
through the thyroid cartilage, and laterally through the lateral pharyngeal wall. The
primary tumor blends with a parajugular metastatic adenopathy (asterisk). Key Points: Cervical Lymphadenopathy
■ Clinical evaluation of neck lymph nodes is not very precise
Level System of Lymph Node Classification ■ Radiological evaluation of neck lymph node disease is better,
The level system of lymph node classification is a nomenclature
but both false-positive and false-negative results do occur
dividing the palpable cervical lymph nodes into seven regions or
■ The radiological criteria are lymph node size (>1 cm) and the
“levels;” some lymph nodes are not part of any of these levels and
presence of central hypodensity
are described by their anatomical location (e.g., retropharyngeal
■ Ultrasonography with FNAC can provide significantly
nodes, parotid nodes, facial nodes). Although this classification was
better results than CT or MRI in detecting cervical lymph-
devised using surgical landmarks, translation into an imaging-based
adenopathy
nodal classification is feasible (Table 28.6, Fig. 28.21). A precise as
■ The distribution and prognostic implications of nodal
possible application of this classification on CT or MR studies
metastasis for nasopharyngeal cancer is different from those
considerably enhances communication between the clinician and
of other head and neck cancer sites
radiologist on neck nodal disease.
597
 primary tumor evaluation and staging

Figure 28.19 Contrast-enhanced CT image showing an enhancing soft tissue mass in the inferior part of the right piriform sinus, extending between the arytenoid
cartilage (a) and thyroid cartilage, infiltrating into the paraglottic space (white arrowhead). The mass nearly reaches an unossified island in the thyroid cartilage (black
arrowhead). Extension into the anterior submucosal layer of the inferior hypopharynx is visible (asterisk). The posterior submucosal layer is not infiltrated (arrow). On
the left side, the different tissue layers of the inferior hypopharynx are labeled: m, opposing anterior and posterior mucosal layers; 1, anterior submucosal fat; 2, posterior
submucosal fat; 3, inferior pharyngeal constrictor muscle. (A) About 12 mm caudal to (B); the posterior cricoarytenoid muscle (dots) can be recognized between the
cricoid arcus (c) and the anterior submucosal layer (1). At the side of the lesion, the anterior submucosal layer still appears infiltrated (arrow). 2, posterior submucosal
fat; 3, inferior pharyngeal constrictor muscle. This inferior retrocricoidal extent was clinically occult.

(A) (B)

(C) (D) (E)

Figure 28.20 Gadolinium-enhanced T1-weighted turbo-spin echo (TSE)-image (A) showing a large tumor (arrows) in the left side of the oral tongue. (B) A normal
shaped lymph node with regular contours, shortest transverse diameter of 0.8 cm and homogeneous contrast-enhancement in ipsilateral level 2 (arrow) is visible, con-
sidered as a normal lymph node by TSE-MRI. (C) This lymph node is hyperintense on b0 and (D) b1000 diffusion-weighted image (arrows), corresponding to (E) an
ADC of 0.00073 mm2/sec, suspicious for metastatic adenopathy. Histopathological examination confirmed a large metastatic deposit in this lymph node.

598
 tumors of the pharynx, tongue, and mouth

Table 28.6 Imaging-Based Neck Nodal Classification

Level
I Submental and submandibular nodes
IA Submental nodes, between the medial margins of the anterior bellies of the digastric muscles
IB Submandibular nodes, lateral to level IA nodes and anterior to the back of the submandibular salivary gland
II Upper internal jugular nodes, posterior to the back of the submandibular salivary gland, anterior to the back of the
sternocleidomastoid muscle and above the level of the bottom of the body of the hyoid bone
III Middle jugular nodes, between the level of the bottom of the body of the hyoid bone and the level of the bottom of the cricoid
arch, anterior to the back of the sternocleidomastoid muscle
IV Low jugular nodes, between the level of the bottom of the cricoid arch and the level of the clavicle, anterior to a line connecting
the back of the sternocleidomastoid muscle and the posterolateral margin of the anterior scalene muscles; they are lateral to the
carotid arteries
V Posterior triangle nodes, posterior to the back of the sternocleidomastoid muscle, and posterior to the line described in level IV
VA Above the level of the bottom of the cricoid arch
VB Between the level of the bottom of the cricoid arch and the level of the clavicle
VI Upper visceral nodes, between the carotid arteries from the level of the bottom of the body of the hyoid bone to the level of the
top of the manubrium
VII Superior mediastinal nodes, between the carotid arteries below the level of the top of the manubrium and above the innominate vein
Supraclavicular nodes Nodes at, or caudal to, the level of the clavicle and lateral to the carotid artery
Retropharyngeal nodes Nodes behind the pharynx, medial to the internal carotid artery, from the skull base down to the level of the hyoid bone
Source : Adapted from Ref. 36.

suspect abnormality is seen on the plain film. Chest CT seems jus-

SEARCH FOR DISTANT METASTASIS IN UPPER
AERODIGESTIVE TUMORS
Cancer of the head and neck first spreads to the regional lymph
nodes and, more rarely, metastasizes to distant sites. Identification
of distant metastasis is important as it has a pronounced impact
on prognosis and treatment (37). Modern multimodality treatment
improves locoregional control, but may be associated with meta-
static disease developing late as a sole site of recurrence (38).
The single most frequent site of distant metastasis is the lung.
Depending on the study, bone or liver metastases are the second
(or third) most frequent sites. Both bone and liver metastasis are
nearly always associated with lung metastasis (39).
The search for distant metastasis must be balanced against its
cost (40). Conceiving a cost-effective algorithm demands identifi-
cation of patients at greater risk for distant metastasis. A variety of
factors influence this risk:
• Tumor site: some sites, such as the glottis, skull base, and
sinonasal cancer have a relatively low rate of distant
metastasis, while nasopharyngeal cancers have a clearly
increased rate (between 3% and 40%, increasing with
advanced stages of disease)
• Stage at presentation is clearly related to the risk of distant
metastasis, especially N2 or N3 nodal disease (39,41)
• Histology: patients with adenoid cystic carcinoma have
a clearly increased risk of developing distant metastasis
at some time. Tumor differentiation, extranodal tumor
spread, evidence of perineural or vascular invasion and
neo-angiogenesis (42) are other factors found to be
associated with an increased risk of distant metastasis
Apart from clinical examination, the minimum screening for dis-
tant metastasis at first presentation should include chest X-ray
(40). Computed tomography of the chest is the next step when a
tified in an advanced stage of the primary tumor and/or bulky neck
disease; a fluorodeoxyglucose positron emission tomography (FDG
PET) scan can be considered as alternative in such patients.
A more extensive work-up is indicated in nasopharyngeal carci-
noma, including bone scintigraphy, liver ultrasound, and an FDG
PET scan.
Screening for distant disease in patients with recurrent locore-
gional disease can be carried out as described earlier. In patients
without evidence of recurrent disease, most U.S. head and neck
surgeons screen for distant metastasis by chest X-ray every year,
reserving other methods for specific symptoms (43). However, the
effectiveness of the routine use of chest X-ray in non-symptomatic
patients has been questioned (44).
Key Points: Distant Metastases in Upper
Aerodigestive Tumors
■ The need for extensive imaging to identify metastatic disease
depends on consideration of tumor site, stage of disease, and
histology
■ Nasopharyngeal and adenoid cystic carcinomas hence have
an increased risk of developing distant metastases
POST-THERAPEUTIC IMAGING
Expected Tissue Changes After Radiotherapy
After irradiation of a neck cancer, a number of tissue changes
become visible on CT and MR images of the neck. These expected
postradiation alterations should not be misinterpreted as evidence
of persistent or recurrent tumor.
Within the first two weeks after radiotherapy, there is an acute
inflammatory reaction within the deep tissues. Increased permeability,

599
 primary tumor evaluation and staging

Internal carotid artery

Submandibular
gland Digastric muscle
Digastric muscle (posterior belly)
(anterior belly)

Mylohyoid muscle
Internal jugular vein
Hyoid bone Internal carotid artery
Omohyoid muscle
Sternocleidomastoid muscle

Cricoid cartilage
Trapezius muscle

Right common
carotid artery

Anterior scalene muscle

Manubrium
Internal jugular vein

Left common carotid artery

Jugular fossa
Posterior boundary
of submandibular gland

IB
IA
IIA IIB
Lower border
of hyoid bone
III

VA
Lower margin
of cricoid cartilage
VI VB
Right common
IV
carotid artery

Top of manubrium
VII

Internal jugular vein

Left common carotid artery

Figure 28.21 Level system of lymph node classification. Diagram of the neck as seen from the left anterior view. Upper: the pertinent anatomy that relates to the nodal
classification. Lower: an outline of the levels of the classification. Note that the line of separation between levels I and II is the posterior margin of the submandibular
gland. The separation between levels II and III and level V is the posterior edge of the sternocleidomastoid muscle. However, the line of separation between levels IV and
V is an oblique line extending from the posterior edge of the sternocleidomastoid muscle to the posterolateral edge of the anterior scalene muscle. The posterior edge of
the internal jugular vein separates level IIA and IIB nodes. The top of the manubrium separates levels VI and VII.

600
 tumors of the pharynx, tongue, and mouth

Table 28.7 N-Staging Head and Neck Cancer (Excluding Expected Tissue Changes After Surgery
Nasopharyngeal Cancer) (26) The limits of surgical therapy are determined by the balance
NX Regional nodes cannot be assessed
between obtaining cure by radical resection of the tumor, and
N0 No regional nodal metastasis leaving the patient in a functionally and aesthetically acceptable
N1 Metastasis in a single ipsilateral lymph node <3 cm in greatest dimension situation. More extensive resections are possible by the introduc-
N2a Metastasis in a single ipsilateral lymph node >3 cm but <6 cm in tion of various reconstructive materials, such as pedicled or free
greatest dimension soft tissue flaps, grafts, and prostheses.
N2b Metastasis in multiple ipsilateral lymph nodes, <6 cm in greatest
dimension
Tissue transferred to close a defect, while maintaining its original
N2c Metastasis in bilateral or contralateral lymph nodes, <6 cm in greatest vascular pedicle, is called a pedicled flap. Pedicled flaps may be har-
dimension vested locally (in the immediate area of the defect), regionally (from
N3 Metastasis in a lymph node >6 cm in greatest dimension the same area, but not contiguous to the defect), or at distance from
Source : From Ref. 64. the defect. The most commonly used distant flaps are musculocuta-
neous flaps, such as the pectoralis major flap. The pectoralis major
flap has an excellent blood supply and gives acceptable functional
Table 28.8 N-Staging of Nasopharyngeal Carcinoma (26) and cosmetic results. It is commonly used to reconstruct the pharyn-
NX Regional nodes cannot be assessed
geal defect after laryngectomy with partial pharyngectomy; it is also
N0 No regional nodal metastasis very useful for closing defects in the irradiated neck as it introduces
N1 Unilateral node(s) <6 cm above supraclavicular fossa tissue with a fresh blood supply. On imaging studies the pectoralis
N2 Bilateral node(s) <6 cm above supraclavicular fossa major flap appears initially as a bulky soft tissue structure, showing
N3 Metastasis in node(s) the characteristics of muscle; gradually, denervation atrophy appears,
N3a >6 cm
N3b In supraclavicular fossa
causing volume loss and fatty replacement of the muscle (Fig. 28.22).
At the time of imaging the muscle denervation may be incomplete;
Source : From Ref. 64.
fiber-like structures with muscle density within the flap should not
be confused with tumor recurrence.
due to detachment of the lining endothelial cells within small When a flap is vascularized by local vessels and anastomosed to
blood and lymphatic vessels, results in interstitial oedema. After the flap by microvascular techniques, it is called a free flap. Different
this initial period of a few weeks, there is progressive thickening of kinds of free flaps are in use, for example, cutaneous flaps to
the connective tissue. Endothelial proliferation is also seen, eventu- reconstruct defects in the oral cavity, osseous flaps (e.g., fibula) to
ally resulting in complete obstruction of the vessels. The reduction reconstruct mandibular defects, and free jejunal interposition
in venous and lymphatic drainage results in further accumulation to reconstruct the defect created by a total laryngopharyngectomy.
of interstitial fluid. Then the fibrosis becomes progressively more Neck dissection is a surgical procedure to remove neck nodal
advanced, but the interstitial oedema may be reduced by formation metastasis. Several procedures are distinguished. In radical neck
of collateral capillary and lymphatic channels. dissection, unilateral en bloc removal of the neck lymph nodes
The changes visible on post-treatment CT and MR images depend levels I to V, including the sternocleidomastoid muscle, internal
on the radiation dose and rate, the irradiated tissue volume, and the jugular vein, submandibular gland, and spinal accessory nerve is
time elapsed since the end of radiation therapy (45,46). performed. If the spinal accessory nerve is preserved, the proce-
Changes that may be seen include: dure is called a modified radical neck dissection. Prelevation of
the right sternocleidomastoid muscle may cause hypertrophy of
the ipsilateral scapula levator muscle.
• Symmetrical thickening of the skin and platysma muscle
If the spinal accessory nerve and one more of the above-
• Reticulation of the subcutaneous fat and the deep tissue
mentioned structures, removed in a radical neck dissection, is
fat layers
preserved, the procedure is called a functional or conservative
• Edema in the retropharyngeal space
neck dissection. This type of dissection is performed when there
• Increased enhancement of the major salivary glands,
are no or only small clinically or radiographically positive lymph
followed by size reduction of these glands: postirradiation
sialadenitis nodes present in the neck.
In a selective neck dissection, a more limited number of lymph
• Atrophy of lymphatic tissue in both the lymph nodes
nodes levels are removed. A commonly performed selective neck
and Waldeyer’s ring
dissection is a supraomohyoid neck dissection; this includes removal
• Symmetrical thickening and increased enhancement of
of levels I, II, and III and is performed when a small cancer of the
the pharyngeal walls
oral cavity is removed and no positive lymph nodes are present.
• Symmetrical thickening of the laryngeal structures, with
increased density of the fat in the pre-epiglottic and
paralaryngeal spaces
Surveillance Imaging of the Primary Tumor Site
These tissue changes are most pronounced during the first few It is useful to obtain a follow-up CT or MRI after surgical, radia-
months after the end of radiation therapy and diminish or even tion, or combined treatment for a head and neck neoplasm with a
resolve with time. It is important to note that the expected tissue high-risk profile. Probably the best time to obtain such a baseline
changes after radiation therapy appear symmetrical, unless the study is about three to six months after the end of treatment. Such
neck was irradiated using asymmetric radiation portals. a baseline study allows treatment-caused changes in the head and

601
 primary tumor evaluation and staging
Figure 28.22 Axial contrast-enhanced CT image in a patient treated by total
laryngopharyngectomy. The neopharynx is reconstructed by a free radial forearm
flap (arrowheads; inner enhancing rim is skin); the soft tissues are anteriorly
covered by a pedicled pectoralis major flap (arrows).
neck tissues to be documented. By comparing subsequent studies
with the baseline study, it becomes possible to detect with more
confidence tumor recurrences or treatment complications, and
this at an earlier stage than is possible with clinical follow-up alone
(Figs. 28.23–28.25).
There is evidence that the baseline study itself carries important
predictive information regarding the eventual local outcome; sev-
eral studies show that CT may be useful in the early differentiation
of treatment responders from non-responders in irradiated laryn-
geal and hypopharyngeal cancer (47,48). In this regard, the value
of MRI is less well established.
Based on the appearance of the larynx/hypopharynx on an early
post-radiotherapy CT study, a prediction of long-term local out-
come can be made according to the following scores:
• 1 = expected post-radiotherapy changes, i.e., complete
resolution of the tumor at the primary site and symmet-
rically appearing laryngeal and hypopharyngeal tissues,
as described earlier
• 2 = focal mass with a maximal diameter of <1 cm and/or
asymmetric obliteration of laryngeal tissue planes
• 3 = focal mass with a maximal diameter of >1 cm, or
<50% estimated tumor volume reduction (48,49).
The postradiotherapy CT score 1 was shown to be a very strong pre-
dictor of long-term local control; patients with such findings on
post-radiotherapy CT will probably not benefit from further follow-up
imaging studies. Conversely, patients with a first follow-up exami-
nation classified as CT-score of 3 do very poorly; almost all these
patients will develop a local failure (49). Further exploration in such
post-radiotherapy CT score 3 patients is warranted. FDG PET,
thallium PET or single-photon emission computed tomography
602
(SPECT) imaging may prove to be a useful intermediate step in cases
where biopsy is considered too risky, or if a biopsy result is returned
as negative. Indeed, the predictive value of a negative biopsy for local
control after radiotherapy is reported to be only 70%; (50) this is
likely due to sampling error as tumor recurrences initially develop
submucosally and cannot therefore be accurately targeted. In cases
of contradiction between the clinical findings, CT findings, results of
radionuclide studies and/or biopsy, close clinical follow-up, and
repeat imaging studies are needed.
The local outcome of patients initially classified as post-
radiotherapy CT score 2 is indeterminate. Unless clinical exami-
nation is already suspect for local failure, further follow-up CT
studies are needed in these patients; a time interval of three to four
months is recommended, to be continued up to two years after
completion of radiation treatment (Fig. 28.25).
Use of this imaging-based information could lead to more prompt
salvage surgery and potentially improve the survival of these patients
(48). Proof of such a survival benefit requires further study.
Imaging of Nodal Disease After (Chemo)Radiotherapy
Patients with advanced head and neck cancer, treated by (chemo)
radiotherapy, may show persisting nodal disease at the end of
treatment. In such patients, the role of surgery, i.e., a planned
neck dissection, is not well defined (51). Such a planned neck dis-
section may reduce the regional failure rate and improve survival.
However, many of these neck resection specimens do not contain
tumor, meaning that the patient was exposed to the inherent risks
of surgery, without benefit.
CT of the neck obtained early after the end of (chemo)radio-
therapy, was shown to be a reliable method to predict the absence
of residual nodal disease (52). However, both the clinical exami-
nation and CT have a low positive predictive value, meaning that
many patients with positive findings will eventually not show
regional tumor recurrence (Fig. 28.26).
FDG-PET is recommended by some authors for detecting residual
nodal disease. While FDG-PET obtained early after the end of therapy
is not very reliable (53), more reliable results are obtained when FDG-
PET is performed three to four months after the end of treatment,
resulting in a negative predictive value of 97% to 100% (54,55).
Preliminary results indicate that DW-MRI may be a valuable
method to select patients who may benefit from an added neck
dissection (56).
TREATMENT COMPLICATIONS
Complications After Surgery
Many surgical complications occur early after treatment and are
dealt with on a clinical basis. Imaging may be required in the
detection and visualization of fistulae originating from the oral
cavity or pharynx. Most of these fistulae will close spontaneously,
but some may need reintervention. Imaging may also be of use in
the confirmation of flap failure (necrosis).
Complications After Radiotherapy
Acute effects of radiotherapy (skin and mucosal reactions)
occur during or immediately after treatment, and usually settle
spontaneously.
 tumors of the pharynx, tongue, and mouth

(A) (B)

Figure 28.23 (A) Patient with a right-sided T2 piriform sinus cancer, before radiotherapy. The enhancing soft tissue thickening on the right aryepiglottic fold corresponds
with the tumor (arrow). (B) Anatomically corresponding image, 6 months after radiotherapy. Thickening of the infrahyoid epiglottis (arrow), as well as pronounced and
symmetric thickening and increased attenuation of the aryepiglottic folds is seen (asterisks). Note also the thickening of the hypopharyngeal walls (black arrowheads)
and the retropharyngeal edema (white dots). Also, slight thickening of the platysma muscles is seen (white arrowheads). These are expected findings after radiotherapy.
The tumor remained locally controlled.

(A) (B)

Figure 28.24 Patient treated by surgery for left-sided cancer of the floor of the mouth, abutting the mandible; rim resection of the mandible was included. The patient
received postoperative irradiation. Baseline CT study 6 months after completion of therapy showed expected post-therapeutic changes, but also a more or less nodular
area in front of the hyoid bone, without clear enhancement (A, arrows). Based on these findings, a follow-up CT study was recommended. A larger and enhancing
nodular lesion was seen in the same region 3 months later: suspect for recurrent tumor (B, arrows). Clinically no evidence of recurrent tumor was present. Based on the
radiological findings, resection was performed about 1 month later and confirmed tumor recurrence.

Tissue necrosis is a rare complication of radiotherapy in the
head and neck region, usually appearing months to years after the
end of radiation treatment. Several risk factors have been identi-
fied, including high radiation doses and large radiation fields. Soft
tissue, cartilage, and bone necrosis may be encountered; several
tissue types may be involved at the same time.
Osteoradionecrosis may involve the mandible, the ossified
cartilage of the larynx, the temporal bone and the hyoid bone
(Fig. 28.27) (57,58). The pathogenesis is not fully understood. A
popular theory is that irradiation produces hypoxic, hypocellular,
and hypovascular tissue, unable to remodel following tissue loss,
thus leading to breakdown (59). Trauma is often associated with

603
 primary tumor evaluation and staging

(A) (B)

Figure 28.25 Patient treated by irradiation for a right-sided T3 piriform sinus cancer. (A) CT study obtained 6 months after completion of therapy. Clinically there is no
evidence of disease. Subtle infiltration of the retrocricoidal submucosal fat layers is visible on the right side (arrows), especially in the anterior one. This is not an expected
finding after radiotherapy (CT score 2) and a follow-up CT study was recommended. (B) CT study obtained 4 months later. Clinically there is no evidence of disease.
Now a nodular heterogeneously enhancing mass is seen in the anterior retrocricoidal fat plane (CT score 3). This is very suspect for tumor recurrence. Endoscopic biopsy
revealed carcinoma.

(A) (B)
Figure 28.26 Patient with T4aN2c oropharyngeal cancer. (A) Axial contrast-enhanced CT image obtained before therapy shows centrally necrotic adenopathy at level III
on left side (arrows). (B) CT image obtained 2 months after the end of chemoradiotherapy. The primary tumor (not shown) responded well to treatment. The adenopa-
thy (arrows) is only slightly diminished in size (diameter at that time about 1.4 cm). A wait-and-see policy was adopted, no neck dissection was performed. The adenop-
athy gradually decreased in size on follow-up CT studies. There was no evidence of disease 4 years after end of treatment.

the appearance of osteoradionecrosis as it creates a demand for
tissue repair beyond the capabilities of the irradiated tissue. The
radiological findings include bony abnormalities (cortical inter-
ruptions and loss of spongiosa trabeculation), sequestration,
pathological fractures, soft tissue thickening (sometimes gas
containing), and fistula formation (Fig. 28.27).
Radiologically, differentiation from tumor recurrence may be
difficult. In the mandible, some findings, such as the association
with cortical defects away from the position of the original tumor
(at the buccal surface or in the heterolateral side of the mandi-
ble), make the diagnosis of mandibular osteoradionecrosis more
likely (60).

604
 tumors of the pharynx, tongue, and mouth

It has been suggested that FDG PET may allow differentiation

between tumor recurrence and tissue necrosis as a complication
of therapy (61,62). However, false-positive results may occur as
tissue necrosis may be associated with an important inflamma-
tory reaction, increased metabolism, and thus increased uptake of
the tracer (Fig. 28.28).
Fibrosis after radiotherapy may lead to contraction and harden-
ing of the cervical tissues. Fibrosis-induced laryngeal dysfunction
may lead to aspiration due to immobilization of the epiglottis and/
or delayed closure of the laryngeal vestibulum and glottis; second-
ary aspiration may be caused by ineffective clearance of the phar-
ynx. Dysphagia may be caused by pharyngeal stenosis, which is
most often seen in the neopharynx after total laryngectomy (63).
Fibrosis of the masticatory muscles may occur, particularly if
they were involved by the cancer. The MRI signal characteristics of
fibrosis are variable; often follow-up studies are needed to rule out
tumor recurrence with a sufficient degree of confidence.
Other long-term complications of radiotherapy include arte-
riopathy, delayed central nervous system reaction, radiation
myelopathy, cranial nerve palsy, and secondary tumors (63).

Key Points: Imaging After Treatment

Figure 28.27 Patient treated 5 years earlier for left-sided oral cavity cancer by
surgery and postoperative external radiotherapy. The patient suffered oral ulcer-
ation and pain for several months, and presented with more pronounced symp-
toms and soft tissue swelling. CT (bone window) shows osteolytic changes in the
mandibular symphysis and left corpus, complicated by a pathological fracture
(between arrowheads). Bone sequesters are seen (arrows) as well as some
intraosseous gas bubbles. The perimandibular soft tissue appears to be swollen.
There is heterolateral bone defect (asterisk). Mandibular osteoradionecrosis was
diagnosed.
■ Irradiation produces tissue changes on post-treatment
imaging studies, not to be misinterpreted as evidence of
persistent or recurrent disease
■ Expected changes after radiotherapy appear symmetric, unless
the neck was irradiated using asymmetric radiation portals
■ Early imaging identification of recurrent tumor is facilitated by
obtaining a baseline study about three to six months after therapy

(A) (B)

Figure 28.28 Patient irradiated for right-sided tonsillar cancer. The patient suffers from persisting pain in this region; clinically, an ulceration is visible. (A) Follow-up CT
obtained about 18 months after the completion of irradiation shows soft tissue ulceration, with some surrounding soft tissue infiltration and slightly increased enhance-
ment (arrowheads); this was reported as possibly reflecting recurrent tumor. Biopsies were negative for cancer but an additional FDG PET (B) study showed focal tracer
uptake at the same level (arrows), reported to be consistent with tumor recurrence. A partial oropharyngectomy including resection of the adjacent part of the mandible
was performed. The resection specimen showed soft tissue radionecrosis but no evidence of malignancy.

605
 primary tumor evaluation and staging
Summary
■ Most malignant tumors of the oral cavity and pharynx are
SCCs
■ Imaging is essential in defining local extent, lymph node
involvement, and distal metastasis
■ Head and neck cancer is not a single disease. Each site in the
head and neck has its own characteristics regarding locore-
gional cancer behavior, response to treatment and risk for
recurrent disease. This fact, and the anatomic complexity of
the region, means that diagnostic procedures and treatment
may have to be tailored to each individual patient
■ Perineural tumor spread does not cause clinical symptoms in
up to 40% of patients; its detection by imaging is essential to
avoid undertreatment and persistent/recurrent cancer
■ Subclinical adenopathies may be detected by imaging stud-
ies; particular attention should be paid to clinically inacces-
sible nodal sites such as the retropharyngeal and paratracheal
lymph nodes
■ It is essential to know what to expect on imaging studies
after radiotherapy and/or surgery, so that these changes are
not misinterpreted as evidence for cancer recurrence. Con-
versely, care should be taken not to misinterpret recurrent
cancer as post-treatment changes; biopsy, a repeat CT/MRI
or an additional FDG PET study may be appropriate
depending on the situation and available technology
■ Careful imaging surveillance in high-risk patients allows
identification of recurrent cancer earlier than clinical exami-
nation in a substantial number of patients
■ Tissue necrosis after radiotherapy may be difficult to differ-
entiate from recurrent tumor. In such circumstances, patient
management mainly depends on the combination of clinical
and imaging findings, including evolution of time
■ Biopsy results may be false negative in cases of recurrent
tumor. In case of a contradiction between clinical, imaging
and/or biopsy findings, close follow-up and repeat imaging
studies are needed
REFERENCES
1. Chong VF, Mukherji SK, Ng SH, et al. Nasopharyngeal carci-
noma: review of how imaging affects staging. J Comput Assist
Tomogr 1999; 23: 984–93.
2. Hermans R, Lenz M. Imaging of the oropharynx and oral
cavity. Part I: Normal anatomy. Eur Radiol 1996; 6: 362–8.
3. Farina D, Hermans R, Lemmerling M, Op Beeck K. Imaging
of the parapharyngeal space. JBR-BTR 1999; 82: 234–9.
4. Som PM, Curtin HD. Lesions of the parapharyngeal space.
Role of MR imaging. Otolaryngol Clin North Am 1995; 28:
515–42.
5. Robbins KT, Kumar P, Regine WF, et al. Efficacy of targeted
supradose cisplatin and concomitant radiation therapy for
advanced head and neck cancer: the Memphis experience. Int
J Radiat Oncol Biol Phys 1997; 38: 263–71.
6. Keberle M, Tschammler A, Hahn D. Single-bolus technique
for spiral CT of laryngopharyngeal squamous cell carcinoma:
606
comparison of different contrast material volumes, flow rates,
and start delays. Radiology 2002; 224: 171–6.
7. van den Brekel MW, Castelijns JA, Stel HV, et al. Occult meta-
static neck disease: detection with US and US-guided fine-
needle aspiration cytology. Radiology 1991; 180: 457–61.
8. van den Brekel MW, Castelijns JA, Stel HV, et al. Modern
imaging techniques and ultrasound-guided aspiration cytol-
ogy for the assessment of neck node metastases: a prospective
comparative study. Eur Arch Otorhinolaryngol 1993; 250:
11–17.
9. Jones T. The imaging science of positron emission tomo-
graphy. Eur J Nucl Med 1996; 23: 807–13.
10. Kubota R, Yamada S, Kubota K, et al. Intratumoral distri-
bution of fluorine-18-fluorodeoxyglucose in vivo: high
accumulation in macrophages and granulation tissue
studied by microautoradiography. J Nucl Med 1992; 33:
1972–80.
11. Haberkorn U, Bellemann ME, Altmann A, et al. PET 2-fluoro-
2-deoxy-D-glucose uptake in rat prostate adenocarcinoma
during chemotherapy with gemcitabine. J Nucl Med 1997; 38:
1215–21.
12. Fukui MB, Blodgett TM, Snyderman CH, et al. Combined
PET-CT in the head and neck: Part 2. Diagnostic uses
and pitfalls of oncologic imaging. Radiographics 2005; 25:
913–30.
13. Castaigne C, Muylle K, Flamen P. Positron emission tomogra-
phy in head and neck cancer. In: Hermans R, ed. Head and
Neck Cancer Imaging. Berlin, Heidelberg, New York: Springer
Verlag, 2006: 329–43.
14. Hermans R, Horvath M, De Schrijver T, Lemahieu SF,
Baert AL. Extranodal non-Hodgkin lymphoma of the head
and neck. J Belge Radiol 1994; 77: 72–7.
15. Prudhomme-Lacroix F, Jaubert J, Mosnier JF, Guyotat D.
Hodgkin disease of the palatine tonsil. Clinical, histological,
immunophenotype study and association with Epstein–Barr
virus. Presse Med 2000; 29: 935–8.
16. Boyle P. Global burden of cancer. Lancet 1997; 349(Suppl II):
23–6.
17. Krolls SD, Hoffman S. Squamous cell carcinoma of the oral
soft tissue: a statistical analysis of 14,253 cases by age, sex and
race of patients. J Am Dent Assoc 1976; 92: 571–4.
18. Ginsberg LE, DeMonte F. Imaging of perineural tumor
spread from palatal carcinoma. Am J Neuroradiol 1998; 19:
1417–22.
19. Nemzek WR, Hecht S, Gandour-Edwards R, Donald P,
McKennan K. Perineural spread of head and neck tumors:
how accurate is MR imaging? Am J Neuroradiol 1998; 19:
701–6.
20. Watkinson JC, Gaze MN, Wilson JA, eds. Stell and Maran’s
Head and Neck Surgery, 4th edn. Oxford: Butterworth Heinemann,
2000: 322–38.
21. Budach W, Hehr T, Budach V, Belka C, Dietz K. A meta-analysis
of hyperfractionated and accelerated radiotherapy and com-
bined chemotherapy regimens in unresected locally advanced
squamous cell carcinoma of the head and neck. BMC Cancer
2006; 6: 28.
22. Sakata KI, Hareyama M, Tamakawa M, et al. Prognostic factors
of nasopharyngeal tumors investigated by MR imaging and
 tumors of the pharynx, tongue, and mouth
the value of MR imaging in the newly published TNM staging.
Int J Radiat Oncol Biol Phys 1999; 43: 273–8.
23. Chong VFH, Fan YF. Skull base erosion in nasopharyngeal
carcinoma: detection by CT and MRI. Clin Radiol 1996; 51:
625–31.
24. Curtin HD, Ishwaran H, Mancuso AA, et al. Comparison of
CT and MR imaging in staging of neck metastases. Radiology
1998; 207: 123–30.
25. Chong VFH, Fan YF. Imaging: Pathological anatomy. In:
Chong VFH, Tsao SY, eds. Nasopharyngeal Carcinoma. Singapore:
Armour Publishing Pte Ltd, 1997: 50–64.
26. International Union Against Cancer. TNM Classification of
Malignant Tumors, 6th edn. New York: Wiley-Liss, 2002.
27. Altun M, Fandi A, Dupuis O, et al. Undifferentiated naso-
pharyngeal cancer (UCNT): current diagnostic and therapeu-
tic aspects. Int J Radiat Oncol Biol Phys 1995; 32: 859–77.
28. Hermans R, Van den Bogaert W, Rijnders A, Doornaert P,
Baert AL. Predicting the local outcome of glottic squamous cell
carcinoma after definitive radiation therapy: value of computed
tomography-determined tumor parameters. Radiother Oncol
1999; 50: 39–46.
29. Hermans R, Van den Bogaert W, Rijnders A, Baert AL. Value
of computed tomography determined tumor parameters as
outcome predictor of supraglottic cancer treated by definitive
radiation therapy. Int J Radiat Oncol Biol Phys 1999; 44:
755–65.
30. Pameijer FA, Mancuso AA, Mendenhall WM, et al. Evaluation
of pretreatment computed tomography as a predictor of local
control in T1/T2 piriform sinus carcinoma treated with defin-
itive radiotherapy. Head Neck 1998; 20: 159–68.
31. Sigal R, Vogl T, Casselman J, et al. Lymph node metastases
from head and neck squamous carcinoma: MR imaging with
ultrasmall superparamagnetic iron oxide particles (Sinerem
MR) – results of a phase-III multicenter clinical trial. Eur
Radiol 2002; 12: 1104–13.
32. Mack MG, Balzer JO, Straub R, et al. Superparamagnetic iron
oxide-enhanced MR imaging of head and neck lymph nodes.
Radiology 2002; 222: 239–44.
33. Abdel Razek AA, Soliman N, Elkhamary S, Alsharaway M,
Tawfik A. Role of diffusion-weighted MR imaging in cervical
adenopathy. Eur Radiol 2006; 16: 1468–77.
34. Vandecaveye V, De Keyzer F, Dirix P, et al. Dépistage des
ganglions metastatiques dans les cancers ORL par IRM de
diffusion. J Radiol 2007; 88: 1446 (abst).
35. Yousem DM, Hatabu H, Hurst RW, et al. Carotid artery inva-
sion by head and neck masses: prediction with MR imaging.
Radiology 1995; 195: 715–20.
36. Som PM, Curtin HD, Mancuso AA. An imaging-based classi-
fication for the cervical nodes designed as an adjunct to recent
clinically based nodal classifications. Arch Otolaryngol Head
Neck Surg 1999; 125: 388–96.
37. Ferlito A, Buckley JG, Rinaldo A, Mondin V. Screening tests to
evaluate distant metastases in head and neck cancer. ORL J
Otorhinolaryngol Relat Spec 2001; 63: 208–11.
38. León X, Quer M, Orús C, del Prado Venegas M, López M.
Distant metastases in head and neck cancer patients who
achieved loco-regional control. Head Neck 2000; 22: 680–6.
39. de Bree R, Deurloo EE, Snow GB, Leemans CR. Screening
for distant metastases in patients with head and neck cancer.
Laryngoscope 2000; 110: 397–401.
40. Johnson JT. Proposal of standardization on screening tests for
detection of distant metastases from head and neck cancer.
ORL J Otorhinolaryngol Relat Spec 2001; 63: 256–8.
41. Leemans CR, Tiwari R, Nauta JJ, van der Waal I, Snow GB.
Regional lymph node involvement and its significance in the
development of distant metastases in head and neck carci-
noma. Cancer 1993; 71: 452–6.
42. Sauter ER, Nesbit M, Watson JC, et al. Vascular endothelial
growth factor is a marker of tumor invasion and metastasis in
squamous cell carcinomas of the head and neck. Clin Cancer
Res 1999; 5: 775–82.
43. Marchant FE, Lowry LD, Moffitt JJ, Sabbagh R. Current
national trends in the posttreatment follow-up of patients
with squamous cell carcinoma of the head and neck. Am J
Otolaryngol 1993; 14: 88–93.
44. de Visscher AV, Manni JJ. Routine long-term follow-up
in patients treated with curative intent for squamous cell
carcinoma of the larynx, pharynx, and oral cavity. Does it
make sense? Arch Otolaryngol Head Neck Surg 1994; 120:
934–9.
45. Mukherji SK, Mancuso AA, Kotzur IM, et al. Radiologic
appearance of the irradiated larynx. Part I. Expected changes.
Radiology 1994; 193: 141–8.
46. Nömayr A, Lell M, Sweeney R, Bautz W, Lukas P. MRI appear-
ance of radiation-induced changes of normal cervical tissues.
Eur Radiol 2001; 11: 1807–17.
47. Mukherji SK, Mancuso AA, Kotzur IM, et al. Radiologic
appearance of the irradiated larynx. Part II. Primary site
response. Radiology 1994; 193: 149–54.
48. Hermans R, Pameijer FA, Mancuso AA, Parsons JT,
Mendenhall WM. Laryngeal or hypopharyngeal squamous
cell carcinoma: can follow-up CT after definitive radiotherapy
be used to detect local failure earlier than clinical examination
alone? Radiology 2000; 214: 683–7.
49. Pameijer FA, Hermans R, Mancuso AA, et al. Pre- and post-
radiotherapy computed tomography in laryngeal cancer:
imaging-based prediction of local failure. Int J Radiat Oncol
Biol Phys 1999; 45: 359–66.
50. Keane TJ, Cummings BJ, O’Sullivan B, et al. A randomized
trial of radiation therapy compared to split course radiation
therapy combined with Mitomycin C and 5 Fluorouracil as
initial treatment for advanced laryngeal and hypopharyngeal
squamous carcinoma. Int J Radiat Oncol Biol Phys 1993; 25:
613–18.
51. Pellitteri PK, Ferlito A, Rinaldo A, et al. Planned neck dis-
section following chemoradiotherapy for advanced head
and neck cancer: is it necessary for all? Head Neck 2006; 28:
166–75.
52. Liauw SL, Mancuso AA, Amdur RJ, et al. Postradiotherapy
neck dissection for lymph node-positive head and neck cancer:
the use of computed tomography to manage the neck. J Clin
Oncol 2006; 24: 1421–7.
53. Rogers JW, Greven KM, McGuirt WF, et al. Can post-RT
neck dissection be omitted for patients with head-and-neck
607
 primary tumor evaluation and staging
cancer who have a negative PET scan after definitive radia-
tion therapy? Int J Radiat Oncol Biol Phys 2004; 58:
694–7.
54. Yao M, Graham MM, Hoffman HT, et al. The role of post-
radiation therapy FDG PET in prediction of necessity for
post-radiation therapy neck dissection in locally advanced
head-and-neck squamous cell carcinoma. Int J Radiat Oncol
Biol Phys 2004; 59: 1001–10.
55. Porceddu SV, Jarmolowski E, Hicks RJ, et al. Utility of positron
emission tomography for the detection of disease in residual
neck nodes after (chemo)radiotherapy in head and neck cancer.
Head Neck 2005; 27: 175–81.
56. Vandecaveye V, De Keyzer F, Nuyts S, et al. Detection of head
and neck squamous cell carcinoma with diffusion weighted
MRI after (chemo)radiotherapy: correlation between radio-
logic and histopathologic findings. Int J Radiat Oncol Biol
Phys 2007; 67: 960–71.
57. Hermans R. Imaging of mandibular osteoradionecrosis. Neuro-
imaging Clin N Am 2003; 13: 597–604.
608
58. Hermans R, Pameijer FA, Mancuso AA, Parsons JT,
Mendenhall WM. CT findings in chondroradionecrosis of
the larynx. Am J Neuroradiol 1998; 19: 711–18.
59. Marx RE. Osteoradionecrosis: a new concept of its patho-
physiology. J Oral Maxillofac Surg 1983; 41: 283–8.
60. Hermans R. Imaging of mandibular osteoradionecrosis. Neuro-
imag Clin North Am 2003; 13: 597–604.
61. Anzai Y, Carroll WR, Quint DJ, et al. Recurrence of head and
neck cancer after surgery or irradiation: prospective compari-
son of 2-deoxy-2-[F-18]fluoro- D-glucose PET and MR imag-
ing diagnoses. Radiology 1996; 200: 135–41.
62. McGuirt WF, Greven KM, Keyes JW, Jr, Williams DW 3rd, Wat-
son N. Laryngeal radionecrosis versus recurrent cancer: a clini-
cal approach. Ann Otol Rhinol Laryngol 1998; 107: 293–6.
63. Becker M, Schroth G, Zbären P, et al. Long-term changes
induced by high-dose irradiation of the head and neck region:
imaging findings. Radiographics 1997; 17: 5–26.
64. Sobin LH, Wittekind C, eds. TNM Classification of Malignant
Tumours, 6th edn. Wiley-liss, 2002.
 29 Laryngeal Tumors
Robert Hermans
INTRODUCTION
The larynx is one of the most frequent sites of head and neck can-
cer. Nearly all laryngeal malignancies are squamous cell carcino-
mas. Cigarette smoking and excessive alcohol consumption are
well-known risk factors. An important factor in the treatment
planning of laryngeal neoplasms is the accuracy of pretherapeutic
staging. As most laryngeal tumors are mucosal lesions, they often
can be seen directly or indirectly, but the limitations of clinical
and endoscopic tumor evaluation are well recognized. The clinical
and radiological evaluation of laryngeal tumors is complementary
and when taken in combination will lead to the most accurate
determination of tumor extent. Imaging may be used to monitor
tumor response and to detect recurrent or persistent disease as
early as possible.
NORMAL ANATOMY
Essentially the larynx consists of a supporting skeleton, a mucosal
surface, and between these a soft tissue layer containing fat, some
ligaments, and muscular structures (Figs. 29.1–29.3).
Laryngeal Skeleton
The laryngeal skeleton is made up of cartilage and fibrous bands.
The foundation of the larynx is the cricoid cartilage. The cricoid
cartilage is the only complete cartilaginous ring in the airway. Its
horizontal ring-shaped part is known as the arch (arcus), while
the higher posterior part is called the lamina. Two paired facets are
found at the upper margin of the lamina, allowing articulation
with the arytenoid cartilages.
The largest supporting cartilage is the thyroid cartilage,
essentially consisting of two wings or laminae. The teardrop-
shaped epiglottis extends downward and attaches to the inner
side of the thyroid cartilage. Only a small part of the epiglottis
extends above the hyoid bone, the suprahyoid, or free margin
of the epiglottis.
The vocal ligament stretches from the vocal process of the
arytenoid to the inner side of the thyroid cartilage; it forms the
medial support of the true vocal cord. The ventricular ligament
stretches from the upper arytenoid to the thyroid cartilage, forming
the medial margin of the false vocal cord. The epiglottis is held in
place by the hyo-epiglottic ligament, running through the fatty
pre-epiglottic space.
Mucosal Layer and Deeper Laryngeal Spaces
The inner larynx is dominated by two prominent parallel
bands, the true and false vocal cord, separated by a slit-like
opening towards the laryngeal ventricle. The true vocal cord
largely consists of a muscle, running parallel and lateral to the
vocal ligament, between the arytenoid and thyroid cartilage,
hence known as the thyro-arytenoid muscle. The false vocal
cord largely consists of fat. In between, the vocal cord rises into
the laryngeal tissue space between the mucosa and supporting
skeleton. The relationship of pathological conditions to these
three parallel structures is significant in the evaluation of
laryngeal cancer.
Above the false vocal cords, from the arytenoid cartilages, the
mucosa reflects upwards towards the epiglottis, forming the
aryepiglottic folds.
The part of the larynx at the level of the true vocal cords is called
the glottis. The region beneath the lower surface of the true vocal
cords down to the lower edge of the cricoid cartilage is the sub-
glottis. Above the level of the true vocal cords is the supraglottis.
Within these different levels, further subsites are distinguished,
important for staging purposes (Table 29.1).
The bare area between the anterior attachment of the true vocal
cords, where no or only minimal soft tissue is present against the
cartilage, is known as the anterior commissure. The area between
the arytenoids is known as the posterior commissure.
The fat-containing space between the mucosa and the sup-
porting skeleton is variable in size. The part of this deep space,
anterior to the epiglottis, is known as the pre-epiglottic space.
This pre-epiglottic space is continuous with the more lateral
submucosal spaces, extending into the aryepiglottic folds and
false vocal cords. These lateral spaces are known as the paraglottic
spaces. At the level of the glottis, the paraglottic spaces are
reduced to a very thin stripe of fat just lateral to the thyro-
arytenoidal muscles.
The paraglottic fat tissue is continuous with a thin infraglottic
fat plane, bordered by the conus elasticus. The preepiglottic and
paraglottic spaces together are sometimes called the paralaryngeal
space (1).
Normal Radiological Anatomy
The normal radiological anatomy of the larynx is shown in
Figure 29.4.
The appearance of the laryngeal cartilages can vary consider-
ably, depending on the degree of ossification and the amount of
fatty marrow in the ossified medullar space. In children, the CT
density of the laryngeal cartilages is similar to soft tissue. The
endochondral ossification of hyaline cartilage starts early in the
third decade of life. A high degree of variation exists between indi-
viduals, and this ossification process is more pronounced in men
than in women (2). The thyroid cartilage shows the greatest vari-
ability in ossification; its ossification may occur in an asymmetri-
cal fashion. The cricoid and arytenoids show less variability in
ossification. The epiglottis and vocal process of the arytenoids are
composed of yellow fibrocartilage; this type of cartilage usually
does not ossify.
609
 primary tumor evaluation and staging

Aryepiglottic folds

Thyroarytenoid
muscle

H
H E
E
M
F

T A

False cord
Ventricle
True cord

(A) (B) (C)

Figure 29.1 Sagittal diagram of the lateral wall of the larynx, as seen from the midline looking out laterally. (A) View on the mucosal layer; the slitlike ventricle separates
the true vocal cord and the false vocal cord. E, epiglottis; H, hyoid bone; T, thyroid cartilage. (B) The mucosa of the true vocal cord has been opened to reveal the thyro-
arytenoid muscle. F, pre-epiglottic space. (C) The mucosa and most of the underlying soft tissues have been removed, to display the laryngeal framework. A, arytenoid
cartilage; C, cricoid arch; E, epiglottis; H, hyoid bone; M, thyrohyoid membrane; T, inner aspect of the thyroid cartilage. The vocal ligament coursing from the arytenoid
to the thyroid cartilage marks the edge of the true vocal cord.

E
TAM Vocal ligament

C A
Ventriclular T
appendix False cord

Figure 29.2 Diagram of the larynx viewed from above, showing the relation of the Ventricle True cord
cartilages, vocal ligament, and thyro-arytenoid muscle (TAM). Abbreviations: A,
arytenoid cartilage; C, cricoid cartilage; T, thyroid cartilage.

TAM
Key Points: Normal Anatomy C

■ The larynx is divided into three subsites: supraglottis, glottis,

and subglottis
■ Basically, the larynx consists of a mucosal layer, the laryngeal
framework, and a deep tissue layer in between
■ The appearance of the laryngeal cartilage is age and
gender dependent
■ Even within the same gender and age group, the degree of
laryngeal cartilage calcification and ossification is very
variable
Figure 29.3 Coronal diagram of the larynx. The true vocal cord consists mainly of
the bellies of the thyro-arytenoid muscle (TAM), while the false vocal cord largely
consists of fatty tissue (F). The true and false vocal cords are separated by the
laryngeal ventricle, which is extending superolaterally in the paraglottic space as
the sacculus laryngis or ventricular appendix. Abbreviations: C, cricoid cartilage; E,
epiglottis; T, thyroid cartilage.

610
 laryngeal tumors

Table 29.1 Subsites Within the Larynx (94) IMAGING MODALITIES

Supraglottis
Suprahyoid epiglottis (including tip, lingual, and laryngeal surfaces) Computed Tomography
Infrahyoid epiglottis
Aryepiglottic fold, laryngeal aspect
In many institutions, CT is the preferred imaging method for
Arytenoid evaluation of laryngeal cancer (3). In most cases, a dedicated CT
Ventricular bands (false vocal cords) study will answer all the clinician’s questions; in such a setting,
Glottis MRI is used as complementary tool to solve remaining questions.
True vocal cords
Anterior commissure
The images are obtained with the patient supine and during
Posterior commissure quiet respiration. The neck should be in slight extension. The head
Subglottis is aligned in the cephalo-caudal axis in order to make it possible to

(A) (B)

(C) (D)
Figure 29.4 Axial CT images through normal appearing larynges (different patients), from cranial to caudal, illustrating normal radiological anatomy. (A) Level of the
free epiglottic margin (arrowhead), at the superior edge of the hyoid bone. (B) Level of the hyoid bone (H). The glosso-epiglottic ligament (curved arrow) separates both
valleculae (asterisks). The epiglottis separates the oropharyngeal valleculae from the laryngeal vestibule (dots). The pharyngo-epiglottic folds correspond to the
anterocranial margin of the pyriform sinuses. Submandibular salivary gland (SM). (C) Level of superior margin of thyroid cartilage (black arrowhead). Epiglottis (white
arrowhead), aryepiglottic fold (arrow), pyriform sinuses (asterisks). The fatty space just in front to the epiglottis is the preepiglottic space (PES). The more lateral fatty
spaces are called the paraglottic spaces; in the left paraglottic space, the air-containing tip of the laryngeal ventricle is seen (curved arrow). (D) Level of thyroid cartilage
(black arrowhead). Thyroid notch (curved arrow). Superior thyroid cornu (arrow). (Continued)

611
 primary tumor evaluation and staging

(E) (F)

(G)
Figure 29.4 (Continued) (E) Level of false vocal cords. Within the fatty paraglottic space, some tissue with higher density can be seen, corresponding to intrinsic laryn-
geal muscles and the collapsed laryngeal ventricles (white arrow). The thyroid cartilage shows areas of calcification (black arrowheads), ossification (black arrows), and
non-calcified cartilage (white arrowheads). (F) Level of true vocal cords. Arytenoid cartilage (A, partially ossified); lamina of cricoid cartilage (C). The fatty paraglottic
spaces are reduced to a thin fatty line (white arrows) between the thyroid cartilage and vocal muscles. Posteriorly, the paraglottic spaces are continuous with the anterior
submucosal fat plane in the retrocricoidal part of the hypopharynx (black arrowhead). Hypopharyngeal mucosa (black arrows), posterior submucosal fat plane in retro-
cricoidal hypopharynx (white arrowheads), pharyngeal constrictor muscle (curved arrow). (G) Level of subglottis. Arch of cricoid cartilage (C). The denser areas cor-
respond to islands of non-ossified cartilage (arrow) within the otherwise ossified cricoid. Inferior thyroid cornu (black arrowhead). Posterior crico-arytenoid muscle
(white arrowhead).

compare the symmetry of structures. Malposition may result in Table 29.2 MDCT Data Acquisition and Native Image
an appearance that simulates disease. Every effort should be made Reconstruction Parameters
to make the patient feel comfortable; this will help the patient 4-row 16-row 64-row
dropping the shoulders to a position as low as possible (4).
Collimation 4 × 1 mm 16 × 0.75 mm 64 × 0.6 mm
State-of-the-art CT of the head and neck requires the use of multi- Feed/rotation 4 mm 9.9 mm 34.5 mm
dectector CT (MDCT). The rapid acquisition results in a volumetric Rotation time 0.75 sec 1 sec 1 sec
data set, reconstructed to a stack of thin and overlapping native KV 120 120 120
images; this reduces partial volume averaging and motion artefacts. mAseff 200a 250a 250a
The technical details on the MDCT parameters used currently in the Sliceeff 2 mm 1.5 mm 1.5 mm
University Hospitals of Leuven are summarized in Table 29.2. Slice interval 1 mm 0.7 m 0.7 mm
a
Injection of a contrast agent is necessary. A single bolus technique Effectively used mAs may be lower (determined by automatic exposure
with an injection rate of 1 cc/sec is appropriate on modern CT control system).

612
 laryngeal tumors
machines (5). A total amount of 100 ml is sufficient in MDCT. It
is essential to wait sufficiently before starting the acquisition as the
contrast agent needs some time to diffuse in the normal and
pathologic soft tissues. If one uses an MDCT machine, allowing a
rapid entire neck examination without gantry angulation, the
scan should be started only after injection of the entire contrast
volume (i.e., after 100 seconds). A subsequent saline injection at
the same injection rate is recommended.
Images are acquired without gantry tilt from the skull base to
the lower border of the sternoclavicular joints. The field of view
(FOV) must be as small as possible, to optimize spatial resolution.
The recommended FOV for neck studies varies between 16 and
20 cm, depending on the size of the patient. The native images are
reconstructed using a soft tissue algorithm; in case of possible
subtle cartilage erosion, additional image reconstruction using a
high resolution (bone) algorithm may be helpful.
The optimal display slice thickness for evaluation of neck struc-
tures is 3 mm; adjacent slices should be obtained. In laryngeal and
hypopharyngeal neoplasms, it is useful to reconstruct an addi-
tional series of images coned down to the laryngohypopharyngeal
region, with a FOV of about 10 cm and a slice thickness of 2 mm.
The image plane should be parallel to the vocal cords. The vocal
cord plane sometimes can be recognized on the lateral scout views,
or more consistently on sagittally reformatted images; alterna-
tively, the image reformatting plane can be tilted parallel to the
intervertebral disk space at the level of C4–C5 or C5-C6. Refor-
matting in other planes (coronal and/or sagittal plane) is done
based on the findings on the axial images.
Dynamic maneuvers during scanning can improve the visual-
ization of particular anatomic structures. During prolonged
phonation of [i], arytenoid mobility can be judged and a better
visualization of the laryngeal ventricle can be achieved; the
slight distension of the pyriform sinuses may also allow better
delineation of the aryepiglottic folds (6). A modified Valsalva
maneuver (blowing air against closed lips, puffing out the
cheeks) produces substantial dilatation of the hypopharynx,
allowing better visualization of the pyriform sinuses, including
the postcricoid region.
Magnetic Resonance Imaging
In many institutions, MRI plays only a minor or no role in the
evaluation of laryngeal cancer. In the author’s institution, MRI is
hardly ever performed for the evaluation of local staging of these
neoplasms, as in routine it does not provide additional informa-
tion, is technically more difficult to perform and more expensive.
Furthermore, the image quality is regularly degraded by motion
artefacts.
The use of a surface coil is essential, and high resolution T1- and
T2-weighted spin echo images should be acquired (7).
A few studies addressed the value of a specific contrast agent
(ultrasmall superparamagnetic iron oxide, USPIO) in MRI to
detect lymph node metastases. From a theoretical point of view,
use of this contrast agent should have a diagnostic accuracy that is
more reliable than gadolinium-enhanced MRI; however, the
reported results are somewhat variable (8,9).
In selected indications, MRI may have an advantage over CT or
nuclear imaging. For example, promising results are reported with
diffusion-weighted MRI in distinguishing radiotherapy-induced
tissue changes and tumor recurrence (10), and in staging of neck
lymph nodes (11,12).
Ultrasonography
Ultrasound has no role in the evaluation of the primary laryngeal
cancer. In combination with fine needle aspiration cytology
(FNAC), ultrasound is the most accurate method for neck nodal
staging in most head and neck cancers (13). However, execution
of this procedure is time-consuming, and the obtained results
are operator-dependent (14). Also, in a multicenter study where
both computed tomography and ultrasound of the neck were
applied for staging of head and neck cancer, the addition of
ultrasound-guided FNAC did not provide significant additional
value (15). Therefore, in most institutions, the radiological evalu-
ation of lymphatic neck spread is combined with evaluation of the
primary tumor, usually by CT. This also allows the comprehensive
evaluation of the entire head and neck region, for example, also
allowing detection of possible retropharyngeal adenopathies.
Nuclear Imaging
Nuclear imaging techniques such as single photon emission com-
puted tomography (SPECT) and positron emission tomography
(PET) are increasingly being used in the evaluation of advanced
head and neck cancer. PET and PET-CT particularly, using fluorine-
18-labeled 2-fluoro-2-deoxy-D-glucose (FDG) as tracer, have
received a lot of attention over the last few years. PET can be used
in the pretreatment staging process, during radiotherapy plan-
ning, and in the posttreatment work-up. Overall, PET has a
higher sensitivity for detecting tumor than compared to CT or
MRI. However, this is achieved at a relatively low specificity.
Physiological tracer uptake, for example, in the thyroid gland,
lymphoid tissue, salivary glands, and in active muscles may
cause confusion. Tracer accumulation in inflammation, such
as observed in therapy-induced tissue changes, may also cause
false-positive results (16). Other pitfalls of PET-imaging are
the low spatial resolution and the lack of tracer uptake in some
neoplasms, causing false-negative results (17). The high cost
of PET-imaging is an important drawback.
Key Points: Imaging Techniques
■ Multidectector CT is the imaging modality of choice for
laryngeal pathology
■ In highly selected cases, MRI of the larynx may be useful
■ Ultrasound has no important role to play in imaging laryngeal
cancer
■ PET has no role in the initial locoregional staging of laryngeal
cancer
TUMOR TYPES
Squamous Cell Carcinoma
Squamous cell carcinoma is the most common laryngeal malig-
nancy. These neoplasms originate from the mucosa but often
infiltrate the submucosal tissues. Cartilaginous structures often
613
 primary tumor evaluation and staging

divert these tumors to easier pathways of extension in the soft tis- deposits in non-enlarged nodes and to differentiate reactively
sues; cartilage invasion is usually a late phenomenon. Lymph node enlarged (inflammatory) lymph nodes from metastatic nodes.
infiltration follows invasion of capillary lymphatics. Supraglottic Currently no such ideal imaging method is available. Radiological
cancer has a high incidence of metastatic lymph nodes, while this criteria used to diagnose neck lymphadenopathy on CT and MR
is rarely seen in glottic carcinoma. studies are size, shape, and internal structure. A minimum axial
Distant spread is relatively rare, usually occurring in advanced diameter greater than 10 mm or the presence of central hypoden-
locoregional disease; the lungs are usually the first site of metastatic sity, indicating necrosis, are generally accepted criteria of abnor-
disease. mality (25). The size criterion is a compromise between sensitivity
and specificity. Using such criteria, the sensitivity of CT is about
Non-Squamous Cell Malignancies 90% and the specificity about 73%. As normal lymph nodes
Non-squamous cell carcinomas typically grow beneath an intact tend to be elongated, rounded lymph nodes are suspicious (Fig.
mucosal layer. A variety of epithelial non-squamous neoplasms 29.6). The results with CT are generally slightly better than
(such as adenoid cystic cancer) and non-epithelial neoplasms (such with standard MR sequences (26). Recent research suggests that
as chondrosarcoma) can be encountered within the larynx (18,19). diffusion-weighted MRI, mainly by showing diffusion restriction
in subcentrimetric metastatic adenopathies, is complementary
to standard MR sequences in nodal staging of squamous cell
carcinoma (12).
GENERAL IMAGING FINDINGS
IN LARYNGEAL NEOPLASMS
Distant Disease
Primary Tumor Identification of distant metastases is important as it has a
Imaging criteria used for tumor involvement are abnormal con- pronounced impact on prognosis and treatment (27). Modern
trast enhancement, soft tissue thickening, presence of a bulky mass, multi-modality treatment improves locoregional control, but may
infiltration of fatty tissue (even without distortion of surrounding be associated with metastatic disease developing later as a sole site
soft tissues), or a combination of these (Figs. 29.5 and 29.6). Lesions of recurrence (28).
limited to the mucosa may remain invisible on CT and MRI. The single most frequent site of distant metastases from laryn-
Several studies have compared CT/MRI findings with the results geal cancer is the lung. Depending on the study, bone, or liver
of whole organ sectioning after total or partial laryngectomy, metastases are the second (or third) most frequent sites. Both
showing that both techniques are accurate methods to visualize
laryngeal pathology (20,21). These studies also revealed some pit-
falls: small foci of mucosal tumor may be difficult to detect or may
be invisible, and associated inflammatory and edematous changes
may cause overestimation of the tumor extent; distortion of adja-
cent normal structures may mimic tumoral involvement.
Gross cartilage invasion can be detected with CT. Due to the
large variability in the ossification pattern of the laryngeal carti-
lages, CT often fails to detect early cartilage invasion. By combining
several diagnostic CT criteria, a reasonable accuracy for diagnosing
neoplastic invasion of the laryngeal cartilages can be obtained:
when extralaryngeal tumor and erosion or lysis in the thyroid, cri-
coid, and arytenoid cartilages was combined with sclerosis in the
cricoid and arytenoid (but not the thyroid) cartilages, an overall
sensitivity of 82%, an overall specificity of 79%, and an overall
negative predictive value of 91% was obtained (22) (Fig. 29.6).
MRI is a more sensitive technique than CT for the detection of
cartilage abnormalities (23). Areas of cartilage abnormality will
result in an increase in signal intensity on T2-weighted images and
contrast-enhanced T1-weighted MRI images. However, due to its
high sensitivity for intracartilaginous alterations, in a considerable
number of cases MRI will yield a false positive result (24). The pos-
itive diagnosis of neoplastic invasion of the laryngeal cartilage
should be made with extreme caution on MRI; it has been suggested
that one should describe “abnormal signal intensity in the cartilage”
rather than “invasion of cartilage” (24).
Figure 29.5 Axial contrast-enhanced CT-image in a patient suffering small right
sided glottic squamous cell cancer (arrow), extending in the anterior commis-
Neck Lymphadenopathy sure (arrowhead). The laryngeal cartilages appear normal. As the vocal cord
Non-invasive identification of neck node metastasis is challenging showed normal mobility during clinical examination, this tumor was staged as
as the ideal imaging method should be able to detect small tumoral T1N0.

614
 laryngeal tumors

(A) (B)

(C)

Figure 29.6 Axial contrast-enhanced CT-images in a patient suffering large-volume supraglottic squamous cell cancer. (A) The mass massively infiltrates the pre-
epiglottic space (asterisk) and grows through the thyrohyoid membrane into the extralaryngeal tissues (arrow). The left aryepiglottic fold is expanded by the tumor,
compressing the upper part of the pyriform sinus (white arrowhead). Small, but rounded lymph node (black arrowhead), suspect for metastasis. (B) Section somewhat
lower through supraglottis. Complete infiltration of pre-epiglottic (white asterisk) and left paraglottic space (black asterisk). Diffuse erosion of the left thyroid cartilage
(white arrowheads). (C) Section at level of false vocal cords. Persistent infiltration of pre-epiglottic and paraglottic space. At this level, the left thyroid cartilage wing
appears sclerotic (arrowheads). This can be caused by neoplastic invasion or reactive inflammation. Because of extralaryngeal tumor spread and several ipsilateral
adenopathies, this lesion was staged as T4aN2b.

bone and liver metastasis are nearly always associated with lung
metastasis (29).
The search for distant metastases must be balanced against
its costs (30). Conceiving a cost-effective algorithm demands
identification of patients at greater risk for distant metastasis.
A variety of factors influence this risk, including:
• Tumor site
• Stage at presentation [especially in N2 or N3 nodal
disease (29,31)]
• Histology (patients with adenoid cystic carcinoma have
a clearly increased risk of developing distant metastases
at some time)
Other factors, such as tumor differentiation, extranodal tumor spread,
evidence of perineural or vascular invasion, and neoangiogenesis (32)
are found also to be associated with an increased risk of distant
metastases.
The minimal imaging screen for distant metastasis at first pre-
sentation should include chest X-ray (30). CT of the chest is the
next step if the plain film is equivocal. Chest CT is justified in
• an advanced stage of the primary tumor,
• the presence of large neck adenopathies,
• the radiological detection of extracapsular spread, or
• the visualization of adenopathies low in the neck
FDG-PET, as a whole body imaging method, is also well suited to
the detection of distant disease. Screening with a combination of
CT scan of the thorax and whole body FDG-PET (or combined
PET-CT) decreases the risk of inappropriate treatment of the local
disease in patients (33).

615
 primary tumor evaluation and staging

challenging; however, usually the anterior commissure can be well

Key Points: General Imaging Findings
■ Laryngeal cancer usually appears as a contrast-enhancing
soft tissue mass, possibly infiltrating the submucosal
tissues
■ Superficial tumors may be invisible on cross-sectional imag-
ing; this rules out deep tissue involvement
■ MRI is more sensitive than CT in detecting laryngeal
cartilage involvement, but less specific
■ PET is mainly used to exclude distant metastasis and second
primaries in patients with advanced laryngeal cancer
LARYNGEAL SQUAMOUS CELL CANCER
Clinical Presentation
About 65% to 70% of laryngeal cancers originate at the glottic
level and about 30% at the supraglottic level; laryngeal cancer
originating from the subglottic region is rare. In most cases
patients with glottic cancer present early with hoarseness as the
tumor rapidly interferes with vocal cord function. Supraglottic
cancer is often diagnosed in a more advanced stage as these tumors
have more place to grow without causing immediate discomfort;
presenting symptoms may be sore throat, referred otalgia, and
dysphagia. Patients suffering supraglottic cancer may present
with a neck lump, caused by tumor spread to the lymph nodes.
Subglottic cancer is usually diagnosed when at an advanced stage
the patient presents with dyspnea, by narrowing of the subglottic
airway, and/or hoarseness, by neoplastic invasion of the true vocal
cords.
evaluated during endoscopic examination.
Cancer at the anterior commissure may directly invade the thy-
roid cartilage (Fig. 29.10); involvement of the anterior subglottic
region and/or lower pre-epiglottic space, as well as extralaryngeal
spread through the cricothyroid ligament, may occur.
When the tumor arises from the posterior side of the vocal cord,
extension over the medial facet of the arytenoid cartilage, eventu-
ally involving the posterior commissure, may be seen (Fig. 29.11).
The redundant mucosa at the level of the posterior commissure
should not be misinterpreted as evidence for tumor spread. Inva-
sion of the cricoarytenoid joint may occur from the region of the
posterior commissure.
Obstruction of the opening of the ventricular orifice may cause
a fluid-filled laryngocele (also called saccular cyst) (Fig. 29.11).
Table 29.3 T Staging of Glottic Cancer (94)
T1 Tumor limited to vocal cord(s) with normal mobility (may involve
anterior or posterior commissure)
T1a: limited to one vocal cord
T1b: involving both vocal cords
T2 Extension into supra- and/or subglottis, and/or with impaired vocal
cord mobility
T3 Vocal cord fixation and/or invasion of paraglottic space, and/or
minor thyroid cartilage erosion
T4 Extralaryngeal tumor spread
T4a: tumor invading through thyroid cartilage, or tissues beyond the
larynx (e.g., trachea, soft tissues of the neck, strap muscles, thyroid
gland, esophagus)
T4b: tumor invading prevertebral space, mediastinum, or encasing
carotid artery

Staging and Radiological Features

The clinical criteria used in the T-classification are site-depen-
dent. In the larynx, involvement of different laryngeal subsites Table 29.4 T Staging of Supraglottic Cancer (94)
and reduced vocal cord mobility are important criteria. The local T1
staging criteria for glottic, supraglottic, and subglottic cancer are
summarized in Tables 29.3 to 29.5, and illustrated in Figures T2
29.7 to 29.9.
The regional (neck) staging criteria for laryngeal cancer are T3
similar to those for oro- and hypopharyngeal cancer and sinona-
sal cancer (Table 29.6; see also chap. 28). T4
The validity of any classification is dependent on the diagnostic
methods employed. A marked improvement in accuracy is obtained
when the results of CT or MRI are added to the clinical findings
(34). Imaging is mainly of benefit in the detection of deep soft
tissue extension, such as in the pre-epiglottic space, the laryngeal
cartilages, and base of tongue. Findings from imaging studies
frequently result in an upstaging of the disease.
Table 29.5 T Staging of Subglottic Cancer (94)
Glottic Cancer T1
Local Tumor Spread T2
The most common site of involvement is the anterior portion of the
T3
vocal cord, usually at the free margin or upper surface (Fig. 29.5).
T4
Involvement of the anterior commissure is commonly present and
such lesions may extend over the midline to the contralateral vocal
cord. As the amount of normal soft tissue visible at the level of the
anterior commissure is somewhat variable (35), radiological detec-
tion of subtle tumor spread into this structure by imaging can be
Tumor limited to one subsite of supraglottis with normal vocal
cord mobility
Tumor invades mucosa of more than one adjacent subsite of
supraglottis, glottis or region outside of supraglottis, without
fixation of the larynx
Vocal cord fixation or invasion of postcricoid area, pre-epiglottic
and/or paraglottic space, and/or minor thyroid cartilage erosion
Extralaryngeal tumor spread
T4a: tumor invading through thyroid cartilage, or tissues beyond
the larynx (e.g., trachea, soft tissues of the neck, strap muscles,
thyroid gland, esophagus)
T4b: tumor invading prevertebral space, mediastinum, or encasing
carotid artery
Tumor limited to subglottis
Tumor extends to vocal cord(s) with normal or impaired
mobility
Vocal cord fixation
Extralaryngeal tumor spread
T4a: tumor invading through cricoid or thyroid cartilage, and/or
invades tissues beyond the larynx (e.g., trachea, soft tissues of
the neck, strap muscles, thyroid gland, esophagus)
T4b: tumor invading prevertebral space, mediastinum, or
encasing carotid artery

616
 laryngeal tumors

T1 T1

Invasion of epiglottis Invasion of false cord

T2 T2

T4a T4a

Invasion through thyroid cartilage

and/or invades tissues
beyond the larynx

T4b T4b

Tumor invades prevertebral space,

encases carotid artery,
or invades mediastinal structures
Figure 29.7 T-staging of supraglottic cancer.

Most laryngoceles are not caused by an obstructive mass, but an
underlying neoplasm has to be excluded, both clinically and
radiologically.
Extension into the subglottis may occur along the mucosal
surface or submucosally after penetration of the conus elasti-
cus. As the upper airway wall gradually slopes from the free
edge of the true vocal cords towards the inner side of the cricoid
ring, the precise border between the lower surface of the true
vocal cord and subglottic level is difficult to define on axial
cross-sectional imaging. When soft tissue thickening is seen
adjacent to a glottic neoplasm along the inner side of the cricoid,
the lesion is extending into the subglottis. Coronal images may
be helpful to evaluate more subtle subglottic tumor extension
(Fig. 29.12). A more precise method to measure the inferior
extent of glottic/subglottic cancer is by referring to the lateral
free margin of the true vocal cord.

617
 primary tumor evaluation and staging

T1 T2

T1a

T1b

T4a T4a

Tumor invades through

the thyroid cartilage
and/or invades tissues beyond the larynx

T4b T4b

Tumor invades prevertebral space,

encases carotid artery,
or invades mediastinal structures
Figure 29.8 T-staging of glottic cancer.

Lateral spread of the cancer causes infiltration of the vocal liga-
ment and muscle. In a more advanced stage the paraglottic space
is infiltrated and the perichondrium of the thyroid cartilage is
reached (Fig. 29.13). The tumor is diverted by the thyroid cartilage
to grow further in the paraglottic space, extending cranially into
the supraglottic region of the larynx or caudally into the subglot-
tic region. A glottic cancer growing inferiorly may be laterally
diverted by the conus elasticus, to leave the larynx through the
opening between the thyroid and cricoid cartilage.
Gross cartilage invasion can be detected with CT (Figs. 29.13
and 29.14). Neoplastic cartilage involvement usually occurs in
the ossified parts of the laryngeal framework, most frequently at
the inferior margin of the thyroid cartilage, upper margin of the
cricoid cartilage, or at the level of the anterior commissure (36).

618
 laryngeal tumors

T1 T2

T4a T4a T4a

Tumor invades cricoid or thyroid cartilage and/or invades tissues beyond the larynx

T4b T4b

Tumor invades prevertebral space, encases carotid artery, or invades mediastinal structures
Figure 29.9 T-staging of subglottic cancer.

When growing extralaryngeally, tumor may involve non-fatty soft
tissue structures surrounding the larynx. Neoplastic invasion of the
thyroid gland occurs most frequently in glottic cancer showing
subglottic extension or growing through the thyroid cartilage (37).
Invasion of the subcutaneous layers, and eventually skin, may be
seen in cancer spreading anteriorly. Posterior spread to the retrocricoid
hypopharynx and eventually esophagus may occur.
Rarely, glottic squamous cell cancer, when invading the ante-
rior part of the thyroid cartilage, presents as a prelaryngeal
abscess. This is likely to be due to erosion of the thyroid cartilage
by the neoplasm, or a combination of the neoplasm and an associ-
ated locally aggressive infection creating a pathway for bacteria
to the prelaryngeal soft tissues (Fig. 29.15) (38). The main dif-
ferential diagnosis in such cases is an infected thyroglossal duct

619
 primary tumor evaluation and staging

Table 29.6 N Staging Head and Neck Cancer (Excluding cyst. Infection coexisting with malignancy complicates the clin-
Nasopharyngeal and Thyroid Cancer) (94) ical picture and may lead to a delayed diagnosis of malignancy.
Verrucous carcinoma is a variant of squamous cell carcinoma,
NX Regional nodes cannot be assessed
N0 No regional nodal metastasis
occurring in 1% to 2% of patients with glottic cancer. On imaging
N1 Metastasis in a single ipsilateral lymph node ≤3 cm in greatest studies, verrucous carcinoma is difficult to differentiate from
dimension other types of squamous cell carcinoma, although an exophytic
N2a Metastasis in a single ipsilateral lymph node >3 cm but ≤6 cm in soft tissue mass originating from the true vocal cords, displaying
greatest dimension an irregular surface and no or minimal submucosal extension, is
N2b Metastasis in multiple ipsilateral lymph nodes, ≤6 cm in greatest
dimension
suggestive of this diagnosis (39).
N2c Metastasis in bilateral or contralateral lymph nodes, ≤6 cm in
greatest dimension
N3 Metastasis in a lymph node >6 cm in greatest dimension Lymphatic Spread
Usually glottic cancer only metastasizes to the neck lymph nodes
when growing beyond the glottic region. Level III (parajugular

(A) (B)

(C)

Figure 29.10 Axial contrast-enhanced CT-images in a patient with squamous cell cancer of the anterior glottic region. Thickening and slightly increased enhancement of
the anterior part of both true vocal cords and anterior commissure [arrows, (A) (B)]. Erosion of the anterior part of the thyroid cartilage [arrowheads (A)]. The fat plane
anterior to the cricothyroid ligament is intact: no evidence for extralaryngeal extension at this level [curved arrow (C)].

620
 laryngeal tumors

(A) (B)

Figure 29.11 Axial contrast-enhanced CT-images in a patient with a clinically T3 glottic cancer on the left side. (A) Level of true vocal cords. The left true vocal cord is
markedly thickened. The lesion extends into the anterior commissure (black arrowhead), and grows over the medial facet of the arytenoid into the posterior commissure
(white arrowheads). The left paraglottic space is infiltrated. The left arytenoid cartilage appears sclerotic (arrow). (B) Level of the aryepiglottic folds. Secondary fluid-
filled laryngocoele (arrow). Air-filled ventricle in the right paraglottic space (asterisk). The patient was treated by total laryngectomy. Pathologic examination showed
squamous cell cancer invading the anterior commissure and spreading in the right true vocal cord. The left arytenoid cartilage was invaded by the neoplasm.

lymph nodes, between level of hyoid bone and lower edge of cricoid
cartilage) is the most frequently affected level. Neck adenopathies
are very uncommon in small (T1) lesions, but the risk increases to
about 8% and 30% in T2 and T3 lesions, respectively.

Figure 29.12 Contrast-enhanced CT-image in a patient suffering glottic/subglottic
undifferentiated cancer. Coronal reformatting shows enhancing tumor (arrow-
heads), involving subglottic region and the inferior side of the true vocal cord
(asterisk). Opening of laryngeal ventricle (arrow); cricoid cartilage (c); thyroid
cartilage (t).
Supraglottic Cancer
Local Tumor Spread
Lesions of the suprahyoid epiglottis may grow exophytically. Others
invade the epiglottic tip and spread to adjacent structures, such as
the valleculae, tongue base, and pre-epiglottic space; soft tissue
ulceration and amputation of the epiglottic tip may be present
(Figs. 29.6 and 29.16).
As the infrahyoid epiglottis contains tiny perforations such
lesions easily infiltrate the preepiglottic space; from this space they
may spread upwards towards the valleculae and tongue base, or
downwards to the epiglottic petiolus (Fig. 29.17). Invasion of the
anterior commissure or subglottic spread are rare, but may be
seen in advanced cases.
Extension into the aryepiglottic folds and false vocal cords may
be seen; extension to the true vocal cords mostly occurs in
advanced cases (Fig. 29.17).
Aryepiglottic fold tumors may present as exophytic lesions, or
infiltrative masses invading the paraglottic space (Fig. 29.18).
Along the paraglottic space, they may spread towards the false and
eventually true vocal cords. Invasion of the cricoarytenoid joint
may be seen. Extension towards the pyriform sinus commonly
occurs, and it may be difficult to distinguish between a primary
pyriform sinus cancer and supraglottic cancer.
Also in cancers of the false vocal cord, submucosal tumor spread
is commonly present, with involvement of the paraglottic space at

621
 primary tumor evaluation and staging

(A) (B)

Figure 29.13 Contrast enhanced axial CT-images in a patient with a clinically T3 glottic cancer on the left side. (A) Level of true vocal cords. The left true vocal cord
appears thickened and slightly enhancing. The tumor reaches the anterior commissure (black arrowhead). The left paraglottic space is infiltrated [compare to normal
opposite side (arrow)]. Marked sclerosis of the left arytenoid (white arrowhead). There appears to be some sclerosis of the left thyroid lamina. (B) Level of subglottis.
Enhancing soft tissue thickening on left side (arrowheads). Note slight sclerosis of the cricoid arch on the left (curved arrow). Slight enhancement is seen anteromedially
to the subglottis, possibly corresponding to subtle extralaryngeal tumor spread between the thyroid and cricoid cartilage (arrow).

(A) (B)

Figure 29.14 Contrast-enhanced CT-images in a patient with a large glottic squamous cell carcinoma. (A) Axial image. The tumor mass massively invades and destructs
both wings of the thyroid cartilage, growing into the extralaryngeal soft tissues (arrows). (B) Coronal reformatting. Involvement of the glottic and supraglottic laryngeal
level (arrowheads) is seen, as well as massive destruction of both thyroid cartilage wings and extralaryngeal tumor spread (white arrows).

the level of the infrahyoid epiglottis/aryepiglottic fold and/or at Lymphatic Spread

the level of the true vocal cord (Fig. 29.19). Subglottic tumor As the supraglottic region has a rich network of lymphatic channels,
spread is seen in advanced cases. lymphadenopathy is frequently present in supraglottic cancer. At
Cartilage involvement is less commonly seen than in glottic presentation about 50% to 60% of patients with supraglottic cancer
cancer. have clinically manifest lymphadenopathy. The incidence of neck

622
 laryngeal tumors

(A) (B)

Figure 29.15 Patient presenting with hoarseness, dysphagia, and prelaryngeal soft tissue swelling. Axial contrast-enhanced CT-images show a large prelaryngeal fluid
collection with rim enhancement, compatible with a prelaryngeal abscess [(A) asterisk]. Thickening and enhancement of the left true vocal cord [(A) arrow], and frag-
mentation of the anterior part of the thyroid cartilage [(B) arrows], as well as sclerosis of left arytenoid cartilage is seen [(B) arrowhead], suggesting an underlying
malignancy. Biopsies confirmed presence of glottic squamous cell cancer, complicated by a prelaryngeal abscess. Total laryngectomy was performed; neoplastic invasion
of the arytenoid and thyroid cartilage was present. In the prelaryngeal tissues, only cicatricial and inflammatory tissue changes were found.

(A) (B)

(C)
Figure 29.16 Contrast-enhanced axial CT-images in patient suffering supraglottic cancer. (A) Level of hyoid bone. Thickening and increased enhancement of the epiglot-
tis, as well as infiltration of the pre-epiglottic and paraglottic space, with extension into the left aryepiglottic fold (arrowheads) is seen. Involvement of the upper part of
the left pyriform sinus cannot be excluded. (B) Level of free epiglottic margin. The epiglottic tip (arrowhead) is amputated on the left side. The margins of the left val-
lecula are occupied by tumoral tissue, and there is extension into the posterolateral wall of the oropharynx. Adenopathies are ipsilaterally present (curved arrow). (C) At
a slightly higher level, invasion of the tongue base (arrows), as well as posterolateral oropharyngeal wall (arrowheads), is seen.

623
 primary tumor evaluation and staging

(A) (B)

(C) (D) (E)

Figure 29.17 Contrast-enhanced CT-images in patient suffering supraglottic cancer. (A) Axial image. Thickening and increased enhancement of the infrahyoid epiglottis,
with infiltration of the pre-epiglottic space (arrows). (B) Axial image, more inferiorly, shows downwards tumor extension along the epiglottis and pre-epiglottic space
(arrow), as well as posterolateral growth into the aryepiglottic fold (arrowheads). (C) Axial image, more inferiorly, shows tumoral infiltration of the left false vocal cord
(asterisk). Some sclerosis of left thyroid cartilage wing (arrowhead): aspecific finding. (D) Coronal image. The tumor mass (arrows) extends throughout the left paraglottic
space, abutting and slightly displacing downwards the upper margin of the true vocal cord. Normal right true vocal cord (asterisk), right laryngeal ventricle (arrowhead). (E)
Sagittal image. Tumoral thickening of the infrahyoid epiglottis (arrowheads), extending down to the level just above the anterior commissure. True vocal cord (arrow).

metastasis is about 30% in T1 and T2 lesions, and about 70% in T3

and T4 lesions. Neck level II (parajugular lymph nodes, above level
of hyoid bone) is most commonly affected and, to a lesser extent,
level III (parajugular lymph nodes, between level of hyoid bone and
lower edge of cricoid cartilage) (40).

Figure 29.18 Axial CT-image in patient with supraglottic squamous cell carci-
noma, showing infiltrating lesion in left aryepiglottic fold (arrowhead). Pathologic
lymph node along left internal jugular vein (arrow).
Subglottic Cancer
By the time of diagnosis subglottic cancer has usually invaded the
true vocal cords, and it may be difficult to distinguish between a
cancer originating in the glottis or subglottis. Subglottic cancer is
commonly bilateral or even circumferential at presentation. Cricoid
cartilage invasion occurs early; extralaryngeal extension, anteriorly
through the cricothyroid membrane or inferiorly into the trachea,
is also commonly present.
Lymphatic dissemination is seen in about 10% of cases, but in
some series lymph node involvement is reported in up to 50% of
patients. Among the lymph nodes that may become involved are
the Delphian node, lying anterior to the cricothyroid membrane,
and paratracheal lymph nodes (41).
Imaging shows a subglottic enhancing soft tissue mass (nor-
mally no soft tissue is seen between the subglottic air column and
the cricoid cartilage), with more or less circumferential extension
along the cricoid cartilage (Fig. 29.20). The findings may include
cricoid cartilage alterations (such as sclerosis and/or lysis),

624
 laryngeal tumors

(A) (B)

Figure 29.19 Squamous cell carcinoma of the left false vocal cord. (A) Axial contrast-enhanced CT-image shows small infiltrating lesion (arrows) in the right paraglottic
space, at the level of the false vocal cords; the lesion extends into the anterior midline (lower part of pre-epiglottic space, level of epiglottic petiole). (B) Coronal reformat-
ting. Enhancing soft tissue lesion in the right false vocal cord (arrowheads), just above the normal true vocal cord (asterisk).

(A) (B)
Figure 29.20 Subglottic squamous cell carcinoma. Axial CT-images [(A) obtained 3 mm above (B)] show contrast-enhancing lesion (asterisk) in the right subglottis,
anteriorly reaching the midline, but posteriorly crossing the midline (arrowheads). The cricoid cartilage appears normal.

intratracheal soft tissue thickening, and infiltration of the glottic

and prelaryngeal soft tissues (Figs. 29.21 and 29.22). Advanced
Key Points: Laryngeal Squamous Cell Cancer
lesions may invade other adjacent tissues, such as the thyroid gland. ■ The extension pattern of glottic, supraglottic, and subglottic
cancer is different
Differential Diagnosis
■ Imaging is used to determine tumor extent
Small or superficially spreading mucosal tumors cannot be distin-
■ Imaging plays no role in diagnosing cancer
guished from inflammation on imaging; correlation with clinical
■ The imaging findings largely determine the T-staging of
findings and/or histological findings is necessary. Although the
laryngeal cancer
imaging features may allow a specific diagnosis, such as in the case of
■ The risk of lymphatic dissemination depends on the point of
a chondrosarcoma (18), the imaging findings in non-squamous cell
origin of the laryngeal cancer. The N-staging of laryngeal
neoplasms usually do not allow differentiation from squamous cell
cancer is largely determined by imaging
cancer.

625
 primary tumor evaluation and staging
Figure 29.21 Subglottic squamous cell carcinoma. Axial CT-image shows circum-
ferential soft tissue thickening in the subglottis (arrowheads), with pronounced
mixed osteolytic and sclerotic changes in the cricoid cartilage (arrows): massive
neoplastic cartilage invasion.
Figure 29.22 Axial contrast enhanced CT-image in a patient with subglottic squamous
cell cancer. Anterior subglottic soft tissue thickening (asterisk), with bilateral posterior
spread along the subglottic wall (arrowheads). Extralaryngeal spread through the crico-
thyroid membrane (curved arrow). Centrally hypodense nodule (arrow), presumably
corresponding to necrotic prelaryngeal (“Delphian”) lymph node.
TREATMENT OPTIONS AND PROGNOSTIC FACTORS
IN LARYNGEAL CANCER
Glottic Cancer
In T1 and T2 tumors radiation treatment is usually preferred, as the
voice quality is better than after partial laryngectomy and fewer
626
complications are encountered. Patients with small, well defined
lesions can be treated with either laser resection or radiotherapy (42).
Favorable T3 tumors, confined to one side of the larynx with-
out significant airway compromise, may be cured either with
radiotherapy or total laryngectomy with possible postoperative
irradiation. Failures after radiotherapy may be cured by salvage
laryngectomy (43). This concept of “radical radiotherapy with
surgery for salvage” is controversial as, according to some authors,
this treatment policy means that a number of patients will die in
order that others have their larynx spared (44).
Patients with more advanced disease (large tumor bulk, laryn-
geal framework destruction, and/or extralaryngeal spread on
imaging studies) are in the unfavorable group for radiotherapy
and are advised to undergo total laryngectomy.
In selected patients with advanced glottic cancer, extended par-
tial laryngectomy may still be feasible. This group includes patients
with arytenoid cartilage fixation and subglottic tumor extension
reaching the upper border of the cricoid cartilage (45).
Supraglottic Cancer
Patients with a T1, T2, or a “favorable” T3 lesion can be treated
with either irradiation or supraglottic laryngectomy (46). A T3
tumor, not staged as such because of vocal cord fixation and pre-
cluding supraglottic laryngectomy, is considered as “favorable.” As
the resection line in supraglottic laryngectomy passes through the
ventricles it is important that submucosal tumor spread in the
paraglottic space, along the ventricles, is excluded by imaging.
Supraglottic laryngectomy probably produces a higher initial local
control rate but, based on anatomic and coexisting medical con-
siderations, is suitable only for a small subset of patients and has a
higher risk of complications compared with radiotherapy (47).
Bulky, endophytic T3 lesions and most T4 lesions are consid-
ered unfavorable for radiotherapy; often they will show vocal cord
fixation and/or airway compromise. Total laryngectomy, with or
without postoperative radiotherapy, is often recommended in
these patients as the local control rates are better for the surgically
treated patients.
There is a need for better selection of patients into the favorable
group for radiotherapy (see below). Chemotherapy is useful as
concurrent therapy in patients with advanced, large volume
tumors (48). Imaging findings can be helpful to select patients in
whom radiotherapy has a good chance of success or in whom
concomitant treatment may be useful.
These guidelines are for the N0 patient; most patients will have
metastatic neck adenopathies and this may influence the treat-
ment decision process. Also, deviation from these guidelines is
possible, depending on the overall medical condition of the
patient, comorbidity, or patient preference.
Subglottic Cancer
Most patients suffering subglottic cancer will be treated by
total laryngectomy.
Influence of tumor Volume and Cartilage Abnormalities
on Local Outcome After Treatment
Concerns have been expressed about the weakness of the T clas-
sification for laryngeal cancer as the cure rates reported in the
literature vary and prognosis is not sufficiently related to the T
 laryngeal tumors
values (49). A quantitative analysis of imaging findings such as tumor
volume calculation offers complementary information regarding
the prognosis of head and neck tumors. Success in controlling a
tumor by radiotherapy depends on killing all clonogenic cells. As the
clonogen number increases more or less linearly with tumor volume,
this parameter is a powerful predictor of local outcome. However,
the volume of a tumor is difficult to estimate clinically.
By using cross-sectional imaging to quantify tumor volume, an
important variability in tumor volume was found within each T
category; also an important overlap of tumor volumes was noted
between different T categories (50,51).
Several studies have reported the prognostic value of CT-
determined tumor volume for outcome after definitive radiation
therapy in laryngeal cancer. One such study identified those
patients with T1–T4 supraglottic carcinomas who had a higher
likelihood of local control based on pre-treatment CT volumetric
analysis (tumors of ≤6 ml had a probability of 83% of local control,
while tumors of >6 ml had a control rate of only 46%) (52). In a
similar way, patients with T3 glottic carcinoma could be stratified
into groups with different likelihood of local control (tumors of
≤3.5 ml had a probability of 85% of local control, while tumors of
>3.5 ml had a local control rate of only 22%) (53). Other studies
(50,51) not only strongly corroborated these findings but also
indicated the prognostic value of deep tissue invasion, as identified
on CT studies.
Laryngeal cartilage invasion is often considered to predict a low
probability for radiation therapy alone to control the primary
tumor site, and also to indicate an increased risk of late complica-
tions, such as severe edema or necrosis (54,55). Before the era of
computer-assisted cross-sectional imaging only gross cartilage
destruction, usually occurring in large volume laryngeal tumors,
could be detected clinically or by conventional radiography. More
subtle degrees of laryngeal cartilage invasion are detectable by CT
and MRI (22). Some earlier studies described an association
between CT-depicted cartilage involvement in laryngeal carci-
noma and a poor outcome after radiation therapy (56,57). How-
ever, according to others, involvement of laryngeal cartilage is not
necessarily associated with a reduced success rate of radiation
therapy (58). In large retrospective studies, cartilage abnormalities
on CT were not an independent predictor of local failure after
radiotherapy (50,51).
On MRI, cartilage involvement in patients with small sized
tumors (under 5 cc) does not correlate with tumor recurrence;
however, an abnormal MR signal pattern in cartilage combined
with large tumor volume (above 5 cc) worsens the prognosis sig-
nificantly (24). Consequently, abnormal MR signal pattern in
laryngeal cartilage should not automatically imply laryngectomy,
especially in lesions with smaller volumes. It is incorrect to postu-
late that radiotherapy cannot cure a substantial number of lesions
with cartilage involvement on MRI. Similar to CT, the presence of
cartilage abnormalities on MRI studies may just reflect a large
tumor volume and deep tumor spread, and as such only indirectly
correlate with local outcome after radiotherapy (59).
It is often suggested that cartilage involvement precludes voice-
sparing partial laryngectomy (22,24,60). However, a recent study
indicated that cartilage alterations, as seen on preoperative CT, are
not correlated with the local outcome of patients treated by a speech-
preserving surgical technique (61). The surgical technique in this
study (extended hemilaryngectomy with tracheal autotransplanta-
tion) allows resection of the hemilarynx, including half of the cricoid
cartilage (45,62). Therefore, areas of possible neoplastic cartilage
were very likely to be included in the resection specimen (61).
Key Points: Treatment Options and Prognostic
Factors
■ The prognosis of laryngeal cancer is more dependent on
the pretreatment imaging findings (such as primary tumor
volume) than on the T-staging
■ Minor cartilage abnormalities, as visible on CT and MRI, do not
clearly influence the treatment outcome of the patient
■ In many patients suffering laryngeal cancer, organ-preserving
therapy (such as radiotherapy with or without chemotherapy)
can be applied, with surgery for salvage
IMAGING AFTER RADIOTHERAPY
Patients in whom pretherapy imaging has shown a high risk of recur-
rence (large tumor volume, deep tumor spread), in whom organ-
conserving therapy was performed require intensive post-treatment
imaging surveillance (see below). In such patients, post-treatment
studies allows the detection of a substantial number of local tumor
recurrences at an earlier stage than clinical examination alone (63).
Expected Findings After Radiotherapy
Within the first two weeks after radiotherapy there is an acute
inflammatory reaction within the deep tissues. Increased permea-
bility, due to detachment of the lining endothelial cells within small
blood and lymphatic vessels, results in interstitial edema. After this
initial period of a few weeks, progressive thickening of the connec-
tive tissue occurs. Endothelial proliferation is also seen, eventually
resulting in complete obstruction of the vessels. The reduction in
venous and lymphatic drainage results in further accumulation of
interstitial fluid. Then the fibrosis becomes progressively more
advanced, but the interstitial edema may be reduced by formation
of collateral capillary and lymphatic channels (64).
The tissue changes induced by radiotherapy, and visible on
post-treatment CT and MR images, depend on the radiation dose
and rate, the irradiated tissue volume, and the time elapsed since
the end of radiation therapy (65,66).
The expected neck tissue changes which may be seen after
radiotherapy include:
• Thickening of skin and platysma muscle
• Streaky infiltration of fat layers
• Retropharyngeal space edema
• Increased enhancement of the major salivary glands,
later followed by size reduction of these glands: postir-
radiation sialadenitis
• Lymphatic tissue atrophy (lymph nodes and Waldeyer’s
ring)
• Thickening and increased enhancement of pharyngeal
walls
• Thickening of laryngeal structures, with increased attenua-
tion of the pre-epiglottic and paraglottic fat (Fig. 29.23)
627
 primary tumor evaluation and staging

(A) (B)

(C) (D)

Figure 29.23 Axial and coronal contrast-enhanced CT images in a patient suffering glottic squamous cell carcinoma, treated by radiotherapy. Before radiotherapy (A)
(B), a left-sided glottic tumor mass (asterisk) is seen, infiltrating the left paraglottic space; extension over the medial facet of the sclerotic left arytenoid [arrowhead, (A)],
and some subglottic extension [arrowhead, (B)] is seen. Four months after radiotherapy (C) (D). No enhancing mass lesion can be recognized anymore; diffuse laryngeal
soft tissue thickening is seen as result of radiotherapy. The paraglottic fatty space re-appeared at the level of the left true vocal cord [(C), arrows]. The degree of arytenoid
sclerosis diminished. These findings indicate good response to radiation treatment. Patient is now two years after radiotherapy, with a functional larynx and without
evidence of disease.

These tissue changes are most pronounced during the first few
months after radiation therapy, and diminish or even resolve
with time. These expected tissue changes appear symmetrical,
unless the neck was irradiated using asymmetric radiation
portals.
The laryngeal cartilages are not expected to show changes after
irradiation. Reduction in the degree of cartilage sclerosis in the
neighborhood of the tumor has been described, and this appears
to correlate with local control (Fig. 29.23) (67).
On MR images, the findings are comparable to what can be seen
on CT. The irradiated tissues often show an increased intensity on
T2-weighted images, as well as increased enhancement.
Persisting or Recurrent Cancer
Nearly all recurrent cancers occur within two years after the end
of radiotherapy. Up to 40% of recurrent tumors can be detected
with cross-sectional imaging (CT or MRI) prior to their discovery
on clinical examination (68). This is related not only to the simi-
larity of post-radiotherapy changes and recurrent tumor on clini-
cal examination, but also to the often submucosal localization of
these tumors, making them difficult to detect by endoscopy.
Primary site tumor recurrence usually appears as an asymmetric
tissue swelling, often solid and enhancing (Fig. 29.24). However,
early tumor recurrence may also be difficult to distinguish on imag-
ing from tissue changes induced by therapy. A baseline follow-up

628
 laryngeal tumors
Figure 29.24 Axial contrast-enhanced CT-image, one year after radiation treatment
for squamous cell carcinoma in left aryepiglottic fold. Laryngeal edema (asterisk)
and thickened, enhancing hypopharyngeal mucosa (black arrowheads), caused by
irradiation. On the left side, an enhancing soft tissue mass is seen in the aryepiglot-
tic fold (white arrowheads), as well as a small necrotic lymph node in the left neck
(arrow). Biopsy revealed squamous cell carcinoma in left ary-epiglottic fold.
study after radiotherapy for a laryngeal neoplasm in patients at high
risk of recurrence, obtained about three to six months after the end
of treatment, is very useful as it documents treatment-induced
changes in the head and neck tissues, and allows the selection of
patients who may benefit from further imaging surveillance. Patients
showing only the expected tissue changes after radiotherapy, as
described above, have a very high chance of permanent local control,
and do not need further imaging surveillance. Further imaging fol-
low-up is useful if some soft tissue asymmetry persists (63,69). By
comparing subsequent studies with the baseline study, tumor recur-
rences can be detected with more confidence and at an earlier stage
than by clinical follow-up alone (Fig. 29.25). Although in asymp-
tomatic patients, the impact of post-treatment imaging on survival
time has not been proven as yet, in some of these patients curative
salvage of an early detected tumor recurrence may be feasible.
Using MRI, the findings are similar to CT. Promising results are
reported with diffusion-weighted MRI in distinguishing radio-
therapy-induced tissue changes and tumor recurrence (10,70).
The correlation between the extent of the tumor recurrence, as
visible on imaging studies, and the histological findings after laryn-
gectomy, is relatively poor. The local extent of many recurrent
tumors is underestimated on imaging (71).
Treatment Complications
Laryngeal radionecrosis is largely due to impaired vascular and
lymphatic flow caused by endothelial damage and fibrosis. Laryn-
geal necrosis may be induced by trauma or infection. The inci-
dence of laryngeal necrosis peaks during the 12 months following
treatment, more or less contemporaneous with the peak incidence
of tumor recurrence. However, cases of laryngeal necrosis more
than 10 years after radiation treatment do occur (72).
Patients with laryngeal necrosis often have neck and/or ear pain,
some degree of dysphagia, and anterior neck swelling. Hoarseness
and dyspnea are caused by increasing edema with impairment
of vocal cord mobility, resulting in cord fixation. Inflammatory
changes in the overlying skin, or cutaneous fistulae may be
present. Palpation of the laryngeal region is usually painful.
On CT studies, a variable degree of laryngeal soft-tissue swelling
may be seen (73). These soft tissue changes can be very pro-
nounced and may be the only visible abnormality, making the dif-
ferentiation from recurrent tumor very difficult. Furthermore,
laryngeal necrosis and tumor recurrence may occur simultane-
ously. In laryngeal necrosis, some fluid may be seen surrounding
the cartilages. Cartilaginous abnormalities are often visible in
chondroradionecrosis, but in some patients the cartilage changes
may only become apparent on later follow-up CT studies.
Necrosis of the thyroid cartilage may cause fragmentation and
collapse of this cartilage, with or without gas bubbles visible adja-
cent to or in it (Fig. 29.26). Patients with arytenoid cartilage
necrosis may show anterior dislocation of this cartilage; this could
be due to crico-arytenoidal joint effusion secondary to inflamma-
tion or infection. Progressive lysis of the arytenoid is possible,
showing a crumbly aspect evolving to complete disappearance
(74). Also, sloughing of the arytenoid cartilage into the airway has
been described (73). The adjacent part of the cricoid cartilage may
appear sclerotic. Cricoidal sclerosis or destruction may be also
seen in association with lysis of the thyroid cartilage.
On MR studies, laryngeal necrosis may appear as focal swelling
of the laryngeal soft tissues, loss of the normal high signal in the
medullary space of ossified laryngeal cartilage on T1-weighted
images, and enhancement of the affected cartilage after injection
of gadolinium (75). As mentioned above, diffusion-weighted MRI
may in some cases be helpful in making the distinction between
tumor recurrence and radionecrosis (10).
Use of PET After Radiotherapy for Laryngeal Cancer
FDG-PET may provide complementary information to anatom-
ical imaging modalities, allowing earlier diagnosis of recurrent
laryngeal cancer (76). However, treatment-induced inflamma-
tory changes and the low spatial resolution of this technique lead
to a low positive predictive value in the post-RT setting. The
negative predictive value of PET is reported to be very high (77).
The impact of FDG-PET, systematically performed after irradia-
tion, is significantly less than when motivated by clinical suspicion
of tumor recurrence (78). The exact role of FDG-PET in the
follow-up of irradiated laryngeal cancer is currently not well
established (79).
Key Points: Imaging After Radiotherapy
■ Good knowledge of expected tissue changes after radiotherapy
is essential
■ A CT study, obtained about four months after radiotherapy,
carries important prognostic information
■ Persistent or recurrent cancer after radiotherapy can often be
detected earlier on by CT than by clinical examination alone
■ CT may help to distinguish radionecrosis from tumor
recurrence
■ The use of PET in the post-treatment situation is not yet
clearly defined
629
 primary tumor evaluation and staging

(A) (B)

(C)

Figure 29.25 Axial contrast-enhanced CT-images in a patient with a T2N0 supraglottic cancer. (A) Pretreatment image. Left-sided, enhancing infiltrating soft tissue mass
in the lower supraglottic soft tissues (arrows), abutting the tip of the sclerotic arytenoid cartilage (arrowhead). (B) Baseline follow-up CT study, four months after radio-
therapy. Clinically no evidence of disease. The tumoral mass disappeared. However, the persistent infiltration in the left retro-arytenoid fat plane (arrow, compare to
opposite side, arrowhead) is doubtful. A follow-up CT study was recommended. (C) Eight months after end of radiotherapy. The patient has no symptoms. Clinical
examination showed some interarytenoid erythema. On CT, new soft tissue thickening (arrows) is seen surrounding the tip of the arytenoid; this is suspect for tumor
recurrence. Direct laryngoscopy was performed, showing edema and some necrotic tissue on the lower left aryepiglottic fold. Biopsies confirmed presence of cancer.
Subsequently, total laryngectomy was performed.

IMAGING AFTER SURGERY
Expected Imaging Findings After Surgery
The limits of surgical therapy are determined by the balance
between obtaining a cure by radical resection of the tumor, and
leaving the patient in a functionally and aesthetically acceptable
situation. The available surgical procedures range from a limited
excision to total laryngectomy (80).
The expected findings after transoral laser excision of a laryngeal
cancer depend on the amount of tissue resected. The laryngeal soft
tissues may appear normal or show a focal tissue defect (Fig.
29.27). After a more extensive resection the laryngeal soft tissue
may be replaced by scar, appearing as homogenous but rela-
tively dense tissue with a straighter inner border (81); in such
cases, differentiation from recurrent tumor may be difficult and
correlation with endoscopic findings is necessary. In case of
doubt, biopsy is warranted.
The aim of partial laryngectomy is to combine radical tumor
resection with preservation of laryngeal function. Traditional par-
tial laryngectomies include horizontal supraglottic laryngectomy

630
 laryngeal tumors

(A) (B)

Figure 29.26 Patient treated 29 years earlier by radiotherapy for a T1 glottic squamous cell carcinoma. The patient now suffers hoarseness, pain, and dysphagia. Clinical
examination shows laryngeal airway narrowing. (A, B) Axial contrast-enhanced images show fragmentation (white arrowheads) of the anterior part of the thyroid car-
tilage, fluid adjacent to the cartilage (arrows), as well as presence of small gas bubbles (black arrowheads). These findings are suggestive for laryngeal necrosis. Surgical
debridement and reconstruction by placement of a soft tissue flap over the larynx was performed. Symptoms resolved and the patient kept a functional larynx.

(A) (B)

Figure 29.27 (A) Recurrent glottic squamous cell cancer, presenting as soft tissue thickening (arrows), two years after radiotherapy for a right-sided glottic cancer
(T2N0). (B) Situation seven months after partial cordectomy by transoral laser resection: a soft tissue defect is seen in the anterior half of the right true vocal cord
(arrows); no evidence for recurrent cancer.

and vertical hemilaryngectomy, but more complex surgical
techniques are also being employed (45,81,82). The postoperative
radiological findings depend on the technique employed. Changes
in the laryngeal framework offer landmarks for interpreting
postoperative findings. The postoperative soft tissue changes are
less predictable, depending on technical adaptations needed for
adequate tumor resection, individual differences in healing, and
variations in amount of edema and scarring (81). The differentiation
between redundant or hypertrophic mucosa as well as scar tissue
from recurrent cancer may be difficult.
Basically, horizontal supraglottic laryngectomy can be per-
formed in supraglottic cancer by removing almost the entire lar-
ynx above the level of the ventricles. The residual thyroid cartilage
is pulled upwards and sutured to the hyoid bone (Fig. 29.28).
Limited glottic cancer can be treated by vertical hemilaryngec-
tomy. The most limited variant of this procedure is a cordectomy,

631
 primary tumor evaluation and staging

Figure 29.28 Diagram of a supraglottic laryngectomy. In the top diagram, the inci-
sion plane (dotted line) is depicted through the ventricle just above the level of the
true vocal cord. The epiglottis and supraglottic part of the larynx are removed. In
the lower diagram, the postoperative appearance is shown schematically: the
supraglottic part of the larynx was removed. The right upper thyroid lamina is
shown resected, but in practice, the amount of thyroid cartilage removed is vari-
able and this may be done bilateral.
where the entire vocal cord is removed from the anterior commis-
sure to the vocal process of the arytenoid. In a frontolateral laryn-
gectomy the true and false vocal cord is removed, as well as the
greatest part of the ipsilateral thyroid cartilage, including the angle
to encompass the anterior commissure; the vocal process of the
arytenoid can also be included. In a frontal laryngectomy
the anterior portion of both vocal cords is removed, together with
the anterior commissure; Tucker’s “near-total” technique is a
modified frontal laryngectomy using the epiglottis as reconstructive
tissue (Fig. 29.29).
If more extensive involvement of the arytenoid (possibly with
involvement of the cricoarytenoid joint) and/or subglottic exten-
sion is present, extended hemilaryngectomy may be an alternative.
During this procedure half of the larynx, including half of the
cricoid cartilage, is removed. The large defect in the larynx is
reconstructed with a tracheal patch, revascularized by a freely

(A) (B)

(C)

Figure 29.29 Contrast-enhanced CT-images in a patient who was treated by a frontal laryngectomy (according to Tucker) for a carcinoma in the anterior commissure.
Three years later, the patient presents with increasing dysphonia. Clinically, swelling of the right false vocal cord is noted with an intact mucosa. (A) Axial section at the
level of the arytenoid cartilages (arrowheads). Defect in the anterior part of the thyroid cartilage (double-headed arrow); the anterior part of the left true vocal cord
(curved arrow) has been resected. On the right side, a centrally necrotic soft tissue mass is seen (asterisk), indicating tumor recurrence. (B) Coronal reformatting. Level
of true vocal cord is indicated on left side by arrow. The recurrent tumor on the right (arrowheads) grows from the false vocal cord region into the true vocal cord; early
subglottic extension may be present (lower arrowhead). (C) Sagittal reformatting. The epiglottis (arrows) has a more anterior course as normally expected, as this
structure was used to close the thyroid cartilage defect. The recurrent tumor (asterisk) abuts the upper margin of the cricoid arch, appearing sclerotic (arrowhead).
No neoplastic cartilage invasion was present histologically.

632
 laryngeal tumors

transplanted radial forearm soft tissue flap. Full height cricoid
defects can be closed using this patch in a position comparable to
unilateral laryngeal paralysis. This is a functional reconstruction,
allowing the patient to breathe and speak through his larynx, and
to swallow without aspiration (45) (Fig. 29.30).
Some advanced glottic and supraglottic cancer can be treated by
supracricoid partial laryngectomy (SPL), entailing en bloc resec-
tion of all tissues between the upper margin of the cricoid carti-
lage and the inferior margin of the hyoid bone, including the true
and false vocal cords. Only the arytenoid on the less involved site
is left in place. For glottic cancers without involvement of the
supraglottis, the upper two-thirds of the epiglottis can be pre-
served; this variant is known as SPL with cricohyoidoepiglottopexy
(CHEP) (83).
Complete removal of the larynx may be required as primary
treatment of extensive laryngeal cancer, or for salvage of tumor
recurrence after radiation treatment or failed partial laryngec-
tomy. When the larynx is removed, the airway and upper digestive
tract become completely separated. The airway will then end at a
tracheostomy in the base of the neck. If, following the laryngec-
tomy, insufficient hypopharyngeal tissue is left for creating a
neopharyngeal lumen of acceptable diameter, a soft tissue flap is
used to create a wider lumen. A pedicled pectoralis major muscu-
locutaneous flap is commonly used for this purpose (Fig. 29.31).
On imaging studies the pectoralis major flap appears initially as a
bulky soft tissue structure showing the characteristics of muscle;
gradually, denervation atrophy appears causing volume loss and
fatty replacement of the muscle. Other flaps, such as a radial fore-
arm flap or an intestinal structure, may also be used to create a
neopharynx (Fig. 29.32).
During laryngectomy thyroid tissue is often removed. The
remnant thyroid tissue is usually easy to recognize because it
shows a high density on CT, related to the high iodine concentra-
tion in the gland and its strong vascularization. However, as the
normal shape of the thyroid gland is lost, these remnants usually
show a rounded or oval appearance. Thyroid tissue may appear

(A) (B)

(C)

Figure 29.30 Contrast-enhanced CT images in a patient treated by extended hemilaryngectomy for a right sided true vocal cord carcinoma. (A) Axial section at the level
of the left true vocal cord. Left arytenoid (arrowhead). The right hemilarynx was resected, and the defect closed by a tracheal patch (arrows). The fatty structure along
the tracheal patch (asterisk) corresponds to the radial forearm fascial flap. (B) Axial section at the level of the subglottis. The subglottic airway is reconstructed by the
tracheal transplant. (C) Coronal reformatting shows restoration of the laryngeal airway by the tracheal transplant (arrows). Left true vocal cord (arrowhead); cricoid
cartilage (c); thyroid cartilage (t).

633
 primary tumor evaluation and staging
Figure 29.31 Axial contrast-enhanced CT image. Situation after total laryngec-
tomy. The neopharynx is reconstructed by residual pharyngeal tissue (arrows)
and a musculocutaneous soft tissue flap (pectoral major flap), containing skin
(arrowheads), subcutaneous fat (white asterisk) and muscle (black asterisk).
Figure 29.32 Axial contrast-enhanced CT-image, in a patient treated by total
laryngectomy. The neopharynx is reconstructed by a free radial forearm flap
(arrowheads; inner enhancing rim is skin); the soft tissues are anteriorly covered
by a pedicled pectoralis major flap (arrows).
heterogeneous due to nodular hyperplasia, adenomas, or cysts.
Such thyroid remnants should not be confused with recurrent
cancer (Fig. 29.33).
Tumor Recurrence After Surgery
As complete removal of the tumor can be histologically confirmed
on the resection specimen, surveillance imaging is not indicated
after surgical treatment. Imaging is performed where there is clin-
ical suspicion of tumor recurrence. The most reliable imaging
finding in recurrent tumor is an enhancing soft tissue mass (Figs.
29.29 and 29.34); destruction of residual laryngeal cartilage may
be seen after partial laryngectomy.
634
Figure 29.33 Axial contrast-enhanced CT image. The neopharynx is seen lying
between both thyroid lobes (black asterisks). The thyroid isthmus was resected
during the laryngectomy. The heterogeneous appearance of the thyroid lobes is
caused by nodular hyperplasia. Absence of left internal jugular vein along the com-
mon carotid artery (arrowhead), resected during radical neck dissection. Soft tis-
sue flap (white asterisk).
Figure 29.34 Axial contrast-enhanced CT-image, after total laryngectomy for
squamous cell carcinoma. Enhancing soft tissue mass (asterisk) at the anterolateral
side of the neopharyngeal lumen (arrow): recurrent cancer.
Complications After Surgery
Most surgical complications occur early after treatment and are
dealt with on a clinical basis. Imaging may be required in the
detection and follow-up of a fistula after partial or total laryngec-
tomy. Many of these fistulas will close spontaneously but some
may need reintervention.
After conservative surgery, swallowing co-ordination may be
impaired. The postoperative swallowing function can be analyzed
by videofluoroscopy or videofluorography, providing information
for the planning of rehabilitation (81). In some cases, surgical
intervention may be required; and in the case of severe aspiration,
total laryngectomy may be necessary.
Imaging may also be of use in the confirmation of flap failure
due to necrosis.
 laryngeal tumors

located in the supra- and subglottic region; the glottis is devoid

Key Points: Imaging After Surgery
■ Imaging is not routinely required after surgical treatment of
laryngeal cancer
■ Imaging is often not required in the management of early
surgical complications
■ When tumor recurrence is suspected after surgery, imaging is
used for confirmation and assessing the extent of the tumor
of minor salivary glands. Adenoid cystic carcinoma is the most
frequent neoplasm of the minor salivary glands, but also ade-
nocarcinoma and muco-epidermoid carcinoma arise from
these glands.
In the larynx, these tumors usually present as a submucosal
soft tissue mass in the subglottis (Fig. 29.35). As they grow sub-
mucosally they are often locally more extensive than clinically
suspected.

NON-SQUAMOUS CELL MALIGNANCIES Chondrosarcoma

Non-squamous cell carcinomas are rare. They typically grow
beneath an intact mucosal layer. Clinical and endoscopic diagnosis
of a submucosal laryngeal mass lesion is more difficult and the
initial biopsy results of such lesions may be returned as inconclu-
sive or negative.
CT and MR studies demonstrate the presence and extension of
such submucosal mass lesions. The radiological differentiation
between a benign and malignant submucosal mass may be diffi-
cult. Signs suggesting malignancy include cartilage destruction,
the presence of adenopathies, a multifocal appearance, and/or
widely infiltrating behavior.
A variety of epithelial non-squamous neoplasms and non-
epithelial neoplasms can be encountered within the larynx (18).
The following discussion is limited to malignant lesions.
Minor Salivary Gland Neoplasms
Minor salivary glands are found throughout the mucosa of the
oral and upper respiratory tract. In the larynx, these glands are
Among the rare mesenchymal neoplasms in the larynx, chondro-
sarcoma is the most common (84). Around 70% arise from the
cricoid cartilage and the thyroid cartilage is the next most com-
mon site of origin. These neoplasms are usually low-grade sarco-
mas. True chondromas of the larynx are probably very rare. It is
difficult to firmly establish the diagnosis of benign laryngeal
chondroma on a small amount of tissue obtained by biopsy. Com-
pared to chondroma, low-grade chondrosarcoma may display
only minimally increased cellularity and nuclear atypia, a pattern
overlapping with benign chondromas; there is also no appreciable
degree of mitotic activity in such lesions (85).
On CT, cartilaginous tumors of the larynx appear as hypodense,
well circumscribed masses centered within the laryngeal cartilage,
with coarse or stippled calcification within the lesion (86) (Fig.
29.36). The imaging findings do not distinguish between a benign
and malignant chondroid tumor, although in high-grade chond-
rosarcomas nodal metastasis in the head and neck may rarely be
seen. MRI is less specific for diagnosing such a lesion as it does not
depict the intratumoral calcifications as well as CT; on MRI,

(A) (B)

Figure 29.35 Patient presenting with hoarseness; endoscopically, a submucosal mass lesion is suspected. (A) The axial T2-weighted MR image shows a hyperintense mass
lesion (arrows) in the subglottis and distal hypopharynx. (B) On the sagittal gadolinium-enhanced T1-weighted image, the mass is seen to infiltrate the larynx (upper
arrowhead), proximal trachea (lower arrowhead), distal hypopharynx (upper arrow), and proximal esophagus (lower arrow). Adenoid cystic carcinoma.

635
 primary tumor evaluation and staging
the tumor matrix shows a relatively high signal intensity on
T2-weighted images; the tumor enhancement after injection of
gadolinium is variable (Fig. 29.37).
Hematopoietic Neoplasms
Extranodal extralymphatic non-Hodgkin lymphoma may infiltrate
any tissue of the head and neck; however, laryngeal lymphoma
Figure 29.36 Coincidently discovered mass lesion in cricoid cartilage, on occasion
of a MR study of the cervical spine. Clinical examination showed submucosal
swelling underneath the left true vocal cord. Axial CT-image (bone window) con-
firms an expansile lesion in the left posterolateral part of the cricoid arch (arrows).
The lesion contains punctiform calcifications. The patient was treated by extended
hemilaryngectomy; histological examination showed low-grade chondrosarcoma.
(A)
Figure 29.37 MR appearance of a large low-grade chondrosarcoma originating from the cricoid cartilage. (A) Axial T2-weighted spin echo image shows a lobulated mass
(arrows) with high signal intensity. (B) Gadolinium-enhanced axial T1-weighted spin-echo image shows irregular enhancement of the mass lesion (arrows).
636
rarely occurs (Fig. 29.38) (19,87). Also, other hematopoietic
neoplasms, such as plasmacytoma, are very rarely seen in the
larynx (88). The larynx is a rare site for metastasis. In most cases
the metastasis involves the supra- or subglottic submucosal tis-
sues, or the ossified laryngeal framework. The most common
primary tumors are malignant melanoma, renal cell carcinoma,
gastro-intestinal cancer, breast cancer, and pulmonary cancer
(89,90). Laryngeal metastasis may be asymptomatic or cause
symptoms similar to primary laryngeal tumors.
Key Points: Non Squamous Cell Malignancies
■ Non squamous cell malignancies of the larynx are rare
■ Chondrosarcoma is the most common tumor type
■ These tumors occur submucosally; imaging is essential for
diagnosis and to determine the tumor extent
IMAGING OF VOCAL CORD PARALYSIS
Vocal cord paralysis is caused by palsy of the recurrent laryngeal
nerve. This nerve is a branch of the vagal nerve and innervates
most intrinsic muscles of the larynx. The offending lesion may be
on the course of the recurrent laryngeal nerve itself (distal vagal
neuropathy), or more proximal in the suprahyoid course of the
vagal nerve (proximal vagal neuropathy).
Distal vagal neuropathy results in isolated endolaryngeal symp-
toms (hoarseness, and sometimes also aspiration). Imaging should
be directed toward searching for a lesion on the course of the dis-
tal vagal nerve in the carotid space, and along the course of the
recurrent laryngeal nerve in the tracheo-esophageal groove,
extending around the subclavian artery on the right and around
the aortic arch within the aortopulmonary window on the left.
At the suprahyoid level, the vagal nerve is quite close to the
glossopharyngeal (IX), spinal accessory (XI) and hypoglossal
(B)
 laryngeal tumors

nerve (XII); injury to the vagal nerve at this level is commonly

Figure 29.38 Axial contrast-enhanced CT image shows large, homogenous soft tissue
mass (asterisk) in the right aryepiglottic fold and paraglottic space, associated to a large,
homogenous parajugular adenopathy (arrow). These imaging findings suggest, but are
not pathognomonic for lymphoma. Biopsy showed non-Hodgkin lymphoma.
accompanied by symptoms related to injury of these cranial
nerves. Imaging should then be directed to the proximal part of
the vagal nerve, from its origin in the brain stem to the level of the
hyoid bone (91).
Excluding primary laryngeal neoplasms, extralaryngeal malig-
nancies are the most common cause of unilateral vocal cord
immobility. About 80% of these tumors are of pulmonary or
mediastinal origin, and cause vocal cord paralysis by interfering
with the function of the recurrent laryngeal nerve (92). This
explains why left vocal cord paralysis is slightly more common, as
the intrathoracic part of the left recurrent laryngeal nerve is
vulnerable to neoplastic invasion by such thoracic malignancies.
Less commonly, vocal cord paralysis is caused by esophageal, met-
astatic, or thyroid neoplasms.
Rarely, vocal cord paralysis is due to benign disease in or
extending into the tracheo-esophageal groove; it has been
reported to be caused by multinodular goiter, thyroid abscess,
and parathyroid cyst.
Iatrogenic causes for vocal cord immobility are increasing (92).
Procedures such as the anterior approach to cervical spine disease
and carotid endarterectomy may be complicated by vocal cord

(A) (B)

Figure 29.39 Patient presenting with hoarseness, and left vocal cord paralysis at clinical examina-
tion. Axial contrast-enhanced CT-images. (A) Atrophy of the left vocal cord muscle (curved arrow),
relative dilatation of left pyriform sinus (arrow), and slight anteromedial displacement of left
arytenoid (arrowhead). (B) Atrophy of the left posterior cricoarytenoid muscle (arrow); compare
with normal right posterior cricoarytenoid muscle (arrowhead). (C) During the same CT study,
images were acquired through the upper mediastinum, showing a soft tissue mass in the left upper
(C) lung lobe, infiltrating the aortopulmonary window: this turned out to be a primary lung cancer.

637
 primary tumor evaluation and staging

paralysis. Thyroid surgery and esophageal cancer surgery are a

relatively common cause of both uni- and bilateral vocal cord
paralysis. Prolonged intubation may cause vocal cord immobility
either by compression injury to the recurrent laryngeal nerve or
fixation or disruption of the crico-arytenoid joint.
In many patients no definite explanation for the vocal cord
paralysis can be found after thorough examination. These patients
with idiopathic vocal cord paralysis typically show spontaneous
recovery (92).
The CT features of vocal cord paralysis are volume reduction
of the thyroarytenoid muscle, possibly appearing more
hypodense than the contralateral muscle due to fatty infiltra-
tion. Relaxation and volume loss of the vocal cord muscle leads
to anteromedial deviation of the arytenoid cartilage, enlarge-
ment of the ipsilateral laryngeal ventricle and pyriform sinus,
and a paramedian position of the vocal cord (91). Palsy of the
recurrent laryngeal nerve may also lead to atrophy of the poste-
rior crico-arytenoid muscle which it also innervates (Fig. 29.39)
(93). The entire course of the vagal and recurrent laryngeal
nerve should be investigated to rule out an underlying disease
(Fig. 29.39).
Key Points: Vocal Cord Paralysis
■ Imaging is used to rule out a lesion along the course of the
vagal nerve and recurrent laryngeal nerve
■ Many cases are idiopathic
■ In a case of left-sided paralysis, the CT study must include
the upper mediastinum as the left recurrent laryngeal nerve
lies underneath the aortic arch
10. Vandecaveye V, De Keyzer F, Vander Poorten V, et al. Evalua-
Summary
■ The vast majority of laryngeal neoplasms are squamous cell
cancers
11. Sumi M, Sakihama N, Sumi T, et al. Discrimination of meta-
■ Imaging is mainly used to determine primary tumor extent,
including the involvement of the deep laryngeal fat planes,
laryngeal framework invasion, and extralaryngeal tumor
spread. Imaging is also very important to detect neck nodal
12. Abdel Razek AA, Soliman NY, Elkhamary S, Alsharaway MK,
disease
■ Multidetector CT is the imaging modality of choice for
laryngeal cancer
13. van den Brekel MW, Castelijns JA. What the clinician wants to
■ The imaging findings have prognostic significance; especially
large tumor volume and deep tissue invasion on imaging
studies are associated with a reduced chance of tumor
14. Takes RP, Knegt P, Manni JJ, et al. Regional metastasis in head
control by organ-preserving treatment modalities
■ The minimal imaging study to rule out metastatic disease is
a chest X-ray; in advanced primary tumors, or when advanced
15. Takes RP, Righi P, Meeuwis CA, et al. The value of ultrasound
nodal disease is present, chest CT or PET-scan should also be
performed. PET-CT appears to be the best modality to rule
out distant disease in advanced laryngeal cancer
■ CT is very helpful in the follow-up of laryngeal cancer after
radiotherapy, providing prognostic information and allowing
16. Rogers JW, Greven KM, McGuirt WF, et al. Can post-RT neck
earlier detection of tumor recurrence than clinical examination
alone. The use of PET in the post-treatment situation is not
yet well defined
638
REFERENCES
1. Sato K, Kurita S, Hirano M. Location of the preepiglottic space
and its relationship to the paraglottic space. Ann Otol Rhinol
Laryngol 1993; 102: 930–4.
2. Yeager VL, Lawson C, Archer CR. Ossification of the laryngeal
cartilages as it relates to computed tomography. Invest Radiol
1982; 17: 11–19.
3. Rumboldt Z, Gordon L, Gordon L, Bonsall R, Ackermann S.
Imaging in head and neck cancer. Curr Treat Options Oncol
2006; 7: 23–34.
4. Wirth S, Meindl T, Treitl M, Pfeifer KJ, Reiser M. Comparison
of different patient positioning strategies to minimize shoulder
girdle artifacts in head and neck CT. Eur Radiol 2006; 16:
1757–62.
5. Keberle M, Tschammler A, Hahn D. Single-bolus technique
for spiral CT of laryngopharyngeal squamous cell carcinoma:
comparison of different contrast material volumes, flow rates,
and start delays. Radiology 2002; 224: 171–6.
6. Lell MM, Greess H, Hothorn T, et al. Multiplanar functional
imaging of the larynx and hypopharynx with multislice spiral
CT. Eur Radiol 2004; 14: 2198–205.
7. Schmalfuss IM. Imaging of the hypopharynx and cervical
esophagus. Neuroimaging Clin N Am 2004; 14: 647–62.
8. Sigal R, Vogl T, Casselman J, et al. Lymph node metastases
from head and neck squamous cell carcinoma: MR imaging
with ultrasmall superparamagnetic iron oxide particles
(Sinerem MR) - Results of a phase-III multicenter clinical
trial. European Radiology 2002; 12: 1104–13.
9. Mack MG, Balzer JO, Straub R, Eichler K, Vogl TJ. Superpara-
magnetic iron oxide-enhanced MR imaging of head and neck
lymph nodes. Radiology 2002; 222: 239–44.
tion of the larynx for tumour recurrence by diffusion-weighted
MRI after radiotherapy: initial experience in four cases. Br
J Radiol 2006; 79: 681–7.
static cervical lymph nodes with diffusion-weighted MR
imaging in patients with head and neck cancer. AJNR Am
J Neuroradiol 2003; 24: 1627–34.
Tawfik A. Role of diffusion-weighted MR imaging in cervical
lymphadenopathy. Eur Radiol 2006; 16: 1468–77.
know: surgical perspective and ultrasound for lymph node imag-
ing of the neck. Cancer Imaging 2005; 5 (Spec No. A): S41–S49.
and neck squamous cell carcinoma: revised value of US with
US-guided FNAB. Radiology 1996; 198: 819–23.
with ultrasound-guided fine-needle aspiration biopsy com-
pared to computed tomography in the detection of regional
metastases in the clinically negative neck. Int J Radiat Oncol
Biol Phys 1998; 40: 1027–32.
dissection be omitted for patients with head-and-neck cancer
who have a negative PET scan after definitive radiation therapy?
Int J Radiat Oncol Biol Phys 2004; 58: 694–7.
 laryngeal tumors
17. Stuckensen T, Kovacs AF, Adams S, Baum RP. Staging of the
neck in patients with oral cavity squamous cell carcinomas: a
prospective comparison of PET, ultrasound, CT and MRI.
J Craniomaxillofac Surg 2000; 28: 319–24.
18. De Foer B, Hermans R, Van der Goten A, Delaere PR, Baert
AL. Imaging features in 35 cases of submucosal laryngeal mass
lesions. Eur Radiol 1996; 6: 913–19.
19. Hermans R, Horvath M, De Schrijver T, Lemahieu SF, Baert
AL. Extranodal non-Hodgkin lymphoma of the head and
neck. J Belge Radiol 1994; 77: 72–7.
20. Zbaren P, Becker M, Lang H. Pretherapeutic staging of laryn-
geal carcinoma. Clinical findings, computed tomography, and
magnetic resonance imaging compared with histopathology.
Cancer 1996; 77: 1263–73.
21. Daisne JF, Duprez T, Weynand B, et al. Tumor volume in phar-
yngolaryngeal squamous cell carcinoma: comparison at CT,
MR imaging, and FDG PET and validation with surgical spec-
imen. Radiology 2004; 233: 93–100.
22. Becker M, Zbaren P, Laeng H, et al. Neoplastic invasion of the
laryngeal cartilage: comparison of MR imaging and CT with
histopathologic correlation. Radiology 1995; 194: 661–9.
23. Becker M, Zbaren P, Delavelle J, et al. Neoplastic invasion of
the laryngeal cartilage: reassessment of criteria for diagnosis at
CT. Radiology 1997; 203: 521–32.
24. Castelijns JA, Becker M, Hermans R. Impact of cartilage inva-
sion on treatment and prognosis of laryngeal cancer. Eur
Radiol 1996; 6: 156–69.
25. Castelijns JA, van den Brekel MW. Imaging of lymphadeno-
pathy in the neck. Eur Radiol 2002; 12: 727–38.
26. Curtin HD, Ishwaran H, Mancuso AA, et al. Comparison of
CT and MR imaging in staging of neck metastases. Radiology
1998; 207: 123–30.
27. Ferlito A, Buckley JG, Rinaldo A, Mondin V. Screening tests to
evaluate distant metastases in head and neck cancer. ORL J
Otorhinolaryngol Relat Spec 2001; 63: 208–11.
28. León X, Quer M, Orús C, del Prado Venegas M, López M. Dis-
tant metastases in head and neck cancer patients who achieved
loco-regional control. Head Neck 2000; 22: 680–6.
29. de Bree R, Deurloo EE, Snow GB, Leemans CR. Screening for
distant metastases in patients with head and neck cancer.
Laryngoscope 2000; 110: 397–401.
30. Johnson JT. Proposal of standardization on screening tests for
detection of distant metastases from head and neck cancer.
ORL J Otorhinolaryngol Relat Spec 2001; 63: 256–8.
31. Leemans CR, Tiwari R, Nauta JJ, van der Waal I, Snow GB.
Regional lymph node involvement and its significance in the
development of distant metastases in head and neck carci-
noma. Cancer 1993; 71: 452–6.
32. Sauter ER, Nesbit M, Watson JC, et al. Vascular endothelial
growth factor is a marker of tumor invasion and metastasis in
squamous cell carcinomas of the head and neck. Clin Cancer
Res 1999; 5: 775–82.
33. Senft A, de Bree R, Hoekstra OS, et al. Screening for distant
metastases in head and neck cancer patients by chest CT or
whole body FDG-PET: A prospective multicenter trial. Radio-
therapy and Oncology 2008; 87: 221–9.
34. Zbaren P, Becker M, Lang H. Pretherapeutic staging of laryn-
geal carcinoma. Clinical findings, computed tomography, and
magnetic resonance imaging compared with histopathology.
Cancer 1996; 77: 1263–73.
35. Kallmes DF, Phillips CD. The normal anterior commissure of
the glottis. Am J Roentgenol 1997; 168: 1317–19.
36. Kurita S, Hirano M, Matsuoka H, Tateishi M, Sato K. A histo-
pathological study of carcinoma of the larynx. Auris Nasus
Larynx 1985; 12(Suppl 2): S172–S177.
37. Dadas B, Uslu B, Cakir B, et al. Intraoperative management of
the thyroid gland in laryngeal cancer surgery. J Otolaryngol
2001; 30: 179–83.
38. Op de beeck K, Hermans R, Delaere PR, Van den Bogaert W,
Marchal G. Laryngeal squamous cell carcinoma presenting as
a prelaryngeal neck abscess: report of two cases. Eur Radiol
2001; 11: 2479–83.
39. Becker M, Moulin G, Kurt AM, et al. Atypical squamous
cell carcinoma of the larynx and hypopharynx: radiologic fea-
tures and pathologic correlation. Eur Radiol 1998; 8:
1541–51.
40. Redaelli de Zinis LO, Nicolai P, Tomenzoli D, et al. The distri-
bution of lymph node metastases in supraglottic squamous
cell carcinoma: therapeutic implications. Head Neck 2002; 24:
913–20.
41. Ferlito A, Rinaldo A. The pathology and management of
subglottic cancer. Eur Arch Otorhinolaryngol 2000; 257:
168–73.
42. Mendenhall WM, Werning JW, Hinerman RW, Amdur RJ,
Villaret DB. Management of T1-T2 glottic carcinomas. Cancer
2004; 100: 1786–92.
43. Mendenhall WM, Parsons JT, Mancuso AA, et al. Definitive
radiotherapy for T3 squamous cell carcinoma of the glottic
larynx. J Clin Oncol 1997; 15: 2394–402.
44. DeSanto LW. T3 glottic cancer: options and consequences of
the options. Laryngoscope 1984; 94: 1311–15.
45. Delaere PR, Hermans R. Tracheal autotransplantation as a
new and reliable technique for the functional treatment of
advanced laryngeal cancer. Laryngoscope 2003; 113: 1244–51.
46. Million RR. The larynx … so to speak: everything I wanted to
know about laryngeal cancer I learned in the last 32 years. Int
J Radiat Oncol Biol Phys 1992; 23: 691–704.
47. Hinerman RW, Mendenhall WM, Amdur RJ, et al. Carcinoma
of the supraglottic larynx: treatment results with radiotherapy
alone or with planned neck dissection. Head Neck 2002; 24:
456–67.
48. Milas L, Mason KA, Liao Z, Ang KK. Chemoradiotherapy:
emerging treatment improvement strategies. Head Neck 2003;
25: 152–67.
49. Piccirillo JF, Lacy PD. Classification and staging of laryngeal
cancer. In: Ferlito A, ed. Diseases of the Larynx. London:
Arnold, 2000. 563–74.
50. Hermans R, Van den Bogaert W, Rijnders A, Baert AL. Value of
computed tomography as outcome predictor of supraglottic
squamous cell carcinoma treated by definitive radiation therapy.
Int J Radiat Oncol Biol Phys 1999; 44: 755–65.
51. Hermans R, Van den Bogaert W, Rijnders A, Doornaert P,
Baert AL. Predicting the local outcome of glottic squamous
cell carcinoma after definitive radiation therapy: value of
computed tomography-determined tumour parameters.
Radiother Oncol 1999; 50: 39–46.
639
 primary tumor evaluation and staging
52. Mancuso AA, Mukherji SK, Schmalfuss I, et al. Preradiother-
apy computed tomography as a predictor of local control in
supraglottic carcinoma. J Clin Oncol 1999; 17: 631–7.
53. Pameijer FA, Mancuso AA, Mendenhall WM, Parsons JT,
Kubilis PS. Can pretreatment computed tomography predict
local control in T3 squamous cell carcinoma of the glottic
larynx treated with definitive radiotherapy? Int J Radiat Oncol
Biol Phys 1997; 37: 1011–21.
54. Lloyd GA, Michaels L, Phelps PD. The demonstration of carti-
laginous involvement in laryngeal carcinoma by computerized
tomography. Clin Otolaryngol Allied Sci 1981; 6: 171–7.
55. Castelijns JA, Golding RP, van SC, Valk J, Snow GB. MR findings
of cartilage invasion by laryngeal cancer: value in predicting
outcome of radiation therapy. Radiology 1990; 174: 669–73.
56. Isaacs JH Jr, Mancuso AA, Mendenhall WM, Parsons JT. Deep
spread patterns in CT staging of T2-4 squamous cell laryn-
geal carcinoma. Otolaryngol Head Neck Surg 1988; 99:
455–64.
57. Silverman PM. Medullary space involvement in laryngeal
carcinoma. Computed tomographic demonstration. Arch
Otolaryngol 1985; 111: 541–2.
58. Million RR. The myth regarding bone or cartilage involve-
ment by cancer and the likelihood of cure by radiotherapy.
Head Neck 1989; 11: 30–40.
59. Ljumanovic R, Langendijk JA, Schenk B, et al. Supraglottic
carcinoma treated with curative radiation therapy: identifica-
tion of prognostic groups with MR imaging. Radiology 2004;
232: 440–8.
60. Tart RP, Mukherji SK, Lee WR, Mancuso AA. Value of laryn-
geal cartilage sclerosis as a predictor of outcome in patients
with stage T3 glottic cancer treated with radiation therapy.
Radiology 1994; 192: 567–70.
61. Thoeny HC, Delaere PR, Hermans R. Correlation of local
outcome after partial laryngectomy with cartilage abnormali-
ties on CT. Am J Neuroradiol 2005; 26: 674–8.
62. Delaere P, Goeleven A, Vander Poorten V, et al. Organ preser-
vation surgery for advanced unilateral glottic and subglottic
cancer. Laryngoscope 2007; 117: 1764–9.
63. Hermans R, Pameijer FA, Mancuso AA, Parsons JT,
Mendenhall WM. Laryngeal or hypopharyngeal squamous
cell carcinoma: can follow-up CT after definitive radiation
therapy be used to detect local failure earlier than clinical
examination alone? Radiology 2000; 214: 683–7.
64. Alexander FW. Micropathology of radiation reaction in the
larynx. Ann Otol Rhinol Laryngol 1963; 72: 831–41.
65. Mukherji SK, Mancuso AA, Kotzur IM, et al. Radiologic
appearance of the irradiated larynx. Part I. Expected changes.
Radiology 1994; 193: 141–8.
66. Nomayr A, Lell M, Sweeney R, Bautz W, Lukas P. MRI appear-
ance of radiation-induced changes of normal cervical tissues.
Eur Radiol 2001; 11: 1807–17.
67. Pameijer FA, Hermans R, Mancuso AA, et al. Pre- and post-
radiotherapy computed tomography in laryngeal cancer:
imaging-based prediction of local failure. Int J Radiat Oncol
Biol Phys 1999; 45: 359–66.
68. Hermans R, Pameijer FA, Mancuso AA, Parsons JT,
Mendenhall WM. Laryngeal or hypopharyngeal squamous
cell carcinoma: can follow-up CT after definitive radiation
640
therapy be used to detect local failure earlier than clinical
examination alone? Radiology 2000; 214: 683–7.
69. Schwartz DL, Barker J Jr, Chansky K, et al. Postradiotherapy
surveillance practice for head and neck squamous cell carci-
noma – too much for too little? Head Neck 2003; 25: 990–9.
70. Vandecaveye V, De Keyzer F, Nuyts S, et al. Detection of head
and neck squamous cell carcinoma with diffusion weighted
MRI after (chemo)radiotherapy: correlation between radiologic
and histopathologic findings. Int J Radiat Oncol Biol Phys
2007; 67: 960–71.
71. Zbaren P, Christe A, Caversaccio MD, Stauffer E, Thoeny HC.
Pretherapeutic staging of recurrent laryngeal carcinoma: clinical
findings and imaging studies compared with histopathology.
Otolaryngol Head Neck Surg 2007; 137: 487–91.
72. O’Brien PC. Tumour recurrence or treatment sequelae fol-
lowing radiotherapy for larynx cancer. J Surg Oncol 1996;
63: 130–5.
73. Hermans R, Pameijer FA, Mancuso AA, Parsons JT,
Mendenhall WM. CT findings in chondroradionecrosis of the
larynx. AJNR Am J Neuroradiol 1998; 19: 711–18.
74. De Vuysere S, Hermans R, Delaere P, Marchal G. CT findings
in laryngeal chondroradionecrosis. JBR-BTR 1999; 82: 16–18.
75. Bousson V, Marsot-Dupuch K, Lashiver X, Tubiana JM. [Post-
radiation necrosis of the cricoid cartilage: an uncommon
case]. J Radiol 1995; 76: 517–20.
76. Brouwer J, de Bree R, Comans EF, et al. Improved detection of
recurrent laryngeal tumor after radiotherapy using 18FDG-
PET as initial method. Radiother Oncol 2008; 87: 217–20.
77. Conessa C, Herve S, Foehrenbach H, Poncet JL. FDG-PET scan
in local follow-up of irradiated head and neck squamous cell
carcinomas. Ann Otol Rhinol Laryngol 2004; 113: 628–35.
78. Perie S, Hugentobler A, Susini B, et al. Impact of FDG-PET to
detect recurrence of head and neck squamous cell carcinoma.
Otolaryngol Head Neck Surg 2007; 137: 647–53.
79. de Bree R, van der Putten L, Hoekstra OS, et al. A randomized
trial of PET scanning to improve diagnostic yield of direct
laryngoscopy in patients with suspicion of recurrent laryngeal
carcinoma after radiotherapy. Contemp Clin Trials 2007; 28:
705–12.
80. Ferreiro-Arguelles C, Jimenez-Juan L, Martinez-Salazar JM,
et al. CT Findings after Laryngectomy. Radiographics 2008;
28: 869–82.
81. Maroldi R, Farina D, Battaglia G, Palvarini L, Maculotti P.
Imaging after laryngeal surgery. In: Hermans R, ed. Imaging of
the Larynx. Berlin: Springer, 2001: 124–5.
82. Maroldi R, Battaglia G, Nicolai P, et al. CT appearance of the
larynx after conservative and radical surgery for carcinomas.
Eur Radiol 1997; 7: 418–31.
83. Gavilan J. Cancer of the glottis. In: Ferlito A, ed. Diseases of
the Larynx. London: Arnold, 2000: 615.
84. Baatenburg de Jong RJ, van Lent S, Hogendoorn PC. Chon-
droma and chondrosarcoma of the larynx. Curr Opin Otolar-
yngol Head Neck Surg 2004; 12: 98–105.
85. Devaney KO, Ferlito A, Silver CE. Cartilaginous tumors of the
larynx. Ann Otol Rhinol Laryngol 1995; 104: 251–15.
86. Wang SJ, Borges A, Lufkin RB, Sercarz JA, Wang MB. Chon-
droid tumors of the larynx: computed tomography findings.
Am J Otolaryngol 1999; 20: 379–82.
 laryngeal tumors
87. King AD, Yuen EH, Lei KI, Ahuja AT, Van HA. Non-Hodgkin
lymphoma of the larynx: CT and MR imaging findings. Am J
Neuroradiol 2004; 25: 12–15.
88. Lewis K, Thomas R, Grace R, et al. Extramedullary plasmacy-
tomas of the larynx and parapharyngeal space: imaging and
pathologic features. Ear Nose Throat J 2007; 86: 567–9.
89. Batsakis JG, Luna MA, Byers RM. Metastases to the larynx.
Head Neck Surg 1985; 7: 458–60.
90. Nicolai P, Puxeddu R, Cappiello J, et al. Metastatic neoplasms to
the larynx: report of three cases. Laryngoscope 1996; 106: 851–5.
91. Chin SC, Edelstein S, Chen CY, Som PM. Using CT to localize
side and level of vocal cord paralysis. Am J Roentgenol 2003;
180: 1165–70.
92. Benninger MS, Gillen JB, Altman JS. Changing etiology of
vocal fold immobility. Laryngoscope 1998; 108: 1346–50.
93. Romo LV, Curtin HD. Atrophy of the posterior cricoarytenoid
muscle as an indicator of recurrent laryngeal nerve palsy. Am
J Neuroradiol 1999; 20: 467–71.
94. Sobin LH, Wittekind Ch, eds. UICC: TNM Classification of
Malignant Tumors, 6th edn. New York: Wiley-Liss, 2002.
641
 30 Thyroid Cancer
Polly S Richards, Norbert Avril, Ashley B Grossman, and Rodney H Reznek
INTRODUCTION
The role of imaging in thyroid cancer is determined to a large extent
by the histology of the tumor. Different histological types behave
very differently in their tendency to metastasize or to involve
regional lymph nodes. In the great majority of cases, patients pres-
ent with a clinically solitary thyroid nodule. As the overwhelming
majority of thyroid nodules are benign, a major role of imaging lies
in attempting to distinguish between benign and malignant lesions.
In the past, reliance was placed on radionuclide imaging to make a
distinction, although recent practice has been increasingly to pro-
ceed to fine needle aspiration cytology (FNAC). As metastases are
relatively infrequent and, as in most cases, the primary tumor has to
be removed, preoperative staging is seldom exhaustive. Nevertheless,
imaging does play an important role following thyroidectomy.
EPIDEMIOLOGY
Thyroid cancer is uncommon. In most countries, it accounts for
around 1.6% of all cancers in women, 0.6% of all cancers in men,
and 0.5% of all cancer deaths (1,2). The incidence is higher in females
and the female:male ratio varies from about 1.5:1 to 4:1. There is
a steady increase in incidence with age in men, but there is also a
substantial incidence in young women aged 25 to 35 years (1).
The incidence of newly reported cases of thyroid carcinoma
shows considerable geographical variation, from less than one in
100,000 women in the British Isles to 15 in 100,000 women in the
islands of Iceland and Hawaii; this is thought to be the result of
dietary and environmental factors rather than race and heredity
(1,3). Geographical variation is also seen in the distribution of
papillary and follicular carcinomas. Both these histological types
are associated with dietary iodine. In areas of iodine deficiency
follicular and anaplastic carcinomas predominate (4), whereas in
iodine-rich areas papillary carcinomas are more common (3).
Reports from Switzerland have shown a decrease in the percentage
of follicular carcinomas and an increase in papillary carcinoma
following iodization of salt (3). An upward trend in the incidence
of papillary carcinoma has, however, been seen in most affluent
countries, regardless of the iodine status of the population (4).
As with many slow-growing malignancies, the frequency of the
neoplasm is actually higher than is detected clinically. For exam-
ple, post-mortem studies of women show an incidence of thyroid
carcinoma as high as 28% in Japanese women resident in Hawaii
(1,3). Such cancers should be correctly labeled as “occult cancers”
of no clinical significance. Most thyroid cancers are indolent
growths and few patients die from the disease. Occult and micro-
scopic cancers are seldom invasive and usually remain undiag-
nosed during the individual’s lifetime. Thyroid cancer is rare in
childhood and adolescence, but presents in a more advanced
stage than in adults, with a higher incidence of metastasis at the
642
time of presentation (5). There has been a massive increase in
childhood thyroid cancer in the wake of the Chernobyl accident
(see section “Etiology”). Many surveys in different geographical
regions have also demonstrated an increased incidence in differ-
entiated thyroid cancers in recent years, but more detailed analy-
sis has shown that these are predominantly, if not wholly, papillary
carcinomas <1 cm in diameter (6–10). This is almost certainly
due to more frequent screening with ultrasound (US) and, as dis-
cussed below, most of these are of little clinical significance
(although the role of diagnostic CT scanning in their increased
incidence remains of some concern). However, their optimal
management remains controversial.
ETIOLOGY
Exposure to radiation, either therapeutically or accidentally, is a
major and definite etiological factor in thyroid carcinoma. Ioniz-
ing radiation to the head and neck received in infancy and child-
hood for various malignant and non-malignant conditions (for
example, treatment of ringworm infection of the scalp, tubercu-
lous adenitis, “thymic enlargement,” therapeutic irradiation of
acne, skin tumors of the head and neck, Hodgkin’s, and non-
Hodgkin’s lymphoma) is associated with an increased risk of
developing thyroid cancer (3,11,12). Higher doses of radiation to
the thyroid [for example, radiotherapy treatment for laryngeal
carcinoma or iodine-131 (131I) treatment for Graves’ disease] are
not associated with cancer induction; such patients are liable to
develop hypothyroidism (3).
Accidental exposure to radiation also results in an increased inci-
dence of cancer. Surveys of children irradiated in Hiroshima and
Nagasaki have all revealed a significant increase in the incidence
of papillary carcinoma (1), and a study of the population on the
Marshall Islands, a site of nuclear testing from 1946 to 1958, showed
an increase in the incidence of thyroid cancer in women who were
children during the years of nuclear testing (13). Furthermore,
after major radioactive fallout, the incidence of cancer increases;
for example, following the Chernobyl accident, a definite increase
in the incidence of papillary thyroid cancer was noted in children
living in a nearby region (Belarus and Ukraine) as early as four
years after the accident (14). These cancers were characterized by a
short latent period, a predominance in young children, an equal
sex incidence, and aggressive behavior with intraglandular dissem-
ination, capsular invasion, and lymph node metastases (15,16). A
study conducted eight years after the Chernobyl accident on nearly
2000 clean-up workers from Estonia, whose mean age at the time
of arrival at Chernobyl was 32 years, showed no significant increase
in nodular thyroid disease (including thyroid cancer) associated
with the exposure to external radiation (17).
There is a linear dose–response relationship between external
irradiation of the thyroid and the later development of cancer
(18). Doses reported to have induced thyroid carcinoma vary from
 thyroid cancer

0.07 Gy (1 Gy = 100 rad) to 15 Gy (1500 rad). The carcinogenic risk

factor has been calculated to be 1% per 1 Gy in 20 years (3,18).
The minimum latent period is five years and the incidence peaks
after 15 to 25 years. The risk appears to continue for 35 to 40 years,
and there is an increased risk in people irradiated at younger ages.
Females are more susceptible than males to the carcinogenic
effects of radiation (13).
Another possible etiological factor may be prolonged thyroid
stimulation by thyroid-stimulating hormone (TSH) secondary to
iodine deficiency, but epidemiological surveys have not shown an
increased incidence of thyroid cancer in iodine-deficient areas
(13). It is also unclear as to whether malignant change occurs in
longstanding adenomas, and the current opinion is that malignant
change in an adenoma must be rare since adenomas are extremely
common, whereas follicular carcinoma is rare (3). However, there
is clear evidence that in patients with neck irradiation or previous
thyroid carcinoma, suppression of TSH decreases the risk of de
novo or recurrent carcinoma.
The incidence of thyroid carcinoma is higher in iodine-rich areas
(Iceland, Hawaii), suggesting a possible relation to excessive iodine
consumption (3,16). Alcohol consumption is also reported to be
related to thyroid cancer, which is 2.5 times as common in wine,
beer, or hard liquor drinkers in both sexes and all ages (1). A positive
correlation between multiparity and the incidence of differentiated
thyroid carcinoma has been observed (16). In view of the frequency
Figure 30.1 Lymphatic drainage of the thyroid gland.
of occult thyroid carcinomas, it has been suggested that these might
be in situ carcinomas that are sometimes promoted to invasiveness
by unknown endogenous or environmental factors or both (3).
Genetically-induced thyroid cancer occurs in the multiple endocrine pericardiac, and cardiac areas. There can be a pyramidal lobe, usually
neoplasia (MEN) syndromes, dyshormonogenesis, and several other arising from the upper isthmic region of the left lobe.
inherited syndromes. The lymphatic drainage of the gland is widespread (Fig. 30.1).
It drains to deep and superficial cervical chains, para- and pre-
tracheal nodes, and also to nodes around the esophagus and lar-
Key Points: Epidemiology/Etiology
ynx. It communicates with supraclavicular nodes laterally and
■ All forms of thyroid cancer occur more frequently in females submandibular nodes superiorly. Involvement of the anterior
than males superior mediastinal nodes in thyroid cancer is via retrograde or
■ The peak incidence of thyroid cancer is in young women collateral lymphatic flow (19). The Delphic node, palpable near
aged 25 to 35 years the isthmus and predicting the presence of cancer, is more of
■ Follicular and anaplastic carcinomas predominate in iodine- anecdotal than practical value.
deplete areas, whereas in iodine-rich areas papillary carcino-
mas are more common
■ Radiation is an important etiological factor
PATHOLOGY OF THYROID CANCER
■ Other possible etiological factors include iodine excess,
Thyroid malignancy can originate from many different cells:
genetic factors, and alcohol excess
■ Thyroid cancer in childhood/adolescence is unusual; it usually • Tumors arising from the thyroid cells, ranging from
presents at a more advanced stage than in adulthood papillary and follicular to anaplastic
• Medullary cancer arising from the parafollicular C cells
• Primary thyroid lymphoma from the lymphoid series
ANATOMY AND LYMPHATIC DRAINAGE • Rare tumors arising from the constitutional cells of the
gland, e.g., fibrosarcoma and hemangioendothelioma
The thyroid is a bi-lobed, pinkish organ of about l5 to 30 g mass
in an adult; it curves around the trachea and thyroid cartilage, and
• Metastatic disease to the thyroid gland

is connected by a thin isthmus across the trachea. The gland orig-

inates from three parts: a median anlage from the pharyngeal
pouch and a pair of lateral components in front of the caudal part
of the embryonic pharynx. Ectopic thyroid tissue can arise in any
site from the foramen caecum in the tongue, sublingual, infrahyoid,
and in the thyroglossal tract or cyst, the pretracheal, mediastinal,
Histological Classification
The classification of thyroid cancer has been continually reas-
sessed over the past decades. The most widely used is the WHO
classification (Table 30.1) (20). The Thyroid Cancer Cooperative
Group (21) has contributed to and confirmed the validity of

643
 primary tumor evaluation and staging
Table 30.1 WHO Histological Classification of Thyroid
Cancer (20)
Type Incidence (%)
Thyroid cell
Follicular—well differentiated 17 (10–40)
Follicular—less differentiated
Papillary—including mixed 60 (50–80)
Anaplastic—giant, spindle, and small cell 12 (5–40)
Medullary carcinoma 4 (5–10)
Malignant lymphoma 5 (5–10)
Miscellaneous
Fibrosarcoma Rare (1)
Malignant hemangioendothelioma Rare (1)
Others Rare (1)
Secondary tumors
the WHO classification, especially in relation to prognosis and
natural history (1). Immunohistochemistry and recent hybridiza-
tion techniques have brought about an understanding of the his-
togenesis and the pathological diagnosis of thyroid malignancy,
and have also led to the recognition of new tumor entities that
have been incorporated into the second edition of the WHO
International Classification of Thyroid Tumors (22).
Papillary Thyroid Carcinoma
Papillary carcinoma is the commonest thyroid cancer, compris-
ing 50% to 80% of all thyroid malignancies. There is a wide age
range at presentation, with a mean of 30 to 40 years and a
female:male ratio of about 3:1 (11,23–25). Papillary carcinoma is
more common in iodine-rich areas and was found to increase
after iodine prophylaxis in iodine-deficient areas. It is also the
main cancer induced by radiation in children; about 85% of
known radiation-induced malignant tumors are papillary and
occur in younger individuals after radiotherapy to the head and
neck in childhood (1,11). A significant increase in its incidence
has been reported after major nuclear energy accidents, for exam-
ple, at Windscale, United Kingdom, in 1957 and particularly at
Chernobyl in 1986 (1).
Activation of the ret oncogene apparently plays an important
role in the etiology of papillary carcinoma (26). Familial cases do
occur (27) and it has been described in association with other syn-
dromes. Increasingly, activating mutations of the BRAF oncogene
are being identified, especially the mutation V600E.
The characteristic feature of papillary carcinoma is its low-grade
malignant potential. It has a propensity to spread to regional
lymph nodes, where the cells may exist for many years without
further spread (23). Macroscopically, the tumor can be cystic or
solid, encapsulated or infiltrating the surrounding thyroid, the
thyroid capsule, and even surrounding neck structures. Macroscopic
calcification and necrosis may occur (24). Microscopically, these
tumors are easily recognized, not only by their small papillae but
also by the “ground-glass” or overlapping “shingle-roofed” nuclei.
Small, spherical, calcified psammoma bodies are often clues to the
diagnosis. The tumor is also marked by a desmoplastic reaction
and multicentricity (25).
Lymph node infiltration is a characteristic feature. When rou-
tine lymph node dissections are performed in young adult patients
with papillary thyroid carcinoma, lymph node metastasis will be
644
detected in 75% or more of cases (25,28). Distant metastases are
uncommon and are usually pulmonary, but may rarely occur in
bone, liver, and brain (25,29).
The term “papillary carcinoma of the thyroid” includes carcino-
mas that have any papillary elements whatsoever. Whatever the
proportion of papillary elements in the cancer, the biological
behavior is identical and the clinical behavior differs from that of
pure follicular carcinoma (25,30). The very common mixed papil-
lary and follicular tumors should be included in the papillary
group if there are any papillae identifiable at all (1). Lymphatic
vessel involvement is not infrequent and occasional blood vessel
invasion can be seen. Several variants of papillary carcinoma have
been described (24,31,32), including:
• Follicular
• Diffuse
• Oxyphil cell type, which has a biological behavior more
similar to follicular carcinoma
• The “tall” cell variant, which predominates in older
persons (over 40 years) and shows an aggressive biological
behavior
Several other variants have also been described (31). The diffuse
variety is further subdivided into “diffuse sclerosing,” which occurs
in children and young adults and has a good prognosis, and “diffuse
aggressive.”
Papillary microcarcinomas are tumors of <1 cm in diameter.
Their prevalence at autopsy varies: the highest reported inci-
dence is 36.5% for the Finnish population (33). Such tumors
should be correctly classified as “occult cancer,” They are usually
clinically silent and incidentally found at autopsy or in glands
excised for unrelated reasons. Occasionally, their first manifesta-
tion is an enlarged metastatic cervical lymph node or rarely dis-
tant metastasis. However, recent studies have suggested that even
microcarcinomas may be metastatic to local lymph nodes.
Prognosis (Fig. 30.2) (34)
The prognosis in papillary carcinoma of the thyroid is almost always
excellent (24,31). The principal prognostic factor is the age of the
patient at the time of presentation; the younger the patient, the bet-
ter the prognosis. Uniquely in human cancers, lymph node metasta-
ses have no bearing on overall prognosis (25,31). In children and
young or early middle-aged adults (female 50 years or less, male
40 years or less), even with relatively advanced primary disease of the
thyroid or lymph node metastases, a 100% cure rate can be achieved
(25,35). In the older age group, the prime determinants of prognosis
are the size and extent of the primary tumor and the presence of
distant metastases. Large tumors (>5 cm) or extension outside the
thyroid gland indicates a poor prognosis in older patients but has no
impact on prognosis in younger patients (36). Similarly, pulmonary
metastases from papillary thyroid carcinoma are often highly lethal
in the elderly but not necessarily so in the young (25,29).
Clinical Presentation
Papillary thyroid carcinoma almost always presents as a mass in
the neck, due either to the primary lesion in the thyroid gland
itself or, frequently in young people, due to a metastatic lymph
node, which is palpable in the ipsilateral neck, often at some dis-
tance from the thyroid gland itself. Of young adult patients and
 thyroid cancer

Papillary carcinoma Follicular carcinoma

100 100
Occult
Non-invasive
80 80

Survival (%)
Survival (%)

Intrathyroid
60 60
Invasive

40 40
Extrathyroid

20 20

0 0
0 5 10 15 20 25 30 35 40 0 5 10 15 20 25 30 35 40
Time (yr) Time (yr)

Medullary carcinoma Anaplastic carcinoma

100 100

80 80
Survival (%)

Survival (%)
Negative nodes
60 60

40 40 Anaplastic
Positive nodes

20 20

0 0
0 2 4 6 8 10 12 14 16 18 20 0 10 20 30 40 50 60 70 80
Time (yr) Time (mo)

Figure 30.2 Survival data for thyroid cancer (34). (Dotted lines show survival of normal persons of comparable age and sex).

children, 25% will present with lymph node enlargement (25).
Only very rarely will a papillary carcinoma present with a meta-
static lesion other than a cervical lymph node. Distant metastases
occur in 5% of patients, mainly to the lungs (24).
Key Points: Papillary Carcinoma
■ Papillary carcinoma accounts for 50% to 80% of all thyroid
malignancies
■ It is characteristically of low-grade malignancy and has an
excellent prognosis, despite a tendency to spread early to
the lymph nodes (75% of lymph nodes are involved)
■ Distant metastases occur in 5%, usually in the lungs
■ It is often multicentric histologically
■ The single most important prognostic factor is the age of the
patient; in the elderly, large tumors have a poorer prognosis
Follicular Thyroid Carcinoma
About 10% to 40% of thyroid cancers are follicular. The
female:male ratio is about 3:1 and the mean age of presentation
is 50 years (23,37). The relative incidence of follicular carcinoma
is higher in iodine-deficient areas, with a decline in its relative
frequency following iodine prophylaxis (24). This is practically
the only type of thyroid carcinoma associated with dyshormono-
genesis (38) and it rarely may occur in families or in association
with Cowden’s syndrome, an autosomal dominant disease with
characteristic skin lesions and a tendency to breast cancer (39).
Radiation is known to be implicated occasionally in the genesis
of follicular carcinoma (40). A variety of oncogenes have been
implicated, with activation of the ras oncogene apparently playing
an important role (24).
Pathology
Like papillary carcinoma, this cancer too is a slow-growing neo-
plasm. Unlike papillary carcinoma, it has a tendency to spread
via the bloodstream and disseminate to bone, liver, or lungs,
and only rarely metastasizes to regional lymph nodes (23); it is
rarely multifocal and does not calcify or develop a desmoplastic
reaction (30). The histological diagnosis of follicular carcinoma
is more difficult than in other types of thyroid cancer. Follicular
carcinomas most closely resemble normal mature or developing
thyroid tissue and can be difficult to differentiate from a follicu-
lar adenoma (37). The cell pattern varies from well-differentiated
follicular structures to solid sheets of anaplastic cells. The well-
differentiated cancers can only be proven to be malignant by
demonstrating vascular invasion or metastasis (24). The less
differentiated or anaplastic group includes those with solid
masses of cells and a trabecular pattern. The cytoplasm is usually
like that of normal follicles but Askanazy, Hürthle, or clear cells
may be found and can even predominate, and are subclassified
according to the predominant cell type. No papillae should be
present (1).

645
 primary tumor evaluation and staging
Prognosis
The prognosis depends on:
• Degree of tumor invasion of adjacent structures
• Presence or absence of distant metastasis (which depends
on tumor size and degree of invasion)
• Degree of tumor differentiation
In a study of 68 cases of follicular carcinoma by Khan et al. (41),
49 (70%) had capsular invasion and 33 (49%) vascular invasion.
They found that distant metastases developed in 14% of patients
with capsular invasion only, 27% of patients with vascular inva-
sion only, 50% of patients with both capsular and vascular inva-
sion, and 75% of patients with thyroid capsular vessel, extrathyroid
vessel, and tissue invasion. The incidence of metastatic disease
also increases with increasing tumor size, so that tumors <2 cm in
size have a 17% incidence of metastases, while tumors >6 cm have
a 73% chance of distant metastases. The degree of atypia and
mitotic activity does not correlate significantly with the incidence
of distant metastasis (41). Follicular carcinomas are also divided
according to their degree of differentiation into well, moderately,
or poorly differentiated types. The latter type is associated with
the worst prognosis.
Clinical Presentation
The patient usually complains of a symptomless mass in the neck,
although large tumors may give rise to local compressive symptoms.
Of patients with follicular carcinoma, 25% will present with extrathy-
roidal invasion, 5% to 10% with regional adenopathy and 10% to
20% with distant metastases to the bones and lungs (24,42).
Key Points: Follicular Carcinoma
■ Follicular carcinoma accounts for 10% to 40% of all thyroid
cancers
■ Although slow-growing, follicular carcinoma tends to metastasize
to bone, liver, and lungs, but less commonly to lymph nodes
■ Follicular carcinoma may closely resemble an adenoma
pathologically
■ Prognosis depends on the degree of invasion of the capsule
and adjacent vessels, presence of metastases and the degree
of tumor differentiation
■ Up to one-fifth of patients will present with distant metastases
Undifferentiated (Anaplastic) Thyroid Carcinoma
Of all the thyroid malignancies, undifferentiated (anaplastic)
cancer, albeit rare, is the most malignant. This tumor accounts for
about 15% of thyroid malignancies, with a female:male ratio of
about 1.5:1; the age of presentation is usually after the fifth decade
of life (23,43). Undifferentiated carcinomas may be found in asso-
ciation with a better differentiated tumor (43). Radiation is a
recognized causative factor, reducing the age of presentation (44).
Pathology
Tissue diagnosis is often established by needle aspiration or biopsy.
Gross specimens are not commonly available, since surgery is not
the treatment of choice for these tumors and is only performed
for symptomatic relief (43). Macroscopically, the tumor appears
fleshy and greyish-white, invading one or both thyroid lobes and
646
neighboring structures of the neck. Uni- or bilateral cervical
lymph node involvement is almost the rule (23). Microscopically,
these tumors consist of giant or spindle cells, the latter sometimes
miscalled sarcoma (1). Areas of more differentiated tumor are
commonly found; these can be either papillary or follicular.
Anaplastic transformation of differentiated carcinoma may occur
in metastatic sites (43).
Prognosis
The prognosis is extremely poor, with death due to widespread
metastases usually occurring within one year of diagnosis. Large
differentiated tumors showing a small focus of undifferentiated
tumor may have a better prognosis (43). Early regional lymph node
metastasis is frequent and is followed by distant dissemination.
Clinical Presentation
Rapid growth of a goiter in an elderly person is a common clinical
feature. In many, the cancer has already progressed beyond cure at
the time of presentation. On examination, the thyroid gland is dif-
fusely enlarged, firm-to-hard, and generally fixed to adjacent
structures. The overlying skin may be brawny and reddened. The
patient is usually euthyroid at presentation (23) or rarely hyper-
thyroid, probably due to hormone release from disrupted thyroid
follicles (24). After confirmation of the diagnosis, surgery may be
considered for symptomatic relief, particularly to decompress the
trachea, but is not curative and external radiation, usually with
dexamethasone, may slow tumor progression.
Key Points: Anaplastic Carcinoma
■ Undifferentiated (anaplastic) carcinoma accounts for 15% of
all thyroid cancers
■ It is the most malignant of all thyroid cancers and the prognosis
is extremely poor
■ They tend to occur in older patients
■ Treatment is usually by radiotherapy, with surgery as a possible
palliative modality
Insular Carcinoma of the Thyroid
Insular carcinoma is intermediately aggressive, between well-dif-
ferentiated and anaplastic thyroid carcinoma. Patients with this
tumor have poorer outcomes compared with patients of similar
age who have differentiated types of thyroid carcinoma with
tumors of a similar size (45). Although metastatic insular carci-
noma shows radioactive iodine uptake, the clinical benefit from
this treatment is rare (46). Therefore, vigorous initial surgical
treatment is warranted, and novel and multimodal therapies
should be explored (45,46).
Medullary Carcinoma of the Thyroid
Medullary carcinoma of the thyroid (MTC) accounts for 5% to
10% of all thyroid malignancies and originates from the parafol-
licular C cells. The sexes are nearly equally affected, with only a
slight female predominance (23,24,47). The major identifying
characteristic is the presence of amyloid pathologically, due to cal-
citonin deposition (1).
 thyroid cancer
Medullary carcinoma occurs in either a sporadic or a familial
form. The sporadic form may occur at almost any age, but mainly
in the fifth or sixth decade and is usually unilateral (47). The
familial form encompasses 21% to 25% of all MTCs (48) and is
inherited as an autosomal dominant trait linked to the ret onco-
gene on chromosome 10, with 100% penetrance and variable
expressivity (24,47). Familial tumors are commonly bilateral (18).
Familial MTC is an important component of three well-defined
familial syndromes:
• Multiple endocrine neoplasia type IIa (MEN 2A)
• Multiple endocrine neoplasia type IIb (MEN 2B)
• Familial medullary thyroid carcinoma
In MEN 2A, bilateral MTC occurs in virtually every affected
patient and can be associated with pheochromocytoma (<50%)
or parathyroid hyperplasia (<50%); the peak age of incidence is in
the second or third decade. Medullary carcinoma also occurs in
MEN 2B in association with pheochromocytoma, mucosal neuro-
mas, diffuse ganglioneuromas of the gastrointestinal tract, skeletal
abnormalities, and a “Marfanoid habitus.” When associated with
MEN 2B, the disease occurs earlier than in MEN 2A (before 2 years
of age) and is a very aggressive tumor (47). A familial pattern,
unassociated with other endocrine neoplasms, also occurs (49).
This entity is termed familial medullary thyroid carcinoma
(FMTC), usually arises in the fifth decade of life, and is more
indolent biologically (23).
The most specific immunohistochemical marker for MTC is
calcitonin, with elevated basal plasma levels which increase
markedly following the IV administration of pentagastrin (47).
Although uncommon, MTC cells may inappropriately produce
and secrete a variety of peptides, amines, and other products
such as adrenocorticotrophic hormone (ACTH) and histamine.
Elevated plasma carcino-embryonic antigen (CEA) level is a reli-
able, though non-specific marker for MTC, especially with more
aggressive disease, and can be useful in following patients with
metastatic disease (47,50).
Pathology
Macroscopically, MTC usually presents as a solitary mass located
in the upper two-thirds of a thyroid lobe. The tumor is often
well demarcated but only occasionally encapsulated; it has a
firm consistency. Calcification, necrosis, hemorrhage, cyst, and
bone formation are not uncommon. Microscopically, it is a
solid cellular tumor without follicles, and a variable amount of
stromal amyloid is seen in up 82% of cases (23,24). Inherited
MTC shows similar pathological and immunohistochemical
characteristics to sporadic cases, but the tumors are often smaller
(if found by screening), multiple, bilateral, and accompanied by
C-cell hyperplasia (24).
Clinical Presentation
The patient usually presents with painless nodular thyroid enlarge-
ment often accompanied by cervical and mediastinal lymphade-
nopathy. Symptoms of excessive or ectopic hormone production
may occur, such as diarrhea and flushing. In advanced tumors,
symptoms of local compression and metastasis may be present.
Patients with MEN 2A and 2B may also present with signs and
symptoms of the associated pathological conditions. Metastasis is
to lungs, liver, and bone.
Key Points: Medullary Carcinoma
of the Thyroid (MTC)
■ Accounts for 5% to 10% of all thyroid malignancies
■ In 21% to 25% of cases MTC occurs as part of a familial
syndrome
■ The most specific marker for MTC is calcitonin
Lymphoma of the Thyroid (See also Chapter 33)
Most thyroid lymphomas are follicular, of centroblastic–centrocytic
cell types, occasionally plasma cell and rarely Hodgkin’s disease
(22). Lymphoma accounts for 10% of thyroid malignancies.
This tumor predominates in females and most affected indi-
viduals are middle-aged or older (1,24). Many may occur on a
background of Hashimoto’s thyroiditis. It tends to involve
lymph nodes and spread to the gastrointestinal tract, and is
sensitive to chemo- and radiotherapy. The histology of mucosa-
associated lymphoid tumors (MALTs) has a better prognosis
than non-MALT lymphomas.
Other Tumors
Other primary tumors are rare. Fibrosarcomas and hemangio-
endothelioma usually behave like anaplastic tumors. Squamous
cell carcinoma occurs with an equal incidence in males and females
(1). Metastasis to the thyroid gland is rare, at least in terms of
clinical presentation, but is seen most commonly in patients with
bronchogenic and renal cell carcinomas, and malignant melano-
mas. Primary lymphomas outside the thyroid may also present as
a thyroid mass.
STAGING CLASSIFICATION OF THYROID
CARCINOMA (51,52)
Although staging for cancers in other head and neck sites is based
entirely on the anatomic extent of the disease, it is not possible to
follow this pattern for those that arise in the thyroid. Both the
histological diagnosis and the age of the patient are included in
the staging system, as these two factors are of such importance in
the behavior and prognosis of thyroid malignancies.
Rules for Classification
The International Union Against Cancer (UICC) TNM staging
system is the most widely used for staging and classification of
thyroid carcinoma ( Table 30.2 and Fig. 30.3) (52). As with
other tumors, it has clinical and pathological staging classifica-
tions for both the primary tumor and lymph node metastases.
The clinical staging of the primary tumor and nodal disease is
determined by clinical examination and, where appropriate,
radionuclide imaging and ultrasound examination. Where
cross-sectional imaging is used, MRI is recommended to avoid
contamination with iodinated contrast medium used with CT
of the neck. The pathological staging requires histological
647
 primary tumor evaluation and staging

examination of the excised gland, regional lymph nodes (52),
and metastatic lesions.
Regional Lymph Nodes
An adverse prognostic influence of metastases to lymph nodes is
observed only in the older age group. The first echelon of nodal
metastases consists of paralaryngeal, paratracheal, and prelaryngeal
nodes adjacent to the thyroid gland (level VI). Metastases second-
arily involve the mid- and lower jugular, the supraclavicular, the
upper deep jugular, and spinal accessory nodes. Upper mediasti-
nal (level VII) nodal spread occurs frequently both anteriorly and
posteriorly. Bilateral spread is common. Separate stage groupings
are recommended for papillary and follicular, medullary, and
undifferentiated carcinomas (52).

Table 30.2 Definition of TNM

Primary tumor (T)a Fig. 30.3 All anaplastic carcinomas are considered T4 tumors
TX Primary tumor cannot be assessed T4a Intrathyroidal anaplastic carcinoma—surgically resectable
T0 No evidence of primary tumor T4b Extrathyroidal anaplastic carcinoma—surgically unresectable
T1 Tumor ≤2 cm in greatest dimension, limited to Regional lymph nodes (N)
the thyroid Regional lymph nodes are the central compartment, lateral cervical, and upper
T2 Tumor >2 cm but not >4 cm in greatest mediastinal lymph nodes
dimension limited to the thyroid NX Regional lymph nodes cannot be assessed
T3 Tumor >4 cm in greatest dimension, limited to N0 No regional lymph node metastasis
the thyroid or any tumor with minimal N1 Regional lymph node metastasis
extrathyroid extension (e.g., extension to N1a Metastasis to Level VI (pretracheal, paratracheal, and
sternothyroid muscle or perithyroid soft tissues) prelaryngeal/Delphian lymph nodes)
T4a Tumor of any size extending beyond the thyroid N1b Metastasis to unilateral, bilateral, or contralateral cervical or
capsule to invade subcutaneous soft tissues, superior mediastinal lymph nodes
larynx, trachea, esophagus, or recurrent Distant metastasis (M)
laryngeal nerve MX Distant metastasis cannot be assessed
T4b Tumor invades prevertebral fascia or encases M0 No distant metastasis
carotid artery or mediastinal vessels M1 Distant metastasis
a
All categories may be subdivided: (a) solitary tumor; (b) multifocal tumor (the largest determines the classification).

T1a T1b

≤1 cm ≤1 cm

T2a T2b T3

>1–4 cm
>4 cm

Figure 30.3 Staging diagram, thyroid cancer. (Continued)

648
 thyroid cancer

T4a T4a T4a

Tumor of any size extending beyond the thyroid capsule to invade subcutaneous soft tissues, larynx, trachea, eosophagus,
or recurrent laryngeal nerve

T4b T4b

Tumor invades prevertebral fascia, or encases carotid artery or mediastinal vessels

Figure 30.3 (Continued)

IMAGING THYROID CANCER • To follow patients with nodules that have been considered
“indeterminate” (57)
The main purpose of imaging thyroid nodules is to detect those • To detect local tumor recurrence following primary
lesions which are likely to be malignant. This is primarily accom- therapy (58)
plished with US and fine needle aspiration cytology (FNAC).
The investigation and management of thyroid nodules is contro-
Lymph node staging in proven cases of thyroid malignancy is also
versial. Several differing consensus statements have been pub-
largely performed with ultrasound, although cross-sectional imag-
lished since 2005 by specialist panels from a number of American
ing and radionuclide techniques are useful to delineate the extent
societies, including the American Thyroid Association (59), the
of local invasion, to detect non-cervical metastatic disease, and in
American Association of Clinical Endocrinologists (AACE) (60),
the assessment of tumor recurrence. Scintigraphy is still the stan-
The American Society of Radiologists in Ultrasound (61), and the
dard imaging technique for functional thyroid assessment (53,54).
National Cancer Institute (62). There are further discrepancies
between these and published U.K. guidelines (63,64).
The Role of Ultrasound
The ideal diagnostic pathway must be a balance between the
Ultrasound is the imaging modality of choice for the diagnosis of
chance of missing carcinomas of potential clinical aggressiveness
thyroid cancer because it has the greatest spatial resolution for
and reducing the morbidity associated with unnecessary operations
superficial soft tissues. The use of linear array high-frequency trans-
whilst keeping an eye on cost. The apparent rising incidence of thy-
ducers (7.5–10 MHz) allows the detection of thyroid nodules as
roid microcarcinomas (defined as <1 cm in diameter) and the fact
small as 1 to 2 mm (55,56). The ability to characterize nodules over
that nodal metastases, extracapsular extension, and aggressive his-
5 mm in size with both grey scale and Doppler means that US is the
tological features have been described with these small tumors, has
most accurate technique for predicting malignancy. US can also be
led to recommendation that FNAC be performed on all sonograph-
used to guide FNAC of impalpable nodules and it is the most widely
ically visible nodules (65). However, many other authorities advo-
accepted method of staging locoregional lymph nodes.
cate a less aggressive approach, in view of the prevalence of benign
Thyroid ultrasound may be performed for a number of other
nodules, the low incidence of biologically significant thyroid cancer,
reasons (57):
and the fact that papillary carcinoma, which is the commonest
• To determine the solitary or multiple nature of nodular form, is so indolent (65). This inconsistency arises from the fact that
disease there are insufficient data to answer two key questions:
• To provide reproducible objective measurements of
nodule size as a baseline for follow-up (57) • How does the diagnosis and treatment of microcarcino-
• To search for a primary lesion in patients presenting mas affect life expectancy?
with nodal metastases from thyroid cancer • How do the benefits of surgery compare to the risks?

649
 primary tumor evaluation and staging
The suggested approach in the United States depends on diagnos-
tic US and FNAC often being performed by the endocrinologist,
with a low threshold for exploration. In the United Kingdom a less
invasive approach is usually recommended, particularly for papil-
lary microcarcinomas; as the great majority of these do not prog-
ress (66), there would seem to be little point in treating them
aggressively and possibly even attempting to diagnose them.
A diagnostic and management strategy for thyroid nodules
must begin with clinical assessment, because most patients can be
reassured at this stage without further investigation. Ultrasound
should not be performed to screen for thyroid disease and it is not
a substitute for clinical examination (60). The indications for US
are summarized in Table 30.3 and reflect a number of clinical factors
that are known to increase the risk of thyroid malignancy:
Age: Both elderly and young are at increased risk of thyroid cancer.
Sex: The level of suspicion should be higher in men.
Onset: A mass growing over a period of weeks raises the possibility
of lymphoma or anaplastic carcinoma and should undergo FNAC
as a matter of urgency. Masses which develop over a few days usually
result from hemorrhage into a benign nodule or cyst.
Previous neck irradiation: This is especially significant if received
at a young age or if low dose radiotherapy was used, as once given
for conditions such as adenoidal hypertrophy, thymic enlargement,
and tinea capitis, and which is associated with a 40-fold increased
risk of malignancy (67).
Family history: Five percent of papillary and follicular carcinoma
is thought to be familial in nature, although no genetic basis has
been identified (68). Medullary carcinoma is associated with mul-
tiple endocrine neoplasia type II (MEN 2) and familial medullary
thyroid carcinoma (FMTC) syndrome, which together account for
25% of cases (69).
Solitary nodules: A nodule which appears solitary on palpation is
usually a dominant nodule in a multinodular goiter on ultrasound.
There is no consensus as to whether a truly solitary nodule, palpable
or otherwise, is more likely to be malignant than a nodule found in a
multinodular goiter (59–64). However, recent data have suggested
that the risk within a thyroid is equal in multinodular and uninodular
goiters, such that the risk per nodule is greater with a single nodule.
Clinical signs of local or regional extension: Immobility of the
mass, hoarseness, dyspnea, dysphagia, or cervical lymphadenopathy
should be taken very seriously.
Table 30.3 Clinical Indications for Thyroid Ultrasound
in Nodular Thyroid Disease
• Apparently solitary nodule
• Fixed or firm consistency nodule or ill-defined margins on palpation
• Palpable lymphadenopathy
• Hoarseness/dysphagia
• Increasing size
• <25 years
• New presentation >65 years
• Male
• PMH radiotherapy
• FH MTC or MEN 2
• Assess retrosternal extension
650
Sonographic Characterization of Thyroid Nodules
Multiplicity
Around 50% of clinically solitary nodules are actually one of mul-
tiple nodules on US (60). Approximately 10% to 20% of papillary
carcinomas are multifocal. Consensus guidelines offer conflicting
advice as to the risk of cancer in solitary nodules, whether palpa-
ble or clinically occult. The AACE/Associazione Medici Endocri-
nologi (AME) Task Force concluded that the risk is not significantly
higher than a nodule found in a multinodular goiter (60). The
American Society of Radiologists in Ultrasound conclude that,
although the risk of cancer per nodule is lower in a multinodular
goiter, it decreases in proportion to the number of nodules in the
gland such that the overall rate of cancer per patient is stable and
remains similar to that of a patient with a truly solitary nodule (61).
Size
Nodule size is a poor indicator of malignancy (61,70–73). The
reported prevalence of cancer detected by US-guided FNAC is
similar in both clinically occult (Fig. 30.4) and palpable nodules
and ranges from 5.0% to 7.7% (60,61,74–76), with approximately
30% of thyroid cancers being non-dominant nodules within a
multinodular goiter (61). An arbitrary size threshold of usually 10
or 15 mm in maximum diameter, above which an FNAC should
be performed has been recommended to reduce the number of
nodules requiring biopsy, but this is a contentious issue, as aggres-
sively behaving microcarcinomas are occasionally seen. What is
clear is that targeting the dominant nodules in a multinodular
goiter for biopsy because of size alone is no longer appropriate,
and in this situation FNAC of the dominant three to four nodules
>1 cm in diameter is recommended (77).
Other Gray-Scale Features
A number of gray-scale characteristics are described in thyroid can-
cer (Table 30.4). The most specific is microcalcification, small intra-
nodular punctate hyperechoic spots with scanty or no posterior
acoustic shadowing (Fig. 30.5). Microcalcification has been reported
to be 85.5% to 95.5% specific, although the sensitivity is low at
26.1% to 59.1%, giving it a total diagnostic accuracy of 83.3%
(78,79). An irregular or microlobulated nodular margin (Fig. 30.6),
Figure 30.4 Transverse thyroid US showing a papillary microcarcinoma with
punctate calcification.
 thyroid cancer

Table 30.4 US Characteristics of Thyroid Nodules

Echogenicity Relative to background thyroid echogenicity
Majority of hyper- or isoechoic nodules are benign
Most hypoechoic nodules are benign
Majority of malignant nodules are hypoechoic (Fig. 30.7)
Solid or cystic Majority of malignant nodules are solid
Small subset of papillary carcinomas have cystic component
Most mixed cystic/solid lesions result from cystic degeneration or hemorrhage into a benign nodule (Fig. 30.11)
Purely cystic nodules are rarely malignant
Calcification Curvilinear calcification is a benign feature (Fig. 30.12)
Coarse clumps of calcification generally benign, although small foci are reported in malignancy (Fig. 30.12)
Punctate calcification highly specific for papillary or medullary carcinoma (Fig. 30.5)
Punctate calcification often present in nodal metastases (Fig. 30.17)
Vascularity 3 vascular patterns described: peripheral (Type 1), intranodular (Type 2), and mixed (Type 3)
Type 2 and 3 are associated with malignancy (Fig 30.9)
Margins Benign nodules tend to have smooth, well-defined margins.
Irregular, poorly defined margin suggest malignancy (Fig. 30.6)
Halo Hypoechoic rim thought to represent compressed surrounding thyroid tissue (Fig 30.8)
When intact, points towards a benign process
Size Risk of malignancy in small nodules similar to large ones
1/3 of malignancies would be missed if only dominant nodules in multinodular goiters were sampled
Multiplicity Risk of any individual nodule in a multinodular goiter being malignant is slightly lower than a solitary nodule
Overall risk of a multinodular thyroid harboring malignancy is probably equivalent to a solitary nodule
Each nodule within a multinodular thyroid should be assessed on its own merits
Comet tail Hyperechoic foci with trailing reverberation artefact believed to indicate the presence of colloid (Fig. 30.15)
Reported to be 100% specific for benign disease
Shape Eccentric shape with AP diameter greater than transverse associated with malignancy (Fig. 30.10)

(A) (B)
Figure 30.5 Punctate calcification. (A) Longitudinal thyroid US demonstrating punctate calcification in a papillary carcinoma. (B) Transverse thyroid US in a second
patient demonstrating punctate calcification in a papillary carcinoma.

(A) (B)
Figure 30.6 Irregular margins. (A) Longitudinal and (B) transverse thyroid US of papillary carcinoma in different patients demonstrating irregular margins.

651
 primary tumor evaluation and staging

Figure 30.7 Transverse thyroid US demonstrating a hypoechoic papillary carcinoma in the right lobe.

(A) (B)
Figure 30.8 Hypoechoic halo. (A) Transverse thyroid US demonstrating a complete hypoechoic halo surrounding a follicular adenoma (arrow). (B) Transverse thyroid US demon-
strating focal absence of a hypoechoic halo (arrow) in an otherwise benign-looking nodule thought to be a follicular adenoma. Follicular carcinoma was diagnosed at histology.

(A) (B)
Figure 30.9 Patterns of nodular vascularity. Transverse thyroid US in two patients with malignant neoplasms (A) demonstrating a nodule with a chaotic intranodular
vascular pattern and (B) demonstrating a nodule with a predominantly perinodular vascular pattern.

652
 thyroid cancer

hypoechogenicity in comparison to the background thyroid

parenchyma (Fig. 30.7), defects in or absence of the thin
hypoechoic halo frequently associated with benign lesions (Fig.
30.8), chaotic intranodal vascularity indicating neoangiogenesis
(Fig. 30.9), and a rounded or taller (AP) than wide (transverse)
shape (Fig. 30.10) are all associated with malignancy (79–81).
The traditional distinction between cystic and solid lesions also
remains important, because most nodules with a dominant fluid
component will be benign, although it must not be forgotten
that up to 15% of papillary thyroid carcinomas can be cystic
(Fig. 30.11) (82,83).
No single US feature has a high enough positive predictive
value for cancer to reliably dictate which nodules require FNAC
(65). As a result, research has been directed toward the combi-
nation of US criteria in a variety of ways (65,76,79,84,85). In
general, these studies point to the same few features being sig-
nificantly more common in malignant nodules than in benign
ones ( Table 30.5) (65,76,74–86). For example, Leenhardt et al.
looked at 155 consecutive patients presenting with a solitary
thyroid nodule who underwent US and FNAC prior to their
surgery (76). The absence of a hypoechoic halo (p < 0.002), a
solid hypoechoic appearance (p < 0.003), and suspicious or
Figure 30.10 Transverse thyroid US of a papillary carcinoma demonstrating a tall
shape in which the anteroposterior diameter is greater than the transverse.

(A) (B) (C)

(D)
Figure 30.11 Thyroid cysts. Thyroid US demonstrating (A) a hemorrhagic cyst with debris layering posteriorly, (B) a colloid cyst with “comet-tail” artefact, (C) cystic
degeneration of a hyperplastic nodule, and (D) a cystic papillary carcinoma demonstrating punctate calcification in a peripheral mural nodule (arrow).

653
 primary tumor evaluation and staging

Table 30.5 Sensitivity and Specificity of US Characteristics for

Thyroid Malignancy (55)
US feature Sensitivity Specificity Positive Negative
(%) (%) predictive predictive
value (%) value (%)
Hypoechoic 26.5–87.1 43.4–94.3 11.4–68.4 73.5–93.8
Microcalcification 26.1–59.1 85.8–95.0 24.3–70.7 41.8–94.2
Irregular margin or 17.4–77.5 38.9–85.0 9.3–60.0 38.9–97.8
No halo 38
Solid 69.0–75.0 52.5–55.9 15.6–27.0 88.0–92.1
Intranodule 54.3–74.2 52.5–55.9 15.6–27.0 88.0–92.1
vascularity
Tall shape (AP:Tr > 1) 32.7 92.5 66.7 74.8

(A)

malignant cytology (p < 0.001) were all significantly associated

with malignancy. FNAC detected 13 of the 17 carcinomas, one
sample was inadequate and there were three false negative
results. The authors found that if surgery was performed on the
basis of FNAC findings alone, they would have reduced the
number of operations recommended from 155 to 73 while
detecting 14 of the 17 malignancies. By using these two US
characteristics to determine which nodules to aspirate, a further
40 patients would have been spared surgery, with no decrease in
the number of cancers detected.
In a large study published in 2007, Cappelli et al. looked at
7455 nodules in 5198 patients in which 38.4% were <1 cm in
diameter (59). All cases with suspicious cytology underwent
(B) surgery: 349 nodules were resected of which 284 were malig-
nant. Interestingly, histological type and local aggressiveness
were largely independent of nodule size. Tall shape (AP/trans-
verse ratio > 1), microcalcification, blurred margins, solid
hypoechoic appearance, size ≥10 mm, and an intranodular vas-
cular pattern were all more common in malignant nodules.
The authors found that, by performing only FNAC on nodules
with microcalcification, blurred margins or which were solid
and hypoechoic, they would have reduced the number of aspi-
rations and therefore operations by 27% with only a 2%
decrease in malignancy detection. The FNAC rate could be
reduced by a further 16%, missing a total of 7% of malignan-
cies, if only nodules demonstrating two features out of a size
greater than 1 cm, hypoechogenicity, blurred margins, or
microcalcification were aspirated. If a sensitivity of only 84%
was tolerated, then the number of aspirations could be reduced
by a total of 84.3%, by confining them to tall-shaped nodules
with intranodular vascularity, microcalcification, blurred margins,
or hypoechogenicity.

(C)
Figure 30.12 Benign nodular calcification. (A) Transverse thyroid US demonstrating
curvilinear mural calcification in a longstanding thyroid cyst (arrow). (B) Transverse
thyroid US demonstrating course calcification in a benign hyperplastic nodule
(arrow). (C) Transverse thyroid US showing coarse calcification in an invasive
follicular carcinoma (arrow).
Extracapsular Extension
Invasion of anatomical structures around the thyroid gland is a
pathognomonic sign of malignancy, but is seen in less than 10% of
neoplasms. The main signs of invasion on ultrasound are irregular
hypoechoic tissue extension beyond the thyroid capsule, direct
infiltration of strap muscles, and encasement of the great vessels
(53,78). Tracheal and esophageal involvement is best assessed by
cross-sectional techniques.

654
 thyroid cancer

Key Points: Gray-Scale Features

■ Fifty percent of clinically solitary nodules are one of multiple
on US
■ Ten to twenty percent of papillary carcinomas are multifocal
■ The risk of cancer for a solitary nodule is not significantly
higher than a nodule in a multinodular goiter
■ Nodule size is a poor indicator of malignancy
■ Microcalcification, an irregular margin, hypoechogenicity,
defects in or absence of a halo, chaotic intranodal vascularity,
taller than wide shape, and extracapsular extension are all
associated with malignancy

Typical Sonographic Features of Nodular

Thyroid Pathology (A)
Hyperplastic Nodules
The vast majority of thyroid nodules are benign hyperplastic nod-
ules. Histologically, these nodules represent stages of hyperplasia
and involution of thyroid tissue and are commonly filled with
colloid-laden follicles. Their sonographic appearance is varied
(87). Most frequently they are well-defined hypoechoic lesions
which, being microcystic in nature, often contain echogenic linear
striations (Fig. 30.13). Frank cystic or hemorrhagic degeneration
is common. The presence of colloid indicated by echogenic foci
with comet-tail artefact is reassuring (Fig. 30.14).

Hashimoto’s and Other Thyroiditis

Thyroiditis results in lymphocytic infiltration which appears
hypoechoic and often hypervascular in the acute phase on US.
Hashimoto’s thyroiditis is generally a diffuse process and mul-
tiple echogenic linear striations are typical (Fig. 30.15). In
chronic Hashimoto’s thyroiditis, any focal nodularity within (B)
the thyroid should be assessed carefully because of the risk of
lymphoma. By contrast, other causes of autoimmune thyroiditis

Figure 30.13 Transverse thyroid US demonstrating a well defined hypoechoic
nodule with internal cystic foci and linear echogenic streaks typical of a benign
hyperplastic nodule (arrow).
(C)
Figure 30.14 Comet-tail artefact. (A) Transverse thyroid US of a colloid cyst
demonstrating “comet-tail” artefact, which indicates the presence of colloid. (B)
Transverse thyroid US of a benign cystic nodule demonstrating “comet-tail”
artefact in the solid component (arrow). (C) Transverse thyroid US of a solid
colloid nodule demonstrating “comet-tail” artefact.

655
 primary tumor evaluation and staging

are more typically focal and may appear nodular on US. Patients
are usually hyperthyroid and complain of tenderness and pain,
but FNAC can be helpful if in doubt. An increased incidence of
malignancy amongst nodules co-existing with Graves’ disease
rather than in uncomplicated multinodular hyperplasia has
been suggested (60).
Adenomas
Adenomas account for <10% of all thyroid nodules and are
typically follicular in cell type and solitary. Adenomas tend to
be relatively homogeneous in echotexture, with a hypoechoic
halo, and are frequently isoechoic to background thyroid tissue
(Fig. 30.16) (87). They may contain central cystic foci and
coarse calcification. Follicular adenomas cannot be differenti-
ated from microinvasive follicular thyroid carcinoma either
sonographically or cytologically, and for this reason hemithy-
roidectomy is usually recommended with a view to performing
a completion thyroidectomy if malignancy is confirmed.
Papillary Thyroid Carcinoma (PTC)
The majority of PTCs are predominantly solid and hypoechoic
with ill-defined margins and chaotic intranodular vascularity
on US, although about 15% have a cystic component (87,88).
Microcalcification is seen in around 40%, is highly specific
(Fig. 30.4), and believed to correlate to psammoma bodies
(87). Metastatic lymph nodes frequently demonstrate micro-
calcification (Fig. 30.17) (87) and are commonly cystic (43−70%)
(Fig. 30.18) (87,89).
Follicular Thyroid Carcinoma (FTC)
The microinvasive form of FTC is indistinguishable from a
follicular adenoma both on US and FNAC, which typically yield
hypercellular samples devoid of colloid. Macroscopically, inva-
sive FTC is more aggressive. On US it appears more heteroge-
neous and often has an irregular margin and absent halo sign
(Figs. 30.6 and 30.8) (87). Frankly invasive follicular carcinoma
is hypoechoic and irregular, often with extracapsular spread

Figure 30.15 Transverse thyroid US of Hashimoto’s thyroiditis. The gland is diffusely

enlarged and hypoechoic with multiple linear hyperechoic striations.

(A) (B)
Figure 30.16 Follicular neoplasm. (A) Transverse and (B) longitudinal thyroid US demonstrating a well-defined, homogeneous, and isoechoic nodule consistent with a
follicular neoplasm. At surgery this was a benign adenoma. Note the complete hypoechoic halo surrounding the nodule.

656
 thyroid cancer

(A) (B)

(C)
Figure 30.17 Lymph node metastases with punctuate calcification. (A) Longitudinal thyroid US showing a large papillary carcinoma (thick arrow) with a small round
hypoechoic infrathyroid lymph node infiltrated with malignancy (thin arrow). (B) Enlarged lymph node infiltrated with metastasis from papillary carcinoma in the deep
cervical chain, demonstrating punctate calcification. (C) 4 mm node in the same patient, also infiltrated with tumor and showing punctate calcification.

(A) (B)
Figure 30.18 Cystic lymph node metastases. (A) Longitudinal US showing a cystic metastatic lymph node with septa and with little solid component. (B) Transverse neck
US showing a partially cystic metastatic lymph node with punctate calcification (arrow) in papillary carcinoma.

657
 primary tumor evaluation and staging

(A) (B) (C)

Figure 30.19 Medullary carcinoma. (A) Transverse thyroid US demonstrating a large hypoechoic nodule with intermediately coarse calcification commonly associated
with medullary thyroid cancer. (B) Transverse thyroid US of a medullary thyroid carcinoma in a second patient demonstrating a poorly defined, irregular margin and
similar intermediately coarse calcification. (C) US showing a metastatic lymph node (arrow) from medullary thyroid cancer in a patient (A), demonstrating similarly
intermediately coarse calcification.

Figure 30.20 Longitudinal neck US showing a well defined extrathyroidal mass

adjacent to the inferior pole typical of a parathyroid adenoma (arrow) which was
a parathyroid adenoma on a patient with MEN.

and vascular invasion. This is indistinguishable from other

forms of invasive thyroid cancer such as anaplastic carcinoma
and lymphoma (see sections “Anaplastic carcinoma” and “Primary
Thyroid Lymphoma”).
Medullary Thyroid Carcinoma (MTC)
Typical US appearances are similar to PTC with an irregular solid
hypoechoic nodule demonstrating punctate calcification in 80% to
90%, which in this case is due to amyloid deposition (Fig. 30.19)
(87). Similar echogenic foci are present in 50% to 60% of metastatic
lymph nodes (Fig. 30.19). As about 15% MTC occurs in MEN 2A,
search for parathyroid enlargement is prudent (Fig. 30.20).
Anaplastic Carcinoma
Anaplastic carcinoma is a clinical diagnosis, presenting as a
rapidly expanding neck mass, often associated with symptoms
indicating local invasion and compression. US appearances are of
a diffuse, ill-defined heterogeneous mass which usually involves
Figure 30.21 Extracapsular spread. Transverse thyroid US demonstrating a
hypoechoic mass replacing the right lobe of the gland with extracapsular spread
(thin arrows). These appearances are non-specific and may be seen in anaplastic
carcinoma (as in this case) and primary thyroid lymphoma. Note the thrombosed
internal jugular vein (thick arrow).
the entire thyroid gland (87). Areas of necrosis and extracapsular
spread are common with invasion of adjacent structures such as
overlying strap muscles and major neck vessels (Fig. 30.21). The
assessment of tracheal or esophageal involvement requires cross-
sectional imaging (Fig. 30.22). Lymph node or distant metastases
are present in the majority of patients (87). Anaplastic carcinoma
is sonographically indistinguishable from lymphoma.

658
 thyroid cancer

Primary Thyroid Lymphoma
Primary thyroid lymphoma usually presents as a solitary hypoechoic
mass with poorly defined margins and an absent halo (Fig. 30.23),
and 85% of cases occur on a background of Hashimoto’s thyroiditis
(87,90). Diffuse or multifocal disease is less common, develops
rapidly, and may be associated with lymphadenopathy and extra-
capsular spread (74). There may simply be diffuse enlargement of
the gland with normal echotexture (87).
Cross-sectional imaging is required to both fully stage the thyroid
and look for disease at other sites (Fig. 30.24).
hypoechoic, and multiple (Fig. 30.25). Common primary sites
include bronchogenic carcinoma, malignant melanoma, and renal
cell carcinoma (53,87). The use of US to search for metastases to
the thyroid has increased considerably with the advent of 18FDG-
PET, which uncovers incidental thyroid pathology in 2% to 3% of
cases (62,88). These incidentalomas harbor a risk of malignancy
of between 14% and 50%, usually primary thyroid cancers (62).

Metastases
Metastases tend to be hypoechoic and have a predilection for the
lower poles of the gland (87). They are typically large, well-defined,

Figure 30.23 Thyroid lymphoma. Transverse thyroid US demonstrating a poorly

defined hypoechoic thyroid mass with extracapsular extension invading the strap
muscles (arrows).
(A)

(B)
Figure 30.22 (A) Thyroid carcinoma on CT/MRI. Contrast medium-enhanced
axial CT of the thyroid demonstrating a large right-sided mass invading the adja-
cent soft tissues, including the esophagus (arrow), in a patient with anaplastic car- Figure 30.24 Thyroid lymphoma. Contrast medium-enhanced axial CT through
cinoma. (B) T1-weighted axial sequence with gadolinium enhancement in the the thyroid demonstrating a large right-sided thyroid mass displacing the trachea,
same patient, again demonstrating a complex thyroid mass with retrotracheal soft invading the esophagus (thick arrow), and encasing the common carotid artery
tissue invasion and central non-enhancing necrosis. (thin arrow), in a patient with primary thyroid lymphoma.

659
 primary tumor evaluation and staging
Figure 30.25 Metastasis to thyroid. Longitudinal thyroid US showing an intrathy-
roidal metastasis from a squamous cell carcinoma of the hypopharynx.
Key Points: Sonographic Features of Nodular
Thyroid Pathology
■ Hyperplastic nodules: varied sonographic appearance. Usually
well defined and hypoechoic, with echogenic linear striations.
Cystic or hemorrhagic degeneration common. Presence of
colloid reassuring
■ Adenomas: typically follicular in cell type and solitary. Tend
to be homogeneous, with halo, and isoechoic to background
thyroid. Cannot be differentiated from microinvasive follicular
thyroid carcinoma either by US or cytologically
■ Papillary thyroid carcinoma: predominantly solid and
hypoechoic, with ill-defined margins and chaotic intranodular
vascularity. 15% cystic. Microcalcification seen in 40% and
highly specific. Metastatic lymph nodes frequently demonstrate
microcalcification and cystic change
■ Follicular thyroid carcinoma: macroscopically invasive type,
heterogeneous with irregular margin and absent halo. Frankly
invasive type may have extracapsular spread and vascular
invasion, and is indistinguishable from anaplastic carcinoma
and lymphoma
■ Medullary thyroid carcinoma: similar to PTC but punctate
calcification seen in 80% to 90% of primaries and 50% to
60% of metastatic lymph nodes
■ Anaplastic carcinoma: diffuse, ill-defined, heterogeneous
mass which usually involves the entire thyroid gland. Areas of
necrosis and extracapsular spread common. Indistinguishable
from lymphoma on US
■ Primary thyroid lymphoma: usually solitary hypoechoic mass
with poorly defined margins and an absent halo. 85% of
cases have background of Hashimoto’s
■ Metastases: tend to be hypoechoic, have predilection for the
lower poles of the gland, and are typically large, well-defined,
hypoechoic, and multiple
Ultrasound-Guided Fine Needle Aspiration Cytology
US-guided FNAC of thyroid nodules and locoregional lymph
nodes is easy to perform, has a very low complication rate, causes
660
minimal transient patient discomfort and is more accurate than
performing FNAC without image guidance (60,91–94). There
have been no reported cases of seeding of malignant cells by FNAC
of a thyroid nodule (87). Cytology result from thyroid FNAC can
be divided into five categories:
• Inadequate: This results from hemodilution or because
the sample does not contain enough follicular cell clusters.
The reported rate of inadequate samples ranges from 2%
to 21%, with a mean of 17% (70), but with careful attention
to technique, using capillary action and narrow-bore needles
(23–27 gauge) coupled with good cytological support,
this can be brought down to under 5%. Diagnostic
hemithyroidectomy is often recommended if the FNAC is
still inadequate on repeat (95)
• Benign: Abundant thick colloid, hemosiderin-laden
macrophages, and follicular cells indicate a benign
lesion. Thyroiditis will yield lymphocytes
• Indeterminate: Follicular cells, when seen in isolation,
merely indicate that the needle tip was within thyroid
tissue. If the follicular cells are abundant, with a paucity
of colloid, it is suggestive of a follicular neoplasm, but
the possibility of a hyperplastic nodule or microinva-
sive follicular adenocarcinoma can only be excluded
at histology. Diagnostic hemithyroidectomy is often
recommended for indeterminate thyroid nodules
• Suspicious: Diagnostic hemithyroidectomy is usually
recommended
• Malignant
The decision to perform FNAC of a thyroid nodule should not be
taken lightly, as it commits the patient to a management pathway
with a significant chance of culminating in diagnostic hemithyroi-
dectomy. This may be as high as 30% if surgery is offered whenever
FNAC specimens are classified as malignant, suspicious, indeter-
minate, or inadequate. The reported sensitivity and specificity for
thyroid FNAC range from 65% to 98% and 72% to 100%, respec-
tively, with an overall accuracy of around 95% (60,73,75–77,96–98).
However, these figures are often misleading because inadequate or
non-diagnostic samples are excluded from the calculations. For
example, Lin et al. reported a sensitivity of 75% and specificity of
97% but only included patients with malignant or benign cytology
(75). Had they also included all patients with suspicious, inade-
quate, or non-diagnostic cytology in the “malignant” arm of the
treatment pathway, the sensitivity would have increased slightly to
81%, but the specificity would have fallen to 79%. This would have
resulted in the positive predictive value falling from 88.1% to
54.7% and four times as many unnecessary operations.
Key Points: Ultrasound-Guided FNAC
■ Very low complication rate and more accurate than FNAC
without image guidance
■ Sensitivity and specificity range from 65% to 98% and 72%
to 100%, respectively, with overall accuracy of around 95%
■ Inadequate samples due to hemodilution or because not
enough follicular cell clusters. Diagnostic hemithyroidectomy
often recommended if FNAC still inadequate on repeat
 thyroid cancer

is very specific, but is only seen at an advanced stage. Invasion of

■ Indeterminate sample: abundant follicular cells with paucity of
the recurrent laryngeal nerve will result in vocal cord palsy. More
colloid suggest follicular neoplasm, but a hyperplastic nodule
subtle signs of invasion such as loss of the fat plane of the tracheo-
or microinvasive follicular adenocarcinoma cannot be excluded.
esophageal groove or focal changes of the extraluminal wall are
Diagnostic hemithyroidectomy often recommended
more likely to be false positives (88,98). Endoscopic ultrasonogra-
phy has been used for assessing esophagopharyngeal invasion by
Ultrasound Imaging of Locoregional Nodal Metastases thyroid cancer with some success (101). Vascular invasion is
US is the technique of choice for the assessment of cervical lymph equally well demonstrated on US, CT, and MRI. When tumor
node metastases in thyroid cancer (60). It has the highest spatial encases the carotid, vertebral, or mediastinal arteries by more than
resolution of any imaging modality, allows assessment of internal 270°, it is likely to be unresectable.
nodal architecture and vascularity, and can be used to guide FNAC. Thyroid nodules are a common incidental pick-up by cross-
Furthermore, both nodes and primary tumor can be evaluated at sectional imaging, but there is no consensus as to the manage-
the same sitting. Metastatic nodes from differentiated thyroid ment of such findings. A recent retrospective review of
cancer have similar sonographic features to those from squamous 122 patients with incidental thyroid nodules detected on CT
cell carcinoma of the upper aerodigestive tract and tend to be suggested the incidence of malignancy or potential malignancy
round and hypoechoic, with loss of the normal echogenic hilum
and deranged vascularity (88). Nodal metastases in both PTC and
MTC commonly demonstrate punctate calcification, and cystic
components are a feature in 20% of metastatic nodes in PTC (88)
(Figs. 30.17 and 30.18). This may be so dominant as to be misin-
terpreted for a benign cervical cyst such as a branchial cleft cyst.
Nodal metastases from PTC are often very small, making size a
poor discriminating factor. This is confounded by the fact that
these metastatic nodes can remain unchanged for several years.

Computed Tomography and Magnetic

Resonance Imaging
Thyroid nodule characterization by CT and MRI is very limited,
compared to US (60,88,98–100). Both the primary tumor and nodal
metastases in papillary and medullary carcinoma may demonstrate (A)
punctate calcification on CT (Fig. 30.26), and the cystic compo-
nents in papillary carcinoma may also be detectable. Cystic metas-
tases from papillary carcinoma are characteristically hyperintense
on T1-weighted sequences, thought to reflect their high thyroglob-
ulin content or hemorrhage (Fig. 30.27) (99). By comparison, CT
and MRI are invaluable for the assessment of tumor volume, para-
tracheal and substernal extension, and detection of local invasion
into the strap muscles, trachea, larynx, esophagus, and great vessels
(98,99). They also play a key role in the assessment of distant metas-
tases to the lungs, thorax, and spine, and in planning external beam
and intensity-modulated radiotherapy (Fig. 30.26 and Fig. 30.27).
Multidetector computed tomography (MDCT) has several
advantages over 1.5 T MRI. Spatial resolution is higher, it is less
prone to movement and pulsation artifact, and it is the modality
of choice for the assessment of mediastinal and pulmonary meta-
stases. MDCT is also generally more accurate than MRI for the
assessment of cervical lymph nodes. However, the use of iodine-
containing contrast agents will temporarily block iodine uptake
by follicular cells and, therefore, delays subsequent radioiodine
scanning or therapy by at least six weeks; for this reason MRI is
often the cross-sectional imaging modality of choice. For non-
iodine-avid tumors such as anaplastic carcinoma and medullary
cell carcinoma, or in recurrent disease that has become too poorly (B)
differentiated to take up iodine, CT and PET can both be useful
Figure 30.26 Medullary carcinoma on CT. (A) Contrast medium-enhanced
adjuncts to US (Figs. 30.29 and 30.30) (88,98).
axial CT of the thyroid demonstrating a small focus of coarse calcification in a
The ability of both CT and MRI to detect tracheal or esophageal medullary thyroid cancer (arrow). (B) Contrast medium-enhanced axial CT of
invasion depends on degree. The presence of intraluminal tumor the mid-neck demonstrating abnormal right-sided deep cervical lymph node
or of encasement of the trachea by 180° or the esophagus by 270° with intranodal calcification in the same patient (arrow).

661
 primary tumor evaluation and staging

(A) (B)
Figure 30.27 Lymph node metastases on MRI. (A) Axial unenhanced T1 and (B) coronal T2-weighted sequences demonstrate a large right-sided cystic lesion in the right
deep cervical chain in a patient with a small right-sided papillary carcinoma (arrow). This cystic metastatic lymph node demonstrates T1 shortening, thought to be due
to the presence of thyroglobulin or hemorrhage.

(A) (B)
Figure 30.28 Metastatic medullary carcinoma. (A) Indium-111-octreotide scan showing uptake in right hilar nodes. (B) 123I-MIBG scan showing uptake in hilar and
mediastinal nodes (arrow). (Continued)

662
 thyroid cancer

(C) (D)

(E) (F)

(G)
Figure 30.28 (Continued) (C) Chest radiograph showing enlarged hilar nodes. (D) US scan of the liver showing calcified metastasis in the right lobe of the liver, casting
acoustic shadows. A CT scan in the same patient six years later shows (E) heavily calcified lymphadenopathy in the middle mediastinum, both hila and in the anterior
mediastinum. (F) HRCT shows numerous deposits and lymphatic infiltration. (G) A CT scan showing large calcified liver deposits.

663
 primary tumor evaluation and staging

ANT POST

(A) (B)
Figure 30.29 Metastatic thyroid cancer (non-radioiodine-avid). (A) I-123 scan showing no increased uptake. (B) Axial CT chest in same patient with follicular carcinoma
demonstrating a pulmonary metastasis.

(A) (B)

Figure 30.30 FDG-PET/CT in recurrent thyroid cancer. (A) I-131 scan

showing no increased uptake. (B and C) FDG-PET/CT in same patient
showing uptake in the right thyroid bed, which was recurrent papillary
(C)
carcinoma.

664
 thyroid cancer
was around 11% (100). In reality, these patients tend to be
managed on a case-by-case basis, taking into consideration risk
factors, age, thyroid function, and clinical features. In general,
nodules <1 cm are simply observed; even if they represent a
focus of PTC, it is unlikely that this will develop into clinically
significant disease.
Key Points: Computed Tomography and Magnetic
Resonance Imaging
■ Thyroid nodule characterization by CT and MRI is very
limited compared to US
■ Cystic metastases from papillary carcinoma are characteristi-
cally hyperintense on T1, due to high thyroglobulin content
or hemorrhage
■ CT and MRI are invaluable for assessment of extrathyroidal
extension, distant metastases, and in planning external beam
radiotherapy
■ MRI is usually the modality of choice because iodinated con-
trast agents temporarily block iodine uptake by follicular
cells, delaying subsequent radioiodine scanning or therapy
■ Computed tomography has advantages over MRI and is used
to assess non-iodine-avid tumors
■ Incidental thyroid nodules on CT and MRI are common, but
there is no consensus as to their management
IMAGING RECURRENT DISEASE
The combination of serum thyroglobulin and calcitonin assess-
ment, scintigraphy, and clinical evaluation forms the mainstay
for detecting recurrent disease, although US for post-treatment
surveillance is increasing. There are several pitfalls, however.
Regrowth of normal thyroid tissue usually appears hypoechoic
and nodular, and may be misinterpreted as recurrence. Stitch
granulomas can also have very similar appearances to papillary
carcinoma, being hypoechoic with coarse echogenic foci which
cast acoustic shadows (Fig. 30.31). Finally, it is not uncommon
to find small metastatic lymph nodes from papillary carcinoma
persisting for many years after radioactive iodine ablation (88).
Once suspected, the decision as to imaging modality will depend
on iodine avidity. With time, both papillary and follicular carci-
nomas may de-differentiate and lose the ability to accumulate
iodine. At this stage there are no contraindications to the use of
iodinated contrast, and 18FDG-PET/CT becomes a viable alternative
to scintigraphy (102).
Conventional Radiography
Plain films are of minimal value in the evaluation of thyroid cancer
and only chest radiographs should be considered routine to
exclude pulmonary metastases. AP and lateral neck of the thoracic
inlet can demonstrate tracheal narrowing and displacement.
Chest and bone X-rays have a role in the follow-up of patients
after treatment, especially if serum thyroglobulin levels increase
and the disease has become iodine non-avid (102). Most bone
metastases from thyroid carcinoma are osteolytic and vascular,
and may be expansile.
Figure 30.31 Stitch granuloma. Transverse US of the thyroid bed in a patient six
months post-total thyroidectomy for a papillary carcinoma. An 8 mm hypoechoic
structure is seen (arrow) with central echogenicity. This was firm in texture on
FNAC and failed to yield a sample. Appearances are typical of stitch granulomas.
Abbreviations: CCA, common carotid artery; IJV, internal jugular vein.
Radionuclide Imaging
Radionuclides have three major uses:
• Evaluation of a thyroid nodule
• Detection of nodal and distant metastases
• Follow-up of patients for the detection of recurrence
after surgery or radioiodine treatment
Technetium-99m-Pertechnetate Gamma Camera Imaging
Technetium-99m-pertechnetate (TcO4) is the most widely used
thyroid imaging agent (103,104) and the first-line diagnostic tool
for the evaluation of thyroid nodules. This radionuclide is short-
lived, with a half-life of six hours, and is a decay product of molyb-
denum-99 (99Mo). Technetium-99m decays by isomeric transition,
resulting in a high gamma-radiation photon yield with minimal
emission of particulate radiation and, therefore, low radiation
doses to patients (103). Modern gamma cameras have been
optimized to capture the mono-energetic 140 keV photons of
99m
Tc. The monovalent TcO4 anion is actively concentrated across
the epithelium of a number of tissues via the same ion channel as
iodide. These tissues include: choroid plexus, salivary and thyroid
glands, and gastric mucosa. Although 99mTc-pertechnetate is con-
centrated within the thyroid, it is not incorporated into thyro-
globulin, unlike iodide199mTc-pertechnetate, and is excreted
unchanged by the kidneys, salivary glands, and gut (104).
When imaging the thyroid gland with 99mTc-pertechnetate, it is
essential to palpate the neck and place radioactive markers on
palpable abnormalities, the cricoid, and the suprasternal notch.
Imaging usually begins 20 minutes after IV injection of 99mTc-
pertechnetate. Anterior, and occasionally left and right oblique or
lateral planar gamma camera images are obtained, and a measure-
ment of the percentage uptake of the injected activity is made
(normal 0.4–4%). The uptake of 99mTc-pertechnetate provides a
map of the trapping function of thyroid tissue. Normally, there is
uniform tracer uptake throughout both lobes (Fig. 30.32). 99mTc-
pertechnetate may also be concentrated in the isthmus or in a
pyramidal lobe (103,105). The size of nodules that are detectable
by 99mTc-pertechnetate scanning depends on the function and
665
 primary tumor evaluation and staging
Figure 30.32 Normal thyroid gland on 99mTc-pertechnetate study. There is homogeneous distribution of uptake throughout the gland.
location of the nodule; hyperfunctioning nodules may be seen
even if they are very small, but hypofunctioning nodules <0.8 cm
may not be discernible (102,103).
The advantages of imaging with 99mTc-pertechnetate are:
• It is highly sensitive
• It has rapid uptake
• Low-dose radiation
• It has a short test time of one hour compared with up to
20 to 24 hours for radioiodine
• Imaging can be carried out while the patient is still on
T3, T4, or carbimazole
The disadvantage of imaging with 99mTc-pertechnetate is:
• It is only trapped and not organified in the follicles and
therefore differs from radioiodine
Key Points: Technetium-99m
■ Most widely used thyroid imaging agent and provides a map
of the trapping function of thyroid tissue
■ Very high sensitivity for the detection of nodules >2 cm, less
so for those <1 cm
■ Retrosternal extension is difficult to evaluate
Gamma Camera Imaging with Radioiodine
Multiple radioisotopes of iodine are available, but only two—131I
and 123I—are clinically important (102,103). Radioisotopes of
666
iodine permit tracer studies of the entire metabolic pathway of
iodine. This includes:
• Trapping
• Organification
• Coupling
Hormone Storage and Secretion
Radioisotopes of iodine, therefore, provide a physiological map
of these processes. 131I thyroid imaging has a long and distinguished
history, but has been largely replaced by 123I and 99mTc-pertech-
netate (103). Nevertheless, 131I is readily available. It has a long
half-life of eight days, giving relatively high doses of radiation
to the thyroid and the rest of the body. It decays to release a
wide spectrum of beta particles and a high energy photon (364
keV), which is excessively energetic, for optimal imaging with
modern gamma cameras (102,103,106). The beta-ray emission
makes 131I the agent of choice for therapeutic irradiation of the
hyperthyroid gland and thyroid cancer (103,106). Also, despite
its disadvantages, it is still often used in the follow-up of patients
treated for thyroid cancer to detect metastatic disease (2,102).
For thyroid imaging, very small doses of 131I can be used occa-
sionally; it is administered orally on the first day, with measure-
ments of neck uptake at 24 hours followed by neck uptake (102).
131
I imaging requires a gamma camera fitted with a high-energy
collimator.
123
I decays by electron capture with a single gamma-ray of 159
keV photon that is ideal for imaging, and it releases no beta
 thyroid cancer
particles. Its low radiation dose and short physical half-life
(13 hours) makes it an excellent radiotracer for the functional
evaluation of thyroid masses (106). The disadvantage of 123I is
the cost of production, as it requires a cyclotron; this limits its
availability, preventing this radionuclide from replacing all oth-
ers in thyroid imaging (102). Generally, 123I is given intrave-
nously. Imaging is performed 20 to 24 hours after administration,
at which time the majority of radioactivity within the thyroid is
present as radio-iodotyrosine residues on thyroglobulin, reflect-
ing hormonogenesis (103). 48-hour imaging has been suggested
to improve the detection of a weakly avid tumor or remnant
thyroid tissue (107).
Radioactive iodine imaging of the thyroid is reasonably sensi-
tive and highly specific. Sensitivity depends on several factors,
such as tumor size, histological type, and primary versus metastatic
disease, but sensitivity is much reduced by increased total body
iodine from diet, or pharmaceuticals (amiodarone, iodine-
containing antitussives, or radiographic contrast agents), inter-
ference with uptake (perchlorate and thiocyanate), or blocking of
organification (antithyroid drugs) (102).
Although 131I has been shown to be adequate for imaging resid-
ual thyroid tissue, it has also proved less sensitive than 123I for
imaging thyroid cancer metastases. The greater quality of imaging
with 123I, compared with 131I, for whole-body scanning in patients
with differentiated thyroid cancer undergoing thyroid remnant
ablation suggests that 123I imaging may prove to be the preferred
procedure in such settings (108).
Key Points: Radioactive Iodine
■ Radioiodine allows for the study of iodine trapping, organi-
fication, coupling and hormone storage, and secretion
■ 131I has largely been replaced by 123I
■ 123I decays by electron capture with a single gamma-ray of
159 keV, ideal for imaging
(A)
99m
Figure 30.33 Hypofunctioning nodule. (A) A “cold” nodule on a Tc-pertechnetate study. There is decreased uptake in the center of the isthmus (arrow). Uptake in the
rest of the gland is normal. The focal defect coincided with a palpable nodule. (B) Transverse US of the neck demonstrating a well-defined, non-suspicious nodule in the
isthmus, which on FNA was proven to be hyperplastic in nature.
Use of Technetium-99m-Pertechnetate and Iodine
Scanning in Diagnosis of Thyroid Cancer
Although 123I is superior to 99mTc-pertechnetate in all situations of
thyroid imaging (109), there is a very high correlation between the
results of imaging using both radionuclides. Discrepancies in results
with these imaging techniques are rare (110). Technetium-99m-
pertechnetate is used as the baseline imaging study to evaluate the
anatomical location and trapping function of thyroid nodules; it has
no role to play in the detection of metastatic or recurrent disease and
only occasionally is taken up by metastatic cervical nodes.123I is also
used to evaluate the anatomy and function of thyroid nodules. It
may be performed after 99mTc-pertechnetate if the result is equivocal
or for “warm” nodules. 123I may be used to detect metastatic disease
postoperatively as an alternative to 131I. However, 131I plays a major
role in the treatment and follow-up of patients with thyroid cancer.
The majority of thyroid cancers present as a discrete nodule (or
nodules), and less commonly as a diffusely enlarged gland (106).
A solitary thyroid nodule is characterized by its tracer uptake
compared with that of the surrounding thyroid tissue. Nodules
have decreased, increased, or slightly increased tracer uptake (111).
When evaluating a solitary nodule, there are five important results
a thyroid scan may show:
• A solitary hypofunctioning nodule—a “cold nodule”
• A solitary nodule with relatively increased tracer uptake
compared with that of the normal thyroid
• A non-visualized nodule
• A solitary hyperfunctioning nodule with suppression of
uptake elsewhere—a hot nodule
• A dominant nodule in a multinodular goiter
A hypofunctioning nodule is the one most frequently associated
with thyroid cancer. While more than 80% of solitary thyroid
nodules are hypofunctioning, only 10% to 20% of solitary hypo-
functioning nodules are cancers; the remaining 80% are benign
lesions such as cysts, colloid nodules, adenomas, degenerative
nodules, or thyroiditis (Fig. 30.33) (112–115). Hypofunctioning
(B)
667
 primary tumor evaluation and staging
nodules warrant further investigation, usually ultrasound, and, if
solid, biopsy (103).
A nodule with focally mild increased 99mTc-pertechnetate uptake
in a background of normal thyroid uptake comprises approxi-
mately 10% of thyroid nodules, and up to 10% of those will be
malignant (116). Such a nodule should be further evaluated with
123
I imaging, which will usually show it to be hypofunctioning.
If it remains positive on radioiodine imaging, TSH suppression
imaging to exclude a functioning nodule should be carried out by
repeating the scan one week after daily tri-iodothyronine treat-
ment. If the nodule is truly autonomous, it will result in greatly
reduced tracer uptake in the normal thyroid but not in the nodule
(103). If the nodule is hypofunctioning on radioiodine imaging, it
should be further evaluated with ultrasound and FNAC (117).
Occasionally, a palpable nodule may be “non-visualized” on
99m
Tc-pertechnetate imaging. Such a nodule may be non-thyroidal
in nature or it may be truly functioning normally, in which case
the likelihood of it being cancer is negligible. These nodules are
seen in Hashimoto’s thyroiditis, adenoma, or hyperplasia (103).
On the other hand, the nodule may actually be hypofunctioning
but obscured by normal thyroid tissue overlying it, too small to be
resolved by the gamma camera or actually outside the thyroid sil-
houette. Serum measurements of TSH and antithyroid antibody
level, 123I imaging with or without TSH suppression, and careful
localization of the nodule at the time of imaging, together with
oblique views, will help distinguish between some of these possi-
bilities. Otherwise, such nodules should be treated as if they were
cold nodules and investigated with ultrasound (102,103).
Five per cent of thyroid nodules are hyperfunctioning on gamma
camera imaging. Of these, very few (up to 5%) will be associated
incidentally with unrecognized malignant tissue (113,114). A hyper-
functioning nodule shows increased tracer uptake with suppression
of uptake by the surrounding thyroid, indicating efficient and auton-
omously hyperfunctioning thyroid tissue (Fig. 30.34). Such a nod-
ule is so rarely malignant that neither biopsy nor surgical removal
is indicated for this reason. However, a very small fraction of thyroid
malignancies may show associated increased 99mTc-pertechnetate
Figure 30.34 Hyperfunctioning nodule. A “hot” nodule on 99mTc-pertechnetate
study. Markedly increased uptake is seen in the left thyroid lobe. Uptake in the rest
of the thyroid gland is suppressed, consistent with an autonomous adenoma.
668
uptake (discordant nodules) (118,119). The incidence of malignancy
in such nodules is 15% (120). These tumors are usually very vascular
and may, rarely, retain their ability to trap but not organify iodine,
and thus appear hyperfunctioning on 99mTc-pertechnetate imaging
but hypofunctioning on 123I imaging (118). Therefore, patients with
a hyperfunctioning nodule on 99mTc imaging should have biochemi-
cal evaluation of serum TSH, serum-free thyroxine (T4), and free
tri-iodothyronine (T3) levels, and 123I imaging should be performed
(103,118). In the case of an autonomously functioning nodule, the
serum TSH is usually in the lower part of the normal range or below
normal. Tri-iodothyronine and T4 levels may be normal or high,
depending on the activity of the nodule (121). The degree to which
the nodule contributes to overall thyroid function is reflected by the
degree of suppression of tracer uptake in the surrounding thyroid
tissue (103). Thus, the finding of a suppressed TSH level and reduced
tracer uptake in the surrounding normal thyroid tissue, in a patient
with a hyperfunctioning solitary thyroid nodule by 99mTc-pertechne-
tate scanning, confirms that the nodule is almost certainly benign, as
does uptake of 123I by the nodule.
Localized compensatory hypertrophy of thyroid tissue can cause a
palpable nodule that concentrates 99mTc-pertechnetate. This occurs
when there is widespread damage to the gland in Hashimoto’s
thyroiditis (122), after radiotherapy or surgery, and in the congenital
absence of one thyroid lobe (hemiagenesis) (103,121). In these
situations, serum TSH is normal or high. If the specific clinical
details do not exclude cancer with reasonable certainty, further
evaluation is indicated with FNAC or biopsy of the nodule.
Suppression imaging will reduce tracer uptake in the hypertrophic
tissue and will distinguish it from an autonomous nodule (103).
The presence of a dominant hypofunctioning nodule in a multi-
nodular goiter, or in the setting of Hashimoto’s thyroiditis that is
noticed because of its rapid increase in size or hardening consistency,
has a higher probability of being cancerous, and such a nodule should
be evaluated in a similar fashion to a solitary nodule (Fig. 30.35)
Figure 30.35 Multinodular goiter with a dominant hypofunctioning nodule.
Tc-99m-pertechnetate study showing a multinodular goiter. The thyroid gland is
enlarged, with irregular uptake. An area of decreased uptake in the center of the left
lobe corresponded with a dominant nodule on palpation. Aspiration cytology of
this showed papillary carcinoma.
 thyroid cancer
(104,123). A hypofunctioning nodule in a hyperfunctioning thyroid
(Graves’ disease) has a greater incidence of malignancy than a hypo-
functioning nodule in a euthyroid gland.
Key Points: Technetium-99m and Radioiodine in
the Diagnosis of Cancer
■ Hypofunctioning nodules are malignant in 10% to 20% of
cases; the remainder are cysts, colloid nodules, adenomas,
degenerative nodules, and thyroiditis
■ Normal functioning nodules on 99mTc will be malignant in
10% of cases and should be further evaluated with 123I, which
usually shows malignant lesions to be cold
■ Hyperfunctioning nodules are very rarely malignant
■ Non-visualization of a palpable nodule is due to normal function,
e.g., in Hashimoto’s thyroiditis, adenoma, or hyperplasia
Follow-up of Differentiated Thyroid Cancer
Using Radioiodine
Generally, residual thyroid tissue is left when performing a
total thyroidectomy for thyroid cancer, so as to preserve the
parathyroid glands and the recurrent laryngeal nerve. This
residual thyroid tissue is then ablated with radioiodine (131I
radionuclide) therapy. It is highly desirable to assess the size of
the residual thyroid tissue before the ablation dose of 131I using
either 123I or 99mTc-pertechnetate imaging in order to adjust the
administered therapeutic activity if large thyroid remnants are
present. The typical ablation dose ranges from 2 to 6 GBq 131I.
The patient is treated in a designated side ward for radionu-
clide therapy. The patient is imaged two to four days after the
radioiodine is given, with the gamma camera set up for 131I
with a high-energy collimator. This shows the level of uptake
in the thyroid remnant and occasionally it may show iodine-
avid functioning metastases (Fig. 30.36). The reason for thyroid
ablation is to remove all normal thyroid tissue so that serum
thyroglobulin (Tg) measurements can be used for follow-up of
thyroid cancer patients.
In the past, a series of follow-up studies were carried out
using 70 to 200 MBq 131I, typically for a period of five to seven
years. The patient’s thyroxine or liothyronine treatment was
stopped for an appropriate period of time so TSH could rise
above 30 mU/L, 131I was given orally and imaging was then
undertaken two to four days later to see if the thyroid remnant
had disappeared and to detect any functioning metastases. At
the same time, Tg was measured as a second monitor while the
patient was off the thyroid hormones. This protocol was then
repeated at increasing intervals. This approach, using 131I tracer
for imaging, has two main disadvantages. First, 131I is a poor
imaging agent for a gamma camera. Therefore, it was suggested
that the administered dose of 131I should be increased to, for
example, 300 to 400 MBq to enable better imaging. Unfortu-
nately, this causes “stunning:” a small amount of radionuclide
uptake prevents the benefit of a large amount of therapeutic
administered activity. It has been shown that below 200 MBq,
“stunning” is less likely to occur and thus a typical dose for 131I
follow-up is 70 MBq, which is suboptimal for good quality
imaging. It was sometimes observed that the post-131I therapy
scan showed more iodine-avid metastases than the tracer 131I
imaging study. Clearly, imaging undertaken after 5 GBq 131I as
compared with 70 MBq is likely to be better. The alternative
approach, therefore, is to use a radionuclide of iodine with better
imaging properties, i.e., 123I, which is a pure gamma emitter
with an energy level of 159 keV (124–128).
After ablation therapy, low-risk patients are followed only clini-
cally and with Tg serially (off T3 for eight days). If Tg rises, a 123I
study is performed with imaging at 24 hours after confirming that
the TSH is >30 mU/L.
High-risk patients after 131I ablation therapy are imaged with 123I
at six months and Tg measurement (off T3 for eight days, TSH
>30 mU/L). If radioiodine imaging and Tg are normal, follow-up
is with Tg (off T3 eight days) at 6 and 12 months, and if all results
are normal the patient can then be considered “cured,” and treated
with thyroxine and Tg measured at intervals. If Tg subsequently
rises, a further 123I study is performed in a situation where TSH is
high. A positive 123I study leads to 131I therapy, which should be
repeated no earlier than after six months.
If 123I imaging is negative and Tg rises, then 123I is repeated and,
if still negative, a search for non-iodine-avid disease is made,
leading to surgery, radiotherapy or medical treatment, as appro-
priate. Localization of non-iodine-avid thyroid disease was pre-
viously undertaken by 201Tl or by 99mTc sestaMIBI but is now
undertaken by 18FDG PET in combination with radiological
techniques, particularly MRI.
In conclusion, 123I imaging has largely replaced 131I tracer imag-
ing in the follow-up of patients with differentiated thyroid cancer.
Key Points: Radioiodine in Follow-up
■ Thyroidectomy invariably results in some residual thyroid
tissue to spare the parathyroid glands and 131I ablation therapy
is given four weeks after surgery
■ Although most papillary and follicular carcinoma metastases
are radioiodine-avid, anaplastic and medullary carcinomas
never are
■ Patients are re-imaged at set intervals for several years; if
metastases are demonstrated, 131I therapy is given and may be
repeated
■ 123I is a more reliable substitute for 131I in the follow-up of
differentiated carcinoma
Other Less Commonly Used Radionuclide Agents
Thallium-201 is a potassium analogue initially used as a myo-
cardial imaging agent, as are 99mTc-MIBI or 99mTc-tetrofosmin.
All these agents have essentially been replaced by FDG-PET and
FDG-PET/CT. The disadvantage of all these agents, including
18
FDG PET, is that they do not show whether or not the detected
metastases are iodine-avid.
Positron Emission Tomography
Iodine-124, with a half-life of 4.2 days, localizes to the thyroid and
produces both gamma-rays and positrons, which can be used for
thyroid imaging with PET. 2-[F-18]fluoro-2-deoxy-D-glucose
(FDG) has been used to image cancer and its glucose utilization.
This is higher in most malignancies than in benign diseases, due
669
 primary tumor evaluation and staging

(B)

ANT POST
(A) (C)

ANT POST ANT 3 days POST POST 3 days POST

(D) (E)

Figure 30.36 Radioisotope studies in metastatic thyroid can-

cer. (A, B) multiple bone metastases on an I-131 ablation study
in a patient with follicular thyroid cancer. (C) CT confirming
sternal metastasis. (D) Thyroid I-131 ablation study in a
patient with papillary thyroid cancer demonstrating a lung
metastasis (arrow). (E, F) I-131 post-treatment study in a
patient with follicular thyroid cancer demonstrating uptake in
the neck, confirmed on US and FNA to be a small metastatic
(F) lymph node (arrow).

670
 thyroid cancer
to up-regulation of glucose transport proteins and of hexokinase
isoenzymes. Studies reported to date demonstrate a higher aver-
age 18FDG uptake in thyroid malignancies, but there is overlap
with benign adenomas (129,130). Therefore, there is no role for
preoperative FDG-PET in differentiating malignant from benign
thyroid nodules (131). The main indication for 18F-FDG-PET is
for the detection of local recurrence and metastasis of differenti-
ated thyroid cancer in patients with an elevated thyroglobulin
level and negative radioiodine whole-body scan (132), as well as
those with persistently elevated thyroglobulin levels following
total thyroidectomy and radioactive ablation (Fig. 30.30) (133).
Studies (134–137) have shown the sensitivity of 18F-FDG-PET alone
in these patients to be between 69.3% and 94.6%, specificity 25%
to 83%, and accuracy 63.9% to 87.8%.
Using both 131I whole-body scanning and 18F-FDG PET, the
sensitivity for detecting recurrent or metastatic disease increases
over the use of either of these imaging methods alone (137).
18
F-FDG uptake usually occurs in less differentiated or dediffer-
entiated thyroid cancer cells, and patients with metastatic lesions
that concentrate 18F-FDG but not 131I have reduced survival
(138). Most 131I-negative metastases demonstrate 18F-FDG
uptake, reflecting rapid tumor growth and poor differentiation.
Conversely, most 131I-positive metastases are 18F-FDG-PET nega-
tive. The major clinical impact of 18F-FDG PET is not the dem-
onstration of disseminated metastases in patients with
thyroglobulin levels of several thousand ng/ml, who have
received several 131I therapies and have no therapeutic options;
rather, its impact is in the early detection of 131I-negative recur-
rences or metastases in patients with moderately elevated thyro-
globulin levels (10–100 ng/ml) (134,139). In this patient group,
surgery for a single metastasis may be curative.
Thyroid incidentalomas can occasionally be detected on
18
F-FDG PET. Studies (140,141) evaluating the rate and signifi-
cance of these incidentally detected thyroid nodules found them
to occur at a frequency of 2.3% (140). Such thyroid incidentalo-
mas also have a high rate of being clinically relevant malignancies.
These results suggest that such lesions should have tissue diagno-
sis if it will influence patient outcome and management.
Imaging Agents for Medullary Thyroid Carcinoma
Pentavalent Technetium Dimercaptosuccinic Acid
In the past, this has been the imaging agent of choice for MTC
(142). Pentavalent technetium dimercaptosuccinic acid [Tc(V)
Figure 30.37 I-123 MIBG showing uptake in the left lower neck (arrow) in a patient with MEN 2A subsequently proven to be metastasis to a supraclavicular lymph node
from medullary carcinoma.
DMSA] is reported to have a sensitivity of 77% and specificity of
100% for primary MTC, and a sensitivity of 68% and specificity
of 100% for metastatic disease, with excellent uptake in bone and
soft tissue metastases (143,144). The sensitivity can be further
improved by SPECT imaging (142). The agent is not taken up by
normal thyroid tissue (102), is inexpensive, and can be prepared
locally.
Somatostatin Receptor Imaging
Studies using 111In-labelled octreotide (pentetreotide) have
shown that MTC was visualized in 81% of cases (145–147). This
method, although excellent for demonstrating pulmonary
metastases, is insensitive to liver and lymph node metastases
(148,149) and is not as specific as originally thought, as false-
positive uptake occurs in areas of inflammation and granu-
lomatous disease. Indium-111 (111In)-pentetreotide is more
sensitive in detecting minimal residual disease than other imag-
ing modalities (150). Somatostatin receptor detection with a
probe can also be used intraoperatively to localize tumor unde-
tected by 99mTc-DMSA or 131I-MIBG (151). 111In-pentetreotide
is commercially available and does not require special imaging
equipment (102).
Meta-iodobenzylguanidine
123-Iodine/131-iodine-MIBG is useful in imaging tumors that
store catecholamines (102). It has an unpredictable uptake in
medullary thyroid carcinoma, with a positive rate of 30% and a
negative rate of 52%, reflecting the absence of secretory granules
(152). 123I/131I-MIBG is more likely to detect soft tissue than bone
metastases (Fig. 30.37) (102). Although not an ideal agent to image
MTC, it may allow the simultaneous imaging of pheochromo-
cytoma in patients with MEN (Fig. 30.38) (153). In 123I-MIBG-avid
disease, 131I-MIBG therapy is an option.
FDG-PET in Medullary Carcinoma of the Thyroid
18
F-FDG PET has also been established as a sensitive and specific
modality for localizing metastases of MTC, when the serum cal-
citonin levels are elevated, even at levels below 20 pg/ml (154). It
has been shown to be particularly useful for the detection of
lymph node metastases; more so than pulmonary or hepatic
metastases (155). The reported sensitivities and specificities of
18
F-FDG PET imaging in the detection of MTC metastases are
73% to 88% and 79% to 80%, respectively (156–158). Similarly,
671
 primary tumor evaluation and staging
(A) (B)
Figure 30.38 I-123 MIBG in MEN 2A. (A) Anterior and (B) posterior views of an I-123 MIBG study in a patient with MEN 2A and treated medullary carcinoma of the
thyroid demonstrating uptake in the region of both adrenal glands, indicating the presence of bilateral pheochromocytomas (arrows). (C) Contrast medium-enhanced
CT scan showing typical bilateral pheochromocytomas (arrows).
18
F-FDG PET has also been shown to be useful for the follow-up
of patients with Hürthle cell and poorly differentiated insular
thyroid cancer (159,160).
A study (156) on patients with medullary thyroid cancer, who
had elevated calcitonin levels following treatment, compared
131
I-MIBG, 18F-FDG PET, MRI, and CT. The sensitivity of
18
F-FDG PET was higher than CT or MRI for the detection of
lymph node involvement, although CT and MRI had higher sen-
sitivities for the detection of pulmonary and hepatic metastases,
while 131I-MIBG performed poorly (155). Similarly, in a large
multicenter trial (156) comparing 18F-FDG PET, 111In-pen-
treotide, 99mTc-DMSA, 99mTc-MIBI, CT, and MRI in 82 patients
with MTC following thyroidectomy (except for three patients
who had their imaging prior to surgery), 18F-FDG PET showed
the highest lesion detection probability (68%), followed by MRI
(58%), and CT (53%). MRI had the highest sensitivity (82%),
followed by 18F-FDG PET (78%), and CT (50%). The specificity
of 99mTc-MIBI was the highest (100%), but its sensitivity was
only (25%). 18F-FDG PET had a specificity of 79%, MRI 67%,
and CT 20%. The remainder of the tracers had low sensitivities
and higher specificities.
Despite the success of 18F-FDG PET imaging, false-positive
results such as uptake in non-malignant cervical lymph nodes,
laryngeal muscles, vocal cord muscle, and chronic thyroiditis,
and false-negative results such as the lack of uptake in malig-
nant nodes have also been reported (135,161–164). With the
advent of PET/CT, however, most of these limitations are no
longer relevant (154).
672
(C)
Key Point: Medullary Thyroid Cancer
■ The imaging agents of choice in MTC are FDG-PET and
111
In-octreotide
TREATMENT OF THYROID CANCER
The treatment of choice for thyroid carcinoma will depend on
several factors. Extremely important in making this decision is the
histology of the lesion. However, in general, the current authors
advise total thyroidectomy for both papillary and follicular lesions,
for the reasons stated earlier. Lymph node dissection is under-
taken if there is nodal involvement. Postoperative radioactive
iodine therapy is then given, and the patient rescanned with 123I at
three to six months to confirm complete ablation and the absence
of metastatic disease. Thyroid hormone is administered postop-
eratively to inhibit TSH production. Thyroglobulin as a tumor
marker is used in the follow-up of patients after surgery, but can
only be accurate in the complete absence of thyroid tissue (25).
Radical radiotherapy and/or chemotherapy are used for patients
with locally advanced disease or metastatic spread.
Undifferentiated (anaplastic) carcinomas usually require radio-
therapy, either radical or palliative, and possibly adjuvant chemo-
therapy. In early disease, wide excision followed by radical
radiotherapy is always indicated.
Radiotherapy followed by chemotherapy is given for all
stages of thyroid lymphoma. Medullary carcinoma is treated
 thyroid cancer
with surgery and/or radiotherapy in the early stages and with
chemotherapy when advanced disease is present. However, the
disease may often be quite indolent, and intensive chemotherapy
(which is in any case not highly successful) should only be used
with clearly progressive disease. It should also be emphasized
that the efficacy of either chemotherapy or radiotherapy in this
situation has not been definitely established. With 123I-MIBG-avid
tumor, 131I-MIBG therapy may be appropriate. In due course,
octreotide receptor-positive disease may be amenable to radio-
nuclide octreotide treatment.
A PRACTICAL APPROACH TO THE ASSESSMENT
OF THYROID NODULES
In general terms, patients are referred with a thyroid “lump,” and
assessment is made at this stage. Some apparent “thyroid” masses
turn out to be lymphadenopathy on careful examination, espe-
cially in the case of lymphomas. The two most important initial
assessments are the functional status of the patient, particularly
whether the patient is hypothyroid or hyperthyroid, and blood
tests for thyroid function and thyroid antibodies are essential. In
some cases, such as in those patients presenting with a family
history suggestive of endocrine neoplasia, or in children or
young adults, measurement of plasma calcitonin is helpful.
Clearly, where any of these tests are abnormal the patient should
be referred to an endocrine service. Where the thyroid mass is
enlarging rapidly, particularly if diffuse, an FNAC should be per-
formed immediately: if insufficient cells are obtained or it is
non-diagnostic, there should be a low threshold for consider-
ation of a core biopsy.
In all other cases, US is indicated in males, in adults <25 years
or as a new mass at >75 years of age, or where there is an appar-
ently solitary nodule, where there is a history of radiotherapy,
symptoms of hoarseness or dysphagia, or signs of recent enlarge-
ment or lymphadenopathy. A non-contrast CT scan is impor-
tant for the investigation of stridor of exploration of a possible
retrosternal extension. If a solitary nodule is imaged on US, any
nodule <1 cm in diameter without any suspicious features or
lymphadenopathy can be followed up clinically; the presence of
suspicious US features demands a repeat US in six months. This
also applies to any benign-appearing nodules <1 cm in a multi-
nodular goiter. However, any solitary nodule >1 cm in diameter,
or showing suspicious features or associated lymphadenopathy,
requires FNAC. In a multinodular goiter, there is a difference of
opinion internationally; one approach is to sample large nod-
ules, concentrating on the largest and those showing any suspi-
cious features. Alternatively, one can leave any non-suspicious
nodules unless there are any pressure effects, although an endo-
crine opinion may be helpful. Very large unitary or multiple
nodules may require an endocrine opinion if there are any pres-
sure effects, while cysts should be drained with the FNAC and
rescanned in due course.
If the FNAC shows a papillary, medullary or anaplastic carci-
noma, then early referral to a multidisciplinary team specializ-
ing in thyroid tumors is necessary; a lymphoma will additionally
require a core biopsy for staging and thence oncology referral.
Clearly benign lesions on FNAC should be followed up by an
endocrine service. However, follicular cells, or repeated non-
diagnostic taps, should be considered for diagnostic hemithy-
roidectomy (or total thyroidectomy in the context of a
multinodular goiter).
CONCLUSIONS
An Approach to Imaging Thyroid Neoplasia
Preoperative Diagnosis of Thyroid Cancer
There are five important clinical situations in which the possibil-
ity of thyroid malignancy may arise and imaging will be required
to confirm a diagnosis (123):
• A solitary thyroid nodule found on palpation
• A multinodular goiter with clinical features that arouse
suspicion
• Previous exposure of head, neck, or upper thorax to
ionizing radiation
• Rarely, local symptoms such as hoarseness, dysphagia,
or pain in the absence of an abnormal thyroid on
palpation
• Cervical lymphadenopathy or distant metastases when
the primary source is unknown.
Solitary Nodule
The prominent place assumed by the solitary nodule in any
discussion on thyroid cancer is due to the fact that a thyroid
cancer most often presents as a clinically solitary thyroid nodule
(123). Thyroid nodules are extremely common. Clinically
apparent nodules are present in up to 6.4% of females and
1.5% of males (165). However, these figures significantly
understate the problem. Autopsy surveys have found a preva-
lence of nodularity of 37% to 57% (166,167). Most thyroid
nodules are benign and the incidence of malignancy in clini-
cally palpable nodules is 5% to 12% (168,169). A 10% incidence
of malignancy has been reported in nodules detected at routine
autopsy in apparently macroscopically normal thyroid glands
(123,168).
In the past, it was recommended that a clinically palpable
nodule should be evaluated with technetium scanning and
ultrasound to identify its morphological and functional char-
acteristics. However, the possibility of malignancy in even
warm nodules, and the fact that apparent simple cysts may not
be benign, has changed the assessment plan in most major cen-
ters. Most authorities would move to ultrasound assessment
with FNAC of suspicious nodules, performing a number of
“passes” through the gland and collaborating with an experi-
enced cytopathologist. In most such cases the results will allow
malignancy to be excluded, but positive or equivocal results,
particularly the presence of follicular cells, should lead to surgical
exploration.
At the time of scanning, ultrasound should be used to detect
local invasion, cervical nodal metastases, and multifocal tumor. A
chest X-ray is required if the tumor is follicular. Computed tomo-
graphy and MRI may be helpful in detecting the degree of local
invasion (intrathoracic), tumor extension and mediastinal nodal
metastases if tumors are aggressive, but these procedures are not
performed routinely.
673
 primary tumor evaluation and staging
Multinodular Goiter
The finding of a multinodular goiter in a patient suspected of having
a solitary nodule has been thought to decrease the probability of
malignancy, but the cancer rate per thyroid is independent of the
number of nodules. Thirty-six percent of clinically diagnosed
solitary thyroid nodules are shown to be multiple on radionuclide
scanning (169). Probably less than 1% of multinodular goiters
are malignant (123), although in surgical series the incidence is
higher (168). The presence of a large dominant nodule increases
the incidence of cancer and should be dealt with in a similar way
to a solitary nodule with ultrasound assessment and consideration
of FNAC.
It is helpful to bear in mind factors that increase the overall
probability of malignancy, such as:
• Prior head and neck irradiation
• Age under 40 years in male patients
• Fast rate of growth of a dominant nodule
• Fixation
• Hoarseness
• Lymphadenopathy
• Family history of MTC
• A cold nodule in Graves’ disease (168)
Key Points: Thyroid Nodules
■ Of all clinically palpable solitary nodules, 5% to 12% are
malignant
■ Clinically palpable solitary nodules are present in >6% of
females and 1.5% of males
■ Of cystic nodules, 1% to 3% are malignant
■ Of solitary nodules, 36% are shown to be multinodular on
imaging
■ Only 1% of multinodular goiters are malignant, but a large
dominant nodule increases the risk of cancer and requires
further assessment
Follow-up of Patients Treated for Thyroid Cancer
The aim of imaging following thyroidectomy is to detect local
recurrence, as well as regional and distant metastatic disease.
Ultrasound is the initial investigation to detect local recurrence
and cervical lymph node metastases. Fine-needle aspiration can
then be performed on any residual mass. Computed tomogra-
phy or MRI is used if the ultrasound findings are inconclusive
or negative and the clinical suspicion of recurrence is high.
Radionuclides also have an important role in the follow-up of
patients treated for thyroid cancer. Radioactive iodine, together
with serum thyroglobulin measurements, is used to detect
metastases. FDG-PET is also used occasionally to detect recur-
rences. Chest X-rays are used routinely to detect lung metasta-
ses but may not show diffuse infiltration, which is evident on
131
I imaging. Skeletal X-rays and bone scanning are required if
local symptoms are present.
Increasingly, the role of imaging in thyroid cancer has moved to
the assessment of recurrence, particularly using radionuclides, as
this is also relevant to therapy. In initial diagnosis, radionuclide
imaging is progressively being replaced by FNAC and ultrasound
alone, although it is vital that the cells are examined by a cytologist
674
with experience in this area. Whenever uncertainty exists, it is
preferable to proceed to surgical exploration.
Summary
■ The peak incidence of thyroid cancer is in young women
aged 25 to 35 years
■ Papillary carcinoma is the most common thyroid cancer, is
characteristically of low-grade malignancy and tends to
spread early to lymph nodes
■ Follicular carcinoma tends to metastasize to bone, liver, and
lungs, but not lymph nodes
■ Technetium-99m-pertechnetate is the most widely used thy-
roid imaging agent; a solitary cold nodule is associated with
malignancy in 10% to 20% of cases
■ 131-iodine is used mainly in treatment and to detect recurrent
disease
■ Technetium (V) DMSA and 111In-octreotide are the imaging
agents of choice for medullary carcinoma
■ The main indication for 18F-FDG PET is for the detection of
local recurrence and metastases in patients with elevated thy-
roglobulin and negative 131I
■ Ultrasound is the most sensitive technique for detecting focal
pathology and plays an important role in screening those at
risk of developing thyroid malignancy
■ Most thyroid cancers present as a clinically solitary nodule;
although palpable solitary nodules are present in >6% of
females, only 5% to 12% are malignant
REFERENCES
1. Halnan KE. Thyroid. In: Price P, Sikora K, eds. Treatment of
Cancer. London: Chapman and Hall, 1995: 358–89.
2. Price DC. Radioisotopic evaluation of the thyroid and the
parathyroids. Radiol Clin North Am 1993; 31: 991–1015.
3. Doniach I. Carcinoma of the thyroid. In: Besser GM,
Cudworth AG and Thorner MO, eds. Clinical Endocrinology:
An Illustrated Text, 2nd revised edn. Mosby, 1994.
4. Franceschi S. Iodine intake and thyroid carcinoma—potential
risk factor. Exp Clin Endocrinol Diabetes 1998; 106(Suppl 3):
S38–S44.
5. Segal K, Arad-Cohen A, Mechlis S, Lubin E, Feinmesser R.
Cancer of the thyroid in children and adolescents. Clin
Otolaryngol Allied Sci 1997; 22: 525–8.
6. Colonna M, Guizard AV, Schvartz C, et al. A time trend anal-
ysis of papillary and follicular cancers as a function of tumour
size: a study of data from six cancer registries in France
(1983–2000). Eur J Cancer 2007; 43: 891–900.
7. Scheiden R, Keipes M, Bock C, et al. Thyroid cancer
in Luxembourg: a national population-based data report
(1983–1999). BMC Cancer 2006; 6: 102–13.
8. Kent WD, Hall SF, Isotalo PA, et al. Increased incidence of
differentiated thyroid carcinoma and detection of subclinical
disease. CMAJ 2007; 177: 1357–61.
9. Davies L, Welch HG. Increased incidence of thyroid cancer in
the United States, 1973–2002. JAMA 2006; 295: 2164–7.
 thyroid cancer
10. McDougall IR, Camargo CA. Treatment of micropapillary
carcinoma of the thyroid: where do we draw the line? Thyroid
2007; 17: 1093–6.
11. LiVolsi VA. Papillary neoplasms of the thyroid. Pathologic
and prognostic features. Am J Clin Pathol 1992; 97: 426–34.
12. Shafford EA, Kingston JE, Healy JC, et al. Thyroid nodular
disease after radiotherapy to the neck for childhood Hodgkin’s
disease. Br J Cancer 1999; 80: 808–14.
13. Takahashi T, Trott KR, Fujimori K, et al. An investigation
into the prevalence of thyroid disease on Kwajalein Atoll,
Marshall Islands. Health Phys 1997; 73: 199–213.
14. Leenhardt L, Aurengo A. Post-Chernobyl thyroid carcinoma
in children. Baillière’s Best Pract Res Clin Endocrinol Metab
2000; 14: 667–77.
15. Nikiforov Y, Gnepp DR. Pediatric thyroid cancer after the
Chernobyl disaster. Pathomorphologic study of 84 cases
(1991–1992) from the Republic of Belarus. Cancer 1994; 74:
748–66.
16. Salabe GB. Aetiology of thyroid cancer: an epidemiological
overview. Thyroidology 1994; 6: 11–19.
17. Inskip PD, Hartshorne MF, Tekkel M, et al. Thyroid nodularity
and cancer among Chernobyl cleanup workers from Estonia.
Radiat Res 1997; 147: 225–35.
18. Fierro-Roney JF, DeGroot LJ. Radiation associated
thyroid carcinoma. In: Wheeler MH, Lazarus JH, eds. Dis-
eases of the Thyroid. London: Chapman and Hall, 1994:
325–36.
19. Feind CR. Surgical anatomy. In: Werner SC, Ingbar SH, eds.
The Thyroid. Maryland: Harper & Row, 1978: 430–1.
20. Hedinger CE, Sobin LH. Histological typing of thyroid
tumours. WHO International Histological Classification of
Tumours, Series No. 11. Geneva: Springer, 1974: 17–26.
21. Byar DP, Green SB, Dor P, et al. A prognostic index for thy-
roid carcinoma. A study of the E.O.R.T.C. Thyroid Cancer
Cooperative Group. Eur J Cancer 1979; 15: 1033–41.
22. Hedinger C, Williams ED, Sobin LH. Histological typing of
thyroid tumours. WHO International Histological Classifi-
cation of Tumours, 2nd edn. Berlin: Springer-Verlag, 1988.
23. Wang C. Thyroid cancer: clinical. In: Werner SC, Ingbar SH,
eds. The Thyroid. Maryland: Harper & Row, 1978: 554–6.
24. Harach HR, Williams ED. Pathology of thyroid cancer. In:
Wheeler MH, Lazarus JH, eds. Diseases of the Thyroid.
London: Chapman and Hall, 1994: 341–56.
25. Cady B. Papillary carcinoma of the thyroid. Semin Surg
Oncol 1991; 7: 81–6.
26. Lote K, Andersen K, Nordal E, Brennhovd IO. Familial
occurrence of papillary thyroid carcinoma. Cancer 1980; 46:
1291–7.
27. Fabien N, Paulin C, Santoro M, et al. Detection of RET onco-
gene activation in human papillary thyroid carcinomas by in
situ hybridisation. Br J Cancer 1992; 66: 1094–8.
28. Noguchi S, Noguchi A, Murakami N. Papillary carcinoma of
the thyroid. I. Developing pattern of metastasis. Cancer 1970;
26: 1053–60.
29. Zimmerman D, Hay ID, Gough IR, et al. Papillary thyroid
carcinoma in children and adults: long-term follow-up of
1039 patients conservatively treated at one institution during
three decades. Surgery 1988; 104: 1157–66.
30. Donohue JH, Goldfien SD, Miller TR, Abele JS, Clark OH.
Do the prognoses of papillary and follicular thyroid carcino-
mas differ? Am J Surg 1984; 148: 168–73.
31. LiVolsi VA. Well differentiated thyroid carcinoma. Clin Oncol
(R Coll Radiol) 1996; 8: 281–8.
32. Herrera MF, Hay ID, Wu PS, et al. Hürthle cell (oxyphilic)
papillary thyroid carcinoma: a variant with more aggressive
biologic behavior. World J Surg 1992; 16: 669–75.
33. Harach HR, Franssila KO, Wasenius VM. Occult papillary
carcinoma of the thyroid. A “normal” finding in Finland. A
systematic autopsy study. Cancer 1985; 56: 531–8.
34. Woolner LB, Beahrs OH, Black BM, et al. Thyroid carcinoma:
general considerations and follow-up data on 1181 cases.
In: Young I, Inman DR, eds. Thyroid Neoplasia. London:
Academic Press, 1968: 51–76.
35. Ceccarelli C, Pacini F, Lippi F, et al. Thyroid cancer in children
and adolescents. Surgery 1988; 104: 1143–8.
36. Cady B, Rossi R. An expanded view of risk-group definition
in differentiated thyroid carcinoma. Surgery 1988; 104:
947–53.
37. Watne AL, Starke J, McQuitty D, Sohrabi A. Follicular carci-
noma of the thyroid. Semin Surg Oncol 1991; 7: 87–91.
38. Vickery AL Jr. The diagnosis of malignancy in dyshormono-
genetic goitre. Clin Endocrinol Metab 1981; 10: 317–35.
39. Ozaki O, Ito K, Kobayashi K, et al. Familial occurrence of
differentiated, nonmedullary thyroid carcinoma. World J
Surg 1988; 12: 565–71.
40. Brennan MD, Bergstralh EJ, van Heerden JA, McConahey
WM. Follicular thyroid cancer treated at the Mayo Clinic,
1946 through 1970: initial manifestations, pathologic find-
ings, therapy, and outcome. Mayo Clin Proc 1991; 66: 11–22.
41. Khan NF, Perzi KH. Follicular carcinoma of the thyroid: an
evaluation of the histologic criteria used for diagnosis. Pathol
Ann 1983; 1: 221–53.
42. Ruegemer JJ, Hay ID, Bergstralh EJ, et al. Distant metastases
in differentiated thyroid carcinoma: a multivariate analysis
of prognostic variables. J Clin Endocrinol Metab 1988; 67:
501–8.
43. Aldinger KA, Samaan NA, Ibanez M, Hill CS Jr. Anaplastic
carcinoma of the thyroid: a review of 84 cases of spindle and
giant cell carcinoma of the thyroid. Cancer 1978; 41: 2267–75.
44. Sakamoto A, Sakamoto G, Sugano H. History of cervical
radiation and incidence of carcinoma of the pharynx, larynx,
and thyroid. Cancer 1979; 44: 718–23.
45. Hassoun AA, Hay ID, Goellner JR, Zimmerman D. Insular
thyroid carcinoma in adolescents: a potentially lethal endo-
crine malignancy. Cancer 1997; 79: 1044–8.
46. Pellegriti G, Giuffrida D, Scollo C, et al. Long-term outcome
of patients with insular carcinoma of the thyroid: the insular
histotype is an independent predictor of poor prognosis.
Cancer 2002; 95: 2076–85.
47. Lairmore TC, Wells SA Jr. Medullary carcinoma of the thy-
roid: current diagnosis and management. Semin Surg Oncol
1991; 7: 92–9.
48. Block MA, Jackson CE, Greenawald KA, Yott JB, Tashjian AH
Jr. Clinical characteristics distinguishing hereditary from
sporadic medullary thyroid carcinoma. Treatment implica-
tions. Arch Surg 1980; 115: 142–8.
675
 primary tumor evaluation and staging
49. Farndon JR, Leight GS, Dilley WG, et al. Familial medullary
thyroid carcinoma without associated endocrinopathies: a
distinct clinical entity. Br J Surg 1986; 73: 278–81.
50. Ishikawa N, Hamada S. Association of medullary carcinoma
of the thyroid with carcinoembryonic antigen. Br J Cancer
1976; 34: 111–15.
51. Greene FL, Page DL, Fleming ID, et al. AJCC Cancer Staging
Handbook. TNM Classification of Malignant Tumors, 6th edn.
New York: Springer, 2002: 89–98.
52. Sobin LH, Wittekind C. TNM Classification of Malignant
Tumours (UICC), 6th edn. New York: Wiley-Liss, 2002: 52–6.
53. Gooding GA. Sonography of the thyroid and parathyroid.
Radiol Clin North Am 1993; 31: 967–89.
54. Brander A, Viikinkoski P, Tuuhea J, Voutilainen L, Kivisaari L.
Clinical versus ultrasound examination of the thyroid gland
in common clinical practice. J Clin Ultrasound 1992; 20:
37–42.
55. Reading CC, Gorman CA. Thyroid imaging techniques. Clin
Lab Med 1993; 13: 711–24.
56. Katz JF, Kane RA, Reyes J, Clarke MP, Hill TC. Thyroid nod-
ules: sonographic-pathologic correlation. Radiology 1984;
151: 741–5.
57. Lawrence W, Kaplan BJ. Diagnosis and management of
patients with thyroid nodules. J Surg Oncol 2002; 80: 157–70.
58. Rodriguez JM, Reus M, Moreno A, et al. High-resolution
ultrasound associated with aspiration biopsy in the follow-up
of patients with differentiated thyroid cancer. Otolaryngol
Head Neck Surg 1997; 117: 694–7.
59. Cooper DS, Doherty GM, Haugen BR, et al. Management
guidelines for patients with thyroid nodules and differenti-
ated thyroid cancer. Thyroid 2006; 16: 109–42.
60. AACE/AME Task Force on Thyroid Nodules. American
Association of Clinical Endocrinologists and Associazione
Medici Endocrinologi Medical Guidelines for Clinical Prac-
tice for the Diagnosis and Management of Thyroid Nodules.
Endocrine Practice 2006; 12: 63–102.
61. Frates MC, Benson CB, Charboneau JW, et al. Management
of thyroid nodules detected at US: Society of Radiologists in
Ultrasound Consensus Conference Statement. Radiology
2005; 237: 794–800.
62. Baloch ZW, Cibas ES, Vlark DP, et al. The National Cancer
Institute Thyroid fine needle aspiration state of the science
conference: a summation. Cytojournal 2008; 5: 1–17.
63. Perros P, ed. British Thyroid Association, Royal College of
Physicians. Guidelines for the Management of Differentiated
Thyroid Cancer, 2nd edn. Report of Thyroid Cancer Guidelines
Update Group. London: Royal College of Physicians,
2007.
64. Franklyn JA. Comparing USA and UK guidelines for the
management of differentiated thyroid carcinoma. Thyroid
2006; 16: 105–7.
65. Cappelli C, Castellano M, Pirola I, et al. The predictive
value of ultrasound findings in the management of thyroid
nodules. QJM 2007; 100: 29–35.
66. Rossi R, Roti E, Trasforini G, et al. Differentiated thyroid
cancers 11-20 mm in diameter have a clinical and histopatho-
logic characteristics suggesting higher aggressiveness than
those <10 mm. Thyroid 2008; 18: 309–15.
676
67. Walsh RM, Watkinson JC, Franklyn J. The management of
the solitary thyroid nodule: a review. Clin Otolaryngol 1999;
24: 388–97.
68. Malchoff CD, Malchoff DM. Familial nonmedullary thyroid
carcinoma. Cancer Control 2006; 13: 106–10.
69. You YN, Lakhani V, Wells SA, Moley JF. Medullary thyroid
cancer. Surg Oncol Clin N Am 2006; 15: 639–60.
70. Nguyen GK, Lee MW, Ginsber J, Wragg T, Bilodeau D. Fine
needle aspiration of the thyroid: an overview. Cytojournal
2005; 2: 12–24.
71. Ezzat S, Sarti DA,Cain DR, Braunstein GD. Thyroid inciden-
talomas: prevalence by palpation and ultrasonography. Arch
Int Med 1992; 154: 1838–40.
72. Ross DS. Evaluation of the thyroid nodule. J Nucl Med 1991;
32: 2181–92.
73. Gharib H, Goellner JR. Fine needle aspiration biopsy of the
thyroid: an appraisal. Ann Int Med 1993; 118: 282–9.
74. Takashima S, Morimoto S, Ikezoe J, et al. Primary thyroid
lymphoma: comparison of CT and US assessment. Radiology
1989; 171: 439–43.
75. Lin JD, Chao TC, Huang BY, et al. Thyroid cancer in the
thyroid nodules evaluated by ultrasonography and fine-
needle aspiration cytology. Thyroid 2005; 15: 708–17.
76. Leenhardt L, Menegaux F, Franc B, et al. Selection of patients
with solitary thyroid nodules for operation. Eur J Surg 2002;
168: 236–41.
77. Ravetto C, Colombo L, Dottorini ME. Usefulness of fine nee-
dle aspiration in the diagnosis of thyroid carcinoma: a retro-
spective study in 37,895 patients. Cancer 2000; 990: 357–63.
78. Solbiati L, Cioffi V, Ballarati E. Ultrasonography of the neck.
Radiol Clin North Am 1992; 30: 941–54.
79. Peccin S, de Castro JA, Furlanetto TW, et al. Ultrasonogra-
phy: is it useful in the diagnosis of cancer in thyroid nodules?
J Endocrinol Invest 2002; 25: 39–43.
80. Rago T, Vitti P, Chiovato L, et al. Role of conventional ultra-
sonography and color flow-doppler sonography in predict-
ing malignancy in “cold” thyroid nodules. Eur J Endocrinol
1998; 138: 41–6.
81. Bozbora A, Erbil Y, Ozarmagan S, et al. Color Doppler
sonography in cold thyroid nodules for malignancy predic-
tion. Acta Chir Belg 2002; 102: 259–62.
82. Hatabu H, Kasagi K, Yamamoto K, et al. Cystic papillary
carcinoma of the thyroid gland: a new sonographic sign. Clin
Radiol 1991; 43: 121–4.
83. Simeone JF, Daniels GH, Mueller PR, et al. High-resolution
real-time sonography of the thyroid. Radiology 1982; 145:
431–5.
84. Papini E, Guglielmi R, Bianchini A, et al. Risk of malignancy
in nonpalpable thyroid nodules: predictive value of ultra-
sound and color-doppler features. J Clin Endocrinol Metab
2002; 87: 1941–6.
85. Cappelli C, Pirola I, Cumetti D, et al. Is the anteroposterior
and transverse diameter ratio of nonpalpable thyroid nod-
ules a sonographic criteria for recommending fine-needle
aspiration cytology? Clin Endocrinology 2005; 63: 689–93.
86. Kim EK, Park CS, Chung WY, et al. New sonographic criteria
for recommending fine needle aspiration biopsy of nonpalpa-
ble solid thyroid nodules. Am J Roentgenol 2002; 178: 687–91.
 thyroid cancer
87. Wong KT, Ahuha AT. Ultrasound of thyroid cancer. Cancer
Imaging 2005; 5: 167–76.
88. King AD. Imaging for staging and management of thyroid
cancer. Cancer imaging 2008; 8: 57–69.
89. Kessler A, Rappaport Y, Blank A, et al. Cystic appearance of
cervical lymph nodes is characteristic of metastatic papillary
thyroid carcinoma. J Clin Ultrasound 2003; 31: 21–5.
90. Untch BR, Olson JA. Anaplastic thyroid carcinoma, thyroid
lymphoma and metastases to thyroid. Surg Oncol Clin N Am
2006; 15: 661–79.
91. Newkirk KA, Ringel MD, Jelinek J, et al. Ultrasound-guided
fine-needle aspiration and thyroid disease. Otolaryngol Head
Neck Surg 2000; 123: 700–5.
92. Corrias A, Einaudi S, Chiorboli E, et al. Accuracy of fine needle
aspiration biopsy of thyroid nodules in detecting malignancy
in childhood: comparison with conventional clinical, labora-
tory, and imaging approaches. J Clin Endocrinol Metab 2001;
86: 4644–8.
93. Clark KC, Moffat FL, Ketcham AS, Legaspi A, Robinson DS.
Nonoperative techniques for tissue diagnosis in the management
of thyroid nodules and goiters. Semin Surg Oncol 1991; 7:
76–80.
94. Yang GC, Liebeskind D, Messina AV. Ultrasound-guided
fine-needle aspiration of the thyroid assessed by ultrafast
papanicolaou stain: data from 1135 biopies with a 2–6 year
follow-up. Thyroid 2001; 11: 581–9.
95. Alexander EK, Heering JP, Benson CB, et al. Assessment of
nondiagnostic ultrasound-guided fine needle aspirations
of thyroid nodules. J Clin Endocrinol Metab 2002; 87:
4924–7.
96. Leenhardt L, Hejblum G, Franc B, et al. Indications and limits
of ultrasound guided cytology in the management of non-
palpable thyroid nodules. J Clin Endo Metab 1999; 84: 24–8.
97. Hamming JF, Vriens MR, Goslings BM, et al. Role of fine-
needle aspiration biopsy and frozen section examination in
determining the extent of thyroidectomy. World J Surg 1998;
22: 575–80.
98. Galloway RJ, Smallridge RC. Imaging in thyroid cancer.
Endocrinol Metab Clin North Am 1996; 25: 93–113.
99. Miyakoshi A, Dalley RW, Anzai Y. Magnetic resonance imag-
ing of thyroid cancer. Top Magn Reson Imaging 2007; 18:
293–302.
100. Shetty S, Maher MM, Hahn PF, Halpern EF, Aquino SL. Sig-
nificance of incidental lesions detected on CT: correlation
among CT, sonography and pathology. Am J Roentgenol
2006; 187: 1349–56.
101. Koike E, Yamashita H, Noguchi S, et al. Endoscopic ultra-
sonography in patients with thyroid cancer: its usefulness
and limitations for evaluating esophagopharyngeal invasion.
Endoscopy 2002; 34: 457–60.
102. Palmedo H, Bucerius J, Joe A, et al. Integrated PET/CT in
differentiated thyroid cancer: diagnostic accuracy and impact
on patient management. J Nucl Med 2006; 47: 616–24.
103. Shulkin BL, Shapiro B. The role of imaging tests in the diag-
nosis of thyroid carcinoma. Endocrinol Metab Clin North
Am 1990; 19: 523–43.
104. Sodee DB. The study of thyroid physiology utilizing intra-
venous sodium pertechnetate. J Nucl Med 1966; 7: 564.
105. Andros G, Harper PV, Lathrop KA. Pertechnetate-99m local-
ization in man with applications to thyroid scanning and the
study of thyroid physiology. J Clin Endocrinol Metab 1965;
25: 1067–76.
106. Mafee MF, Capek V, Blend M, et al. Modern methodologies
of differentiating thyroid masses. Semin Surg Oncol 1991; 7:
67–75.
107. Gerard SK, Cavalieri RR. I-123 diagnostic thyroid tumor
whole-body scanning with imaging at 6, 24, and 48 hours.
Clin Nucl Med 2002; 27: 1–8.
108. Mandel SJ, Shankar LK, Benard F, Yamamoto A, Alavi A.
Superiority of iodine-123 compared with iodine-131 scan-
ning for thyroid remnants in patients with differentiated
thyroid cancer. Clin Nucl Med 2001; 26: 6–9.
109. Shapiro B, Britton K, Fountos A, et al. A multiobserver com-
parison of 99mTcO4 and 123I thyroid imaging. Eur J Nucl Med
1981; 6: 135–8.
110. Reschini E, Catania A, Ferrari C, et al. Comparison of pertech-
netate and radioiodine thyroid scintiscans in thyroid disease.
J Nucl Biol Med 1993; 37: 12–17.
111. Fogelman I, Maisey MN. The thyroid scan in the manage-
ment of thyroid disease. In: Freeman LM, Weissmann HS, eds.
Nuclear Medicine Annual. New York: Raven Press, 1989:
1–48.
112. Psarras A, Papadopoulos SN, Livadas D, Pharmakiotis AD,
Koutras DA. The single thyroid nodule. Br J Surg 1972; 59:
545–8.
113. Ashcraft MW, Van Herle AJ. Management of thyroid nod-
ules. I: History and physical examination, blood tests, X-ray
tests, and ultrasonography. Head Neck Surg 1981; 3: 216–30.
114. Ashcraft MW, Van Herle AJ. Management of thyroid
nodules. II: Scanning techniques, thyroid suppressive
therapy, and fine needle aspiration. Head Neck Surg 1981;
3: 297–322.
115. Blum M, Rothschild M. Improved nonoperative diagnosis
of the solitary “cold” thyroid nodule. Surgical selection based
on risk factors and three months of suppression. JAMA 1980;
243: 242–5.
116. Wheeler MH. The solitary thyroid nodule. In: Wheeler MH,
Lazarus JH, eds. Diseases of the Thyroid. London: Chapman
and Hall, 1994: 231–43.
117. Britton KE, Bomanji JB. Nuclear medicine imaging in endo-
crinology. In: Besser M, Thorner MO, eds. Atlas of Endocrine
Imaging. London: Wolfe, 1993: 113–42.
118. Shambaugh GE, Quinn JL, Oyasu R, Freinkel N. Disparate
thyroid imaging. Combined studies with sodium pertechne-
tate Tc 99m and radioactive iodine. JAMA 1974; 228: 866–9.
119. Mountford PJ. Risk assessment of the nuclear medicine
patient. Br J Radiol 1997; 70: 671–84.
120. Massin JP, Planchon Z, Perez R. The comparison of Tc-99m
pertechnetate and I-131 scanning of thyroid nodules. Clin
Nucl Med 1977; 2: 324–33.
121. Burgi H. The toxic soliary nodule and toxic multinodular
goitre. In: Wheeler MH, Lazarus JH, eds. Diseases of the
Thyroid. London: Chapman and Hall, 1994. 193–9.
122. Ramtoola S, Maisey MN, Clarke SE, Fogelman I. The thyroid
scan in Hashimoto’s thyroiditis: the great mimic. Nucl Med
Commun 1988; 9: 639–45.
677
 primary tumor evaluation and staging
123. Maisey MN, Ng Tang Fui S. Nuclear medicine in the assess-
ment of thyroid cancer. Recent Results Cancer Res 1980; 73:
68–86.
124. Britton KE, Foley RR, Siddiqi A. I-123 imaging for the pre-
diction of I-131 therapy for recurrent differentiated thyroid
cancer, RDTC, when I-131 tracer is negative but raised thyro-
globulin. Eur J Nucl Med 1999; 26: 1013.
125. Britton KE, Foley RR, Chew SL. Should hTG levels in the absence
of iodine uptake be treated? Eur J Nucl Med 2003; 30: 794–5.
126. Park HM. 123I: almost a designer radioiodine for thyroid
scanning. J Nucl Med 2002; 43: 77–8.
127. Shankar LK, Yamamoto AJ, Alavi A, Mandel SJ. Comparison
of 123I scintigraphy at 5 and 24 hours in patients with differ-
entiated thyroid cancer. J Nucl Med 2002; 43: 72–6.
128. Siddiqi A, Foley RR, Britton KE, et al. The role of 123I-
diagnostic imaging in the follow-up of patients with differ-
entiated thyroid carcinoma as compared to 131I-scanning:
avoidance of negative therapeutic uptake due to stunning.
Clin Endocrinol (Oxf) 2001; 55: 515–21.
129. Adler LP, Bloom AD. Positron emission tomography of
thyroid masses. Thuyroid 1993; 3: 195–200.
130. Bloom AD, Adler LP, Shuck JM. Determination of malig-
nancy of thyroid nodules with positron emission tomography.
Surgery 1993; 114: 728–34.
131. Lind P. Multi-tracer imaging of thyroid nodules: is there a
role in the preoperative assessment of nodular goiter? Eur J
Nucl Med 1999; 26: 795–7.
132. Reske SN, Kotzerke J. FDG-PET for clinical use. Results of
the 3rd German Interdisciplinary Consensus Conference,
“Onko-PET III”, 21 July and 19 September 2000. Eur J Nucl
Med 2001; 28: 1707–23.
133. Helal BO, Merlet P, Toubert ME, et al. Clinical impact of (18)
F-FDG PET in thyroid carcinoma patients with elevated thy-
roglobulin levels and negatie (131)I scanning results after
therapy. J Nucl Med 2001; 42: 1464–9.
134. Schlüter B, Bohuslavizki KH, Beyer W, et al. Impact of FDG
PET on patients with differentiated thyroid cancer who pres-
ent with elevated thyroglobulin and negative 131I scan. J Nucl
Med 2001; 42: 71–6.
135. Frilling A, Tecklenborg K, Görges R, et al. Preoperative diag-
nostic value of [(18)F] fluorodeoxyglucose positron emission
tomography in patients with radioiodine-negative recurrent
well-differentiated thyroid carcinoma. Ann Surg 2001; 234:
804–11.
136. Yeo JS, Chung JK, So Y, et al. F-18-fluorodeoxyglucose posi-
tron emission tomography as a presurgical evaluation modal-
ity for I-131 scan-negative thyroid carcinoma patients with
local recurrence in cervical lymph nodes. Head Neck 2001;
23: 94–103.
137. Feine U, Lietzenmayer R, Hanke JP, et al. Fluorine-18-FDG
and iodine-131-iodide uptake in thyroid cancer. J Nucl Med
1996; 37: 1468–72.
138. Wang W, Larson SM, Fazzari M, et al. Prognostic value of
[18F]fluorodeoxyglucose positron emission tomographic
scanning in patients with thyroid cancer. J Clin Endocrinol
Metab 2000; 85: 1107–13.
139. Lind P, Kresnik E, Kumnig G, et al. 18F-FDG-PET in the follow-
up of thyroid cancer. Acta Med Austriaca 2003; 30: 17–21.
678
140. Mojiminiyi OA, Udelsman R, Soper ND, Shepstone BJ, Dudley
NE. Pentavalent Tc-99m DMSA scintigraphy. Prospective eval-
uation of its role in the management of patients with medullary
carcinoma of the thyroid. Clin Nucl Med 1991; 16: 259–62.
141. Cohen MS, Arslan N, Dehdashti F, et al. Risk of malignancy
in thyroid incidentalomas identified by fluorodeoxyglucose-
positron emission tomography. Surgery 2001; 130: 941–6.
142. Van den Bruel A, Maes A, De Potter T, et al. Clinical relevance
of thyroid fluorodeoxyglucose-whole body positron emission
tomography incidentaloma. J Clin Endocrinol Metab 2002;
87: 1517–20.
143. Hoefnagel CA, Delprat CC, Zanin D, van der Schoot JB. New
radionuclide tracers for the diagnosis and therapy of medullary
thyroid carcinoma. Clin Nucl Med 1988; 13: 159–65.
144. Berná L, Cabezas R, Mora J, et al. 111In-octreotide and
99m
Tc(V)-dimercaptosuccinic acid studies in the imaging of
recurrent medullary thyroid carcinoma. J Endocrinol 1995;
144: 339–45.
145. Kwekkeboom DJ, Reubi JC, Lamberts SW, et al. In vivo soma-
tostatin receptor imaging in medullary thyroid carcinoma.
J Clin Endocrinol Metab 1993; 76: 1413–17.
146. Krausz Y, Ish-Shalom S, Dejong RB, et al. Somatostatin-
receptor imaging of medullary thyroid carcinoma. Clin Nucl
Med 1994; 19: 416–21.
147. Krenning EP, Kwekkeboom DJ, Bakker WH, et al. Somatosta-
tin receptor scintigraphy with [111In-DTPA-D-Phe1]- and
[123I-Tyr3]-octreotide: the Rotterdam experience with more
than 1000 patients. Eur J Nucl Med 1993; 20: 716–31.
148. Frank-Raue K, Bihl H, Dörr U, et al. Somatostatin receptor
imaging in persistent medullary thyroid carcinoma. Clin
Endocrinol (Oxf) 1995; 42: 31–7.
149. Kurtaran A, Scheuba C, Kaserer K, et al. Indium-111-DTPA-
D-Phe-1-octreotide and technetium-99m-(V)-dimercapto-
succinic acid scanning in the preoperative staging of
medullary thyroid carcinoma. J Nucl Med 1998; 39: 1907–9.
150. Dörr U, Würstlin S, Frank-Raue K, et al. Somatostatin recep-
tor scintigraphy and magnetic resonance imaging in recur-
rent medullary thyroid carcinoma: a comparative study.
Horm Metab Res Suppl 1993; 27: 48–55.
151. Waddington WA, Kettle AG, Heddle RM, Coakley AJ. Intra-
operative localization of recurrent medullary carcinoma of
the thyroid using indium-111 pentetreotide and a nuclear
surgical probe. Eur J Nucl Med 1994; 21: 363–4.
152. Bomanji J, Levison DA, Flatman WD, et al. Uptake of iodine-
123 MIBG by pheochromocytomas, paragangliomas, and
neuroblastomas: a histopathological comparison. J Nucl Med
1987; 28: 973–8.
153. Montravers F, Coutris G, Sarda L, Mensch B, Talbot JN. Utility
of thallium-201 and iodine-123 metaiodobenzylguanidine in
the scintigraphic detection of neuroendocrine neoplasia. Eur J
Nucl Med 1993; 20: 1070–7.
154. Bockisch A, Brandt-Mainz K, Görges R, et al. Diagnosis in
medullary thyroid cancer with [18F]FDG-PET and improve-
ment using a combined PET/CT scanner. Acta Med Austriaca
2003; 30: 22–5.
155. Szakáll S Jr, Esik O, Bajzik G, et al. 18F-FDG PET detection
of lymph node metastases in medullary thyroid carcinoma.
J Nucl Med 2002; 43: 66–71.
 thyroid cancer
156. Diehl M, Risse JH, Brandt-Mainz K, et al. Fluorine-18 fluoro-
deoxyglucose positron emission tomography in medullary
thyroid cancer: results of a multicentre study. Eur J Nucl Med
2001; 28: 1671–6.
157. Musholt TJ, Musholt PB, Dehdashti F, Moley JF. Evaluation
of fluorodeoxyglucose-positron emission tomographic scan-
ning and its association with glucose transporter expression
in medullary thyroid carcinoma and pheochromocytoma: a
clinical and molecular study. Surgery 1997; 122: 1049–60.
158. Brandt-Mainz K, Müller SP, Görges R, Saller B, Bockisch A.
The value of fluorine-18 fluorodeoxyglucose PET in patients
with medullary thyroid cancer. Eur J Nucl Med 2000; 27:
490–6.
159. Plotkin M, Hautzel H, Krause BJ, et al. Implication of
2-18fluoro-2-deoxyglucose positron emission tomography
in the follow-up of Hürthle cell thyroid cancer. Thyroid
2002; 12: 155–61.
160. Zettinig G, Leitha T, Niederle B, et al. FDG positron emission
tomographic, radioiodine, and MIBI imaging in a patient
with poorly differentiated insular thyroid carcinoma. Clin
Nucl Med 2001; 26: 599–601.
161. Igerc I, Kumnig G, Heinisch M, et al. Vocal cord muscle activity
as a drawback to FDG-PET in the follow-up of differentiated
thyroid cancer. Thyroid 2002; 12: 87–9.
162. Strauss LG. Fluorine-18 deoxyglucose and false-positive
results: a major problem in the diagnostics of oncological
patients. Eur J Nucl Med 1996; 23: 1409–15.
163. Yasuda S, Shohtsu A, Ide M, et al. Chronic thyroiditis: diffuse
uptake of FDG at PET. Radiology 1998; 207: 775–8.
164. Zhu Z, Chou C, Yen TC, Cui R. Elevated F-18 FDG uptake in
laryngeal muscles mimicking thyroid cancer metastases. Clin
Nucl Med 2001; 26: 689–91.
165. Vander JB, Gaston EA, Dawber TR. The significance of non-
toxic thyroid nodules. Final report of a 15-year study of the
incidence of thyroid malignancy. Ann Intern Med 1968; 69:
537–40.
166. Ross DS. Evaluation of the thyroid nodule. J Nucl Med 1991;
32: 2181–92.
167. Mortensen JD, Woolner LB, Bennett WA. Gross and micro-
scopic findings in clinically normal thyroid. J Clin Endo-
crinol Metab 1955; 15: 1270–80.
168. Perlmutter M, Slater SL. Which nodular goiters should
be removed; a physiologic plan for the diagnosis and
treatment of nodular goiter. N Engl J Med 1956; 255:
65–71.
169. Alderson PO, Sumner HW, Siegel BA. The single palpable
thyroid nodule: evaluation by 99m-Tc-pertechnetate imaging.
Cancer 1976; 37: 258–65.
679
 31 Primary Tumors of the Central Nervous System
Juliet Britton and Matthew Adams
INTRODUCTION
Primary brain tumors are uncommon, in England and Wales,
6500 cases were reported annually between 1995 and 2000 of
which 58% were classed malignant (1). In the United Kingdom in
2005 there were 4555 new cases of brain or central nervous system
cancers diagnosed, around seven per 100,000 population (2).
Every year in the United Kingdom there are over 3500 deaths from
brain and other central nervous system cancers, which accounts
for just over 2% of all cancer deaths (2). There is however evi-
dence that there is significant under reporting within the United
Kingdom, particularly of low grade gliomas. In the United States
there is an estimated incidence of 4.5/100,000.
The World Health Organization (WHO) grading system divides
brain tumors into four groups. Grades 1 to 2 are, in general, either
slow-growing or well-circumscribed lesions which are amenable to
resection and have a relatively good prognosis. The majority of brain
tumors are however of higher grade, 3 and 4. Their diffusely infiltra-
tive nature and rapid growth makes complete resection impossible
and prognosis remains extremely poor. However the division of
benign from malignant on histological grounds does not always fit
well with the reality of clinical management. Slow growing tumors
within the rigid confines of the skull vault may cause a significant
rise in intracranial pressure or compress adjacent anatomical struc-
tures with major neurological consequences. For example, fibrillary
astrocytomas classified as WHO Grade 2 are rarely amenable to
complete resection due to their infiltrative nature, with involvement
of eloquent areas of cerebral cortex. Additionally, with time the
majority of these tumors progress to higher grade.
GENERAL PRINCIPLES OF DIAGNOSIS:
PRIMARY BRAIN TUMORS
There are a large number of histologically different tumors arising
within the central nervous system (CNS) with a wide range of dif-
fering biological activity. They may be divided into basic types
dependent on the cell type of origin as shown in Table 31.1.
In adults, approximately 70% of intracranial tumors are primary
brain tumors, arising either from the brain or from the dura which
surrounds it. Of these, approximately 35% are of glial cell origin
and these are predominantly found in the cerebral hemispheres.
Histological classification of gliomas is constantly evolving in an
attempt to correlate histology with prognosis but, unfortunately,
gliomas do not conform to a simple classification. Even those that
are initially relatively benign tend to progress with time to a higher
grade of malignancy (3). Genetic analysis may be used to try and
assist in predicting prognosis, e.g., neoplasms with TP53 muta-
tions progress more frequently to higher-grade tumor (4). Advances
in histological and genetic techniques are leading to an increasing
number of rare tumors and tumor subtypes being identified.
680
Imaging Techniques
Radiology has always been pivotal in the diagnosis and manage-
ment of central nervous system (CNS) neoplasms. The role of the
radiologist is manifold and includes:
• Initial diagnosis of neoplasia
• Characterization of cell type
• Anatomical localization
• Staging tumor extent
• Assistance in planning surgery and other therapies
• Biopsy guidance
• Monitoring response to treatment
In some circumstances the risks of obtaining tissue to make a histo-
logical diagnosis are considered too great and outweigh any potential
clinical benefit, and the diagnosis will then be made on neuroradio-
logical grounds. These decisions should be made within the context
of a properly constituted brain tumor multidisciplinary team (1).
Computed Tomography and Conventional Magnetic
Resonance Imaging
Computed tomography (CT) remains the primary investigation
for most patients due to its greater availability. Headache, seizures,
and neurological deficit are symptoms commonly seen in general
practice but are only very rarely due to a brain tumor. CT should
be able to detect a tumor in the majority of cases and confirm or
exclude other diagnostic possibilities.
The information derived from CT may be supplementary to that
of magnetic resonance (MR) imaging in the prediction of tumor
type, by virtue of the ability of CT to detect calcification, particu-
larly if the MR imaging examination is confined to conventional
sequences. For example, oligodendrogliomas show particularly
dense peripheral calcification which may even be gyriform in dis-
tribution on CT (Fig. 31.1). Gradient-echo T2-weighted sequences
are more sensitive to calcification than standard spin-echo
sequences and may be used as a supplementary sequence but, even
so, the demonstration of calcification is inferior to that of CT.
Although CT remains a valuable investigation, providing infor-
mation such as the presence of tumor calcification and bone
invasion, MR imaging is now the investigation of choice. The ease
of multiplanar imaging and the high intrinsic soft tissue contrast
afforded by conventional MR imaging makes it a superior modality
for the localization of tumors and their relationship to important
anatomical structures. Contrast enhancement with gadolinium-
DTPA (Gd-DTPA) increases the conspicuity of some tumors,
assists in detecting distant spread of disease and provides some
qualitative information regarding the integrity of the blood
brain barrier and tumor vascularity. Diffusion-weighted imaging
(DWI), which is a routine sequence on most modern MR
machines, has proved useful in many scenarios, particulary
helping to discriminate between tumor and acute infarct and
between necrotic tumor and abscess. The principles of DWI are
discussed further in the section on glioma imaging.
 primary tumors of the central nervous system

Table 31.1 Histological classification of primary malignant

brain tumors
Glial tumors
Astrocytomas
Fibrillary astrocytoma: Low grade
Anaplastic
Glioblastoma multiforme
Pilocytic astrocytoma
Pleomorphic xantho-astrocytoma
Subependymal giant cell astrocytoma
Oligodendroglial tumors
Oligodendroglioma
Oligoastrocytoma
Gliomatosis cerebri
Ependymal tumors
Ependymoma: Cellular
Papillary
Anaplastic ependymoma
Myxopapillary ependymoma (spinal)
Subependymoma
Choroid plexus tumors
Choroid plexus papilloma
Choroid plexus carcinoma
Non-glial tumors Figure 31.1 Frontal oligodendroglioma. Unenhanced axial CT shows the coarse
Neuronal and mixed neuronal-glial tumors calcification typical of these tumors.
Ganglioglioma
Gangliocytoma
Desmoplastic infantile ganglioglioma
Central neurocytoma
Dysembryoplastic neuro-epithelial tumor, Lhermitte-Duclos
• Patient age
Lymphoma
• Intracranial tumor site
Primary or secondary • The presence of calcification
Embryonal tumors • Cyst formation
Cerebellar medulloblastoma • The presence of microcysts
Supratentorial primitive neuro-ectodermal tumors
Germ cell tumors
• The demonstration of hemorrhage, fat, and melanin
within the tumor
Germinoma
Embryonal carcinoma • Assessment of tumor vascularity
Yolk sac tumor • Identifying areas of necrosis
Choriocarcinoma
Teratoma
The age of the patient and site of the tumor are often as good a
Pineal region tumors predictor of tumor type as the imaging characteristics on CT and
Pineoblastoma MR imaging. For instance, in children, brain tumors are the second
Pineocytoma commonest malignancy after leukemia (5). In this age group, pri-
Hemangioblastoma mary brain tumors are relatively common in the posterior fossa
Meningeal tumors
Meningiomas: Benign
and secondary tumors are exceedingly rare. Supratentorial tumors
Atypical in children are more likely to involve the midline structures than
Anaplastic the peripheral cerebral hemispheres. In contrast, the posterior fossa
Tumors of cranial and spinal nerves is a rare site for primary malignancy in adults and an intra-axial
Schwannoma (neuroma, neurilemmoma) mass in the posterior fossa in an adult is more likely to be second-
Malignant peripheral nerve-sheath tumor (malignant schwannoma)
ary to hemorrhage, infarction, or to represent a metastasis than a
Neurofibroma
Paragangliomas primary brain tumor (6). A supratentorial mass in an adult is most
Tumors of the sellar region likely to be a glioma or a metastasis. If the patient is over 55 years
Pituitary adenoma of age the glioma is usually of high grade. The relative incidence of
Craniopharyngioma primary brain tumors is illustrated in Figure 31.2 by tumor type.
Tumors of the skull base
The ability of MR imaging to provide information on intrinsic
Chordoma
Primary bone tumors tissue characterization of a tumor may be of value in refining the
differential diagnosis (7). Certain tumors have a predilection to form
cysts and their presence or absence is important, not only for indi-
cating a particular tumor type, but also for surgical management.
Factors Assisting in Diagnosis On MR imaging, if a structure is isointense to cerebrospinal fluid
Although both CT and MR imaging demonstrate the presence of (CSF) on T1-weighted and T2-weighted images (Fig. 31.3A and C)
a mass, the following factors are of great value in suggesting the and is sharply demarcated, with a round, smooth contour, there is a
tumor type prior to surgical intervention: high probability that the lesion is a cyst. Fluid-attenuated inversion

681
 primary tumor evaluation and staging

Gliomas (e.g. astrocytoma Craniopharyngioma 3%

ependymoma
oligodendroglioma) 45–50%
Schwannoma 6%

Meningioma 15% Lymphoma 1–2%

Pituitary adenoma 5–6% Haemangioblastoma 1–2%

Germ cell tumors 1–3%

Primitive neuro-ectodermal
tumor (PNET,
medulloblastoma) 6–8% Other 5–10%

Figure 31.2 Relative incidence of primary brain tumors. Source : Adapted from Ref. 29.

(A) (B)

(C) (D)
Figure 31.3 Cystic pilocytic astocytoma. (A) Axial T1-weighted MR, (B) axial FLAIR, and (C) coronal T2-weighted MR images. The cystic component of the mass has
the same signal as CSF on all sequences and has the smooth rounded contours typical of a cyst. (D) Axial T1-weighted MR image post Gd-DTPA showing irregular
enhancement of the solid component.

682
 primary tumors of the central nervous system

(A) (B) (C)

(D) (E) (F)

Figure 31.4 Abscess: (A) Axial T2-weighted MR image shows hypointense rim and high signal intensity centre, with surrounding edema. (B) DW-MRI shows restricted
diffusion and (C) ADC map shows decreased signal characteristic of an abscess. Necrotic metastasis: Metastatis with central necrosis. (D) Axial T2-weighted MR image
demonstrating similar appearance to abscess. (E) DWI shows central high signal. (F) ADC confirming no restricted diffusion.

recovery (FLAIR) sequences and diffusion-weighted imaging are of

particular value in proving an area of tumor is cystic (Fig. 31.3B)
(8). Imaging characteristics similar to CSF are more commonly seen
in non-malignant conditions, such as arachnoid cysts, than in cysts
associated with tumors. Malignant cysts usually contain proteina-
ceous or paramagnetic substances which alter the signal intensity
on both T1 and T2 weighting. The presence of a fluid–debris level
within a cyst also helps confirm the diagnosis.
Malignant tumors of higher grade commonly show central
necrosis, on conventional imaging the appearances may be identi-
cal to an abscess; with a rim of enhancement on the post-contrast
scan. Diffusion-weighted imaging is the investigation of choice in
discriminating between the two. An abscess typically shows
increased signal on DWI and decreased diffusion on the apparent
diffusion coefficient (ADC) map due to the viscosity of the pus.
Necrotic tumors have low signal on DWI and appear bright on the
ADC map due to the increased diffusion of cellular necrosis and
the increase in size of the intercellular space (Fig. 31.4).
Certain primary tumors, e.g., high-grade gliomas, oligodendro-
gliomas, ependymomas (Fig. 31.5), and some types of metastasis
have a tendency to acute and chronic hemorrhage. Hemorrhage
is detectable on both CT and MR imaging in the acute phase but
the initial high density on CT rapidly fades to become isodense
Figure 31.5 Ependymoma. Sagittal T2-weighted MR image of the lumbar spine.
and eventually hypointense to adjacent brain. The signal inten- There is an expansile mass involving the cauda equina and conus. The mass is of
sity characteristics of hemorrhage may vary with time on MR mixed signal intensity; the low signal areas are due to old hemorrhage. There is
imaging but persist for longer than on CT. Additionally, hematoma scalloping of the posterior aspect of the vertebral bodies.

683
 primary tumor evaluation and staging

evolution tends to be slower when related to malignant hemor- Conventional MR imaging has the following limitations:
rhage compared with a benign bleed. This may be due to relative
hypoxia within the tumor and, moreover, hemosiderin formation • In most cases the MR appearances are sufficiently char-
acteristic to enable the radiologist to suggest the tumor
is less common.
cell type, but many CNS neoplasms have overlapping
Magnetic resonance imaging may also be able to determine the
imaging features. Similarly within a particular tumor
presence of fat and melanin. Certain tumors are associated with
type there is usually an overlap in appearances between
increased vascularity and the demonstration of multiple signal
different histological grades and genetic subtypes, and
intensity voids adjacent to or within the mass is indicative of a
therefore at the present time surgical biopsy is still
highly vascular lesion (Fig. 31.6). This may be confirmed with
necessary to make an accurate diagnosis
MR angiography (MRA). With increasing grade of malignancy,
tumors develop areas of neovascularity and increased angio- • The diffusely infiltrating nature of some CNS neoplasms
presents problems in accurately determining tumor
genesis. This may be identified as areas of enhancement with
borders, making it difficult to plan surgical resection
gadolinium or by quantitative measurements derived from
margins and radiotherapy fields. It is recognized that in
dynamic contrast-enhanced MR studies.
glial tumors, neoplastic cells extend beyond the margin
All brain tumors can be divided clinically into those which are
of abnormal signal on both contrast-enhanced
potentially surgically curable and those which are not. Preopera-
T1-weighted and T2-weighted sequences (10–13)
tive assessment should be tailored mainly to determine prognosis
(9) and assist in treatment planning. However with the emergence • Resectability is determined by the relationship of the
tumor to normal brain. Localization of eloquent gray and
of new and radical treatments for brain tumors, particularly
white matter on conventional MR imaging is based on
gliomas, accurate tumor typing and grading will become of increasing
identification of structural anatomical landmarks (14,15)
importance.

(A) (B)

(C) (D)
Figure 31.6 Paraganglioma in the left infratemporal fossa extending into the jugular foramen and compressing the naso and oropharynx. (A) Coronal T1-weighted, (B)
coronal T1-weighted post Gd-DTPA, (C) and (D) coronal T2-weighted MR images. Signal intensity voids seen on all sequences indicative of a tumor with increased
vascularity.

684
 primary tumors of the central nervous system
However, in the presence of tumor, normal anatomy
may be grossly distorted. Stereotactic localization of
both tumor and important anatomical structures may
be further complicated by shifts in position during
surgery itself
• The standard method for assessing response to treatment
relies upon detecting changes in tumor size. However,
many CNS neoplasms are complex heterogeneous masses
with irregular margins making image interpretation
and detection of subtle changes difficult. In addition,
discriminating between progressive tumor and post-
treatment sequelae such as radiation change may be
exceedingly difficult as appearances on conventional
sequences may be identical (16–20)
Advanced Imaging Techniques
Conventional MR imaging predominantly provides structural
information. In recent years additional techniques such as proton
MR spectroscopy (1H MRS), perfusion MR imaging, functional
MR imaging (fMRI), and diffusion tensor imaging (DTI) have
been developed. Such techniques provide quantitative and semi-
quantitative in vivo assessment of tissue biology, physiology, and
function. Although these advanced MR techniques have been
largely restricted to the domain of research, many are now finding
increasing application in clinical practice, serving as adjuncts to
standard structural sequences. Intraoperative MR imaging (iMRI)
utilises specially designed scanners within operating suites to pro-
vide neuronavigational assistance and up-to-date information
regarding the status of the brain during surgery. Positron emission
tomography (PET), predominantly using the tracer 18F-fluorode-
oxyglucose (FDG), has proved useful in several aspects of neuro-
oncological imaging; and the development of novel tracers may
increase its range of clinical applications. The principles and
applications of the advanced imaging techniques are outlined
further in the section on imaging of gliomas.
GLIAL CELL TUMORS
Gliomas are tumors which arise from astrocytes, oligodendro-
cytes, or ependymal cells. They fall into two basic types which
differ significantly in prognosis and therapeutic approach. There
is a large group of diffusely infiltrating tumors in which total
excision has not as yet been proved to be curative, and a smaller
potentially surgically curable group which usually occur in chil-
dren and young adults and are non-infiltrative. There is however
evidence that radical resection does seem to prolong time to
relapse and improve quality of life in patients with the infiltrating
gliomas (21–23). In 1993 the WHO grading system was devised in
an attempt to recognize the difference in biological activity of
these two tumor types and to act as an international basis for the
evaluation of tumor response to various therapies (Table 31.2).
The grading system underwent revision in 1999.
The relatively benign group includes the pilocytic astrocytoma,
the giant cell astrocytoma of tuberous sclerosis and the pleomor-
phic xanthoastrocytoma. These tumors, although not encapsu-
lated, have a well-defined margin and, if totally resected, have an
excellent prognosis.
Astrocytomas: Infiltrative Tumors
The fibrillary astrocytomas (low-grade astrocytomas, anaplastic
astrocytomas and glioblastoma multiforme) range from the rel-
atively benign low-grade Grade II to the highly malignant Grade
IV glioblastoma multiforme. Whatever their grade, these tumors
diffusely infiltrate the brain and progress to a higher grade of
malignancy with time, up to 80% progressing to the most malig-
nant form (24). Molecular genetic studies have recently shown
that mutations on the TP53 gene are seen in more than 60% of
diffuse astrocytomas progressing to glioblastoma. This mutation
rate is even higher in gemistocytic astrocytomas (3,4). There is
increasing evidence that this genetic change in fibrillary astrocy-
tomas progresses and parallels the histopathological alteration
in malignancy. Unfortunately, this also means that different
grades of malignancy may be found at different sampling sites
within the tumor which can lead to incorrect grading at the time
of diagnosis (25).
Microscopically, fibrillary astrocytomas show increasing nuclear
pleomorphism and mitoses with increasing grade. Neovascularity
is a significant feature of Grade IV tumors and a large number
of neuropathologists consider the presence of necrosis to be the
diagnostic feature of glioblastoma multiforme. Fibrillary astrocy-
tomas, in particular the lower grades, by their very nature, infiltrate
rather than destroy brain. At the time of presentation, symptoms
may be relatively mild despite extensive areas of brain involvement.
Total macroscopic resection, therefore, has the potential to increase
the patient’s symptoms.
Of the fibrillary astrocytomas, Grade IV glioblastoma multi-
forme is the most common and is one of the most malignant
human neoplasms. Radiologically, there is a progressive change
in appearance with increasing malignancy; however, MR signal
intensity characteristics do not accurately predict tumor type or
grade and biopsy is still necessary (26). There has been exten-
sive research into the use of advanced MR imaging techniques,
in particular 1H MRS, in non-invasively typing and grading
gliomas. At present however, histological analysis remains the
gold standard.
Low-Grade Astrocytoma: WHO Grade II
Age and Site
Grade II fibrillary astrocytomas are most commonly found in
the cerebral hemispheres in young adults, with a peak incidence
in the third and fourth decades. There is an incidence of 1.4
new cases per million of the population per year (24); they are
relatively slow-growing and invade rather than destroy adjacent
brain. Prognosis is initially good, with long-term median sur-
vival of seven to eight years. Their mode of spread is along the
white matter tracts and neurological deficit is therefore minor
in respect to the size of lesion at the time of presentation. The
pontine glioma of childhood is most commonly a fibrillary
astrocytoma but in this group prognosis is poor. Astrocytomas
may also be found in the spinal cord but the cerebellum is a very
uncommon site.
Computed Tomography Appearances
Grade II astrocytomas are of low density and because of their
intact blood–brain barrier should not be expected to enhance
following injection of intravenous (IV) contrast medium. Most
685
 primary tumor evaluation and staging

Table 31.2 WHO Grading System (Malignancy Scale) of Glial Tumors (3)
Tumor group Tumor type Grade I Grade II Grade III Grade IV
Astrocytic tumors Subependymal giant cell •
Pilocytic •
Low grade •
Pleomorphic xanthoastrocytoma • •
Anaplastic •
Glioblastoma •
Oligodendrogliomas Low grade •
Anaplastic •
Oligoastrocytomas Low grade •
Anaplastic •
Ependymal tumors Subependymoma •
Myxopapillary •
Low grade •
Anaplastic •
Choroid plexus tumors Papilloma •
Carcinoma • •

low-grade gliomas are diffusely infiltrating, (27) but some appear

well circumscribed and it is this group which may show mild to
moderate inhomogeneous contrast enhancement (27). The
reported incidence of enhancement in low-grade gliomas may be
falsely elevated as these tumors often show different grades of
malignancy in different areas and failure to obtain a sufficient
number of biopsies may lead to errors in the grading of malig-
nancy (26). Theoretically, relatively little enhancement should be
expected with low-grade fibrillary astrocytomas, with higher
grades showing more extensive areas of enhancement; however,
CT and MR imaging have not proved reliable in discriminating
between the various grades (28). As this group of tumors diffusely
infiltrate they may produce only minor expansion of the struc-
tures involved and therefore may be missed on routine unen-
hanced CT; furthermore, contrast-enhanced studies do not
increase the detection rate. However, calcification may be seen in
10% to 20% of low-grade astrocytomas, which is a useful diagnos-
tic feature (Fig. 31.7) (29). Calcification is infrequent in the
higher-grade tumors unless the higher grade lesion has pro-
gressed from a previously low-grade malignancy.

Magnetic Resonance Imaging Appearances Figure 31.7 Grade-II astrocytoma. Unenhanced CT shows a left frontal tumor
which is mainly of low density but has patchy calcification within it.
On T1-weighted spin-echo sequences these tumors are of low sig-
nal intensity, and on T2-weighted and proton-density sequences
they have relatively high signal intensity in relation to the adjacent
brain. These tumors are solid with little or no adjacent vasogenic Key Points: Fibrillary Astrocytomas
edema and, although they may contain microcysts filled with clear
■ Grade II fibrillary astrocytoma tumors have a peak incidence
fluid, they do not contain hemorrhagic cysts or cystic necrosis (4).
in the third and fourth decades of life
The diffusely infiltrative nature of these lesions is better appreci-
■ In adults they are located in the cerebral hemispheres
ated by MR imaging than on CT. Sometimes the margin of the
■ These tumors diffusely infiltrate brain tissue, resulting in
tumor appears well circumscribed (Fig. 31.8) but even so they are
relatively minor neurological deficit
still infiltrating and their borders are histologically ill-defined.
■ They show little or no enhancement with IV contrast media
The presence of enhancement suggests progression to a higher
■ There is no evidence of necrosis or hemorrhage
grade of malignancy or, in childhood, the possibility that the
■ The median survival is seven to eight years
lesion is a pilocytic astrocytoma, rather than being of the fibrillary
■ Low-grade astrocytomas commonly progress to a higher grade
type. Low-grade fibrillary astrocytomas in children, however,
■ Radical resection prolongs time to recurrence and improves
more commonly enhance than in adults (30) and it should be
quality of life
remembered that glioblastoma are relatively rare in children.

686
 primary tumors of the central nervous system

(A) (B)

(C) (D)
Figure 31.8 Grade-II astrocytoma. (A) and (B) Axial FLAIR MR images showing a high signal intensity mass deep in the right temporal lobe involving the corpus
striatum and shifting the ventricular system to the left. (C) and (D) Coronal T1-weighted MR images demonstrate the apparently well-circumscribed margins of the
mass. There was no enhancement following contrast administration.

Anaplastic Astrocytoma: WHO Grade III
Age and Site
WHO Grade III represents the histological progression point
between Grade II and Grade IV astrocytomas. Radiologically,
there is also some overlap. The peak age incidence is slightly older
than for Grade II; most patients are in their fifth decade. They may
arise de novo or as a result of tumor progression from Grade II.
Microscopically, in comparison to Grade II, these tumors show
increased cellularity, anaplasia and mitotic activity but do not
show necrosis, which is one of the diagnostic criteria for glioblas-
toma multiforme. The cell type may be fibrillary, protoplastic, or
gemistocytic. The presence of gemistocytes is usually a poor prog-
nostic indicator. The presence of at least 20% gemistocytes usually
warrants classification as an anaplastic astrocytoma (31).
Computed Tomography Imaging Appearances
These tumors are mainly of low density with areas of irregular
or ring enhancement following injection of IV contrast media.
They tend to show a greater degree of mass effect than Grade II
astrocytomas; they rarely calcify or reveal cyst formation.
Magnetic Resonance Imaging Appearances
Like most tumors, Grade III anaplastic astrocytomas produce mass
effect with expansion of adjacent brain and are of low signal
intensity on T1-weighted images and high signal intensity on
T2-weighted images (Fig. 31.9A and B). They are more likely to have
areas of greater heterogeneity than Grade II lesions (26,32). Both
Grade III and Grade IV astrocytomas have associated edema. Because
tumor and edema have the same signal intensity characteristics
on both T1- and T2-weighted images they cannot be separately
identified (7,11). Furthermore, edema facilitates the migration of
tumor cells which will therefore be found in areas which appear to
be “edematous.” For these reasons, differentiation between solid
tumor and edema on MR imaging is of doubtful significance.
Enhancement patterns are extremely variable and may be nodular,
homogeneous, or irregular. The presence of enhancement usually

687
 primary tumor evaluation and staging

(A) (B)

(C) (D)

Figure 31.9 Grade-III astrocytoma. (A) and (B) Axial FLAIR MR images showing a mass of high T2 signal intensity involving the left frontal lobe and extending across
the corpus callosum and down the internal capsule. The area of high T2 signal intensity may represent tumor and/or edema. (C) and (D) Coronal T1-weighted MR
images show patchy irregular enhancement within the tumor.

indicates the higher grades of malignancy (Fig. 31.9C and D).
However, it is important to recognize that there is considerable
overlap in appearances between high- and low-grade gliomas (7).
Key Points: Anaplastic Astrocytoma
■ The peak age incidence of Grade III anaplastic astrocytoma
is in the fifth decade
■ Irregular or ring enhancement is seen following IV contrast
media, but enhancement patterns are variable
■ Edema and tumor have the same appearances on T1- and
T2-weighted MR images
Glioblastomas Multiforme: WHO Grade IV
Age and Site
Glioblastoma multiforme is the most common glioma of adults,
accounting for approximately 50%. These patients have a rapidly
progressive clinical course. They are found in the older age group,
with a peak incidence in the sixth decade.
Glioblastomas represent the most malignant end of the spec-
trum and, despite advances in treatment, the prognosis remains
poor, with a median survival of 12 to 18 months. In adults, these
tumors are most commonly found in the cerebral hemispheres.
The typical appearance is that of a mass spreading across the cor-
pus callosum (Fig. 31.10) which occurs in approximately 50% to
75% of cases (33). Histologically, glioblastomas show markedly
increased cellularity and anaplasia with mitotic figures and giant
cells. There is increased vascularity with endothelial proliferation
and necrosis which may or may not be hemorrhagic. Hemorrhage
is common and tends to occur only in high-grade gliomas (32).
The presence of necrosis is one of the major histological criteria
for Grade IV (11). If limited tissue samples are taken, areas of
higher grade may be missed, leading to Grade IV tumors being
under-reported and classified as Grade III lesions.

688
 primary tumors of the central nervous system

As with all astrocytomas, glioblastomas are diffusely infiltrative,

but on both CT and MR imaging and even gross pathological
specimens, they may appear to have a well-circumscribed margin
(Fig. 31.11). This is not the case: tumor cells will be found through-
out the adjacent areas of apparent edema and even in areas of
brain which appear normal on MR imaging (11,12,27,33). The
spread of tumor not only occurs along the white matter tracts but
dissemination will also occur over the leptomeninges and sub-
ependymally around the ventricular walls and into the CSF (Fig.
31.12) (29). Because these tumors are ill-defined and infiltrating it
is not possible to achieve total surgical removal.

Computed Tomography Appearances

With progression to Grade IV, the histological heterogeneity of
these lesions is reflected in the CT appearances. The typical finding
is of a mass with a thick ring of contrast enhancement with sur-
rounding low-density “edematous” change. Central low density
indicates necrosis and is seen in 95% of tumors. Inhomogeneous
patchy enhancement throughout the mass may be observed (29).

Magnetic Resonance Imaging Appearances

Figure 31.10 Glioblastoma multiforme: Enhanced CT showing extension across
the splenium of the corpus callosum.
Mixed signal intensity mass lesions are seen on both T1- and
T2-weighted images (Figs. 31.11 and 31.12). Heterogeneity of the
signal intensity reflects the presence of central necrosis which may
or may not be hemorrhagic, as well as multiple cysts which may
show fluid–debris levels. Frank hemorrhage may also be present,

(A) (B)
Figure 31.11 Glioblastoma multiforme (A) Axial T2-weighted and (B) T1-weighted post Gd-DTPA MR images showing central area of necrosis which is identified by
high signal intensity on T2 and non-enhancement on T1. The surrounding area of irregular low signal on T2 and ring enhancement on T1 suggests a well circumscribed
tumor margin but malignant cells will be found in the surrounding edema best seen as high signal intensity on the T2 sequence.

689
 primary tumor evaluation and staging

(A) (B)
Figure 31.12 Glioblastoma multiforme: (A) T1-weighted sagittal post Gd-DTPA MR image demonstrating involvement of the floor of the third ventricle. Nodular
enhancement around the ventricular margins represent subependymal spread, whilst the fine line of enhancement on the anterior aspect of the brain stem represents
leptomeningeal involvement. (B) Enhanced axial T1-weighted MR image showing extensive enhancement surrounding central necrosis in the left frontal lobe with
extension of tumor into the ventricle and external capsule.

with signal intensities reflecting hemorrhage of different ages.

Irregular signal intensity flow voids consistent with the develop-
ment of increased vascularity may also be seen. Around the main
tumor component, extensive signal intensity abnormality, low on
T1 weighting and high on T2 weighting, is seen extending through
the adjacent brain parenchyma (Fig. 31.11). This, although
described as representing edema, will also contain tumor cells
(11–13). Tumor commonly extends across the corpus callosum,
the posterior and anterior commissures and along the internal
and external capsules (Fig. 31.12). There may be a central area of
irregular thick-walled ring enhancement (11) or multiple areas of
irregular enhancement separate from the main mass. Focal
enhancement does not indicate isolated foci of abnormal cells, as
tumor cells will be found throughout the intervening areas of
non-enhancement. Patches of enhancement are seen where the
cells are of sufficient number to create an area of neovascularity
and breakdown of the blood–brain barrier (13).
On DWI some areas within the gliomas, which are not replaced
by necrosis, may also show restricted diffusion. This is indicative of
increased cellularity and therefore areas of high grade malignancy.
Key Points: Glioblastoma Multiforme
■ Glioblastoma multiforme accounts for 50% of all adult gliomas
■ The peak age of presentation is the sixth decade
■ Glioblastoma multiforme tumors are located in the cerebral
hemispheres
■ They cross the corpus callosum and extend along white
matter tracts
■ Tumor spread also occurs through the CSF
■ Necrosis, cysts, and hemorrhage are a characteristic feature of
these tumors
■ Contrast enhancement is a dominant feature of glioblastoma
multiforme
■ Surrounding edema contains tumor cells
■ Glioblastoma multiforme has a poor prognosis, with a mean
survival of 18 months
Oligodendroglioma
Oligodendroglioma and Oligoastrocytoma: WHO Grades II and III
Age and Site
Oligodendrogliomas and mixed oligoastrocytomas have in the
past been considered to be relatively rare forms of glioma, account-
ing for 4.2% of all primary brain tumors and gliomas (4). Advances
in histological cell typing and the discovery that these tumors are
sensitive to chemotherapy has led to an increase in the number of
gliomas being identified as oligodendrogliomas (34,35). A dele-
tion on the short arm of chromosome 1 not only suggests that the
tumor is an oligodendroglioma but also indicates the likelihood
of increased chemosensitivity (34). Oligodendrogliomas are usu-
ally considered to be relatively benign (36). The peak age incidence
of these tumors is between 35 and 40 years (25). Because of the
sensitivity of these tumors to chemotherapy it is important to try

690
 primary tumors of the central nervous system

to separate them from astrocytomas, both histologically and
radiologically (37).
Oligodendrogliomas are usually relatively well-circumscribed,
slow-growing, peripheral tumors mainly situated in the frontal
lobes. Typically there is a long preoperative history, lasting several
years, of epilepsy and headache. Although the imaging appear-
ances are fairly characteristic, similar appearances may be seen in
many other tumor types.
Computed Tomography Appearances
The most common appearance is that of a well-circumscribed,
ovoid or rounded mass lesion, situated peripherally in the fron-
tal lobe. These lesions arise from oligodendrocytes in the white
matter and extend peripherally. They are usually hypo- or
isodense compared with normal white matter and between 70%
and 90% show calcification (Fig. 31.1), which may be gyriform
in nature (29). Approximately 20% have a cystic component
(13) and contrast enhancement is variably reported but tends to
be faint and indistinct, particularly at lower grade.
Magnetic Resonance Imaging Appearances
Magnetic resonance imaging better delineates the well-circumscribed
nature of these tumors and the extent of involvement of the cortical
gray matter; however, it is less sensitive to the presence of calcifica-
tion than CT. On the T1-weighted sequences there is mixed hypo-
intensity within the lesion. T2-weighted images show mixed signal
intensity with patches of high signal intensity which may represent
cyst formation or hemorrhage and areas of low signal intensity
secondary to old hemorrhage or calcification (Fig. 31.13). Although
symptomatic hemorrhage may occur, it is not very common. Patchy
contrast enhancement is frequent. The degree of enhancement
seems to correlate well with the histological grade and is more
commonly seen in mixed oligoastrocytomas (36), otherwise there
is no particular radiological feature which separates the relatively
benign oligodendroglioma from the malignant.

(A) (B)

(C) (D)

Figure 31.13 Oligodendroglioma: (A) Axial T2-weighted, (B) axial FLAIR, (C) coronal T1-weighted, and (D) coronal T1-weighted post Gd-DTPA images showing a
peripherally situated mixed signal intensity lesion on all sequences with some cyst formation and no significant enhancement.

691
 primary tumor evaluation and staging
Key Points: Oligodendrogliomas
■ The incidence of reported oligodendrogliomas is increasing
with better histological and genetic assessment
■ The peak age of presentation is between 35 and 40 years
■ They are well-circumscribed tumors which develop mainly
in the frontal lobes
■ Involvement of the cortex with cortical thickening is a key
finding
■ Seventy to ninety percent of these tumors are calcified and
20% have a cystic component
■ They reveal mixed signal intensity on MR imaging. Patchy
contrast enhancement is common
■ They respond to chemotherapy better than astrocytomas
■ Mixed oligoastrocytomas have a worse prognosis than
oligodendrogliomas and more commonly show contrast
enhancement
Gliomatosis Cerebri: WHO Grade IV
Gliomatosis cerebri is a term usually reserved for diffusely infiltra-
tive lesions which involve large areas of the brain, including the
brain stem and cerebellum, without the presence of a focal defin-
able mass. The spinal cord may also be involved. There is diffuse
overgrowth of the areas of the brain affected which microscopi-
cally correlates with a proliferation of neoplastic glial cells. There
has been considerable controversy over the classification of this
tumor in the past but the new WHO classification considers it to
be a distinct and separate clinico-pathological entity (38).
Clinical signs and symptoms are mild in comparison to the extent
of brain involvement at the time of presentation (39) and the rate of
clinical progression is variable because the infiltrating cells vary
(A)
Figure 31.14 Gliomatosis cerebri with a diffusely infiltrated and enlarged brain. (A) Axial T2-weighted MR image showing diffuse enlargement of both temporal lobes
with subtle signal intensity change extending into the brain stem. (B) Sagittal T1-weighted MR image showing cerebellar herniation, an enlarged pons and relatively low
lying and thickened floor of the third ventricle.
692
from well-differentiated astrocytes to mitotically active cells. Patients
usually complain of headache and may have altered personality and
mental state. The peak age of presentation of gliomatosis cerebri is
between the second and fourth decades of life.
Imaging
Magnetic resonance imaging and CT demonstrate diffuse enlarge-
ment of more than one hemisphere with effacement of adjacent
CSF spaces. Density change on CT may be only minimal and
the scan may be misinterpreted as normal. On T2-weighted
MR images there is subtle increased signal intensity involving
large areas of brain and including both gray and white matter
(Fig. 31.14). Involvement of the basal ganglia, thalami, and
hypothalamus may be observed, even on CT. Enhancement is
uncommon and probably represents dedifferentiation.
A definitive diagnosis prior to postmortem may be difficult to
obtain. However, the MR imaging appearances, in conjunction
with stereotactic biopsy, should suggest the diagnosis. 18FDG PET
in conjunction with MR imaging may be of value in delineating
the extent of disease and directing surgical biopsy (40).
Key Points: Gliomatosis Cerebri
■ Gliomatosis cerebri involves large areas of the brain, usually
more than one hemisphere as well as the brain stem and
cerebellum
■ There is no definite mass but diffuse enlargement of the
involved areas is observed
■ On CT, density change may be minimal and the scan may be
misinterpreted as normal
(B)
 primary tumors of the central nervous system
■ On MR, T2-weighted images show subtle increased signal
intensity involving large areas of the brain
■ The peak age of presentation is between the second and
fourth decades of life
■ Most patients present with non-specific symptoms, e.g.,
headache
■ The rate of progression is variable, depending on the histo-
logical cell type
Advanced Functional Techniques in Glioma Imaging
Advanced MR imaging techniques, DWI and PET provide the
opportunity to look beyond brain structure to assess tissue bio-
logy, physiology, and function. There has been extensive research
applying these techniques to aspects of neuro-oncology such as
tumor grading, therapeutic planning and neuronavigation. DWI
is now a routine sequence at many institutions and automated
processes incorporated into many modern MR scanners has
increased clinical use of techniques such as 1H MRS. However, as
with conventional imaging, the advanced techniques suffer from
an overlap in characteristics between different tissue types and
there are additional problems with reproducibility, complex data
post-processing and application of sophisticated sequences out-
side the research setting. As a result the Holy Grail of non-invasive
1 2
6 7
11 12
16 17
21 22
Figure 31.15 Chemical shift imaging. Choline map derived from multi-voxel spectroscopy demonstrating elevated levels of choline within the tumor when compared to
the surrounding brain parenchyma. Source: Courtesy of Mr. Greg Fellows, St Georges Hospital, London.
histological tissue diagnosis in individual patients has not yet been
achieved. Nevertheless, the potential clinical applications remain
an exciting prospect.
Proton MR Spectroscopy and Chemical Shift Imaging
1
H MRS utilises the fact that protons in different chemical
environments have different resonant frequencies. This phenom-
enon, known as chemical shift, is used to generate a spectrum
reflecting the chemical composition of the interrogated tissue.
The low signal to noise ratio requires the voxel size to be large and
spatial resolution is correspondingly low. The most important
peaks on 1H spectra are N-acetyl aspartate (NAA), a marker of
neuronal integrity; Choline (Cho), a marker of membrane
turnover; Creatine (Cr), is considered constant in normal brain
and is used as a reference against which other metabolites are
measured; Lactate, which is increased in non-oxidative glycolysis;
and lipids, which increase in necrotic tissue. Due to its relative
ease of application the majority of clinical 1H MRS is single voxel
spectroscopy. Multi-voxel MRS, also known as chemical shift
imaging (CSI), is also possible and better reflects the spatial het-
erogeneity of tumor metabolites. The maps of relative metabolite
levels generated can be represented as a color scale and superim-
posed on conventional structural MR images (Fig 31.15).
3 4 5
8 9 10
13 14 15
18 19 20
23 24 25
693
 primary tumor evaluation and staging

Functional MR Imaging
When an area of brain becomes active the blood flow to it
increases. This increase in flow is not matched by an increase in
oxygen extraction and the concentration of deoxyhaemoglobin
falls. Deoxyhemoglobin is a paramagnetic molecule and when its
concentration within a voxel falls, the signal on T2* dependent
sequences increases. Exploiting changes in blood deoxyhemo-
globin to provide a measure of local blood flow (and a surrogate
marker of neuronal activity) is known as blood oxygen level
dependent (BOLD) contrast and is the basis of fMRI. In clinical
practice fMRI involves using fast echoplanar imaging sequences
to acquire data while the patient performs tasks designed to
demonstrate particular cortical functions. The main neuro-
oncological application of fMRI is in preoperatively demonstrat-
ing the relationship of eloquent cortex and tumor for the purposes
of surgical planning.

Diffusion-Weighted Imaging
Diffusion-weighted imaging (DWI) uses the mobility of water
protons to provide the contrast for image formation. The tech-
nique involves applying a diffusion gradient b in order to “spin
label” protons according to location. Following a refocusing
pulse, protons that have moved from their initial location will be
out of phase with neighboring protons resulting in loss of signal.
On the DWI trace image voxels in which there is relatively free
diffusion (e.g., cerebrospinal fluid (CSF), tumor necrosis and
vasogenic edema) have low signal; whereas those with restricted
diffusion (e.g., regions of high cell density or cellular swelling
secondary to cytotoxic edema) will have high signal. As the DWI
trace image is a T2 dependent sequence, interpretation may be
confounded by lesions with very long T2 relaxation times
(“T2 shine through”). However, by plotting the gradient of signal
intensity change due to different b-values a more representative
measure of water motion can be obtained. This is known as the
apparent diffusion coefficient (ADC) and the image produced
mirrors that of the DWI trace, with free diffusion appearing
bright and restricted diffusion dark.
Diffusion Tensor Imaging and Tractography
Water diffusion within the brain does not occur equally in all
directions. The presence of barriers such as cell membranes and
myelin sheaths results in diffusion occurring preferentially along
the path of least resistance, a process known as anisotropic diffu-
sion (41). Within intact white matter the direction of maximum
diffusivity coincides with the orientation of the fiber tracts.
Mathematically this can be described as a diffusion tensor, an
entity that may be visualized as an ellipsoid whose diameter in
any direction represents the diffusion in that direction and whose
principle axis is oriented in the direction of maximum diffusivity.
Diffusion tensor imaging (DTI) may be displayed as a color coded
map in which the principle axis of the diffusion tensor of each
voxel is assigned either red, green, or blue corresponding to con-
ventional x, y, and z axes, and in which color brightness represents
the degree of anisotropy.
Although fMRI is able to locate regions of eloquent cortex it is
unable to demonstrate the connecting white matter bundles such
as the corticospinal tract that may be equally important function-
ally. However, by following the direction of the diffusion tensor
Figure 31.16 Demonstration of motor pathway distortion as a result of mass effect
visualized using tractography overlaid onto a coronal mean diffusivity map. The
proximity of the motor pathways to the tumor (shown volume rendered in red) is
easily appreciated. Source: Courtesy of Mr. Tiernan Byrnes and Dr. Chris A Clark,
St George’s University of London and UCL institute of Child Health.
voxel-by-voxel from a seed point, it is possible to build a theoretical
map of the white matter tracts, a technique known as tractography
(Fig. 31.16).
Perfusion MR Imaging
It is well recognized that tumor vasculature is very different to that
of normal tissue. Neoangiogenesis plays a fundamental role in
tumor growth and the cytokines released by neoplastic cells to
drive this process also increase endothelial permeability (42).
Further discussion on angiogenesis and functional imaging meth-
ods is found in chapters 63 to 65. The purpose of perfusion MR
imaging in neuro-oncology is to provide non-invasive markers of
this abnormal tumor vasculature. The two main methods in use
are dynamic susceptibility contrast imaging (DSCI) which utilises
the drop in T2* signal caused by the passage of a gadolinium con-
trast bolus; and dynamic contrast enhancement (DCE) which
uses a T1-weighted sequence to measure the change in signal
intensity as a bolus of gadolinium diffuses across the abnormal
blood brain barrier. The main parameters derived from such tech-
niques are relative cerebral blood volume (rCBV) (Fig. 31.17), a
surrogate marker of vessel density; and Ktrans, a composite measure
of blood flow and vascular permeability. Arterial spin labeling is a
newer technique that uses magnetically labelled blood as an endo-
genous contrast agent. This is capable of producing genuinely
quantitative measures of cerebral blood flow but is currently
limited to the realm of research.
Intraoperative MR Imaging
Image-guidance systems that use preoperative cross-sectional
imaging to provide an intraoperative neuro-navigational map
of the brain have proved extremely valuable in neurosurgical

694
 primary tumors of the central nervous system

(A) (B)
Figure 31.17 Perfusion weighted imaging of a Grade 3 oligodendroglioma. (A) T2-weighted MR image demonstrating a large heterogeneous right sided mass with central
complex cyst. (B) Relative cerebral blood volume map obtained using dynamic susceptibility-weighted perfusion imaging demonstrating increased rCBV within the solid
peripheral portions of the tumor (red voxels). Source: Courtesy of Dr. Rolf Jager, National Hospital for Neurology and Neurosurgery, London.

practice. The disadvantage of such systems is that they are unable
to reflect the changes in brain anatomy and physiology that occur
during surgery and therefore do not necessarily provide an
accurate picture once an operation has commenced. Intraoperative
MR imaging has been developed to allow interventions to be
carried out either within or in very close proximity to the magnet
resulting in real-time or near real-time imaging of the patient
(43). Such systems allow the surgeon to compensate for brain
shift and enable intraoperative events such as hemorrhage,
including those remote from the operative site, to be recognized
and dealt with.
Applications of Functional Techniques in
Glioma Imaging
Non-invasive Grading and Genetic Characterization
of Gliomas
As glioma tumor grade increases there is an increase in cellularity
and vascularity (10). The rate of metabolism and cellular prolif-
eration increases and this may be accompanied by regions of
necrosis as metabolic demand outstrips supply. Advanced MR
imaging techniques are used to study these processes in vivo in an
attempt to establish tumor grade non-invasively.
The typical MR spectroscopy findings of an astrocytoma are
increased choline (Cho) and reduced N-acetylaspartate (NAA)
(44). With increasing tumor grade Cho:Cr ratio increases, NAA
falls and lipid/lactate peaks increase (Fig. 31.18) (10,44,45). How-
ever, analysing single metabolite peaks or ratios in individual
patients is fraught with problems due to the variation in published
data and the overlap in values between tumor grades. Programmes
using linear discriminant analysis to automate the interpretation
of whole spectra may prove a useful resource in overcoming such
problems in the future (46).
In the histological grading of astrocytomas, microvascular
proliferation is one of the features that characterises a tumor as
high grade. In regions of neovascularity vessels are tortuous
and disorganized with abnormal permeability. MR perfusion
has attempted to exploit this and several studies have demon-
strated a significant relationship between rCBV (42,47–49),
Ktrans (42) and tumor grade. However, as with MR spectroscopy
the overlap in perfusion parameters between different grades
makes assessment of individual patients difficult. In addition
low-grade oligodendrogliomas have much higher rCBV than
low grade fibrillary astrocytomas (50) and may be mistakenly
diagnosed as a high grade tumor unless their oligodendroglial
origin is already known.
FDG PET uptake is also associated with histological grade and
survival (51). Uptake of FDG in low grade gliomas is usually close
to that of normal white matter, uptake in anaplastic gliomas is
similar to gray matter and glioblastomas demonstrate high uptake
that is often heterogeneous due to regions of necrosis (52).
It is now recognized that, in addition to tumor grade, tumor
genotype plays an important role in determining prognosis and
response to therapy (53,54). As with tumor grading the current
gold standard for genotypic characterization is examination of
biopsy or resection specimens. However, recent studies have
demonstrated that 1p 19q deletion in oligodendrogliomas, an
important predictor of chemosensitivity and long term progno-
sis, is correlated with both MR perfusion and DWI-derived
parameters (55,56).

695
 primary tumor evaluation and staging

mI tCho

tCr

Lactate

4 3 2 1 ppm 0

(A)

Lipids and
lactate

Lipids

MM
tCho
tCr

4 3 2 1 ppm 0

(B)

Figure 31.18 (A) Spectrum from a Grade II glioma; (B) spectrum from a Grade IV glioma. All spectra were acquired with STEAM (stimulated echo-acquisition mode)
spectroscopy using TE = 30 msec, TR = 2000 msec, and 256 averages and a 2 × 2 × 2 cm voxel. Abbreviations: mI, myo-Inositol; MM, macromolecules; tCho, total
cholines; tCr, total creatines. Source: Courtesy of Dr. Franklyn Howe (DPhil), CRC biomedical Magnetic Resonance Research Group, St George’s Hospital Medical
School, London, U.K.

Planning Therapy and Guiding Surgical Intervention
Tumor Boundaries. There is increasing evidence that complete
resection of tumors prolongs survival, particularly in low-grade
gliomas, (21–23,34) although the impact of major surgery for
high-grade gliomas remains controversial. Accurate determina-
tion of tumor boundaries is essential for planning extent of
surgical resection and radiotherapy fields. The diffusely infiltrat-
ing nature of many gliomas makes this very difficult using con-
ventional MR imaging. Utilising the fact that Cho:NAA ratios
increase in tissue infiltrated with tumor, multivoxel MRS has
been used to delineate the tumor boundary of gliomas and to
accurately distinguish tumor from normal, edematous, necrotic
and/or gliotic tissue (57). DTI has also been shown to assist in
determining tumor boundaries by detecting the disruption of
anisotropic water diffusion along white matter tracts caused by
tumor infiltration (58). Intraoperative MR imaging has been
shown to be more sensitive than intraoperative visual inspection
in distinguishing between glioma and normal tissue thereby
allowing a more complete resection of tumor (59,60).
Guiding Biopsy. Histopathological analysis of tissue remains the
gold standard for determining tumor grade. However, gliomas
are often highly heterogeneous with regional variations in tumor
grade, and in order to truly represent the glioma grade, tissue
must be taken from the most malignant part of the tumor.
Conventional MR imaging is relatively insensitive to this hetero-
geneity of tumor grade, which may lead to sampling error when
used alone to guide biopsy (61). By acquiring spectra from mul-
tiple voxels across the breadth of a tumor, CSI is able to reflect
regional variations in metabolites, allowing surgical biopsy to be
directed to the region with the most malignant metabolic profile
(62). Likewise cerebral blood volume maps derived from MR
perfusion studies may be used to direct biopsy to sites of maxi-
mal rCBV indicative of high grade glioma or oligodendroglial cell
type (52,63). 18FDG PET can differentiate benign from malignant
and areas of hypermetabolism can be targeted for biopsy (64).
Unfortunately the accuracy of PET is limited by resolution
constraints and by the fact that benign (hypometabolic) tumor
foci and malignant (hypermetabolic) tumor foci may be present
within the same area of the tumor (64). In addition iMRI may
be used to visualize the trajectory of biopsy needles in realtime,
improving the diagnostic yield of such procedures (65).
Identifying Eloquent Parenchyma. fMRI has been shown to iden-
tify the site of the primary motor cortex in the presence of brain
tumors effectively and is also able to demonstrate reorganization

696
 primary tumors of the central nervous system
Figure 31.19 Functional MR imaging of a patient with a left hemispheric glioma (darker voxels indicated with a white arrow). Axial, coronal and sagittal images demonstrate
increased BOLD activity (colored voxels at the centere of the cross lines) during right hand movement versus rest in the left primary hand motor area. The region of eloquent
cortex is seen to lie outside the margins of the glioma, in the predicted location of the motor hand area. Source: Courtesy of Dr. Lucy Lee, St George’s Hospital, London.
of motor function to other sites (Fig. 31.19) (66). Identification
of language areas is also possible although results tend to be less
reliable (Fig. 31.19) (67). A potential difficulty with the use of
fMRI is that BOLD signal may be lost close to the tumor due
to pathological changes in autoregulation. Another problem is
that although fMRI can locate eloquent regions of cortex it is
unable to demonstrate the associated white matter bundles such
as the corticospinal tract which is often equally important,
However, diffusion tensor tractography is able to demonstrate
the location and orientation of such tracts and has the potential
to discriminate between white matter edema, displacement,
infiltration and disruption (68). More recently fMRI and diffu-
sion tensor tractography have been combined to visualize the
primary motor cortex and separate elements of the corticospinal
tract simultaneously as well as their relationship to adjacent
tumor (69). Integrating detailed structural and functional infor-
mation in this way has the potential to maximize surgical resection
of gliomas whilst preserving vital cerebral tissue.
Monitoring and Predicting Response to Treatment
Patients with gliomas are routinely monitored using MR imaging,
mainly with the aim of identifying an increasing mass, areas of sig-
nal intensity change and areas of new contrast enhancement. The
biological and physiological parameters measured by advanced MR
imaging techniques may better reflect tumor response to therapy
and better predict prognosis.
Response to Treatment. MRS has been used to monitor response
to both chemotherapy and radiotherapy with changes in MRS
spectra preceding changes in conventional MR appearances and
clinical condition (70,71). DWI has been used to monitor response
to treatment based on the assumption that effective therapy
resulting in reduced tumor cellularity would be reflected by an
increase in ADC. There is some evidence that this is this case and
that, as with MRS, changes occur earlier than with conventional
T2-weighted and T1-weighted gadolinium enhanced sequences
(72). Measures derived from MR perfusion have found particular
utility in monitoring response to antiangiogenic chemotherapy
agents (73,74). There is also some evidence that the same para-
meters may be used to predict long term prognosis in gliomas
(42,49) and response to radiotherapy (75), and may identify
tumors with a propensity for malignant transformation (49).
Discriminating Tumor from Treatment Related Changes. Focal
radionecrosis is impossible to distinguish from high-grade
glioma recurrence on conventional MR imaging (Fig. 31.31).
MRS is able to distinguish between pure radiation necrosis and
pure tumor recurrence, with reduced Cho:Cr and increased
NAA:Cr ratios indicating necrosis (76). MRS spectra are less
definitive when there is mixed tumor/necrosis (52). There is
evidence that DWI is capable of making the distinction
between tumor and radiation necrosis, with high ADC values
reflecting necrosis (77), and that combining MRS and DWI
may improve sensitivity (76,78). FDG PET has also been used
in this context although reported sensitivity and specificity is
relatively low (52).
Key Points: Advanced MR Techniques
■ CT and conventional MR are limited in their ability to delineate
tumor margins and assess tumor type and grade
■ Diffusion-weighted MR imaging can help distinguish acute
infarction from tumor and abscess from tumor necrosis
■ MRS measures tumor metabolites and is able to predict
tumor grade with greater accuracy
■ fMRI utilises echoplanar imaging to identify the location of
eloquent cerebral cortex
■ Diffusion tractography and fMRI display normal anatomical
structures and their displacement by tumor, and assist in
surgical planning
■ Co-registration allows abnormal metabolism to be correlated
with structural abnormalities
■ Perfusion MR imaging quantifies tumor capillary permeability
perfusion and relative blood volume and may be used to
predict tumor grade
■ 18FDG PET can differentiate benign from malignant tissue
Prognosis and Follow-up of Anaplastic Astrocytomas
and Oligodendrogliomas
Patients presenting with anaplastic astrocytoma and glioblastoma
multiforme have a poor prognosis. Most patients will initially
have some form of surgery, for example stereotactic biopsy to
confirm the diagnosis, or a debulking procedure to reduce symp-
toms of raised intracranial pressure; an attempt may be made at
complete resection but it remains controversial as to whether or
not radical surgery prolongs life (79). Many patients will also have
radiotherapy at some stage during treatment. There is also evidence
697
 primary tumor evaluation and staging
that certain forms of chemotherapy will prolong life and is used
particularly in relapse following radiotherapy.
The treatment of low-grade fibrillary gliomas and oligodendro-
gliomas is also variable and is still under evaluation (80). Although
survival rates are relatively long, all tumors within this group con-
tinue to progress and many transform to a higher grade of malig-
nancy. In some centers this group of patients will have no further
treatment following diagnosis but will be monitored for tumor
progression and treated symptomatically; in others, radical surgery
will be attempted assisted by functional MR imaging, image-
guided systems, and intraoperative MR. Resection will always be
limited by the wish to preserve areas of neurologically eloquent
brain and the inability of current imaging techniques to fully
identify areas of histological abnormality outside the area depicted
on T2-weighted imaging (11).
Both high- and low-grade gliomas may be treated with radio-
therapy. Conventional radiotherapy is aimed to irradiate the area
of affected brain with a 2 to 3 cm margin using external beam of
60 Gy of megavoltage. This should be within the tolerance of normal
brain but delayed affects of radiation commonly occur as there is
a narrow margin between the radiosensitivity of normal and
abnormal brain. Stereotactic radiosurgery and other high-dose
radiation techniques may also be employed but as yet have not
been proven to confer additional benefits (81).These techniques
are more likely to induce radiation necrosis and other non-
tumorous reactions (82). Despite the fact that tumor cells are
often found outside the areas of enhancement, these treatments
are usually targeted to this area alone (83). Chemotherapeutic
agents, including temazolamide, have been shown to have some
effect on tumor growth. All these treatments and new experimental
therapies need to be assessed and individual patients monitored
using imaging. Patients are routinely monitored using MR imag-
ing, mainly with the aim of identifying an increasing mass, areas
of signal intensity change, and areas of new contrast enhance-
ment. Advanced MR techniques and 18FDG PET may, in the future,
be used to identify areas of progression at an earlier stage.
In order to evaluate tumor response in these patients it is neces-
sary to have an understanding of the postoperative appearances
and of the effects which radiotherapy and chemotherapy may
have on the normal brain as well as the tumor.
Postsurgical Change
Following any surgical intervention there may be intra- or
extracerebral hemorrhage in the operative site, cerebral edema,
infarction, and sometimes changes secondary to infection. The
appearances of all these complications will evolve with time both
on MR imaging and CT. Unfortunately, the postsurgical site,
abscess, or recurrent tumor may have very similar appearances on
CT, making interpretation difficult.
Contrast-Enhanced Computed Tomography
Contrast-enhanced CT has been used to try to detect the amount
of residual tumor following surgery but this is no longer consid-
ered to be the investigation of choice. If CT is used the patient
needs to be scanned during the first few postoperative days when
contrast enhancement is not seen as a result of surgery. Contrast
enhancement frequently develops at the resection margin after
three to four days (84) and typically lasts for three to four weeks,
698
but may still be visible at six months (85). Unfortunately, there is
often hemorrhagic fluid at the operative site, which on CT is
difficult to separate from the areas of enhancement. This, and the
fact that the enhancement may be due to non-specific reaction in
adjacent tissues or to residual disease, makes interpretation of the
postoperative CT unreliable. Sequential imaging is necessary to
differentiate these postsurgical changes from recurring disease
(84,86).
Dural enhancement is not usually detected on CT, except where
there has been a craniectomy. When posterior fossa surgery is per-
formed, the bone flap is not usually replaced so that any build up
in posterior fossa pressure may be dissipated through the defect.
In this situation a thin line of enhancement, representing the dura
as it bridges the bony defect, will be seen (86). Sometimes the
dural enhancement may be relatively thick and it is not usually
possible to differentiate normal postsurgical appearances from
appearances secondary to infection.
Key Points: Postsurgical Change on Computed
Tomography
■ On CT, postsurgical contrast enhancement appears at three
to four days and disappears by six months
■ Dural enhancement is not usually seen on CT except at a
craniectomy site
■ Hemorrhage complicates interpretation of the postoperative
site on CT
■ Enhancement may be due to non-specific reaction
Contrast-Enhanced Magnetic Resonance Imaging
Parenchymal enhancement and dural enhancement is seen
postoperatively on MR and using this technique it is easier to
differentiate residual tumor from the changes secondary to
resection (87,88).
Parenchymal Enhancement on Postsurgical Magnetic Resonance
Imaging. Parenchymal enhancement at the operative site is seen
earlier and persists for longer on MR imaging than on CT. It has
been reported as being present as early as 18 hours (85) but
usually does not appear within the first three to four days (39).
Ideally, in order to identify residual disease following surgery,
MR imaging should be performed within the first 24 hours
(Fig. 31.20) but interpretation can be difficult; consultation with
the surgeon can be of value in interpreting the images. Intra-
operative MR imaging is superior for detecting residual disease
and, furthermore, may facilitate more complete tumor removal.
Whilst contrast enhancement has usually disappeared on CT by
six months, on MR imaging it is usually still present to a moder-
ate degree at this time. However, by one year no contrast enhance-
ment should be present at the operative site (85). Recognition that
enhancement does occur postsurgically is important; however, it
is usually fine and linear, whereas residual or recurrent tumor often
appears as a lobulated mass with thick nodular areas of enhance-
ment (79,88). The advantage of early MR imaging, compared with
CT, is that the characteristic signal intensity changes due to hemo-
globin degradation allow differentiation of high signal intensity
secondary to tumor enhancement from postoperative hemorrhage
during the first four days after surgery (Fig. 31.21). This is also
 primary tumors of the central nervous system

(A) (B) (C)

(D) (E) (F)

Figure 31.20 Postoperative MR images of a pilocytic astrocytoma (same case as Fig. 31.3). At 24 hours: (A) axial T1-weighted image demonstrates a post surgical cavity
with high signal intensity margins from blood but (B) no enhancement on post contrast T1-weighted MR image. (C) On FLAIR the resection cavity is of mixed signal
with signal change in adjacent parenchyma at this time, the significance of this latter change was uncertain. (D), (E), and (F) Same sequences one year later show no
enhancement or high signal on FLAIR, consistent with complete resection at the original operation site.

(A) (B)
Figure 31.21 Grade III fibrillary astrocytoma (A) Coronal T1-weighted MR image, post Gd-DTPA demonstrating an apparently well-circumscribed low signal intensity
mass with no enhancement. (B) Coronal T1-weighted unenhanced image one week post surgery with high signal intensity due to methamoglobin in the surgical cavity
and blood deep to the bone flap.

699
 primary tumor evaluation and staging

the time when benign enhancement, related to surgical trauma, is
unlikely to be present (79).
Although MR imaging may identify residual tumor in the
immediate postoperative period, subsequent follow-up is
mainly dependent on detecting an increasing mass and/or
increasing areas of enhancement. Low-grade fibrillary astro-
cytomas and oligodendrogliomas commonly do not enhance
and therefore it is the increasing areas of altered signal intensity
which are used to detect progression of disease. Fluid-attenuated
inversion recovery sequences are particularly valuable in identi-
fying tumor recurrence adjacent to fluid-filled postsurgical
cavities (Fig. 31.22) (35).
After the fourth day, for up to three months postsurgically, there
can be a very dense area of enhancement around the resection line
preventing recognition of residual tumor (79). Later on, the devel-
opment of enhancement suggests progression to a higher grade of
malignancy. With glioblastoma multiforme, areas of enhancement
separate from the original tumor mass are not an infrequent find-
ing (Fig. 31.23); these foci represent areas of neovascularity (11)
and progressive disease. As well as enhancement at the resection
line, gyriform enhancement may be seen in the adjacent brain,
particularly after temporal lobe resection, which is secondary to
ischemia (79).
Key Points: Postsurgical Change on Magnetic
Resonance Imaging
■ MR imaging is better than CT for assessing the post-
operative site
■ Enhancement on MR imaging may be seen as early as
18 hours postoperatively

(A) (B)

(C) (D)
Figure 31.22 Grade III astrocytoma at one year postresection. (A) and (B) Axial FLAIR MR images with small area of altered signal intensity, equating to tumor in the
medial temporal lobe and thin linear high signal intensity around the resection cavity, indicating possible residual tumor or postsurgical change. (C) and (D) Axial and
coronal images five years postresection show an increase in area of signal intensity change around the resection margin representing recurrence.

700
 primary tumors of the central nervous system
Figure 31.23 One month postresection of Grade IV glioma. Coronal T1-weighted
contrast-enhanced MR image showing thick enhancement around the resection
cavity. Surgical change is indistinguishable from residual disease. Dural enhance-
ment deep to the bone flap is postsurgical in nature. An area of enhancement
which was not present on the preoperative MR indicates an area of neovascularity
and progressive disease lying separate to the original resection site.
■ Enhancement persists for longer on MR imaging than CT, up
to one year
■ Hemorrhage can be separated from residual tumor on MR
imaging
■ Postsurgical change can result in intense ring enhancement
persisting for up to three months
■ New areas of enhancement indicate disease progression
■ Progression is also monitored by extending areas of signal
intensity change on T2-weighted images
■ 18FDG PET may be used to distinguish surgical scarring from
residual disease
Meningeal Enhancement on Postsurgical Magnetic Resonance. Dural
enhancement accompanies the changes in the underlying brain
in the immediate postoperative period. Most commonly this is
limited to the area deep and immediately adjacent to the bone flap
(Fig. 31.21B), but there may be more generalized dural enhance-
ment (Fig. 31.24). It is necessary to recognize that dural thicken-
ing and enhancement may persist for many years following
intracranial surgery. Placement of intraventricular shunts may
also result in thickened and enhancing meninges (73,89). Where
possible, dural enhancement as a complication of surgery needs
to be separated from the dural and leptomeningeal enhancement
(Fig. 31.25) which may occur secondary to metastases of both
intracranial (Fig. 31.25) and extracranial primary malignancies.
Where it is important to know the extent of CSF metastases it is
particularly valuable to image the whole CNS prior to surgery.
Neoplasms adjacent to the meninges may incite a diffuse fibrous
reaction and both the tumor and the meningeal reaction will
Figure 31.24 Axial T1-weighted MR image showing dural thickening and
enhancement 24 hours following insertion of ventriculo-peritoneal shunt.
enhance, making interpretation of the MR images difficult (90).
There are, however, two patterns of meningeal enhancement seen
with metastatic disease:
• Dural/arachnoid pattern
• Pia/arachnoid pattern (90)
The dural/arachnoid pattern follows the dural membrane (Fig.
31.24) and this needs to be differentiated from postsurgical and
post-shunt changes. Postsurgical and post-shunt insertion
enhancement is usually smooth and linear, in recurrence and
malignant involvement dural enhancement is nodular and there-
fore the morphology of the contrast enhancement pattern may be
of value in the differential diagnosis. The pia/arachnoid pattern
follows the surface of the brain and spinal cord, invaginating into
the sulci along the leptomeninges (Fig. 31.25). This appearance is
more likely to represent secondary spread from extracranial
tumors; however, the appearance is non-specific, as it is a common
site of infectious meningitis.
Cytological analysis of the CSF may or may not help in interpre-
tation of the MR findings. The percentage of positive spinal CSF
cytology in cases of primary CNS tumors, with histologically con-
firmed meningeal involvement, varies from 12% to 38%. In glio-
blastoma multiforme, the CSF-positive rate does rise to 63% (90).
In secondary malignancies, seeding to the CSF-positive cytology
occurs in 45% on first puncture, rising to 95% of cases after six
punctures if large volumes are removed and analyzed (91). Patients
with positive CSF cytology may have negative MR findings and
patients with positive MR images may have negative CSF findings.
Gadolinium-enhanced T1 remain the most sensitive of sequences
701
 primary tumor evaluation and staging

(A) (B)

(C) (D)
Figure 31.25 Leptomeningeal metastatic disease is identified as contrast enhancement on (A) axial and (B) coronal T1-weighted MR images, and as high signal intensity
in the surface of the gyri on axial FLAIR images (C) and (D).

for detecting leptomeningeal spread (Figs. 31.25A, B, and Fig.

■ Patients with positive CSF cytology may have a negative MR
31.26B), i.e., at 60% (8,91,92). Although FLAIR sequences will
study
detect metastatic disease (Figs. 31.25C and D), they are not as sen-
■ Positive MR images may be associated with negative CSF
sitive and gadolinium-enhanced FLAIR is of even less value (92).
cytology
■ Gadolinium-enhanced T1 remains the most sensitive
Key Points: Meningeal Enhancement sequence

■ On MR imaging, dural enhancement is usually seen deep to

Radiotherapy and Chemotherapy Changes
the surgical bone flap
Both radiotherapy and chemotherapy may produce iatrogenic
■ Diffuse meningeal enhancement is seen post-surgically and
changes within the brain which need to be differentiated from
also post-insertion of a shunt
progressive malignant disease. There may be focal or diffuse
■ Post-surgical contrast enhancement of the dura may persist
changes in the white matter, vascular occlusion, or damage to the
for many years
cranial nerves, and there is also the potential risk of induction of a
■ Staging of tumors known to metastasise to the meninges is
second malignancy. The incidence of radiation damage is depen-
best performed prior to surgery
dent on the total dose given and the way in which the radiation is
■ Nodular enhancement of the meninges is a good indication of
administered (17). More acute and delayed changes are being seen
tumor spread
with the development of stereotactic radiotherapy and other

702
 primary tumors of the central nervous system
(A)
Figure 31.26 Pineoblastoma. (A) Sagittal T2-weighted MR image with a relatively hypointense mass projecting into an enlarged third ventricle. (B) Coronal T1-weighted
post Gd-DTPA MR image in a second case with an enhancing pineal mass and leptomeningeal metastases at presentation.
localized high-dose regimens. Improvement in long-term survival
of patients treated for brain tumors increases the time available
for the development of late radiation effects (17).
Following radiotherapy, there is usually a latent period before
radiological changes and clinical symptoms develop. Classically
the changes have been characterized as to the time at which they
appear:
• Acute First months
• Early delayed 3 weeks to 3 months
• Delayed 6 months to 2 years (may be as late as
10 or 20 years)
Chemotherapy may potentiate or accelerate the development of
these changes (93). Radiation- and chemotherapy-induced dam-
age closely resemble each other both clinically and radiologically.
Acute Damage
Acute changes are not usually visualized radiographically but, if
seen, they are non-specific. They are thought to be due to local
damage to the capillary endothelium with the development of
vasogenic edema (94). Reactions are usually mild and transient
but diffuse cerebral edema may develop with cerebral herniation
and progression to death. Discontinuation of the treatment in
conjunction with steroids usually results in patient recovery.
Reversible Posterior Leukoencephalopathy Syndrome. Patients
receiving chemotherapy for tumors arising outside the CNS are
more likely to suffer from reversible posterior leukoencephalo-
pathy syndrome (RPLS), otherwise known as posterior reversible
encephalopathy syndrome (PRES), than primary CNS tumors;
this is because of the particular agents that are used. However,
the number of drugs associated with this syndrome is increasing
and some may be used in the treatment of CNS tumors. They
(B)
include intrathecal methotrexate (95) and other drugs used for
acute lymphoblastic leukemia (96), cisplatin, and interferon
alpha (IFN-a). Cisplatin is also used in the treatment of intrac-
ranial germ cell tumors. Presenting symptoms include headache,
confusion, seizures and visual disturbance. Although hyperten-
sion is common it is frequently mild, especially in immune
compromised patients. Imaging findings show a typical sym-
metrical distribution of change in the parietal and occipital
white matter on T2-weighted images (97,98). Fluid-attenuated
inversion recovery sequences will demonstrate gray matter
involvement as well (99). Although there is a predilection for
the posterior circulation, frontal lobe involvement may be seen
in up to 82% of patients (Fig. 31.27) (100). The changes are
secondary to vascular edema from breakdown in cerebral auto-
regulation and leakage of fluid from the capillaries. These
changes are usually reversible vasogenic edema but they may
progress to sub acute infarction. Diffusion-weighted imaging
and calculated ADC maps may be able to discriminate between
vasogenic edema and cytotoxic edema which may herald irre-
versible infarction. Extensive T2 change with high DWI signal
intensity and pseudonormal ADC values are associated with
cerebral infarction and irreversible change (100).
Early Delayed Damage (3 Weeks to 3 Months)
In early delayed damage, patients develop new symptoms of som-
nolence or even a focal deficit. Symptoms either spontaneously
resolve or respond to treatment with steroids. They are presumed
to be secondary to demyelination (17,94). On CT, low-density
change may be seen in the basal ganglia, cerebral peduncles and
deep white matter (17,101). On MR imaging, high signal intensity
change on T2-weighted images with patchy irregular enhance-
ment may be demonstrated separate from the tumor site. Changes
703
 primary tumor evaluation and staging

(A) (B)

(C) (D)

Figure 31.27 Reversible posterior leukoencephalopathy syndrome in a child who had craniospinal irradiation for medulloblastoma and chemotherapy which included
cisplatin. (A) and (B) Extensive white matter change on axial FLAIR images. (C) and (D) Three months later, follow-up imaging shows virtual resolution of white
matter change.

may also occur in the primary tumor, due to necrosis, and should
not be confused with disease progression (102).
Late Radiation Change
Late radiation damage to the white matter may either be focal or
diffuse but both appear to be due to endothelial damage with
preferential involvement of the small arteries and arterioles. This
results in increased capillary permeability and vascular occlusion.
Demyelination and gliosis is followed by axonal loss (17,18,93).
This may eventually lead to necrosis and, when areas of necrosis
coalesce, an enlarging mass may form within the white matter.
Diffuse white matter change usually occurs within six months
to two years of treatment; 70% of changes are seen within this
time-frame. Between 50% and 100% of patients’ scans will show
changes; however, most will remain asymptomatic, only 5% to
14% developing overt clinical symptomatology. This group of
patients develop irreversible dementia, confusion, ataxia and
psychomotor retardation. Older patients seem to be more sus-
ceptible to developing white matter change which is probably
due to acceleration of the normal pathological changes of ageing
and the development of small vessel disease (17,19). Children
treated with radiotherapy, with or without chemotherapy, may
also have learning and speech difficulties. Children and young
infants are particularly susceptible to radiation damage and
radiotherapy is usually avoided in patients under three years of
age (93,103–105).
Imaging. Initially, the changes are seen in the subependymal white
matter but later may extend more peripherally to the gray–white

704
 primary tumors of the central nervous system

(A) (B)
Figure 31.28 Post-radiation white matter change. (A) FLAIR and (B) Axial T2-weighted MR images showing high signal intensity change in the white matter with
preferential involvement of the periventricular areas and sparing of the corpus callosum and basal ganglia.

matter interface, giving a characteristic scalloped appearance and in the subcortical white matter (Fig. 31.29). In children
(Fig. 31.28). More severe changes lead to involvement of the treated for suprasellar tumors, such as craniopharyngiomas and
peripheral arcuate fibers (19). The corpus callosum, internal chiasmatic gliomas, it is important to recognize this pattern of
capsule, posterior fossa structures, and basal ganglia are usually calcification and to distinguish it from recurrent disease. Although
spared. There is no mass effect and the changes are accompanied calcification is almost certainly secondary to necrosis, it is rarely
by widening of the sulci and ventricles as atrophy develops. This symptomatic (17).
is a common finding on both imaging and gross pathology
(18,19). These changes are permanent and irreversible.
Necrotising Leukoencephalopathy. Necrotising leukoencephal- Key Points: Chemotherapy and Radiation Effects
opathy is the most severe form of late delayed white matter
■ Chemotherapy and radiotherapy damage may be focal or
damage and usually occurs in children receiving both radio-
diffuse
therapy and chemotherapy. Pathologically, there is perivascular
■ Injury occurs in the white matter, vessels, and cranial nerves
myelin loss in areas of white matter necrosis, abnormalities of
■ Incidence of radiation damage depends on dose of radiation
small vessels, and numerous axonal swellings. It was first
■ Chemotherapy may potentiate or accelerate radiation damage
observed in patients with acute lymphoblastic leukemia who
■ PRES is associated with chemotherapy. Changes are seen on
were being treated with cranial irradiation and intrathecal
MR imaging in the parietal and occipital lobes
methotrexate (17). Diffuse white matter change is seen on MR
■ Early radiation damage is seen on MR imaging as areas of
imaging and is accompanied by more focal areas of necrosis,
high signal intensity on T2-weighted images in the basal
the borders of which may show enhancement (17,106). Areas
ganglia, cerebral peduncles, and deep white matter
of necrosis may progress to calcification. Drugs associated with
■ Late radiation damage produces diffuse white matter change
necrotising leukoencephalopathy are cyclosporin A, methotrex-
which occurs within six months to two years following therapy
ate, cytarabine, and 5-fluorouracil.
■ Only 5% to 14% of patients are symptomatic with dementia,
Mineralizing Microangiopathy. Mineralizing angiopathy is usually
confusion, etc. The elderly and children are the most susceptible
seen in children treated for extracerebral malignancy but may be
to radiation damage
seen occasionally as a consequence of radiotherapy for intra-
■ White matter change is first seen adjacent to the ventricles; it
cerebral tumors. Approximately 25% to 30% of children treated
then extends peripherally to give a scalloped appearance
with intrathecal methotrexate and cranial irradiation will show
■ Late radiation damage spares the corpus callosum, internal
calcification (26) months after treatment (20). The imaging
capsules, and basal ganglia
changes are most easily recognized on CT as high-density foci due
■ The changes are irreversible
to calcification in the basal ganglia, particularly in the putamina,

705
 primary tumor evaluation and staging
(A)
Figure 31.29 Mineralising microangiopathy, post-radiation for craniopharyngioma. (A) and (B) Unenhanced CT shows dense calcification of the basal ganglia and at
the gray-white matter interface. There is also low density in the white matter and atrophy.
Focal Radiation Necrosis. Focal damage leading to the develop-
ment of a mass may also occur in the first six months to two
years after therapy. Radiation necrosis may, however, occur as late
as 10 years or even later. Changes are irreversible and progressive
and, although the surrounding edema may be reduced with
steroids, if the mass continues to enlarge, surgery will become
necessary.
On CT and routine MR imaging sequences it is impossible to
differentiate focal radiation necrosis from recurrent high-grade
glioma. Following contrast administration on both MR imaging
and CT, an irregular or ring-enhancing mass lesion is demon-
strated which is centered within the white matter (Fig. 31.30C
and D) (17–20). There is a central area of necrosis, which does not
enhance, and surrounding edema, which is demonstrated as low
density on CT and as high signal intensity on T2-weighted MR
images (Fig. 31.30A and B).
To further complicate the diagnosis, radiation necrosis most
commonly occurs either in the site of the previously diagnosed
tumor or adjacent to it. It is also common for radiation necrosis
and tumor recurrence to coexist. It is, however, rare to see radia-
tion necrosis with conventional radiotherapy doses but it is a more
common problem where focally directed high-dose regimens
have been used, e.g., in single fraction radiosurgery including
Gammaknife®, stereotactic fractionated radiotherapy and intra-
lesional brachytherapy. In these cases, it is particularly important
to discriminate between recurrent tumor and radiation-induced
tissue damage.
Advanced imaging techniques have been used to differentiate
recurrence from necrosis. Proton MRS allows assessment of
neuro-metabolism with high choline intensities indicating
706
(B)
tumor progression and low choline indicating radiation necrosis.
DWI has also been shown to be useful in this context, both
alone and in combination with MRS (76,78). 18FDG PET has
had some success in distinguishing between tumor and radia-
tion necrosis with high-grade glioma recurrence exhibiting a
high metabolic rate and necrosis exhibiting a low metabolic
rate (35,107,108). However, it is a costly examination and cur-
rently there is limited clinical access. Seizures during scanning
and inflammation can cause false negative results (82,83).
Although such techniques provide useful additional information,
it is crucial that they are evaluated alongside routine brain
imaging (107,109).
Major Vessel Occlusion. Major vessel occlusion may occur as
a late consequence of radiotherapy (17,107). It is most likely
to be identified in young patients who would otherwise not
be expected to suffer from a stroke. It is particularly seen in
young patients who have had irradiation treatment for cranio-
pharyngiomas, or optic chiasm gliomas. A “Moya Moya-
like” picture may develop with basal ganglia infarction and
narrowing or occlusion of blood vessels demonstrated on
angiography (17).
Telangiectasia and Hemosiderosis. Focally-induced telangiectasia
may be found in and around areas of irradiated brain, particu-
larly in association with radiation necrosis. It is most commonly
seen as a late sequela of the treatment of relatively benign pae-
diatric tumors. On T2-weighted images, telangiectasia is identi-
fied by areas of low signal intensity and closely resembles
cavernous hemangiomas. Chronic hemorrhage leads to hemo-
siderin deposition over the surface of the brain, seen as low
signal intensity on T2-weighting, particularly gradient-echo scans
 primary tumors of the central nervous system

(A) (B)

(C) (D)
Figure 31.30 Radiation necrosis two years following radiotherapy for nasopharyngeal carcinoma. (A) and (B) Axial T2-weighted MR images demonstrating extensive
vasogenic edema. Postcontrast (C) axial and (D) coronal T1-weighted MR images showing irregular enhancement around a central area of non-enhancement.

(Fig. 31.31) (35). Patients develop progressive cranial nerve palsies

and ataxia. Symptomatic hemorrhage may occur occasionally.
Pituitary Gland and Cranial Nerve Damage. Radiation to the
hypothalamic–pituitary area in children may lead to poor growth
of the pituitary gland and short stature (110). Cranial nerve
palsies may occur as a result of stereotactic radiotherapy to an
adjacent area. The optic nerves are most commonly affected.
Second Malignancy. Low doses of radiation have been known
to be associated with the later development of meningiomas
(111) but radiation may induce astrocytomas (Fig. 31.32), fibro-
sarcomas, and other tumors as well. There is a long latent period
of 5 to 30 years and therefore, with increasing survival following
radiotherapy for brain tumors, the number of cases of second
malignancies being reported is increasing (112).
A second malignancy can only be diagnosed if the following
criteria are fulfilled:
• A latent period of several years
• Different histology from the primary tumor
• No genetic or familial disease which predisposes to
malignancy
• The tumor arises within the radiation field Figure 31.31 Siderosis 20 years postradiotherapy for cerebellar pilocytic astrocy-
toma. Patient re-presented with increasing ataxia and cranial nerve palsies. Low
Meningiomas are the most common second malignancies. There signal change is seen on the proton density axial MR image coating the surface of
is an inverse relationship between dose and the time to tumor the brain secondary to hemosiderin deposition from chronic hemorrhage.

707
 primary tumor evaluation and staging
Figure 31.32 Coronal T1-weighted MR image showing glioblastoma arising in
radiation field 15 years after successful treatment of pituitary adenoma.
formation. Additionally, the younger the patient at the time of
irradiation, the shorter the time to the development of second
malignancy (111).
Key Points: Late Radiation Effects
■ Necrotising leukoencephalopathy is the most severe form of
late delayed white matter damage and usually occurs in
children treated with radiotherapy and chemotherapy
■ Mineralising angiopathy is characterized by calcifications in
the basal ganglia and subcortical white matter. It occurs in
children following cranial irradiation and methotrexate
therapy
■ Radiation necrosis has a latent period of six months to two
years
■ The changes of radiation necrosis are irreversible and tend to
be progressive
■ A ring-enhancing lesion with edema is seen on MR imaging
and CT
■ On MR imaging and CT, the appearances of radiation
necrosis are identical to progressive malignancy
■ 18FDG PET, MRS, DWI and other advanced imaging studies
may help to differentiate necrosis from malignancy
■ Major vessel occlusion is a late complication of radiotherapy
■ Telangiectasia may develop in areas of irradiated brain
leading to chronic hemorrhage and superficial siderosis
■ Pituitary gland dysfunction and cranial nerve palsies may
result from radiotherapy
■ Meningiomas are the most common type of second CNS
malignancy
GLIOMA NON-INFILTRATIVE TUMORS
Non-infiltrative Astrocytomas
This group includes:
• Pilocytic astrocytoma—WHO Grade I
• Pleomorphic xanthoastrocytoma—WHO Grade II
• Subependymal giant cell astrocytoma—WHO Grade I
708
These tumors do not diffusely infiltrate the adjacent brain and there-
fore have a better prognosis, which is reflected in their WHO classi-
fication. It cannot be emphasised too strongly that there is a clear
distinction between this group of tumors and the diffusely infiltra-
tive fibrillary astrocytoma, both in histological appearance and prog-
nosis. The prognosis is extremely good, especially if the tumor is
completely resected but even if it cannot be entirely removed (i.e.,
when it extensively involves the structures of the floor of the third
ventricle), the tumor tends to be indolent and slow-growing.
Pilocytic Astrocytoma: WHO Grade I
This is a tumor of childhood, accounting for 30% to 40% of pae-
diatric intracranial tumors with a peak incidence at between 5 and
15 years of age (113). In the past, these tumors have tended to be
called after their site of origin rather than recognising the com-
mon histological origin. The cerebellar hemisphere is the most
frequent site, but it is also found in the floor of the third ventricle,
where it is the most common histology for optic chiasm and hypo-
thalamic gliomas, in the optic nerves, thalamus, and basal ganglia
in the brain stem and rarely in the cerebral hemispheres. Pilocytic
astrocytomas may also be found in the spinal cord (4,113,114).
The presenting symptoms depend on its site of origin.
Whatever their anatomical site, two-thirds of pilocytic astro-
cytomas have a classical imaging appearance: a cyst with mural
nodule (Fig. 31.3) (115). The walls of the cyst are not usually lined
with tumor but the tumor cells secrete a protein-rich material that
forms a collection adjacent to the tumor and compresses normal
brain to create a fluid-filled cavity. The solid component of the
tumor usually enhances intensely but the cyst wall may not. The
cyst’s contents are capable of stimulating vascular proliferation,
which explains the narrow band of enhancement sometimes seen
in the walls (4). Occasionally, cyst degeneration occurs within the
mass itself; in these circumstances the cyst wall will enhance and
contain tumor cells and does require resection. There is no associ-
ated edema and no intratumoral calcification. Necrosis is occa-
sionally seen but is of no prognostic significance. The intense
enhancement seen on CT and MR does not indicate malignancy
itself but is secondary to the high vascularity of the tumor.
18
FDG PET may distinguish between high- and low-grade gliomas
based on the higher uptake by more aggressive lesions (39) but,
although juvenile pilocytic astrocytomas are Grade I, they may show
a high glucose metabolism. This paradoxical 18FDG PET activity
may reflect the unusual vascularity of pilocytic tumors, rather than
tumor activity, as it corresponds to areas of intense contrast enhance-
ment on cross-sectional imaging with CT and MR imaging (116).
Key Points: Pilocytic Astrocytoma
■ Pilocytic astrocytoma is a tumor of childhood with a peak
incidence between five and 15 years of age
■ Pilocytic astrocytoma accounts for 30% to 40% of paediatric
intracranial tumors
■ The majority of these tumors develop in the cerebellar
hemispheres but they also occur in the floor of the third
ventricle and brain stem
■ The CT and MR imaging appearances are those of a cystic
mass with an enhancing mural nodule
■ Calcification is rare
 primary tumors of the central nervous system

Pleomorphic Xanthoastrocytoma: WHO Grade II
This relatively rare (less than 1% of all astrocytic neoplasms)
form of astrocytoma has only recently been recognized as a sepa-
rate biological and histological entity. The importance of making
the radiological diagnosis arises because the cells show marked
pleomorphism on histological examination and may include
bizarre multinucleated giant cells which might be misdiagnosed
as an early-life glioblastoma (117). The majority of cases behave
in a relatively benign way and at present it would seem that total
excision is potentially curative; however, a certain percentage do
recur and pursue an aggressive clinical course with progression to
anaplastic astrocytoma (113).
Pleomorphic xanthoastrocytoma is found most commonly in
children and young adults, two-thirds occurring in patients under
the age of 18 years (113). The tumors are usually peripherally sited
in the cerebral hemispheres (Fig. 31.33) and involve the lepto-
meninges. The most common presentation is with epilepsy.
Computed Tomography and Magnetic Resonance
Imaging Appearances
The diagnosis is suggested by the patient’s age, a relatively long
history of epilepsy, and the superficial location of the lesion
(118). Leptomeningeal involvement may be seen on MR imag-
ing and the dura may be involved, resulting in an enhancing
dural tail sign (Fig. 31.33A) (33). The adjacent skull vault may
be scalloped (Fig. 31.33B) (117). These tumors commonly have
a cystic component lying deep to the solid enhancing mass
(118) and resemble many of the other relatively benign tumors
of childhood, in particular the pilocytic astrocytoma (117).
The mass may be either well-defined or ill-defined; there is
usually some degree of parenchymal infiltration but this fea-
ture is relatively minor. Well-defined contrast enhancement of
the solid portion of the tumor is a fairly constant finding.
Although there may be associated edema and calcification,
these findings are variable.
Treatment and Prognosis
Overall survival has been estimated at 81% at five years (119).
Resection is the treatment of choice. Follow-up imaging should be
tailored to assessment of the operative site for signs of progression
or recurrence. Certain histological features, such as increased
mitotic count, predict an increased likelihood of recurrence; the
presence of necrosis is also a good predictor of the potential to
recur (113).
Subependymal Giant Cell Astrocytoma: WHO Grade I
Over 90% of giant cell astrocytomas are seen in association with
tuberous sclerosis and they occur in up to 16% of patients with
tuberous sclerosis during childhood and early adult life. The diag-
nosis is therefore made in a patient known to have tuberous
sclerosis or where other features of tuberous sclerosis, such as
subependymal hamartomas, are demonstrated on imaging (33).
The tumor typically arises from the head of the caudate nucleus
where it is firmly embedded and grows into the adjacent ventricle
at the level of the foramen of Monro (Fig. 31.34). This usually
results in hydrocephalus. Intense contrast enhancement is com-
mon and although focal calcification may be present it is not as
dense and complete as that which is present in the subependymal

(A) (B)
Figure 31.33 Pleomorphic xanthoastrocytoma in a 12-year-old patient presenting with epilepsy. Peripherally situated enhancing mass with cystic component lying
more centrally. (A) Contrast-enhanced axial T1-weighted MR image with enhancing peripheral nodule and fine dural tail. (B) Axial T2-weighted MR image with solid
(relatively low signal intensity) and cystic (relatively high signal intensity) component and scalloping of adjacent skull vault.

709
 primary tumor evaluation and staging

tubers. Invasion of the brain outside the caudate nucleus does not
occur and this justifies its low WHO classification.
Astrocytomas in Certain Anatomical Sites
Cerebellar Pilocytic Astrocytoma
This tumor most commonly arises in the superior vermis and
extends into the adjacent cerebellar hemisphere but may also arise
within the hemisphere itself. Presentation is due to compression
of the fourth ventricle with the development of hydrocephalus
and therefore headache, nausea, and vomiting.
Computed Tomography Appearances
The solid portion of the tumor is a mural nodule of low density
in comparison with the adjacent brain; it enhances intensely
with contrast medium (115). This is in comparison to medullo-
blastomas, the other common tumor arising within the vermis
in childhood, where the solid portion of the tumor is hyperdense.
Calcification is rare and peritumoural edema is minimal. The cystic
component has a low density on CT.
Magnetic Resonance Imaging Appearances
Because of its multiplanar capacity, MR imaging is able to dem-
onstrate the relationship of the mass to the fourth ventricle, an
important consideration for planning the surgical approach
(Fig. 31.3). The solid mass is of low signal intensity on T1
weighting, high signal intensity on T2 weighting (115) and the
cyst will usually be of higher signal intensity than CSF on both
sequences.
Postsurgical Imaging and Prognosis
If totally excised no other treatment is necessary. Long-term
survival is usually excellent (115,116,120) but there is a subset of

(A) (B)

(C) (D)

Figure 31.34 Subependymal giant cell astrocytoma in a patient with tuberous sclerosis. (A) Axial T2-weighted, (B) post contrast coronal T1-weighted, (C) axial
T1-weighted and (D) postcontrast T1-weighted MR images. Large enhancing intraventricular mass arising from the head of the right caudate nucleus with second
smaller tumor arising from the left. Small subependymal nodules seen projecting into the ventricles, best shown on the axial T2-weighted image (A) (arrows).

710
 primary tumors of the central nervous system
pilocytic astrocytomas which cannot be separated out either histo-
logically or on imaging grounds; these follow an aggressive course.
For this reason, regular follow-up scans are recommended during
the first year and less frequently after that. Histologically, malig-
nant pilocytic astrocytomas have been reported to occur in
patients who have undergone radiation therapy for otherwise
typical pilocytic astrocytomas. There is a latent period of 2 to
52 years and the prognosis is poor (113). There are reported cases
of metastases to distant sites within the CNS, where they tend to
be relatively indolent (Fig. 31.35) (121).
Hypothalamic and Optic Chiasm Glioma: Fibrillary
Astrocytoma and Pilocytic Astrocytoma
Approximately 15% of patients with neurofibromatosis type 1
(NF1) develop pilocytic astrocytomas (4), particularly in the optic
nerve where they are relatively slow growing (122). These tumors
spread along the visual pathways, involving the optic nerves,
chiasm, and tracts and in 50% to 80% of optic pathway tumors
involve the chiasm and hypothalamus (113). Patients usually pres-
ent during the first decade of life, with 65% of children being
under the age of five years. Histologically, most paediatric chias-
matic gliomas are pilocytic astrocytomas; however, in patients
who do not have NF1, a certain percentage will be found to be
fibrillary astrocytomas which unfortunately have very similar
imaging findings but a worse prognosis. The common symptoms
are visual loss and hypothalamic dysfunction but hydrocephalus
may occur due to the mass enlarging up to the level of the fora-
men of Monro.
Gliomas, particularly pilocytic astrocytomas, may arise in the
structures which form the floor of the third ventricle; however,
(A)
Figure 31.35 (A) and (B). Axial T1-weighted MR images post Gd-DTPA. A 12-year-old patient who had a solid pilocytic astrocytoma of the cerebellum resected eight
years previously, now has recurrence at the operative site (A), and metastases in the right temporal horn and suprasellar cistern (B).
because of their tendency to involve adjacent structures it can be
difficult to determine radiologically whether the site of origin is
the chiasm or hypothalamus.
Computed Tomography Appearances
Like all pilocytic astrocytomas, these tumors are of low density
and may or may not enhance with contrast. They may secrete fluid
with cyst formation and cysts may extend into the subarachnoid
space adjacent to the tumor. The absence of calcification in pilo-
cytic astrocytomas may be used to differentiate them from cranio-
pharyngiomas, the other main suprasellar mass found in the
paediatric age group.
Magnetic Resonance Imaging Appearances
The solid component of the mass will be mainly of low signal
intensity on T1-weighted images and high signal intensity on
T2-weighted images and may or may not enhance with IV con-
trast medium (Fig. 31.36). The advantage of MR imaging is its
ability to demonstrate more readily the site of the origin of the
mass and the exact tumor extent. This is particularly valuable for
detecting exophytic components of the tumor which are more
readily resectable.
Treatment and Prognosis
Because of their site, hypothalamic and chiasmatic gliomas are
difficult to completely resect. The advantages and disadvantages
of aggressive surgical therapy, a factor which strongly influences
prognosis, have to be carefully assessed. Despite this they are
relatively benign and patients generally survive for many years;
however, in children under 5 years and adults over 20 years, they
(B)
711
 primary tumor evaluation and staging
Figure 31.36 Pilocytic astrocytoma involving the optic chiasm. Axial postcontrast
T1-weighted MR image showing marked enhancement of the optic chiasm, nerves
and tracts. A large cyst is seen extending laterally. The majority of the cyst wall does
not enhance and will not contain tumor cells.
may behave in a more aggressive manner. There are no definite
clinical, histological or neuro-imaging features that differentiate
between tumors that will behave aggressively and those with an
indolent growth pattern (123).
Neurofibromatosis type 1 optic pathway tumors are particu-
larly indolent and seem to represent a separate subgroup.
Radiologically, optic pathway gliomas in NF1 most commonly
affect the optic nerve which results in fusiform expansion of
the nerve. When the chiasm is involved, it is thickened but the
architecture is preserved. In comparison, non-NF1 patients
have larger more irregular masses with a higher rate of cystic
components and extension outside the visual pathway (122). It
is generally accepted that optic chiasm gliomas in patients with
NF1 do not need to be treated immediately but are best man-
aged by routine surveillance. In patients without NF1, manage-
ment remains controversial. Biopsy may be recommended in
some cases to exclude the possibility of a craniopharyngioma
or germinoma; modern neurosurgical techniques can achieve a
substantial resection and stabilization of disease (124). There
is a response to radiotherapy but the effect of radiotherapy on
the developing brain, particularly in children under the age of
three years, is not to be underestimated and radiotherapy is not
routinely used under five years of age. There is a potential for
severe neuroendocrine damage, especially impaired growth,
reduced intelligence quotient (IQ), development of secondary
malignancy, and vascular occlusion (104). For these reasons,
different chemotherapeutic regimens are being evaluated and
neuroradiological follow-up is used to monitor tumor size.
The MR imaging sequences used should conform to the proto-
cols that are being advised as a part of multicenter trials. If
radiotherapy has been given, radiologists need to be aware of
712
the potential for the development of complications as described
earlier in this chapter. All of these patients require full visual
and endocrine assessment both preoperatively and during
long-term follow-up.
Key Points: Optic Gliomas
■ Optic gliomas may/may not be associated with NF1
■ Optic gliomas spread along optic nerves, chiasm and tracts
■ Fifty percent involve the chiasm or hypothalamus
■ Sixty-five percent of cases are children under the age of five
years
■ The majority of optic gliomas are pilocytic astrocytomas
■ These tumors may form cysts and may/may not enhance
with IV contrast medium. They do not calcify
■ Many tumors, particularly in children with NF1, follow an
indolent course
Brain Stem Glioma
Fibrillary Astrocytoma and Pilocytic Astrocytoma
Brain stem tumors comprise approximately 20% to 30% of infra-
tentorial tumors in children (125,126). Until relatively recently it
was not recognized that brain stem tumors are an inhomogeneous
group of tumors with differing pathological and histological fea-
tures. It has partly been the advances in neuro-imaging which
have led to the identification of different tumor subgroups (127)
with different anatomical locations which are related to a great
variation in prognosis. They may be subdivided into medullary,
pontine, or mesencephalic tumors and tumors associated with
NF1, with further subdivision into focal and diffuse (126,128).
Fibrillary astrocytomas in the pons fare badly, with a mean sur-
vival of two years, whereas focal pilocytic astrocytomas, many of
which are dorsally positioned in the medulla, are more amenable
to surgery (7). Good prognostic indicators associated with brain
stem gliomas include:
• Pilocytic histology
• Located in the midbrain or medulla
• Solid enhancing component of the tumor
• An exophytic element to the tumor
• Site involved amenable to surgery
Diffuse Brain Stem Gliomas
Pontine gliomas are most commonly diffusely infiltrative lesions
causing expansion of the pons (Fig. 31.37) best seen on MR
imaging but also seen as a low-density lesion on CT (7,125).
Focal gliomas in this site are very rare. They rarely enhance on
either modality but when enhancement is present the feature
does not aid in determining prognosis (129). Histologically,
these tumors are almost invariably fibrillary astrocytomas and
theoretically do not require biopsy to confirm the diagnosis. On
MR imaging, the tumor is demonstrated on both T1- and
T2-weighted images but the area of abnormal signal intensity is
more extensive on T2 weighting (125). Areas of hemorrhage and
small cysts may be seen. A common radiological feature, best
seen on MR imaging, is a tendency for the tumor to extend ante-
riorly to wrap around the basilar artery. Imaging in the sagittal
plane is important in displaying the anatomy and involvement
 primary tumors of the central nervous system
(A)
Figure 31.37 Brain stem astrocytoma. (A) Sagittal T1-weighted MR image showing expansion of the brain stem and tonsillar herniation; the tumor is of relatively low signal
intensity and did not enhance after contrast enhancement. (B) Axial T2-weighted MR image showing diffuse expansion of the pons which returns high signal intensity.
of various structures and in aiding radiotherapy planning. The
differential diagnosis of pontine gliomas includes:
• Acute disseminated encephalomyelitis
• Encephalitis
• Osmotic demyelination
• Infarction (rare)
These conditions may usually be excluded on clinical grounds.
Brain stem gliomas, despite their large size at the time of presenta-
tion, commonly have minimal neurological signs which include
isolated cranial nerve palsies or lower long tract signs. Hydroceph-
alus is a late complication. In comparison, inflammatory lesions
and infarcts lead to major neurological deficits with an acute
onset. Unfortunately, inflammatory lesions can have the same
spectra as tumors and MRS cannot therefore discriminate between
the two (130). Acute demyelination shows free diffusion rather
than restricted movement and therefore DWI may be used to dis-
tinguish these entities (131).
Prognosis and Treatment. The prognosis is poor with a median
survival of four months to two years. At present, the majority
of children are treated with radiotherapy and the role of
chemotherapy is being evaluated. The main problem faced in
imaging these children following radiotherapy and chemother-
apy is the inability of CT and MR imaging to differentiate
progressive disease from acute and subacute radiotherapy
change. The patient’s clinical state and imaging appearances may
deteriorate at the completion of such treatment as hyperfrac-
tionated radiotherapy and then may improve without further
intervention. Alternatively, there may be severe clinical deterio-
ration with stable or minimal change in imaging findings.
Contrast enhancement on MR imaging may be due to radiation
necrosis or progressive disease. 18FDG PET may be able to identify
(B)
tumor progression which may occur despite minimal change in
tumor size (132). 18FDG PET, single photon emission computed
tomography (SPECT), and MRS may also be used to separate
radiation-induced neurotoxicity from active tumor (125,133).
Focal Brain Stem Gliomas
In the midbrain and medulla, focal gliomas are more common
than the diffusely infiltrative type. They show similar imaging
characteristics to pilocytic astrocytomas found elsewhere in
the brain. The presence of an intensely enhancing solid mass in
the medulla, which may have a major exophytic component, is
suggestive of pilocytic astrocytoma and indicative of a better
prognosis. Similarly, tumors arising at the cervicomedullary
junction (127) or within the midbrain have a relatively long-term
survival (126). One half of focal midbrain gliomas arise in the
tectal plate, and 83% of these will present with hydrocephalus
(126). The other 50% of tumors arising in the tegmentum
present with long tract signs or cranial nerve palsies. The
majority of midbrain tumors are focal with sharply-defined
margins and show intense contrast enhancement and some
have a cystic component. Histologically, many of these astro-
cytomas are found not to be pilocytic but still follow a benign
indolent course.
Treatment and Prognosis. Surgical resection, where possible,
is the treatment of choice for well-defined enhancing gliomas
arising in the midbrain, medulla or cervicomedullary junction
(126,127). Involvement of adjacent structures may make this
practically impossible and results are therefore dependent on
the experience and skill of the surgeon. The presence of a
large exophytic component will aid surgical resectability. Tec-
tal plate gliomas may be sufficiently benign only to require
shunting (126).
713
 primary tumor evaluation and staging

Radiologically, it is important to identify and carefully define
the anatomy of the subgroups of brain stem gliomas. If not sepa-
rately identified, focal pilocytic astrocytomas may be treated with
radiotherapy. Because these tumors have a good prognosis,
affected children tend to survive long term and therefore will
develop the serious sequelae of irradiation unnecessarily, which
include intellectual difficulties, epilepsy, hearing loss, and growth
retardation.
Key Points: Brain Stem Gliomas
■ Brain stem gliomas may be fibrillary astrocytomas or pilocytic
astrocytomas
■ There is a need to separate diffuse fibrillary astrocytomas from
focal pilocytic astrocytomas because the latter are amenable to
surgery
■ Fibrillary astrocytomas are found mainly in the pons and
produce diffuse expansion
■ Brain stem fibrillary astrocytomas do not usually enhance
with IV contrast media and may be missed on CT
■ Hydrocephalus is a late complication of pontine gliomas
■ Fibrillary astrocytomas have a poor prognosis with a mean
survival of two years
■ Focal treatment is with radiotherapy and chemotherapy
■ Pilocytic astrocytomas are most commonly found in the
midbrain and medulla
■ They show intense contrast enhancement and may have a
major exophytic component
■ Tumors located in the midbrain or medulla are treated by
surgical resection
Ependymoma: WHO Grades II to III
Age and Site
Intracranial ependymomas are infrequent CNS tumors account-
ing for 1.2% to 9% of all intracranial masses and are mainly found
in the paediatric age group but there is a second peak in posterior
fossa ependymomas in the mid-30s. Seventy percent of these
tumors are located in the posterior fossa where they arise from the
ependymal cells lining the fourth ventricle, 30% are supratento-
rial where they are more commonly extraventricular in location
arising from ependymal cells in the white matter (134). Typically,
they are slow-growing neoplasms but rarely they show progressive
anaplasia, with an ultimate histological picture reminiscent of
glioblastoma multiforme (25,135). Although subarachnoid seed-
ing does occur, it is rare at initial presentation and is more com-
monly found at the time of recurrence (28,135–137). Mean time
from diagnosis to dissemination is 6.8 years (138). Propensity to
seed also increases with histological grade and younger age.
Posterior Fossa Ependymoma
The peak incidence is between one and five years of age.
Ependymomas account for 15% of all posterior fossa tumors in
childhood and 30% of CNS tumors in under three-year-olds
(29,135). They are relatively soft tumors which grow to fill the
fourth ventricle and extend out through the foramina of
Luschka and Magendie into the adjacent subarachnoid spaces
(Fig. 31.38). There is little invasion of adjacent structures, but
involvement of the floor of the fourth ventricle and infiltration
around the cranial nerves limits the ability to totally resect the
tumor (135–137). Total removal is rare and recurrence high.
The age of the patient, the site of tumor and morphological
appearances suggest the diagnosis of ependymoma.

(A) (B)
Figure 31.38 Fourth ventricular ependymoma. (A) Postcontrast sagittal T1-weighted MR image with an irregularly enhancing mass situated within an expanded and
obliterated fourth ventricle. The lateral extension of the mass has displaced the brain stem away from the midline, giving the impression on this single slice, of brain stem
involvement. There is also extension through the foramen of magendie. (B) The axial T2-weighted image demonstrates the large lateral extension through the foramen
of Luschka and the brain stem displacement.

714
 primary tumors of the central nervous system
Computed Tomography Appearances
The most characteristic CT appearance is that of a fourth ven-
tricular tumor of mixed density, 25% to 50% of which will show
chunks or small punctate areas of calcification and a more vari-
able percentage will show cystic elements. The mass typically
extends through the lateral recesses or foramen of Magendie
(134,139). Up to 70% will show irregular enhancement with con-
trast medium (29), but the pattern is non-specific (134). There is
commonly hydrocephalus at the time of presentation.
Magnetic Resonance Imaging Appearances
Magnetic resonance imaging has the ability to demonstrate the
site of origin of the tumor and its relationship to the fourth ven-
tricle and may therefore be able to differentiate ependymoma
from one of the other posterior fossa tumors of childhood—the
medulloblastoma. Both of these tumors may have similar signal
intensity characteristics, but medulloblastoma more commonly
arises from the roof of the fourth ventricle and the vermis, whereas
the ependymomas more commonly arise from the floor of the
fourth ventricle. Multiplanar imaging is of particular value, espe-
cially sagittal sequences, but differentiation can still be difficult
(140). The triangular shape of the ependymoma conforming to
the outline of the fourth ventricle (Fig. 31.38A), in comparison to
the more rounded shape of the medulloblastoma, and extension
out of the fourth ventricle are helpful radiological signs (139).
Ependymomas show mixed signal intensity on T1- and
(A) (B)
Figure 31.39 Metastases from a fourth ventricular ependymoma. (A) Sagittal T2-weighted MR image, (B) and (C) postcontrast T1-weighted sagittal MR images showing
metastatic seedings.
T2-weighted images, cysts may be demonstrated and also areas of
hemorrhage (141). Low signal intensity may be present secondary
to irregular calcification. Contrast enhancement is usually present
and inhomogeneous. The MR imaging examination should be
directed towards determining the site of origin of the tumor and
the presence or absence of spinal metastases. As yet, MRS has not
been able to reliably determine the histological type of a posterior
fossa mass prior to surgery.
Treatment, Prognosis, and Follow-up Imaging
These tumors are commonly believed to have a good prognosis
because of their benign histology. However, long-term survival is
variable and can be particularly poor in the younger age group
(136). Prognosis is mainly affected by resectability rather than
histological grade with low- and high-grade tumors having similar
five-year survival rates (136). Tumors arising from the roof of the
fourth ventricle, the least common site, are the most easily resect-
able and have the best prognosis. Tumors arising laterally and
extending through the foramen of Luschka are difficult to sepa-
rate from adjacent cranial nerves and vessels and have the worst
prognosis (142). Follow-up imaging is to monitor recurrence at
the primary site where progression of disease most commonly
occurs. The reported prevalence of spinal seeding and the timing
of its occurrence is variable; some authors indicate that it mainly
occurs at the time of recurrence and others that it is more
common at the time of presentation (Fig. 31.39) (136,137). Some
(C)
715
 primary tumor evaluation and staging

authors have indicated that only 6% of infratentorial ependymo-
mas develop spinal seedings (136). It has not been shown conclu-
sively that either cranial spinal irradiation or prophylactic spinal
irradiation reduces the incidence of seeding. The place of prophy-
lactic radiation is therefore uncertain; however, postsurgical
radiotherapy for non-anaplastic ependymomas seems to give the
greatest chance of long-term survival (135).
Supratentorial Ependymoma
Approximately 75% of supratentorial ependymomas are extra-
ventricular (143) and are therefore difficult to differentiate
from other brain neoplasms including gliomas and primitive
neuroectodermal tumors. More than 70% of anaplastic
ependymomas are located supratentorially (Fig. 31.40) and
supratentorial ependymomas are reported to have a worse prognosis
than the infratentorial group (136). There is a peak incidence
between one and five years.
Computed Tomography Appearances
Supratentorial ependymomas are usually large tumors situated in
the white matter of the parietal or frontal lobe. The characteristic
site is adjacent to the trigone of the lateral ventricle (139). On
unenhanced images they are iso- or hypodense to normal brain
and show a variable contrast enhancement pattern, either ring
enhancement, homogeneous enhancement or less commonly an
irregular diffuse pattern is seen. Dense punctate calcification is
found in 50% of cases and is a useful sign for suggesting the
correct diagnosis. A cystic element is seen in 70% of cases and,

(A) (B)

(C) (D)
Figure 31.40 Anaplastic ependymoma in a 4-year-old girl arising adjacent to but also involving the lateral ventricle. (A) and (B) Coronal T2-weighted MR images showing
increased vascularity and mixed signal intensity; (C) axial T1-weighted image showing evidence of recent hemorrhage and (D) postcontrast axial T1-weighted image
with extensive intense enhancement.

716
 primary tumors of the central nervous system
although these tumors are hemorrhagic, this feature is not usually
identified on CT (139,142).
Magnetic Resonance Imaging Appearances
The site of the tumor and its relationship to the ventricle is better
delineated on MR imaging. The presence of multiple signal inten-
sity voids, indicating increased vascularity (Fig. 31.40A) and areas
of acute and chronic hemorrhage (Fig. 31.40C), are more com-
monly identified on MR imaging than CT. There are, however,
no signal intensity characteristics to allow ependymomas to be
differentiated from other gliomas (141).
Surgery is the usual treatment of choice but the natural history
is recurrence of disease at the primary site with a 45% survival
rate at five years.
Subependymomas: WHO Grade I
Subependymomas arise either adjacent to the fourth ventricle, or
to lateral ventricles. They are covered by a layer of intact ependyma
and are thought to develop from subependymal glia although the
exact cell of origin seems to be debatable (4); they are histologi-
cally distinct from ependymomas. They are slow-growing and
non-invasive, and were initially recognized as incidental autopsy
findings. However, with the advent of MR imaging, they are
increasingly being recognized as asymptomatic masses. If they
grow to sufficient size they may cause obstructive hydrocephalus,
a particular feature in those arising adjacent to the foramen of
Monro (Fig. 31.41) (33).
On MR imaging and CT, they are diagnosed by their site of
origin (141). They are usually nodular tumors which are partly
calcified and are usually non-enhancing with contrast media,
particularly if they are supratentorial. Surgery is usually curative
but, if asymptomatic, they may be managed conservatively.
Figure 31.41 Subependymoma. Coronal T1-weighted MR image post Gd-DTPA
with a mixed signal intensity mass in the right lateral ventricle involving the foramen
of Monro. There is no contrast enhancement.
Key Points: Ependymomas
■ Ependymomas are a paediatric tumor of which 70% are
infratentorial and 30% are supratentorial
■ Infratentorial tumors are nearly all intraventricular
■ Supratentorial tumors are commonly extraventricular
■ The best diagnostic signs on imaging are identification of the
site of origin and the characteristic local extension outside
the confines of the fourth ventricle
■ Calcification is present in 25% to 50% of both infra- and
supratentorial masses
■ On MR imaging there is heterogeneity of signal intensity due
to cysts, hemorrhage, and calcification
■ The prognosis of ependymomas mainly depends on
resectability
■ Recurrence usually occurs at the primary site
■ Spinal seeding most frequently occurs at the time of recurrence
Choroid Plexus Tumors
Age and Site
Choroid plexus tumors are most commonly papillomas, WHO
Grade I, but 20% to 40% are choroid plexus carcinomas, WHO
Grade III (144). They account for less than 1% of intracranial
tumors overall but in children they account for 10% to 20% of
intracranial tumors. They are most commonly seen arising from
the glomus of the choroid plexus in a child under the age of five
years. They are usually accompanied by four-ventricular hydro-
cephalus, which is now thought to be secondary to a combination
of overproduction as well as impaired circulation of CSF due to
adhesions from previous hemorrhage (7).
Imaging Appearances
On CT, these tumors are well-defined, lobulated, and hyperdense
with variable calcification. Magnetic resonance imaging better
delineates their intraventricular nature. Cerebrospinal fluid trapped
between the papillae gives most choroid plexus papillomas a some-
what mottled appearance on T1- and T2-weighted images (29).
They enhance intensely with IV contrast medium (Fig. 31.42).
Although relatively benign, the choroid plexus papilloma may
seed through the CSF. The malignant choroid plexus carcinoma is
usually seen under the age of one year. These more aggressive
tumors invade adjacent brain and metastasise early in the disease
process.
There is a second peak incidence of choroid plexus papillomas
in young adults. Rather than being found in the lateral ventricle,
these smaller tumors originate in the fourth ventricle and extend
into the lateral recess and cerebellopontine (CP) angle cistern
(145). In this situation, patients are less likely to develop hydro-
cephalus. Treatment of choroid plexus papilloma is by surgery
and recurrence is unlikely.
NON-GLIAL TUMORS
Neuronal and Mixed Neuronal Glial Tumors
Tumors that arise from neuronal tissue are relatively benign and
their incidence is 1 in 100 in comparison to glial tumors. Diagnosis
717
 primary tumor evaluation and staging

Figure 31.42 Choroid plexus papilloma in the lateral ventricle. Postcontrast axial T1-weighted MR images showing a multiobulated mass with contrast enhancement; the
ventricles are moderately enlarged.

is usually suggested by their site and the young age of the Table 31.3 WHO Grading System (Malignancy Scale)
patient at presentation. In general, even if only partially excised, of Non-Glial Tumors (3)
there is a good prognosis and no additional treatment is neces-
Tumor Grade I Grade II Grade III Grade IV
sary. The importance of recognizing neuronal tumors is that
radiotherapy is not generally indicated and aggressive treat- Gangliogliomas • • Very rare Very rare
ment needs to be avoided (3). Unfortunately, it is not always Gangliocytomas •
Desmoplastic infantile •
possible to identify the tumor type radiologically prior to sur-
ganglioglioma
gery. The different tumors included in this group are shown in Central neurocytoma •
Table 31.3. Dysembryoplastic •
neuroepithelial
Ganglioglioma and Gangliocytoma: WHO Grades I and II tumors (DNT)
Gangliogliomas and gangliocytomas are rare tumors of young Lhermitte duclos •
adults, with 80% presenting under the age of 30 years, usually
with a long history of partial seizures (146). Gangliocytomas are or partially cystic but usually appear well-defined (Fig. 31.43).
histologically composed of large multipolar neurones. Ganglio- Enhancement patterns are variable and they cannot be differen-
gliomas show an additional neoplastic glial component (4). The tiated from the low-grade (benign) astrocytomas of childhood
tumors occur peripherally in the hemisphere but may be found prior to surgery. Calcification may be seen in up to 50% of cases
in the cerebellum and, like other benign peripheral tumors, may (147,148). Total resection, where possible, is indicated in these
remodel the adjacent skull vault (Fig. 31.43). They may be solid patients (Fig. 31.43).

718
 primary tumors of the central nervous system

(A) (B) (C)

(D) (E)
Figure 31.43 Ganglioglioma in a nine year old child with a long history of clumsiness, minor behavioral problems and six months of increasing headache. (A) Coronal
T1-weighted MR image showing mixed signal intensity mass, the whole of the right frontal bone has been remodeled altering the shape of the skull and face. (B) Axial
T1-weighted gadolinium-enhanced MR image showing an enhanced mass in the right frontal lobe (C) T2-weighted axial MR image showing a mixed but mainly high
signal intensity lesion arising in the right frontal lobe but extending under the falx. (D) Postcontrast axial T1-weighted MR image and (E) axial FLAIR postsurgery
follow-up scans at six years showing no residual tumor but gliotic change adjacent to the resection margin. The significance of the lesion in the left thalamus is unknown
at the present time.

Desmoplastic Infantile Ganglioglioma: WHO Grade I Central Neurocytoma: WHO Grade I

Desmoplastic infantile gangliogliomas have recently been sepa-
rated from gangliogliomas as a subgroup of tumors found in
infants and young children under two years of age. The lesions are
usually massive at presentation with 60% involving more than
one lobe of the hemisphere (Fig. 31.44). The infants present with
increasing head size (149). The majority of the mass is a large cyst
with a solid enhancing component commonly situated adjacent to
the meninges (150). There is usually a fibrocartilagenous element
and the combination of different tissues gives a heterogeneous
appearance on MR imaging. The more solid component is isoin-
tense to cortex on T1 and T2; this may allow differentiation from
a pilocytic astrocytoma where the solid component is of high
intensity on T2.
A significant number of these tumors were formerly misdiag-
nosed as intraventricular oligodendrogliomas. They occur in
children and young adults and usually present with symptoms
and signs of raised intracranial pressure due to obstructive
hydrocephalus (151–153). They arise from the septum pellu-
cidum adjacent to the foramen of Monro and grow in a lobu-
lated fashion within the ventricle. They do not seed into the
subarachnoid space. On CT, they are relatively dense and partly
calcified in the majority of cases. On MR imaging, they have
mixed signal intensity on T1- and T2-weighted images and may
show hemorrhage and cyst formation (154). Contrast enhance-
ment varies from none to extensive but is usually inhomoge-
neous (151–153).

719
 primary tumor evaluation and staging

(A) (B)

(C) (D)
Figure 31.44 Desmoplastic infantile ganglioglioma. (A) Coronal T2-weighted MR image, (B) axial FLAIR, (C) pre Gd-DTPA and (D) post Gd-DTPA T1-weighted coro-
nal MR images. Massive tumor occupying left frontal and temporal lobes which is expanding the left hemicranium. Heterogeneity of signal intensity is pronounced. The
FLAIR sequence (B) demonstrated a significant cystic element; only a small area of the tumor shows enhancement.

Dysembryoplastic Neuroepithelial Tumors: WHO Grade I Lhermitte-Duclos Disease (Dysplastic Cerebellar

Dysembryoplastic neuroepithelial tumors (DNT) are a group of
supratentorial cortical benign lesions which superficially resemble
astrocytomas, oligodendrogliomas, or mixed tumors and may be
associated with cortical dysplasia (155). The diagnosis should be
suggested when a lesion is detected peripherally in the hemisphere
of a patient with partial seizures which have usually commenced
before the age of 20 years. They are most commonly found in the
temporal lobe, where they may cause remodeling of adjacent
bone. On MR imaging, they are of low signal intensity on T1 and
high signal intensity on T2 (Fig. 31.45) and commonly have a
multicystic appearance. Some show enhancement with contrast
and evidence of previous hemorrhage. There is usually little or no
mass effect and no edema (156,157). On CT, they are hypodense
and may show calcification.
Gangliocytoma): WHO Grade I
This extremely rare tumor is found in the cerebellum where there
is diffuse overgrowth of the affected hemisphere and a coarse
gyral pattern. Histologically, there is a characteristic appearance
secondary to the dysmorphic cerebellar folia and what has been
referred to as the appearance of an inverted cerebellar cortex (4).
Although it is hamartomatous, it gradually enlarges with time
and does not usually present until adult life. On MR imaging,
there is a “stripey” appearance to the brain due to the enlarged
folia and bands of abnormal myelination (Fig. 31.46). There is no
enhancement. There is an association with Cowden’s syndrome,
which is frequently caused by a mutation on the PTEN/MMAC1
gene (158), in approximately 50% of patients. There is a frequent
association with an area of cortical dysplasia (155).

720
 primary tumors of the central nervous system

(A) (B)
Figure 31.45 Dysembryoplastic neuro-epithelial tumor (DNT). A peripherally sited tumor with little mass effect and pronounced low signal on (A) axial T1-weighted
MR image and slightly raised signal intensity on (B) an axial FLAIR image.

(A) (B)

(C) (D)
Figure 31.46 Lhermitte Duclos. (A) Coronal T2-weighted, (B) coronal FLAIR, (C) axial T2-weighted, and (D) coronal T1-weighted MR images demonstrating “stripey”
appearance of the cerebellum due to dysmorphic cerebellar folia.

721
 primary tumor evaluation and staging
Key Points: Neuronal Tumors
■ Neuronal tumors are a relatively newly described entity
■ They are out-numbered by glial tumors 100:1
■ Most neuronal tumors present in children and young adults
with a history of epilepsy
■ It is important to recognize their benign nature to provide
appropriate management
■ The majority are difficult to differentiate from other relatively
benign glial tumors of childhood on radiological grounds
Lymphoma
Primary CNS lymphomas affect three main categories of
patient:
• Patients with AIDS who have an average age at presentation
of 33 years
• Patients who are immunocompromised, recipients of
organ transplants (presenting on average at 37 years)
and patients with inherited immunodeficiency, presenting
at a mean age of 10 years
• Immunologically normal patients where the peak inci-
dence at presentation is in the sixth and seventh decades
There has been a 10-fold increase in intracerebral lymphoma
between 1973 and 1992 from 2.5 to 30 cases per 10 million. The
main increase has been seen in patients with AIDS where it is
significantly more common than in the general population but
does not usually develop until the late stage. In the immuno-
logically normal age group, there has been an increase in the
(A)
Figure 31.47 Primary cerebral lymphoma. (A) Axial T2-weighted MR showing a large mass crossing the corpus callosum anteriorly with a second lesion in the left basal
ganglia. They are isointense with gray matter, typical of lymphoma. There is surrounding high signal intensity edema. (B) Second case of primary lymphoma: axial
contrast-enhanced T1-weighted MR image showing solid enhancement of basal ganglia and periventricular lesions.
722
incidence of lymphoma but the degree varies with different
series (159–161).
The cellular origin of this tumor is controversial but 98% are
malignant B cell lymphomas and are thought to arise from the
periadventitial cells in the perivascular spaces of Virchow–
Robin (160).
Computed Tomography Appearances
The usual appearance on CT of intracerebral lymphoma is that
of a relatively well-defined isodense or hyperdense mass in com-
parison to adjacent gray matter. The mass shows homogeneous
intense contrast enhancement (160,162) and multiple lesions at
presentation have been reported in between 11% and 53% of
cases (160). In contrast to most intracranial neoplasms, these
tumors commonly abut the ventricular margin or the meninges.
Tumor location is the most characteristic finding on imaging
(162). In common with other small cell tumors with a high
nuclear to cytoplasmic ratio, these tumors are commonly of high
density on CT and either isointense or of relatively low signal
intensity on T2-weighted images.
Magnetic Resonance Imaging Appearances
Magnetic resonance imaging in multiple planes enables the rela-
tionship of the tumor to the basal ganglia and corpus callosum to
be better defined (Fig. 31.47). Although the tumor margins appear
well defined, as with gliomas, the area of altered signal intensity
and enhancement does not delineate the true extent of tumor cells
(160). On T2-weighted images, an area of relatively low intensity
(Fig. 31.47) is seen which corresponds to areas of enhancement
seen with gadolinium on T1-weighted images (Fig. 31.47B) (7).
(B)
 primary tumors of the central nervous system

In AIDS-related CNS lymphoma, ring enhancement seems to
be a common feature (160,163) with more extensive edema. How-
ever, the tumor’s periventricular position, especially if there is
subependymal spread, (162,163) is one of the best indicators of
histological type.
The imaging characteristics of lymphoma on CT and MR over-
lap with those of other intracranial masses, e.g., metastasis, high-
grade gliomas, and even meningiomas. In AIDS patients, it can
be difficult to differentiate lymphoma from toxoplasmosis. The
usual clinical course is to treat for toxoplasmosis and monitor
response. These lymphomas are highly malignant and grow
quickly; therefore lack of response should be appreciated sooner
rather than later, within 10 to 14 days. Single photon emission
computed tomography (SPECT) and MRS have been reported as
being able to discriminate between lymphoma and toxoplasmosis.
Although hemorrhage is more common in AIDS-related lym-
phoma than in lymphomas in non-immuno-compromised
patients, the presence of hemorrhage and necrosis is usually more
indicative of the presence of toxoplasmosis (163). A useful imag-
ing finding in lymphoma is enhancement along the perivascular
spaces (Fig. 31.48A and B), an imaging finding only otherwise
reported in sarcoidosis and not seen in toxoplasmosis.
Treatment and Prognosis
Stereotactic biopsy is still necessary to make a firm diagnosis of
lymphoma and resection has little or no place. There can be very

(A) (B)

(C) (D)
Figure 31.48 Intracerebral lymphoma in a patient with AIDS. (A) and (B) Axial T1-weighted MR images showing linear or punctate enhancement along perivascular
spaces on post Gd-DTPA. (C) and (D) Diffuse high signal intensity change is shown on FLAIR images.

723
 primary tumor evaluation and staging

rapid response to steroid therapy on MR imaging and CT, and
these tumors are initially radiosentive. However, prognosis
remains poor with early recurrence usually occurring at the
primary site. The mean survival rate is between 15 and 20 months,
but systemic chemotherapy combined with radiotherapy has
recently increased survival rates.
Key Points: Lymphoma
of 3 and 12 years; boys are affected more than girls, with a ratio of
3:1 (25,139). They are usually midline vermian tumors but up to
40% may be found more laterally in the cerebellar hemispheres.
This eccentric position is more common when a medulloblastoma
is found in a young adult (166). As one of the common posterior
fossa tumors of childhood, an attempt may be made to differenti-
ate it radiologically from the juvenile pilocytic astrocytoma (JPA)
and the rarer ependymoma.

■ Cerebral lymphoma lesions are typically periventricular and Presentation

found within the basal ganglia The history of headache, nausea, and vomiting is usually short –
■ Intense contrast enhancement of the central area of the lesion less than a month – reflecting the rapid growth of these tumors
is seen on CT and MR imaging and their site in the posterior fossa. Children appear generally
■ Areas of enhancement do not delineate the extent of tumor unwell in comparison to pilocytic astrocytoma where the history
accurately of symptoms is usually a lot longer.
■ Enhancement along perivascular spaces suggests lymphoma
or sarcoidosis Computed Tomography Appearances
■ The central area of altered signal intensity is relatively low on The most common appearance is of a hyperdense, relatively
T2-weighted imaging well-defined, and commonly rounded tumor situated in the
■ AIDS-related lymphoma is difficult to differentiate from midline and projecting into the fourth ventricle (Fig. 31.49)
toxoplasmosis on MR imaging (139). The fourth ventricle appears as a thin crescent of
■ SPECT or MRS can discriminate toxoplasmosis from hypodensity anterior to the mass. Compression of the fourth
lymphoma ventricle leads to enlargement of the other three ventricles.
■ Lymphoma is not amenable to surgery but initially there is There may be areas of relatively low density within the mass
good response to steroids, radiotherapy, and chemotherapy secondary to cyst formation and necrosis and, although there is
■ Early recurrence is seen at the primary site usually homogeneous contrast enhancement, it can be very
variable on CT and MR imaging (167). Calcification does occur
Embryonal Tumors: WHO Grade IV in between 10% and 20% of cases (139,166). Hemorrhage is
Embryonal tumors are a group of highly malignant neoplasms very uncommon.
which form a significant fraction of paediatric brain tumors. The
cell of origin and histopathological classification of CNS embryonal
cell tumors remains controversial but histologically they are com-
posed of small round cells with a high nuclear-to-cytoplasmic ratio.
This histological feature has been suggested as the cause of the typi-
cal radiological features common to this group of tumors. The most
common is the cerebellar medulloblastoma, which accounts for
80% of CNS primitive neuro-ectodermal tumors (PNET) (164).
Other tumors included in this group are ependymoblastomas,
neuroblastomas, supratentorial PNETs, teratoid/rhabdoid tumors,
medulloepithelioma, and pineoblastomas.
All of these tumors are highly malignant but, although atypical
teratoid/rhabdoid tumors and medulloepitheliomas have a simi-
lar radiological appearance to medulloblastomas and supratento-
rial PNETs, they form a distinct subset with a younger onset (mean
age 16.5 months) (165), different histology, and worse prognosis.
They do not respond to standard medulloblastoma therapy and
patients usually die within a year of diagnosis.
All embryonal tumors grow rapidly and disseminate throughout
the CSF pathways, with 64% to 100% of cases showing seeding at
postmortem (139); 20% will have subarachnoid intracranial spread
at presentation and there is a similar incidence of spinal subarach-
noid spread detected on MR imaging (164). Medulloblastomas
may also metastasize to areas outside the CNS, particularly to bone,
an unusual feature for a primary CNS tumor.
Figure 31.49 Unenhanced axial CT of a cerebellar medulloblastoma. There is a
Cerebellar Medulloblastoma: WHO Grade IV predominantly hyperdense mass in the vermis of the cerebellum and edema in
Medulloblastomas constitute 15% to 20% of intracranial neo- surrounding brain. The fourth ventricle is compressed and difficult to identify.
plasms in children and are most commonly seen between the ages There is early enlargement of the third and lateral ventricles.

724
 primary tumors of the central nervous system

The other common posterior fossa tumor of childhood which
needs to be distinguished from the medulloblastoma preopera-
tively is the JPA. It is typically hypodense, rather than hyperdense,
prior to contrast enhancement and the solid part of the tumor
uniformly enhances. The presence of a cyst, the margins of which
do not enhance, assists with the diagnosis of JPA; ependymomas
more commonly calcify.
Magnetic Resonance Imaging Appearances
Magnetic resonance imaging allows better delineation of the tumor
and its relationship to the fourth ventricle. Medulloblastomas are
typically well defined, particularly in younger patients, and arise
from the roof of the fourth ventricle and, although they may extend
through the foramen of Magendie, do not extend into the lateral
recess. In contrast, ependymomas arise from the floor of the fourth
ventricle and commonly extend laterally. Ependymomas tend to
conform to the triangular shape of the fourth ventricle, whereas
medulloblastomas usually have a more rounded shape. On
T1-weighted images, the solid component of the mass is iso- or
hypointense in relationship to cortical gray matter. In contradis-
tinction to most CNS tumors, the solid component of medulloblas-
tomas may be of similar signal intensity to gray matter on
T2-weighted images rather than being of increased signal intensity
(Fig. 31.50A and B). Areas of mixed signal intensity may be seen in
relationship to cysts and necrotic areas (167). Cerebellar astro-
cytomas are usually hyperintense and the appearance on T2-weighted
MR imaging may therefore be a useful discriminator. Homo-
geneous contrast enhancement has been described (Fig. 31.50D)

(A) (B)

(C) (D)
Figure 31.50 Cerebellar medulloblastoma. (A) Axial and (B) sagittal T2-weighted MR images showing a ball shaped mass lying in the fourth ventricle, isointense with
brain. Surrounding hyperintensity is consistent with edema in the cerebellum. (C) and (D) Pre- and post Gd-DTPA axial T1-weighted MR images. The mass demonstrates
enhancement with well-defined margins.

725
 primary tumor evaluation and staging

but irregular and minimal enhancement also occurs (167).

Metastatic disease may be demonstrated as an irregular, thin layer
of enhancement over the cerebral and cerebellar hemispheres cor-
responding to the sugar-coating appearance found at surgery or
nodular areas of enhancement anywhere in the CSF pathways.
Atypical findings, including cyst formation, calcification, and
cerebellar hemispheric location, are more common in adolescents
and young adults (166).

Radiological Staging Prior to Surgery

In no other group of tumors is it more important to fully assess the
whole CNS prior to surgery, and the advent of MR has allowed this
to be performed non-invasively. Unfortunately, this means a
lengthy examination in a group of patients who commonly do not
tolerate MR imaging well even for short periods of time. Children
also present acutely and there is a need to operate quickly, but even
so, every attempt should be made to obtain a full MR examination
prior to surgery although this frequently necessitates a general
anaesthetic. Contrast-enhanced MR imaging is now the investiga-
tion of choice for detecting metastases (168). Imaging of the whole
head and spine, both pre- and post contrast medium, is recom-
mended. Triple-dose gadolinium increases the detection rate, but
even normal lumbar nerve roots will enhance with this high dose
of contrast medium and this may make interpretation difficult.
The presence of metastases, either over the brain itself or within
the spinal canal at the time of diagnosis, is indicative of a worse
prognosis and necessitates the use of a more aggressive treatment
protocol. Leptomeningeal metastatic disease may be seen as either
linear enhancement over the surface of the brain and spinal cord
Figure 31.51 Contrast-enhanced sagittal T1-weighted MR image showing
or as a nodular pattern (Fig. 31.51). The lesions may be small and leptomeningeal metastases on the surface of the spinal cord from a PNET.
difficult to detect. If scanning of the spine is left until the post-
operative period, blood spilt within the subarachnoid space makes
interpretation of images difficult and can lead to error in diagno- able to detect residual and recurrent disease outside the enhancing
sis of metastatic disease (169). If for any reason the spine cannot tumor bed (133).
be imaged prior to surgery, it is best delayed for a minimum of
10 days postoperatively. However, postoperative and postventric- Prognosis
ulo-peritoneal shunt enhancement is well recognized and will still Although modern chemotherapy and radiotherapeutic regimens
lead to confusion in interpreting the images. have improved survival rates at five years it is not without cost.
Cerebellar mutism has been increasingly recognized in the last These patients tend to suffer from complications of their treat-
20 years and is a distressing clinical condition which fortunately ment almost as much as from the disease itself. Growth can be
seems to be transitory. It is mainly seen following surgery to the inhibited, there may be considerable intellectual impairment and
vermis but has been described following surgery to more remote some chemotherapy regimens result in deafness. There is also the
areas. In this group of patients there is comprehension of speech risk of inducing second malignancies.
but an inability for the patient to speak themselves. Children
afflicted with this condition can be very distressed. Radiologists Supratentorial Primitive Neuro-ectodermal Tumors
need to be aware of this condition, although in itself it does not These tumors may occur in the cerebral hemispheres or in the
have any radiological features apart from evidence of recent sur- pineal region, where they are also known as pineoblastomas, and
gery, in particular surgery to the superior vermis. Symptoms usually have very similar imaging characteristics to medulloblastomas in
resolve spontaneously but may persist for several months. the posterior fossa (164). They are slightly hyperdense prior to
contrast enhancement on CT and of relatively low signal intensity
Magnetic Resonance Spectroscopy on the T2-weighted sequences (Fig. 31.26A). At presentation, they
Proton MRS is used in some units preoperatively but has not been are usually large and appear deceptively well-defined. Peritumoral
shown to be reliable in discriminating between the different tumor edema is seen in 90% of cases and calcification is relatively com-
types prior to surgery. Typically, metabolically active PNET show mon (139). These tumors also require a full examination of the
an elevated choline, reduced NAA, and creatine and sometimes whole neuraxis to look for metastatic disease prior to surgery as
increased lactate and lipid (170,171) but low-grade pilocytic there is a risk of leptomeningeal spread with the same “sugar coat-
astrocytomas may show low NAA : choline ratio (172). Spectro- ing” metastases (Fig. 31.26B) as seen in the infratentorial PNET or
scopy is of greater value in postoperative assessment where it is medulloblastoma.

726
 primary tumors of the central nervous system

Key Points: Primitive Neuro-ectodermal Tumors

■ PNET are composed of small round cells with a high nuclear-
to-cytoplasmic ratio
■ Cerebellar medulloblastoma accounts for 80% of CNS PNET
■ Medulloblastoma constitutes 15% to 20% of intracranial
neoplasms in children
■ They usually arise in the roof of the fourth ventricle and within
the vermis but 40% arise in the cerebellar hemispheres
■ Supratentorial PNET arise in the cerebral hemispheres or in
the pineal region (pineoblastomas)
■ On CT, these tumors appear as hyperdense, relatively
well-defined lesions. Contrast enhancement is variable
■ On MR imaging, they appear as relatively low signal intensity
lesions on T2-weighted images (similar to gray matter)
■ They may show cyst formation and necrosis
■ Calcification may occur
■ It is important to image the whole brain and spine with
contrast enhancement to identify metastatic deposits
■ Metastases may occur outside the CNS; the predominant site
is bone

Germ Cell Tumors and Tumors Arising in the

Pineal Region
Only 0.3% to 2.7% of intracranial tumors arise in the pineal region and
the majority of these are germ cell tumors (173,174). Pineocytomas
and pineoblastomas arise from neuroepithelial cells within the pineal
gland itself but are very rare. Any other intracranial tumor type can
arise in the brain or meninges adjacent to the pineal gland and may
invade it. They will give the appearance of pineal tumors; however, with
multiplanar MR imaging it should be possible to determine the site of
origin of the tumor and therefore whether or not it is a true pineal
tumor. Classification of germ cell tumors is shown in Table 31.4.
It is important for the radiologist to recognize that simple pineal
cysts are common, being found in 40% of autopsies, and they are of
no clinical significance. Most malignant pineal tumors are not cystic
and the rounded morphology of pineal cysts is well demonstrated
on sagittal MR imaging.
As well as being found in the pineal gland, germ cell tumors may
also be found in the suprasellar region; this may be either a pri-
mary site or a secondary lesion from a primary pineal-based
tumor. Germ cell tumors are nearly always found in the midline
but may rarely be located in the basal ganglia (7).
Germinoma
The most common germ cell tumor and the most common pineal
mass is the germinoma (Fig. 31.52), accounting for over 50% of
tumors in this site. Ninety percent of pineal germinomas are found in
young males. The peak incidence is the second decade (175), with the
Table 31.4 Classification of Germ Cell Tumors
Germinoma
Benign teratoma
Choriocarcinoma
Endodermal sinus (yolk sac) tumor
Embryonal cell tumor
Immature teratoma
Mixed germ cell tumor
Figure 31.52 Germinoma. Postcontrast Gd-DTPA axial T1-weighted MR image
showing uniformly enhancing mass lesion in the posterior end of the third
ventricle.
majority of patients aged under 30 years. Suprasellar germinomas in
comparison are slightly more common in females (Fig. 31.53) but
there is no difference in the prognosis between the two sites (175).
Germinomas respond rapidly to radiotherapy and have a good
prognosis with long-term survival rates of 70% to 100% being
reported (176). This is in comparison to the other intracranial
germ cell tumors (excluding benign teratomas) which show a
poor initial response and long-term survival. Germ cell tumors
also tend to metastasise through the CSF.
Presentation
Pineal germinomas usually present after a relatively short history,
primarily with symptoms of raised intracranial pressure due to
obstructive hydrocephalus, but they may also present with
Perinaud’s syndrome (173,175) (vertical gaze palsy with papillary or
oculomotor paresis) due to compression of the tectal plate or motor
impairment with ataxia and dysmetria. Even without hypothalamic
involvement, a significant proportion of patients have diabetes insip-
idus and germinomas may be associated with the development of
precocious puberty in males. Suprasellar germinomas present with
diabetes insipidus, visual deficit, and hypopituitarism.
Some germ cell tumors secrete hormones which act as tumor
markers and should be measured in the serum and CSF as they aid
in presurgical diagnosis (173,175). These include:
• Germinoma – placental alkaline phosphatase (PLAP)
• Choriocarcinoma – human chorionic gonadotrophin
(HCG)
• Endodermal sinus – alpha-fetoprotein (AFP)
• Embryonal carcinoma – AFP and HCG
• Mixed germ cell – AFP and HCG (173)

727
 primary tumor evaluation and staging
(A)
Figure 31.53 Ten-year-old girl with a suprasellar germinoma. (A) T1-weighted enhanced sagittal MR image showing an enhancing suprasellar mass with involvement of
the floor and anterior third ventricle. (B) Following radiotherapy there is a resolution of the mass, the residual enhancement of the pituitary stalk was considered to be
within normal limits.
Imaging
When imaging pineal tumors, a knowledge of the age and the
sex of the patient is of great value in suggesting the diagnosis. A
male patient in his teens with an enhancing mass in the pineal
region is most likely to have a germinoma. However, MR imag-
ing may be able to distinguish between benign and malignant
pineal tumors (7), particularly in separating out the benign
teratomata.
Computed Tomography Appearances
Germinomas are usually iso- or hyperdense in comparison to
adjacent brain and for this reason may be difficult to differentiate
from normal nervous tissue but this enables them to be differenti-
ated from gliomas which in the suprasellar region are typically
hypodense (174,175). They do show intense enhancement with
contrast medium and appear well margined. Normal pineal calci-
fication becomes engulfed by the enhancing tumor mass, but the
tumor itself rarely calcifies (7).
Subependymal and subarachnoid spread are common and may
be seen on CT but are better evaluated on MR imaging.
Magnetic Resonance Imaging Appearances
Most germinomas are of homogeneous signal intensity on T1-
and T2-weighted images. Because these tumors are composed
of cells with high nuclear : cytoplasmic ratio they are of similar
signal intensity to gray matter on T2-weighted images. Larger
tumors may show necrosis and hemorrhage leading to a more
heterogeneous appearance (175). These tumors enhance
intensely following injection of IV contrast medium (Fig.
31.52). Edema in the adjacent brain may or may not be present
(7,174). Metastatic spread is readily recognized on MR imag-
ing and the whole of the brain and spine should be imaged to
look for it.
728
(B)
Apart from benign teratomas, other germ cell tumors have
similar imaging appearances to germinomas. Pineoblastomas also
show similar signal intensity and enhancement characteristics.
Computed Tomography and Magnetic Resonance
Imaging of Benign Teratomas
Teratomas are the second most common of the pineal tumors and
may be either benign or malignant. There is a male predominance
and most patients are usually aged under 10 years; they may even
be found in very young children. Benign teratomas have charac-
teristic imaging features with fatty, cystic, and calcified compo-
nents (173). Magnetic resonance imaging will show the position
of the tumor and its relationship to adjacent structures to greater
effect than CT, which is important for surgical planning. Benign
teratomas are curable by total surgical excision; however, because
of their site, the surgical approach needs to be carefully planned.
Additionally, when these tumors occur in infants, the prognosis is
usually poor because of the large tumor size and the severe hydro-
cephalus. There are certain advantages to CT as it is better able to
detect calcification and can help to confirm the presence of a fatty
component of the tumor (Fig. 31.54) (173), thereby suggesting
the histological diagnosis. Enhancement of teratomas both on CT
and MR imaging is variable.
Treatment and Prognosis of Germ Cell Tumors
The preoperative assessment, surgical and postsurgical man-
agement of this group of patients remains controversial. Mag-
netic resonance imaging using gadolinium to demonstrate the
lesion in multiple planes is essential and should also include
imaging of the whole CNS to look for metastatic disease. The
reported percentage of patients with spinal metastasis varies
from 3% to 37% (176). Histology is the most important prog-
nostic factor, benign teratomas and pure germinomas having a
 primary tumors of the central nervous system
(A)
Figure 31.54 Pineal teratoma. (A) Unenhanced CT showing a mass arising at the posterior end of the third ventricle which contains fat and calcified components. (B)
Axial T1-weighted MR image demonstrating fatty elements as high signal and low signal intensity cystic areas.
good prognosis, with non-germinoma germ cell tumors not
doing so well. Initially, tumor markers are looked for in blood
and CSF and if found may be used to confirm the diagnosis
without the need for resection or biopsy. However, many of
these patients present with hydrocephalus and, whilst this may
sometimes be managed conservatively with dexamethasone,
treatment of the hydrocephalus may be necessary. This is pref-
erably with endoscopic third ventriculostomy which reduces
the risk of peritoneal seeding and metastatic disease. Germino-
mas are highly radiosensitive and cure rates are excellent with
radiotherapy alone, long-term survival rates of 70% to 95% at
five years being reported (176).
The long-term sequelae of radiotherapy on the immature
brain need to be considered and the addition of cisplatin-based
chemotherapy regimens has allowed reduction of the radiation
field (177). Surgery is therefore reserved in certain treatment
protocols for patients with marker-negative single-site disease
or where residual disease is detected after two to four courses of
chemotherapy (178). The place of surgical resection in non-
germinoma germ cell tumors is more controversial. There is
evidence that the extent of surgical resection in hormone-
secreting tumors does not seem to improve the tumor-free sur-
vival in comparison to radiotherapy or radiotherapy with
chemotherapy (179). However, in certain centers, a radical surgical
resection is still advocated as these tumors commonly show
mixed cell histology. Excision allows a larger tissue sample to be
obtained and this will increase the detection of different cell
types (180).
The extent of disease at the time of diagnosis is also believed to
affect prognosis and the extent of excision has been reported to
increase the disease-free interval in the more malignant non-
germinoma germ cell tumors; a more radical surgical approach
(B)
may therefore be considered appropriate. New microsurgical
techniques have dramatically reduced the traditionally high surgical
mortality rates in this area (180), which may make surgery a more
appropriate option.
Patients with spinal metastases will have radiotherapy targeted
to the involved sites of disease. Patients who do not have spinal
metastases do not require radiotherapy to this area with its atten-
dant morbidity. Patients who have received spinal radiotherapy
are at risk of developing:
• Axial growth arrest
• Bone marrow suppression
• Gonadal irradiation resulting in infertility
• A second malignancy
For this reason, accurate staging with MR imaging not only
improves long-term survival by identifying disease but may also
improve the long-term quality of life by avoiding unnecessary
treatment in patients without spinal metastases.
Follow-up Imaging of Germ Cell Tumors
The follow-up imaging of pure germinomas should show only
minimal residual abnormality or should be normal, with total
resolution of areas of enhancement secondary to tumor (Fig.
31.53B) seen on T1-weighted MR imaging. However, enhance-
ment may be seen secondary to any surgery and there may be
persistent distortion of normal anatomical structures even
following radiotherapy alone.
In all germ cell tumors, the majority of relapses occur within
two years; these are mainly at the primary site rather than in the
form of disseminated disease. These tumors metastasise outside
the CNS to the abdominal cavity via the ventriculo-peritoneal
shunt and also to the lung and bone.
729
 primary tumor evaluation and staging
Key Points: Germ Cell Tumors
■ Germinomas are more common in boys and have a significantly
better prognosis than non-germinoma germ cell tumors
■ Benign teratomas occur in a younger age group, are most
common in boys and can be cured by surgery alone
■ Germinomas are highly radiosensitive with total resolution
of the mass on follow-up imaging
■ Accurate staging allows radiotherapy to be targeted to
involved areas and decreases long-term morbidity as well as
obviating the need for radiotherapy in patients without
metastases
■ Recurrence usually occurs within two years at the primary site
Pineal Parenchymal Tumors (Table 31.5)
Pineoblastoma: WHO Grade III to IV
Pineoblastomas are usually classified as PNET tumors and they
share common imaging findings with other tumors in this group
such as medulloblastoma (Fig. 31.26). They are rare tumors of
childhood and show no sex predilection.
Computed Tomography and Magnetic Resonance
Imaging Appearances
Pineoblastomas have a similar appearance to germinoma on CT
and MR imaging. The presence of tumor calcification is an impor-
tant differentiating feature; it is rare in germinomas and common
in pineoblastomas and for this reason CT is of value (173). The
signal intensity characteristics on MR imaging are variable, most
tumors enhance with IV contrast medium (Fig. 31.26B) and there
is a tendency to hemorrhage. Cerebrospinal fluid metastatic spread
occurs early and therefore the whole craniospinal axis requires
imaging to stage the tumor prior to surgery.
Pineocytoma: WHO Grade II to III
Pineocytomas occur in adult patients, most cases being reported
in middle age. They are relatively slow-growing and have a good
long-term prognosis. On imaging, pineocytomas are frequently
well-defined solid masses which, on CT, may show calcification
and contrast enhancement. On MR imaging, they are isointense
or of mixed low signal intensity on T1-weighted images and of
high signal intensity on T2-weighted images. The presence of a
cyst is usually indicative that the lesion is a benign pineal cyst but
the distinction between pineocytoma and normal pineal paren-
chyma or a benign pineal cyst may be difficult both histologically
and on imaging criteria (29). If the tumor is purely a pineocy-
toma, surgery should be curative; however, some tumors show a
mixture of cell types giving an overall higher WHO grade.
Table 31.5 WHO Grading System (Malignancy Scale) of Pineal
Region Tumors (3)
Pineal cell origin Grade
I II III IV
Pineocytoma • •
Pineocytoma/pineoblastoma • •
Pineoblastoma • MR imaging in the detection of small lesions (181).
730
Key Points: Pineoblastomas
■ In a child, the differential diagnosis of a germ cell tumor
includes pineoblastoma
■ Both pineoblastomas and germ cell tumors metastasize early
through the CSF and therefore require evaluation of the head
and spine prior to surgery
■ In a female patient with a calcified mass, a pineoblastoma
should be considered the most likely diagnosis despite its
rarity
■ Histological confirmation is necessary
Hemangioblastoma: WHO Grade I
Age and Site
Hemangioblastomas are a primary benign brain tumor predomi-
nantly found within the posterior fossa, with 83% to 86% occur-
ring within the cerebellum itself. They are also found in the
medulla (2–3%), spinal cord (3–13%) and cerebral hemispheres
(1–5%) (181,182). Hemangioblastomas account for only 1% to
2.5% of intracranial neoplasms but within the posterior fossa
they are a relatively common primary tumor accounting for
between 7% and 12%.
Most patients present in the fourth to sixth decades, 10% to 20%
of patients will have von Hippel–Lindau syndrome (25), which is
an autosomal dominant disorder. Multiple hemangioblastomas
only occur with von Hippel–Lindau syndrome and multiple lesions
are found in 42% of this group of patients.
Hemangioblastomas are either solid (40%) or cystic with a solid
tumor nodule (60%) (25,183). The cell of origin remains contro-
versial but they are histologically benign tumors composed of
thin-walled blood vessels enclosing islands of stromal cells (25).
Computed Tomography Appearances
Hemangioblastomas are usually small, rounded, isodense lesions
and, if cystic, there is an associated well-circumscribed cyst with a
thin wall (181). The mural nodule shows intense enhancement
and the cyst wall typically does not enhance as it is formed from
compressed adjacent brain tissue. If the cyst wall enhances, it indi-
cates neoplastic extension. The tumor is always in contact with the
leptomeninges at some point (25). Ring enhancement has been
described in some of the solid tumors.
Magnetic Resonance Imaging Appearances
The solid component of the hemangioblastoma is commonly
hypointense on T1- and hyperintense on T2-weighted sequences.
There may be heterogeneity of signal intensity secondary to hem-
orrhage. The hallmark of this tumor is the intense enhancement
(Fig. 31.55D) and the identification of serpentine signal intensity
voids adjacent to the mass secondary to the high vascularity of the
lesion (Fig. 31.55A) (181,183,184). Magnetic resonance is more
sensitive to the detection of multiple hemangioblastomas, as many
lesions are small and peripherally located within the cerebellum
making them difficult to detect on CT (184). On preoperative
assessment, multiple hemangioblastomas should be sought on
gadolinium-enhanced MR (Fig. 31.55C). Angiography detects
hemangioblastomas because of their intense “tumor” blush and
the technique has been reported as being more sensitive even than
 primary tumors of the central nervous system

(A) (B)

(C) (D)
Figure 31.55 Hemangioblastoma arising from inferior aspect of the left cerebellar hemisphere. (A) Axial T2-weighted MR image showing mass extending into the lower end of
the fourth ventricle with surrounding signal intensity voids indicative of tumor vascularity. (B) Sagittal T2-weighted and (D) sagittal T1-weighted post Gd-DTPA MR images
show the solid component of the mass to be of relatively low signal intensity on the T2 and intensely enhancing postcontrast, with an inferior cystic component extending
through the foramen of magendie. (C) The parasagittal contrast-enhanced T1-weighted image demonstrates a second tumor in the posterior aspect of the cerebellum.

Treatment and Prognosis Meningioma

The treatment of choice is surgical resection, with 85% of patients
surviving 5 to 20 years. Perioperative morbidity and mortality is
related to the site of the tumor and to its vascularity. Solid heman-
gioblastomas have been found to have a higher incidence of com-
plications (183). The recurrence rate is 8% to 16%, but the recurrent
tumor does not necessarily have the same morphology as the orig-
inal tumor: for instance previously demonstrated solid tumors
may recur with a cystic component.
Key Points: Hemangioblastomas
■ Hemangioblastomas are most commonly found in the
posterior fossa, but may also be found in the spinal cord
and cerebral hemispheres
■ Multiple lesions occur particularly in association with von
Hippel–Lindau syndrome
■ The hallmark on MR is the detection of multiple signal
intensity voids in association with an intensely enhancing
rounded mass within the posterior fossa
Age and Site
Meningiomas are benign, usually slow-growing tumors which
account for 15% of intracranial neoplasms and are the second
most common intracranial tumor after glioblastoma multiforme
(24,185). There is a peak prevalence between 40 and 60 years of
age and they are a common incidental finding at postmortem,
being found in 16% of the 60- to 80-year age group. Although
rare they do occur in childhood. Hormone receptors have been
demonstrated within meningiomas (186,187) and this may be at
least part of the reason why there is an increased incidence in
women, 3:2 in comparison with men. There is also a tendency to
increase in size during pregnancy and there is an association with
breast cancer. Multiple meningiomas are found in NF2; this is due
to a genetic mutation, related to chromosome 22 (188). Menin-
giomas are also the commonest intracranial malignancy induced
by previous radiotherapy.
Meningiomas arise from meningothelial cells which are most
often found in association with arachnoid granulations. As a
result, the most common intracranial site for meningioma is

731
 primary tumor evaluation and staging

adjacent to the falx, the next being the meninges adjacent to the
suture lines. There are two common morphological types, the flat,
carpeting “en-plaque” variety (Fig. 31.56) and the spherical or
lobulated mass which indents adjacent brain (Fig. 31.57). In both
types there is usually a clear interface between the tumor and
adjacent brain. Traditionally, these tumors were subdivided into
meningothelial, fibroblastic, transitional, and angioblastic sub-
groups according to their histological appearance. Unfortunately,
tumors that appear histologically benign may recur early, either
locally or metastasize, and for this reason the cell type is of little
prognostic significance. Thus, there is increasing acceptance of the
new WHO classification which correlates better with biological
behavior (Table 31.6) (189).
Meningiomas which histologically are papillary in appearance
are also graded as II to III as they frequently invade brain or bone
and tend to show early recurrence. The papillary pattern is seen in
a minority of cases.
Resectability is the single greatest factor predicting prognosis
(188). The overall frequency of recurrence of meningiomas is
21%. If a tumor is excised completely with its dural attachment,
the recurrence rate is reduced to 5% to 9% as compared with 39%
for tumors where there is only partial excision (190,191). It is the
relationship of the tumor to other intracranial structures that will
determine its resectability and therefore the prognosis of an indi-
vidual tumor. The role of the neuroradiologist is therefore to
localize the tumor, define the anatomy of adjacent structures and
assess resectability rather than attempt to predict the histology.
Parasagittal and Convexity Meningiomas
The majority of meningiomas (45%) are found in these sites. The
most critical feature in preoperative assessment is the involvement
of the superior sagittal sinus. Twenty-five percent of intracranial
meningiomas belong to the parasagittal group and, of these, half
will either partially or totally obliterate the superior sagittal sinus at
the time of presentation. If the sinus is totally obliterated, prior to
surgery, the tumor may safely be removed (Figs. 31.57A–D). How-
ever, if the middle third of the sinus is only partially obliterated,
total surgical excision cannot be achieved as attempts at abrupt
obliteration of the superior sagittal sinus usually result in death.
Unfortunately, 60% of parasagittal meningiomas involve this mid-
dle third of the sinus, with only 13% involving the anterior third
which may be surgically obliterated with safety.

(A) (B)

(C) (D)
Figure 31.56 Sphenoid wing meningioma. (A) and (B) Fat-suppressed contrast-enhanced T1-weighted MR images with hyperostosis of the bone seen as an area of low
signal intensity. The meningioma en plaque is represented by the thickened enhancing tissue posterior to the sphenoid bone. (C) and (D) CT demonstrating extensive
hyperostosis of the sphenoid bone.

732
 primary tumors of the central nervous system

(A) (B)

(C) (D)
Figure 31.57 Parasagittal meningioma. (A) Coronal T2-weighted MR image. This shows an extra-axial mass indenting the adjacent brain parenchyma and defined by a
thin rim of high signal from trapped CSF. It involves the superior sagittal sinus. (B) Sagittal MRV image shows no flow in the middle third of the superior sagittal sinus
at the site of the meningioma, consistent with the sinus being obliterated in that area. (C) Coronal T1-weighted and (D) post Gd-DTPA coronal T1-weighted images.

Table 31.6 WHO Classification of Meningiomas involve adjacent bone, resulting in hyperostosis (Fig. 31.56). The
tumor traverses the bone to involve adjacent structures such as the
Type Incidence Recurrence rate WHO
(%) at 5 yrs (%) grade orbit, optic canal, and the temporal fossa and may involve the tem-
poralis muscle. Resection needs to be extensive and can be damag-
Meningiomas (benign 88–94 3 I
or typical)
ing in its own right. For this reason, radical surgery is often delayed
Atypical meningiomas 5–7 33 II to try to preserve remaining function for as long as possible.
Aplastic or malignant 1–2 75 III
Olfactory Groove Meningiomas
These tumors account for 5% to 10% of all meningiomas and often
Convexity meningiomas arising adjacent to the sylvian fissure, produce few symptoms apart from personality change; they there-
and therefore growing into it, need to be assessed with regard to fore attain a large size by the time of diagnosis. They indent the
their relationship to the middle cerebral artery branches. inferior aspects of the frontal lobes and extend superiorly into the
inferior aspect of the interhemispheric fissure. The relationship to
Sphenoid Ridge Meningiomas the anterior cerebral artery needs to be assessed. Occasionally, these
Sphenoid wing meningiomas, which account for 15% to 20% of tumors do extend through the floor of the anterior cranial fossa,
meningiomas overall, are commonly of the “en plaque” variety and leading to CSF leaks.

733
 primary tumor evaluation and staging

Parasellar Meningiomas Posterior Fossa Meningiomas

Between 5% and 10% of meningiomas arise from the tuberculum
sellae, they grow up and over the planum sphenoidale displacing the
chiasm (Fig. 31.58) and the pituitary stalk posteriorly. Tumors may
also arise from the adjacent diaphragma sellae and affect structures
abutting the suprasellar cisterns. Imaging needs to be tailored to
demonstrating the relationship of the tumor to the major vessels.
Cavernous Sinus Meningiomas
Cavernous sinus meningiomas invade the cavernous sinus and
encase the internal carotid artery (Fig. 31.59). Posteriorly, they
extend to involve the tentorium cerebelli and invade down the
posterior aspect of the clivus. Total resection is impossible.
Meningiomas may either arise from the petrous bone or the cli-
vus. If they arise from the petrous bone, they commonly have a
broad base laterally, and medially indent the adjacent brain stem
structures. They may extend into the internal auditory meatus,
with enhancement being demonstrated within the canal. Cerebro-
spinal fluid may become trapped laterally, leading to the appear-
ance of a cyst in relationship to the tumor. They are the second
most common CP angle tumor but only form 9% of these tumors
overall.
Approximately 5% of meningiomas do not have a dural attach-
ment and may be found in the ventricles or arise in the diploic
space.

(A) (B)
Figure 31.58 Suprasellar meningioma. (A) Unenhanced and (B) contrast-enhanced sagittal T1-weighted MR images. The enhancing mass is seen to indent the anterior
aspect of the third ventricle and extend within the sellar but not involve the pituitary gland. A tail of enhancement is seen to extend along the floor of the anterior cranial
fossa, the “dural tail” sign.

(A) (B) (C) (D)

Figure 31.59 Patient with a cavernous sinus meningioma. (A) On T1-weighted MR imaging, the tumor has similar signal intensity to gray matter and slightly high signal
on the T2-weighted image (B) with CSF cleft of high signal intensity demarcating the lesion from brain. (C) MR angiography displays displacement and some narrowing
of right-sided vessels. (D) Coronal T2-weighted MR image also demonstrates encasement and displacement of the terminal carotid artery and middle and anterior
cerebral arteries by meningioma (coincidental arachnoid cyst on the left).

734
 primary tumors of the central nervous system
(A) (B)
Figure 31.60 Same case as Fig. 31.59. As well as a cavernous sinus meningioma the patient also had a second meningioma arising in the posterior fossa. (A) and (B) CT
shows the anterior mass to be isodense with the brain with hyperostosis of the anterior clinoid process. (C) and (D) Following contrast enhancement the posterior tumor
is densely calcified. There is uniform enhancement of the cavernous sinus meningioma.
Computed Tomography Appearances
The typical appearance is that of a well-defined hyperdense mass
arising from the dura and displacing adjacent brain (Figs. 31.60A
and B). However, 25% to 33% may be isodense and rarely they
are found to be hypodense (185). Calcification is seen in 20% to
25% (Fig. 31.60A). The density of the lesions is not necessarily
related to calcification and cannot be used as a factor to predict
how hard or gritty the tumor will be at operation. Hyperostosis
(Figs. 31.56C and 31.60A), or more rarely, bone destruction may
occur in 15% to 20% of cases (192). Following injection of IV
contrast medium, the vast majority will show intense enhance-
ment (Figs. 31.60C and D) (185,192). Other patterns are seen but
this does not predict tumor type. Edema is also seen to involve
white matter in the adjacent brain in up to 60% of cases (185).
Edema can be extremely extensive and is more prominent in
meningiomas of the syncytial or angioblastic cell type but this,
along with the other features seen on CT, is not a good prognostic
indicator of tumor type.
Magnetic Resonance Imaging Appearances
Attempts have also been made to correlate MR appearances with
tumor type but no single reliable sign has been found (193,194).
The signal intensity characteristics on the T1-weighted images are
not contributory. Meningiomas are usually of similar signal inten-
sity to gray matter on both T1- (Figs. 31.58 and 31.59A) and
T2-weighted images (Fig. 31.59D) and enhance uniformly with
contrast material (Fig. 31.58B). Fibroblastic meningiomas may be
of lower signal intensity because of the increased incidence of cal-
cification in this group (195,196). Some authors have also reported
increased signal intensity on T2 weighting in angioblastic menin-
giomas but there have been conflicting results. More importantly
there are no specific factors to suggest that any one tumor is more
likely to show a higher grade of malignancy.
The attachment to the dura and the relationship to vascular struc-
tures is, however, better defined on MR than on CT (Figs. 31.59 and
31.60). Meningiomas are usually well circumscribed and most have
a surrounding low signal intensity rim on T1 weighting and high
intensity on T2 weighting (Fig. 31.59D). This represents the CSF
(C) (D)
cleft seen on pathological specimens (185) and is lost when the men-
ingioma invades the adjacent parenchyma. Magnetic resonance is
also able to demonstrate the intrinsic vascularity of the tumor.
Although meningiomas have a fairly typical radiological appear-
ance, other tumors can appear very similar to them on both CT
and MR. These include:
• Schwannomas
• Gliomas
• Metastases
• Metastatic neuroblastoma in childhood
• Large tuberculous granulomas
Angiography and Embolization
Angiography may be performed to assess vessel displacement and
the integrity of the venous sinuses; however, this technique is now
largely replaced by vascular MR examinations (Fig. 31.57). Tumors
that are highly vascular may be embolized prior to surgery to
reduce operative blood loss.
Treatment and Follow-up Imaging
As stated above, the more complete the resection, the less likely
there is to be recurrence (190). Radiotherapy may be used for
recurrent disease and may halt progression. Convexity menin-
giomas are the easiest to remove as they do not involve adjacent
structures and therefore, on the whole, have the best prognosis.
The need for routine imaging following surgery is usually deter-
mined by the patient’s symptomatology.
Tumors that are classified as moderately malignant or recurrent
tumors may be referred for radiotherapy. Interpretation of post-
surgical images requires a detailed understanding of potential
postsurgical change in comparison to recurrent disease.
At the time of diagnosis, 60% of meningiomas will have a sur-
rounding area of dural thickening and enhancement. Initial
reports suggested that, if there was dural thickening and enhance-
ment, there was definite tumor involvement of these structures.
However, subsequent reports suggest that this enhancement may
in some cases be entirely due to reactive change and does not imply
the presence of tumor cells. This cuff of abnormal enhancement
735
 primary tumor evaluation and staging
has been termed the dural tail sign (Fig. 31.58B) (192,197).
Although it is highly suggestive of meningioma, it is also seen in
other tumors such as glioblastoma multiforme and metastases.
Any intracranial procedure will lead to enhancement of the
dura postoperatively, particularly immediately adjacent to the
bone flap. For this reason, uniformly enhancing dura adjacent to
the resection site does not necessarily mean that there is either
residual or recurrent tumor. Nodular thickening of the meninges
is more indicative of recurrence but, as previously stated, the
detection of early recurrence seldom alters immediate manage-
ment. Although anaplastic meningiomas are more likely to recur
than typical or benign meningiomas, this is not always the case
and histologically benign meningiomas are known to metastasize.
For this reason, it is very difficult to determine a protocol for the
imaging follow-up of these patients. Progression is most com-
monly at the primary site and is assessed by increasing size of
abnormal areas of nodular enhancement.
Key Points: Meningiomas
■ Most meningiomas are histologically benign
■ Prognosis is affected by resectability and therefore tumor site
■ Most commonly meningiomas are situated parasagittally or
on the convexity of the parietal bone
■ Tumors may be rounded or may spread “en-plaque” over the
dura
■ The most common CT appearance is that of a hyperdense
well-defined lesion
■ Twenty to twenty-five percent of meningiomas are calcified
■ Fifteen to twenty percent show changes in adjacent bone
■ The vast majority of meningiomas enhance with IV contrast
media
■ Edema does not predict a malignant histology
■ MR imaging displays the dural origin of the mass and its
relationship to adjacent structures better than CT
■ Imaging is important for determining the relationship of the
tumor to adjacent structures
■ Meningiomas are the most common tumors to be induced by
radiation
Schwannomas (Neuroma and Neurilemmoma)
Schwannomas arise from the nerve sheath cells of intracranial
nerves and have a definite predilection for the sensory division.
They occur in middle-aged patients and by far the most common
is the acoustic schwannoma (neuroma) (25). They may also arise
on the trigeminal nerve and less commonly from the IX, X, or XI
nerves in the jugular foramen or on the hypoglossal nerve.
Acoustic Schwannomas (Neuromas)
Acoustic schwannomas are benign, slow-growing tumors that arise
from the nerve sheath of the VIIIth cranial nerve, most commonly
the vestibular portion (25). They account for 60% to 90% of all CP
angle neoplasms. There is a high incidence of acoustic schwanno-
mas in patients with NF2, and bilateral tumors are pathognomonic
of this condition. As the tumor enlarges it compresses the VIIIth
and VIIth nerves within the internal auditory meatus, leading to
hearing loss and tinnitus, and then encroaches upon the brain
stem, cerebellum, and other cranial nerves. Magnetic resonance is
736
now the investigation of choice because of its increased sensitivity
for small lesions and also because its multiplanar capability enables
the relationship of the mass to other intracranial structures to be
well demonstrated. Heavily T2-weighted volume acquisition, high-
resolution axial, and coronal scans through the IAMs are usually
considered to be sufficiently sensitive to detect small acoustic
schwannomas (Fig. 31.61A and B) and in many centers have
replaced contrast enhanced T1-weighted scans as the imaging
procedure of choice.
T1-weighted images reveal an iso- or slightly hypointense mass
which shows uniform intense enhancement with contrast medium
in the majority of cases (Fig. 31.61C and D) (31). Where cystic
degeneration has occurred, especially in larger tumors, enhance-
ment is less heterogeneous. With time the mass expands the internal
auditory meatus and bulges into the CP angle cistern; as it does so,
the tumor forms an acute angle with the petrous bone (Fig. 31.62).
The majority of tumors 74% (18) are both intra- and extracanalicu-
lar, with only 17% being purely intracanalicular. T2-weighted
images show the schwannoma to have increased signal intensity in
relationship to adjacent brain. The signal intensity change, particu-
larly on a T2-weighted image, may be inhomogeneous secondary to
cyst formation, hemorrhage, and calcification. Arachnoid cysts may
be identified adjacent to the tumor (Fig. 31.62) and peritumoural
edema may been seen in adjacent brain when the mass is large.
Prognosis and Follow-up Imaging
Acoustic schwannomas are considered benign and complete surgi-
cal removal should result in cure; however, small fragments of
tumor may be left behind, either inadvertently or intentionally in an
attempt to preserve function of the facial nerve. Some patients will
receive radiotherapy, which does not shrink the tumor but is aimed
to prevent further growth. Single-fraction stereotactic radiosurgery
has a reported success rate of 90% to 95% progression-free survival
at five years (198) but is associated with a high risk of VIIIth nerve
neuropathy and VIIth nerve palsy. Fractionated conformal stereo-
tactic radiotherapy has a lower risk of nerve damage and early
reports suggest similar results to surgery and radiosurgery (199).
Follow-up imaging is directed towards finding an enlarging
mass. On enhanced MR imaging, peripheral linear enhancement
within the internal auditory meatus is a usual finding after surgery,
but this will fade with time (200). Nodular irregular enhancement,
particularly if there is an increase in size with time, is of greater
significance than persistent enhancement. Changes may also be
seen in the labyrinth on postsurgical images. The labyrinth may
appear hyperintense on precontrast MR and may enhance following
injection of IV contrast medium.
Following radiotherapy, the signal intensity characteristics of
the mass may change, reflecting necrosis but growth of the mass is
arrested. Development of cranial nerve palsies does not necessarily
indicate progressive disease but may be a consequence of the
radiotherapy itself.
Differential Diagnosis of a CP Angle Tumor
The acoustic schwannoma is the most common tumor in the CP
angle cistern. However, meningiomas also occur in this site, have
very similar signal intensity characteristics and present at the same
age. The differential diagnosis may be made on the morphology of
the tumor. Meningioma usually extends along the petrous bone
 primary tumors of the central nervous system

(A) (B)

(C) (D)
Figure 31.61 Right acoustic schwannoma. (A) and (B) Volume acquisition axial T2-weighted MR image showing tumor in the right internal auditory meatus and normal
ventricular and cochlear divisions of the eighth nerve on the left. (C) Coronal T1-weighted pre- and (D) post Gd-DTPA images showing enhancement of the mass.

forming an obtuse angle in contrast to the acute angle seen with

an acoustic schwannoma (201). However, meningiomas may
extend into the internal auditory meatus and the dural tail sign,
although more common with meningioma, may also be seen with
an acoustic schwannoma (197).
Epidermoids are the third most common tumor in the CP
angle cistern; they do not enhance with IV contrast medium and
morphologically appear very different from other tumors in this
site as they “creep” around the adjacent brain stem and basal
arteries. They account for 5% of CP angle tumors and need to be
differentiated from arachnoid cysts arising in this area.
Rarer masses found in the CP angle cistern include:
• Aneurysms
• Extension of trigeminal schwannoma
• Metastases
• Paragangliomas
Figure 31.62 Large left acoustic schwannoma. Axial T2-weighted MR image
• Ependymoma
showing a mass of inhomogeneous signal intensity which forms an acute angle • Lipoma, dermoid
with the posterior aspect of the petrous bone. There are adjacent arachnoid cysts • Exophytic brain stem glioma
and the left middle cerebellar peduncle is compressed. • Chordoma or choroid plexus papilloma

737
 primary tumor evaluation and staging
Key Points: CP Angle Tumors
■ The most common CP angle tumor is the acoustic schwan-
noma
■ Meningiomas may also occur in this site; they account for
10% of CP angle tumors
■ Differential diagnosis between meningioma and acoustic
schwannoma is made on morphology rather than signal
intensity characteristics on MR imaging
■ Epidermoids are the third most common tumor in the CP
angle tumors, accounting for 5%. They do not enhance and
are morphologically distinct from acoustic schwannoma and
meningioma
■ Complete surgical removal is the treatment of choice for
acoustic neuromas, meningiomas, and epidermoids
Trigeminal Schwannomas
Trigeminal schwannomas are the second most common intra-
cranial schwannomas after the acoustic schwannoma but still
only account for 2% to 3% of all neuromas. They may occur any-
where along the course of the trigeminal nerve but are most
(A)
(C)
Figure 31.63 (A) and (B) Axial, (C) and (D) coronal T2-weighted MR images of a trigeminal nerve schwanoma. The lobulated inhomogeneous mass is seen to follow the
course of the Vth nerve through the pontine cistern (B) across the petrous apex to Mekel’s cave and then (C) and (D) through the expanded foramen ovale. The posterior
extension has a fluid/debris level secondary to hemorrhage into a cyst.
738
commonly found arising from the gasserian ganglion within
Meckel’s cave (53%) or extend in an hourglass fashion along the
course of the nerve above and below the tentorium (27%).
In 80% to 90% of cases, patients present with pain, paraesthesia,
and atrophy of the masseter muscle. When the lesion is mainly
within the posterior fossa, they present with the same symptoms
as any other CP angle tumor, with ataxia and facial and auditory
nerve dysfunction (202).
Computed Tomography and Magnetic Resonance Imaging
Magnetic resonance is the investigation of choice for trigeminal
neuroma as it allows accurate planning of the surgical approach;
the relationship to the carotid artery and the wall of the cavernous
sinus determines resectability. Magnetic resonance also allows
delineation of the extent of the tumor along the divisions of the
Vth nerve (Fig. 31.63). These tumors show intense enhancement
on MR and CT. There are no signal intensity or enhancement
characteristics which reliably differentiate a neuroma from a para-
sellar meningioma, the most common tumor in this site, but neu-
romas commonly show cystic degeneration and evidence of
previous small hemorrhages (Fig. 31.63D). Enhancement may be
(B)
(D)
 primary tumors of the central nervous system

inhomogeneous whereas meningiomas usually show uniform
enhancement (202). Computed tomography, however, demon-
strates bone erosion where the schwannoma extends through the
neuroforamen. This fact may aid in the differential diagnosis.
Prognosis and Follow-up
Neuromas are benign slow-growing tumors; however, the close
relationship of the tumor to the cavernous sinus and carotid arter-
ies limits their resectability. It is also the major cause of operative
morbidity. Permanent damage to the branches of the trigeminal
nerve is fairly inevitable. Follow-up imaging is aimed to look for a
recurrent enlarging mass.
Schwannomas of the Lower Cranial Nerves
Schwannomas may arise from the IXth, Xth, or XIth cranial
nerves within the jugular foramen, or the twelfth nerve within
the hypoglossal canal (Fig. 31.64). Schwannomas present with
cranial nerve deficits secondary to compression of the nerve
within the bony confines of their respective canals. A hypoglos-
sal nerve tumor will, for instance, present with weakness and
deviation of the tongue towards the ipsilateral side. Atrophy of
the affected tongue musculature may be demonstrated on MR
imaging (Fig. 31.64C). On CT, the affected foramen shows
enlargement with a well-corticated scalloped margin which
helps to differentiate neuromas from paragangliomas, and may
also affect the jugular foramen. On MR imaging, T1-weighted
images demonstrate a lobulated soft tissue mass centered on the
jugular foramen, which is of similar signal intensity to adjacent
brain on T1 weighting and following injection of contrast
medium shows intense uniform enhancement. On T2-weighted
images, the lesion is of relatively high signal intensity. The
absence of flow voids on either sequence distinguishes this tumor

(A) (B)

(C) (D)
Figure 31.64 Left XIIth nerve schwannoma. (A) Coronal T1-weighted unenhanced and (B) contrast-enhanced MR images with an intensely enhancing mass adjacent to
the left side of the medulla extending laterally out into the hypoglossal canal. (C) Coronal T1-weighted MR image showing high signal intensity change in the left side of
the tongue. This is due to fatty infiltration, secondary to denervation atrophy, resulting from the presence of the schwannoma. (D) Coronal T2-weighted MR image
showing mixed signal intensity commonly seen in all schwannomas.

739
 primary tumor evaluation and staging

from the more vascular paraganglioma. Extension of the tumor

through the canal into the intra- and extracranial compartment
is well demonstrated by MR imaging.

Differential Diagnosis of Masses in the Jugular Foramen

Differential diagnosis of a tumor in this site includes paragan-
glioma and meningioma. A paraganglioma in the jugular foramen
may also present with cranial nerve defects but may produce pul-
satile tinnitus if the tumor is highly vascular. Computed tomography
is helpful in differentiating these tumors as paragangliomas tend
to be associated with a greater degree of bone destruction. Several
other highly malignant tumors may also extend to involve this
area. These include:

• Squamous cell carcinoma

• Metastases
• Rhabdomyosarcoma (in children)
• Non-Hodgkin’s lymphoma
• Clival chordoma
• Chondrosarcoma
Meningiomas do not usually arise within the jugular foramen but
from the meninges adjacent to it and then grow within it. Com-
puted tomography and MR imaging characteristics are similar to
meningiomas in other sites and have been described above. Figure 31.65 Cerebral angiogram, right external carotid injection showing intense
vascular blush due to a paraganglioma.

Paragangliomas
Glomus jugulari tumors arise from paraganglia cells normally
distributed along specific nerves found in the region of the middle
ear cavity, jugular bulb, and descending facial nerve canal. Para-
gangliomas may only involve the jugular foramen when they are
known as glomus jugulari tumors or extend to involve the middle
ear cavity when they are known as glomus jugulotympanicum
tumors. When the middle ear is involved, examination of the
external auditory meatus may reveal the presence of a reddish/
purple retrotympanic mass. Jugulari tumors may enlarge to involve
the CP angle cistern where they account for 2% of tumors. They
are slow-growing, highly vascular, and most commonly found in
females aged 40 to 60 years.
Computed Tomography Appearances
Bone destruction in this tumor has a characteristic irregular
moth-eaten appearance and is not well-corticated. The mass is
seen in the region of the jugular foramen and is associated with
the bone destruction; intense enhancement with contrast medium
is typical (203).
Magnetic Resonance Imaging Appearances
As these tumors are highly vascular, signal intensity voids may
be seen within the tumor on both T1- and T2-weighted images.
On the T1-weighted images, the mass is of similar signal inten-
sity to adjacent brain, but on both T1 and T2 weighting there
may be a mottled appearance which has previously been
described as “salt and pepper” (Fig. 31.6A, C, and D), second-
ary to either small focal areas of hemorrhage or dilated vessels
with relatively slow flow (203). Following administration of
intravenous contrast medium, there is intense enhancement
(Fig. 31.6B). Magnetic resonance imaging is also able to dem-
onstrate occlusion of the jugular bulb and this may be further
illustrated by the use of MR angiography (MRA) and MR
venography (MRV) (204).
Angiography
Angiography is still used routinely to diagnose glomus jugulari
tumors (Fig. 31.65). In addition, embolization may be performed
to reduce vascularity, thereby limiting blood loss during surgery.
Key Points: Jugular Foramen Masses
■ CT is useful for discriminating between tumors because it
shows the pattern of bone destruction
■ Schwannomas of IXth, Xth, and XIth cranial nerves expand
the canal and extend through the skull base
■ Paragangliomas have a “salt and pepper” appearance on
T1- and T2-weighted MR images. They show intense contrast
enhancement
■ Meningiomas can be demonstrated to arise from adjacent
dura rather than within the foramen
Epidermoids
Although congenital in origin, epidermoids grow with age sec-
ondary to desquamation of stratified epithelium and the forma-
tion of keratin and cholesterol. These tumors are of similar
density to CSF on CT and similar signal intensity on conventional
T1- and T2-weighted MR imaging and are identified because of
displacement of adjacent brain. They do not enhance with con-
trast. Fluid-attenuated inversion recovery (FLAIR) sequences
have proved superior to the conventional sequences in detecting
these lesions but identification of tumor margin is commonly
unclear secondary to CSF pulsation artefact. Echoplanar DWI

740
 primary tumors of the central nervous system

provides the best visualization. High signal intensity change seen

on these sequences is not caused by diffusion restriction but by
T2 shine-through effect (205,206). Epidermoid cysts usually arise
and spread within the subarachnoid space, most commonly the
basal cisterns displacing adjacent brain and wrapping around the
cranial nerves and arteries.

Treatment and Prognosis

These are slow-growing tumors, treated by surgical excision.

Tumors of the Sella Region

There are two tumors arising at the base of the brain that are not
strictly formed from nervous tissue but are included under the
WHO classification of neoplasms of the CNS. They are grouped
together under tumors of the sella region and are the pituitary
adenoma and craniopharyngioma. Both tumors are relatively
common; pituitary adenomas account for 10% of all intracranial
tumors and are found nearly exclusively in adults (29). Cranio-
pharyngioma is a tumor of childhood and also accounts for 3% to
6% of intracranial neoplasms. Figure 31.66 Sagittal T1-weighted MR image of a large pituitary adenoma shows
Craniopharyngiomas and pituitary adenomas extend to com- high signal intensity on its posterior aspect but outside the sela due to “pituitary
press the adjacent brain and for this reason affect neurological stalk obstruction”.
function but may also cause endocrine dysfunction. Imaging
assists in the prediction of tumor type and is also important in
preoperative planning.
hormone (ACTH) secretion. Approximately 25% of patients have
non-functioning tumors and 75% of patients display clinical signs
Pituitary Adenoma
of hormone excess (7).
Pituitary adenomas are benign, slow-growing tumors composed
of cells of ectodermal endothelial origin and arise in the anterior
pituitary gland. These tumors are not encapsulated and expand to Key Points: Pituitary Microadenomas
compress and displace normal cells to the periphery. Despite the
compression of normal tissue, hypopituitarism is rare (25). ■ Microadenomas are defined as being smaller than 10 mm in
Radiologically and clinically, pituitary tumors are classified into size
macroadenomas, those which are over 10 mm in diameter, and ■ They are usually hormone-secreting; the most common is

microadenomas, which are under 10 mm in diameter. prolactinoma

Pituitary macroadenomas usually become symptomatic in ■ Eighty to eighty-five percent are visible on unenhanced

middle age and are rare in childhood. They first enlarge with T1-weighted MR imaging
expansion of the sella and then extend outside its confines. ■ Thirty-three to fifty percent are seen as areas of hyper-

Microadenomas usually present because of endocrine dysfunction. intensity on T2-weighted imaging

Macroadenomas are more likely to be non-functioning and ■ Enhancement with dynamic imaging is only necessary to look

present because of mass affect on adjacent structures. They may for the minority of tumors that are isointense on T1- and
be very large by the time of presentation. Superior extension T2-weighting
results in visual impairment owing to compression of the optic ■ Bromocriptine may cause hemorrhage

chiasm and is the presenting feature in 85% (Fig. 31.66) (25). ■ The necessity for routine follow-up imaging is questionable

Compression of the hypothalamus may lead to hypothalamic or

endocrine dysfunction and extension into the third ventricle
will lead to hydrocephalus. Macroadenomas also extend laterally
into the cavernous sinus where infrequently they cause cranial
nerve palsies. Diabetes insipidus is not a presenting feature of
macroadenomas (207,208).
Functioning adenomas are usually smaller and are either con-
fined to an expanded sella or are microadenomas. However,
tumors that are large and extrasellar may also secrete hormones
(25). Functioning tumors may result in acromegaly or gigantism
due to excess growth hormone. Prolactinomas (the most common
functioning adenomas) present with amenorrhoea, galactorrhoea,
or infertility. A relatively small number of patients may present
with Cushing’s syndrome secondary to adrenocorticotrophic
Imaging of Microadenomas
Magnetic resonance imaging is now the investigation of choice
and, whilst new sequences are constantly being developed,
certain techniques appear to be reliable for demonstrating
microadenomas in the majority of cases.
High-resolution T1-weighted spin-echo sequences in the coronal
plane should show microadenomas as focal areas of hypointensity
in 80% to 85% of cases (Fig. 31.67A) (209). Intratumoural hem-
orrhage most commonly occurs in macroadenomas (Fig. 31.68A)
but may be seen in microadenomas (210); this will lead to high
signal intensity change on both T1- and T2-weighted images.
At surgery, these lesions are usually cystic and contain old blood
degradation products. On T2-weighted images, between 30% and

741
 primary tumor evaluation and staging

(A) (B)
Figure 31.67 Pituitary microadenoma in a patient with galactorrhoea and amenorrhoea who was found to have high serum prolactin level. (A) Unenhanced coronal
T1-weighted MR image demonstrating focal area of relative low signal intensity towards the left side of the gland. (B) Contrast-enhanced coronal T1-weighted MR image
showing relative non-enhancement of the left side of the gland.

(A) (B)

(C) (D)
Figure 31.68 Pituitary macroadenoma in a patient presenting with gradual visual loss; there was no history suggestive of an acute bleed. (A) The sella is enlarged and the
mass displaces the optic chiasm superiorly. Coronal T1-weighted MR image shows high signal hemorrhagic cyst and lateral extension into the left cavernous sinus. (B)
Coronal T1-weighted post Gd-DTPA image demonstrating uniform enhancement of solid component. (C) Coronal T2-weighted MR image showing an isointense mass
with high signal in the hemorrhagic cyst. (D) Sagittal T1-weighted MR image demonstrating compression of the optic chiasm.

742
 primary tumors of the central nervous system
50% of microadenomas are hyperintense. Differences in signal
intensity on both T1 and T2 weighting may be subtle and recogni-
tion of these changes may require manipulation of data on the
diagnostic console.
Contrast-enhanced images obtained with dynamic scanning
during or immediately after injection of a bolus of intravenous
contrast medium (Fig. 31.67B) may allow visualization of tumors
that are isointense on precontrast T1- and T2-weighted studies.
Deviation of the pituitary stalk and localized bulging of the gland
are of less value than signal intensity change in the identification
of microadenomas.
Adrenocorticotrophic hormone-secreting adenomas are usually
the smallest tumors, with an average size of 3 mm in diameter.
Sixty-five percent of tumors should be identified on unen-
hanced MR imaging with an increase to 75% following injec-
tion of gadolinium (211). This still leaves a significant number
of false negative investigations. Petrosal venous sampling may
be used to confirm that the site of ACTH secretion is within the
pituitary and not ectopic in origin. This technique is not as reli-
able in lateralising the tumor as confirming that the tumor is in
the pituitary. However, accuracy in lateralization seems to be
related to size, with the greatest degree of accuracy occurring
with the smaller tumors, i.e., those that have been hardest to
find on MR imaging.
18
FDG PET has also been shown to be as effective as MR imaging
in detecting microadenomas (211).
Follow-up of Microadenomas
Most microadenomas are treated medically. It is extremely rare
for microadenomas to increase significantly in size over the years,
especially if they are prolactinomas (7). Therefore there is little
indication for repeated imaging rather than following these
patients by monitoring the prolactin level.
(A)
Figure 31.69 (A) Coronal and (B) sagittal T1-weighted MR images showing appearance at six months post surgery in the same patient as shown in Fig. 31.68. There is
marked reduction in the size of the mass. Note high signal at the base of the pituitary stalk presumed to be due to neurosecretory granules. This scan acts as a base line
for further follow-up imaging.
In patients receiving bromocriptine, hemorrhages are a fairly
common finding on MR imaging. An incidence of 45% has been
reported in patients receiving the drug as opposed to 13% in
patients not receiving it (212).
Imaging of Macroadenomas
Macroadenomas usually present because of pressure effects on
adjacent structures and, although medical management may be
successful in reducing tumor size, surgery is the usual treatment,
particularly in patients with non-functioning adenomas with
rapidly deteriorating vision. Transsphenoidal hypophysectomy
is the surgical approach of choice (213). Prior to surgery the full
extent of the tumor needs to be evaluated (Fig. 31.68), particu-
larly its relationship to the major vessels and cavernous sinuses.
Magnetic resonance is now the investigation of choice because it
has multiplanar imaging capacity and the ability to demonstrate
the relationship of the mass to adjacent vessels. Imaging of
macroadenomas reveals a soft tissue mass expanding the sella
which commonly extends into the suprasellar cisterns. On
T1-weighted images, macroadenomas are of low signal intensity
(Fig. 31.66). The normal pituitary tissue is not usually identifi-
able as a separate structure. An area of high signal intensity
change on T1 weighting may be seen lying in the posterior aspect
of the tumor outside the sella (Fig. 31.66). Although the exact
cause of the high signal intensity remains unknown it is consid-
ered to represent neurosecretory granules that consist of anti-
diuretic hormone (ADH) – neurohysin (a carrier protein)
packaged within a phospholipid membrane (208,214). Because
of the large size of the mass this material cannot descend through
the stalk to its normal position. A similar phenomenon may be
seen to develop on postoperative images (Fig. 31.69) and its
absence may be useful in predicting long-term postsurgical dia-
betes insipidus. The majority of the mass enhances with contrast
(B)
743
 primary tumor evaluation and staging
medium but there may be areas of non-enhancement due to cystic
degeneration, necrosis, or hemorrhage.
Macroadenomas are more commonly hemorrhagic than micro-
adenomas. Hemorrhage may be seen as areas of high signal inten-
sity on both T1- (Fig. 31.68A and D) and T2-weighted images (Fig.
31.68C). Focal areas of hemorrhage are frequently asymptomatic
and not associated with pituitary apoplexy (210).
On T2-weighted images, macroadenomas are more commonly
hyperintense than microadenomas. Hyperintensity on T2-weighted
images has been presumed to indicate that the tumor is relatively
soft or necrotic, more amenable to suction and hence to surgical
management (215). This finding, however, has not been found to
be consistent by all workers and therefore it cannot be concluded
that high signal intensity change on T2 weighting is a good indicator
of tumor consistency (7).
Superior extension of the tumor and its relation to the chiasm
and optic nerves is well demonstrated on MR imaging. Lateral
extension and involvement of the cavernous sinus is more difficult
to evaluate. The medial wall of the cavernous sinus is thin and, as
yet, MR imaging has proved unreliable in detecting early involve-
ment. With more extensive tumor there is lateral displacement of
the lateral wall of the cavernous sinus (Fig. 31.68A–C). Widening
of the distance between the carotid artery and the lateral wall of
the cavernous sinus is also indicative of invasion. The internal
carotid arteries may be encased by tumor but are rarely com-
pressed. Careful assessment of the encasement by tumor of the
carotid artery may aid in predicting involvement of the cavernous
sinus (216).
Inferior extension of tumor occurs into the sphenoid sinus and
the tumor may also destroy the bony walls and clivus. Both of these
features are readily appreciated on MR imaging; however, if recog-
nition of this pattern of destruction is essential for differentiating a
pituitary tumor from another tumor type, then CT has advantages
over MR. Assessment of the bony trabeculae within the sphenoid
(A)
Figure 31.70 Postsurgical appearance, at five days, in the same patient as shown in Fig. 31.66. Coronal (A) T1-weighted and (B) T2-weighted MR images. The mass is
of virtually identical size to the preoperative scan, the central inhomogeneity is from Surgicel used as packing. A defect is seen in the floor of the fossa and a “surgical”
channel in the inferior part of the mass. High signal intensity within the sphenoid sinus is from retained secretions.
744
sinus may be made either by CT or MR imaging and is of value to
the surgeon when planning the trans-sphenoidal route.
Follow-up Imaging of Macroadenomas
Following surgery, especially in the immediate postoperative
period, the size of the mass may appear virtually identical to the
preoperative scans (Fig. 31.70) and there will be a persistent supra-
and intrasellar component (213,217,218). In most patients, rou-
tine postoperative scanning is not performed and the patient is
assessed clinically with hormonal and visual-field studies (213).
However, the normal postsurgical appearances need to be appre-
ciated if complications of surgery are suspected or if alternative
treatment is planned and a baseline needs to be established.
During surgery, the cavity may be packed with gelfoam, surgicel,
or similar material, or with fat. The sphenoid sinus may also be
packed with fat and sometimes muscle. The sinus is commonly
obliterated in the immediate postoperative period due to mucosal
thickening and retained secretions. Initially, the pituitary mass is of
similar size to the preoperative scan, both on CT and MR imaging
and may even be shown to have increased (213,217,218). The mass
commonly shows rim enhancement with contrast medium; the
enhancing rim may, especially if nodular, indicate residual tumor;
if fine and linear it is probably a pseudocapsule or residual com-
pressed normal pituitary tissue (219). More centrally, placed within
the lesion where there is packing material, there is inhomogeneous
signal intensity (Fig. 31.70), the signal intensity characteristics of
which are partly dependent on the material used.
Delayed imaging after four to six months usually demonstrates
that the pituitary gland has returned towards normal size (Fig.
31.69) and the size of the soft tissue mass at this stage acts as a base-
line. Gelfoam is resorbed within a few months, when a new baseline
can be obtained (213). When fat is used as the packing material,
the mass effect persists for longer with deformity of the gland
and is very difficult to differentiate from recurrent tumor (213).
(B)
 primary tumors of the central nervous system
Incomplete trans-sphenoidal resection of macroadenomas extend-
ing into the chiasmatic cistern, cavernous sinuses, or dorsal to the
clivus is not uncommon. Contrast-enhanced MR imaging in the first
few days after surgery may be used to identify residual tumor and
prompt a second operation to effect more radical excision (219).
With time, herniation of the optic nerves and tracts may occur
into the enlarged but mainly empty sella (Fig. 31.71) and may or
may not result in visual symptoms (213). The focal area of high
signal intensity seen on the surface of the gland at the lower end of
the pituitary stalk can usually be identified on the postoperative
scans. The suspected mechanism is blockage of the hypophyseal–
pituitary axis with an accumulation of neurosecretory granules at
the diaphragm sellae (Fig. 31.69) (219).
It is not possible to resect the tumor totally via the trans-
sphenoidal route in between 20% and 50% of patients with acro-
megaly. These patients will usually go on to have radiation therapy
or medication. Octreotide, which is a long-acting somatostatin
analogue, has been shown to reduce growth hormone levels and
also to reduce tumor size (220). Most of the shrinkage occurs
within the first 6 to 12 months of starting medication but further
small decreases in volume may be seen over succeeding years.
Unenhanced imaging is probably sufficient follow-up to docu-
ment tumor shrinkage but hormone levels and monitoring visual
fields are also important. Local tumor control for irradiated non-
functioning adenomas is excellent, ranging from 80% to 90%
(112). Control for secreting tumors depends on the series but
appears to be in the range of 50% to 80%. Considerable concern
has been raised about the effect of radiation on adjacent normal
brain structures in this group of patients, particularly as they may
be relatively young and therefore are likely to survive long-term so
that the delayed effect of radiation becomes relevant. Some of
the complications that have been reported are possibly due to
treatment protocols which are no longer in use. Optimal radiation
dose and technique yield a risk rate in the range of 1% for cerebral
radiation necrosis or optic atrophy (112). Optic atrophy usually
occurs within a year of treatment and is more common in
Figure 31.71 Pituitary adenoma treated with surgery and radiotherapy. Coronal
T1-weighted MR image demonstrating only small residual tissue left in the floor of
the enlarged sella, and slight downward herniation of the chiasm.
acromegalics, Cushing’s disease and hypertensives. Radiation-
induced optic neuritis usually presents with sudden painless loss
of vision. The diagnosis may be made by demonstrating enhance-
ment of the optic nerves on MR imaging (7).
In young patients, there is the risk of developing secondary
malignancy. The latent period is usually four to 12 years and the
most common form of tumors are meningiomas, astrocytomas
(Fig. 31.32) and fibrosarcomas (112).
Key Points: Pituitary Macroadenomas
■ Macroadenomas compress the optic chiasm and visual
pathways and may be non-functioning
■ MR signal intensity characteristics do not necessarily assess
the consistency of the tumor accurately
■ The superior and inferior extent of tumor is well assessed on
MR imaging
■ The lateral extent of tumor into the cavernous sinus is more
difficult to assess on MR imaging
■ The size of the immediate postoperative mass is very similar
to the size of the preoperative mass
■ With resorption of packing material the pituitary mass
decreases in size during the first few months post-
operatively
■ The optimum time for baseline scanning has not been fully
determined, but is probably approximately three to four
months
■ Tumor progression or response to the treatment is evaluated
by alteration in tumor size
■ Medical treatment has been shown to reduce tumor size
■ Radiotherapy is an excellent method of achieving tumor
control
Craniopharyngioma
Craniopharyngiomas are one of the most common supratentorial
tumors of childhood. Fifty percent of cases occur in the first and
second decade with a second peak incidence in the fifth decade
(25). The sites of involvement, in order of frequency are:
• Hypothalamic region – 75%
• Suprasellar and intrasellar – 21%
• Purely intrasellar – 4% (221)
The tumor is composed of epithelial cells which probably arise
from squamous cell rests normally found at the junction of the
pituitary stalk and pars distalis; this is considered to be remnants
of Rathke’s pouch (25). There are two histological subtypes:
adamantinomatous, occurring mainly in children, and a papillary
type, which is more common in adults (222). The tumors form
keratin and large cysts with calcification being common. At the
margins of the tumor there is a pronounced tendency of the epi-
thelial fronds to penetrate deep into brain tissue making resection
difficult (25).
Patients present because of failing vision secondary to compres-
sion of the chiasm or with headache due to hydrocephalus when
the tumor extends far enough superiorly to obstruct CSF flow at
the foramen of Monro. They may also have endocrine dysfunction
secondary to compression of the anterior pituitary, resulting in
745
 primary tumor evaluation and staging

growth failure and involvement of the pituitary stalk leading to
diabetes insipidus.
In children with the adamantinomatous type tumor, the hall-
mark on imaging studies is cyst formation and calcification in the
characteristic suprasellar site (Fig. 31.72), features seen in 90% of
patients. Contrast enhancement is also seen in 90% of cases. In
adults, the tumors are commonly solid and any cystic component
relatively small.
Computed Tomography Appearances
The suprasellar cyst is well demonstrated on CT; there may be a
simple, rounded cyst but many are lobulated and can be very exten-
sive (Fig. 31.73). The contents of the cyst are usually of slightly
higher density than CSF and may occasionally show evidence of
hemorrhage. The cyst wall may show contrast enhancement but
more commonly the associated nodular mass that lies in the cyst
wall enhances and also shows calcification.
Magnetic Resonance Imaging Appearances
The suprasellar location of the lesion and its relationship to the
pituitary and optic chiasm are usually clearly demonstrated on
sagittal and coronal images (221,223). The relationship to the
chiasm determines the surgical classification into prechiasmatic
(with extension of the mass anterior to the chiasm between the
optic nerves) and retrochiasmatic (with the mass involving the
third ventricle and extending posterior to the dorsum sellae).
The contents of craniopharyngioma cysts can be highly variable.
Some are described as containing clear, straw-like fluid, others as
containing an engine-oil-like substance. These features lead to
different signal intensity characteristics being observed on MR
imaging. Hemorrhage may also complicate the picture. The most
common appearance on MR imaging is a cyst of slightly higher
signal intensity than CSF on T1-weighted images (Fig. 31.72A
and B) and with a very bright signal intensity on T2-weighted
images (Fig. 30.72C) (223). However, the cyst contents may also

(A) (B)

(C) (D)
Figure 31.72 Craniopharyngioma. (A) Sagittal T1-weighted and (B) coronal T1-weighted MR images post Gd-DTPA. Suprasellar mass with cystic and solid enhancing
components. (C) Coronal T2-weighted MR images demonstrating elevation of the optic chiasm and (D) the heterogeneous signal in the solid component.

746
 primary tumors of the central nervous system
Figure 31.73 Craniopharyngioma. Unenhanced CT with calcification in the third
ventricle and in the cyst walls with multiple cyst formation.
be of marked hyperintensity on T1 weighting secondary to a
high protein content. Although the solid and cystic components
are both of high signal intensity on T2 weighting, the solid
component is relatively hypointense (Fig. 31.72D). In 25% of
paediatric tumors, the cysts may be very large, extending into the
anterior, middle, and posterior cranial fossae (224). Contrast
enhancement of the solid component of the tumor usually
occurs (Fig. 31.72B).
Differential Diagnosis
The main differential diagnosis in children is that of a chiasmatic
glioma (described in the section on pilocytic astrocytoma), which
may also have a large cystic component. However, a central tumor
with a smooth-walled cyst is most likely to be a craniopharyngioma.
The presence of calcification is also highly suggestive of a cranio-
pharyngioma (Fig. 31.73) and therefore CT, in addition to MR
imaging, should be used to assist in the differential diagnosis (221).
Proton MRS shows a broad lipid spectrum, very different from the
spectra found in astrocytomas (225). In adults, although pituitary
adenoma is the most common tumor in this site, craniopharyn-
gioma must also be considered in the diagnosis, particularly if there
is a large cystic or necrotic component to a suprasellar mass.
Prognosis and Treatment
Craniopharyngiomas are slow-growing and relatively benign but
without treatment there is usually a gradual progression of disease
leading eventually to death. Microsurgical techniques have
improved the ability to remove these tumors totally and therefore
improve survival. As previously described, these tumors may be
intimately related to the adjacent brain and therefore difficult to
dissect (226). For this reason, there may be long-term sequelae,
including hypothalamic and endocrine dysfunction, requiring
long-term medical management. Damage to major vessels may
occur at the time of surgery, leading to infarction of the brain.
These patients may also receive radiotherapy for residual or recur-
rent disease but it is to be avoided in very young children, particu-
larly under the age of six years. Because of the relatively benign
natural history of craniopharyngioma, patients may survive for
many years and therefore have the potential to develop the late com-
plications of radiotherapy. Patients presenting under the age of five
years with hydrocephalus and hypothalamic dysfunction are most
likely to have severe long-term hypothalamic dysfunction (227).
Key Points: Craniopharyngiomas
■ Craniopharyngioma is one of the most common supra-
tentorial tumors of childhood
■ Seventy-five percent of craniopharyngiomas arise in the
hypothalamic region
■ The characteristic feature of a craniopharyngioma is a
suprasellar tumor showing cyst formation and calcification
■ These tumors are rarely intrasellar lesions
■ The MR imaging appearances are usually those of a cyst with
very high signal intensity on T2-weighted images and slightly
higher signal intensity than CSF on T1-weighted images
■ On MR imaging, contrast enhancement of the solid compo-
nent of the tumor is usually seen
■ The main differential diagnosis of a craniopharyngioma in
childhood is a chiasmatic glioma
■ Microsurgical techniques have improved the ability to
totally remove these tumors but there is a risk of long-term
hypothalamic dysfunction
■ Radiotherapy has a place in patient management but not in
young children under the age of six years
Tumors Arising from the Skull Base
Tumors and inflammatory disease may arise within the base of
the skull and extend to affect the adjacent brain resulting in cranial
nerve palsies and compression of major cerebral vessels. Some of
these tumors, including meningiomas, schwannomas, paragan-
gliomas, and pituitary adenomas, have already been covered.
Malignant or inflammatory disease may arise within the sinuses
and nasopharynx and extend through the skull and dura leading
to a neurological presentation. Primary disease of the bone may
arise within the skull base and include:
• Metastases from, in particular, carcinoma of breast
• Paget’s disease
• Eosinophilic granuloma
• Fibrous dysplasia
• Plasmacytoma/myeloma
• Primary bone tumors, particularly those of chondroid
origin
In diagnosing these tumors, CT is usually of value in determining
the differential diagnosis as it is able to delineate the pattern and
distribution of bone destruction. Magnetic resonance imaging has
the advantage of being able to delineate the full extent of soft
tissue and bone marrow disease in different anatomical planes,
thereby determining surgical resectability. Imaging may also
suggest that the skull base lesion is part of a more systemic disease
process, thereby alerting the clinician to seek evidence from
alternative imaging, biochemical or hematological tests.
747
 primary tumor evaluation and staging
Chordomas
Chordomas are histologically benign tumors arising from intra-
osseous vestigial remnants of the notochord. They are firm lobu-
lated masses which are commonly partly hemorrhagic. They are
locally invasive and capable of extensive bone destruction (25).
Approximately one-third of chordomas arise in the basi-sphenoid
(the others being spinal in origin), where they may extend exten-
sively into the nasopharynx, superiorly into the sellar and parasellar
Figure 31.74 Sagittal T1-weighted MR image of a chordoma. There is a large mass
centered on the clivus which extends posteriorly to indent the brain stem. The
cortical margins of the clivus are destroyed by the tumor which also extends
upwards into the supersellar region and anteriorly into the nasopharynx.
(A) (B)
Figure 31.75 Following the mobilization of skin and facial muscle an osteotomy is performed and the maxilla is separated along the lines indicated in (A). It is then
retracted, (B) allowing greater access to tumors arising in the skull base. Following surgery the two parts of maxilla are realigned and wired together. Source: Courtesy of
Miss Anne Moore, Consultant Neurosurgeon, Atkinson Moreley’s Hospital.
748
region, or posteriorly to invade the posterior fossa and compress the
brain stem. They rarely invade the dura but affect the adjacent brain
by direct pressure or vascular occlusion. The peak incidence of these
tumors is between 20 and 40 years of age.
Imaging
Computed tomography usually demonstrates a midline soft tissue
mass centered on the clivus with destruction of the adjacent bone.
The relationship of the tumor to the adjacent structures is best
demonstrated on sagittal T1-weighted MR imaging (Fig. 31.74).
The normal high signal intensity of the adult fatty bone marrow is
replaced by the low signal intensity of the mass. The main clue to
the diagnosis is the location of the mass in the midline with its
epicentere in the posterior aspect of the clivus. Signal intensity
characteristics are variable and may reflect the highly vascular
nature of the tumor with hemorrhagic areas. On T2-weighted
images the tumor is usually hyperintense but shows heterogeneity.
Contrast enhancement is a common feature (228).
Magnetic resonance venography, MRA, or conventional angio-
graphy may be used to demonstrate the displacement or occlusion
of major vessels prior to surgery.
Prognosis and Treatment
New surgical techniques are being developed to improve access
to the skull base and therefore allow more extensive surgical
removal. Prognosis depends on excision of the tumor and
slowing or halting the progression of disease. Faciomaxillary
surgeons are able to mobilize the facial bones and structures by
means of a Le Four maxillotomy to improve access to the skull
base and therefore enable a larger area of tumor to be resected
(Fig. 31.75) (229).
 primary tumors of the central nervous system
Repeat operations may be performed, using the same operative
technique, to remove recurrent disease and thereby improve long-
term survival. Follow-up imaging is required to identify an enlarging
soft tissue mass indicating disease progression. Differentiation needs
to be made from postsurgical change and the assessment of these
tumors is improved if both MR and CT images are obtained.
Primary Bone Tumors
Primary bone tumors, both benign and malignant, may be found
rarely in the basi-sphenoid. The clivus and skull base develop by
endochondral ossification and, for this reason, chondroid tumors,
both benign and malignant, are more common in this site than
osteogenic tumors. Chondrosarcomas may have a very similar
appearance to chordoma; however, they are more likely to be
eccentric in position. Computed tomography should be performed
to delineate the pattern of bone destruction. Small punctate areas
of calcification are more commonly seen in chondrosarcomas (Fig.
31.76). Some primary bone tumors are amenable to the same radi-
cal surgery approach as has been described for chordomas.
Key Points: Skull Base Tumors
■ There is a wide differential diagnosis of tumors arising in the
skull base
■ Chordoma is a histologically benign tumor arising from
vestigial remnants of the notochord
■ Approximately one-hird of chordomas arise in the
basi-sphenoid
■ Chondrosarcomas may also arise in the basi-sphenoid but
are more likely to be eccentric in position than chordoma
■ CT is of value to determine the pattern of bone destruction
and to look for new bone formation in chondrosarcomas
Figure 31.76 Chondrosarcoma. Unenhanced CT showing a soft tissue mass centered
on the basi-sphenoid and containing areas of punctate calcification.
SPINAL NEOPLASMS
Spinal tumors can be categorized on an anatomical basis into
those arising outside the dura (extradural) and those arising within
the dura (intradural). Extradural tumors originate in the:
• Osseous structures
• Adjacent soft tissues
• Epidural space
The most common extradural malignant tumor in adults is meta-
static disease. Primary extradural malignant tumors are much less
common and include:
• Plasmacytoma
• Chordoma
• Hodgkin’s disease
• Non-Hodgkin’s lymphoma
• Osteosarcoma
• Granulocytic sarcoma
Intradural tumors may arise from within the spinal cord itself
(intramedullary), or from the linings of the cord and nerve roots
(extramedullary). Establishing the location of the tumor in relation
to the dura, the cord, and the nerve roots is critical to the differential
diagnosis of spinal tumors. The ability of MR imaging to do just
this makes it the investigation of choice for all spinal neoplasms.
Computed tomography may also be helpful if more detailed bony
assessment is required, particularly if surgery is contemplated.
Intramedullary Tumors
The vast majority of tumors arising within the spinal cord are glial
neoplasms. Astrocytomas and ependymomas make up 90% of this
group. Astrocytomas are the most common intramedullary tumor
in children, but in the adult population they are less common than
ependymomas. Rarer tumors include gangliocytomas, ganglioneu-
romas, hemangioblastoma, and paraganglioma. Gangliocytomas
and ganglioneuromas have been under-reported in the past and
diagnosed as astrocytomas (230). Differentiation among the differ-
ent histological types is not usually possible on imaging in the
majority of cases. Imaging is performed to define the structures
involved, confirm the lesion is intramedullary and exclude the
possibility of acute demyelination or congenital syrinx.
Astrocytomas
The majority of spinal cord astrocytomas are fibrillary astro-
cytomas of low histological grade; 75% are low grade in adults
and 90% are low grade in children (231,232). Microscopically,
these tumors show local infiltration in a similar manner to low-
grade fibrillary tumors in the brain (231). High-grade tumors
(Grade IV) occur rarely and have a poor prognosis. The natural
history of low-grade astrocytomas is long, as is the duration of
symptoms at the time of presentation. Overall survival at five
years is 68% but depends on tumor grade (232). Patients with
high-grade gliomas rarely survive more than two years; high-
grade gliomas are more common in children. Some children will
have pilocytic astrocytomas of the cord; these are associated with
a significantly better prognosis than fibrillary astrocytoma
(233). Back pain is a common presenting complaint, with sensory
749
 primary tumor evaluation and staging
(A) (B)
Figure 31.77 Astrocytoma of the cervical cord in a patient with neck pain of several months’ duration and only minor neurological signs. (A) Sagittal T2-weighted MR
image with extensive high signal change and expansion of the cord. (B) Sagittal T1-weighted MR image with ill-defined low signal. (C) On the post Gd-DTPA image there
is patchy enhancement which does not define the extent of tumor.
Figure 31.78 Cervical cord astrocytoma. Enhanced sagittal T1-weighted MR image
with extensive expansion of the cervical cord and spinal canal with an enhancing
nodular mass at the T1 level. The cystic areas above the enhancing tumor mass do
not show any enhancement and represent non-neoplastic cysts. The enhancing
nodule represents the tumor.
impairment and weakness developing later. Children may present
with a progressive scoliosis. Treatment options include radiother-
apy alone or radiotherapy as an adjunct to surgery; however, there
are advocates of radical surgery alone (231). Local recurrence can
occur but is less likely in younger patients (232).
750
(C)
Magnetic Resonance Imaging Appearances
Diffuse expansion of the cord over a number of levels is character-
istic of these tumors; the thoracic cord is the commonest site of
involvement. Lesions are iso- or hypointense on T1-weighted
sequences and hyperintense on T2-weighted sequences (Fig. 31.77A
and B). In comparison to low-grade gliomas in the brain, most cord
tumors, despite their low-grade, show at least partial enhancement
after gadolinium injection (234). The extent and pattern of contrast
enhancement does not delineate tumor extent or predict tumor
grade (Fig. 31.77C). Intratumoural (enhancing) cysts may be distin-
guished. Non-enhancing cysts, or a syrinx (Fig. 31.78), lying above
or below the tumor are often identified and can be extensive. If the
cyst wall does not enhance they are usually non-neoplastic and
although they may be of relatively high signal intensity due to their
high protein content, do not contain tumor (235,236). They usually
resolve following surgery for the solid component of the mass.
Ependymomas
These are the commonest intramedullary tumors found in adults;
the mean age at presentation is 43 years. They arise from ependy-
mal cells lining the central canal or from within the filum termi-
nale. The commonest site is in the conus and filum terminale
when tumors are usually of the myxopapillary subtype, generally
associated with a better prognosis. The cervical cord is the second
most common location; these are usually of the cellular sub-
type. Rarely, myxopapillary ependymomas occur ectopically out-
side the CNS in the sacrum and presacral tissues. Ependymomas
are well-defined tumors often showing areas of hemorrhage
and cystic degeneration. However, there is no clear correlation
between histological features and biological aggressiveness in these
tumors (237). Treatment is surgical, often followed by localized
 primary tumors of the central nervous system

radiotherapy, as there is a possibility of late local recurrence, 10%
to 19%, particularly if resection is subtotal (238).
Magnetic Resonance Imaging Appearances
Expansion of the cord or filum terminale is typical. Widening of the
canal and scalloping of the vertebral bodies is seen in a minority of
cases and reflects the slow-growing nature of ependymomas. Tumors
are isointense on T1-weighted sequences and hyperintense on
T2-weighted sequences, although they may be heterogeneous. Low
signal intensity on T2-weighted sequences, indicative of hemosid-
erin, is strongly suggestive of ependymoma (Fig. 31.5) (239). Cystic
change is also seen. Reliable differentiation between astrocytomas
and ependymomas is not always possible on MR imaging, but the
presence of hemorrhage may be helpful in suggesting ependymoma.
Although the enhancement of astrocytomas has been noted to be
more patchy and irregular, this is not a reliable discriminator (234).
Ependymomas also tend to be more well-defined than astrocytomas
and in adults sited on or adjacent to the conus.
Spinal Hemangioblastoma
Most intramedullary tumors are diffuse and extensive at the time of
presentation; in comparison, hemangioblastomas (which constitute
3% of intramedullary tumors) are usually small and focal. The area of
intense enhancement delineates the tumor and separates it from
associated cysts and the extensive edema which is demonstrated above
and below the tumor on T2-weighted imaging. The focal area of
intense enhancement (Fig. 31.79) with extensive edema usually dif-
ferentiates these tumors from astrocytomas and ependymomas but

(A) (B)

(C)
Figure 31.79 Spinal hemangioblastoma. (A) Sagittal T2-weighted MR image demonstrating small, well-defined isointense tumor with adjacent high signal intensity cyst
and edema extending up and down the cord. (B) Sagittal and (C) axial postcontrast T1-weighted MR image showing intensely enhancing tumor nodule situated adjacent
to the pial surface.

751
 primary tumor evaluation and staging

(A) (B)
Figure 31.80 Meningioma. (A) Sagittal T2-weighted MR image of the cervical spine shows an intradural extramedullary mass displacing the cord anteriorly. The mass
is isointense with the cord (just as intracranial meningiomas are often isointense with gray matter). (B) Contrast-enhanced sagittal T1-weighted MR image showing
well-defined, enhancing mass.

metastases to the cord from breast, bronchus, kidney, and colon as

well as melanoma and lymphoma can give similar appearances. There
may be serpiginous signal intensity voids representing tumor vessels.
Although most commonly intramedullary, hemangioblastomas may
also be intradural extramedullary. They may also be multiple.

Treatment
Complete surgical resection is the treatment of choice and tumors
rarely recur. Follow-up imaging will show resolution of edema but
the cord is usually atrophied.

Intradural Extramedullary Tumors

Meningiomas and nerve sheath tumors account for 90% of these
lesions. Paragangliomas and other lesions are rare.
Meningiomas
These typically occur in women in the fifth and sixth decades of
life. They are generally the benign type of meningioma, are amen-
able to surgical excision and rarely recur (240). The thoracic spine
is the commonest site. Multiple spinal meningiomas are rare,
except in neurofibromatosis.
Magnetic Resonance Imaging Appearances
Spinal meningiomas have the same signal intensity characteristics
as intracranial meningiomas [predominantly isointense to gray
matter on both T1- and T2-weighted sequences (Fig. 31.80)] and
homogeneous enhancement is typical (241). Although the vast
majority of meningiomas are entirely intradural, a few show a
“dumb-bell” configuration, being partly intra- and partly extra-
dural, and rarely they are purely extradural. Occasionally, calcified
meningiomas will return very low signal intensity on MR imaging.
Figure 31.81 Spinal neurofibromas. Axial T2-weighted MR image demonstrates
a high signal intensity mass (isointense with CSF) extending through the right
lumbar nerve root foramen which is enlarged. On the left, a high signal intensity
mass in the left psoas muscle is part of another neurofibroma.
Nerve Sheath Tumors
Schwannomas and neurofibromas can occur throughout the
spine, though the lumbar region is the commonest site. Magnetic
resonance imaging cannot reliably distinguish between these two
types of nerve sheath tumor. Malignant nerve sheath tumors are
rare. More than one-third of patients with nerve sheath tumors
have neurofibromatosis (242).
Magnetic Resonance Imaging Appearances
The majority of these lesions are isointense on T1-weighted
sequences and hyperintense on T2-weighted sequences (Fig. 31.81).

752
 primary tumors of the central nervous system
Cystic degeneration is common in schwannomas, which may cause
heterogeneous signal intensity. Enhancement may be homo-
geneous or mainly involve the periphery of the lesion. There are
often associated bony changes, typically enlargement of neural
foramina (Fig. 31.81). Dumb-bell lesions, which are both intra-
and extradural, can be associated with paraspinal masses.
Key Points: Spinal Tumors
■ Spinal tumors are classified as either extradural or intradural
■ In adults, the most common extradural malignant tumor is a
metastasis
■ Intradural tumors may be intramedullary or extramedullary
■ Astrocytomas and ependymomas account for 95% of primary
intramedullary tumors
■ The majority of spinal cord astrocytomas are fibrillary astro-
cytomas of low histological grade
■ On MR imaging, astrocytomas show diffuse expansion of the
cord over several levels. The cervical and thoracic region are
the most common sites of involvement
■ Ependymomas are the commonest intramedullary tumors in
adults
■ The most common site of ependymoma is the conus and
filum terminale
■ Ependymomas are well-defined tumors, often showing
hemorrhage and cystic degeneration
■ Treatment of primary spinal cord tumors is surgical, often
followed by local radiotherapy
■ The most common intradural extramedullary tumors are
meningiomas and nerve sheath tumors, accounting for 90%
of these lesions
■ Meningiomas typically occur in women in the fifth and sixth
decades of life and are usually benign, as are schwannomas and
neurofibromas
ACKNOWLEDGMENTS
We would like to thank Caroline Eley for her assistance in the
preparation of this manuscript.
REFERENCES
1. Department of Health. Improving Outcomes for People with
Brain and CNS Tumors, 2006. National Institute for Health
and Clincial Excellence.
2. Cancer Research UK, CancerStats. [Available from: http://
info.cancerresearchuk.org/cancerstats/types/brain].
3. Kleihues P, Burger PC, Scheithauer BW. The new WHO
classification of brain tumours. Brain Pathol 1993; 3:
255–68.
4. Kleihues P, Sobin LH. Pathology and Genetics of Tumours of
the Nervous System. Lyon: IARC Press, 2000.
5. Russell DS, Rubinstein LJ. Pathology of Tumours of the Nervous
System, 5th edn. Baltimore: Williams and Wilkins, 1989.
6. Bilaniuk LT. Adult infratentorial tumors. Semin Roentgenol
1990; 25: 155–73.
7. Scott W. Magnetic Resonance Imaging of the Brain and
Spine, 3rd edn. Lippincott: Williams & Wilkins, 2002.
8. Singer MB, Atlas SW, Drayer BP. Subarachnoid space dis-
ease: diagnosis with fluid-attenuated inversion-recovery
MR imaging and comparison with gadolinium-enhanced
spin-echo MR imaging—blinded reader study. Radiology
1998; 208: 417–22.
9. Zakhary R, Keles GE, Berger MS. Intraoperative imaging
techniques in the treatment of brain tumors. Curr Opin
Oncol 1999; 11: 152–6.
10. Price SJ. The role of advanced MR imaging in understanding
brain tumour pathology. Br J Neurosurg 2007; 21: 562–75.
11. Watanabe M, Tanaka R, Takeda N. Magnetic resonance imag-
ing and histopathology of cerebral gliomas. Neuroradiology
1992; 34: 463–9.
12. Tovi M. MR imaging in cerebral gliomas analysis of tumour
tissue components. Acta Radiol Suppl 1993; 384: 1–24.
13. Earnest F, Kelly PJ, Scheithauer BW, et al. Cerebral astrocy-
tomas: histopathologic correlation of MR and CT contrast
enhancement with stereotactic biopsy. Radiology 1988; 166:
823–7.
14. Yousry TA, Schmid UD, Alkadhi H, et al. Localization of the
motor hand area to a knob on the precentral gyrus. A new
landmark. Brain 1997; 120: 141–57.
15. Quinones-Hinojosa A, Ojemann SG, Sanai N, Dillon WP,
Berger MS. Preoperative correlation of intraoperative corti-
cal mapping with magnetic resonance imaging landmarks to
predict localization of the Broca area. J Neurosurg 2003; 99:
311–18.
16. Kumar AJ, Leeds NE, Fuller GN, et al. Malignant gliomas:
MR imaging spectrum of radiation therapy- and chemo-
therapy-induced necrosis of the brain after treatment.
Radiology 2000; 217: 377–84.
17. Valk PE, Dillon WP. Radiation injury of the brain. AJNR Am
J Neuroradiol 1991; 12: 45–62.
18. Curnes JT, Laster DW, Ball MR, Moody DM, Witcofski RL.
MRI of radiation injury to the brain. AJR Am J Roentgenol
1986; 147: 119–24.
19. Tsuruda JS, Kortman KE, Bradley WG, et al. Radiation effects
on cerebral white matter: MR evaluation. AJR Am J Roent-
genol 1987; 149: 165–71.
20. Bleyer WA, Griffin TW. White matter necrosis, mineralising
microangiopathy and intellectual abilities in survivors of
childhood leukemia. In: Gilbert HA, Kagan AR, eds. Radiation
Damage to the Nervous System: A Delayed Therapeutic
Hazard. New York: Raven Press, 1980; 150–74.
21. Berger MS, Deliganis AV, Dobbins J, Keles GE. The effect of
extent of resection on recurrence in patients with low
grade cerebral hemisphere gliomas. Cancer 1994; 74:
1784–91.
22. Piepmeier J, Christopher S, Spencer D, et al. Variations in the
natural history and survival of patients with supratentorial
low-grade astrocytomas. Neurosurgery 1996; 38: 872–8.
23. Sawaya R. Extent of resection in malignant gliomas: a critical
summary. J Neurooncol 1999; 42: 303–5.
24. Russell DS, Rubinstein LJ. Pathology of Tumours of the
Nervous System, 5th edn. Baltimore: Williams and Wilkins,
1989.
753
 primary tumor evaluation and staging
25. Okazaki H. Fundamentals of Neuropathology, 1st edn. New
York: Igaku-Shion Medical Publishers Inc., 1983.
26. Dean BL, Drayer BP, Bird CR, et al. Gliomas: classification
with MR imaging. Radiology 1990; 174: 411–15.
27. Castillo M, Scatliff JH, Bouldin TW, Suzuki K. Radiologic-
pathologic correlation: intracranial astrocytoma. Am J Neu-
roradiol 1992; 13: 1609–16.
28. Atlas SW. Primary brain tumours. In: ASNR Core Curricu-
lum in Neuroradiology. Part II: Neoplasms and Infectious
Diseases, 1996: 33–9.
29. Osborn AG. Chapter 13. In: Osborn A, edr. Diagnostic Neu-
roradiology. St Louis: Mosby, 1994: 529–78.
30. Zimmerman RA. Suptratentorial pediatric brain tumors. In:
ASNR Core Curriculum in Neuroradiology. Part II: Neo-
plasms and Infectious Diseases, 1996: 103–11.
31. Krouwer HG, Davis RL, Silver P, Prados M. Gemisto-
cytic astrocytomas: a reappraisal. J Neurosurg 1991; 74:
399–406.
32. Tervonen O, Forbes G, Scheithauer BW, Dietz MJ. Diffuse
“fibrillary” astrocytomas: correlation of MRI features with
histopathologic parameters and tumor grade. Neuroradiol-
ogy 1992; 34: 173–8.
33. Smirniotopoulos JG. The new WHO classification of central
nervous system neoplasms. In: ASNR Core Curriculum in
Neuroradiology. Part II: Neoplasms and Infectious Diseases,
1996: 5–9.
34. Gutin PH, Posner JB. Neuro-oncology: diagnosis and man-
agement of cerebral gliomas––past, present, and future. Neu-
rosurgery 2000; 47: 1–8.
35. Ogawa T, Kanno I, Shishido F, et al. Clinical value of PET
with 18F-fluorodeoxyglucose and L-methyl-11C-methionine
for diagnosis of recurrent brain tumor and radiation injury.
Acta Radiol 1991; 32: 197–202.
36. Lee YY, Van Tassel P. Intracranial oligodendrogliomas: imag-
ing findings in 35 untreated cases. AJR Am J Roentgenol
1989; 152: 361–9.
37. Kyritsis AP, Yung WK, Bruner J, Gleason MJ, Levin VA. The
treatment of anaplastic oligodendrogliomas and mixed
gliomas. Neurosurgery 1993; 32: 365–70.
38. Felsberg GJ, Silver SA, Brown MT, Tien RD. Radiologic-
pathologic correlation. Gliomatosis cerebri. AJNR Am J Neu-
roradiol 1994; 15: 1745–53.
39. Yanaka K, Kamezaki T, Kobayashi E, et al. MR imaging of dif-
fuse glioma. AJNR Am J Neuroradiol 1992; 13: 349–51.
40. Dexter MA, Parker MD, Besser M, Ell J, Fulham MJ. MR
and positron emission tomography with fludeoxyglucose
F 18 in gliomatosis cerebri. AJNR Am J Neuroradiol 1995;
16: 1507–10.
41. Jellison BJ, Field AS, Medow J, et al. Diffusion tensor imaging
of cerebral white matter: a pictorial review of physics, fiber
tract anatomy, and tumor imaging patterns. AJNR Am J
Neuroradiol 2004; 25: 356–69.
42. Mills SJ, Patankar TA, Haroon HA, et al. Do cerebral blood
volume and contrast transfer coefficient predict prognosis in
human glioma? AJNR Am J Neuroradiol 2006; 27: 853–8.
43. Albayrak B, Samdani AF, Black PM. Intra-operative magnetic
resonance imaging in neurosurgery. Acta Neurochir (Wien)
2004; 146: 543–56.
754
44. Sibtain NA, Howe FA, Saunders DE. The clinical value of
proton magnetic resonance spectroscopy in adult brain
tumours. Clin Radiol 2007; 62: 109–19.
45. Law M, Yang S, Wang H, et al. Glioma grading: sensitivity,
specificity, and predictive values of perfusion MR imaging
and proton MR spectroscopic imaging compared with con-
ventional MR imaging. Am J Neuroradiol 2003; 24: 1989–98.
46. Tate AR, Underwood J, Acosta DM, et al. Development of a
decision support system for diagnosis and grading of brain
tumours using in vivo magnetic resonance single voxel spec-
tra. NMR Biomed 2006; 19: 411–34.
47. Boxerman JL, Schmainda KM, Weisskoff RM. Relative cere-
bral blood volume maps corrected for contrast agent extrava-
sation significantly correlate with glioma tumor grade,
whereas uncorrected maps do not. AJNR Am J Neuroradiol
2006; 27: 859–67.
48. Sugahara T, Korogi Y, Kochi M, et al. Correlation of MR
imaging-determined cerebral blood volume maps with his-
tologic and angiographic determination of vascularity of
gliomas. AJR Am J Roentgenol 1998; 171: 1479–86.
49. Law M, Oh S, Babb JS, et al. Low-grade gliomas: dynamic
susceptibility-weighted contrast-enhanced perfusion MR
imaging—prediction of patient clinical response. Radiology
2006; 238: 658–67.
50. Cha S, Tihan T, Crawford F, et al. Differentiation of low-grade
oligodendrogliomas from low-grade astrocytomas by using
quantitative blood-volume measurements derived from
dynamic susceptibility contrast-enhanced MR imaging.
AJNR Am J Neuroradiol 2005; 26: 266–73.
51. Padma MV, Said S, Jacobs M, et al. Prediction of pathology
and survival by FDG PET in gliomas. J Neurooncol 2003; 64:
227–37.
52. Herholz K, Coope D, Jackson A. Metabolic and molecular
imaging in neuro-oncology. Lancet Neurol 2007; 6: 711–24.
53. Xu GW, Mymryk JS, Cairncross JG. Inactivation of p53 sen-
sitizes astrocytic glioma cells to BCNU and temozolomide,
but not cisplatin. J Neurooncol 2005; 74: 141–9.
54. van den Bent MJ, Looijenga LH, Langenberg K, et al. Chro-
mosomal anomalies in oligodendroglial tumors are corre-
lated with clinical features. Cancer 2003; 97: 1276–84.
55. Jenkinson MD, Smith TS, Joyce KA, et al. Cerebral blood
volume, genotype and chemosensitivity in oligodendroglial
tumours. Neuroradiology 2006; 48: 703–13.
56. Jenkinson MD, Smith TS, Brodbelt AR, et al. Apparent diffu-
sion coefficients in oligodendroglial tumors characterized by
genotype. J Magn Reson Imaging 2007; 26: 1405–12.
57. McKnight TR, dem Bussche MH, Vigneron DB, et al. Histo-
pathological validation of a three-dimensional magnetic
resonance spectroscopy index as a predictor of tumor presence.
J Neurosurg 2002; 97: 794–802.
58. Stadlbauer A, Ganslandt O, Buslei R, et al. Gliomas: histo-
pathologic evaluation of changes in directionality and mag-
nitude of water diffusion at diffusion-tensor MR imaging.
Radiology 2006; 240: 803–10.
59. Knauth M, Wirtz CR, Tronnier VM, et al. Intraoperative MR
imaging increases the extent of tumor resection in patients
with high-grade gliomas. AJNR Am J Neuroradiol 1999; 20:
1642–6.
 primary tumors of the central nervous system
60. Martin AJ, Hall WA, Liu H, et al. Brain tumor resection:
intraoperative monitoring with high-field-strength MR
imaging-initial results. Radiology 2000; 215: 221–8.
61. Jackson RJ, Fuller GN, Abi-Said D, et al. Limitations of
stereotactic biopsy in the initial management of gliomas.
Neuro Oncol 2001; 3: 193–200.
62. Hall WA, Martin A, Liu H, Truwit CL. Improving diagnostic
yield in brain biopsy: coupling spectroscopic targeting with
real-time needle placement. J Magn Reson Imaging 2001; 13:
12–15.
63. Maia AC Jr, Malheiros SM, da Rocha AJ, et al. Stereotactic
biopsy guidance in adults with supratentorial nonenhancing
gliomas: role of perfusion-weighted magnetic resonance
imaging. J Neurosurg 2004; 101: 970–6.
64. Hochberg FH, Fischman AJ, Metz R. Imaging of brain
tumors. Cancer 1994; 74: 3080–2.
65. Bernays RL, Kollias SS, Khan N, et al. Histological yield, com-
plications, and technological considerations in 114 consecu-
tive frameless stereotactic biopsy procedures aided by open
intraoperative magnetic resonance imaging. J Neurosurg
2002; 97: 354–62.
66. Fandino J, Kollias SS, Wieser HG, Valavanis A, Yonekawa Y.
Intraoperative validation of functional magnetic resonance
imaging and cortical reorganization patterns in patients
with brain tumors involving the primary motor cortex.
J Neurosurg 1999; 91: 238–50.
67. Roux FE, Boulanouar K, Lotterie JA, et al. Language func-
tional magnetic resonance imaging in preoperative assess-
ment of language areas: correlation with direct cortical
stimulation. Neurosurgery 2003; 52: 1335–45.
68. Witwer BP, Moftakhar R, Hasan KM, et al. Diffusion-tensor
imaging of white matter tracts in patients with cerebral neo-
plasm. J Neurosurg 2002; 97: 568–75.
69. Smits M, Vernooij MW, Wielopolski PA, et al. Incorporating
functional MR imaging into diffusion tensor tractography
in the preoperative assessment of the corticospinal tract in
patients with brain tumors. AJNR Am J Neuroradiol 2007;
28: 1354–61.
70. Balmaceda C, Critchell D, Mao X, et al. Multisection 1H
magnetic resonance spectroscopic imaging assessment of
glioma response to chemotherapy. J Neurooncol 2006; 76:
185–91.
71. Laprie A, Pirzkall A, Haas-Kogan DA, et al. Longitudinal
multivoxel MR spectroscopy study of pediatric diffuse brain-
stem gliomas treated with radiotherapy. Int J Radiat Oncol
Biol Phys 2005; 62: 20–31.
72. Moffat BA, Chenevert TL, Lawrence TS, et al. Functional dif-
fusion map: a noninvasive MRI biomarker for early stratifi-
cation of clinical brain tumor response. Proc Natl Acad Sci
U S A 2005; 102: 5524–9.
73. Jackson A, Kassner A, Annesley-Williams D, et al. Abnor-
malities in the recirculation phase of contrast agent bolus
passage in cerebral gliomas: comparison with relative blood
volume and tumor grade. Am J Neuroradiol 2002; 23: 7–14.
74. Cha S, Knopp EA, Johnson G, et al. Dynamic contrast-
enhanced T2-weighted MR imaging of recurrent malignant
gliomas treated with thalidomide and carboplatin. AJNR Am
J Neuroradiol 2000; 21: 881–90.
75. Cao Y, Tsien CI, Nagesh V, et al. Survival prediction in high-
grade gliomas by MRI perfusion before and during early
stage of RT [corrected]. Int J Radiat Oncol Biol Phys 2006;
64: 876–85.
76. Rock JP, Scarpace L, Hearshen D, et al. Associations among
magnetic resonance spectroscopy, apparent diffusion coef-
ficients, and image-guided histopathology with special
attention to radiation necrosis. Neurosurgery 2004; 54:
1111–17.
77. Asao C, Korogi Y, Kitajima M, et al. Diffusion-weighted
imaging of radiation-induced brain injury for differentiation
from tumor recurrence. Am J Neuroradiol 2005; 26:
1455–60.
78. Zeng QS, Li CF, Liu H, Zhen JH, Feng DC. Distinction
between recurrent glioma and radiation injury using mag-
netic resonance spectroscopy in combination with diffusion-
weighted imaging. Int J Radiat Oncol Biol Phys 2007; 68:
151–8.
79. Forsting M, Albert FK, Kunze S, et al. Extirpation of glioblas-
tomas: MR and CT follow-up of residual tumor and regrowth
patterns. AJNR Am J Neuroradiol 1993; 14: 77–87.
80. Philippon JH, Clemenceau SH, Fauchon FH, Foncin JF.
Supratentorial low-grade astrocytomas in adults. Neuro-
surgery 1993; 32: 554–9.
81. Khoo VS, Oldham M, Adams EJ, et al. Comparison of
intensity-modulated tomotherapy with stereotactically guided
conformal radiotherapy for brain tumors. Int J Radiat Oncol
Biol Phys 1999; 45: 415–25.
82. Schlemmer HP, Bachert P, Herfarth KK, et al. Proton MR
spectroscopic evaluation of suspicious brain lesions after
stereotactic radiotherapy. AJNR Am J Neuroradiol 2001;
22: 1316–24.
83. Graves EE, Nelson SJ, Vigneron DB, et al. Serial proton MR
spectroscopic imaging of recurrent malignant gliomas after
gamma knife radiosurgery. AJNR Am J Neuroradiol 2001;
22: 613–24.
84. Rao CV, Kishore PR, Bartlett J, Brennan TG. Computed
tomography in the postoperative patient. Neuroradiology
1980; 19: 257–63.
85. Elster AD, DiPersio DA. Cranial postoperative site: assess-
ment with contrast-enhanced MR imaging. Radiology 1990;
174: 93–8.
86. Lanzieri CF, Som PM, Sacher M, Solodnik P, Moore F. The
postcraniectomy site: CT appearance. Radiology 1986; 159:
165–70.
87. Hartmann M, Jansen O, Heiland S, et al. Restricted diffusion
within ring enhancement is not pathognomonic for brain
abscess. AJNR Am J Neuroradiol 2001; 22: 1738–42.
88. Bird CR, Drayer BP, Medina M, et al. Gd-DTPA-enhanced
MR imaging in pediatric patients after brain tumor resection.
Radiology 1988; 169: 123–6.
89. Burke JW, Podrasky AE, Bradley WG, Jr. Meninges: benign
postoperative enhancement on MR images. Radiology 1990;
174: 99–102.
90. Destian S, Heier LA, Zimmerman RD, Morgello S, Deck MD.
Differentiation between meningeal fibrosis and chronic sub-
dural hematoma after ventricular shunting: value of enhanced
CT and MR scans. AJNR Am J Neuroradiol 1989; 10: 1021–6.
755
 primary tumor evaluation and staging
91. Fukui MB, Meltzer CC, Kanal E, Smirniotopoulos JG. MR
imaging of the meninges. Part II. Neoplastic disease. Radiol-
ogy 1996; 201: 605–12.
92. Sze G. Leptomeningeal tumor: the “plain vanilla” approach
remains the best. AJNR Am J Neuroradiol 2002; 23: 745–6.
93. van der Knapp MS, Valk J. Leukoencephalopathy after chemo-
therapy and/or radiotherapy. Magnetic Resonance of Myelin,
Myelination and Myelin Disorders, 2nd edn. Berlin, Heidleberg,
New York: Springer-Verlag, 1995.
94. Hecht-Leavitt C, Grossman RI, Curran WJ Jr, et al. MR of
brain radiation injury: experimental studies in cats. AJNR
Am J Neuroradiol 1987; 8: 427–30.
95. Yaffe K, Ferriero D, Barkovich AJ, Rowley H. Reversible
MRI abnormalities following seizures. Neurology 1995; 45:
104–8.
96. Shin RK, Stern JW, Janss AJ, Hunter JV, Liu GT. Reversible
posterior leukoencephalopathy during the treatment of
acute lymphoblastic leukemia. Neurology 2001; 56:
388–91.
97. Ito Y, Arahata Y, Goto Y, et al. Cisplatin neurotoxicity presenting
as reversible posterior leukoencephalopathy syndrome. AJNR
Am J Neuroradiol 1998; 19: 415–17.
98. Hinchey J, Chaves C, Appignani B, et al. A reversible poste-
rior leukoencephalopathy syndrome. N Engl J Med 1996;
334: 494–500.
99. Casey SO, Sampaio RC, Michel E, Truwit CL. Posterior
reversible encephalopathy syndrome: utility of fluid-attenuated
inversion recovery MR imaging in the detection of corti-
cal and subcortical lesions. AJNR Am J Neuroradiol 2000; 21:
1199–206.
100. Covarrubias DJ, Luetmer PH, Campeau NG. Posterior reversible
encephalopathy syndrome: prognostic utility of quantitative
diffusion-weighted MR images. AJNR Am J Neuroradiol
2002; 23: 1038–48.
101. Yamashita J, Handa H, Yumitori K, Abe M. Reversible delayed
radiation effect on the brain after radiotherapy of malignant
astrocytoma. Surg Neurol 1980; 13: 413–17.
102. Graeb DA, Steinbok P, Robertson WD. Transient early computed
tomographic changes mimicking tumor progression after
brain tumor irradiation. Radiology 1982; 144: 813–17.
103. Wiznitzer M, Packer RJ, August CS, Burkey ED. Neurological
complications of bone marrow transplantation in childhood.
Ann Neurol 1984; 16: 569–76.
104. Hoppe-Hirsch E, Brunet L, Laroussinie F, et al. Intellectual
outcome in children with malignant tumors of the posterior
fossa: influence of the field of irradiation and quality of surgery.
Childs Nerv Syst 1995; 11: 340–5.
105. Ball WS Jr, Prenger EC, Ballard ET. Neurotoxicity of radio/
chemotherapy in children: pathologic and MR correlation.
AJNR Am J Neuroradiol 1992; 13: 761–76.
106. Robain O, Dulac O, Dommergues JP, et al. Necrotising leukoen-
cephalopathy complicating treatment of childhood leukaemia.
J Neurol Neurosurg Psychiatry 1984; 47: 65–72.
107. Taylor JS, Langston JW, Reddick WE, et al. Clinical value
of proton magnetic resonance spectroscopy for differenti-
ating recurrent or residual brain tumor from delayed
cerebral necrosis. Int J Radiat Oncol Biol Phys 1996; 36:
1251–61.
756
108. Patronas NJ, Di Chiro G, Brooks RA, et al. Work in progress:
[18F] fluorodeoxyglucose and positron emission tomography
in the evaluation of radiation necrosis of the brain. Radiology
1982; 144: 885–9.
109. Leeds NE, Jackson EF. Current imaging techniques for the
evaluation of brain neoplasms. Curr Opin Oncol 1994; 6:
254–61.
110. Paakko E, Talvensaari K, Pyhtinen J, Lanning M. Decreased
pituitary gland height after radiation treatment to the
hypothalamic-pituitary axis evaluated by MR. AJNR Am J
Neuroradiol 1994; 15: 537–41.
111. Mack EE, Wilson CB. Meningiomas induced by high-dose
cranial irradiation. J Neurosurg 1993; 79: 28–31.
112. Fisher BJ, Gaspar LE, Noone B. Radiation therapy of pitu-
itary adenoma: delayed sequelae. Radiology 1993; 187:
843–6.
113. Giannini C, Scheithauer BW. Classification and grading of
low-grade astrocytic tumors in children. Brain Pathol 1997;
7: 785–98.
114. Palma L, Guidetti B. Cystic pilocytic astrocytomas of the
cerebral hemispheres. Surgical experience with 51 cases and
long-term results. J Neurosurg 1985; 62: 811–15.
115. Kaschten B, Stevenaert A, Sadzot B, et al. Preoperative eval-
uation of 54 gliomas by PET with fluorine-18-fluorodeox-
yglucose and/or carbon-11-methionine. J Nucl Med 1998;
39: 778–85.
116. Fulham MJ, Melisi JW, Nishimiya J, Dwyer AJ, Di Chiro G.
Neuroimaging of juvenile pilocytic astrocytomas: an enigma.
Radiology 1993; 189: 221–5.
117. Kepes JJ. Pleomorphic xanthoastrocytoma: the birth of a
diagnosis and a concept. Brain Pathol 1993; 3: 269–74.
118. Lipper MH, Eberhard DA, Phillips CD, Vezina LG, Cail WS.
Pleomorphic xanthoastrocytoma, a distinctive astroglial
tumor: neuroradiologic and pathologic features. AJNR Am J
Neuroradiol 1993; 14: 1397–404.
119. Giannini C, Scheithauer BW, Burger PC, et al. Pleomorphic
xanthoastrocytoma: what do we really know about it? Cancer
1999; 85: 2033–45.
120. Strong JA, Hatten HP Jr, Brown MT, et al. Pilocytic astrocy-
toma: correlation between the initial imaging features and
clinical aggressiveness. Am J Roentgenol 1993; 161: 369–72.
121. Mishima K, Nakamura M, Nakamura H, et al. Leptomenin-
geal dissemination of cerebellar pilocytic astrocytoma. Case
report. J Neurosurg 1992; 77: 788–91.
122. Kornreich L, Blaser S, Schwarz M, et al. Optic pathway
glioma: correlation of imaging findings with the presence
of neurofibromatosis. Am J Neuroradiol 2001; 22: 1963–9.
123. Alshail E, Rutka JT, Becker LE, Hoffman HJ. Optic chiasmatic-
hypothalamic glioma. Brain Pathol 1997; 7: 799–806.
124. Hoffman HJ, Soloniuk DS, Humphreys RP, et al. Manage-
ment and outcome of low-grade astrocytomas of the mid-
line in children: a retrospective review. Neurosurgery
1993; 33: 964–71.
125. Kane AG, Robles HA, Smirniotopoulos JG, Heironimus JD,
Fish MH. Radiologic-pathologic correlation. Diffuse pontine
astrocytoma. AJNR Am J Neuroradiol 1993; 14: 941–5.
126. Vandertop WP, Hoffman HJ, Drake JM, et al. Focal midbrain
tumors in children. Neurosurgery 1992; 31: 186–94.
 primary tumors of the central nervous system
127. Freeman CR, Bourgouin PM, Sanford RA, et al. Long term
survivors of childhood brain stem gliomas treated with
hyperfractionated radiotherapy. Clinical characteristics and
treatment related toxicities. The Pediatric Oncology Group.
Cancer 1996; 77: 555–62.
128. Barkovich AJ. Pediatric Neuroimaging, 3rd edn. Philadelephia:
Lippincott, Williams & Wilkins, 2000.
129. Fischbein NJ, Prados MD, Wara W, et al. Radiologic classifi-
cation of brain stem tumors: correlation of magnetic reso-
nance imaging appearance with clinical outcome. Pediatr
Neurosurg 1996; 24: 9–23.
130. Krouwer HG, Kim TA, Rand SD, et al. Single-voxel proton
MR spectroscopy of nonneoplastic brain lesions suggestive
of a neoplasm. AJNR Am J Neuroradiol 1998; 19: 1695–703.
131. Saindane AM, Cha S, Law M, et al. Proton MR spectroscopy
of tumefactive demyelinating lesions. AJNR Am J Neurora-
diol 2002; 23: 1378–86.
132. Bruggers CS, Friedman HS, Fuller GN, et al. Comparison of
serial PET and MRI scans in a pediatric patient with a brain-
stem glioma. Med Pediatr Oncol 1993; 21: 301–6.
133. Tzika AA, Zarifi MK, Goumnerova L, et al. Neuroimaging in
pediatric brain tumors: Gd-DTPA-enhanced, hemodynamic,
and diffusion MR imaging compared with MR spectroscopic
imaging. AJNR Am J Neuroradiol 2002; 23: 322–33.
134. Swartz JD, Zimmerman RA, Bilaniuk LT. Computed tomog-
raphy of intracranial ependymomas. Radiology 1982; 143:
97–101.
135. Healey EA, Barnes PD, Kupsky WJ, et al. The prognostic sig-
nificance of postoperative residual tumor in ependymoma.
Neurosurgery 1991; 28: 666–71.
136. Lyons MK, Kelly PJ. Posterior fossa ependymomas: report of
30 cases and review of the literature. Neurosurgery 1991; 28:
659–64.
137. Nazar GB, Hoffman HJ, Becker LE, et al. Infratentorial
ependymomas in childhood: prognostic factors and treat-
ment. J Neurosurg 1990; 72: 408–17.
138. Rezai AR, Woo HH, Lee M, et al. Disseminated ependymomas
of the central nervous system. J Neurosurg 1996; 85: 618–24.
139. Naidich TP, Zimmerman RA. Primary brain tumors in chil-
dren. Semin Roentgenol 1984; 19: 100–14.
140. Smirniotopoulos JG. Intraventricular tumours: radiologic-
pathologic correlation. In: ASNR Core Curriculum in Neuro-
radiology. Part II: Neoplasms and Infectious Diseases, 1996:
113–19.
141. Spoto GP, Press GA, Hesselink JR, Solomon M. Intracranial
ependymoma and subependymoma: MR manifestations.
AJNR Am J Neuroradiol 1990; 11: 83–91.
142. Ikezaki K, Matsushima T, Inoue T, et al. Correlation of micro-
anatomical localization with postoperative survival in poste-
rior fossa ependymomas. Neurosurgery 1993; 32: 38–44.
143. Armington WG, Osborn AG, Cubberley DA, et al. Supratentorial
ependymoma: CT appearance. Radiology 1985; 157: 367–72.
144. Berger C, Thiesse P, Lellouch-Tubiana A, et al. Choroid plexus
carcinomas in childhood: clinical features and prognostic
factors. Neurosurgery 1998; 42: 470–5.
145. Martin N, Pierot L, Sterkers O, Mompoint D, Nahum H.
Primary choroid plexus papilloma of the cerebellopontine
angle: MR imaging. Neuroradiology 1990; 31: 541–3.
146. Diepholder HM, Schwechheimer K, Mohadjer M, Knoth R,
Volk B. A clinicopathologic and immunomorphologic study
of 13 cases of ganglioglioma. Cancer 1991; 68: 2192–201.
147. Tampieri D, Moumdjian R, Melanson D, Ethier R. Intracerebral
gangliogliomas in patients with partial complex seizures: CT
and MR imaging findings. AJNR Am J Neuroradiol 1991; 12:
749–55.
148. Castillo M, Davis PC, Takei Y, Hoffman JC Jr. Intracranial
ganglioglioma: MR, CT, and clinical findings in 18 patients.
AJNR Am J Neuroradiol 1990; 11: 109–14.
149. VandenBerg SR. Desmoplastic infantile ganglioglioma and
desmoplastic cerebral astrocytoma of infancy. Brain Pathol
1993; 3: 275–81.
150. Martin DS, Levy B, Awwad EE, Pittman T. Desmoplastic
infantile ganglioglioma: CT and MR features. AJNR Am J
Neuroradiol 1991; 12: 1195–7.
151. Goergen SK, Gonzales MF, McLean CA. Interventricular
neurocytoma: radiologic features and review of the litera-
ture. Radiology 1992; 182: 787–92.
152. Wichmann W, Schubiger O, von Deimling A, Schenker C,
Valavanis A. Neuroradiology of central neurocytoma. Neu-
roradiology 1991; 33: 143–8.
153. Hassoun J, Soylemezoglu F, Gambarelli D, et al. Central neu-
rocytoma: a synopsis of clinical and histological features.
Brain Pathol 1993; 3: 297–306.
154. Smoker WR, Townsend JJ, Reichman MV. Neurocytoma
accompanied by intraventricular hemorrhage: case report
and literature review. Am J Neuroradiol 1991; 12: 765–70.
155. Daumas-Duport C. Dysembryoplastic neuroepithelial
tumours. Brain Pathol 1993; 3: 283–95.
156. Ostertun B, Wolf HK, Campos MG, et al. Dysembryoplastic
neuroepithelial tumors: MR and CT evaluation. AJNR Am
J Neuroradiol 1996; 17: 419–30.
157. Koeller KK, Dillon WP. Dysembryoplastic neuroepithelial
tumors: MR appearance. AJNR Am J Neuroradiol 1992; 13:
1319–25.
158. Vinchon M, Blond S, Lejeune JP, et al. Association of
Lhermitte-Duclos and Cowden disease: report of a new case
and review of the literature. J Neurol Neurosurg Psychiatry
1994; 57: 699–704.
159. Hao D, DiFrancesco LM, Brasher PM, et al. Is primary CNS
lymphoma really becoming more common? A population-
based study of incidence, clinicopathological features and
outcomes in Alberta from 1975 to 1996. Ann Oncol 1999; 10:
65–70.
160. Roman-Goldstein SM, Goldman DL, Howieson J, Belkin R,
Neuwelt EA. MR of primary CNS lymphoma in immuno-
logically normal patients. AJNR Am J Neuroradiol 1992; 13:
1207–13.
161. Poon T, Matoso I, Tchertkoff V, Weitzner I Jr., Gade M. CT
features of primary cerebral lymphoma in AIDS and non-
AIDS patients. J Comput Assist Tomogr 1989; 13: 6–9.
162. Jack CR Jr, O’Neill BP, Banks PM, Reese DF. Central nervous
system lymphoma: histologic types and CT appearance.
Radiology 1988; 167: 211–15.
163. Cordoliani YS, Derosier C, Pharaboz C, et al. Primary cerebral
lymphoma in patients with AIDS. MR Findings in 17 cases.
Am J 1992; 159: 841–7.
757
 primary tumor evaluation and staging
164. Rorke LB, Trojanowski JQ, Lee VM, et al. Primitive neuroec-
todermal tumors of the central nervous system. Brain Pathol
1997; 7: 765–84.
165. Rorke LB, Packer RJ, Biegel JA. Central nervous system atypical
teratoid/rhabdoid tumors of infancy and childhood: definition
of an entity. J Neurosurg 1996; 85: 56–65.
166. Sandhu A, Kendall B. Computed tomography in manage-
ment of medulloblastomas. Neuroradiology 1987; 29:
444–52.
167. Meyers SP, Kemp SS, Tarr RW. MR imaging features of
medulloblastomas. AJR Am J Roentgenol 1992; 158: 859–65.
168. Kochi M, Mihara Y, Takada A, et al. MRI of subarachnoid
dissemination of medulloblastoma. Neuroradiology 1991;
33: 264–8.
169. Cronqvist S, Greitz D, Maeder P. Spread of blood in cerebro-
spinal fluid following craniotomy simulates spinal metastases.
Neuroradiology 1993; 35: 592–5.
170. Girard N, Wang ZJ, Erbetta A, et al. Prognostic value of pro-
ton MR spectroscopy of cerebral hemisphere tumors in chil-
dren. Neuroradiology 1998; 40: 121–5.
171. Tzika AA, Vajapeyam S, Barnes PD. Multivoxel proton MR
spectroscopy and hemodynamic MR imaging of childhood
brain tumors: preliminary observations. AJNR Am J Neuro-
radiol 1997; 18: 203–18.
172. Hwang JH, Egnaczyk GF, Ballard E, et al. Proton MR spectro-
scopic characteristics of pediatric pilocytic astrocytomas.
AJNR Am J Neuroradiol 1998; 19: 535–40.
173. Zee CS, Segall H, Apuzzo M, et al. MR imaging of pineal
region neoplasms. J Comput Assist Tomogr 1991; 15: 56–63.
174. Muller-Forell W, Schroth G, Egan P J. MR imaging in tumors
of the pineal region. Neuroradiology 1988; 30: 224–31.
175. Hoffman HJ, Otsubo H, Hendrick EB, et al. Intracranial
germ-cell tumors in children. J Neurosurg 1991; 74: 545–51.
176. Wolden SL, Wara WM, Larson DA, et al. Radiation therapy
for primary intracranial germ-cell tumors. Int J Radiat Oncol
Biol Phys 1995; 32: 943–9.
177. Matsutani M, Ushio Y, Abe H, et al. Combined chemotherapy
and radiation therapy for central nervous system germ cell
tumors: preliminary results of a Phase II study of the Japa-
nese Pediatric Brain Tumor Study Group. Neurosurg Focus
1998; 5: e7.
178. Manning J. SIOP Intracranial Germ Cell Tumours Protocol
(GCT 96). 1996. Universityof Leicester.
179. Sawamura Y, de Tribolet N, Ishii N, Abe H. Management of
primary intracranial germinomas: diagnostic surgery or rad-
ical resection? J Neurosurg 1997; 87: 262–6.
180. Parsa AT, Pincus DW, Feldstein NA, et al. Pineal region
tumors. In: Keating RF, Goodrich JT, Packer RJ, eds. Tumors
of the Pediatric Nervous System. New York, Stuttgart: Thieme,
2001: 308–25.
181. Ho VB, Smirniotopoulos JG, Murphy FM, Rushing EJ.
Radiologic-pathologic correlation: hemangioblastoma.
AJNR Am J Neuroradiol 1992; 13: 1343–52.
182. Silbergeld J, Cohen WA, Maravilla KR, Dalley RW, Sumi M.
Supratentorial and spinal cord hemangioblastomas: gadolinium
enhanced MR appearance with pathologic correlation.
J Comput Assist Tomogr 1989; 13: 1048–51.
758
183. Young S, Richardson AE. Solid haemangioblastomas of the
posterior fossa: radiological features and results of surgery.
J Neurol Neurosurg Psychiatry 1987; 50: 155–8.
184. Elster AD, Arthur DW. Intracranial hemangioblastomas: CT
and MR findings. J Comput Assist Tomogr 1988; 12: 736–9.
185. Sheporaitis LA, Osborn AG, Smirniotopoulos JG, et al.
Intracranial meningioma. AJNR Am J Neuroradiol 1992; 13:
29–37.
186. Black PM. Meningiomas. Neurosurgery 1993; 32: 643–57.
187. Bouillot P, Pellissier JF, Devictor B, et al. Quantitative imaging
of estrogen and progesterone receptors, estrogen-regulated
protein, and growth fraction: immunocytochemical assays in
52 meningiomas. Correlation with clinical and morphological
data. J Neurosurg 1994; 81: 765–73.
188. Vagner-Capodano AM, Grisoli F, Gambarelli D, et al. Cor-
relation between cytogenetic and histopathological find-
ings in 75 human meningiomas. Neurosurgery 1993; 32:
892–900.
189. Jaaskelainen J, Haltia M, Servo A. Atypical and anaplastic
meningiomas: radiology, surgery, radiotherapy, and outcome.
Surg Neurol 1986; 25: 233–42.
190. Kallio M, Sankila R, Hakulinen T, Jaaskelainen J. Factors
affecting operative and excess long-term mortality in 935
patients with intracranial meningioma. Neurosurgery 1992;
31: 2–12.
191. Bonnal J, Brotchi J. Surgery of the superior sagittal sinus in
parasagittal meningiomas. J Neurosurg 1978; 48: 935–45.
192. Naidich TP. Meningiomas. In: ASNR Core Curriculum in
Neuroradiology. Part II: Neoplasms and Infectious Diseases,
1996: 53–68.
193. Rohringer M, Sutherland GR, Louw DF, Sima AA. Incidence
and clinicopathological features of meningioma. J Neurosurg
1989; 71: 665–72.
194. Demaerel P, Wilms G, Lammens M, et al. Intracranial menin-
giomas: correlation between MR imaging and histology in
fifty patients. J Comput Assist Tomogr 1991; 15: 45–51.
195. Elster AD, Challa VR, Gilbert TH, Richardson DN, Contento JC.
Meningiomas: MR and histopathologic features. Radiology
1989; 170: 857–62.
196. Kaplan RD, Coons S, Drayer BP, Bird CR, Johnson PC.
MR characteristics of meningioma subtypes at 1.5 tesla.
J Comput Assist Tomogr 1992; 16: 366–71.
197. Goldsher D, Litt AW, Pinto RS, Bannon KR, Kricheff II. Dural
“tail” associated with meningiomas on Gd-DTPA-enhanced
MR images: characteristics, differential diagnostic value, and
possible implications for treatment. Radiology 1990; 176:
447–50.
198. Flickinger JC, Kondziolka D, Lunsford LD. Dose and diame-
ter relationships for facial, trigeminal, and acoustic neuropa-
thies following acoustic neuroma radiosurgery. Radiother
Oncol 1996; 41: 215–19.
199. Brada M, Kitchen N. Radiosurgery – an alternative view. Crit
Rev Neurosurg 1997; 7: 304–9.
200. Weissman JL, Hirsch BE, Fukui MB, Rudy TE. The evolving
MR appearance of structures in the internal auditory canal
after removal of an acoustic neuroma. AJNR Am J Neuro-
radiol 1997; 18: 313–23.
 primary tumors of the central nervous system
201. Mulkens TH, Parizel PM, Martin JJ, et al. Acoustic schwan-
noma: MR findings in 84 tumors. Am J Roentgenol 1993;
160: 395–8.
202. Beges C, Revel MP, Gaston A, et al. Trigeminal neuromas:
assessment of MRI and CT. Neuroradiology 1992; 34:
179–83.
203. Olsen WL, Dillon WP, Kelly WM, et al. MR imaging of para-
gangliomas. AJR Am J Roentgenol 1987; 148: 201–4.
204. Vogl TJ, Juergens M, Balzer JO, et al. Glomus tumors of the
skull base: combined use of MR angiography and spin-echo
imaging. Radiology 1994; 192: 103–10.
205. Tsuruda JS, Chew WM, Moseley ME, Norman D. Diffusion-
weighted MR imaging of the brain: value of differentiating
between extraaxial cysts and epidermoid tumors. AJNR Am J
Neuroradiol 1990; 11: 925–31.
206. Chen S, Ikawa F, Kurisu K, et al. Quantitative MR evalua-
tion of intracranial epidermoid tumors by fast fluid-
attenuated inversion recovery imaging and echo-planar
diffusion-weighted imaging. AJNR Am J Neuroradiol 2001;
22: 1089–96.
207. Freda PU, Wardlaw SL, Post KD. Unusual causes of sellar/
parasellar masses in a large transsphenoidal surgical series.
J Clin Endocrinol Metab 1996; 81: 3455–9.
208. Saeki N, Hoshi S, Sunada S, et al. Correlation of high signal
intensity of the pituitary stalk in macroadenoma and post-
operative diabetes insipidus. AJNR Am J Neuroradiol 2002;
23: 822–7.
209. Kucharczyk W, Davis DO, Kelly WM, et al. Pituitary ade-
nomas: high-resolution MR imaging at 1.5 T. Radiology
1986; 161: 761–5.
210. Ostrov SG, Quencer RM, Hoffman JC, et al. Hemorrhage
within pituitary adenomas: how often associated with
pituitary apoplexy syndrome? AJR Am J Roentgenol 1989;
153: 153–60.
211. Colombo N, Loli P, Vignati F, Scialfa G. MR of corticotropin-
secreting pituitary microadenomas. AJNR Am J Neuroradiol
1994; 15: 1591–5.
212. Yousem DM, Arrington JA, Zinreich SJ, Kumar AJ, Bryan RN.
Pituitary adenomas: possible role of bromocriptine in intra-
tumoral hemorrhage. Radiology 1989; 170: 239–43.
213. Dina TS, Feaster SH, Laws ER Jr, Davis DO. MR of the
pituitary gland postsurgery: serial MR studies following
transsphenoidal resection. AJNR Am J Neuroradiol 1993;
14: 763–9.
214. Colombo N, Berry I, Kucharczyk J, et al. Posterior pituitary
gland: appearance on MR images in normal and pathologic
states. Radiology 1987; 165: 481–5.
215. Snow RB, Johnson CE, Morgello S, Lavyne MH, Patterson
RH Jr. Is magnetic resonance imaging useful in guiding the
operative approach to large pituitary tumors? Neurosurgery
1990; 26: 801–3.
216. Cottier JP, Destrieux C, Brunereau L, et al. Cavernous sinus
invasion by pituitary adenoma: MR imaging. Radiology
2000; 215: 463–9.
217. Teng MM, Huang CI, Chang T. The pituitary mass after
transsphenoidal hypophysectomy. AJNR Am J Neuroradiol
1988; 9: 23–6.
218. Kaplan HC, Baker HL, Jr, Houser OW, et al. CT of the sella
turcica after transsphenoidal resection of pituitary adenomas.
AJR Am J Roentgenol 1985; 145: 1131–40.
219. Yoon PH, Kim DI, Jeon P, et al. Pituitary adenomas: early
postoperative MR imaging after transsphenoidal resection.
AJNR Am J Neuroradiol 2001; 22: 1097–104.
220. Lundin P, Eden EB, Karlsson FA, Burman P. Long-term
octreotide therapy in growth hormone-secreting pituitary
adenomas: evaluation with serial MR. AJNR Am J Neurora-
diol 1997; 18: 765–72.
221. Zimmerman RA. Imaging of intrasellar, suprasellar, and
parasellar tumors. Semin Roentgenol 1990; 25: 174–97.
222. Sartoretti-Schefer S, Wichmann W, Aguzzi A, Valavanis A.
MR differentiation of adamantinous and squamous-
papillary craniopharyngiomas. AJNR Am J Neuroradiol
1997; 18: 77–87.
223. Pusey E, Kortman KE, Flannigan BD, Tsuruda J, Bradley WG.
MR of craniopharyngiomas: tumor delineation and charac-
terization. AJR Am J Roentgenol 1987; 149: 383–8.
224. Young SC, Zimmerman RA, Nowell MA, et al. Giant cystic
craniopharyngiomas. Neuroradiology 1987; 29: 468–73.
225. Sutton LN, Wang ZJ, Wehrli SL, et al. Proton spectroscopy of
suprasellar tumors in pediatric patients. Neurosurgery 1997;
41: 388–94.
226. Hoffman HJ, De Silva M, Humphreys RP, et al. Aggressive
surgical management of craniopharyngiomas in children.
J Neurosurg 1992; 76: 47–52.
227. De Vile CJ, Grant DB, Kendall BE, et al. Management of
childhood craniopharyngioma: can the morbidity of radical
surgery be predicted? J Neurosurg 1996; 85: 73–81.
228. Meyers SP, Hirsch WL Jr, Curtin HD, et al. Chordomas of
the skull base: MR features. AJNR Am J Neuroradiol 1992;
13: 1627–36.
229. Uttley D, Moore A, Archer DJ. Surgical management of
midline skull-base tumors: a new approach. J Neurosurg
1989; 71: 705–10.
230. Patel U, Pinto RS, Miller DC, et al. MR of spinal cord
ganglioglioma. AJNR Am J Neuroradiol 1998; 19: 879–87.
231. Epstein FJ, Farmer JP, Freed D. Adult intramedullary astrocy-
tomas of the spinal cord. J Neurosurg 1992; 77: 355–9.
232. Sandler HM, Papadopoulos SM, Thornton AF Jr, Ross DA.
Spinal cord astrocytomas: results of therapy. Neurosurgery
1992; 30: 490–3.
233. Minehan KJ, Shaw EG, Scheithauer BW, Davis DL, Onofrio
BM. Spinal cord astrocytoma: pathological and treatment
considerations. J Neurosurg 1995; 83: 590–5.
234. Parizel PM, Baleriaux D, Rodesch G, et al. Gd-DTPA-
enhanced MR imaging of spinal tumors. AJR Am J Roent-
genol 1989; 152: 1087–96.
235. Brunberg JA, DiPietro MA, Venes JL, et al. Intramedullary
lesions of the pediatric spinal cord: correlation of findings
from MR imaging, intraoperative sonography, surgery, and
histologic study. Radiology 1991; 181: 573–9.
236. Slasky BS, Bydder GM, Niendorf HP, Young IR. MR imaging
with gadolinium-DTPA in the differentiation of tumor,
syrinx, and cyst of the spinal cord. J Comput Assist Tomogr
1987; 11: 845–50.
759
 primary tumor evaluation and staging
237. Ross GW, Rubinstein LJ. Lack of histopathological correla-
tion of malignant ependymomas with postoperative survival.
J Neurosurg 1989; 70: 31–6.
238. Sonneland PR, Scheithauer BW, Onofrio BM. Myxopapillary
ependymoma. A clinicopathologic and immunocytochemi-
cal study of 77 cases. Cancer 1985; 56: 883–93.
239. Nemoto Y, Inoue Y, Tashiro T, et al. Intramedullary spinal
cord tumors: significance of associated hemorrhage at MR
imaging. Radiology 1992; 182: 793–6.
760
240. Solero CL, Fornari M, Giombini S, et al. Spinal meningiomas:
review of 174 operated cases. Neurosurgery 1989; 25:
153–60.
241. Matsumoto S, Hasuo K, Uchino A, et al. MRI of intradural-
extramedullary spinal neurinomas and meningiomas. Clin
Imaging 1993; 17: 46–52.
242. Varma DG, Moulopoulos A, Sara AS, et al. MR imaging of
extracranial nerve sheath tumors. J Comput Assist Tomogr
1992; 16: 448–53.
 32 Neuroendocrine Tumors
Andrea G Rockall, Norbert Avril, Ashley B Grossman, and Rodney H Reznek
INTRODUCTION
Neuroendocrine tumors (NETs), which include those that arise
in the pancreas (also known as pancreatic neuroendocrine tumors
or pancreatic NETs), the gastrointestinal tract and from neuroen-
docrine cells scattered in other tissues (carcinoids) are rare. These
tumors were initially believed to arise from a putative common
precursor, the amine precursor uptake and decarboxylation
(APUD) cell, although this is now known not to be the case.
These NETs are histologically closely related to melanoma, pheo-
chromocytoma, and medullary carcinoma of the thyroid, which
are described elsewhere (see chaps. 16, 30, and 48). All NETs have
the potential to synthesize and secrete hormones. Functioning
tumors are those in which hormone secretion by the tumor
results in a clinical syndrome. Non-functioning tumors are those
in which either there is no hormone secretion or hormone secre-
tion does not result in a recognizable clinical syndrome. Func-
tioning tumors usually present relatively early, due to the clinical
syndrome, and may be a challenge for the radiologist to localize
as they are often small. In contrast, non-functioning tumors gen-
erally go unrecognized for many years and present much later
with mass effects.
The malignant potential of NETs varies. Malignancy is more com-
mon in some types, such as gastrinoma, whereas in others, such as
insulinoma, malignancy is rare, but clinical behavior is often difficult to
predict. In some cases, the tumors are associated with genetic disorders
such as the multiple endocrine neoplasia type 1 (MEN 1) syndrome.
Imaging of functioning tumors, in particular, is primarily
directed at localization and staging of the tumor. Preoperative
localization reduces the likelihood of surgical complications and
increases the chances of surgical resection, the only form of cura-
tive treatment for these tumors. Cross-sectional imaging is also
valuable in the follow-up of recurrent or metastatic disease, and
nuclear imaging techniques may be used to direct treatment with
radiopharmaceuticals.
In this chapter, the clinical and imaging features of gastro-
enteropancreatic NETs will be described. The roles of the different
imaging and radionuclide techniques used will be discussed.
CLINICAL FEATURES: PANCREATIC NEUROENDOCRINE
TUMORS
Pancreatic neuroendocrine tumors (NETs) arise from the islet cells of
Langerhans and include:
• Insulinoma
• Gastrinoma
• VIPoma
• Glucagonoma
• Somatostatinoma
• Pancreatic polypeptidoma (PPoma)
Epidemiology
Pancreatic NETs are rare, with a reported incidence of 1.2 to 1.6 per
million and a prevalence of 10 per million of population (1,2). The
incidence of clinically significant pancreatic NETs is four per million
people per year. In early publications, the majority of pancreatic NETs
were reported as functioning, with only 15% to 30% being non-func-
tioning (3,4). However, in more recent data obtained from the Surveil-
lance, Epidemiology and End Results (SEER) Program, a minority of
cases were reported as functioning (2,5). The SEER database on islet cell
tumors is the largest population-based study of islet cell tumors, with
1310 cases, but as this database only captures cases that were deemed to
be malignant, it is unlikely to reflect the incidence of the small benign
lesions, such as most insulinomas (2). The SEER data reports that 1.3%
of all new pancreatic tumors are NETs. The peak incidence occurred in
patients between 65 and 69 years of age with a median age at presenta-
tion of 59 and no sex prevalence. In other series, insulinomas, which are
usually benign, are by far the most common pancreatic NETs, account-
ing for up to 50% of all cases (6). Benign insulinomas occur slightly
more frequently in women (F3:M2), with an equal sex incidence in the
rare malignant insulinomas. Other pancreatic NETs are more likely to
be malignant, with gastrinoma being the next most common type.
Gastrinomas account for 20% of pancreatic NETs (3), are seen in 0.5 to
3 patients per million people per year and slightly more commonly in
males. In 10% to 20% of patients with a gastrinoma, there is a family
history of disease and findings are consistent with MEN 1 (7). There is
an equal sex incidence in the remainder of pancreatic NETs, PPomas
being the next most common (although these do not produce a clinical
syndrome). The other pancreatic NETs are rarer and may also be found
in the context of MEN 1. Patients with MEN 1 generally present
younger, usually have multiple tumors and may have prolonged
survival compared to sporadic cases. Pancreatic NETs may also be
associated with von Hippel–Lindau disease.
Etiology
The etiology of pancreatic NETs remains obscure. Abnormalities
on chromosome 11q13 have been found in patients with MEN 1
and in patients with a sporadic gastrinoma (8,9). MEN 1 is inher-
ited as an autosomal dominant trait: the syndrome comprises
hyperplasia and/or tumors of several endocrine organs, the para-
thyroid gland being most commonly involved, followed by the
pancreas, in which islet cell tumors are seen in over 50% of
patients. Pituitary tumors, particularly prolactinomas, are the
third major arm of the syndrome, but a variety of other tumors
such as lipomas and adrenocortical tumors are also seen. One
third of sporadic cases of gastrinoma have been shown to have
similar chromosomal mutations to patients with MEN 1.
Histology, Classification, and Clinical Presentation
(Table 32.1)
The histological appearance of pancreatic NETs is similar to that of
other NETs, characterized by uniform sheets of small round cells.
761
 primary tumor evaluation and staging

Table 32.1 Classification of Pancreatic Neuroendocrine Tumors (3,4,6,7,21)

Tumor name % frequency Syndrome Pancreatic Hormone % malignant Anatomical Typical size
islet cell produced location
Insulinoma 50% Insulinoma B cell Insulin 10–15% Pancreas >99% <2 cm 90%; <1 cm 40%
(Head = body = tail)
Gastrinoma 20–30% Zollinger–Ellison G cell Gastrin 60–75% Pancreas 30–60%a 0.3–3.0 cm
syndrome Duodenum
30–40%a Lymph
nodes 10–15%a
Other <5
Non-functioning 15–30% No syndrome D1 cell None or pancreatic 60–90% Pancreas (most Large
and PPoma polypeptide frequently in the
head)
VIPoma 3% Verner–Morrison D2 cell Vasoactive 50–80% Pancreas 90% Large
syndrome; WDHA intestinal peptide (usually tail)
Adrenal 10%
Glucagonoma Rare Glucagonoma A cell Glucagon 60% Pancreas 2–10 cm
Somatostatinoma Rare Somatostatinomab D cell Somatostatin 50–70% Pancreas 56% 2–10 cm
Jejunum 44%
a
90% are within the gastrinoma triangle (see p. 764).
b
Somatostatinoma may be associated with NF 1.

NETs is based on the presenting clinical syndrome, which is caused

Figure 32.1 Benign insulinoma. T2-weighted MRI demonstrates an 8 mm high
signal intensity lesion in the tail of pancreas (arrow). Most insulinomas are benign
and measure less than 2 cm in diameter.
by the predominant hormone secreted by the tumor (Table 32.1). If
no clinical syndrome is evident, the tumor is either classified by the
hormone secreted (usually PPoma) or, if no hormone is secreted, it is
called a non-functioning pancreatic NET.
The WHO clinicopathological classification of pancreatic NETs
has three main divisions, well-differentiated endocrine tumor, well
differentiated endocrine carcinoma, and poorly differentiated
endocrine carcinoma-small cell carcinoma (10,11). Within each of
these divisions, the tumors may be classified as functioning or non-
functioning. A recently developed TNM classification, which is yet
to be validated, has been found to be highly predictive of patient
outcome and this may be combined with histopathological par-
mameters to classify pancreatic NETs (12).Well-differentiated
endocrine tumors include those with benign behavior and those
with uncertain behavior. Tumors with benign behavior are
small (<2 cm), confined to the pancreas, have a low mitotic and
proliferative index, and no angioinvasion. Those with uncertain
behavior are confined to the pancreas but are >2 cm, have a slightly
higher proliferative rate, or have angioinvasion.
Well-differentiated endocrine carcinomas of the pancreas are
those which exhibit low-grade malignant signs with visible local
invasion or metastases.
Poorly differentiated endocrine carcinoma-small cell carcino-
mas demonstrate high-grade malignant features and resemble
small cell carcinoma of the lung. These tumors behave very aggres-
sively and often present with widespread metastases.

Several different patterns of growth have been described: a glandular
pattern, a solid pattern, a gyriform pattern, and an unclassified
pattern. However, the pattern of growth does not correlate with
hormone production or malignant potential (7). In general, immu-
nostaining with chromogranin and synaptophysin will confirm the
neuroendocrine nature of the tumor, while special immunostains
(insulin, gastrin, etc.) will identify specific secretory characteristics.
It is now recognized that most pancreatic NETs secrete a variety of
hormonally active peptides. However, the classification of pancreatic
Insulinomas (Figs. 32.1–32.4)
Insulinomas are solitary and intrapancreatic in over 90% of cases,
with an equal distribution in the head, body, and tail of the
gland (6,13). Of these tumors, 90% measure <2 cm and 40% <1 cm
in diameter (4,14,15). Insulinomas almost invariably present with
the clinical syndrome caused by hypoglycemia. The symptoms are
variable and may be intermittent. There may be changes in person-
ality or work performance, and in the elderly there may be confu-
sion or dementia. The association of symptoms with fasting may

762
 neuroendocrine tumors

(A) (B)

Figure 32.2 Malignant insulinoma. This 37-year-old male patient presented with vague abdominal pain. (A) Non-contrast CT at the level of the pancreas demonstrates
diffuse enlargement of the entire pancreas (arrows). (B) Arterial phase contrast-enhanced image demonstrates diffuse heterogeneous enhancement of the gland with
large areas of necrosis (arrow). The gland was infiltrated by a large malignant insulinoma, which was non-functioning.

(A) (B)

(C) (D)

Figure 32.3 Malignant insulinoma. (A) CT, post-contrast, demonstrates an enhancing mass in the region of the head and neck of pancreas (arrows). This is causing
obstruction of the main pancreatic duct, with atrophy of the tail (arrowhead). (B) At a slightly more cranial level, there is encasement of the celiac axis and the hepatic
and splenic arteries (arrows). (C) Arterial phase (AP) CT through the stomach demonstrates large varices along the anterior wall of the stomach (arrow). This was
secondary to portal vein thrombosis, due to tumor infiltration. (D) AP rim enhancement of a liver deposit indicates metastatic disease (arrow).

763
 primary tumor evaluation and staging

(A) (B)

Selective pancreatic
arterial catheterisation

200
Insulin (mU/l)

150
100
50 SA
0
0
60
120 DPA
180
Time (seconds)
GDA

(C)

Figure 32.4 Multifocal insulinoma. (A) T2-weighted axial image through the tail of the pancreas. A well-defined high-signal lesion is demonstrated in the tail of pancreas
(arrow). No other lesion was seen on T2-weighted images. (B) On T1 weighting, a second lesion is demonstrated in the head of pancreas, which has a high signal inten-
sity on T1 weighting (arrow). This was initially missed. (C) Selective pancreatic arterial catheterization and venous sampling were performed. A secretagogue was injected
into the splenic artery (SA), the duodenopancreatic artery (DPA) and the gastroduodenal artery (GDA). Venous sampling revealed no insulin surge from the region of
the body or tail of pancreas, thus indicating that the lesion in the tail was non-functioning. However, there was marked insulin secretion following secretagogue injection
in the region of the head of pancreas (via the GDA), indicating the presence of a functioning insulinoma in the head of the pancreas.

not be evident to the patient. The diagnosis is established clinically
and biochemically prior to localization, on the basis of Whipple’s
triad, i.e., hypoglycemic attacks in the fasting state, blood glucose
levels <2.2 mmol/l during an attack, with relief of symptoms fol-
lowing glucose administration. Other characteristic features include
unusually high levels of insulin and C-peptide, and a negative screen
for sulphonylureas or related drugs (16,17).
Key Points: Insulinomas
■ The most common pancreatic NET is the insulinoma
■ Diagnosis is made clinically and biochemically
■ Ninety percent are benign, 90% measure <2 cm, 40%
measure <1 cm
■ The primary tumor is almost invariably located in the pan-
creas, whether single or multiple
Gastrinomas (Figs. 32.5–32.7)
Gastrinomas are the second most common pancreatic NETs,
comprising some 20% to 30% of the total. About 60% of
gastrinomas are malignant with hepatic metastases at presen-
tation, although there is a higher incidence of malignancy in
those associated with MEN 1 (3,6). Metastases are usually to
peripancreatic lymph nodes and liver, but bone metastases
have been reported in approximately 30% of cases (18). About
90% of gastrinomas are located in the “gastrinoma triangle”;
formed by the junction between the neck and body of the pan-
creas medially, the second and third parts of the duodenum
inferiorly, and the junction of the cystic and common bile
ducts superiorly (7).
Compared to insulinomas, these tumors tend to be even
smaller, ranging in size from 0.3 to 3 cm, less vascular, and
more often extrapancreatic (19). Patients generally present
with recurrent, multiple or “ectopic” peptic ulceration, the
Zollinger–Ellison syndrome (ZES), although in some cases
ulceration may be mild. Diarrhoea and malabsorption due to
acid inactivation of pancreatic enzymes may be predominant.
The finding of an elevated gastrin level together with a high
basal acid output is diagnostic of a gastrinoma (20). If possible,
investigation should be undertaken in the absence of histamine

764
 neuroendocrine tumors

(A) (B)

(C) (D)

Figure 32.5 Multiple gastrinomas in a patient with MEN 1. (A) Axial T1-weighted scan with fat saturation demonstrates two lesions of low signal intensity within the
body and tail of the pancreas (arrows). (B) On T2-weighted imaging, the lesions are of high signal intensity (arrows). (C) Dynamic T1-weighted image with fat satura-
tion, 30 seconds following IV gadolinium administration. Both lesions demonstrate rim enhancement (arrows). (D) Dynamic T1-weighted image with fat saturation,
90 seconds following IV gadolinium administration. The lesions demonstrate further central enhancement (arrows).

Key Points: Gastrinomas

■ Sixty percent are malignant with hepatic metastases at pre-
sentation
■ Ninety percent are located in the gastrinoma triangle
■ Association with MEN 1 occurs frequently and features
should be sought

Other Functioning Pancreatic NETs (Figs. 32.8 and 32.9)

Figure 32.6 Malignant gastrinoma in a patient with von Hippel-Lindau disease.
Portal venous-phase CT demonstrates a large mass in the region of the head of
pancreas, which has heterogeneous enhancement and central necrosis (white
arrow). Varices are seen around the periphery of the tumor (black arrow) due to
obstruction of the SMV and portal vein. Note the cystic renal cell carcinoma in the
left kidney, related to the VHL.
antagonists (>48 hours) or proton pump inhibitors (>2 weeks).
Once the diagnosis of a gastrinoma has been confirmed, localiza-
tion with imaging should be undertaken to identify the primary
site and to stage the disease.
The other functioning pancreatic NETs are very rare, frequently
associated with MEN 1 and frequently malignant: 60% to 70% of
glucagonomas, 50% to 80% of VIPomas and 50% to 70% of soma-
tostatinomas are malignant (Table 32.1).
VIPomas (Fig. 32.8)
These comprise three percent of the total number of pancreatic NETs.
Eighty percent are located within the pancreas (usually in the tail) but
may also arise in the extrapancreatic tissue, particularly the retroperi-
toneal sympathetic chain and the adrenal medulla (6,7). The VIPoma
syndrome, also known as WDHA (watery diarrhoea, hypokalemia,
and achlorhydria), or the Verner–Morrison syndrome, is caused by
the secretion of vasoactive intestinal peptide. The symptoms are of
marked watery diarrhoea, causing hypokalemia which can be life-
threatening. Death may occur due to cardiac arrest. The diagnosis is
made on clinical and biochemical features, with the demonstration
of an elevated plasma VIP. Other peptides such as neurotensin and
PHM (peptidylglycine α-hydroxylating monooxygenase) may also

765
 primary tumor evaluation and staging
(A)
Figure 32.7 Malignant gastrinoma. (A) Postcontrast CT demonstrates a central tumor mass (*) with extensive nodular deposits of tumor in the omental and peritoneal
fat (arrows). (B) Following open biopsy, a diagnosis of malignant gastrinoma was confirmed (arrow indicates surgical clip).
Figure 32.8 Malignant VIPoma. CT following IV contrast medium demonstrates
an enhancing pancreatic mass (arrowheads), liver metastases (long arrow),
a peritoneal deposit (short arrow), and ascites (*).
be elevated, but while they may be used as tumor markers their role
in the presentation of the clinical syndrome is unclear.
Glucagonomas (Fig. 32.9)
These tumors often arise within the body or tail of the pancreas
and they are usually large (2–10 cm) at the time of diagnosis (6,7,21).
The glucagonoma syndrome presents with a characteristic necro-
lytic migratory erythematous rash, seen typically in the groin
region in 75% of patients. This may be associated with glossitis and
angular stomatitis. The diagnosis is confirmed by demonstrating
elevated plasma glucagon levels. Glucagonomas tend to present
late, usually with metastases, which are most frequently hepatic but
may also be within lymph nodes or the mesentery. The prognosis
is usually poor.
Somatostatinomas (Fig. 32.10)
Found in the pancreas in over half of affected individuals (most often
in the pancreatic head), up to 50% of these tumors are located in the
766
(B)
duodenum and jejunum, where they may be associated with neuro-
fibromatosis (7,22). Somatostatinomas are very slow-growing tumors
with relatively mild non-specific symptoms (including diabetes mel-
litus, diarrhoea, steatorrhoea, and weight loss), and the tumors thus
tend to be very large at presentation. Metastases are present in up to
90% of malignant somatostatinomas, most commonly to the liver,
but also to lymph nodes, and bone (23). Duodenal somatostatinomas
are sometimes associated with neurofibromatosis type 1.
Non-Functioning Pancreatic NETs (Fig. 32.11)
PPomas and pancreatic NETs that do not secrete any hormones
do not result in a clinical syndrome and therefore sporadic cases
present late as tumors causing mass effects (4). They are slow-
growing tumors and tend to be large at diagnosis; approximately
60% to 90% are malignant (6,21). They usually lie in the pancre-
atic head and thus presentation may be similar to that of pancre-
atic adenocarcinoma, with biliary obstruction. In family groups
with MEN 1, screening of the pancreas may identify non-
functioning tumors at an early stage. They may also be seen in
the von Hippel-Lindau syndrome.
Key Point
■ Sixty to ninety percent of non-functioning pancreatic NETs
are malignant and tend to be large at diagnosis
CLINICAL FEATURES: “CARCINOID” NEUROENDOCRINE
TUMORS
The term “carcinoid” was first used in 1907 to describe a tumor of the
gastro-intestinal (GI) tract that was slow-growing and not as aggres-
sive as an adenocarcinoma. In the 1950s the tumors were found to
contain serotonin, and the carcinoid syndrome was described, where
patients with a small intestinal carcinoid tumor and liver metastases
presented with the characteristic symptoms of diarrhoea, flushing,
asthma, and right heart failure. However, overall only about 10% of
such tumors are associated with the classical syndrome, although for
small bowel carcinoids some elements of the syndrome may be
present in around 30% of cases. The cells arise from the diffuse
 neuroendocrine tumors

(A) (B)

(C) (D)
Figure 32.9 Diffusely infiltrating malignant glucagonoma on portal-venous phase CT. (A) CT scan following IV contrast medium demonstrates a large enhancing mass
in the region of the head of pancreas (arrowheads). Areas of necrosis are seen in the central part of the mass. There is marked atrophy of the pancreatic tail, indicating
the longstanding nature of the tumor (arrow). (B) In a different patient, the tumor was octreotide-avid (arrow). (C) In a different patient, the body and tail of pancreas
are expanded by an ill-defined tumor. There is extensive calcification along the posterior margin of the tumor (arrows). (D) In a different patient, the tumor has
infiltrated the head of pancreas, which is enlarged and heterogeneous (white arrow).

neuroendocrine system and have the potential to secrete a wide typical in certain age groups: carcinoids of the cervix present in the
variety of amines and peptides, and therefore are now often referred fourth decade, small intestine and respiratory tract in the early
to as NETs to reflect the wide range of clinical presentations (24,25). seventh, and rectal carcinoids in the late seventh decade (24,27,29).

Epidemiology (Table 32.2) Etiology

Carcinoid NETs occur much more frequently than pancreatic NETs
and account for 2% of malignant tumors of the GI tract. The
reported incidence of GI carcinoids is 7.1 per million people for
men and 8.7 per million for women (26). However, the annual inci-
dence is higher in autopsy studies, at 21 per million (27). NETs are
most frequently diagnosed in the GI tract, where 66% are found.
The second most common site is the bronchopulmonary system,
accounting for 31% of NETs (28). Carcinoids present between the
second and ninth decades of life, with certain sites being more
The etiology of carcinoids is not well understood. Certain disease
states that result in hypergastrinemia, such as pernicious anemia
and atrophic gastritis, appear to be predisposed to gastric carcinoids
(see p. 770). In the Zollinger-Ellison syndrome, the development of
a gastric carcinoid occurs most frequently in patients with MEN 1.
Various tumor growth factors may influence the development of
carcinoids and, as in patients with MEN 1, changes in chromosome
11q13 have been reported in patients with sporadic NETs, particu-
larly foregut NETs, which are most commonly associated with

767
 primary tumor evaluation and staging
(A)
Figure 32.10 Somatostatinoma demonstrated on (A) portal-venous phase CT and (B) Octreotide scan. A large, relatively homogeneous mass in the body of pancreas is
demonstrated (arrow). Over 50% of somatostatinomas arise in the pancreas, usually presenting as a mass. 80% are malignant and 95% are receptor-positive.
Figure 32.11 Non-functioning malignant PET. CT following IV contrast adminis-
tration demonstrates a large mass in the tail of pancreas with extensive peripheral
calcification (arrowheads), indicating the longstanding nature of the mass. Large
necrotic liver metastases are present, with rim-enhancement (arrows). There was
no clinical syndrome associated with this non-functioning endocrine tumor.
MEN 1 (25). NETs may also be seen in association with von Hippel-
Lindau syndrome and neurofibromatosis (30).
Histology
Histologically, the tumor is comprised of sheets of uniform round
cells arising from the enterochromaffin cells, which are APUD cells
of the diffuse endocrine system. It is not possible to differentiate
benign from malignant carcinoids based on histological features
alone. It is the presence of local invasion or metastases that indicate
malignancy. In addition, carcinoids cannot be differentiated histo-
logically from pancreatic NETs. The tumors may be characterized
by the histological staining patterns, which reflect the type of neu-
rosecretory granules and cytoplasmic proteins. The tumor cells
contain neurosecretory granules that contain a wide variety of
768
(B)
amines and peptides, such as 5-hydroxytryptamine (5-HT),
neuron-specific enolase, hydroxytryptophan, synaptophysin, chro-
mogranins A and C, and several hormones such as insulin, growth
hormone, adrenocorticotrophic hormone (ACTH), and gastrin as
well as many others. More recently, certain immunohistochemical
markers have been used to categorize the tumors, including
serotonin, chromogranin A and B, and neuron-specific enolase
(NSE) (25,31,32). In general, most are diagnosed with the combina-
tion of chromogranin and synaptophysin immunostains, although
others may be added to confirm suspicious or uncertain cases.
Classification and Clinical Presentation (Table 32.3)
Neuroendocrine carcinoid tumors are traditionally classified
according to their site of origin: the secretory products and hence
the clinical manifestations and immunohistochemical staining
patterns are similar for tumors arising from particular anatomical
sites (Table 32.3). Foregut carcinoids include NETs arising from
the thymus, bronchus, gastric, or duodenal mucosa, and pancreas.
Midgut carcinoids arise in the jejunum, ileum, and proximal colon;
while hindgut tumors arise in the distal colon and rectum (33). A
more recent classification has been proposed, replacing the term
“carcinoid” with NETs (31). This WHO classification is based on
the size, proliferative rate, location, differentiation, and hormone
production. All GI and most other NETs can be categorized as:
• Well-differentiated endocrine tumors
• Well-differentiated endocrine carcinomas
• Poorly-differentiated endocrine carcinomas
• Mixed endocrine/exocrine tumors (WHO, 2005) (10)
Carcinoids can arise in a very wide variety of sites, but are most
commonly reported at four sites (Table 32.2): bronchus (25%),
jejuno-ileum (15%), appendix (2%), and rectum (19%), although
in autopsy studies 76% are jejuno-ileal.
 neuroendocrine tumors

Table 32.2 Distribution of Carcinoids by Site at Presentation from the National Cancer Institute Database (28,47,152)
Location Location (% of total) Incidence of metastases (%)
1950–1971 (n = 4349) 1973–1991 (n = 5468) 1992–1999 (n = 4989) 1950–1971 1973–1991 1992–1999
Foregut
Stomach 2 3.8 5.9 22 31 10–33
Duodenum 2.6 2.1 3.8 20 – –
Bronchus, lung 11.5 32.5 25.3 20 27 27–35
Midgut
Jejunum 1.3 2.3 1.5 35 70 58–64
Ileum 23 17.6 13.4 35
Appendix 38 7.6 2.4 2 35 39–45
Colon 4.3 6.3 7.6 60 71 51–61
Hindgut
Rectum 13 10 18.5 3 14 4–18

Table 32.3 Classification of Carcinoid Neuroendocrine Tumours (24,25)

Origin Carcinoid syndrome
Foregut May occur; usually in
cases with liver
metastases
Midgut “classical Occurs frequently, in cases
carcinoid” with metastases
Hindgut Rare
Abbreviations: ACTH, adrenocorticotrophic hormone; CGRP, calcitonin gene-related peptide; CRH, corticotrophin-releasing hormone; GHRH, growth hormone-
releasing hormone; 5-HT, 5-hydroxytryptamine, serotonin; 5-HTP, 5-hydroxytryptophan; hCG, human chorionic gonadotrophin; PP, pancreatic polypeptide;
PYY, peptide YY.
Metastases to bone Organ Clinical symptoms Hormone production
Occur Thymus Cushing’s syndrome CRH, ACTH, GHRH,
Lung Acromegaly (low 5-HT)
Cushing’s syndrome CRH, ACTH, GHRH, PP,
Acromegaly hCG alpha, neurotensin
5-HTP, (low 5-HT),
histamine
Stomach Cushing’s syndrome CRH, ACTH, GHRH,
Pernicious anaemia gastrin
Acromegaly, ZES
Duodenum Somatostatinoma Gastrin, somatostatin,
syndrome, ZES neurotensin tachyki-
nins, (low 5-HT)
Rare Ileum Jejunum Proximal Carcinoid syndrome Tachykinins, bradykinins
colon CGRP High 5-HT
Appendix Not hormone related (Tachykinins, 5-HT)
Occur Distal colon Rectum Not hormone related PP, HCG-alpha, PYY,
somatostatin, (rarely
5-HT)

Foregut Carcinoids
Bronchial Carcinoids (Fig. 32.12)
Bronchial carcinoids, or bronchopulmonary NETs, are NETs of
the bronchial epithelium arising from Kulschitsky cells, neuroepi-
thelial bodies, or pluripotential bronchial epithelial stem
cells (34,35). They have been classified into four groups by the
WHO, (36) according to their malignant potential:
• Low grade typical carcinoid tumor (classical or benign
bronchial carcinoid)
• Intermediate grade atypical carcinoid tumor
• Two high-grade malignancies: large cell neuroendocrine
carcinoma (LCNEC) and small-cell carcinoma (SCLC)
The prognosis for bronchopulomary NETs has decreased consid-
erably over the last 30 years, with the five-year survival rate (ysr)
decreasing from 84.7% to 47.3%. This phenomenon may be due
to changes in histopathology reporting (37). The prognosis is
excellent for typical bronchial carcinoids (approximately 88%
5 ysr) and poor for small cell carcinomas (<5% 5 ysr) (38). Bronchial
carcinoids now account for 25% of all carcinoid tumors (up from
11.5%, Table 32.2). This increase may also be due to changes in
classification or increased recognition of broncopulmonary
carcinoids by pathologists (38). Typical low-grade carcinoid
tends to occur in younger patients between the fifth and sixth
decade, and the relationship to smoking is uncertain (38,39).
The high-grade LCNEC and SCLCs are more frequent in men
and typically occur in the seventh decade, and are strongly corre-
lated with a smoking history (40,41). Although 25% of patients
are asymptomatic, clinical presentation is usually related to bron-
chial obstruction, with cough and wheezing, and hemoptysis
occurs in 50% of patients, due to the highly vascular nature of the
lesion. Cushing’s syndrome (due to ACTH secretion) and carci-
noid syndrome (in patients with liver metastases) occur in approx-
imately 2% of cases (42). Metastases may be seen in the liver, bones,
adrenal glands, and brain.
Thymic Carcinoids (Fig. 32.13)
NETs of the thymus are rare and may be part of MEN 1. The tumor
is usually non-functioning and presents with an anterior mediasti-
nal mass. If functioning, then the tumor usually secretes ACTH,

769
 primary tumor evaluation and staging

(A)

(B) (C)

Figure 32.12 Bronchial carcinoid in a patient presenting with ACTH-dependent Cushing’s syndrome. (A) There is marked bilateral adrenal hyperplasia secondary to
ACTH production (arrows). No pituitary adenoma was identified and thus an ectopic source of ACTH was sought. (B) Supine CT of the thorax was unremarkable, apart
from dependent changes at the bases (arrow). (C) Prone CT revealed a 5 mm solitary pulmonary nodule (arrow). This was resected and was confirmed to be a peripheral
bronchial carcinoid.

causing ectopic ACTH-dependent Cushing’s syndrome, which
occurs in one third of patients with a thymic NET (42). In these
cases, bilateral adrenal hyperplasia may be seen (43). Other hor-
mones may also be produced, including corticotrophin-releasing
hormone, growth hormone-releasing hormone, and 5-HT (44).
The carcinoid syndrome has never been described in association
with a thymic NET. The prognosis is generally poor (42).
Gastric Carcinoids (See Chap. 12) (Fig. 32.14)
NETs arising in the stomach are rare, accounting for 0.3% of
gastric neoplasms but 11% to 41% of GI NETs (45). They have
been divided into three subtypes based on predisposing factors,
endoscopic appearances, and clinical course:
• Type I gastric carcinoid is the most common subtype
and is associated with hypergastrinemia and chronic
atrophic gastritis, with or without pernicious anemia.
Hypergastrinemia results in hyperplasia of enterochro-
maffin-like cells, which may lead to the development of
the carcinoid tumor. Tumors are multicentric lesions
<1 cm predominantly found in the fundus and body of
stomach, and are surrounded by enterochromaffin cell
hyperplasia. The diagnosis is often made incidentally at
endoscopy for dyspepsia. The disease is almost always
benign, with metastases present in only 2% of cases.
• Type II gastric carcinoids are rare (5–10% of cases). They
are associated with ZES and MEN 1: 30% of patients
with MEN 1 have gastric carcinoids. Tumors arise from
the enterochromaffin-like cells, are multicentric, but
have an increased tendency to metastasize to regional
lymph nodes, although the prognosis is generally good.
• Type III gastric carcinoids are sporadic, are not associated
with hypergastrinemia and account for 13% of cases of
gastric carcinoid. There is a strong male predominance
(80%). The tumor is usually solitary, large and may
ulcerate. Local invasion and metastases are common,
and there is only a 20% five-year survival rate (45).

770
 neuroendocrine tumors

(A) (B)

Figure 32.13 Thymic carcinoid on CT. (A) A large heterogeneous mass is demonstrated in the anterior mediastinum (arrow). There is no fat plane visible between the mass
and the pericardium and pericardial invasion cannot be ruled out. (B) There is bilateral adrenal hyperplasia (arrows) secondary to ACTH production by the tumor (arrows).

(A) (B)

Figure 32.14 Gastric carcinoid type II in a patient with MEN 1. CT at the level of (A) the greater curve of the stomach (arrow) and (B) the gastro-esophageal junction.
Multiple small enhancing lesions are demonstrated (arrows), arising from the gastric mucosa.

Key Points: Foregut Carcinoids
■ Bronchial carcinoids range from benign tumors (typical
bronchial carcinoid) to highly malignant (poorly differentiated
large or small cell carcinoma)
■ Thymic carcinoids are usually non-functioning and usually
have a poor prognosis
■ Gastric carcinoids account for only 0.3% of all gastric neoplasms
Midgut Carcinoids (Figs. 32.15–32.19)
Midgut carcinoids are defined as NETs arising beyond the liga-
ment of Treitz to the level of the mid-transverse colon and are the
commonest primary malignant tumor of the small intestine. They
tend to have a high serotonin content, with relatively high urinary
5-HIAA levels. Of all GI carcinoids, 42% arise in the small
bowel (28). Over the last 50 years, small bowel carcinoids account
for approximately 20% to 30% of all carcinoid tumors and are the
commonest cause of metastatic carcinoid (Table 32.2) (46,47).
However, the percentage of all carcinoids that arise in the small
bowel has decreased gradually during this period. This may be due
to changes in classification. Abdominal pain is a relatively com-
mon presenting feature of carcinoid tumors of the GI tract and
40% present with symptoms of obstruction. Patients may have
colicky abdominal pain and diarrhoea due to increased intestinal
motility. Obstruction may be due to the primary tumor, either
with or without intussusception, although frequently the tumor is
very small. Tumor-associated desmoplastic fibrosis, which causes
tethering and kinking of the small bowel mesentery, may also
cause obstruction. It is probably due to local production of fibro-
genic agents such as 5HT and TGF, and may compromise the arte-
rial or venous vasculature. Dissemination of these agents beyond

771
 primary tumor evaluation and staging

the liver into the venous circulation gives rise to right-sided cardiac
valvular abnormalities. Metastases occur to liver (resulting in the
carcinoid syndrome), bone, and lung (25). The incidence of
metastases from midgut carcinoids is dependent on tumor
size (25,46). In tumors <1 cm, 15% to 25% have metastases; in
tumors between 1 and 2 cm, metastases are present in 58% to
80%; and in tumors >2 cm over 70% have metastases.

Key Points: Midgut Carcinoids

■ This is the most common primary malignancy of the small
intestine, and the commonest cause of metastatic carcinoid.
It is frequently associated with the carcinoid syndrome
■ It includes all the tumors from the ligament of Treitz to the
mid-transverse colon

Figure 32.15 Midgut carcinoid. A barium follow-through study showing focal
mesenteric thickening in the right iliac fossa with distortion of the surrounding
loops of small bowel, which demonstrates spiculation, tethering, and slight fold
thickening. The appearances are consistent with a desmoplastic response second-
ary to the presence of a mesenteric carcinoid tumor.
Hindgut Carcinoids
Hindgut carcinoids include those arising in the colon (distal to the
mid-transverse colon) and rectum. Rectal carcinoids are the most
common hindgut carcinoid and, in a large series between 1992 and
1999, these accounted for 27% of all GI carcinoid tumors (28). The
proportion of GI carcinoids that are rectal has increased, as they

(A) (B)

(C)
Figure 32.16 Midgut carcinoid. (A) CT following IV contrast medium demonstrates a mesenteric mass (arrow) which has a markedly spiculated appearance due to a
fibrotic desmoplastic response in the surrounding tissues. (B) Coronal T1-weighted MR image demonstrates the marked spoke-wheel spiculation around the mesenteric
mass (arrowheads). Liver metastases are also present (arrows). (C) Multiple enlarged mesenteric lymph nodes are seen within the mesenteric fat (arrows).

772
 neuroendocrine tumors
represented 17% of all GI carcinoids in the period between 1950
and 1969 (28). Rectal carcinoids account for 1% of all anorectal
neoplasms (48). The tumors are usually slow-growing. However, in
one large series, 30% of patients had metastatic disease at presenta-
tion (49). Metastases, which occur to the liver, lungs and bones, are
more common in patients with atypical histology and the incidence
increases with the size of the tumor (49,50).
Key Point: Hindgut Carcinoids
■ Rectal carcinoids are the commonest hindgut carcinoid and
account for close to 30% of all GI carcinoids
IMAGING THE PRIMARY TUMOR: PANCREATIC
NEUROENDOCRINE TUMORS
Localization
A wide variety of imaging methods are advocated in the literature
for the localization of the primary site of disease and detection of
Figure 32.17 Ileal carcinoid on CT. There is a focal segment of thickened ileum
(arrow). Several distended loops of small bowel are seen proximal to the lesion.
(A) (B)
Figure 32.18 CT of appendiceal carcinoid in a patient with Cushing’s syndrome. (A) The appendix is clearly demonstrated (arrow). (B) On the next slice superiorly,
a mass is seen arising from the tip of the appendix, which contains speckled calcifications (arrow). A carcinoid tumor was confirmed at histology.
metastases. This reflects the difficulties encountered in satisfactorily
demonstrating these tumors. The use of different modalities in
the literature also reflects differences in local expertise and experi-
ence. In addition, the diagnostic performances that are quoted in
the literature reflect techniques at different stages of development,
making comparison of techniques challenging. The various
techniques and imaging features of pancreatic NETs are now
described, together with a discussion concerning the advantages
and disadvantages of each technique.
Ultrasound
Transabdominal Ultrasound
Transabdominal ultrasound (US) is non-invasive and widely
available, and does not use radiation, but has a relatively low sen-
sitivity for localizing small pancreatic NETs, in the range of 20%
to 86% (13,17,51). However, it has been shown to have a high
specificity. The scanning technique should be tailored to optimize
pancreatic visualization. The patient should drink water prior to
scanning to allow the stomach to be used as an acoustic window;
positioning the patient in both the standing position and lying in
the left posterior oblique position may allow a more complete
assessment. As with most of the imaging techniques available,
sensitivity increases with the size of the lesion (51,52).
The tumor appearance is of a well-defined round mass, which is
homogeneously hypoechoic in relation to the pancreas, and vascu-
lar on Doppler imaging. There may be a hyperechoic halo or distor-
tion of the gland, an appearance that may help in detecting the
lesion, particularly in younger patients, in whom the tumors tend to
be less conspicuous due to the generally lower echogenicity of the
pancreas. Tumors that lie along the surface of the pancreas or in the
duodenum are less conspicuous. US contrast agents have been
shown to have a high specificity of 90% to 100% in differentiating
pancreatic ductal adenocarcinoma from other solid neoplastic
masses, including NETs, on transabdominal US (53). Ductal ade-
nocarcinomas are characterized by lesion hypovasculity in relation
to the surrounding enhancing pancreatic parenchyma post-contrast
medium administration. Conversely, iso- or hypervascularity is
characteristic of other pancreatic neoplasms, including NETs.
773
 primary tumor evaluation and staging

(A) (B)

(C) (D)

Figure 32.19 Carcinoid liver metastases. (A) Non-contrast CT demonstrates ill-defined low attenuation lesions (arrows). (B) In the early arterial-phase following con-
trast enhancement, the metastases are relatively poorly demonstrated. (C) In the late arterial phase (AP), extensive liver metastases are demonstrated, which enhance
intensely. Many lesions could not be appreciated on the non-contrast or early AP CT. (D) Octreotide scanning demonstrates the multiple liver metastases, indicating that
radiopharmaceutical therapy may be considered.

The patterns of enhancement of pancreatic lesions on contrast-
enhanced ultrasound have been found to correlate with the
enhancement on Computed Tomography (CT) (54).
Endoscopic Ultrasound
Endoscopic ultrasound (EUS) enables close proximity of the
transducer to the pancreas, allowing a high frequency US probe
to be used (7.5–10 mHz), resulting in greatly improved image
resolution. The pancreatic head and duodenum are scanned
with the probe positioned in the duodenum, and the body and
tail are scanned through the stomach. Although EUS is invasive
and operator-dependent, it greatly improves the sensitivity for
the detection of small tumors (55,56). The advantages of the
technique are:
• Localization of small tumors
• Localization of multiple tumors, particularly in MEN 1
• Detection of small tumors in the pancreatic head, which
may be difficult to palpate at surgery
• Detection of tumors arising in the duodenal wall
• Detection of lymph node enlargement to improve staging
accuracy
• Accurate depiction of the relations between vascular and
biliary structures, and the tumor
• Fine needle aspiration biopsy can be undertaken
The disadvantages of the technique are:
• Technically challenging, requiring specialist training,
and therefore not widely available; may not be suitable
for all patients, for example, where there is duodenal
scarring in ZES
• Reduced sensitivity in extrapancreatic lesions or in the
tail of the pancreas
• The liver cannot be fully assessed

774
 neuroendocrine tumors
Although the diagnostic performance of EUS is difficult to evaluate,
reports indicate that overall the technique is highly sensitive,
with sensitivities as high as 79% to 100% reported (56,57). As
on transabdominal US, pancreatic NETs are iso- or hypervascu-
lar following administration of US contrast medium. This feature
is helpful in differentiating these lesions from ductal adenocar-
cinoma (53). Fine needle aspiration of suspected pancreatic
NETs may be undertaken during EUS. There is a close correla-
tion between the aspiration cytology and the final histology
post-resection (58–60).
Intraoperative Ultrasound
This technique has similar advantages to EUS and may improve
the intraoperative sensitivity for identifying small lesions in the
head and multiple lesions to up to 92% to 97% and is a useful
adjunct to palpation of the gland (17,61). It has been shown to
change operative management in 10% of ZES cases, by identifying
multiple gastrinomas or by demonstrating the malignant nature
of a lesion (62). Intraoperative ultrasound (IOUS) has the advan-
tage, over EUS, of being able to assess the liver. However, it is not
as sensitive as surgical palpation in detecting extra-pancreatic
lesions. The disadvantages of the technique are:
• Increased time and complexity of operation, as complete
mobilization of the pancreas is required
• Specialist experience is required for performing and
interpreting the scan
• Preoperative tumor localization is still needed
• Poor sensitivity in extrapancreatic/duodenal lesions
Overall, the technique is a useful addition to surgical palpation,
particularly in small tumors such as insulinomas
Key Points: Pancreatic NETs on US
■ Transabdominal US has high specificity but low sensitivity
■ Lesion appears homogeneously hypoechoic in relation to the
pancreas
■ Lesion may have hyperechoic rim or cause distortion of the
pancreas
■ Lesion is iso- or hypervascular to the surrounding pancreas
following enhancement
■ EUS improves sensitivity for detection of small/multiple
tumors in the head and neck of pancreas, but the tail of the
pancreas is difficult to visualize
■ IOUS improves sensitivity for the detection of small/multi-
ple tumors in the head and neck of pancreas and the liver,
and is a useful adjunct to palpation
Computed Tomography
CT is the most widely used diagnostic tool for the localization
and staging of pancreatic NETs. It has the advantage of being
widely available and is not subject to some of the difficulties
encountered with US, such as potentially poor visibility and
operator-dependence. Multidetector CT (MDCT) has enhanced
the diagnostic strength of CT, allowing very rapid acquisition of
the images, ensuring accurate arterial-phase images, and reduced
movement artifact.
CT Technique
Optimal technique is essential for the accurate detection of these
lesions. The patient should be fasted to ensure that the stomach
and duodenum are emptied of their contents. The stomach is
distended with water and IV hyoscine butylbromide or another
anti-peristaltic agent is administered. An initial precontrast scan is
performed to identify the level of the pancreas. Following IV
administration of 150 ml of contrast medium at a rate of 3–5 ml/
sec, biphasic scanning is recommended. Arterial-phase scanning
is started either by bolus tracking or after a delay of approximately
30 seconds and portal venous scanning after a delay of 60 to
70 seconds. The section thickness should not exceed 5 mm and the
entire liver should be included in all phases. The images are then
reconstructed to 1 to 2 mm in slice thickness, and coronal or sagit-
tal reformats may be made. Images should also be viewed on nar-
row window settings in order to augment the difference between
the enhancing tumor and the pancreas (63–65).
CT Appearance
Functioning tumors are usually small (see p. 762–66 and Table 32.1)
and subtle, with low inherent contrast between the tumor and sur-
rounding pancreas. They are usually isodense with the pancreas on
precontrast images and do not usually distort the contour of the
pancreas. As in the angiography literature, a majority of islet cell
tumors are hypervascular and will be best seen after intravenous
injection of contrast medium. However, the best phase for the dem-
onstration of those hyperattenuating small lesions is unclear. The
authors’ experience concurs with others who report that tumor-to-
pancreas contrast is greatest on arterial-phase (AP) images com-
pared to portal venous phase (PVP) imaging (66–68). However,
others have found the PVP significantly more helpful in identifying
these tumors (69). At present, therefore, we recommend biphasic
imaging following IV injection of contrast medium to optimize the
sensitivity of the technique. Narrow window settings may help to
improve detection (Fig. 32.20). Rarely, insulinomas may be hypo-
vascular or cystic and appear hypodense to the surrounding pan-
creas. Cystic pancreatic NETs represented four of 38 pancreatic
NETs in one series, and these represented 14% of all pancreatic cys-
tic lesions identified over a 10-year period (70). Cystic pancreatic
NETs are usually benign and non-functioning, and cannot be reli-
ably differentiated from other cystic pancreatic lesion neoplasms on
imaging alone (70,71). In patients with a suspected gastrinoma,
particular attention should be given to the “gastrinoma triangle”
(see section “Gastrinomas” p. 770).
Large tumors are more likely to be non-functioning and necrotic
centrally, and are more likely to be malignant (Fig. 32.2). The features
that are associated with malignancy include large size, necrosis, overt
infiltration of the surrounding retroperitoneal structures such as
vessels, and calcification (Figs. 32.2, 32.3, and 32.11) (4,63). In one
study, calcification was associated with well-differentiated tumors (72).
Diagnostic Performance of CT
Early studies using non-spiral CT techniques reported a relatively
high sensitivity of 78% for the detection of lesions (4). Detection
of the primary tumor is directly related to tumor size, with no
tumors identified <1 cm, 30% of tumors detected between 1 and
3 cm, and 95% of tumors >3 cm in diameter demonstrated (4,7,73).
The location of the tumor also influences the ability of CT to
775
 primary tumor evaluation and staging
(A)
Figure 32.20 Multiple gastrinomas on CT: Importance of window settings. Arterial-phase CT on (A) narrow window settings and (B) wide window settings. Two brightly
enhancing gastrinomas are seen; one shown here in the wall of the duodenum (white arrow) and another extrapancreatic gastrinoma adjacent to the uncinate process
(black arrow). Note the unopacified IVC (asterisk). It is important to use oral water rather than Gastrografin in order to appreciate duodenal gastrinomas.
detect the lesion. One prospective study detected 68% of primary
tumors and 86% of hepatic metastases (confirmed at surgery,
autopsy or percutaneous biopsy), 90% of pancreatic head tumors,
80% of pancreatic body tumors, and 45% of pancreatic tail
tumors (73,74). Small tumors of <1 cm in the duodenum are often
missed on CT, and CT sensitivity for the detection of extrahepatic
and extrapancreatic gastrinomas, which are often small at presen-
tation, is only 30% to 50% (19,73). With the development of mul-
tidetector CT and the use of thin reformats, there has been a
reported increase in sensitivity for the detection of insulinomas to
94% (75). In the same publication, a 100% sensitivity was achieved
if the MDCT results were combined with EUS.
Key Points: Pancreatic NETs on CT
■ Small functioning tumors are usually isodense to the pancreas
and enhance strongly postcontrast
■ Best visualization is on arterial phase but portal venous phase
is complementary
■ Cystic lesions occur but are rare
■ Large tumors are more likely to be non-functioning
■ Signs of malignancy include large size, necrosis, calcification,
and invasion/infiltration of surrounding structures
Magnetic Resonance Imaging
Early studies with magnetic resonance (MR) imaging reported a
lower sensitivity than CT for the detection of both the primary
tumor and metastatic disease. However, with the marked improve-
ments in MR technology that have occurred in the past decade,
the diagnostic performance of MR has improved and in several
studies has been shown to exceed or equal that of CT (69,76,77).
MR has a higher sensitivity than angiography or CT for metastatic
disease (78). However, angiography remains more sensitive than
MR for identifying the primary tumor. A sensitivity of 94% for
pancreatic lesions, but less for extra-pancreatic lesions, has been
reported (76,79). As with the other cross-sectional modalities,
tumor detection increases with tumor size. Multiple tumors, as in
patients with MEN 1, are particularly difficult to detect.
The sensitivity of MR does depend on good quality images.
Where there is image degradation due to movement artifact and a
776
(B)
poor signal-to-noise ratio, for example, in obese patients, sensitivity
may be reduced. Optimal technique requires a quadrature phased-
array coil. The imaging sequences should include:
• Axial fat-suppressed T1-weighted spin-echo and
gradient-echo
• Axial fast spin-echo, T2 weighted with and without fat
suppression
• Axial dynamic contrast-enhanced gradient echo sequence
The tumors usually appear to be of low signal intensity on
T1-weighted sequences and high on T2-weighted sequences in
relation to the pancreas (Fig. 32.5). The tumors are most conspic-
uous on the fat-suppressed T1-weighted image whether spin-echo
or gradient-recalled (76,79). Tumors that contain a high collagen or
fibrous tissue content may return a low signal intensity on T2-weighted
images, but this is rare (69). Following IV gadolinium administration,
there is characteristic marked homogeneous enhancement, reflecting
the highly vascular nature of these tumors (Fig. 32.5). In cystic lesions,
rim enhancement may be seen (76). Liver-specific contrast agents,
such as mangofadopir DPDP, may have a role in improved lesion
detection, but this is currently under investigation (80,81).
Key Points: Pancreatic NETs on MR Imaging
■ Best seen on fat-saturated T1-weighted sequences
■ Usually hypointense to the pancreas on fat-saturated
T1-weighted image
■ Usually hyperintense to the pancreas on FSE T2-weighted
image
■ Homogeneous enhancement post gadolinium (rim enhanceent
in cystic lesions)
Angiographic Techniques
Angiography
Angiography is rarely used nowadays in most centres and when
used is usually combined with venous sampling. In order not
to miss a lesion, detailed assessment of the vasculature is
required with selective catheterization of all the branches of
the coeliac and superior mesenteric arteries. Sensitivities are
 neuroendocrine tumors
fairly high. Both the primary tumor and liver metastases are
seen as a well-defined blush in the capillary to early venous
phases. Difficulties in diagnosis arise:
• When a tumor lies adjacent to a loop of bowel or spleen
and the blush is not separately visible
• When the tumor is very small
• When there are multiple lesions
• When the tumor is hypovascular
All these problems may lead to false negative results. False positives
arise from the blush of a splenunculus or normal pancreas or
bowel.
Transhepatic Portal Venous Sampling
The principle of this technique is that the vein draining the
tumor will have an abnormally high concentration of hormone.
Transhepatic portal venous sampling (THPVS) may involve per-
cutaneous catheterization of a portal venous branch. Blood is
then sampled from the splenic vein, superior, and inferior mes-
enteric veins, pancreatic veins and portal trunk. Thus a tumor
may be broadly localized to the tail, body or head of the pan-
creas/duodenum (these cannot be reliably distinguished using
this technique). This method is only useful for tumors that
secrete a hormone and false-negative results may occur if hor-
mone secretion is intermittent. It has a limited role in patients
with multiple tumors.
Arterial Stimulation and Venous Sampling
Arterial stimulation venous sampling (ASVS) combines simulta-
neous hepatic venous sampling with selective arterial injection of
a pancreatic secretagogue, a technique that is less invasive than
THPVS. Many different specific secretagogues have been used in
the past, but generally now calcium gluconate is used regardless of
the specific secretory product. Following injection of the secret-
agogue, hepatic venous sampling is performed every 30 seconds
for two minutes (Fig. 32.4C). A two- or threefold increase in the
level of hormone indicates the presence of tumor, allowing the
depiction of the tumor region, as with THPVS. This technique is
most useful in cases where the tumor remains occult on other
imaging modalities, predominantly with very small functional
tumors. It can be performed as part of pancreatic angiography
and is liable to some of the risks associated with THPVS, such as
hepatic arteriovenous fistulae, hematoma, and superior mesen-
teric arterial occlusion. Reported sensitivities are high, up to 93%,
and the stimulation technique improves the sensitivity of
angiography alone (7). In one case series, 10 of 11 insulinomas
were correctly localized, with histological confirmation (82).
Key Points: Imaging of Functioning Pancreatic NETs
■ These tumors are usually small (1–2 cm) at presentation
■ They are markedly vascular
■ Many different imaging techniques are advocated, including
cross-sectional, interventional, and nuclear medicine
■ Local expertise should guide the imaging algorithm
CHOICE OF IMAGING TECHNIQUE IN LOCALIZING
PANCREATIC NETS
Several factors have to be taken into account when considering
the choice of the most appropriate investigation for localizing
biochemically proven pancreatic NETs, including such consider-
ations as availability, cost, local experience, and expertise. Most
investigators would initiate investigation with cross-sectional imag-
ing, either CT or MR. Advantages and limitations of both are given
above. This will clearly identify the largest lesions, allow assessment
of the entire abdomen and provide valuable information on the
presence of hepatic metastases. We believe that the investigation of
choice for the precise localization of pancreatic NETs is EUS, which
should follow cross-sectional imaging, especially where the findings
are equivocal. In the context of multiple endocrine neoplasia it
will help to identify whether the lesions are multifocal. Radionuclide
scintigraphy (which is described on p. 783-86) is helpful in
• Associating an anatomical abnormality with functional
evidence
• Identifying unsuspected metastases
• Assessing possible therapeutic options
The technique of ASVS, being more invasive, is used more spar-
ingly. Where the imaging is unequivocal, it is not usually necessary
to perform it. However, ASVS becomes extremely valuable in the
context of MEN1, when the patient shows multifocal lesions and
it is unclear which are responsible for a given hormonal hyperse-
cretion. In such patients, pancreatic surgery may be limited to
removal of selected lesions.
It has been argued in the past that for small pancreatic NETs,
especially insulinomas, all that is needed is a confirmed biochem-
ical diagnosis, and to proceed directly to surgery using IOUS.
However, we believe that the treatment of NETs, in general, has
become more individualized and precise radiological demonstra-
tion of the size, the functionality, and metastases will determine
optimum outcomes, especially where a partial pancreatectomy or
laparoscopic removal is the most appropriate procedure.
IMAGING THE PRIMARY TUMOR: CARCINOID
NEUROENDOCRINE TUMORS
Localization
In some cases, the diagnosis of a carcinoid tumor is made at endos-
copy, particularly for gastric, duodenal, rectal, or colonic lesions.
Endobronchial carcinoids may be diagnosed bronchoscopically.
However, imaging is used extensively for the localization of many
primary NETs, as well as in staging the tumor. Many carcinoids do
not present with a specific clinical syndrome, such as the carcinoid
syndrome, and imaging may be performed to investigate non-
specific symptoms of abdominal discomfort or diarrhoea. Image-
guided biopsy of a mass, liver lesions, or lymph nodes may help to
establish the diagnosis. CT is the main cross-sectional imaging
modality for localizing and staging carcinoid tumors (83). US is used
predominantly in the detection of liver metastases and for guiding
biopsy. It is not a primary diagnostic tool in localizing the tumor.
Imaging is also useful in the investigation of second primary tumors,
777
 primary tumor evaluation and staging

(A) (B)

(C)
Figure 32.21 Large cell NET of the lung. (A) CXR demonstrates complete opacification of the right hemithorax. (B) CT at 25 minutes post-intravenous contrast medium
administration demonstrates a very large tumor mass in the right lower thorax (white arrows). Multiple vessels are clearly seen running through the tumor, mimicking
the configuration to the pulmonary vessels (the “pulmonary angiogram” sign). The liver is seen anteriorly on (B) arterial-phase and (C) portal-venous phase images
(black arrow). There is an associated right pleural effusion.

such as GI and genitourinary tract adenocarcinoma, which are
frequently described in association with carcinoid NETs (28,84).
Appearance of Primary Carcinoids
Foregut Carcinoids
Bronchial Carcinoid
Imaging features of the primary bronchial carcinoid are similar
regardless of the grade of the tumor and the features depend on
whether the tumor is located in the airways of the central/middle
third of the lung (80% of cases) or the peripheral airways
(Fig. 32.12) (39). The tumor may be detected with plain radiology
with the appearance of a well-demarcated round or ovoid mass,
often notched (85). Centrally located tumors may result in air-
ways obstruction, with recurrent infection, lobar collapse, and a
central mediastinal or hilar mass, which is usually smooth and
lobulated, 2 to 5 cm in diameter (85). However, they are usually
small and thus CT scanning is the most sensitive cross-sectional
technique available. On CT, the mass may be visible within the
bronchial lumen, usually with both an intra- and extraluminal
component. A peripheral bronchial neuroendocrine lesion is seen
in 20% of cases, with the appearance of a solitary pulmonary
nodule (Fig. 32.12). The mass is typically round or ovoid with a
smooth or lobulated border. Calcification is fairly common, either
punctate or diffuse. Cavitation and hilar adenopathy are rare in
typical carcinoids (85). Rarely, there may be two lesions, in which
case it may be impossible to separate the appearance from pulmo-
nary metastases (85). Aggressive lesions (large or small cell carci-
nomas) (Fig. 32.21) may demonstrate direct mediastinal invasion.

778
 neuroendocrine tumors
(A)
Figure 32.22 Foregut carcinoid. (A and B) CT of the thorax demonstrates a lobulated mass in the anterior mediastinum (arrow in B) that extends into the lower medi-
astinum and displaces the heart to the left. There is associated lymph node enlargement (arrow in A) and a large right pleural effusion.
Collapse or air trapping beyond the central lesion can be seen if
there is a ball-valve obstruction of the bronchial lumen. Following
IV contrast medium, there is usually intense homogeneous
enhancement, although this is not seen in all cases. Marked
enhancement can create diagnostic difficulty, as the appearance
may mimic a pulmonary varix or pulmonary artery aneurysm,
and a small vascular lesion may be overlooked or interpreted as a
normal vessel (39). In patients with occult ectopic ACTH secre-
tion, bronchial carcinoids are the most common source but can be
elusive and difficult to identify (Fig. 32.12). When a pulmonary
lesion is suspected but cannot be seen on CT, MR may play a role
in localization. Bronchial carcinoids have high signal intensity on
T2-weighted and short tau inversion recovery (STIR) images,
allowing distinction between a small mass and the pulmonary
vasculature of the central and middle third of the lung (86). In
some cases, imaging with somatostatin receptor scintigraphy may
help in the localization and characterization of a small peripheral
lesion. Marked nodular adrenal hyperplasia may be incidentally
noted, if the lesion secretes ACTH, causing Cushing’s syndrome.
Key Points: Bronchial Carcinoids
■ Eighty percent of bronchial carcinoids are located in the
bronchi of the central or middle third of the lung
■ Central lesions are small vascular masses, with intra- and
extrabronchial components, which may cause signs of air-
ways obstruction
■ Thirty percent of these calcify
■ MR imaging may help detect small, centrally located lesions
in patients with an occult source of ectopic ACTH secretion
■ Twenty percent are located peripherally and have the appear-
ance of a solitary pulmonary nodule
Thymic Carcinoids
These tumors usually present as an anterior mediastinal mass
(Fig. 32.13). The mass may be partly calcified and may cause SVC
obstruction (43,87). There is usually evidence of invasive disease,
with seven of eight patients in one series having extension into
(B)
the pleura, pericardium, great vessels, or regional lymph nodes
(Fig. 32.22) (88). If the tumor is functioning and producing ACTH,
then bilateral adrenal hyperplasia may also be seen (43). Bone
metastases, which may be sclerotic, and lung and liver metastases
may be present at the time of diagnosis (87–90).
Gastric Carcinoids (See Chap. 12)
Type I gastric carcinoids are small (<1 cm), multicentric, and pre-
dominantly found in the fundus and body of the stomach. The diag-
nosis is usually made endoscopically, not on imaging. The disease is
almost always benign, with metastases present in only 2% of cases.
Type II gastric carcinoids, (Fig. 32.14) which are associated with
the ZES and MEN-1, are multicentric. On CT, multiple masses are
present within the gastric wall, which is diffusely thickened sec-
ondary to ZES. There is an increased tendency to metastasize to
regional lymph nodes, although the prognosis is good (91).
Type III sporadic gastric carcinoids are usually solitary, large,
and may ulcerate. Local invasion and metastases are common.
Midgut Carcinoids (Figs. 32.15–32.18)
The primary tumor may not be seen in midgut carcinoids as it is
usually a small tumor that is not conspicuous against the small
bowel or the ascending/transverse colon from which it arises. There
may be multiple primary sites. The most frequent imaging findings
are secondary features, which are described in detail later in the sec-
tion on metastatic disease in NETs. Liver metastases are the most
frequent finding, followed by tumor-associated desmoplastic fibro-
sis, which causes tethering and kinking of the small bowel mesen-
tery and may also cause obstruction. Bone and lung metastases also
occur. The incidence of metastases from midgut carcinoids is
dependent on tumor size (25). In tumors <1 cm, 15% to 25% have
metastases; in tumors between 1 and 2 cm, metastases are present in
58% to 80%; while in tumors >2 cm, over 70% have metastases.
CT
The primary bowel wall tumor is rarely demonstrated on CT
and in one large series was only seen in one of 52 cases, where
an ileal tumor was causing an intussuception into the cecum (92).
779
 primary tumor evaluation and staging
Figure 32.23 CT enteroclysis demonstrating an ileal carcinoid reformatted as a
coronal MIP. The small bowel has been distended by an infusion through a naso-
jejunal tube. An enhancing mass is seen in the region of the terminal ileum, which
was confirmed to be a carcinoid neuroendocrine tumor at histology (arrow).
Source: Courtesy of Dr. Martin Gore.
Detecting small primary tumors in the small bowel remains
one of the most difficult challenges yet to be overcome on
imaging (92,93).
Enteroclysis (Fig. 32.23)
There are a few reports of CT enteroclysis in the detection of small
bowel carcinoid (94,95). On MDCT enteroclysis both transverse
and multiplanar reformats were used to evaluate the small bowel:
focal bowel wall thickening, small bowel masses, or stenosis, mes-
enteric stranding, lymph nodes or visceral metastases were
recorded. In this series of 55 patients, carcinoid tumor was con-
firmed histologically in 19. Carcinoid tumors were seen as focal
nodular lesions in the small bowel wall, demonstrating marked
enhancement following IV contrast medium. In this series, there
was an overall false-positive rate of 2.3% and false-negative rate of
4.1%, and there was an overall diagnostic accuracy of 84.7% (94).
MR
MR has been shown to demonstrate the primary tumor in 8 of
12 patients with a GI carcinoid (96). The best sequence for demon-
strating the primary tumor was the post-gadolinium T1-weighted
fat-suppressed image. In four cases, the tumor was a nodular mass
arising from the bowel wall; in four cases there was regional uniform
bowel wall thickening. The primary tumor enhanced moderately/
intensely following gadolinium administration (96).
Other Imaging Techniques
Angiography of the superior and inferior mesenteric artery has a
reasonable sensitivity for the localization of the primary tumor,
lymph node and liver metastases. Rarely, THPVS may be helpful in
780
localization of tumors in the upper abdomen, but this is no longer in
common use. Barium follow-through may be abnormal if there is a
fibrotic or desmoplastic reaction within the mesentery, resulting in
distortion of the small bowel loops (Fig. 32.15). However, the tech-
nique is not sensitive in demonstrating the primary lesion. Echocar-
diography should be performed in all patients with carcinoid
syndrome to identify signs of carcinoid heart disease. There is recent
evidence that the presence of structural heart disease secondary to
carcinoid syndrome is an independent poor prognostic factor (97).
Capsule Endoscopy
This novel technique requires ingestion of a capsule that transmits
images by video-telemetry whilst travelling through the bowel. It
has been shown to demonstrate the site of the primary small bowel
NET in 45% of cases in one series of patients with metastatic small
bowel NET in whom CT and enteroclysis were negative (98). In
this series, nuclear imaging had a similar diagnostic yield, but could
not differentiate a small bowel tumor from mesenteric disease.
Key Points: Imaging Midgut Carcinoids
■ These are the commonest primary malignancy of the small
bowel
■ The primary bowel wall tumor mass is usually occult
radiologically
■ Liver metastases are common
■ Mesenteric masses are common and usually have radiating
strands of soft tissue and are often calcified
■ Retroperitoneal or mesenteric lymphadenopathy is seen in
20% to 30% of cases
Hindgut Carcinoids
These lesions are usually diagnosed at endoscopy, although bar-
ium studies may demonstrate an extrinsic filling defect. At endo-
scopy, they appear as solitary yellowish submucosal lesions and are
typically between 1 and 2 cm in diameter (48,99). As these lesions
are small and disease is often confined to the rectum, minimally
invasive techniques to allow local resection is the treatment of
choice (99,100). However, these techniques are only suitable in
Stage T1 (tumor confined to the mucosa and submucosa) and T2
(invasion of muscularis propria) disease, with no evidence of
extension to the serosa. Imaging may be used to identify cases
suitable for local resection. Endoscopic US demonstrates the
lesion as a homogeneously hypoechoic submucosal mass (101).
Endoscopic US may demonstrate invasion of the full rectal wall
(Stage T3) and invasion into adjacent structures (T4) (100). In
these cases, extended resection is required. MR may have a role in
local staging of the primary mass. Both CT and MR can be used to
stage lymph node disease and distant metastatic disease as part of
the preoperative planning. In one large series, 30% of patients had
metastatic disease at presentation (49,50).
METASTASES FROM PANCREATIC AND CARCINOID NETS
Metastases are a common finding in NETs. In a large autopsy
series, 29% of patients with a carcinoid NET were found to have
metastatic disease, the majority (61%) arising from small bowel
carcinoids (27). In this series, 90% of metastases were in the lymph
 neuroendocrine tumors
(A)
Figure 32.24 Hypervascular liver metastases from a carcinoid tumor: importance of timing. (A) Arterial-phase T1-weighted MRI with fat saturation, acquired in the
arterial phase following IV administration of gadolinium. Multiple brightly enhancing metastases are seen. (B) At the portal-venous phase several of the lesions are no
longer visible and those that can be seen are isointense to the liver and are no longer conspicuous.
nodes, 44% in the liver, 14% in the lungs, 14% in the peritoneum,
and 7% in the pancreas. The imaging appearances of metastatic
disease from both pancreatic and carcinoid NETs are similar and
will be considered together.
Liver Metastases
Liver metastases are seen in 40% to 80% of patients with a midgut
carcinoid at presentation, depending on the site of the primary
tumor. Liver metastases are present at the time of initial diagnosis
in 40% of ileal lesions and up to 80% of caecal lesions (28). Liver
metastases are the most common imaging finding (92). The extent
of liver metastases is an important prognostic factor in pancreatic
NETs (18). In patients with a malignant gastrinoma, the presence
of liver metastases alone moderately decreases survival. However,
the development of Cushing’s syndrome or bone metastases in
combination with liver metastases results in a markedly decreased
survival rate (18). In patients with a metastatic carcinoid, the five-
year survival rate of patients with no liver metastases is not sig-
nificantly different to patients with a few liver metastases (fewer
than five) (73% vs. 79%). However, there is a significant decrease
in the five-year survival rate to 47% in patients with extensive liver
metastases (more than five) (102).
Ultrasound
On transabdominal US, liver metastases tend to be hyperechoic,
particularly in cases of metastatic gastrinoma, and are detected
with a sensitivity of approximately 60%, although lesion conspi-
cuity is reduced in patients with a fatty, hyperechoic liver (21,52).
EUS is not reliable in detecting liver metastases, due to its limited
depth of penetration. Intraoperative ultrasound can be helpful in
the assessment of liver metastases, allowing accurate depiction of
the relationship between a lesion and hepatic vessels, which may
help in determining resectability (103).
CT
Neuroendocrine hepatic metastases may be difficult to identify
and delineate on CT as they may be isointense to the liver on PVP
(B)
imaging. A combination of precontrast, hepatic arterial-dominant
phase (HAP), and PVP imaging will improve the sensitivity of
detection, as in some cases a lesion may only be seen on one of the
three phases (104). Evidence indicates that the HAP is particularly
helpful in the detection of liver metastases (Fig. 32.19).
Liver metastases are most frequently of low attenuation in rela-
tion to the surrounding parenchyma on precontrast images and
enhance strongly postcontrast, mimicking a hemangioma. Like
the primary tumor, large lesions may become necrotic and may
calcify. If the peak enhancement is missed due to the timing of the
scan, the lesion may become isodense to the liver and thus lesion
detection may be challenging.
In one study, CT was compared with selective angiography; the
latter technique detected 20% more liver metastases than CT, with
a very high rate of detection (74).
MR
On MR, 75% of neuroendocrine liver metastases appear as having
low-signal intensity on T1- (Fig. 32.25) and high-signal intensity
on T2-weighted images, with 94% of metastases being hypervas-
cular on HAP post-gadolinium images (Fig. 32.24): 15% of hepatic
metastases were only seen on the immediate post-gadolinium
images in one series (96).
The use of mangofadopir-DPDP may increase the detection of
small liver metastases and has been shown to be highly reproduc-
ible (Fig. 32.25) (80). In our institution, this technique is used
prior to planning resection of liver metastases in order to ensure
detection of all lesions.
Mesenteric Masses and Peritoneal Disease
Secondary mesenteric masses >1.5 cm are seen in approximately
50% to 75% of cases of midgut carcinoid, with a median size of
3 cm (92,96). Masses are of soft tissue density and commonly
have a “spoke-wheel” appearance, with radiating strands of soft
tissue (64–100%) (Fig. 32.16). The degree of radiating strands
increases as the degree of fibrosis increases, as seen on histology,
and is caused by hormonally active substances, particularly
781
 primary tumor evaluation and staging

(A) (B)

(C)

Figure 32.25 Liver metastases: use of liver-specific contrast medium. (A) Portal-venous phase CT demonstrates several poorly defined low attenuation liver metastases
(arrows). (B) On T2-weighted MRI the metastases have a higher signal intensity than the surrounding liver. (C) T1-weighted image following administration of
MnDPDP demonstrates enhancement of the liver parenchyma, increasing the liver-to-lesion signal intensity ratio. The liver metastases are highly conspicuous
(arrows). Additional lesions could also be identified in this case.

mass (32). Masses usually arise within the fat or nodal tissue of the
small bowel mesentery, although the exact nidus of metastatic
tumor growth in the mesentery is not certain (32).
Diffuse mesenteric/peritoneal disease, with peritoneal studding
or ascites, is seen in 20% to 30% of patients with a GI carcinoid and
may be associated with obstruction (Fig. 32.16C) (92,105). Perito-
neal disease is less common in pancreatic NETs; it was seen in 11%
of non-gastrinoma pancreatic NETs but did not occur in association
with a gastrinoma in one series (Figs. 32.7 and 32.8) (105)

Lymph Node Metastases

Figure 32.26 Retroperitoneal nodes in a patient with metastatic carcinoid. There
are bilateral para-aortic (arrows) and retro-caval nodes which demonstrate marked
peripheral enhancement but have undergone central necrosis.
serotonin. Calcification is commonly seen within mesenteric
masses (40–70%), and may be small stippled calcifications or
bulky and conglomerate (32,92). On histology, calcification is
localized within areas of mature fibrous scarring within the
Regional lymph node metastases are the most frequent metastatic
site at autopsy (27). Retroperitoneal or mesenteric lymph node
enlargement is seen in approximately 20% to 30% of patients with
a midgut carcinoid (Figs. 32.16C and 32.26) (92). Retroperitoneal
fibrosis may be seen in cases with retroperitoneal lymph node
metastases and may cause ureteric obstruction. In thymic NETs,
mediastinal lymph node metastases are present in 60% at the time
of resection (Figs. 32.22 and 32.27) (106).
Lung Metastases
Lung metastases, which arise from a variety of NETs, may be
hormone-secreting although in most patients they are

782
 neuroendocrine tumors

asymptomatic. Diagnosis is accurately made on CT. Local metasta-

sectomy, where clinically appropriate, has been shown to improve
outcomes when compared with medical management (107).

Bone Metastases
Bone metastases are more commonly associated with foregut
and hindgut carcinoids than midgut carcinoid tumors. The
metastases are frequently sclerotic and may have the appearance
of multiple small punctate sclerotic deposits (43). Bone metas-
tases have been reported in up to 30% of patients with malignant
gastrinoma and are indicative of a poor prognosis, particularly
when associated with liver metastases (18). Whole-body MR
and somatostatin receptor scintigraphy (SRS) have been used to
detect bone metastases in patients with well-differentiated gas-
(A) tro-entero-pancreatic endocrine cancer and have been found to
be equally sensitive (86% vs. 81%, p = 0.56) (108). The authors
concluded that bone staging should be undertaken using SRS
and spine MR in bronchial-thymic or unknown primary cases.
In patients with a duodenal-pancreatic or ileal primary, bone
staging may be restricted to those with liver metastases (108).

Key Points: Metastases from Pancreatic and

Carcinoid NETs
■ Liver metastases occur in 40% to 80% of midgut carcinoid tumors
at presentation and are the most common imaging finding
■ Liver metastases tend to be hypervascular on contrast-
enhanced CT and MR, and are imaged optimally on the
hepatic arterial phase following contrast medium injection
■ Secondary mesenteric masses are common, usually of soft
tissue density, often with a spoke-wheel appearance, and
often with flecks of calcium
■ Lymph node metastases are the most frequent metastatic site
at autopsy

(B)
MOLECULAR IMAGING IN NETS

NETs often express high levels of peptide receptors, which can be

(C)
Figure 32.27 Nodal disease in a patient with a metastatic carcinoid of unknown
primary site. Nodal metastases (arrows) are demonstrated (A) in the retrocrural
nodes; (B) in the posterior mediastinum; and (C) in the left supraclavicular
nodes.
targeted by radiolabeled receptor ligands. Successful approaches
include the use of somatostatin (SST), vasoactive intestinal pep-
tide (VIP), bombesin, and cholecystokinin-B/gastrin analogues.
Both gamma camera imaging and positron emission tomography
(PET) can be applied using appropriate radiolabeled receptor
ligands. Gamma camera imaging generally includes planar scin-
tigraphy often with additional Single Photon Emission Com-
puted Tomography (SPECT). SPECT is being replaced by SPECT/
CT, which provides co-registered functional and anatomical
information. The most common radionuclides for gamma cam-
era imaging are 111Indium, 99mTechnetium and iodine radioiso-
topes (131iodine and 123iodine). PET radiopharmaceuticals include
18
fluorine-labelled fluorodeoxyglucose (FDG) and 68gallium-la-
belled peptides. Gamma camera imaging and PET provide an
in vivo characterization of tissue and are often more sensitive and
specific than conventional anatomical imaging modalities.
Regulatory peptides bind and act through transmembrane G
protein coupled receptors. Peptides, in contrast to larger molecules
such as antibodies and proteins, have the advantage of easily pen-

783
 primary tumor evaluation and staging
etrating into all tissues except the brain as they are hydrophilic (109).
In order to fulfill their purpose for imaging, rapid degradation by
peptidases, and thus fast inactivation, is very important. However,
their short biological half-lives limit their use as radiopharmaceu-
ticals. Hence a major focus of peptide research is the development
of metabolically stable peptides for therapy and imaging.
Radiopeptide Scintigraphy
Although many regulatory peptide receptors are expressed on
various tumors, to date somatostatin receptor analogues have
gained the widest clinical application. Somatostatin receptors
are present on many tumor types including carcinoma of the
lung, breast, some sarcomas, and lymphoma. Five different
subtypes of the human somatostatin receptor (SSTR1-5) are
currently recognized, bound to varying degrees by the analogues
111
In-octreotide (also called pentetreotide), 111In-lanreotide,
and P829 (Neospect, Depreotide), a technetium-99m (99mTc)
analogue (110).
111
In-octreotide is the most widely available somatostatin ana-
logue for imaging. The biologically active ring of octreotide is
intact and a DTPA bridge is coupled to the phenylalanine group
for labelling with 111Indium. It has moderate affinity to SSTR2 and
SSTR5 with virtually none to SSTR1, 3, and 4. 111In-octreotide has
an accepted role for tumor localization and staging, particularly in
gastro-entero-pancreatic NETs. The role of 111In-octreotide in
NETs has been extensively reviewed (111–113) and shown to be of
particular value in the localization of small lesions, in determining
the local extent of disease, identification of metastases and detect-
ing relapsed disease. Furthermore, it can be used to monitor
results of surgery, radiotherapy, and chemotherapy. Occasionally
it is shown to be of value in the detection of paragangliomas
and pheochromocytomas if these tumors express somatostatin
receptors (114–117).
Octreotide receptor imaging in NETs may therefore be used for:
• The detection of small primary or recurrent tumors, in
the knowledge that a negative result is not exclusive, for
example, gastrinoma, medullary thyroid carcinoma,
insulinoma, and a proportion of other NETs (Fig. 32.9)
• The prediction of the success of therapeutic doses of
unlabeled octreotide where the level of uptake of radiola-
beled peptide ligands suggests therapy will be beneficial
• Guiding radiopeptide therapy with octreotide or lanreotide
derivatives labeled with 90Yttrium
The main limitation of radiolabeled octreotide as a diagnostic
agent is its wide spectrum of activity with insufficient sensitivity
for all tumors of a particular class, since some tumors will be
receptor negative (Table 32.4).
Table 32.4 Percentage Frequency of Positive Imaging in
NETs (85–88)
Type 123
I-MIBG (%) 111
In-octreotide (%)
Carcinoid tumors 50–75 67–96
Pancreatic neuroendocrine tumors 9–25 80–95
Medullary carcinoma of thyroid 35–50 71–100
Paraganglioma, pheochromocytoma 90–100 70–95
Neuroblastoma 88–95 80–90
784
Technique
Somatostatin receptor scintigraphy with 111In-octreotide is gener-
ally performed as whole body planar scintigraphy approximately
24 hours after radiotracer injection. The addition of SPECT helps
to localize potential abnormalities. The sensitivity can be further
enhanced by fusion of SPECT imaging with CT. Since a new gen-
eration of combined SPECT/CT is now available, providing spa-
tially co-registered SPECT and CT images, the addition of SPECT/
CT is often very useful to differentiate normal from abnormal
111
In-octreotide uptake and to exactly localize disease.
PET Imaging
Recently, radiolabeled somatostatin receptor ligands for PET
imaging have been developed of which 68Ga-DOTATOC is the
most commonly used (Fig. 32.28). Whole-body PET images are
usually acquired 45–90 minutes following IV injection of 68Ga-
DOTATOC. Preliminary evidence indicates that 68Ga-DOTATOC
is more sensitive than 111In-octreotide (118). For example, in a
study of eight patients with metastatic carcinoids, a total of 207
lesions were located using 68Ga-DOTATOC compared with only
124 detected by using 111In-octreotide (119). The spatial resolu-
tion of 111In-octreotide gamma camera imaging is limited, even
with SPECT (approximately 1.5cm). In addition, PET offers a sig-
nificantly higher sensitivity (counts per Bq) compared to gamma
camera imaging. The latest PET and PET/CT scanner generation
provides a spatial resolution of less than 0.5 cm.
Comparisons have been made between 111In-octreotide and FDG-
PET (120–123). In poorly differentiated tumors, when 111In-octreotide
imaging is negative, FDG-PET may localize disease. Well differentiated
NETs, however, are often negative on FDG-PET. This is primarily due
to the high differentiation grade and low anerobic glycolysis of these
tumors (124). Nevertheless, FDG-PET appears to be the preferred
functional imaging modality for staging and treatment monitoring
of SDHB-related metastatic paraganglioma (see chap. 16).
Other PET somatostatin analogues such as 64Cu-TETA-octreotide
and 86Y-DOTATOC have been found to be inferior to 68Ga-DOTA-
TOC (125–128). For these reasons, and the fact that several studies
have already shown the benefit of this tracer, (118,119,129,130)
68
Ga-DOTATOC is currently the most attractive option for improv-
ing diagnosis and staging in patients with NETs.
Key Points: PET
■ PET provides superior sensitivity and spatial resolution com-
pared to conventional gamma camera imaging for detection
of somatostatin receptor-positive tissue
■ 68Ga-DOTATOC is the preferred radiopharmaceutical for
PET imaging of NETs
■ Other PET somastostatin analogues have been found to be
inferior to 68GaDOTATOC
Other Radiolabeled Peptides
Cholecystokinin (CCK) and gastrin are gut-brain peptides with
multiple functions in the gastrointestinal tract and in the brain.
CCK2/Gastrin receptor expression has been demonstrated in vitro
in medullary thyroid cancer, small cell lung cancer, astrocytomas,
stromal ovarian carcinomas, NETs, and in very high densities in
 neuroendocrine tumors

gastrointestinal stromal tumors (131–133). Gastrin-releasing pep-

tide (GRP) receptor is highly expressed in lung, breast, prostate,
and pancreatic cancers. The neuropeptide bombesin has high
affinity for GRP receptors and bombesin analogues are being
developed for imaging labeled with Tc-99m, In-111, Ga-68, and
F-18 (134,135). Many of the analogues have high hepatobiliary
clearance limiting abdominal scintigraphy. VIP receptor expres-
sion is more widespread than somatostatin receptor expression
particularly in common cancers such as breast and prostate (136).
In vivo data with radio-iodinated VIP is encouraging with local-
ization of most VIP expressing colorectal and pancreatic adeno-
carcinomas (137).

IMAGING WITH 123I-MIBG

(A) The first compounds which were evaluated for imaging the adrenal
medulla were analogues of radiolabeled catecholamines. In 1980,
Wieland and his colleagues found avid concentration of radio-
iodinated iodobenzylguanidines in the adrenal medulla with the
metaisomer metaiodobenzylguanidine (MIBG) demonstrating faster
uptake and less background activity in vivo (138). Radiolabeled
MIBG is useful for imaging adrenal medullary tumors and shows
increased uptake in medullary hyperplasia but far less uptake in the
normal adrenal medulla. The uptake of radiolabeled MIBG is via the
norepinephrine re-uptake mechanism with entry of MIBG into cat-
echolamine storage vesicles. Therefore, drugs which interfere with
norepinephrine re-uptake such as reserpine and tricyclic antidepres-
sants, may cause false-negative results and need to be discontinued
prior to imaging. In the past, 131iodine was predominately used for
labeling of MIBG, whereas 123I-MIBG is now becoming more widely
available. 123I has several advantages over 131I; 123I is a pure gamma
emitter and can therefore be administered in higher activities
(B) resulting in improved image quality. In addition, the photon energy
of 159 keV is much better suited for gamma camera imaging.
There are two main indications for the use of 123MIBG:
• Detection of amine-secreting NETs, for example, pheo-
chromocytomas (Fig. 32.29) (see chap. 16)
• To test whether therapy with 131I-MIBG would be appro-
priate in conditions where radiolabeled MIBG uptake is
usual, as in malignant paragangliomas or, relatively less
frequently, such tumors as carcinoids, medullary carci-
nomas of the thyroid or malignant pancreatic NETs
123
I-MIBG gamma camera imaging is generally performed as
whole-body planar scintigraphy approximately 24 hours after
radiotracer injection. The addition of SPECT/CT enhances the
sensitivity and specificity, and has largely replaced more complex
early and delayed gamma camera imaging to identify the position
of the kidneys, renal pelvis, and other areas of normal radiola-
beled MIBG uptake. Only tumors that show radiolabeled MIBG
(C)
uptake at 24 hours are likely to benefit from 131I-MIBG therapy.
Figure 32.28 Patient with a midgut carcinoid. (A) The CT was difficult to inter-
pret regarding the extent of liver metastases. (B) Unfused image and (C) fused MIBG Compared with Radiopeptide Scintigraphy
image 68Ga-DOTA-TOC PET/CT was performed. In these transaxial images at
Many comparisons of 123I-MIBG and 111In-octreotide imaging in
least four liver metastases are clearly depicted. Source: Courtesy of Dr. Anders
Sundin. pancreatic and carcinoid NETs have been reported (114–117).
A comparison of 99mTc-P829, Neospect, and 111In-octreotide was
made by Lebtahi et al. (139). 123I-MIBG scintigraphy appeared to
be more sensitive for sympatho-adrenomedullary tumors, but

785
 primary tumor evaluation and staging
123
Figure 32.29 I-MIBG scan. Extensive multiple metastases are demonstrated from an MIBG-avid neuroendocrine tumor.
111
In-octreotide detects more tumors in all other neuroendocrine
conditions (Table 32.4). The reason for imaging with 123I-MIBG
continues to be the availability of 131I-MIBG therapy. This may
change when 90Y-octreotide therapy (or a related analog) becomes
available on a regular basis. Potential future MIBG substitutes
include 11C-hydroxyephedrine (140), 11C-DOPA (141), and 18F-
iodobenzylguanidine (142).
Key Points: Molecular Imaging in Neuroendocrine
Tumors
■ Radiolabeled somatostatin analogues for gamma camera
imaging and PET bind to somatostatin receptors which are
present in 80% to 90% of pancreatic NETs and 67% to 96%
of carcinoids
■ Imaging the level of uptake of radiolabeled somatostatin
ligands is important as a guide to therapy with octreotide
derivatives with pharmacologic agents or with therapeutic
radiopharmaceuticals
■ 123I-MIBG is used in NETs as a guide to whether therapy with
131
I-MIBG is appropriate, even though it is substantially less
sensitive than 111In-octreotide in the detection of pancreatic
and GI NETs
■ FDG-PET is potentially useful in aggressive NETs
786
NET RADIONUCLIDE THERAPY (TABLE 32.5)
Molecular imaging identifies, by imaging with an appropriate
radiopharmaceutical, whether NETs have particular antigens or
receptors. The radionuclide used for imaging, which is either
gamma- or positron-emitting, is then substituted with a therapy
radionuclide. Generally, therapy radionuclides are beta-emitting,
attached to the same molecular probe, so that only those patients
who have been demonstrated by imaging to have tumors which
show significant and specific uptake of the radiopharmaceutical
are exposed to radionuclide therapy. Those with poor radiotracer
uptake are considered unlikely to benefit and are saved from hav-
ing unnecessary radiation. Beta-emitting radionuclides include
90
Ytrium (90Y) and 177Lutetium (177Lu) which differ in their physi-
cal properties. The higher energy of 90Ytrium results in longer
ranges in tissue and may be preferable for treating larger tumors
and tumors with heterogeneous receptor distribution (143).
90
Ytrium and 177Lutetium form stable metal complexes with the
chelator DOTA. DOTA coupled therapeutic radiopeptides include
90
Y-DOTA-octreotide 90Y-DOTA-lantreotide and 177Lu-DOTA-
octreotate. These have different SSTR affinity profiles with the
DOTATATE derivatives having highest affinity to SSTR 2 and the
DOTA-lantreotide having considerable SSTR 5 affinity (136,144).
In some series, 10% to 30% of patients achieved complete or
 neuroendocrine tumors
Table 32.5 Strategy for the Radionuclide Therapy
of Neuroendocrine Tumors
123
I-MIBG imaging Avid Æ I-131 MIBG therapy
111
Non-avid Æ In-octreotide
Imaging
111 90
In-octreotide Avid Æ Y-octreother therapy
99
mTc-octreotide Avid Æ 90
Y-octreother therapy
Non-avid Æ 111
In-lanreotide imaging
111 90
In-lanreotide Avid Æ Y-lanreotide therapy
Non-avid Æ Chemotherapy
partial responses following radiopeptide therapy (145–147).
Gastro-ntero-pancreatic NETs seem to show better response rates,
which are in the range of 36% to 38% (146,148,149).
FOLLOW-UP OF NEUROENDOCRINE TUMORS
Surgical resection is the only curative technique in pancreatic and
carcinoid NETs. However, in non-resectable tumors, imaging may
play a role in treatment planning. Palliation of symptoms may be
achieved by embolization or chemo-embolization of hepatic
metastases if the portal vein is patent (150).
Response to treatment of liver metastases following transcatheter
arterial embolisation can be assessed on MR both following
contrast enhancement MR and on diffusion-weighted imaging (151).
In this study, 66 targeted neuroendocrine liver metastases were
evaluated. The percentage enhancement in the arterial and
portal-venous phase decreased significantly following treatment, as
did the apparent diffusion coefficients. This finding was of particular
importance as the use of RECIST criteria demonstrated partial
response in only 23% of patients.
CT or MR is used to assess the response to therapy both in pri-
mary and metastatic disease. MR imaging is the preferred modal-
ity for following up patients with disorders such as MEN 1, where
repeated imaging may be required for prolonged surveillance due
to the often indolent nature of the disease.
Summary
■ The majority of pancreatic NETs are functioning (only
15–30% are non-functioning) and the purpose of imaging is
preoperative localization and staging.
■ Insulinomas are the most common pancreatic NETs, usually
small, solitary intrapancreatic and malignant in only 10% of
cases; gastrinomas are often extrapancreatic and malignant
in 60%.
■ CT is the most widely used technique for detection of pan-
creatic NETs, and the majority are small and hypervascular.
On MR a fat-suppressed T1-weighted sequence is the best for
their detection.
■ Carcinoid tumors arise from the diffuse neuroendocrine
system, secrete a variety of amines and peptides, and most
commonly arise from the bronchus (32.5%), jejuno-ileum
(20%), appendix (8%), and rectum (10%).
■ Metastases from NETs involve lymph nodes most frequently
(90%) and liver (44%). Mesenteric masses > 1.5 cm are
commonly seen in midgut carcinoids.
■ Scintigraphy using radiolabeled somatostatin analogues and
radio-iodinated met-iodobenzylguanidine are employed to
localize functioning pathology, to detect metastases, and to
predict suitability for octreotide or 131I-MIBG therapy.
REFERENCES
1. Metz DC. Diagnosis and treatment of pancreatic neuroendo-
crine tumors. Semin Gastrointest Dis 1995; 6: 67–78.
2. Yao JC, Eisner MP, Leary C, et al. Population-based study of
islet cell carcinoma. Ann Surg Oncol 2007; 14: 3492–500.
3. Kent RB, III, van Heerden JA, Weiland LH. Nonfunctioning
islet cell tumors. Ann Surg 1981; 193: 185–90.
4. Stark DD, Moss AA, Goldberg HI, Deveney CW. CT of pan-
creatic islet cell tumors. Radiology 1984; 150: 491–4.
5. Halfdanarson TR, Rabe KG, Rubin J, Petersen GM. Pancre-
atic neuroendocrine tumors (PNETs): incidence, prognosis
and recent trend toward improved survival. Ann Oncol 2008;
19: 1727–33.
6. Aldridge MC, Williamson RC. Surgery of endocrine tumours
of the pancreas. In: Lynn J, Bloom SR, eds. Surgical Endocri-
nology. Oxford: Butterworth-Heinemann, 1996: 503–18.
7. Alexander HR, Jensen RT. Pancreatic endocrine tumors.
In: Devita VT, Hellman S, Rosenberg SA, eds. Principles and
Practice of Oncology. Philadelphia: Lippincott-Raven, 2001:
1788–813.
8. Chandrasekharappa SC, Guru SC, Manickam P, et al. Posi-
tional cloning of the gene for multiple endocrine neoplasia-
type 1. Science 1997; 276: 404–7.
9. Zhuang Z, Vortmeyer AO, Pack S, et al. Somatic mutations of
the MEN1 tumor suppressor gene in sporadic gastrinomas
and insulinomas. Cancer Res 1997; 57: 4682–6.
10. Solcia E, Kloppel G, Sobin LH. Histological typing of endo-
crine tumours. World Health Organization. International
Histological Classification of Tumours, 2nd edn. Berlin:
Springer, 2000.
11. Rindi G, Capella C, Solcia E. Introduction to a revised clinico-
pathological classification of neuroendocrine tumors of the
gastroenteropancreatic tract. Q J Nucl Med 2000; 44: 13–21.
12. La Rosa S, Klersy C, Uccella S, et al. Improved histologic and
clinicopathologic criteria for prognostic evaluation of pan-
creatic endocrine tumors. Hum Pathol 2009; 40: 30–40.
13. van Heerden JA, Grant CS, Czako PF. Occult functioning
insulinomas: which localizing studies are indicated? Surgery
1992; 112: 1010–15.
14. Service FJ, Dale AJ, Elveback LR, Jiang NS. Insulinoma: clini-
cal and diagnostic features of 60 consecutive cases. Mayo
Clin Proc 1976; 51: 417–29.
15. Berends FJ, Cuesta MA, Kazemier G, et al. Laparoscopic
detection and resection of insulinomas. Surgery 2000; 128:
386–91.
16. Marks V. Insulinoma. In: Grossman AB, ed. Clinical Endocri-
nology. Oxford: Blackwell Science, 1998: 531–9.
787
 primary tumor evaluation and staging
17. Grant CS. Surgical aspects of hyperinsulinemic hypoglyce-
mia. Endocrinol Metab Clin North Am 1999; 28: 533–54.
18. Yu F, Venzon DJ, Serrano J, et al. Prospective study of the
clinical course, prognostic factors, causes of death, and sur-
vival in patients with long-standing Zollinger-Ellison syn-
drome. J Clin Oncol 1999; 17: 615–30.
19. Doppman JL, Shawker TH, Miller DL. Localization of
islet cell tumors. Gastroenterol Clin North Am 1989; 18:
793–804.
20. O’Shea D, Wynick D, Bloom SR. Islet cell tumours (excluding
insulinomas and carcinoids). In: Grossman AB, ed. Clinical
Endocrinology. Oxford: Blackwell Science, 1998: 540–8.
21. King CM, Reznek RH, Dacie JE, Wass JA. Imaging islet cell
tumours. Clin Radiol 1994; 49: 295–303.
22. Hammond PJ, Jackson JA, Bloom SR. Localization of
pancreatic endocrine tumours. Clin Endocrinol (Oxf) 1994;
40: 3–14.
23. Vinik AI, Strodel WE, Eckhauser FE, Moattari AR, Lloyd R.
Somatostatinomas, PPomas, neurotensinomas. Semin Oncol
1987; 14: 263–81.
24. Oberg K. Carcinoid syndrome. In: Grossman AB, ed.
Clinical Endocrinology. Oxford: Blackwell Science, 1998:
607–20.
25. Jensen RT, Doherty GM. Carcinoid tumors and the carcinoid
syndrome. In: Devita VT, Hellman S, Rosenberg SA, eds.
Cancer: Principles and Practice of Oncology. Philadelphia:
Lippincott-Raven, 2001: 1813–33.
26. Newton JN, Swerdlow AJ, dos SS, et al. The epidemiology of
carcinoid tumours in England and Scotland. Br J Cancer
1994; 70: 939–42.
27. Berge T, Linell F. Carcinoid tumours. Frequency in a defined
population during a 12-year period. Acta Pathol Microbiol
Scand [A] 1976; 84: 322–30.
28. Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715
carcinoid tumors. Cancer 2003; 97: 934–59.
29. Norheim I, Oberg K, Theodorsson-Norheim E, et al. Malig-
nant carcinoid tumors. An analysis of 103 patients with
regard to tumor localization, hormone production, and
survival. Ann Surg 1987; 206: 115–25.
30. Zikusoka MN, Kidd M, Eick G, Latich I, Modlin IM. The
molecular genetics of gastroenteropancreatic neuroendo-
crine tumors. Cancer 2005; 104: 2292–309.
31. Capella C, Heitz PU, Hofler H, Solcia E, Kloppel G. Revised
classification of neuroendocrine tumors of the lung, pan-
creas and gut. Virchows Arch 1995; 425: 547–60.
32. Pantongrag-Brown L, Buetow PC, Carr NJ, Lichtenstein JE,
Buck JL. Calcification and fibrosis in mesenteric carcinoid
tumor: CT findings and pathologic correlation. Am J Roent-
genol 1995; 164: 387–91.
33. Williams ED, Sandler M. The classification of carcinoid
tumours. Lancet 1963; 1: 238–9.
34. Paladugu RR, Benfield JR, Pak HY, Ross RK, Teplitz RL.
Bronchopulmonary Kulchitzky cell carcinomas. A new clas-
sification scheme for typical and atypical carcinoids. Cancer
1985; 55: 1303–11.
35. Colby TV, Koss MN, Travis WD. Carcinoid and other
neuroendocrine tumors. In: Colby TV, Koss MN, Travis WD,
788
eds. Atlas to Tumor Pathology: Tumors of the Lower Respira-
tory Tract. Washington, DC: Armed Forces Institute of
Pathology, 1995: 287–317.
36. Beasley MB, Brambilla E, Travis WD. The 2004 World Health
Organization classification of lung tumors. Semin Roent-
genol 2005; 40: 90–7.
37. Gustafsson BI, Kidd M, Modlin IM. Neuroendocrine tumors
of the diffuse neuroendocrine system. Curr Opin Oncol
2008; 20: 1–12.
38. Gustafsson BI, Kidd M, Chan A, Malfertheiner MV, Modlin IM.
Bronchopulmonary neuroendocrine tumors. Cancer 2008;
113: 5–21.
39. Jeung MY, Gasser B, Gangi A, et al. Bronchial carcinoid
tumors of the thorax: spectrum of radiologic findings. Radio-
graphics 2002; 22: 351–65.
40. Takei H, Asamura H, Maeshima A, et al. Large cell neuro-
endocrine carcinoma of the lung: a clinicopathologic study
of eighty-seven cases. J Thorac Cardiovasc Surg 2002; 124:
285–92.
41. Govindan R, Page N, Morgensztern D, et al. Changing epide-
miology of small-cell lung cancer in the United States over
the last 30 years: analysis of the surveillance, epidemiologic,
and end results database. J Clin Oncol 2006; 24: 4539–44.
42. Dusmet ME, McKneally MF. Pulmonary and thymic carci-
noid tumors. World J Surg 1996; 20: 189–95.
43. Wollensak G, Herbst EW, Beck A, Schaefer HE. Primary
thymic carcinoid with Cushing’s syndrome. Virchows Arch
A Pathol Anat Histopathol 1992; 420: 191–5.
44. Wilander E, Lundqvist M, Oberg K. Gastrointestinal carci-
noid tumours. Histogenetic, histochemical, immunohisto-
chemical, clinical, and therapeutic aspects. Prog Histochem
Cytochem 1989; 19: 1–88.
45. Rindi G, Bordi C, Rappel S, et al. Gastric carcinoids and
neuroendocrine carcinomas: pathogenesis, pathology, and
behavior. World J Surg 1996; 20: 168–72.
46. Burke AP, Thomas RM, Elsayed AM, Sobin LH. Carcinoids of
the jejunum and ileum: an immunohistochemical and clini-
copathologic study of 167 cases. Cancer 1997; 79: 1086–93.
47. Modlin IM, Sandor A. An analysis of 8305 cases of carcinoid
tumors. Cancer 1997; 79: 813–29.
48. Winburn GB. Multiple rectal carcinoids: a case report. Am
Surg 1998; 64: 1200–3.
49. Koura AN, Giacco GG, Curley SA, et al. Carcinoid tumors of
the rectum: effect of size, histopathology, and surgical treat-
ment on metastasis free survival. Cancer 1997; 79: 1294–8.
50. Danikas D, Theodorou SJ, Matthews WE, Rienzo AA. Unusually
aggressive rectal carcinoid metastasizing to larynx, pancreas,
adrenal glands, and brain. Am Surg 2000; 66: 1179–80.
51. Bottger TC, Weber W, Beyer J, Junginger T. Value of tumor
localization in patients with insulinoma. World J Surg 1990;
14: 107–12.
52. London JF, Shawker TH, Doppman JL, et al. Zollinger-Ellison
syndrome: prospective assessment of abdominal US in the
localization of gastrinomas. Radiology 1991; 178: 763–7.
53. Dietrich CF, Ignee A, Braden B, et al. Improved differentiation
of pancreatic tumors using contrast-enhanced endoscopic
ultrasound. Clin Gastroenterol Hepatol 2008; 6: 590–7.
 neuroendocrine tumors
54. Oshikawa O, Tanaka S, Ioka T, et al. Dynamic sonography of
pancreatic tumors: comparison with dynamic CT. Am J
Roentgenol 2002; 178: 1133–7.
55. Ueno N, Tomiyama T, Tano S, et al. Utility of endoscopic
ultrasonography with color Doppler function for the diag-
nosis of islet cell tumor. Am J Gastroenterol 1996; 91: 772–6.
56. Rosch T, Lightdale CJ, Botet JF, et al. Localization of pancre-
atic endocrine tumors by endoscopic ultrasonography. N
Engl J Med 1992; 326: 1721–6.
57. Fein J, Gerdes H. Localization of islet cell tumors by endo-
scopic ultrasonography. Gastroenterology 1992; 103: 711–12.
58. Baker MS, Knuth JL, DeWitt J, et al. Pancreatic cystic neu-
roendocrine tumors: preoperative diagnosis with endoscopic
ultrasound and fine-needle immunocytology. J Gastrointest
Surg 2008; 12: 450–6.
59. Jani N, Khalid A, Kaushik N, et al. EUS-guided FNA diagno-
sis of pancreatic endocrine tumors: new trends identified.
Gastrointest Endosc 2008; 67: 44–50.
60. Chang F, van der WJ. Fine needle aspiration and core biopsy
from a 43-year-old man with multiple abdominal masses.
Cytopathology 2006; 17: 307–10.
61. Nikfarjam M, Warshaw AL, Axelrod L, et al. Improved con-
temporary surgical management of insulinomas: a 25-year
experience at the Massachusetts General Hospital. Ann Surg
2008; 247: 165–72.
62. Norton JA, Cromack DT, Shawker TH, et al. Intraoperative
ultrasonographic localization of islet cell tumors. A pro-
spective comparison to palpation. Ann Surg 1988; 207:
160–8.
63. Buetow PC, Parrino TV, Buck JL, et al. Islet cell tumors of the
pancreas: pathologic-imaging correlation among size, necro-
sis and cysts, calcification, malignant behavior, and func-
tional status. Am J Roentgenol 1995; 165: 1175–9.
64. Kalra MK, Maher MM, Mueller PR, Saini S. State-of-the-art
imaging of pancreatic neoplasms. Br J Radiol 2003; 76:
857–65.
65. Fidler JL, Fletcher JG, Reading CC, et al. Preoperative detec-
tion of pancreatic insulinomas on multiphasic helical CT.
Am J Roentgenol 2003; 181: 775–80.
66. Stafford-Johnson DB, Francis IR, Eckhauser FE, Knol JA,
Chang AE. Dual-phase helical CT of nonfunctioning islet cell
tumors. J Comput Assist Tomogr 1998; 22: 335–9.
67. Van Hoe L, Gryspeerdt S, Marchal G, Baert AL, Mertens L.
Helical CT for the preoperative localization of islet cell
tumors of the pancreas: value of arterial and parenchymal
phase images. Am J Roentgenol 1995; 165: 1437–9.
68. Chung MJ, Choi BI, Han JK, et al. Functioning islet cell tumor
of the pancreas. Localization with dynamic spiral CT. Acta
Radiol 1997; 38: 135–8.
69. Ichikawa T, Peterson MS, Federle MP, et al. Islet cell tumor of
the pancreas: biphasic CT versus MR imaging in tumor
detection. Radiology 2000; 216: 163–71.
70. Ahrendt SA, Komorowski RA, Demeure MJ, Wilson SD,
Pitt HA. Cystic pancreatic neuroendocrine tumors: is preop-
erative diagnosis possible? J Gastrointest Surg 2002; 6: 66–74.
71. Imaoka H, Yamao K, Salem AA, et al. Pancreatic endocrine
neoplasm can mimic serous cystadenoma. Int J Gastrointest
Cancer 2005; 35: 217–20.
72. Rodallec M, Vilgrain V, Couvelard A, et al. Endocrine pancre-
atic tumours and helical CT: contrast enhancement is corre-
lated with microvascular density, histoprognostic factors and
survival. Pancreatology 2006; 6: 77–85.
73. Wank SA, Doppman JL, Miller DL, et al. Prospective study of
the ability of computed axial tomography to localize gastri-
nomas in patients with Zollinger-Ellison syndrome. Gastro-
enterology 1987; 92: 905–12.
74. Maton PN, Miller DL, Doppman JL, et al. Role of selective
angiography in the management of patients with Zollinger-
Ellison syndrome. Gastroenterology 1987; 92: 913–18.
75. Gouya H, Vignaux O, Augui J, et al. CT, endoscopic sono-
graphy, and a combined protocol for preoperative evalua-
tion of pancreatic insulinomas. Am J Roentgenol 2003; 181:
987–92.
76. Owen NJ, Sohaib SA, Peppercorn PD, et al. MRI of pancre-
atic neuroendocrine tumors. Br J Radiol 2001; 74: 968–73.
77. Semelka RC, Custodio CM, Cem BN, Woosley JT. Neuroen-
docrine tumors of the pancreas: spectrum of appearances on
MRI. J Magn Reson Imaging 2000; 11: 141–8.
78. Pisegna JR, Doppman JL, Norton JA, Metz DC, Jensen RT.
Prospective comparative study of ability of MR imaging and
other imaging modalities to localize tumors in patients with
Zollinger-Ellison syndrome. Dig Dis Sci 1993; 38: 1318–28.
79. Thoeni RF, Mueller-Lisse UG, Chan R, Do NK, Shyn PB.
Detection of small, functional islet cell tumors in the pan-
creas: selection of MR imaging sequences for optimal sensi-
tivity. Radiology 2000; 214: 483–90.
80. Rockall AG, Planche K, Power N, et al. Detection of neuro-
endocrine liver metastases with MnDPDP-enhanced MRI.
Neuroendocrinology. In press.
81. Wang C. Mangafodipir trisodium (MnDPDP)-enhanced
magnetic resonance imaging of the liver and pancreas. Acta
Radiol Suppl 1998; 415: 1–31.
82. Chavan A, Kirchhoff TD, Brabant G, et al. Role of the intra-
arterial calcium stimulation test in the preoperative localiza-
tion of insulinomas. Eur Radiol 2000; 10: 1582–6.
83. Modlin IM, Latich I, Zikusoka M, et al. Gastrointestinal car-
cinoids: the evolution of diagnostic strategies. J Clin Gastro-
enterol 2006; 40: 572–82.
84. Habal N, Sims C, Bilchik AJ. Gastrointestinal carcinoid
tumors and second primary malignancies. J Surg Oncol 2000;
75: 310–16.
85. Nessi R, Basso RP, Basso RS, et al. Bronchial carcinoid tumors:
radiologic observations in 49 cases. J Thorac Imaging 1991;
6: 47–53.
86. Doppman JL, Pass HI, Nieman LK, et al. Detection of ACTH-
producing bronchial carcinoid tumors: MR imaging vs CT.
Am J Roentgenol 1991; 156: 39–43.
87. Brown LR, Aughenbaugh GL, Wick MR, Baker BA, Salassa
RM. Roentgenologic diagnosis of primary corticotropin-
producing carcinoid tumors of the mediastinum. Radiology
1982; 142: 143–8.
88. Wang DY, Chang DB, Kuo SH, et al. Carcinoid tumors of the
thymus. Thorax 1994; 49: 357–60.
89. Brown LR, Aughenbaugh GL. Masses of the anterior medi-
astinum: CT and MR imaging. Am J Roentgenol 1991; 157:
1171–80.
789
 primary tumor evaluation and staging
90. Fujiwara K, Segawa Y, Takigawa N, et al. Two cases of atypical
carcinoid of the thymus. Intern Med 2000; 39: 834–8.
91. Binstock AJ, Johnson CD, Stephens DH, Lloyd RV, Fletcher
JG. Carcinoid tumors of the stomach: a clinical and radio-
graphic study. Am J Roentgenol 2001; 176: 947–51.
92. Woodard PK, Feldman JM, Paine SS, Baker ME. Midgut car-
cinoid tumors: CT findings and biochemical profiles. J Com-
put Assist Tomogr 1995; 19: 400–5.
93. Sugimoto E, Lorelius LE, Eriksson B, Oberg K. Midgut
carcinoid tumors. CT appearance. Acta Radiol 1995; 36:
367–71.
94. Pilleul F, Penigaud M, Milot L, et al. Possible small-bowel
neoplasms: contrast-enhanced and water-enhanced multi-
detector CT enteroclysis. Radiology 2006; 241: 796–801.
95. Minordi LM, Vecchioli A, Guidi L, et al. Multidetector CT
enteroclysis versus barium enteroclysis with methylcellulose
in patients with suspected small bowel disease. Eur Radiol
2006; 16: 1527–36.
96. Bader TR, Semelka RC, Chiu VC, Armao DM, Woosley JT.
MRI of carcinoid tumors: spectrum of appearances in the
gastrointestinal tract and liver. J Magn Reson Imaging 2001;
14: 261–9.
97. Moller JE, Connolly HM, Rubin J, et al. Factors associated
with progression of carcinoid heart disease. N Engl J Med
2003; 348: 1005–15.
98. van Tuyl SA, van Noorden JT, Timmer R, et al. Detection
of small-bowel neuroendocrine tumors by video capsule
endoscopy. Gastrointest Endosc 2006; 64: 66–72.
99. Maeda K, Maruta M, Utsumi T, et al. Minimally invasive sur-
gery for carcinoid tumors in the rectum. Biomed Pharmaco-
ther 2002; 56(Suppl 1): 222s–226s.
100. Schindl M, Niederle B, Hafner M, et al. Stage-dependent
therapy of rectal carcinoid tumors. World J Surg 1998; 22:
628–33.
101. Matsumoto T, Iida M, Suekane H, et al. Endoscopic ultra-
sonography in rectal carcinoid tumors: contribution to selec-
tion of therapy. Gastrointest Endosc 1991; 37: 539–42.
102. Janson ET, Holmberg L, Stridsberg M, et al. Carcinoid tumors:
analysis of prognostic factors and survival in 301 patients
from a referral center. Ann Oncol 1997; 8: 685–90.
103. Zeiger MA, Shawker TH, Norton JA. Use of intraoperative
ultrasonography to localize islet cell tumors. World J Surg
1993; 17: 448–54.
104. Paulson EK, McDermott VG, Keogan MT, et al. Carcinoid
metastases to the liver: role of triple-phase helical CT. Radi-
ology 1998; 206: 143–50.
105. Vasseur B, Cadiot G, Zins M, et al. Peritoneal carcinomatosis
in patients with digestive endocrine tumors. Cancer 1996;
78: 1686–92.
106. Fukai I, Masaoka A, Fujii Y, et al. Thymic neuroendocrine
tumor (thymic carcinoid): a clinicopathologic study in
15 patients. Ann Thorac Surg 1999; 67: 208–11.
107. Khan JH, McElhinney DB, Rahman SB, et al. Pulmonary
metastases of endocrine origin: the role of surgery. Chest
1998; 114: 526–34.
108. Leboulleux S, Dromain C, Vataire AL, et al. Prediction
and diagnosis of bone metastases in well-differentiated
gastro-entero-pancreatic endocrine cancer: a prospective
790
comparison of whole body magnetic resonance imaging and
somatostatin receptor scintigraphy. J Clin Endocrinol Metab
2008; 93: 3021–8.
109. Behr TM, Gotthardt M, Barth A, Behe M. Imaging tumors with
peptide-based radioligands. Q J Nucl Med 2001; 45: 189–200.
110. Menda Y, Kahn D. Somatostatin receptor imaging of non-
small cell lung cancer with 99mTc depreotide. Semin Nucl
Med 2002; 32: 92–6.
111. Krenning EP, Kwekkeboom DJ, Bakker WH, et al. Somatosta-
tin receptor scintigraphy with [111In-DTPA-D-Phe1]- and
[123I-Tyr3]-octreotide: the Rotterdam experience with more
than 1000 patients. Eur J Nucl Med 1993; 20: 716–31.
112. Kwekkeboom D, Krenning EP, de Jong M. Peptide receptor
imaging and therapy. J Nucl Med 2000; 41: 1704–13.
113. Kwekkeboom DJ, Krenning EP. Somatostatin receptor imaging.
Semin Nucl Med 2002; 32: 84–91.
114. Hoefnagel CA. MIBG and radiolabeled octreotide in neuroen-
docrine tumors. Q J Nucl Med 1995; 39(4 Suppl 1): 137–9.
115. Ramage JK, Williams R, Buxton-Thomas M. Imaging second-
ary neuroendocrine tumours of the liver: comparison of
I123 metaiodobenzylguanidine (MIBG) and In111-labelled
octreotide (Octreoscan). QJM 1996; 89: 539–42.
116. Kaltsas G, Korbonits M, Heintz E, et al. Comparison of soma-
tostatin analog and meta-iodobenzylguanidine radionuclides
in the diagnosis and localization of advanced neuroendocrine
tumors. J Clin Endocrinol Metab 2001; 86: 895–902.
117. Bombardieri E, Maccauro M, De Deckere E, Savelli G, Chiti A.
Nuclear medicine imaging of neuroendocrine tumours. Ann
Oncol 2001; 12(Suppl 2): S51–61.
118. Gotthardt M, Boermann OC, Behr TM, Behe MP, Oyen WJ.
Development and clinical application of peptide-based radio-
pharmaceuticals. Curr Pharm Des 2004; 10: 2951–63.
119. Mariani G, Erba PA, Signore A. Receptor-mediated tumor
targeting with radiolabeled peptides: there is more to it than
somatostatin analogs. J Nucl Med 2006; 47: 1904–7.
120. Adams S, Baum R, Rink T, et al. Limited value of fluorine-18
fluorodeoxyglucose positron emission tomography for the
imaging of neuroendocrine tumours. Eur J Nucl Med 1998;
25: 79–83.
121. Pasquali C, Rubello D, Sperti C, et al. Neuroendocrine tumor
imaging: can 18F-fluorodeoxyglucose positron emission
tomography detect tumors with poor prognosis and aggres-
sive behavior? World J Surg 1998; 22: 588–92.
122. Le Rest C, Bomanji JB, Costa DC, et al. Functional imaging
of malignant paragangliomas and carcinoid tumours. Eur J
Nucl Med 2001; 28: 478–82.
123. Virgolini I, Patri P, Novotny C, et al. Comparative somatosta-
tin receptor scintigraphy using in-111-DOTA-lanreotide
and in-111-DOTA-Tyr3-octreotide versus F-18-FDG-PET
for evaluation of somatostatin receptor-mediated radionu-
clide therapy. Ann Oncol 2001; 12(Suppl 2): S41–S45.
124. Reubi JC. Regulatory peptide receptors as molecular targets
for cancer diagnosis and therapy. Q J Nucl Med 1997; 41:
63–70.
125. Reubi JC, Schar JC, Waser B, et al. Affinity profiles for human
somatostatin receptor subtypes SST1–SST5 of somatostatin
radiotracers selected for scintigraphic and radiotherapeutic
use. Eur J Nucl Med 2000; 27: 273–82.
 neuroendocrine tumors
126. de Herder WW, Hofland LJ, van der Lely AJ, Lamberts SW.
Somatostatin receptors in gastroentero-pancreatic neuro-
endocrine tumours. Endocr Relat Cancer 2003; 10: 451–8.
127. Blum J, Handmaker H, Lister-James J, Rinne N. A multicenter
trial with a somatostatin analog (99m)Tc depreotide in the
evaluation of solitary pulmonary nodules. Chest 2000; 117:
1232–8.
128. Ruszniewski P, Ducreux M, Chayvialle JA, et al. Treatment of
the carcinoid syndrome with the longacting somatostatin
analogue lanreotide: a prospective study in 39 patients. Gut
1996; 39: 279–83.
129. Valkema R, de Jong M, Bakker WH, et al. Phase I study of
peptide receptor radionuclide therapy with [In-DTPA]oct-
reotide: the Rotterdam experience. Semin Nucl Med 2002;
32: 110–22.
130. Anthony LB, Woltering EA, Espenan GD, et al. Indium-111-
pentetreotide prolongs survival in gastroenteropancreatic
malignancies. Semin Nucl Med 2002; 32: 123–32.
131. Reubi JC, Schaer JC, Waser B. Cholecystokinin(CCK)-A and
CCK-B/gastrin receptors in human tumors. Cancer Res 1997;
57: 1377–86.
132. Reubi JC, Korner M, Waser B, Mazzucchelli L, Guillou L.
High expression of peptide receptors as a novel target in gastro-
intestinal stromal tumors. Eur J Nucl Med Mol Imaging 2004;
31: 803–10.
133. Behr TM, Behe MP. Cholecystokinin-B/Gastrin receptor-
targeting peptides for staging and therapy of medullary thy-
roid cancer and other cholecystokinin-B receptor-expressing
malignancies. Semin Nucl Med 2002; 32: 97–109.
134. Lin KS, Luu A, Baidoo KE, et al. A new high affinity tech-
netium-99m-bombesin analogue with low abdominal accu-
mulation. Bioconjug Chem 2005; 16: 43–50.
135. Zhang H, Schuhmacher J, Waser B, et al. DOTA-PESIN, a DOTA-
conjugated bombesin derivative designed for the imaging and
targeted radionuclide treatment of bombesin receptor-positive
tumours. Eur J Nucl Med Mol Imaging 2007; 34: 1198–208.
136. Heppeler A, Froidevaux S, Eberle AN, Maecke HR. Receptor
targeting for tumor localisation and therapy with radio-
peptides. Curr Med Chem 2000; 7: 971–94.
137. Virgolini I, Raderer M, Kurtaran A, et al. Vasoactive intestinal
peptide-receptor imaging for the localization of intestinal
adenocarcinomas and endocrine tumors. N Engl J Med 1994;
331: 1116–21.
138. Wieland DM, Brown LE, Tobes MC, et al. Imaging the pri-
mate adrenal medulla with [123I] and [131I] meta-iodo-
benzylguanidine: concise communication. J Nucl Med 1981;
22: 358–64.
139. Lebtahi R, Le Cloirec J, Houzard C, et al. Detection of neuro-
endocrine tumors: 99mTc-P829 scintigraphy compared with
111In-pentetreotide scintigraphy. J Nucl Med 2002; 43: 889–95.
140. Shulkin BL, Wieland DM, Baro ME, et al. PET hydroxyephed-
rine imaging of neuroblastoma. J Nucl Med 1996; 37: 16–21.
141. Ahlstrom H, Eriksson B, Bergstrom M, et al. Pancreatic neu-
roendocrine tumors: diagnosis with PET. Radiology 1995;
195: 333–7.
142. Vaidyanathan G, Affleck DJ, Zalutsky MR. Validation of
4-[fluorine-18]fluoro-3-iodobenzylguanidine as a positron-
emitting analog of MIBG. J Nucl Med 1995; 36: 644–50.
143. de Jong M, Breeman WA, Valkema R, Bernard BF, Krenning EP.
Combination radionuclide therapy using 177Lu- and 90Y-la-
beled somatostatin analogs. J Nucl Med 2005; 46(Suppl 1):
13S–17S.
144. Krenning EP, Teunissen JJ, Valkema R, et al. Molecular radio-
therapy with somatostatin analogs for (neuro-)endocrine
tumors. J Endocrinol Invest 2005; 28(11 Suppl Int):
146–50.
145. Paganelli G, Bodei L, Handkiewicz JD, et al. 90Y-DOTA-D-
Phe1-Try3-octreotide in therapy of neuroendocrine malig-
nancies. Biopolymers 2002; 66: 393–8.
146. Waldherr C, Pless M, Maecke HR, et al. Tumor response and
clinical benefit in neuroendocrine tumors after 7.4 GBq (90)
Y-DOTATOC. J Nucl Med 2002; 43: 610–16.
147. Bodei L, Cremonesi M, Zoboli S, et al. Receptor-mediated
radionuclide therapy with 90Y-DOTATOC in association
with amino acid infusion: a phase I study. Eur J Nucl Med
Mol Imaging 2003; 30: 207–16.
148. Kwekkeboom DJ, Mueller-Brand J, Paganelli G, et al. Over-
view of results of peptide receptor radionuclide therapy
with 3 radiolabeled somatostatin analogs. J Nucl Med 2005;
46(Suppl 1): 62S–66S.
149. Bodei L, Cremonesi M, Grana C, et al. Receptor radionuclide
therapy with 90Y-[DOTA]0-Tyr3-octreotide (90Y-DOTA-
TOC) in neuroendocrine tumours. Eur J Nucl Med Mol
Imaging 2004; 31: 1038–46.
150. Wallace S, Ajani JA, Charnsangavej C, et al. Carcinoid tumors:
imaging procedures and interventional radiology. World J
Surg 1996; 20: 147–56.
151. Liapi E, Geschwind JF, Vossen JA, et al. Functional MRI
evaluation of tumor response in patients with neuro-
endocrine hepatic metastasis treated with transcatheter
arterial chemoembolization. Am J Roentgenol 2008; 190:
67–73.
152. Godwin J D. Carcinoid tumors. An analysis of 2,837 cases.
Cancer. 1975; 36: 560–9.
791
 33 Lymphoma
Sarah J Vinnicombe, Rodney H Reznek, and Norbert Avril
INTRODUCTION
The lymphomas, Hodgkin’s lymphoma (HL) and non-Hodgkin’s
lymphoma (NHL), are a diverse group of neoplasms that vary
widely in age of presentation, patterns of tumor growth, and sur-
vival rates. Hodgkin’s disease, or HL was first described by Thomas
Hodgkin in 1832, but it is only during the last two decades that the
prognosis has improved so that currently HL is curable in the
majority of patients. NHL has a variable course, ranging from
slow and indolent to aggressive and rapidly fatal. As with HL,
improvements in survival rates are largely attributed to advances
in therapy. However, the impact of modern imaging methods on
the accurate delineation of disease extent and identification of
risk factors, both of which facilitate optimized individualized risk-
adapted treatment with resultant survival benefits, cannot be
understimated.
In the lymphomas, imaging plays a vital role in the correct
deployment of combined modality treatment at the time of diag-
nosis and staging, in monitoring response to therapy and in the
detection of disease relapse.
The objectives of initial staging are to define as accurately as
possible the local extent of clinically overt disease and to search
for occult disease elsewhere with a full knowledge of the likely pat-
tern of tumor spread (1). It should also identify adverse prognos-
tic features such as extranodal disease and factors which may
influence delivery of therapy, such as venous obstruction or hydro-
nephrosis. Choice of the appropriate imaging method requires an
appreciation of:
• The likelihood of particular sites being affected given the
patterns of tumor spread
• The sensitivity and specificity of particular tests chosen
to investigate those sites
• The likely impact of a positive result on treatment choice
INCIDENCE
Lymphoma accounts for 5% to 6% of all malignancies in adults
in the United Kingdom and about 10% of all childhood cancers
(2,3). In the United States in 2008 it was estimated that there
would be 66,120 new cases of NHL and 19,160 deaths (4). Each
year in the United States NHL accounts for 5% of new cancers in
men and 4% of new cancers in women. According to the National
Cancer Institute, the United States age-adjusted incidence rate
for NHL was 15.5 per 100,000 people in 1996 (5). HL is less
common than NHL, accounting for about 15% of all lympho-
mas. It was estimated that in the United States there would be
8220 new cases of HL and 1350 deaths in 2008 (4). In the United
Kingdom there were 10,003 new cases of NHL and 1519 new
cases of HL in 2004; there were 4451 deaths from NHL and 291
792
deaths from HL in 2005. The lifetime risk of developing NHL is
approximately 1 in 83, and males are affected slightly more often
than females in both types of lymphoma with the following
ratios (2):
• Hodgkin’s lymphoma M:F 1.4:1
• Non-Hodgkin’s lymphoma M:F 1.1:1
In the United States, while the incidence of HL has remained
approximately stable, that of NHL has risen by approximately
60% since 1960. The increased incidence is evident for all age
groups, but particularly for the elderly (6). It is also more
marked in men than in women, and in White more than non-
White ethnic groups. Internationally, the incidence of NHL var-
ies 8 to 10 fold, being much more common in the West (7), but
even so this markedly increased incidence has been noted in
international cancer registries of seven European countries (8)
as well as in all geographical areas of the Unites States (5). The
overall mortality for NHL has also increased steadily over the
last few decades, and in the United States this trend in mortality
is most evident in the elderly. Despite this, the survival rate for
each subtype of NHL has increased with time, reflecting steady
advances in treatment.
Several hypotheses have been used to explain the striking
increase in incidence. Some may be artifactual, where new NHL
classification techniques and systems have led to a diagnosis of
NHL in some patients who would previously have had other
diagnoses (9). Improved imaging techniques have undoubtedly
led to more NHL diagnoses, particularly lymphoma of the cen-
tral nervous system (CNS) (9). It has also been estimated that in
10% to 15% of cases a reclassification of cases previously diag-
nosed as HL contributes to the apparent increase in NHL inci-
dence (10). Part of the increase in the late 80s and early 90s was a
consequence of the increased incidence of lymphomas associated
with immune deficiency, particularly secondary to human immu-
nodeficiency virus (HIV) infection. However, the incidence of
those cases of NHL associated with HIV (primary CNS lym-
phoma or PCNSL, Burkitt lymphoma and immunoblastic lym-
phoma) has been falling since the introduction of highly active
antiretroviral therapies in 1995 (11). Even when factors such as
accuracy of diagnosis, the effect of HIV and occupational expo-
sures are considered, the reason for most of the increase in NHL
remains unexplained (12).
HL used to show an obvious bimodal peak distribution, the
first in the third decade of life, and the second between 65 and
75 years of age; but in recent years this has become less obvious,
with a decrease in the incidence in patients over 55 years. In
part this is attributable to the reclassification of cases that would
previously have been called HL as NHL, as described above.
NHL is a disease mainly of the elderly with an increasing inci-
dence over the age of 50 years (13) and a median age at diagno-
sis of 65 years (14).
 lymphoma
Key Points: Incidence
■ The incidence of NHL has increased by 60% over the last two
decades in the United States and United Kingdom, while the
incidence of HL is stable
■ HL has a peak incidence between the ages of 30 and 40 years
and also in those aged over 65 years. NHL is seen in children
and in those over 50 years of age
ETIOLOGY
There is an association between the Ebstein-Barr virus (EBV)
and HL but debate continues regarding the exact etiological role
of EBV in this disease. It is interesting that the suggestion of EBV
infection having a causal relationship with HL was originally
made by Hodgkin himself in his first description of the morbid
anatomy of the condition. Patients with HL have a higher anti-
body titer to the EBV viral capsular antigen than normal adults
and the risk of HL amongst patients who have had infectious
mononucleosis is trebled (15). EBV can be found in the malig-
nant cells of HL (the Hodgkin’s and Reed-Sternberg cells). There
is some evidence for the role of other infective agents such as
human herpes virus 6 (HHV) and also HIV1, which is associ-
ated with the mixed cellularity subtype of classical HL.
Infective agents are also implicated in the development of NHL.
EBV may be an important etiological factor in Burkitt lymphoma
(BL), particularly in the endemic African form where virtually
100% of cases have EBV. In the sporadic form the incidence is
15% to 30%. The rare primary effusion lymphomas are associated
with HHV 8. Helicobacter pylori infection is necessary for the
development of gastric lymphoma of mucosa-associated lymphoid
tissue (MALT) type. The HTLV-1 retrovirus is known to have a
causal relationship with adult T-cell leukemia/lymphoma, which
is seen in South Japan and the Caribbean (16). It is thought that
the disease represents a clonal expansion of HTLV1 infected T
lymphocytes. Borrelia burgdorferi infection is associated with a
low-grade cutaneous B cell lymphoma which can resolve once the
infection is eradicated (17).
Genetic factors have limited importance in the etiology of HL,
with approximately 5% of cases being familial. The incidence is
increased in siblings, first-degree relatives of affected individuals
and in monozygotic twins of sufferers. This may relate to changes in
the HLA class 1 region of chromosome 6. Genetic studies have also
revealed the importance of mutation, altered expression and loss of
function of genes in the development and progression of NHL (18)
and familial aggregation of NHL is well recognized. Immunosup-
pression is a very important etiological factor in NHL, with a high
incidence in AIDS patients and those on long-term immunosup-
pressant therapy; for example, following renal transplantation
(19,20). The latter is associated with diffuse large B cell lymphoma
(DLBCL), extranodal and central nervous system disease. Up to
25% of patients with congenital immunodeficiency syndromes such
as ataxia-telangiectasia, Wiskott-Aldrich syndrome and X-linked
immunodeficiencies will develop malignancies. Lymphoprolifera-
tive disorders (including HL and EBV-driven NHL), account for
over 50% of these (21). Non organ-specific autoimmune diseases
such as rheumatoid arthritis are associated with DLBCL, whereas
organ-specific autoimmune diseases predispose to the development
of extranodal marginal zone lymphomas of MALT type within the
affected organs (for example, the thyroid and salivary glands).
Key Points: Etiology
■ There is a link between the Epstein–Barr virus (EBV), HL,
and NHL
■ Various other infective agents are associated with a number of
specific types of NHL
■ Congenital and acquired immunodeficiency states predispose to
the development of lymphoproliferative disorders
PATHOLOGY
Classification
Non-Hodgkin Lymphoma
A robust classification has to be clinically relevant and must be
translatable to allow communication of new knowledge and com-
parison of clinical results (22). In this context, the reproducibility
and widespread use of the Rye modification of the Luke–Butler
classification (introduced in 1966) has proved to be reliable for
HL (Table 33.1) (23,24). This contrasts greatly with the profusion
of classifications for NHL, although since its introduction in 1982
the working formulation, described below, has resulted in some
degree of consensus (25). The functional anatomy of the lymph
node and its relationship to lymphoma is shown in Figure 33.1.
The recognition that most NHLs arise from the cells of the germi-
nal follicle of the lymph node led to the development of a Working
Formulation of NHL for clinical usage (25). This classification
was widely employed, until the introduction of the REAL (Revised
European American Classification of Lymphoid Neoplasms)
classification, and completely superseded the plethora of previous
classifications, which were largely unsatisfactory (26,27). The
Working Formulation was based upon the idea that lymphoma is
a result of clonal expansion of T or B lymphocytes at a particular
point in their normal maturation (28). B lymphocytes (bone
marrow-derived) are concerned with antibody production and
develop into plasma cells that produce immunoglobulin. If
normal maturation is prevented, the arrested cell multiplies. This
results in lymphoma whose type and grade depends on the stage
of maturation at the time of insult. T lymphocytes (thymic-
derived) do not contain immunoglobulin but are also concerned
with immune response. T-cell lymphomas are either central
T-cell lymphomas that are immature (e.g., diffuse lymphoblastic
lymphoma), or those derived from more mature T lymphocytes,
which are termed peripheral T-cell lymphomas. Histiocytic
lymphomas do not fall into either of these categories.
Table 33.1 Rye Classification of Hodgkin’s Lymphoma with
Approximate Distribution of Frequency (23,24)
Histology Frequency (%)
Lymphocyte predominance 5
Nodular sclerosis 65
Mixed cellularity 25
Lymphocyte depletion 5
793
 hematology malignancy

Afferent
lymphatic

Subcapsular sinus

Fibrous capsule

Fibrous trabecula

Cortex Medullary sinus

Mantle Medullary cords
Secondary follicle
Germinal Hilar sinus
center
Efferent
lymphatic
Paracortex

Primary follicle

High endothelial venules

Afferent
lymphatic

Secondary follicle:
Cortex Primary follicle
mantle

• B lymphocytes • B lymphocytes
• B lymphocyte domain
• Some T lymphocytes • Some T lymphocytes

Secondary follicle:
Paracortex
germinal center
• B lymphocytes
• Some T lymphocytes
• Dendritic reticulum cells

Figure 33.1 Relationship of functional lymph node anatomy to normal cell type and lineage of the NHLs.

The majority of NHL (over 90%) are B-cell lymphomas.
NHLs which arise at stages of development occurring within
the germinal center of the node have a follicular pattern,
whereas those that arise outside the germinal center have a dif-
fuse architectural pattern. The Working Formulation desig-
nated each lymphoma according to characteristics of the cell
type at the time of arrested maturation and overall divided
NHL into low-grade, intermediate, and high-grade tumors.
The “miscellaneous” group did not fulfil all the requirements
of the three main categories.
The Working Formulation had important practical implications:
• Therapy was based on the grade of lymphoma
• The grade of lymphoma carried important prognostic
significance
• The classification of lymphoma predicted possible
transformation into a higher grade
• The detailed subclassification of lymphomas allowed
standardization of therapies and comparison of results
from different centers

794
 lymphoma

However, since the classification was based upon treatment out- subsets (germinal center B-cell type and activated B-cell type)
comes rather than the recognition of the cell of origin or of dis- which have independent prognostic significance (33), and this is
crete disease entities, it was difficult to gain an understanding of likely to be included in the next iteration of the classification. Other
the pathogenesis of the various conditions. Many common additions include pediatric follicular lymphoma, primary DLBCL
entities were not recognized at all, which hindered research into of the central nervous system (PCNSL), B-cell lymphoma with fea-
tumor biology. tures intermediate between DLBCL and classical HL, and B-cell
More recently, in 1994, improvement in the understanding of lymphoma with features intermediate between DLBCL and BL.
NHL and the recognition of new clinico-pathological entities
resulted in the introduction of the REAL classification by the Hodgkin’s Lymphoma
International Lymphoma Study Group, which was adopted inter- Since biological and clinical studies have shown that HL is a true
nationally (29). The REAL classification is a consensus list of all lymphoma, the term HL is preferred to “Hodgkin’s disease”. Cen-
lymphoid neoplasms that appear to be distinct clinical entities. tral to the diagnosis of HL is the demonstration of the neoplastic
Unlike the Working Formulation, it utilizes all available features Reed–Sternberg (Fig. 33.2) and Hodgkin cells in a background of
(morphology, immunophenotype, genetics, and clinical features) non-neoplastic inflammatory cells. The Rye modification of the
to define each entity according to cell of origin (principally B or T Luke–Butler classification divides HL into four subgroups based
cell) and stage of differentiation, if known. This practical consen- on the proportion of lymphocytes in relation to the number of
sus approach differentiated it from previous morphological clas- Hodgkin and Reed–Sternberg cells, and the type of connective
sifications and enabled widespread usage by pathologists and tissue background. However, as recognized in the REAL and WHO
clinicians. classifications, HL comprises two distinct entities:
In 1995, under the auspices of the WHO, the European Associa-
tion for Haematopathology and the Society for Hematopathology • Nodular lymphocyte predominant Hodgkin’s lymphoma
(NLPHL) (5%)
collaborated on a project to classify all tumors of hematopoietic and
lymphoid lineages. The proposals were reviewed by a Clinical Advi- • Classical Hodgkin’s lymphoma (CHL) (95%)
sory Committee (CAC) and the result is the WHO Classification of
Tumors of Hematopoietic and Lymphoid Tissues (30), which is an
updated version of the REAL classification (Table 33.2). Table 33.2 Summary of the Who Classification of Tumors
The WHO classification stratifies neoplasms by lineage: myel- of Lymphoid Tissues
oid, lymphoid, histiocytic/dendritic, and mast cell. The classifica-
B-cell neoplasms T-cell and NK-cell neoplasms
tion is a list of over 40 disease entities with distinct clinical features Precursor B-cell neoplasm Precursor T-cell neoplasms
defined by a combination of morphology, immunophenotype, Precursor B lymphoblastic Precursor T lymphoblastic leukemia/
and genetic features. It recognizes three major groups of lymphoid leukemia/lymphoma lymphoma
neoplasms: B cell, T cell, and natural killer (NK) cell; and HL. It is Mature B-cell Blastic NK cell lymphoma
now clear that the malignant cell in HL is lymphoid, hence its CLL/small lymphocytic lymphoma Mature T-cell and NK neoplasms
inclusion in the classification. Indeed, the distinction between HL B-cell prolymphocytic leukemia T-cell prolymphocytic leukemia
Lymphoplasmacytic lymphoma T-cell large granular lymphocytic
and NHL is not always straightforward, with composite and Splenic marginal zone lymphoma leukemia
sequential cases occurring. It includes the leukemias, as they rep- Hairy cell leukemia Aggressive NK cell leukemia
resent circulating phases of particular neoplasms. Thus B-cell Plasma cell myeloma Adult T-cell leukemia/lymphoma
chronic lymphocytic leukemia and B-cell small lymphocytic lym- Solitary plasmacytoma Extranodal NK/T-cell lymphoma,
phoma are the same entity, as are lymphoblastic lymphoma and of bone nasal type
Extraosseous plasmacytoma Enteropathy-type T-cell lymphoma
lymphoblastic leukemia. Within the B and T/NK categories two Extranodal marginal zone B-cell Hepatosplenic T-cell lymphoma
major groups are recognized—precursor neoplasms (correspond- lymphoma of Subcutaneous panniculitis-like T-cell
ing to the early stages of differentiation) and mature or peripheral mucosa associated lymphoid tissue lymphoma
neoplasms, corresponding to more differentiated stages. Further- (MALT) Mycosis fungoides
more, many entities such as follicular lymphoma have a range of Nodal maginal zone B-cell lymphoma Sezary syndrome
Follicular lymphoma Primary cutaneous anaplastic large cell
grade and aggressiveness. Since variations in cytological grade can Mantle cell lymphoma lymphoma
inform treatment decisions, grading schemes and other prognos- Diffuse large B-cell lymphoma Peripheral T-cell lymphoma,
tic markers are included in the classification. The main lymphoid Mediastinal (thymic) large B-cell unspecified
groups are shown in Table 33.2. lymphoma Angioimmunoblastic T-cell lymphoma
The approach is thought to represent a significant advance in the Intravascular large B-cell lymphoma Anaplastic large cell lymphoma
Primary effusion lymphoma T-cell proliferation of uncertain
ability to identify and treat disease entities, with international con- Burkitt’s lymphoma/leukemia malignant potential
sistency. A study to address this issue of consistency showed that
B-cell proliferations of uncertain Lymphoid papulosis
expert hematopathologists, given adequate material, agreed on the malignant potential Hodgkin’s lymphoma
classification of the entity in over 95% of cases (31,32). A key Lymphomatoid granulomatosis Nodular lymphocyte predominant HL
advantage of the classification is that it permits refinement or elab- Post-transplant lymphoproliferative Classical HL
oration. A second edition is in the process of being drafted and disorder, polymorphic Nodular sclerosis classical HL
within it there are a number of new entities. For example, it has Lymphocyte rich classical HL
recently been shown that gene expression profiling in DLBCL with Mixed cellularity classical HL
Lymphocyte depleted classical HL
cDNA microarrays enables the recognition of a number of discrete

795
 hematology malignancy
Figure 33.2 Histological section of mixed cellularity HL showing Reed–Sternberg
cells, lymphocytes, and neutrophils.
These two differ in clinical features, behavior, morphology, and
immunophenotype, whereas the four CHL subtypes all share the
same immunophenotype.
Most cases of NLPHL were probably misclassified as lympho-
cyte predominance Hodgkin’s disease in the past. It represents 5%
of all HL. Patients are mostly male in the 30 to 50-year age group.
Most patients present with Stage I or II peripheral adenopathy
affecting one or two nodal groups only (axillary, cervical, or ingui-
nal); mediastinal, splenic, and marrow involvement are rare.
Latent EBV infection is not seen in the malignant cells. The disease
has an indolent course with a high relapse rate but, paradoxically,
excellent survival even with relapsed disease.
CHL accounts for 95% of all cases. Patients with infectious mono-
nucleosis have a higher incidence, and familial and geographic
clustering is seen. The cervical lymph nodes are involved in over
75% of cases. Overall, the incidence of splenic and bone marrow
involvement at presentation is low (25% and 5%, respectively).
In nodular sclerosing HL, nodules of lymphoid tissue are sepa-
rated by dense bands of collagen. It is the most frequent subgroup,
accounting for approximately 70% of CHL. The median age is
around 25 years and it is the only form of HL without a male
preponderance. Anterior mediastinal disease occurs in 80% of
cases, bulky disease in around 50%, splenic and/or lung involve-
ment in 10%. Most patients are Stage II at presentation with
disease confined to two nodal groups on the same side of the
diaphragm, and B symptoms are seen in 40%. Males are affected
as often as females in this subtype.
Mixed cellularity HL comprises 20% to 25% of CHL. It is more
common in HIV patients and in developing countries. Of those
affected, 70% are male. Stage III or IV disease is common, as are B
symptoms. Peripheral nodal disease is frequent, splenic involve-
ment occurs in up to 30%, and marrow involvement in 10% of
affected individuals. Mediastinal disease is uncommon. This sub-
type is most commonly associated with EBV positivity.
Lymphocyte-rich CHL comprises 5% of all HL; 70% of these are
male with a higher median age. Stage I or II peripheral nodal dis-
ease is typical, without mediastinal involvement or B symptoms.
Survival appears slightly better in this subtype.
Lymphocyte-depleted CHL is the rarest subtype, accounting for
less than 5% of cases; 75% of the affected individuals are male,
796
with a median age of 35 to 40 years. It is often associated with
HIV infection and is seen more often in developing countries.
Peripheral lymph nodes are relatively spared, with involvement
instead of abdominal organs, retroperitoneal nodes and bone
marrow. Stage III or IV disease is common (70%) as are B symp-
toms (80%). Most HIV-positive cases are EBV infected and have
relatively aggressive courses. This is now an infrequent diagnosis,
as in the past this condition was often misdiagnosed; many cases
were in fact NHL.
Key Points: Classification of Lymphomas
■ HL comprises two distinct entities: NLPHL and CHL
■ CHL is made up of four subtypes: nodular sclerosing (70%),
mixed cellularity (20–25%), lymphocyte rich (5%), and
lymphocyte-depleted (<5%)
■ The WHO update of the REAL classification stratifies
lymphoma by myeloid, lymphoid, histiocytic/dendritic and
mast cell lineage, and provides a list of distinct disease entities
STAGING CLASSIFICATIONS
The Ann Arbor staging system was introduced for HL in 1970. It
takes into account the extent of nodal disease and the presence of
extranodal extension. However, an increasing recognition of the
influence of tumor bulk as an independent prognostic indicator
within each stage, and the routine application of new diagnostic
techniques, such as computed tomography (CT) or magnetic
resonance (MR) imaging led to a modification of the Ann Arbor
classification in 1989 called the Cotswolds classification (Table 33.3)
(34). This system is similar to the Ann Arbor classification, but
Stage III is subdivided and an additional qualifier “X” denotes
bulky disease. Both the Ann Arbor and Cotswolds systems are
applied to NHL, but are of less value, as the prognosis in NHL is
Table 33.3 Staging of Lymphoma (Cotswolds Classification) (34)
Stage Area of involvement
I One lymph node region or extralymphatic site
II Two or more lymph node regions on the same side of the
diaphragm
III Involvement of lymph node regions or structures on both sides of
diaphragm, subdivided thus:
III(1a) With involvement of spleen and/or splenic hilar, coeliac, and portal
nodes
III(2a) With para-aortic, iliac, or mesenteric nodes
IV Extranodal sites beyond those designated E
Additional qualifiers
A No symptoms
B Fever, sweats, weight loss (to 10% of body weight)
E Involvement of single extranodal site, contiguous in proximity to a
known nodal site
Xa Bulky disease
Mass >1/3 thoracic diameter at T5
Mass >10 cm maximum dimension
CEa Clinical stage
PSa Pathological stage: PS at a given site denoted by a subscript (i.e., M,
marrow; H, liver; L, lung; O, bone; P, pleural; D, skin)
a
Modifications from Ann Arbor system.
 lymphoma

more dependent on histological grade and other parameters such very rare and can only be diagnosed after a thorough search for
as tumor bulk and specific organ involvement, than on stage disease in other sites.
(35,36). In NHL, the critical question is whether or not disease is
limited and, therefore, potentially treatable with radiotherapy, or Non-Hodgkin’s Lymphoma
whether it is disseminated. As in HL, the majority of patients with NHL present with
Childhood NHL exhibits a clinical spectrum somewhat differ- nodal enlargement, but extranodal disease is far commoner
ent to adult lymphoma with more frequent extranodal involve- and the overwhelming majority has advanced stage disease at
ment, there being a very high incidence of lymphoma in the presentation.
gastro-intestinal tract, solid abdominal viscera including the In low-grade lymphoma, lymphadenopathy may be intermit-
kidneys and pancreas, and extranodal sites in the head and neck tent and the median age at diagnosis is between 55 and 60 years.
(37,38). The staging system of Murphy is most widely used They are rarely diagnosed under the age of 30 years and account
( Table 33.4). for 30% to 45% of all lymphomas.
Intermediate-grade lymphoma usually includes both follicular
and diffuse forms. The diffuse large B-cell lymphoma (DLBCL)
CLINICAL FEATURES accounts for 35–40% of all NHL and is the commonest B-cell
NHL, usually presenting with rapidly enlarging lymph nodes.
HL and NHL are diseases of the lymph nodes, both of which may
Together with follicular lymphoma (FL), these tumors comprise
present as truly localized processes involving a single nodal group
70% to 80% of all lymphomas. FL accounts for around 30% of all
or organ, or as widely disseminated disease. However, recognizable
newly diagnosed NHL and the WHO classicification includes
differences distinguish the clinical presentation in the two diseases
three grades depending on the number of centroblasts per high
(Table 33.5). Broadly, NHL is disseminated at presentation more
power field. Grade 3 is further subdivided into a and b depending
frequently than HL and, although the majority of adult patients
on the presence or absence of centrocytes in addition to centro-
with NHL present with superficial lymphadenopathy, involve-
blasts. FL grade 3b may be more closely related to DLBCL (39).
ment of the viscera is more common in all types of NHL than it is
They usually present between the ages of 50 and 55 years and may
in HL.
be associated with extranodal disease at presentation. DLBCL is
aggressive but responds well to therapy. Recent work on gene
Hodgkin’s Lymphoma expression profiling has resulted in the recognition of two main
Most patients with HL present with painless asymmetrical lymph variants of DLBCL: germinal center-like signature, which has a
node enlargement, which may be accompanied with sweats, fever, relatively good outcome, and activated B cell signature, with a
weight loss, and pruritus in about 40% of patients. Alcohol- poorer prognosis (33).
induced pain is a rare complaint. High-grade lymphomas are the most aggressive tumor subtype
On clinical examination the commonest site of nodal involve- but many patients have apparently localized disease at the time of
ment is the cervical region, present in 60% to 80% of patients. presentation. Overall, approximately 20% of patients with NHL
Axillary nodal involvement is also common, occurring in 6% to have systemic symptoms such as fever, sweat, and weight loss,
20% of patients, and inguinal/femoral nodal disease is seen in 6% compared to 40% of patients with HL. NHL is a disseminated dis-
to 15%. Exclusive infradiaphragmatic lymphadenopathy occurs ease involving lymph node groups haphazardly, multiple organs
in less than 10% of patients at diagnosis. Splenomegaly is found and bone marrow (40).
on clinical examination in about one third of patients.
HL tends to spread in a contiguous fashion from one lymph Table 33.5 Key Differences Between the Clinical Features of HL
node group to the next adjacent group. Primary extranodal HL is and NHL
HL NHL
Clinical features
Table 33.4 Murphy’s Staging System for Childhood NHL Fever, night sweats, 40% 20%
Stage Criteria for extent of disease loss of weight
Spread Tends to be contiguous Multiple remote nodal
I A single tumor (extranodal) or single anatomical area (nodal) with groups are often involved
the exclusion of the mediastinum or abdomen Age Uncommon in childhood More frequent 40–70 yr
II A single tumor (extranodal) with regional nodal involvement
Nodal groups
Two or more nodal areas on the same side of the diaphragm
Thoracic 65–85% 25–40%
Two single (extranodal) tumors with or without regional node
Para-aortic 25–35% 45–55%
involvement of the same side of the diaphragm
Mesenteric 5% 50–60%
A primary GI tract tumor, usually in the ileocaecal area, with or
without involvement of associated mesenteric nodes only, grossly Extranodal disease
completely resected CNS <1% 2%
III Two single tumors (extranodal) on opposite sides of the diaphragm GI tract <1% 5–15%
Two or more nodal areas above and below the diaphragm Genitourinary tract <1% 1–5%
ALL primary intrathoracic tumors (mediastinal, pleural, thymic) Bone marrow 3% 20–40%
ALL extensive primary intra-abdominal disease, unresected Lung parenchyma 8–12% 3–6%
ALL paraspinal or epidural tumors, regardless of other tumor site(s) Bone <1% 1–2%
IV Any of the above with initial CNS and/or bone marrow involvement Stage at diagnosis >80% Stages I–II >85% Stages III–IV

797
 hematology malignancy
Key Points: Clinical Aspects
■ The majority of patients with HL and NHL present with
painless enlargement of a group of lymph nodes
■ In HL, most patients present with Stage I or II disease, and in
NHL the majority of patients have Stage III or IV disease at
diagnosis
■ Systemic symptoms are seen more frequently in HL than
NHL
PROGNOSIS AND TREATMENT OPTIONS
Hodgkin’s Lymphoma
There has been a dramatic improvement in survival from HL in
the past 30 years, mortality rates falling by more than 60% from
the late 1960s to the 1990s. Current mortality rates are around
0.5/100,000 for men and 0.3/100,000 for women. For early stage
disease, there is a five year survival rate of over 90% (41). The prog-
nosis of HL depends upon a number of factors (15), including:
• Age—Older patients have a worse prognosis (for early
stage disesase, five year survival is 45% over the age of
65, cf > 90% for younger patients)
• Tumor subtype—Those with mixed cellularity and
lymphocyte depletion have a worse prognosis than with
nodular sclerosis and lymphocyte-predominant HL
• Raised erythrocyte sedimentation rate (ESR)
• Multiple sites of involvement
• Bulky mediastinal disease
• Systemic symptoms
Patients with HL have traditionally been divided into two or three
prognostic groups, chiefly according to stage and B symptoms,
but also taking various other factors into consideration. Each
group is associated with a typical standard treatment strategy, but
this strategy has changed quite markedly since the advent of effec-
tive combination chemotherapy. HL is highly radiosensitive and
can be cured by radiotherapy alone (34). Hence, the standard
treatment for early-stage HL used to be radiotherapy to the
involved nodes as well as the adjacent lymph node chains (extended
field radiotherapy). Administration of mantle radiotherapy for
cervical lymphadenopathy included irradiation to the bilateral
cervical nodes, the supraclavicular and axillary nodes, together
with mediastinal nodes, extending down to the lower border of
the vertebral body of T10. The overall 10-year survival rate in
patients with Stages I and II HL treated with radiotherapy is
greater than 90% (42,43). However, increasing recognition of the
long-term toxicity from radiotherapy — including a vast excess of
breast cancer in women and thyroid cancer in both men and
women who have received mantle radiotherapy — has prompted
development of efficacious chemotherapeutic regimens which
reduce the need for radiotherapy (44). Thus, major developments
in treatment have been aimed at reducing toxicity while at the
same time maintaining efficacy. The different regimes have differ-
ent side effects ranging from nausea, vomiting, and hair loss to
bone marrow suppression, sterility and leukemogenesis (45–47).
Only in nodular lymphocyte predominant HL, which commonly
presents with stage I disease involving the groin or axilla, would
798
radiotherapy alone be considered now. Treatment according to
prognostic grouping is summarized below:
• Early stages, favorable: combination chemotherapy plus
involved field radiotherapy
• Early stages, unfavorable: more intense chemotherapy
plus radiotherapy
• Advanced stages: extensive chemotherapy with or with-
out consolidatory (usually local) radiation to sites of
bulk disease or a residual mass
In the past, staging laparotomy was routinely undertaken in patients
with HL to identify splenic involvement and intra-abdominal lymph
node spread. Although it is known that the spleen is involved in
about 30% of patients with Stage I and Stage II HL, the technique
has been abandoned for the following reasons:
• Combination chemotherapy is more frequently used
in the treatment of HL, thereby obviating the need for
splenectomy
• In the rare instance of patients treated with radiotherapy
alone, subsequent infradiaphragmatic relapse can be
successfully salvaged with subsequent chemotherapy
• Staging laparotomy is a major procedure, and splenec-
tomy increases the risk of overwhelming infection and
may have a causal relationship with the subsequent
development of leukemia (48)
HL is chemosensitive and chemotherapy combined with radio-
therapy is widely used in patients with unfavorable prognostic
indicators in early-stage disease, for example, those presenting
with bulky mediastinal masses or multiple sites of involvement.
Omission of radiotherapy altogether in this situation has been
shown to give poorer results. Chemotherapy with or without irra-
diation is also the standard approach for the treatment of Stages
III and IV disease. In patients with bulky disease the aim is to use
chemotherapy to reduce bulk, followed by radiotherapy to that
site, in order to avoid excessive irradiation of lung parenchyma
and subsequent radiation fibrosis. Thus, the role of radiotherapy
has become more consolidatory reducing the relapse rate by 25%
and increasing overall survival. The commonest treatment is six
courses of ABVD chemotherapy (doxorubicin or Adriamycin®,
bleomycin, vinblastine, and dacarbazine) whereas the Stanford V
protocol utilizes a shorter course of chemotherapy with irradia-
tion of all sites originally larger than 5 cm, or to the spleen if
clinically involved.
Overall, in patients with more advanced disease (bulky Stage II,
Stage III, and IV), 50% to 80% will achieve complete remission
following multi-agent chemotherapy, but of these 30% to 50%
will subsequently relapse within five years. Combination chemo-
therapy for recurrence after primary treatment with radiotherapy
alone has been successful in achieving a prolonged second remis-
sion (49). Patients failing initial chemotherapy for advanced HL
have a poor prognosis, but high-dose chemotherapy with hemo-
poietic stem cell rescue is being increasingly employed, although
its long-term benefits are yet to be established (50).
Second Malignancies After HL
HL is curable in the vast majority of patients and with such pro-
longed survival, long-term consequences of the disease and the
 lymphoma
treatment have become more apparent. Indeed, in those patients
with early stage disease treated when they were younger than 50,
the absolute excess risk of mortality actually increases with time
because of the increased incidence of cardiac disease and second
tumors as a result of treatment (51). The most important long-
term complication of treatment is the development of a second
malignancy. The commonest malignancies are acute myeloid leu-
kemia (AML) and NHL (DLBCL or Burkitt-like) (52). AML usu-
ally develops two to five years after successful treatment. The risk
of NHL is relatively low (2% for classical HL), but increased
after combined chemoradiation. This may in part be secondary
to the immunodeficiency associated with HL. Large B cell
lymphomas can occur after NLPHL and this may represent clonal
expansion of the original malignancy, since composite forms can
occur (53).
Non-Hodgkin’s Lymphoma
The prognosis of NHL varies hugely. Unlike HL, histological sub-
type is the major determinant of treatment, and prognosis and
treatment are dependent on a combination of histological subtype
and stage. Low-grade lymphomas, although incurable, often have
a prolonged indolent course. For example the median survival for
patients with follicular lymphoma is 10 years, but some live more
than 15 years. It is slowly progressive and has a tendency to
become histologically more diffuse, with a greater number of
large blast cells with time. Such transformation to large B cell
NHL has grave implications for prognosis and therefore an
impact on treatment strategy. It may be a terminal event in up to
70% of cases (54). Intermediate and high-grade lymphomas
carry a worse prognosis, especially those with larger cells and
blast forms. In these patients, however, cure is possible with
advanced chemotherapeutic regimens. Untreated, the median
survival for patients with DLBCL is under one year. Over 40% of
patients with DLBCL are cured with anthracycline-based combi-
nation chemotherapy and can expect long-term disease-free sur-
vival; the rest eventually succumb to the disease. The International
Prognostic Index (IPI) was developed by an international collab-
orative group in recognition of the fact that appropriate choice of
therapy for a patient and comparison of therapies can only be
achieved with a uniform prognostic system in place (55). In
aggressive lymphomas such as DLBCL, five factors were found to
have prognostic significance:
• Age >60 years
• Elevated serum lactate dehydrogenase (LDH)
• Eastern Cooperative Oncology Group (ECOG) perfor-
mance status >1 (i.e., non-ambulatory) (56)
• Advanced Stage (III or IV)
• Presence of >1 extranodal site of disease
Four risk groups are recognized depending on the number of
prognostic features that are present. Prognostic stratification in
this way enables choice of more aggressive therapies for those at
higher risk. Patients in the low risk group (0 or 1 prognostic factor
present) have an 87% complete response rate with five year sur-
vival greater than 70%. In contrast, patients in the high-risk group
(4 or 5 factors present) have only a 25% five year survival. The IPI
is, strictly speaking, only applicable to DLBCL and does not have
sufficient discriminatory ability for low-grade lymphomas. More
recently, a similar prognostic index has been developed for FL
(57), where the important factors are considered to be:
• Age >60 years
• Elevated serum LDH
• Hemoglobin <12g/dl
• Advanced Stage 3 or 4
• More than 4 nodal sites of disease
For the purposes of this index, nine nodal sites are recognized:
right and left cervical, right and left axillary, mediastinal, para-
aortic (including iliac), mesenteric, right and left inguinal.
Although the REAL and WHO classifications have changed our
understanding of the clinical pattern and prognosis of the disease,
the treatment in the individual NHL subtypes is still largely
dictated by the previous broad categorization into low- and high-
grade lymphomas, as well as the sites of involvement. At one end
of the scale, asymptomatic patients presenting with low-grade
lymphomas may simply be followed without treatment until
symptoms develop or transformation occurs. At the other end of
the scale, patients presenting with high-grade disease may be
successfully treated with multi-agent anthracycline-containing
chemotherapy with most attaining a remission and up to 50% of
patients achieving long-term disease-free survival (58).
The development of antibody therapies has added a new
dimension to NHL and the immunological subtype is now a
critical consideration in defining treatment, particularly for B-cell
lymphomas, which express a variety of surface antigens against
which monoclonal antibodies may be raised. There are a number
which have NICE and FDA approval. The best known is rituximab,
a chimeric monoclonal antibody against CD20, which is found in
more than 95% of B-cell tumors. It can be used as a single agent,
for example in indolent NHL, but is also additive with chemo-
therapy. Thus CHOP-rituximab (CHOP-R) is now standard treat-
ment for advanced stage DLBCL and for early stage bulky DLBCL.
It is also possible to combine monoclonal antibodies with toxins,
to form immunotoxins, and with radioactive isotopes, to form
radioimmunoconjugates. The anti-CD20 antibody, tositumomab,
combined with iodine131 (Bexxar®), is used to treat follicular
lymphoma. As it is a gamma emitter it can be used for imaging as
well as treatment. The combination of an anti-CD20 antibody,
ibritumomab, with yttrium90 (ibritumomab tiuxetan or Zevalin®)
is also used for FL. This is a beta emitter, which has higher energies
and is better for larger tumors. It has the advantage of being safe
to administer on an outpatient basis. Both drugs show response
rates of 65% to 80% in relapsed lymphoma.
Most relapses occur within the first two years after treatment.
Once relapse occurs, particularly if remission is short, it is difficult
to sustain further response to salvage chemotherapy, with or with-
out immunotherapy. Current investigation is directed towards
high-dose therapy with autologous bone marrow transplant after
pre-conditioning with second-line chemotherapy (59).
Radiotherapy has a role in localized low and intermediate-
grade NHL, for example in some MALT lymphomas and in rare
instances of Stage 1 or 2 FL, where regional or involved field
radiotherapy may be the treatment of choice if surgical excision
is not an option. As 80% of NHL are widespread at presenta-
tion, it is usually inappropriate for first line therapy, but it is
799
 hematology malignancy
frequently used as consolidatory therapy in many forms of
NHL; for example, in primary mediastinal large B-cell lymphoma
(PMBCL). It also has a role in high-dose salvage therapies and
is extremely useful in local palliation, most NHL being very
radiosensitive.
Key Points: Prognosis and Treatment
■ In HL, disease stage is the most important prognostic factor
and determines the intensity and nature of treatment
■ HL is curable in the vast majority of cases
■ In NHL, the histological subtype is the major determinant of
treatment
■ Paradoxically, cure is is most often achieved in the more
aggressive large cell lymphomas
NODAL DISEASE
In HL, lymph node involvement is usually the only manifesta-
tion of disease, whereas in NHL nodal disease is frequently asso-
ciated with extranodal sites of tumor. Lymph node enlargement
tends to be greater in NHL than HL, but both types may produce
either huge conglomerate tumor masses or no significant nodal
enlargement. In nodular sclerosing and lymphocyte-depleted
HL, involved lymph nodes tend to be normal in size or only
moderately enlarged. A characteristic feature of lymphoma is
that involved nodes tend to displace structures rather than
invade them and in this respect they differ from carcinomas, an
exception being the large cell high-grade lymphomas that are
often locally invasive.
Imaging Techniques
Cross-Sectional Imaging
The introduction of computed tomography (CT) had a major
impact on the way lymphoma was staged, rendering staging lapa-
rotomy largely redundant. Furthermore, the therapeutic impact
of CT increased with time, as newer generation scanners were
introduced (60). The ability of CT to demonstrate enlarged lymph
nodes throughout the body and detect associated pathology in
soft tissue structures, together with its reproducibility, has con-
tributed to CT becoming the modality of choice for the staging
and follow-up of lymphoma. Not only does it accurately demon-
strate the full extent of disease, it also enables localization of the
most appropriate lesion for consideration of percutaneous image-
guided biopsy.
Ultrasound (US) will readily show lymph node enlargement in
the celiac region, splenic hilum and porta hepatis (61–65). Fre-
quently, however, the entire retroperitoneum cannot be shown,
limiting its value in staging. Typically, lymphomatous nodal
involvement produces uniformly hypoechoic, lobulated masses,
appearances that are non-specific. The pattern of nodal vascular
perfusion as assessed by power Doppler sonography may suggest
a diagnosis of lymphoma, lymphomatous nodes being highly per-
fused in both the nodal center and periphery (66). The main value
of US in lymphoma lies not in routine staging (67), for which it is
not sufficiently reliable, but in confirming that a palpable mass is
in fact nodal. It helps in solving specific problems in the liver,
800
spleen, or kidneys (68), and in providing image guidance for biopsy
at many sites.
Although the accuracy of MR in detecting lymph node involve-
ment is equal to that of CT (69–71), it has no particular advantage
over CT. Its role is essentially adjunctive,used to solve problems in
the identification of lymph node pathology (for example in the
pelvis or supraclavicular fossa) or in monitoring response to
treatment (72). As with CT and US, involved lymph nodes can be
diagnosed only by size criteria (73). They are easily identified as
relatively low/intermediate signal intensity masses on T1-weighted
images and are of intermediate/high signal intensity in T2-weighted
images (Fig. 33.3). As a result of advances in scanner technology,
whole-body MR imaging has now become feasible for staging lym-
phoma. A combination of T1 weighted and fluid-sensitive short-tau
inversion recovery (STIR) sequences enables identification of nodal
enlargement as well as marrow infiltration. On STIR sequences,
enlarged nodes may have very high signal intensity. Though whole
body scanning at 3 T is faster, there is insufficient evidence for its
superiority over conventional 1.5 T scanning (74). Similarly, there
is no robust data on whole-body diffusion weighted imaging of
lymphoma, though it may have a role in the differentiation of
lymphoma from other causes of malignant nodal enlargement (75).
At present, MR-specific lymphographic agents in the form of ultra-
small superparamagnetic iron oxide particles do not have a role in
the detection of lymphomatous involvement of normal-sized nodes
(76,77). Though magnetic resonance spectroscopy (MRS) is not
used for staging of lymphoma, preliminary evidence indicates a
potential role in evaluation of response to treatment (78). Treated
nodes, particularly in nodular sclerosing HL, may become necrotic
and the nodes then have a signal intensity similar to that of fluid
(Fig. 33.4). Calcification may occasionally develop following
treatment for HL, which is clearly seen on CT. On MR the signal
intensity of calcified nodes is markedly reduced.
Nuclear Medicine
For all three of the anatomical cross-sectional imaging modali-
ties, recognition of nodal disease depends almost entirely on size
criteria, and detection of disease in normal-sized nodes is not
possible (though clustering of multiple small prominent nodes,
for example in the anterior mediastinum or mesentery, is sugges-
tive). Conversely, it is not possible to differentiate between nodes
that are enlarged by lymphoma or reactive hyperplasia. Both
distinctions are possible with functional radioisotope studies.
Gallium-67 (Ga-67) and the positron emitter 2-[F-18]fluoro-2-
deoxy-d-glucose (18FDG) can demonstrate viable tumor cells
within nodes with high sensitivity (79,80). Ga-67 is a cyclotron-
produced radionuclide with a half-life of 3.2 days, which can be
used in the citrate form as a tumor- and inflammation-localizing
radiotracer. The accuracy of Ga-67 is dependent on several fac-
tors including cell type, and the location and size of the lesions.
Its accuracy is greater for HL and high-grade lymphoma than for
other forms. Its sensitivity diminishes for lesions under 2 cm in
size, especially below the diaphragm, because of the limited reso-
lution of gamma camera imaging and confounding bowel and
splenic uptake. Furthermore some lymphomas, especially low-
grade NHL, are non-gallium avid, resulting in too many false
negative studies to render it effective as an isolated staging tool in
NHL or HL (81–83). Thus, Ga-67 imaging has largely been
 lymphoma

(A) (B)

(C) (D)
Figure 33.3 Axial MR images showing enlarged lymph nodes in the upper cervical region in a patient with HL. (A) T1-weighted image. (B)T1-weighted image post-
intravenous gadolinium-DTPA. Note moderate uniform enhancement. (C) STIR image. Note marked T2 hyperintensity of right and left level 2 lymph nodes. (D) Coronal
T2-weighted MR showing bilateral enlarged lymph nodes from level 2 to 4. Notice heterogeneous T2 hyperintensity of the large left level 2 node.

(A) (B)

Figure 33.4 MR images of a patient with HL. (A) Pretreatment turbo spin-echo T2-weighted image shows a high signal intensity residual lymph node in the subcarinal
space (arrowed). No further treatment was given. (B) A follow-up examination four months later shows complete resolution of the node, presumed to be necrotic.

801
 hematology malignancy
replaced by positron emission tomography using 2-[F-18]fluoro-
2-deoxy-D-glucose (FDG).
Positron Emission Tomography
In the last decade there have been numerous studies of the effi-
cacy of 2-[F-18]fluoro-2-deoxy-D-glucose positron emission
tomography (FDG PET) in the staging and re-staging of HL
and NHL. Glucose metabolism is often increased in malignant
tumors including HL and NHL, resulting in increased cellular
uptake of FDG. Recent studies give results at least comparable
to or better than CT for the detection of nodal and extranodal
disease (84,85), with a trend to greater positivity for FDG PET
on a lesion-by-lesion or site-based analysis. FDG PET tends to
demonstrate a higher site positivity rate than Ga-67 (86,87),
resulting in clinically significant upstaging in 10% to 20% of
patients. It is more sensitive than Ga-67 for small masses
(1–2 cm), below the diaphragm, and in the assessment of low-grade
lymphomas (88–90).
In HL, upstaging as a result of FDG PET can lead to changes in
therapy, for example, from radiotherapy to chemotherapy, or
alteration of radiotherapy portals (91,92), but it is not recom-
mended as an isolated staging tool (91), because of rare instances
of false negative studies in specific anatomical sites such as the
lung parenchyma.
In NHL, staging FDG PET gives important information for all
grades of tumors by indicating tumor burden as well as the pres-
ence of extranodal disease. Most low-grade tumors do show
increased uptake, the exceptions being some mucosa-associated
lymphoid tissue (MALT) types, cutaneous lymphomas and small
lymphocytic types (93,94). As with HL, it is not recommended for
use as an isolated staging tool for this reason.
An important limitation of using FDG PET alone is its lack
of precision in localization of abnormalities due to the lack of
reliable anatomical landmarks, and the limited spatial resolution
(A)
Figure 33.5 Lymphangiogram in Hodgkin’s lymphoma. (A) Oblique view of the lumbar spine showing filling defects in involved left para-aortic lymph nodes (arrow).
(B) Computed tomographic scan in the same patient as (A) performed on the same day, showing opacified unenlarged lymph nodes shown to be involved on
LAG (arrow).
802
of current PET scanner technology. FDG PET imaging is particu-
larly challenging in the neck, abdomen, and pelvis due to variable
physiologic FDG uptake in lymphatic, bowel, and muscle tissue as
well as by the renal excretion of the radiotracer, which can con-
found image interpretation. The introduction of PET/CT into
clinical practice undoubtedly heralds a new era in staging HL and
NHL, allowing accurate localization of morphological abnormali-
ties together with their associated functional changes. Combined
PET/CT devices acquire PET and CT images that are concurrent
and co-registered, merging the functional information from PET
with the anatomical information from CT. PET/CT is unique
because it provides tissue characterization as well as assessment of
the exact localization and the extent of tumor tissue. Debate is
now centerd on whether it is necessary to carry out a full diagnos-
tic CT scan as part of the PET/CT study, or whether a low dose CT
for the purposes of attenuation correction and anatomical corre-
lation, possibly in combination with a high resolution CT of the
lungs, is sufficient (95,96).
After the introduction of third and fourth generation CT scanners
and highly effective combination chemotherapy, lymphangiography
as a method of evaluating non-enlarged infradiaphragmatic retro-
peritoneal lymph nodes was essentially abandoned. Though it
remains the only imaging technique that demonstrates nodal
architecture, the complementary yield over CT for lymph nodes
of 1 cm or less is negligible (Fig. 33.5) (97). A recent study comparing
FDG PET with lymphangiography in 28 patients with HL and a
normal abdominal CT did not show any advantage for lymphangiog-
raphy over FDG PET, but it was responsible for one false positive
FDG PET finding as a result of inflammation produced by the
lymphangiogram (98).
Nodal disease in HL and NHL may involve any site where lymph
nodes are found anatomically, but for convenience this descrip-
tion is divided into the following sections: neck, thorax, abdomen,
and pelvis.
(B)

(A)
Figure 33.6 NHL involving lymph nodes in the neck. (A) Contrast-enhanced CT shows discrete enlargement of lymph nodes bilaterally at presentation. The involved
nodes are larger on the right. Submandibular nodes (s), jugular node (j), spinal accessory node (arrows); (B) Contrast-enhanced CT in a patient with low-grade NHL
showing bilateral midjugular and posterior triangle nodes.
Key Points: Nodal Imaging: General
■ Recognition of nodal disease with CT and MR depends on
size criteria alone
■ CT and MR are equally efficacious in the depiction of lymph
node enlargement above and below the diaphragm
■ US is too insensitive to be used as a staging tool, but has a role
in problem-solving and guidance for biopsy
■ Functional techniques particularly FDG PET, enable
identification of disease in normal-sized lymph nodes
■ PET-CT provides unique information on disease extent and
localization
Neck
Patients with HL most commonly present with a group of enlarged
cervical lymph nodes, seen in 60% to 80% of cases. It may also be
the presenting feature in NHL. HL typically involves the internal
jugular chain of nodes initially, with further spread to the spinal
accessory chain and the transverse cervical chain, these nodes
forming the deep lymphatic chains of the neck (99). The internal
jugular chain follows the course of the internal jugular vein, the
spinal accessory nodes are found between the sternocleidomas-
toid and trapezius muscles in the posterior triangle, and the trans-
verse cervical nodes join the internal jugular and spinal accessory
nodes in the lower neck (Fig. 33.6). Nodes in the submandibular,
submental, parotid, and retropharyngeal regions are occasionally
involved. Patients with bulky supraclavicular or bilateral neck
adenopathy are at increased risk of infradiaphragmatic disease.
The pattern of NHL is more haphazard than HL because of
hematogenous spread and is more likely to be associated with
extranodal and bulky disease.
Lymph nodes greater than 1 cm in short axis diameter are gen-
erally considered enlarged on CT. Although level 2 jugulodigastric
lymph nodes may normally have a short axis diameter greater
than 1 cm, most authorities would still call these enlarged if they
exceed 1 cm short axis diameter. Minimally enlarged discrete
lymphoma
(B)
lymph nodes seen in the neck in patients with lymphoma usually
have a well-defined contour, but once the tumor has broken
beyond the confines of the node, the fat planes between the nodal
mass and adjacent structures are lost. Fibrosis following radio-
therapy may also eliminate the fat planes, making post-treatment
assessment difficult on clinical examination and CT. This is one
anatomical area where the routine use of IV contrast material
undoubtedly facilitates nodal evaluation. Central necrosis within
a lymph node is rarely seen in the lymphomas, a striking contrast
to the typical features seen in squamous carcinoma nodal metas-
tasis on contrast-enhanced CT. Enhancement following IV injec-
tion of contrast medium is usually mild to moderate though
occasionally marked (100).
Imaging, particularly CT, has a useful role in evaluating the neck
in patients with lymphoma as it may:
• Identify involved nodes that are clinically impalpable
• Provide a baseline for assessing treatment response,
particularly in patients treated with radiotherapy
• Identify recurrence in patients with thickened tissues
due to previous radiotherapy (Fig. 33.7)
MR imaging may be particularly useful for defining the extent of
lymphomatous masses in the lower neck and supraclavicular fossa
(Fig. 33.8) (101).
Thorax
The frequency and distribution of intrathoracic lymph node
involvement in HL and NHL differ, although the appearances on
imaging are similar. As in the neck, lymph nodes >1 cm in diam-
eter are considered enlarged both on CT and MR. However, the
number of nodes present should also be taken into account; mul-
tiple nodes under 1 cm in diameter within the anterior mediasti-
num should certainly be regarded as suspicious. Nodes within the
thorax are involved at the time of presentation in 60% to 85% of
patients with HL and 25% to 40% of patients with NHL
(36,102–103). Any intrathoracic group of nodes may be involved
803
 hematology malignancy

in patients with lymphoma, but all the mediastinal sites are more
frequently involved by HL than NHL, except the paracardiac and
posterior mediastinal nodes, where the reverse is the case. The
frequency of nodal involvement in HL is as follows:

• Prevascular and paratracheal (84%)

• Hilar (28%)
• Subcarinal (22%) (Fig. 33.9)
• Other sites (approx. 5%)
° Aortopulmonary window
Anterior diaphragmatic
° Internal mammary
° Posterior mediastinal
°
The frequency of intrathoracic nodal involvement in NHL was
analysed by Castellino et al. (104) as follows:

• Superior mediastinal (34%)

Figure 33.7 Recurrent low-grade NHL. A nodal mass on the right side of the neck
is seen on contrast-enhanced CT, which has an ill-defined contour. The patient had
previously been treated with radiotherapy.
• Hilar (9%)
• Subcarinal (13%)
• Other sites (up to 10%) (Fig. 33.10)
In most cases lymphadenopathy is bilateral but asymmetric.
Almost all patients with nodular sclerosing HL have disease in the
anterior mediastinum. The great majority of cases of HL show
enlargement of two or more nodal groups, whereas only one nodal
group is involved in up to half of the cases of NHL. Hilar nodal
enlargement is rare without associated mediastinal involvement,
particularly in HL. The posterior mediastinum is infrequently
involved but if disease is present in the lower part of the mediasti-
num, contiguous retrocrural disease is likely (105). Although
nodes in the internal mammary chains and paracardiac regions

(A) (B)
Figure 33.8 (A) Coronal T1-weighted MR image in a patient with HL. The nodes are seen as intermediate signal intensity masses (arrowed). (B) Axial T2-weighted image
in a different patient with NHL. There is excellent soft tissue contrast between the infiltrative mass in the left supraclavicular fossa, the adjacent musculature and fat. Note
extension of tumour into the intervertebral foramen and vertebral body.

804
 lymphoma

(A) (B) (C)

(D) (E)

Figure 33.9 Extensive mediastinal lymph node and lung parenchymal involvement in NHL. (A) Subcarinal lymph node enlarged (arrowed). (B) Scan above the level at
(A) showing lymph node enlargement in the paratracheal region (arrow) and in the aortopulmonary region (arrowhead). (C) Lymph node enlargement in the azygo-
esophageal region in the same patient as (A). (D) In the same patient as shown in (A–C) when viewed on lung settings, there is peribronchial and juxtamediastinal lung
parencymal involvement with linear shadowing and more discrete peripheral nodularity also shown in Figure 33.9 (E).

(A) (B)

Figure 33.10 (A) CT scan showing right internal mammary lymph node enlargement (arrowed) together with left axillary (arrowhead) and middle mediastinal lymph
node enlargement. (B) CT scan of a patient with NHL. There are bilateral peridiaphragmatic nodes (arrows) in addition to a large right retrocrural node.

are rarely involved at presentation, they become important as sites
of recurrence as they may not be included in conventional radia-
tion fields (Fig. 33.10) (106).
On CT, enlarged nodes may be discrete or matted together, and
usually show only minor enhancement after injection of IV con-
trast medium (Fig. 33.11). Calcification prior to therapy is
extremely rare, and does not appear to have any prognostic impli-
cations, though it is common in more aggressive subtypes
(107,108). It is seen occasionally following therapy. Cystic degen-
eration seen rarely in both HL and NHL may persist following
therapy when the rest of the nodal masses shrink away (Fig. 33.4)
(109). Cystic change is more likely with large anterior mediastinal

805
 hematology malignancy

(A) (B) (C)

Figure 33.11 Massive mediastinal lymph node enlargement in a patient with HL. (A) Plain chest radiograph. (B) Contrast-enhanced CT scan showing anterior
mediastinal lymph node mass. (C) Coronal reformatted image in another patient with HL beautifully demonstrates the effect of the mass on the mediastinal structures.

(A) (B)

Figure 33.12 Cystic change within lymph nodes. (A) Cystic change within a mediastinal mass of nodes. Notice also severe extrinsic compression of the superior vena cava
(arrowed). (B) Ring enhancement following IV injection of contrast medium due to cystic change within a paratracheal lymph node.

masses, but again this does not have any prognostic significance,
nor does it indicate a particular pathological subtype, occurring in
both nodular sclerosing HL and primary mediastinal large B-cell
lymphoma (Fig. 33.12) (109).
In about 10% of patients with HL, CT demonstrates enlarged
mediastinal nodes despite a normal chest radiograph (Fig. 33.13)
(103). Patients with HL who have even a moderate volume of
unsuspected intrathoracic disease at CT have a poorer progno-
sis (110). CT will change clinical stage in up to 16% of patients
with lymphoma and management may be altered in up to 25%,
particularly where radiotherapy is planned. Thus, the effect of
CT is more pronounced in patients with HL than NHL
(103,104,111–113).
Even in patients with bulky disease, CT frequently provides
additional information such as:
• The inferior extent of the mass and its relationship to the
heart
• The presence of pericardial thickening and effusion, which
can be distinguished from lymphadenopathy
• The presence of significant airway narrowing and central
venous occlusion

806
 lymphoma

(A) (B)

Figure 33.13 (A) Plain chest radiograph and (B) CT scan in a patient with NHL. The plain chest radiograph appears normal but CT shows multiple enlarged lymph
nodes in the mediastinum, indicating intrathoracic disease. Note left internal mammary and bilateral axillary lymph node enlargement.

(A) (B)

Figure 33.14 CT scans in two patients with HL. (A) Before treatment there is a large anterior mediastinal mass, probably involving the thymus. Note an area of low
density within the mass on the left which either represents necrosis or cystic change. (B) Following treatment in a different patient there is a small residual mass containing
a central low attenuation area surrounded by a rim of calcification.

Large anterior mediastinal masses usually represent thymic infil-
tration as well as a nodal mass (114) (Fig. 33.14). Enlarged nodes
can usually be distinguished from a thymic mass but in up to
30% of cases, thymic involvement can only be diagnosed on eval-
uation of follow-up studies after treatment, when the thymus has
resumed its normal shape (115). Thymic infiltration may be seen
in both HL and NHL. Although the thymus is usually seen on CT
as a homogeneous soft tissue mass, cystic areas within the mass
may be identified both on CT and MR, especially with primary
mediastinal large B-cell lymphoma (Fig. 33.12) (116). These cysts
are more frequently detected on MR (117). It has been shown
that in NHL high-grade tumors tend to be more heterogeneous
on pre- and post-contrast CT scans than low-grade tumors of
comparable size, but the clinical relevance of this is uncertain
(118). Similarly, there is some evidence that heterogeneous high
T2 signal intensity within mediastinal masses is associated with
high-grade tumors and poorer survival (119,120). A large anterior
mediastinal mass, especially when it exceeds one third of the
transthoracic diameter at the level of T6, is an adverse prognostic
factor in HL, as recognized in the Ann Arbor classification. CT
also depicts local complications of the more aggressive lympho-
mas, such as airway compromise and central venous obstruction,
both of which are particular features of primary mediastinal large
B cell lymphoma (121).
Impalpable axillary nodal enlargement is also frequently detected
on CT in HL and NHL, and may be unilateral or bilateral (Figs. 33.10
and 33.13b). Occasionally uninvolved nodes contain fat centrally,
helping distinguish nodes involved by lymphoma from those with
benign reactive hyperplasia.
MR imaging of the chest may provide additional information to
CT in a problem-solving role, for example in the demonstration
of nodal enlargement in areas where CT evaluation is difficult,
such as the subcarinal space and aortopulmonary window
(Fig. 33.15). MR imaging is also helpful for defining the full extent
of disease, for example infiltration of the chest wall.
When reporting thoracic CT for staging HL or NHL, it is
always important to check all possible sites of involvement
because minimally enlarged nodes in such sites as the internal

807
 hematology malignancy
(A)
Figure 33.15 MR images in a patient with HL showing nodal enlargement in the anterior mediastinum and aortopulmonary window. Turbo spin-echo T1-weighted
images: (A) axial; (B) coronal. The enlarged nodes have an intermediate signal intensity lower than that of fat but higher than that of muscle. Note an enlarged lymph
node in the left supraclavicular fossa (arrowed).
mammary group or diaphragmatic nodes are easily overlooked
(Fig. 33.10A and B).
Key Points: Supradiaphragmatic Nodal Disease
■ Sixty to eighty percent of patients with HL present with
enlarged neck nodes. It is also a common presentation in
NHL
■ Sixty to eighty percent of patients with HL and 25% to 40%
of patients with NHL have prevascular and paratracheal
lymphadenopathy at diagnosis
■ Ten percent of patients with HL have enlarged nodes detected
on CT but a normal chest radiograph
■ Hilar lymphadenopathy is rarely seen in isolation
■ A large anterior mediastinal mass may represent lymphoma-
tous infiltration of the thymus
■ Enlarged axillary nodes are found in 6% to 20% of HL at
diagnosis
Abdomen and Pelvis
At presentation, the retroperitoneal nodes are involved in 25% to
35% of patients with HL, and 45% to 55% of patients with NHL
(122–124). Mesenteric lymph nodes are involved in more than
half of patients with NHL and <5% of patients with HL (122–125).
Other sites, as in the porta hepatis and around the splenic hilum,
are also less frequently involved in HL than NHL. In HL, nodal
spread is predictably from one lymph node group to contiguous
groups (126,127). In this context, the term “contiguous” does not
mean physical contiguity but through directly connected lymphatic
808
(B)
pathways. Thus, involvement of retrocrural nodes should prompt
close scrutiny of the coeliac axis nodes. Nodes are frequently of
normal size or only minimally enlarged (97). In NHL, nodal
involvement is frequently non-contiguous, bulky, and is more
frequently associated with extranodal disease.
In HL the coeliac axis, splenic hilar and porta hepatis nodes are
involved in about one third of patients, and splenic hilar nodal
involvement is almost always associated with diffuse splenic infil-
tration (Figs. 33.16 and 33.17). In the porta hepatis, the node of
the foramen of Winslow (portocaval node) is important. It lies
between the portal vein and inferior vena cava (Fig. 33.18) and has
a triangular or lozenge shape; its normal transverse diameter is up
to 3 cm and in the anterio-posterior plane is approximately 1 cm
(128). Enlargement of this node is easily overlooked, which is
particularly important if it is the only site of relapse. In the coeliac
axis, multiple normal-sized nodes may be seen, which can be diffi-
cult to evaluate because involved normal-sized nodes are frequent
in HL (127). In this context, the functional information provided
by FDG PET can be extremely helpful.
In NHL, discrete mesenteric nodal enlargement or masses may
be seen with or without retroperitoneal nodal enlargement
(Fig. 33.19). Large-volume nodal disease in both the mesentery
and retroperitoneum, may give rise to the so-called “hamburger”
sign, in which a loop of bowel is compressed between the two large
nodal masses (Fig. 33.19C). In NHL, regional nodal involvement
is frequently seen in patients with primary extranodal lymphoma
involving an abdominal viscus. Enhancement following IV injec-
tion of contrast medium is mild and calcification is rare before
treatment. Analysis of enhancement characteristics of nodes may
 lymphoma

(A) (B)

(C)

Figure 33.16 HL. CT scans showing involvement of (A) coeliac axis lymph nodes and a retrocrural lymph node on the left (arrowed). Note focal deposits in the spleen.
(B) At a lower level there is an enlarged lymph node at the splenic hilum and a further enlarged node is seen in the superior mesenteric group (arrowed). The portal node
is prominent but not enlarged on CT criteria. (C) At the level of the upper poles of the kidneys, enlarged retroperitoneal lymph nodes are seen.

(A) (B)
Figure 33.17 Lymph node involvement in the gastrohepatic ligament. (A) A large node lies cephalad to (B) multiple smaller nodes. Notice also focal splenic
lesion.

809
 hematology malignancy

help differentiate lymphoma from infectious causes such as TB or
atypical infections. Central necrosis, peripheral or multilocular
enhancement favor infection (129). Multiple normal-sized mes-
enteric nodes should be regarded with suspicion for the diagnosis
of lymphoma, as should nodularity and streakiness within the
mesentery. The latter presumably reflects dilatation and obstruction
of lymphatic vessels.
In the pelvis all nodal groups may be involved in both HL and
NHL (Fig. 33.20). Presentation with enlarged inguinal/femoral
lymphadenopathy is seen in less than 20% of cases of HL. How-
ever when it does occur, careful attention must be paid to the
evaluation of pelvic nodes on imaging as these will be the next
contiguous sites of tumor spread. In patients with massive pelvic
disease, MR is helpful for delineating the full extent of tumor in
the coronal and axial planes. It can also help differentiate between
engorged venous tributaries and lymph nodes, and in problem-
solving (69,71).

Key Points: Abdominal Nodal Disease

■ Retroperitoneal lymphadenopathy is more commonly seen
in NHL than HL
■ Mesenteric lymphadenopathy is seen in over 50% of cases
in NHL
■ The coeliac, splenic hilar, and porta hepatis nodes are involved
Figure 33.18 A patient with NHL showing an enlarged portocaval lymph node in about 30% of HL patients. Splenic hilar lymphadenopathy
(arrowed). There is also nodal enlargement in the porta hepatis, around the coeliac is almost invariably accompanied by splenic infiltration
axis and the aorta, as well as multiple small focal splenic lesions.

(A) (B)

(C)

Figure 33.19 CT scans in three different patients with NHL. (A) A large mesenteric mass without evidence of retroperitoneal lymph node involvement. (B) Discrete nodal
enlargement of mesenteric lymph nodes associated with retroperitoneal lymphadenopathy. (C) A large mass in the mesentery associated with a mass of retroperitoneal
lymph nodes. These masses compress an opacified loop of bowel, giving rise to the “hamburger” sign.

810
 lymphoma
(A)
Figure 33.20 Pelvic lymph node enlargement in two different patients with NHL. (A) Moderate obturator and external iliac disease on the right. (B) Massive disease on
the left more than the right, displacing and compressing the pelvic viscera.
EXTRANODAL DISEASE
In about 40% of cases, the vast majority of which are NHL, lym-
phoma arises primarily in extranodal sites. The pathological sub-
types that most commonly arise extranodally are DLCBL,
mucosa-associated lymphoid tissue (MALT) types and FL. The
most common locations affected in decreasing order of frequency
are Waldeyer’s ring, the stomach and small intestine, the soft tis-
sues and the orbit. There is a propensity for lymphomas associ-
ated with immunodeficiency and also those that develop in
childhood to arise extranodally. Secondary extranodal lymphoma
occurs due to spread of lymph node disease into adjacent struc-
tures and organs, and may be seen in both HL and NHL. The pres-
ence of extranodal disease is an adverse prognostic factor as
recognized in the IPI (55), though localized DLBCL (stage I or
IIE) does not have a worse prognosis than stage IV disease unless
it arises in the testis. The increase in incidence of NHL has been
much more marked for extranodal sites, especially in the gastro-
intestinal (GI) tract, central nervous system (CNS), and eyes (6).
Furthermore, visceral lymphoma can mimic many other disease
entities, making recognition of the radiological appearances of
extranodal lymphoma increasingly important.
As with nodal disease, CT is generally excellent in the depiction
of extranodal lymphoma. There are specific areas where MR and
US perform better, as indicated in the relevant sections. In addi-
tion, FDG PET is generally more sensitive and accurate in the
staging of extranodal disease, largely because of its ability to dem-
onstrate bone marrow involvement (85). Data also indicates that
FDG PET and PET-CT are more sensitive than CT in identifying
organ involvement, reaching sensitivities of 86% and 73% for PET
and PET-CT respectively, with only 37% sensitivity for CT (130,131).
The use of PET or PET-CT can result in disease being upstaged in
up to 40% of cases, most frequently secondary to demonstration
of splenic or extranodal disease undetected by CT (130, 131).
However, there are certain areas where CT is more sensitive than
FDG PET, for example in the depiction of miliary pulmonary
parenchymal involvement. The advantages of PET/CT over
(B)
isolated FDG PET or CT are obvious in this respect, enabling
accurate anatomical localization of extranodal, and nodal, disease.
A modified Ann Arbor staging classification is used, with iso-
lated involvement of one extranodal site generally being regarded
as stage IE disease. Concomitant involvement of locoregional
lymph nodes is stage IIE. However, some authorities consider any
bone marrow involvement, even if associated with primary bone
lymphoma, as stage IV.
Thorax
Lung
Secondary involvement of the lung parenchyma at presentation
in HL is most commonly by direct invasion from involved hilar
and mediastinal nodes, hence the frequent perihilar or juxta-
mediastinal location. In this situation, there is no effect on stag-
ing: the “E” lesion. However, peripheral subpleural masses or
consolidation without a visible connection to enlarged nodes in
the mediastinum or hila also occur in both HL and NHL, indi-
cating stage IV disease. On chest radiography, lung parenchy-
mal involvement is seen three times more frequently in HL
(12%) than in NHL (102) (Fig. 33.21). Parenchymal involve-
ment in HL is almost invariably accompanied by intrathoracic
adenopathy, whereas in NHL pulmonary or pleural lesions may
be seen without mediastinal or hilar lymphadenopathy in as
many as 50% of cases (132). However, if the mediastinal and
hilar nodes have been previously irradiated, recurrence con-
fined to the lungs may be seen in both HL and NHL (133). Thus,
in a patient with HL who has not received radiotherapy, in
whom there is no evidence of hilar or mediastinal disease, a
pulmonary abnormality probably represents pathology other
than HL (103,132). In the presence of widespread extrathoracic
disease, parenchymal involvement is more common, especially
in AIDS-related lymphoma (ARL) (134).
The radiographic changes in both HL and NHL are varied and
difficult to characterize. Pulmonary involvement is frequently
perihilar or juxtamediastinal (Fig. 33.9) (135). The most common
pattern is one or more discrete nodules resembling primary or
811
 hematology malignancy
(A)
Figure 33.21 (A), (B) CT scan at two different levels showing pulmonary involvement in a patient with HL. There are multiple areas of consolidation and poorly defined
nodules, some of which are cavitating.
Figure 33.22 Chest radiograph on a patient with HL, bilateral hilar lymph node
enlargement and cavitating lung nodules in both lungs (arrowed).
Figure 33.23 Pulmonary involvement in a patient with high-grade NHL. The CT
scan shows consolidation with air bronchograms and cavitation.
metastatic carcinoma, but usually less well-defined, which may
also cavitate (Figs. 33.9, 33.21, and 33.22) (136–138).Rounded or
segmental consolidation with visible air bronchograms, often
subpleural, is another common pattern (Figs. 33.23 and 33.24).
Peribronchial pulmonary nodules (Fig. 33.25) extending from the
812
(B)
hila, or focal streaky shadowing, also peribronchial, may be seen
in association with the consolidation, reflecting spread along the
peribronchial lymphatics. The least common pattern is widespread
reticulonodular (lymphangitic) shadowing. This is sufficiently rare
in HL to necessitate excluding other conditions causing interstitial
lung disease. Endobronchial disease causing atelectasis is extremely
rare, but is still more likely than extrinsic occlusion by neighbor-
ing lymph node enlargement (139).
Primary (or isolated) pulmonary lymphoma is uncommon (1%
of all extranodal presentations), and is usually due to NHL. Low-
grade B-cell lymphomas comprise the majority of primary NHL
of the lung. Most are lymphomas of mucosa- (or bronchus-) asso-
ciated lymphoid tissue (MALT or BALT), the so-called extranodal
marginal zone lymphomas (140,141). These low-grade lympho-
mas occur most frequently in patients in their fifth to sixth decades
of life, the clinical course is indolent, and there is an 80% to 90%
survival rate at five years. Many patients are asymptomatic. As
with other subtypes, the radiographic findings are non-specific.
Solitary nodules are identified on chest radiographs in >50% of
cases, ranging from 2 to 20 cm. Multiple nodules may occur, or
there may be localized or multiple areas of consolidation (142).
Ill-defined alveolar multifocal opacities are also seen (143). Imag-
ing appearances are variable, but focal consolidation is more com-
mon than nodulation, and both are more often multiple than
solitary (144). Bronchiolitis and interstitial disease are infrequent.
Fairly low level FDG uptake has also been described (144). Hilar
or mediastinal lymph nodes are rarely involved.
MALT lymphoma constitutes the majority of primary pulmo-
nary lymphomas, high-grade DLBCL accounting for the remain-
ing 15% to 20% (142). These patients are usually symptomatic
with dyspnea, cough, and B symptoms. Solitary or multiple nod-
ules are the most common radiographic pattern, and rapid growth
is a feature that can cause diagnostic confusion (145). These
tumors are often locally aggressive with involvement of adjacent
structures including the chest wall.
Primary pulmonary HL is extremely rare (142). The most com-
mon findings are single or multiple nodules with an upper zone
predominance and a relatively high incidence of cavitation
(146,147).
 lymphoma
(A)
Figure 33.24 (A) Segmental consolidation bilaterally in a patient with NHL. (B) The same patient as in (A) following treatment showing almost complete resolution of
the parenchymal disease, but with residual mild bilateral bronchiectasis (arrowed).
(A) (B)
Figure 33.25 Pulmonary involvement in a patient with HL. (A) A predominantly right-sided anterior mediastinal mass. (B) A CT scan showing peribronchial pulmonary
nodules extending from the hila.
The diverse appearances of pulmonary lymphoma provide a
particular diagnostic challenge because many of these patients
have other reasons for developing lung disease, such as:
• Opportunistic infection either following or during
chemotherapy
• Pneumonitis following radiotherapy
• Drug-related pulmonary fibrosis
In one study of 60 patients with HIV, cavitation, size <1 cm
and centrilobular distribution favored infection rather than lym-
phoma (148). However, a differential diagnosis is difficult and the
diagnosis of pulmonary lymphoma, particularly in previously
treated patients, must take into account full clinical information.
Diagnosis requires an adequate biopsy specimen and though
percutaneous or transbronchial biopsy will often establish the
diagnosis, open biopsy may be necessary.
(B)
Pleural Disease
Pleural effusions due to lymphoma occur in up to 10% of patients
at presentation and are nearly always accompanied by mediastinal
lymph node enlargement, and sometimes by pulmonary involve-
ment, visible on a chest radiograph (102). Most effusions are uni-
lateral, are usually exudates and may disappear with irradiation of
mediastinal nodes. Such effusions probably result from venous or
lymphatic obstruction by enlarged mediastinal nodes, rather than
direct neoplastic involvement, and may be detected on CT in over
50% of patients with mediastinal nodal involvement (Fig. 33.26)
(137). Chylothorax is only occasionally encountered. Solid soft
tissue pleural masses are rare at presentation and are seen more
often in recurrent disease, usually accompanied by an effusion. In
one review, 40% of patients with an effusion had adjacent extra-
pleural or pleural soft tissue disease, with nodules or thickening of
the parietal pleura being a common finding (Fig. 33.26B) (149).
813
 hematology malignancy

(A) (B)

Figure 33.26 Pleural and pericardial involvement in two different patients with NHL. (A) Pericardial involvement in a high-grade NHL. The CT scan shows massive
pericardial disease with a large soft tissue mass encasing the pericardium. There is also discrete paracardiac lymph node enlargement (arrows). Note too, the bilateral
pleural effusions. (B) A large pleurally based mass posteriorly invades the chest wall. There is an associated pleural effusion. A second mass is involving the sternum.

(A) (B)

Figure 33.27 Pericardial, cardiac, and adrenal involvement in NHL. (A) CT scan through the heart following IV injection of contrast medium showing a moderate-sized
pericardial effusion and mass lesions involving the right ventricle (arrow) and left ventricle (arrowhead). (B) CT scan of the abdomen in the same patient showing lym-
phomatous masses in both adrenal glands (arrowed).

Chest Wall
Involvement of the chest wall occurs most commonly in HL as a result
of direct extension from an anterior mediastinal mass. Less commonly,
large masses of NHL may arise primarily in the soft tissues of the tho-
racic wall. Both direct invasion and primary chest wall lymphoma are
better demonstrated on MR than CT. T2-weighted images are prefer-
able to T1-weighted images because of excellent contrast between the
high signal intensity mass and the low signal intensity of the normal
muscles of the chest wall. In this way MR may allow more accurate
planning of radiotherapy portals (150,151). Bony destruction is
uncommon and suggests infection or carcinoma.
Pericardium and Heart
Pericardial effusions are seen on CT in 6% of patients with HL at
presentation (152). Effusions are presumptive evidence of pericardial
involvement and in all such patients there is coexistent large
mediastinal adenopathy extending over the cardiac margins. Pericar-
dial effusions are frequently seen in patients undergoing therapy for
HL and NHL. They are usually distinguishable from pericardial
lymphomatous involvement (Figs. 33.26 and 33.27) because they
develop when the patient is on chemotherapy and are usually small
and resolve spontaneously.
Direct invasion of the heart may be seen in patients with aggressive,
bulky mediastinal masses and in this rare situation MR is the best
technique for defining the presence and extent of cardiac involvement
(Fig. 33.27) (153). Intracardiac masses can occur with high-grade
T-cell lymphomas and large B-cell lymphoma, especially in the setting
of ARL or post-transplant lymphoproliferative disorder (PTLD).
Thymus
Thymic involvement occurs in 30% to 50% of patients with newly
diagnosed HL (114). It may be impossible to distinguish the

814
 lymphoma
enlarged thymus on CT or MR from adjacent lymph node enlarge-
ment, which is usually but not invariably present (Fig. 33.14). On
CT, the gland may be of homogeneous soft tissue density, similar
to adjacent lymph nodes. On MR too the signal intensity on both
T1- and T2-weighted images is similar to that of enlarged nodes.
Primary mediastinal B-cell lymphoma also involves the thymus,
and in contradistinction to most other types of lymphoma can
cause vascular occlusion and airway obstruction. SVCO is present
in over 40% of affected individuals (Fig. 33.12A). Cysts and calci-
fication may be seen within the enlarged gland, either at presenta-
tion or during follow-up on both CT and MR (115,117). Cysts are
better appreciated on MR but calcification is more easily recog-
nized on CT (117). As with other malignancies, benign thymic
rebound hyperplasia can develop after completion of chemother-
apy, which can be difficult to differentiate from recurrent disease.
Unfortunately, functional imaging with Ga-67 or FDG PET may
not always differentiate between the two and clinical correlation
combined with follow-up studies may be necessary.
Key Points: Extranodal Thoracic Disease
■ Secondary involvement of the lung parenchyma is seen three
times more frequently in HL than NHL. Lung involvement
in HL is almost invariably associated with mediastinal
lymphadenopathy
■ Most primary low-grade lymphomas of the lung are MALT
or BALT tumors
■ Pleural effusions are associated with mediastinal lymphade-
nopathy in over 50% of cases
■ Chest wall invasion occurs most commonly in HL by direct
extension of a mediastinal mass
■ Thymic infiltration occurs in 30% to 50% of patients newly
diagnosed with HL
Breast
Primary breast lymphoma is rare, accounting for less than 1% of
all breast tumors and approximately 2% of all lymphomas. In the
majority of cases of primary breast lymphoma, masses are soli-
tary, but synchronous bilateral disease and metachronous contra-
lateral disease are well recognized. Utrasound demonstrates fairly
well-defined hypoechoic lesions, often with pronounced vascular-
ity on power Doppler (154). An echogenic rim and posterior
acoustic enhancement occur in approximately one third of cases
(155). A more diffuse pattern is occasionally seen resembling
inflammatory carcinoma (156). This is well recognized in preg-
nancy and lactation, especially in cases of Burkitt’s and other
high-grade lymphomas. In secondary lymphoma, multiple masses
(not infrequently impalpable) with associated large volume axil-
lary adenopathy are seen. Masses tend to be better defined than in
primary disease (157). Calcification and distortion are rare in pri-
mary and secondary forms, and as anticipated, lesions usually
enhance markedly at dynamic contrast-enhanced MR and are
FDG-avid.
Abdomen
Spleen
The spleen is involved in 30% to 40% of patients with HL
(124,158). In the majority of cases this occurs in the presence of
nodal disease above and below the diaphragm (159). It is the sole
abdominal focus of disease in 10% of adults presenting with HL
clinically confined to sites above the diaphragm. For the purposes
of staging, the spleen is regarded as a lymph node in the Ann
Arbor classification and therefore, a patient with supradiaphrag-
matic nodal disease and splenic involvement would be stage III(s).
To date, all imaging techniques have been unreliable in the detec-
tion of splenic involvement, partly because in the vast majority of
cases of splenic HL, infiltration is usually microscopic, or there are
nodules under 1 cm in size. An enlarged spleen is not a reliable
indicator of disease as one third of patients with HL and spleno-
megaly do not have involvement of the spleen. However, one third
of normal-sized spleens in patients with HL or NHL are found to
contain tumor at laparotomy (123,124).
Occasionally, focal splenic nodules >1 cm are seen on cross-
sectional imaging (Figs. 33.16 and 33.17). These lesions have a
non-specific appearance, are usually hypoechoic on US, isodense
on unenhanced CT, and enhance to a lesser extent than normal
parenchyma following IV injection of contrast medium
(Fig. 33.16). Splenic lymphoma can take the form of a solitary
lesion, miliary nodules or multiple low-attenuation masses.
Detection of such lesions has improved with the advent of multi-
detector CT, since the entire spleen can be imaged in the portal
venous phase of enhancement, and lesions no larger than a few
millimeters can be identified. The differential diagnosis of focal
lesions includes opportunistic infection, and occasionally sarcoid
or metastases, which can appear identical. Infectious nodules
tend to be smaller and more uniform in size (160).
In early studies, the sensitivity of US in demonstrating splenic
involvement was extremely low (not exceeding 35%) (61), although
in a more recent study US was more sensitive than CT (63% vs.
37%), detecting nodules down to 3 mm in size and identifying dif-
fuse infiltration more often than CT (63). Although this low sensi-
tivity for the detection of splenic involvement on imaging is
disappointing, failure to detect splenic infiltration in HL is now of
less clinical importance than before, since most patients with early-stage
disease who have occult splenic infiltration will be treated with
multi-agent chemotherapy. This has also resulted in the cessation
of staging laparotomy for Stages I and II HL in Europe.
Up to 40% of patients with NHL have splenic involvement at
some stage. Primary splenic NHL is rare, accounting for 1% to
2% of all NHL. It is a particular feature of mantle cell and splenic
marginal zone lymphoma, where massive splenomegaly can
occur. In contradistinction to HL, the presence of splenomegaly
generally indicates involvement by lymphoma, and infarction is a
frequent complication (Fig. 33.28). Primary disease usually pres-
ents as a mass or masses rather than splenomegaly alone (161).
Serial measurements of splenic volume during treatment may be
helpful in the assessment of response to treatment where there is
diffuse infiltration (162). However, despite excellent results in
some series, splenic volumes and indices have not gained wide-
spread acceptance, as measurement is somewhat cumbersome
(163–165). Unfortunately, the intrinsic tissue contrast of MR is
insufficient for consistent recognition of diffuse infiltration (73),
though IV superparamagnetic iron oxide (SPIO) may improve
detection of diffuse and focal infiltration (166–168). FDG PET
detects splenic infiltration more accurately than CT or Ga-67
scintigraphy (85,169).
815
 hematology malignancy
Figure 33.28 Post-contrast CT scan showing splenic infarction (arrow) in a patient
with mantle-cell NHL.
Key Points: Splenic Involvement
■ In 10% of HL, the spleen is the only site of subdiaphragmatic
disease
■ An enlarged spleen is not a reliable indicator of disease in HL
■ Staging laparotomy is no longer undertaken because early
relapse due to undetected splenic involvement can be sal-
vaged by treatment with chemotherapy
Liver
In HL, around 5% of patients have liver involvement at presenta-
tion, nearly always associated with splenic involvement (159,170).
In NHL about 15% of patients have hepatic infiltration, though the
incidence is higher in the pediatric population and in recurrent dis-
ease. True primary lymphoma of the liver is extremely rare, though
the incidence is increasing, especially in immunocompromised
patients. It is indistinguishable radiologically from other forms of
hepatic malignancy such as hepatocellular carcinoma or metastatic
disease. Up to 25% of patients are hepatitis B or C positive.
As with splenic disease, in untreated patients, hepatic lymphoma
usually takes the form of microscopic infiltration with small foci
of tumor confined to the portal triad (171).
Detection of liver involvement by cross-sectional imaging is
usually difficult. Large focal areas of involvement, detectable on
US, CT or MR, are seen in only 5% to 10% of patients with liver
disease and resemble metastatic disease from other sources
(Fig. 33.29). In both HL and NHL, the lesions are well-defined,
frequently large, hypoechoic on US and hypodense relative to the
normal parenchyma on both enhanced and unenhanced CT scans.
As in metastatic disease, on MR images the lesions display
T1 hypointensity and T2 hyperintensity relative to the liver paren-
chyma. It has been suggested that MR may be more sensitive than
CT in the detection of focal hepatic pathology (172). Occasionally,
especially in children, a form of liver infiltration is demonstrated
as low density soft tissue infiltrating the porta hepatis and the
margins of the portal veins (Fig. 33.30) (38,173).
816
Cross-sectional imaging is relatively insensitive to the detection
of the more common diffuse microscopic liver infiltration. How-
ever, in contradistinction to the unreliability of splenomegaly,
liver enlargement is strongly suggestive of infiltration, particularly
in NHL. To date, despite initial enthusiasm (174), attempts to
detect the diffuse form on MR have not been successful (73,175),
though some work suggests that SPIO may increase the sensitivity
of MR for small focal lesions (176).
Involvement of the bile ducts and gall bladder is rare, but has
been described in AIDS-related lymphoma (see section on “AIDS-
Related Lymphomas”).
Key Points: Liver Involvement
■ Liver involvement is almost invariably associated with splenic
infiltration
■ Only 5% to 10% of patients with liver disease have focal
lesions detectable on cross-sectional imaging
■ Enlargement of the liver is a strong indicator of lymphomatous
infiltration
■ Periportal low attenuation may be a feature of NHL
Gastro-Intestinal Tract
The GI tract (GIT) is the most common site of primary extra-
nodal lymphoma, being the initial site of involvement in 5% to
10% of adult patients (177). HL of the GIT is extremely rare.
Primary GI lymphomas develop from the lymphoid elements in
the lamina propria and constitute about 1% of GI tumors. They occur
most frequently in two age-related peaks, the first below the age of
10 years, usually Burkitt lymphoma (BL), and a second between the
ages of 50 and 60 years (most of which are the MALT type and also
high-grade intestinal T-cell type associated with enteropathy). Primary
lymphomas of the GIT usually involve only one site. The criteria for
the diagnosis of primary GI lymphoma include:
• Absence of superficial or intrathoracic lymph nodes
• Normal white cell count
• No involvement of liver or spleen
• Lymph node involvement, if present, must be confined to
the drainage area of the involved segment of gut (178)
A modified Ann Arbor staging system takes account of these
criteria. Stage I is where disease is confined to the visceral wall,
and Stage II where there is local extension to adjacent organs (IIE)
or draining lymph nodes (179).
Secondary GI involvement is common because of the frequent
origin of lymphoma in the mesenteric or retroperitoneal nodes.
Typically, multiple sites are involved.
In both the primary and secondary forms, the stomach is the
most commonly involved organ (50%), followed by the small bowel
(35%), large bowel (15%), and esophagus (<1%). In 10% to 50% of
cases the involvement is multicentric (177). In children, the disease
appears almost exclusively in the ileum and ileocaecal region.
Stomach (See also Chap. 12, “Gastric Cancer”)
Primary lymphoma of the stomach accounts for about 2% to 5%
of gastric tumors (177,180) and the incidence appears to be rising.
Pathologically, the commonest sybtypes are DLBCL and MALT
type lymphomas. In DLCBL, the radiological appearances reflect
 lymphoma

(A) (B)

(C)
Figure 33.29 Liver involvement in a patient with NHL. (A) Transverse ultrasound scan showing multiple large inhomogeneous focal abnormalities of varying echogenicity.
(B) Post-contrast CT scan in the same patient also showing multiple focal partially enhancing lesions of decreased attenuation within the liver. (C) Contrast-enhanced
CT scan in a different patient showing multiple hepatic masses, some of which have a target-like appearance.

the gross pathological findings. Common appearances are multiple

Figure 33.30 CT in a child with NHL, showing periportal infiltration by low-
density lymphomatous tissue (arrowed).
nodules, some with central ulceration, seen readily at endoscopy or
barium meal, or a large fungating lesion with or without ulcer-
ation. About one third of cases present with diffuse infiltration
with marked thickening of the wall and narrowing of the lumen,
sometimes with extension into the duodenum, indistinguishable
from scirrhous carcinoma. Localized polypoid forms have also
been described (181). Only about one-tenth are characterized by
diffuse enlargement of the gastric folds (Fig. 33.31), similar to the
pattern seen in hypertrophic gastritis and Ménétrièr’s disease.
Because the disease originates in the submucosa, these features
are best demonstrated endoscopically or on barium studies, but
these studies do not demonstrate the extent of the disease
(Fig. 33.31). CT has proved particularly valuable, often showing
extensive gastric wall thickening with a smoothly lobulated bor-
der. Unlike gastric carcinoma, the walls of the stomach are usually
clearly separable from the surrounding organs (Fig. 33.32) (182).
Gastric MALT lymphomas, especially low-grade ones, are local-
ized at diagnosis in more than two-thirds of cases and usually result
in minimal gastric mural thickening, which may not be recogniz-
able even with dedicated CT studies utilizing an oral water load

817
 hematology malignancy

and IV smooth muscle relaxants (183). Endoscopic US is of more

value in local staging and assessment of response to treatment, but
since multi-organ involvement occurs in up to 25% of patients,
extensive imaging for staging may be necessary (184,185).

Figure 33.31 Stomach involvement in NHL. The barium meal shows diffuse
enlargement of the gastric folds due to submucosal infiltration.
Small Bowel
Lymphoma accounts for up to 50% of all primary tumors of the
small bowel (178), occurring most frequently in the terminal
ileum and becoming less frequent proximally. It accounts for up
to 35% of all cases of GI lymphoma. Of the tumors in this region,
over 60% are of B-cell lineage, usually DLBCL but also mantle
cell lymphoma. Patients with AIDS are prone to GI lymphoma
and the pattern resembles that found in immunocompetent
patients (186). Multifocal disease is present in up to 50% of cases.
As it usually originates in the lymphoid follicles, mural thicken-
ing is typical and results in constriction of segments of bowel
with obstructive symptoms, which are common at presentation.
Thickening of the bowel is well demonstrated on CT (Figs. 33.33
and 33.34) with displacement of adjacent loops. Alternating areas
of dilatation and constriction are the most common manifesta-
tion (178). Occasionally, the lymphomatous infiltration is pre-
dominantly submucosal, resulting in multiple nodules or polyps
of varying size, scattered throughout the small bowel but pre-
dominantly in the terminal ileum. This form is particularly prone
to intussusception, which is a classical mode of presentation

(A) (B)

(C)
Figure 33.32 Burkitt’s lymphoma of the stomach in a child. (A) Transverse ultrasound scan showing massive thickening of the wall of the body of the stomach. (B) CT scan cor-
relating with the ultrasound appearances in (A), again showing massive thickening of the wall, which is clearly separable from the surrounding organs. (C) Follow-up CT scan
following chemotherapy two months after (B) showing an excellent response to chemotherapy. Only a minor amount of thickening of the wall of the gastric antrum persists.

818
 lymphoma

(A) (B)

(C)
Figure 33.33 A rare instance of duodenal NHL. (A) There is massive circumferential thickening of the wall of the second part of the duodenum, causing biliary and
pancreatic ductal obstruction. (B) At a higher level there is massive dilatation of the common bile duct and a large left adrenal mass. (C) After treatment the biliary
obstruction has completely resolved and there is a small low density residual mass in the left adrenal gland, which has assumed a more adreniform shape.

(A) (B)
Figure 33.34 Involvement of the bowel by NHL. (A) This shows marked uniform thickening of the wall of a loop of ileum in the left iliac fossa (arrows). (B) CT scan
of the same patient showing diffuse uniform thickening of the transverse colon due to infiltration by NHL.

(Fig. 33.35), usually ileocecal or ileoileal. This is the commonest
cause of intussusception in children older than six. Barium stud-
ies may show multiple polypoid filling defects, with or without
irregular thickening and ulceration of the valvulae. The nature
and extent of intestinal lymphoma may also be demonstrated
with MR enterography (187).
Enteropathy-associated T-cell lymphoma (associated with glu-
ten-sensitive enteropathy) and immunoproliferative small intesti-
nal disease (alpha-chain disease) affect the jejunum and ileum;
malabsorption and acute abdominal presentations secondary to
perforation are common. This form of lymphoma may result in
aneurysmal dilatation of the small bowel, where the tumor spreads

819
 hematology malignancy

through the submucosa and muscularis propria, creating a tube-
like segment that ultimately becomes aneurysmal, presumably
because of destruction of the muscularis and autonomic plexus in
the affected segment. Long segments of affected bowel also sug-
gest this diagnosis (187). Immunoproliferative small intestinal
disease is thought to be a MALT type lymphoma, possibly related
to Campylobacter jejuni infection (188).
Secondary invasion of the small bowel by large mesenteric
lymph node masses causing displacement, encasement or com-
pression may also be seen. Omental thickening, peritoneal
enhancement and ascites cannot be differentiated from perito-
neal carcinomatosis and usually occur in advanced abdominal
disease, though they may be seen at presentation in BL
(Fig. 33.36) (189).

(A) (B)

(C) (D)
Figure 33.35 Duodeno-jejunal intussusception due to lymphoma. (A) A barium follow-through examination showing an apparent mass lesion in the region of the jeju-
num with dilatation of the jejunum proximal to this “mass.” Note too the thickening of the valvulae conniventes. (B) Ultrasound examination in the mid-abdomen in
the region of the “mass” showing marked thickening of the wall of the loop of small bowel. (C and D) CT scans showing thickening of the wall of the loop of jejunum
with a classic “coiled spring” appearance due to intussusception.

(A) (B)
Figure 33.36 Small bowel infiltration in NHL. (A) Marked thickening of the valvulae conniventes in a loop of jejunum. (B) CT scan performed slightly inferior to (A) also
shows thickening of the valvulae in the ileum. Note in (A) and (B) the extensive infiltration of the omentum, perivascular thickening and thickening of the peritoneum.

820
 lymphoma
Colon and Rectum
Primary lymphoma accounts for only 0.05% of all colonic neo-
plasms and usually involves the caecum and rectum rather than
other parts of the colon. Conversely, secondary involvement is
usually widely distributed and multicentric. The most common
form of the disease is a diffuse or segmental distribution of
nodules 0.2 to 2 cm in diameter, typically with the mucosa intact
(Fig. 33.34B). A focal form appears as a large polypoid mass,
often in the caecum, where it is indistinguishable from colonic
cancer unless there is concomitant involvement of the terminal
ileum, which is more suggestive of lymphoma. Elsewhere, con-
centric structuring masses are seen (Fig. 33.37). The mass may
Figure 33.37 Primary colonic NHL. There is a constricting mass of the transverse
colon with transmural spread into the adjacent pericolonic fat, radiologically
indistinguishable from a colonic carcinoma.
(A) (B)
Figure 33.38 Rectal involvement in a patient with lymphoma and AIDS. (A) A sagittal fast spinecho T2-weighted MR image showing thickening of the rectal wall and a
high-signal intensity fistula extending into the perineum. (B) A coronal STIR image in the same patient showing the marked thickening and a marked increase in signal
intensity of the rectal wall. This scan also shows the high signal intensity of the complex fistula extending from the left side of the rectal wall into the perineum
(arrowed).
have a large intraluminal component. In very advanced disease,
there may be marked thickening of the colonic or rectal folds,
resulting in focal strictures or ulcerative masses with fistula for-
mation (Fig. 33.38). Colonic involvement is a particular feature
of ARL and BL, but MALT types also occur, usually causing
nodularity (see section on “MALT Lymphoma”).
Esophagus
Intrinsic esophageal involvement is extremely uncommon, usu-
ally involves the distal third of the esophagus and can result in a
smooth tapered narrowing. Occasionally, both the fundus and
distal esophagus are involved by a bulky fungating tumor.
Pancreas
Primary pancreatic lymphoma is extremely rare and accounts for
only 1.3% of all cases of pancreatic malignancy (190) and 2% of
patients with NHL (191). Secondary pancreatic involvement usu-
ally occurs in association with disease elsewhere, most commonly
due to direct infiltration from adjacent nodal masses, which may
be focal or massive (192). Intrinsic involvement of the pancreas
most commonly results in a solitary mass lesion, indistinguishable
from a primary adenocarcinoma on US, CT, or MR (Fig. 33.39)
(192). Biliary and pancreatic ductal obstruction as well as invasion
or narrowing of the portal vein are commonly seen at CT (193).
Calcification and necrosis are rare. The presence of a large mass in
the head of the pancreas, with only mild biliary or pancreatic duc-
tal dilatation, should raise the possibility of lymphoma, especially
if there is retroperitoneal nodal enlargement below the level of the
renal veins (194). Less commonly, diffuse palpable masses or dif-
fuse uniform enlargement of the pancreas is seen. Involvement is
far more common in NHL than HL, particularly in ARL.
821
 hematology malignancy

(A) (B)
Figure 33.39 Primary pancreatic lymphoma. (A) Note a large mass of decreased attenuation following contrast medium replacing the normal body of the pancreas due
to primary pancreatic NHL. (B) A CT scan performed three months following chemotherapy shows complete resolution of the lymphomatous mass with marked atro-
phy of the remaining pancreas.

(A) (B)
Figure 33.40 Renal lymphoma. (A) CT scan showing multiple masses enhancing less than the adjacent renal parenchyma following IV injection of contrast medium.
Note the absence of retroperitoneal lymph node enlargement. (B) CT scan performed four months after (A) following chemotherapy shows complete resolution of the
multiple renal masses with marked scarring of the kidneys following treatment.

Key Points: Gastro-Intestinal Tract Kidney

■ The stomach is the most frequent site of either primary or
secondary GI lymphoma
■ Lymphoma accounts for up to 50% of all primary tumors of
the small bowel and is multifocal in 50% of cases
■ Intussusception is a characteristic feature at presentation with
predominantly submucosal nodular/polypoid lymphoma
■ Involvement of the colon and rectum accounts for only 0.5%
of colonic neoplasms
■ Pancreatic lymphoma is usually secondary due to invasion
by adjacent lymph node masses
Genitourinary Tract
The genitourinary tract is infrequently involved at the time of
presentation, although in end-stage disease more than 50% of
cases will have involvement of some part of the genitourinary
tract. The testicle is the most commonly involved organ, followed
by the kidney and perirenal space. Involvement of the bladder,
prostate, uterus, vagina, and ovaries is extremely rare (195).
Renal involvement is detected in about 3% of all patients under-
going abdominal imaging for the staging of lymphoma (196–198).
Primary or isolated renal lymphoma is rare. Although CT is more
sensitive in identifying lymphomatous renal masses than US or
urography, a large discrepancy exists between the radiological
detection and incidence at autopsy (up to 50% having involve-
ment in autopsy series), presumably because renal involvement is
a late phenomenon. It is extremely unusual for the detection of
renal involvement to alter the disease stage. Close to 90% of cases
are due to high-grade NHL, renal function is usually normal and
in more than 40% of patients the disease occurs at the time of
recurrence only. DLBCL and BL are the histological subtypes that
most commonly involve the kidneys.
Multiple masses is the most frequent pattern of disease, seen in
up to 60% of cases. CT may show a typical “density reversal pat-
tern” before and after contrast administration.The lesions are
more dense than the surrounding parenchyma before contrast
medium administration and less dense after contrast medium
administration (Fig. 33.40) (196).

822

Solitary masses occur less frequently (10–20%) and may be
indistinguishable from renal cell carcinoma (196). An important
feature of renal masses occurring in NHL is that in over 50% of
cases there is no evidence of retroperitoneal lymph node enlarge-
ment on CT, suggesting that the kidneys are involved by hematog-
enous spread.
Direct infiltration of the kidney is the secondmost common
type of renal involvement, occurring in 25% of cases. Invasion
occurs from the retroperitoneum into the renal hilum and sinus,
encasing the renal vessels and simulating a transitional cell carci-
noma, an important differential diagnosis (Fig. 33.41). Frequently,
a soft tissue mass is seen in the perirenal space, occasionally
encasing the kidney without evidence on CT of invasion of the
parenchyma (Fig. 33.42).
Diffuse infiltration of the kidneys (Fig. 33.43) with global renal
enlargement without focal nodules is a less common manifesta-
tion, usually without lymph node enlargement. The appearance
after IV contrast medium injection is variable, but usually the
normal parenchymal enhancement is replaced by homogeneous
Figure 33.41 Renal lymphoma simulating transitional cell tumor. CT scan on a
patient with NHL showing a mass within the right renal pelvis (arrowed), extend-
ing into the renal parenchyma.
(A)
Figure 33.42 Perirenal lymphomatous infiltration. Two different instances, (A) with and (B) without accompanying retroperitoneal lymph node enlargement.
lymphoma
non-enhancing tissue. This pattern can be seen with BL. After suc-
cessful treatment, the appearance can revert entirely to normal. A
particularly rare form of disease is isolated periureteric lymphoma,
which has been described in NHL and HL (199).
Bladder and Prostate
Although primary lymphoma of the bladder is extremely rare,
secondary lymphoma of the bladder is more common and is
found in 10% to 15% of patients with lymphoma at autopsy
(195,200). Such secondary involvement can affect the wall of the
bladder intrinsically or in contiguity from adjacent involved
nodes. Microscopic involvement is far more common than gross
involvement, but this too can be associated with hematuria. The
appearances on CT and MR are non-specific (Fig. 33.44) with
either diffuse widespread thickening of the bladder wall or a large
nodular mass, both patterns indistinguishable from transitional
cell carcinoma (201).
Primary bladder lymphoma accounts for less than 1% of all
bladder tumors. There is a female preponderance in the sixth and
seventh decades, and a history of cystitis is common, explaining
the high incidence of MALT-type lymphomas. Solitary or
occasionally multiple sessile masses are most often seen (202).
Unlike primary lymphoma of the bladder, where the response
to chemotherapy/radiotherapy is good, lymphomatous involve-
ment of the prostate carries a poor prognosis. It is usually inter-
mediate or high grade and produces irritative obstructive
symptoms. Solitary nodules are uncommon and in the majority
of cases there is diffuse infiltration throughout the prostate and
periprostatic tissue. Secondary involvement of the prostate is far
more common than primary prostatic involvement and direct
extension into the prostate from pelvic lymph nodes is often seen
in very advanced disease.
Testis
Testicular lymphoma is the most common testicular tumor
occurring in individuals over the age of 60, but accounts for only
5% of all testicular neoplasms (203). The vast majority are
DLBCL. At presentation it is seen in about 1% to 2% of men with
NHL (more commonly in BL) but is practically non-existent in HL.
At presentation 80% are localized to the testis and abdominal or
(B)
823
 hematology malignancy

(A) (B)

Figure 33.43 Diffuse lymphomatous infiltration of the kidney in a patient with high-grade
NHL. (A) Longitudinal ultrasound scan through the right kidney showing marked enlarge-
ment of the kidney (the right kidney measures 16 cm, the left 16.5 cm). There is diffuse
increased reflectivity of the renal parenchyma with resultant prominent lucency of the renal
papillae. The normal outline of the kidney is preserved. (B) CT scan following IV injection of
contrast medium in the same patient as (A), showing diffuse infiltration of both kidneys by
lymphomatous tissue. There is preservation of a rim of normal renal parenchyma. Note the
absence of retroperitoneal lymph node enlargement and the presence of a focal lesion in the
inferior aspect of the right lobe of the liver. (C) Post-contrast CT scan demonstrating massive
bilateral renal infiltration, more marked on the left than the right, with virtually no normally
(C) enhancing renal parenchyma.

(A) (B)
Figure 33.44 NHL of the bladder. (A) CT scan showing large soft tissue mass occupying a major part of the base of the bladder. (B) Sagittal spin-echo T2-weighted MR
image showing extensive involvement of the anterior abdominal wall in the same patient.

824
 lymphoma
pelvic lymph nodes (Stage IIE). As in other sites of lymphomatous
involvement of the genitourinary tract, the frequency of involve-
ment discovered at autopsy is much higher: 18% of men with NHL.
There is an association with lymphoma of Waldeyer’s ring, the
CNS, and skin. The outcome is poorer than other DLBCL of equiv-
alent stage, probably because of the tendency for CNS relapse.
On US, the lesions usually have a non-specific appearance,
with focal areas of decreased echogenicity. However, a well-
recognized pattern is a diffuse decrease in reflectivity of the
testicle without any focal abnormality. As involvement is bilat-
eral in 10% to 25% of cases, it is extremely important to examine
the contralateral side. MR offers little advantage over US in
evaluation of the testis (204).
Female Genitalia
In advanced, widespread lymphomatous disease, the female
genital organs are frequently involved secondarily (26). However,
isolated lymphomatous involvement is rare, accounting for
approximately 1% of extranodal NHL. Most are diffuse large B
cell in type. Around 70% of women affected are postmenopausal
and present with vaginal bleeding. The tumors originate predom-
inantly in the uterine cervix, where on CT and MR a large mass
can be seen (Fig. 33.45). Involvement of the uterine body usually
produces diffuse enlargement, often with a lobular contour simi-
lar to a fibroid, with relatively homogeneous signal intensity on all
sequences in spite of the large tumor size (205). Similarly, primary
lymphoma of the cervix and/or vagina is characterized by a large,
exophytic, soft tissue mass.
Involvement of these gynecological structures is best demon-
strated by MR, since masses are seen as intermediate to high signal
intensity lesions on T2 weighting and are therefore clearly distin-
guished from the surrounding normal tissues, including the
Figure 33.45 Primary NHL of the cervix. Sagittal fast spin-echo T2- weighted MR
image showing a very large mass in the uterine cervix due to high-grade NHL.
There was no evidence of disease elsewhere in this patient.
uterus, cervix, and vaginal wall. MR is excellent in follow-up and
assessment of response to treatment (206). Ovarian lymphoma is
less common and carries a worse prognosis than uterine lym-
phoma because the tumors are usually more advanced at the time
of discovery. The appearance on cross-sectional imaging is indis-
tinguishable from primary epithelial ovarian carcinoma (207).
Involvement is often bilateral, and DLBCL or BL are the usual
subtypes. The presence of large bilateral homogeneous masses
with moderate enhancement on MR, without hemorrhage, necrosis
or calcification, may suggest this diagnosis (208).
Key Points: Genitourinary Tract
■ Renal involvement is seen in about 3% of cases undergoing
abdominal CT
■ Lymphomatous involvement of the kidneys is not usually
associated with renal impairment
■ Primary lymphoma of the prostate carries a poor prognosis
whereas primary lymphoma of the bladder has a good
prognosis
■ The testis is the most frequent site of involvement of the
genitourinary tract with lymphoma
■ Lymphoma of the testis accounts for only 5% of all testicular
tumors
■ Primary lymphoma of the female genital tract is rare and is
best demonstrated on MR
Adrenal Glands
Primary adrenal lymphoma is rare, usually occurring in men over
the age of 60. Secondary involvement of the adrenal glands in
lymphoma is usually demonstrated on routine abdominal CT for
staging (where it is seen in up to 6% of cases of NHL) as presenta-
tion with adrenal insufficiency is extremely rare (195,207).
Involvement is usually bilateral and the appearances are indistin-
guishable from bilateral metastases, but readily distinguishable
from adenomas (Figs. 33.27B and 33.33). Non-lymphomatous
bilateral hyperplasia of the adrenal glands has been described
(209). The reason for this is unclear, but probably due to ectopic
production of an ACTH-like substance (210).
Central Nervous System
Primary
Primary CNS lymphoma (PCNSL) is initially localized to the
CNS at presentation. It occurs almost exclusively within the
brain, as the spinal cord is only very rarely the site of origin
(<1%) (211, 212). Although in the mid-1980s primary lymphoma
accounted for only 1.5% of all brain tumors, its frequency
increased markedly in the early 1990s, partly due to an association
with immunosuppressive therapy following cardiac or renal trans-
plants and acquired immunodeficiency. Up to 5% of AIDS patients
can be expected to develop primary CNS lymphoma during the
course of the disease (213), but the introduction of HAART has
resulted in a decline in the incidence of AIDS-related PCNSL.
Cases of PCNSL have been reported from the age of two months
to 90 years, but presentation between the fourth and sixth decades
appears to be the most frequent. There is a separate peak in the
first decade of life. It now accounts for over 3% of brain tumors
825
 hematology malignancy

and up to 30% of cases of NHL in some series. There are differ-
ences in the clinical features of AIDS-related PCNSL and PCNSL
in immunocompetent patients. The former are younger, more
likely to be male and to present with fits and altered mental
status rather than focal neurology and signs of raised intracranial
pressure.
On CT or MR, more than 50% of lesions occur within the cere-
bral white matter, close to or within the corpus callosum (212).
Most abut the ependyma of the ventricles or the ependymal sur-
face. A butterfly distribution with spread across the corpus callo-
sum is seen (214). In about 15% of cases, the deep cortical grey
matter of the basal ganglia, thalamus and hypothalamus are
involved. In 10% of cases, lymphoma develops in the posterior
fossa and is multifocal in a further 20% of cases. In AIDS-related
PCNSL, multifocality is much more common, being seen in up to
50% of cases. On CT, the tumor mass is typically of increased
density on unenhanced CT and the majority of lesions enhance
homogeneously after IV injection of contrast medium. Only about
10% of lesions do not enhance (211). Calcification is very rare and
surrounding vasogenic edema relatively mild (214). On MR, the
typical appearance is of a tumor mass hypo- or isointense relative
to the surrounding normal tissue on T1-weighted sequences. There
is usually uniform enhancement after injection of gadolinium–
DTPA (Fig. 33.46), but ring enhancement can be a feature of
AIDS-related primary CNSL. The appearance of primary and
secondary lymphoma within the brain is essentially similar on CT
and MR.
Secondary
Cerebral involvement occurs in 10% to 15% of patients with NHL
at some time during the course of their disease (71,215). Certain
groups are at risk: those with stage IV disease, testicular or ovarian

(A) (B)

(C) (D)

Figure 33.46 Primary cerebral NHL of the parietal lobe. (A) A fast spinecho T1-weighted sagittal MR image showing a hypointense mass in the parietal lobe. (B) Follow-
ing IV administration of gadolinium-DTPA, the mass enhances intensely. (C) Axial T2-weighted MR showing a mass in the genu of the corpus callosum with marked
surrounding vasogenic edema. (D) T1-weighted post-contrast MR showing enhancing mass in typical butterfly distribution in the corpus callosum.

826
 lymphoma
presentations, high-grade T-cell lymphomas, immunoblastic, and
BL (216). Secondary cerebral involvement is so rare in HL that a
space-occupying lesion in the brain of a patient with known HL
should prompt a second diagnosis (217). Secondary lymphoma is
distinguishable from the primary form to some extent by its pro-
pensity to involve the extracerebral spaces (epidural, subdural,
and subarachnoid) (Fig. 33.47) and the spinal epidural and suba-
rachnoid spaces (211). MR imaging with direct multiplanar imag-
ing is ideal for detecting extracerebral plaque-like tumor deposits
in the subdural or epidural spaces. Typically, these plaques are
hypo- to isodense on all pulse sequences, but they are made more
obvious on gadolinium–DTPA-enhanced T1-weighted images
(Fig. 33.47). CT is less sensitive, not only in the detection of these
extracerebral lesions, but also in demonstrating leptomeningeal
deposits of lymphoma coating the cranial nerves (218), particularly
when resulting in cranial nerve palsies.
Gadolinium-enhanced MR is also a relatively sensitive, non-
invasive method for demonstrating spinal leptomeningeal involve-
ment by lymphoma and involvement of the spinal cord and nerve
roots. Nonetheless, there is a significant false negative rate that is
higher than that for leptomeningeal carcinomatosis (219). Epidu-
ral extension of tumor into the spinal canal from a paravertebral
nodal mass may also be elegantly demonstrated on MR. Although
extension through the intervertebral foramina may also be clearly
depicted on CT, subtle disease is easily missed (Fig. 33.48) (220).
Compression of the spinal cord or cauda equina due to lym-
phomatous disease is a late manifestation of HL, but is often an
earlier manifestation of NHL. In both types of lymphoma,
extension of nodal spread through the intervertebral neural
foramina is the most common cause. Tumor compresses the
Figure 33.47 NHL showing meningeal disease on a coronal MR image using a
T1-weighted sequence following injection of IV contrast medium (gadolinium–
DTPA). Note intense enhancement of the thickened meninges over the cerebral
hemispheres, cerebellum, and tentorium.
dura, but the dura itself usually acts as an effective barrier to the
intrathecal spread of tumor. Vertebral collapse with cord com-
pression may be seen in some of the aggressive forms of NHL,
but it is less common than compression due to an epidural mass
(Fig. 33.48). On occasion, patients can present with epidural dis-
ease causing back pain and paresis, for example in endemic BL.
The Orbit
NHL is the most common primary orbital malignancy in adults,
accounting for 10% to 15% of orbital masses (211) and about 5%
of all primary extranodal NHL. Primary orbital lymphomas occur
most commonly in patients between 40 and 70 years of age, and
most typically present as a slow-growing, diffusely infiltrative
tumor for which the main differential diagnosis is from the non-
malignant condition known as “orbital pseudotumor.” They can
arise from the conjunctiva, eyelids, lacrimal glands, or retrobulbar
soft tissues. Retrobulbar lymphoma infiltrates around and through
the extraocular muscles causing proptosis and ophthalmoplegia,
but visual acuity is rarely disturbed. In patients with an orbital
lymphomatous mass, up to 50% will be found to have an extra-
central nervous system primary site of origin.
Secondary orbital involvement occurs in approximately 3.5% to
5% of both HL and NHL. In both the primary and secondary forms,
the clinical manifestations will depend on the site of involvement.
Involvement of the lacrimal glands is bilateral in over 20% of cases;
the presenting features are those of bilateral masses with downward
displacement of the globe (Fig. 33.49). The prognosis is generally
good (even with bilateral disease). Relapse in the contralateral orbit
is not uncommon. Involvement of the eyelids and subconjunctival
spaces is readily assessed on clinical examination, whereas MR best
depicts the presence and extent of any intracranial extension.
Key Points: Central Nervous System
■ Primary CNS lymphoma almost exclusively involves the
cerebral white matter
■ Primary cerebral lymphoma is increasing in incidence
■ Secondary lymphoma preferentially involves the extracerebral
spaces and the spinal epidural and subarachnoid spaces
■ Spinal cord compression results from nodal spread through
the intervertebral neural foramina in both HL and NHL
■ NHL is the most common primary orbital malignancy in
adults
Head and Neck Lymphoma
Although HL typically involves the cervical lymph nodes as the
presenting feature, true extranodal involvement of sites in the
head and neck region is rare. Extension from nodal masses in
the neck to Waldeyer’s ring may occur, but this is seen in less
than 1% of patients.
In NHL, extranodal head and neck tumor involvement is rela-
tively common and indeed 10% of patients present with extra-
nodal disease in the head and neck; on investigation about half
will have disseminated lymphoma. Extranodal NHL accounts for
approximately 5% of head and neck cancers (221).
Waldeyer’s ring comprises lymphoid tissue in the nasopharynx,
oropharynx, the faucial and palatine tonsil, and the lingual tonsil on
the posterior third of the tongue. It is the most common site of head
827
 hematology malignancy

(A) (B)

Figure 33.48 T1-weighted MR images

of the lumbar spine (A) pre- and (B)
post-contrast showing extensive
enhancing epidural disease. (C) Axial
contrast-enhanced CT scan (same
patient as Fig. 33.26B) showing exten-
sion of tumour into the epidural
space on the right. However, this is
much more clearly depicted on (D)
the axial T2-weighted MR scan on the
(C) (D) same patient.

Figure 33.49 Orbital lymphoma. T1-weighted coronal MR image. There are bilateral orbital masses of
homogeneous low signal intensity. The masses are symmetrical and occupy the superolateral orbital
compartments. There is no evidence of bone erosion.

828
 lymphoma
and neck lymphoma and there is a pronounced link with involve-
ment of the GIT, which may be synchronous, or metachronous; this
is partly a reflection of the fact that some are of the MALT type.
Hence most centers include a full staging CT and/or endoscopy as
part of staging, since up to 30% will have advanced disease at pre-
sentation. A diagnosis of NHL is suggested by circumferential
involvement or multifocality. Middle-aged women are most often
affected and a history of Sjögren’s syndrome should be sought. The
majority are DLCBL, 60% of which are localized. Secondary inva-
sion from adjacent nodal masses is also a common occurrence.
NHL comprises 8% of tumors of the paranasal sinuses. In the
West, the disease affects middle-aged men and the maxillary sinus
is most commonly involved, nearly always with DLBCL, whereas
the aggressive diffuse T-cell type (that formed part of the “lethal
midline granuloma” syndrome) affects younger Asians and is
linked to EBV. Whilst paranasal sinus involvement often presents
with acute facial swelling and pain, and disease often spreads from
one sinus to the other in a contiguous fashion, bony destruction is
considerably less marked than in squamous cell carcinomas (222).
Nevertheless, these tumors are aggressive and can transgress nor-
mal anatomical barriers, as a consequence of which intracranial
spread through the base of the skull is seen in up to 40% of cases.
Thus, CNS prophylaxis is an important component of treatment.
MR imaging is the preferred imaging technique for evaluating
head and neck lymphoma due to high tissue contrast between
tumor and normal structures; its multiplanar capability allows
clear demonstration of the full extent of disease within the intri-
cate anatomy of the facial region (Fig. 33.50). It also permits
detection of tumor spread into the cranial cavity from the infratem-
poral fossa, orbit, and soft tissue of the face. Fat-suppressed T1
weighted sequences pre-and post intravenous gadolinium-based
contrast medium is most helpful.
Figure 33.50 Axial T2-weighted MR image with fat suppression demonstrating
massive soft tissue thickening of the nasopharynx with resultant obstruction of the
mastoid air cells on the right.
Salivary Glands
All the salivary glands may be involved in lymphoma but the
parotid gland is the most frequent site (223). Most are MALT type.
The patient presents with single or multiple well-defined masses
that are of higher density than the surrounding gland on CT,
hypoechoic on US, and of intermediate signal intensity on T1- and
T2-weighted MR sequences.
Thyroid
NHL accounts for 2% to 5% of malignant tumors of the thyroid
(224). There is an association with Hashimoto’s disease, so the
disease tends to occur in women in their 60s with MALT types.
However, DLBCL also occurs, and these patients present with a
rapidly growing mass and obstructive symptoms. Direct spread of
tumor beyond the gland and involvement of adjacent lymph
nodes is common. On CT these masses usually have a lower atten-
uation than the normal gland and they may show peripheral
enhancement following injection of IV contrast medium
(Fig. 33.51). MR can delineate the local effects on adjacent soft
tissues more accurately than CT, though this is not generally nec-
essary unless radiotherapy is being contemplated (225). Most
present with stage I or II disease and as would be expected, MALT
types have a better prognosis than DLBCL.
Key Points: Head and Neck
■ Extranodal NHL accounts for approximately 5% of all head
and neck cancers
■ Waldeyer’s ring is the most common site of head and neck
lymphoma
■ The parotid is the most frequent salivary gland involved by
lymphoma
■ NHL accounts for up to 5% of all malignant thyroid tumors
Musculoskeletal System
Skeletal involvement may occur in both HL and NHL. Since the
bone marrow is an integral part of the reticuloendothelial system,
lymphomas may arise within the marrow as a true primary
disease. More often, however, the marrow is involved as part of a
Figure 33.51 CT scan showing primary lymphoma of the thyroid. On staging, no
other evidence of disease was found in this patient with biopsy-proven disease.
829
 hematology malignancy
disseminated process and this is categorized as Stage IV disease.
The majority of those with “apparent” primary lymphomas usu-
ally have widespread disease and, therefore, in reality have second-
ary involvement. This is particularly true in children. Hence this
diagnosis is made very rarely, not least because better imaging
enables detection of synchronous disease elsewhere.
Bone and bone marrow are important sites of disease relapse
and any skeletal symptoms following previous treatment for
lymphoma should raise the suspicion of bone disease. Involve-
ment of osseous bone is less widespread and does not necessar-
ily imply bone marrow involvement (226), nor does skeletal
radiography have any predictive value in determining marrow
involvement. Infiltration of bone may also occur by direct inva-
sion of adjacent soft tissue masses. This is designated with the
suffix “E” after the appropriate stage of disease elsewhere, e.g.,
Stage IIE. For the purposes of clarity, involvement of the bone is
distinguished in this description from diffuse involvement of
the bone marrow.
Bone
Primary lymphoma of bone is almost exclusively due to NHL as
primary HL of bone is extremely rare. The criteria for the diagno-
sis of primary lymphoma require that:
• Only a single bone is involved
• There is unequivocal histological evidence of lymphoma
• Other disease is limited to regional areas at the time of
presentation
• The primary tumor precedes metastasis by at least six
months
(A)
Figure 33.52 NHL of upper tibia. (A) Lateral plain radiograph showing a destructive lesion in the upper aspect of the tibia. (B) Coronal T1-weighted MR image showing a large
area of abnormal low signal intensity in the upper tibia that corresponds to the abnormal bone on the plain radiograph. However, in addition, multiple lesions of low signal
intensity are seen throughout both femoral condyles and tibiae, indicating much more extensive disease than had been appreciated clinically and on skeletal radiographs.
830
The average age at presentation is 24 years; 50% of cases occur in
patients between 10 and 30 years of age. Males are affected more
often than females. Primary lymphoma affects the appendicular
skeleton involving the femur, tibia, and humerus, in descending
order of frequency. Primary lymphoma of bone accounts for about
1% of all NHL (227), and under 5% of cases of localized primary
extranodal lymphoma. Nearly all are DLBCL and patients typically
present with localized bone pain, with or without a palpable mass.
Secondary involvement of bones is present in 5% to 6% of patients
with NHL (226,227), although less present with symptoms due to a
skeletal lesion. Bone involvement is more frequent in children with
NHL (38). Radiographic evidence of bone involvement is present in
20% of patients, in HL appearing as the initial presentation in 4%
of cases (226). Systemic (secondary) NHL involves the axial
skeleton more frequently than the appendicular skeleton.
Appearances
Primary NHL of bone is radiologically indistinguishable from
systemic NHL, HL and other bone tumors. While the bone lesions
in NHL (primary or secondary) are usually permeative osteolytic
(77%) (Fig. 33.52), sclerotic in only 4% and mixed in 16%, bony
involvement in HL typically gives a sclerotic or mixed sclerotic
and lytic (86%) and infrequently lytic (14%) picture (228). Bone
scintigraphy is more sensitive than plain radiography, but MR is
the imaging modality of choice for staging and follow-up, depict-
ing the extent of marrow involvement and muscle infiltration
much more accurately (229,230). It has been suggested that FDG
PET is more sensitive and specific than bone scintigraphy, with a
high positive predictive value (PPV) for the detection of osseous
(B)
 lymphoma
involvement (231). There is also some evidence that FDG PET can
demonstrate response to treatment earlier and more accurately
than conventional modalities including MR (232).
In HL, soft tissue disease typically may involve adjacent bones;
anterior mediastinal and paravertebral masses frequently invade
the sternum and vertebrae, respectively, resulting either in destruc-
tion or scalloping. A classic finding is the sclerotic “ivory vertebra.”
Direct invasion of bone by local lymph node disease is denoted by
the suffix “E” added to the appropriate stage.
Because of the relatively low incidence of bone lesions at pre-
sentation, screening for bone involvement is not routine but is
reserved for patients with specific complaints.
Bone Marrow
Involvement of the bone marrow indicates Stage IV disease. It is
rare at presentation in HL but is found in 20% to 40% of patients
with NHL at presentation (128,233–237) and is associated with a
worse prognosis than involvement of the liver, lung, or osseous
bone (236). During the course of HL, marrow involvement occurs
in 5% to 15% of patients (237). Because of these figures, bone
marrow biopsies are not indicated as part of the initial staging of
early stage HL, but the high incidence in NHL justifies its use as a
staging procedure (238), increasing the stage in up to 30% of cases,
mainly from Stage III to Stage IV (238). Bone marrow involve-
(A) (B)
Figure 33.53 Bone involvement in a patient with NHL. (A) Normal skeletal radiograph in a patient with NHL and back pain. The radio-isotope scan was also normal.
(B) T1-weighted sagittal MR image showing loss of the normal high-signal intensity of fat in the body of L1 (arrowed). (C) Fast spin-echo T2-weighted sagittal MR image
showing areas of high-signal intensity within the body of L1 vertebra and also the body of S1 (arrowed). A bone biopsy of S1 showed involvement of the cortical bone as
well as of the bone marrow.
ment in low-grade NHL is typically diffuse but in intermediate-
and high-grade lymphoma it is more likely to be focal. Therefore,
not surprisingly, the performance of bilateral rather than single-
site biopsies increases the pick-up rate by up to 20% (239).
MR imaging is undoubtedly an extremely sensitive technique in
the demonstration of bone marrow involvement (Fig. 33.53). On
T1-weighted images, tumor infiltration is of low signal (Figs.
33.52 and 33.53) (240) and of high signal intensity on STIR. In
one recent study, T1-weighted spin-echo was the most sensitive
sequence, whereas fast STIR and echo-planar imaging (EPI)
sequences were most specific for infiltration (241,242). MR imag-
ing can upstage as many as 33% of patients with negative iliac
crest biopsies. Focal desposits as small as 5 mm can be identified
though false negative studies do occur with microscopic infiltra-
tion (under 5%) and low-grade lymphoma. Compared to CT,
whole-body MR can upstage nearly 20% of patients through dem-
onstration of bone marrow disease (237,240,241,243). Patients
with a positive MR study appear to have a poorer prognosis,
regardless of bone marrow biopsy findings (244).
FDG PET to date has shown reasonable sensitivity and specificity
for bone marrow disease. A small number of false negative PET
findings occur with low-grade lymphoma, often PET negative
elsewhere (245), or with microscopic infiltration. In one study, FDG
PET alone resulted in change of stage twice as often as bone marrow
(C)
831
 hematology malignancy
(A) (B)
Figure 33.54 Soft tissue involvement by lymphoma. (A) Coronal T1-weighted image, (B) coronal (B) and (C) axial T2-weighted images with fat suppression of the thigh
in a patient with massive lymphomatous infiltration of the medial and adductor compartment of the right thigh, with marked accompanying edema.
biopsy. In another, PET/CT changed stage in 21 of 50 patients com-
pared with combined CT and bone marrow biopsy and in 7 of the
21, this was significant (from early stage I or II to stage IV) (246). In
this study, a CT counterpart of the FDG-avid focus was rare, but the
CT facilitated confirmatory image-guided biopsy of the FDG-posi-
tive foci. However, FDG PET has not been shown to be consistently
reliable in detecting bone marrow involvement (247,248). A recent
meta-analysis of 13 studies of FDG PET in the evaluation of bone
marrow infiltration, including 587 patients and using bone marrow
biopsy as the reference standard, showed that only half the patients
with a positive bone marrow biopsy were detected by FDG PET,
whilst more than 90% of cases with a negative bone marrow biopsy
also had a negative PET scan (249).
Preliminary data suggest that superparamagnetic iron oxides
may have a role in the differentiation of normo- and hypercellular
marrow after treatment from persistent or residual infiltration, a
distinction which is difficult with conventional MR imaging and
FDG PET scanning (particularly if granulocyte colony-stimulating
factor has been administered) (250).
Despite the sensitivity (and in some cases specificity) of these
imaging techniques to detect bone marrow infiltration their pre-
cise role in the staging of patients with lymphoma has not yet
been defined, given the obvious need to examine the cytology of
bone marrow in these patients.
Soft Tissues
Soft tissue masses may develop in both HL and NHL, either as
tumor extension from bone involvement, or as an isolated mass
within the muscles. Primary muscle lymphoma is extremely rare
and is based on the absence of clinical or imaging features of lym-
phoma elsewhere. Patients with soft tissue lymphoma usually
present with pain or neurological deficit, but occasionally a pal-
pable mass may be present (251). The commonest radiological
manifestation is muscle enlargement secondary to diffuse infiltra-
tion, with or without regional adenopathy (252). Without ques-
tion, MR is the technique of choice for investigating patients with
persistent pain, and even though a mass may be detected in retro-
spect on CT, the lack of contrast between the mass and adjacent
muscle groups may lead to difficulties in diagnosis (Fig. 33.54).
832
(C)
Key Points: Bone and Bone Marrow
■ Primary lymphoma of bone accounts for only 1% of all cases
of NHL, whereas secondary involvement is seen in 5% to 6%
of cases
■ Secondary bone involvement is seen in 20% of patients with
HL. Primary HL of bone is extremely rare
■ In HL, soft tissue disease may invade adjacent bone but this
is rare in NHL
■ Bone marrow involvement indicates Stage IV disease and is
present in 20% to 40% of patients with NHL at presentation
■ Bone marrow biopsy in NHL increases the stage of
disease in up to 30% of cases (Stage III to IV)
■ In HL, bone marrow involvement occurs in 5% to 15% of
patients during the course of disease
■ Though FDG PET is more sensitive than CT or bone scintig-
raphy, false negative examinations occur with microscpic
infiltrations and low-grade lymphomas
■ MR is the method of choice for detecting soft tissue lym-
phomatous masses, which are usually due to secondary NHL
MUCOSA-ASSOCIATED LYMPHOID TISSUE
(MALT) LYMPHOMA
Whilst extranodal involvement can be seen in any subtype of
NHL, some forms of B-cell NHL occur exclusively in extranodal
locations—the extranodal marginal zone lymphomas. They rep-
resent around 8% of all types of lymphoma and, for convenience,
are divided into MALT types and generic types (31,32).
Pathology and Clinical Features
The MALT lymphomas arise from mucosal sites that normally have
no organized lymphoid tissue, but within which acquired lymphoid
tissue has arisen as a result of chronic inflammation or autoimmu-
nity. Examples include Hashimoto’s thyroiditis, Sjögren’s syndrome
and Helicobacter-induced chronic follicular gastritis. The associa-
tion between gastric MALT lymphoma and H. pylori infection was
 lymphoma

established in 1991 by Wotherspoon et al. (253), who found the

organism in over 90% of cases. The detectability of H. pylori has
been shown to diminish as lymphoma evolves from chronic gastri-
tis (254). Remission of gastric MALT lymphoma can be achieved in
over 60% of patients treated with antibiotics against H. pylori.
Patients with Sjögren’s syndrome or lymphoepithelial sialadeni-
tis have 44 times the risk of developing lymphoma, of which over
80% is MALT type. Patients with Hashimoto’s thyroiditis have a
70-fold increased risk of thyroid lymphoma.
The histological hallmark of MALT lymphoma is the presence
of lymphomatous cells in a marginal zone around reactive folli-
cles, which can spread into the epithelium of glandular tissues to
produce the characteristic lymphoepithelial lesion. In up to 30%,
transformation to large cell lymphoma occurs, for example in the
stomach.
The commonest site of involvement is the GIT (50% of cases),
within which the stomach is most often affected (around 85% of
cases). The small bowel and colon are involved in immunoprolif-
erative small intestinal disease (IPSID), previously known as
alpha-chain disease. Other sites commonly affected include the Figure 33.55 MALT lymphoma of the stomach. Endoscopic ultrasound examina-
lung, head, neck, ocular adnexae, skin, thyroid, and breast. tion showing a submucosal mass of low reflectivity (arrowed).
Most cases occur in adults with a median age of 60 and there is
a slight female preponderance. Most patients present with stage IE
or IIE disease, which tends to be indolent. Bone marrow involve-
ment is seen in 20%, but the frequency varies depending on the be indolent, whether nodular or consolidative. Associated pleural
primary site, being higher with MALT lymphoma of the lung and effusions occur in up to 20%.
ocular adnexae. Multiple extranodal sites are involved in up to
10%, but this does not appear to have the same poor prognostic Other Sites
import as in other forms of NHL, as it may not reflect truly In the thyroid, MALT lymphomas can present as diffuse enlarge-
disseminated disease (255). Nonetheless, extensive staging ment or as large nodules that are hypoechoic at US and relatively
investigations may be necessary (185). hypodense at CT.
Mucosa-associated lymphoid tissue lymphomas of the lacri-
Imaging Features mal glands present as a mass or periorbital swelling. As with
GI Tract gastric MALT lymphoma, regional lymph node involvement is
Often gastric MALT lymphoma, especially low grade, causes common in salivary gland MALT lymphomas. CT and MR
minimal mucosal thickening, and CT may be normal (183), even depict uni- or bilateral enhancing masses with a non-specific
if dedicated gastric CT is carried out with an oral water load appearance.
and IV smooth muscle relaxants (256). It has been suggested that Up to 20% of lymphomas involving Waldeyer’s ring are of
low-grade MALT lymphoma is more likely to cause shallow ulcer- MALT type. The tonsils are most commonly affected, the com-
ation and nodulation, whereas higher grade ones are more likely monest pattern being asymmetric thickening of the pharyngeal
to produce more massive gastric infiltration and polypoid masses mucosa. This is well shown by CT and MR.
(257). Endoscopic US is more accurate than CT pre- and post-
treatment, defining wall depth and lymph node involvement
Key Points: MALT Lymphoma
(Fig. 33.55) (184,258). In addition, staging with EUS can help
predict response to treatment of H. pylori (259). ■ These arise from mucosal sites that normally have no organized
In the colon and small bowel, MALT lymphoma is manifest lymphoid tissue, but arise as a result of chronic inflammation
as mucosal nodularity, which can be appreciated in barium or autoimmunity
studies (260). ■ The commonest site of involvement is the GI tract; the stomach
is involved in 85% of cases
Respiratory Tract ■ Other sites include the thyroid (Hashimoto’s), respiratory
Mucosa-associated lymphoid tissue or BALT lymphoma repre- tract, and lacrimal gland (Sjögren’s)
sents 60% of all primary pulmonary lymphomas. The radiological
pattern is similar to that of other lymphomas, being quite variable.
The commonest patterns are masses, areas of consolidation and BURKITT LYMPHOMA (BL)
nodules with or without air bronchograms, and the CT angio-
gram sign (144,261–263). Multiple lesions are present in up to Burkitt lymphoma is a highly aggressive B-cell variant of NHL,
80% of cases and lesions are often bilateral. Peribronchovascular associated with EBV in a variable proportion of cases. Nearly all
nodularity and thickening is much less common. Lesions tend to have genetic translocations involving the c-myc oncogene.

833
 hematology malignancy
Three clinical variants are recognized:
• Endemic (African) type (264)–EBV positive in 50% to 70%
• Sporadic (non-endemic) (265)–EBV positive in 15%
to 20%
• Immunodeficiency associated
These tumors are extremely aggressive and rapidly growing, but
they are potentially curable. Though they account for only 2% to
3% of NHL in immunocompetent adults, 30% to 50% of all child-
hood lymphomas are BL. Immunodeficiency associated BL is seen
chiefly in association with HIV infection and may be the initial
manifestation of AIDS. EBV is identified in up to 40% of these
cases. Extranodal disease is common and all three variants are at
risk for CNS disease (266).
In the endemic form, the jaws, maxilla, and orbit are involved in
50% of cases, producing the “floating tooth sign” on plain radio-
graphy. The ovaries, kidneys, and breast may be involved. The
sporadic forms have a predilection for the ileocecal region and
patients can present with acute abdominal emergencies such as
intussusception. Again, ovaries, kidneys, and breasts are commonly
involved. Retroperitoneal and paraspinal disease can cause para-
plegia, the presenting feature in up to 15% of affected individuals.
Thoracic disease is relatively rare; in a recent series, 50% had dis-
ease confined to the abdomen (267). Leptomeningeal disease can
be seen at presentation and is a site of relapse.
LYMPHOMA IN THE IMMUNOCOMPROMISED
(SEE ALSO CHAPS. 57–60)
The WHO classification recognizes four broad groupings asso-
ciated with an increased incidence of lymphoma and lympho-
proliferative disorders (268):
• Primary immunodeficiency syndromes
• Infection with HIV
• Iatrogenic immunosuppression after solid organ or bone
marrow allografts
• Iatrogenic immunosuppression from methotrexate
(usually for autoimmune disorders)
The development of lymphoma in these settings is multifactorial,
but mostly related to defective immune surveillance, with or
without chronic antigenic stimulation.
AIDS-Related Lymphomas (ARL)
(See also Chaps. 59 and 60)
The incidence of all subtypes of NHL is increased 60 to 200 fold in
patients with HIV, and lymphoma is the first AIDS-defining ill-
ness in up to 5% of HIV patients. The incidence of HL is also
increased up to eight-fold. Various types of NHL are seen, includ-
ing those seen in immunocompetent patients, such as BL, DLBCL
(especially in the CNS), but some occur much more frequently in
the HIV population (e.g., primary effusion lymphoma and plas-
mablastic lymphoma of the oral cavity). Compared with non-HIV
associated high-grade NHL, the prognosis is poorer with more
frequent relapses and shorter overall survival. Since the advent of
highly active antiretroviral therapy (HAART), the incidence of
ARL have decreased from 6.2 to 3.6 per 1000 person-years (11),
834
but despite this, the proportion of patients for whom NHL is
AIDS-defining has increased (269).
Most ARL have a marked propensity to involve extranodal sites,
especially the GI tract, CNS (less frequent with the advent of
highly active antiretroviral therapy), liver, and bone marrow.
Multiple sites of extranodal involvement are seen in over 75% of
cases (270). Peripheral lymph node enlargement is seen in only
30% of cases at presentation.
Most tumors are aggressive, with advanced stage bulky disease
and a high serum LDH at presentation. DLBCL tends to occur later
on, when CD4 counts are under 100 ×106/L, whereas BL occurs in
less immunodeficient patients. EBV positivity occurs in up to 70%
of cases depending on the precise morphological variant, whereas
PCNSL is associated with EBV in over 90% of cases; interestingly,
EBV positivity is seen in nearly all cases of HL associated with HIV.
In the chest, NHL is usually extranodal; pleural effusion and
lung disease are common, often with nodules, acinar and intersti-
tial opacities. Hilar and mediastinal nodal enlargement is gener-
ally mild. There is a wide differential diagnosis and in one study
the presence of cavitation and nodal necrosis predicted for myco-
bacterial infection rather than lymphoma (271).
Within the abdomen, the GI tract, liver, kidneys, adrenal glands,
and lower genitourinary tract are commonly involved. Mesenteric
and retroperitoneal nodal enlargement is less common than in
immunocompetent patients, but there are no apparent differences
in the CT features of patients with or without AIDS, at least in
relation to the small bowel (186).
Regarding PCNSL, certain features such as rim enhancement and
multifocality are seen more often than in the immunocompetent
population. This can cause confusion with cerebral toxoplasmosis,
though the location of PCNSL in the deep white matter is sugges-
tive (272). Quantitative FDG PET uptake can help in the differen-
tiation of PCNSL, toxoplasmosis and progressive multifocal
leucoencephalopathy (PML), being higher in the former (273).
Post-Transplant Lymphoproliferative Disorders
(Fig. 33.56)
These occur in 2% to 4% of solid organ transplant recipients
depending on the type of transplant, the lowest frequency being
seen in renal transplant recipients (1%) and the highest in heart–
lung or liver–bowel allografts (5%). Marrow allograft recipients
in general have a low risk (1%). Most are associated with EBV
infection and appear to represent EBV-induced monoclonal or,
more rarely, polyclonal B-cell or T-cell proliferation in a setting
of reduced immune surveillance as a consequence of immune
suppression. The clinical features are variable, correlating with
the type of allograft and type of immunosuppression. Post-trans-
plant lymphoproliferative disorders develop earlier in patients
receiving cyclosporin A (mean interval 15 months) rather than
azathioprine (mean interval 48 months). Epstein–Barr-positive
cases occur earlier than EBV-negative cases, the latter occurring
four to five years after transplantation. In all cases, extranodal
disease is common. In patients receiving azathioprine, the
allograft itself and the CNS are often involved, whereas in patients
who have received cyclosporin A, the GI tract is affected more
often than the CNS. The bone marrow, liver, and lung are often
affected, as are the tonsils.
 lymphoma
(A)
Figure 33.56 Post-transplant lymphoproliferative disorder of the liver. (A) CT scan in patient with known autosomal dominant cystic disease of the kidneys who under-
went a renal transplant (see B). Multiple lymphomatous foci are demonstrated within the liver (arrowed) together with the associated benign liver cysts. Note the associ-
ated ascites and the cystic disease of the native left kidney. (B) Renal transplant in the left iliac fossa. A large mesenteric mass is also demonstrated (arrowed) together
with infiltration of the small bowel.
In the lung, multiple or solitary pulmonary nodules occur, with
or without mediastinal adenopathy. Pleural effusions are common
and confluent; patchy airspace opacity is another pattern (274–276).
Reticulonodular opacity is rare.
Abdominal PTLD is characterized by a relatively high fre-
quency of extranodal disease, especially of the GI tract and liver
(Fig. 33.56). Multiple segments of bowel may be affected and
there is a propensity for PTLD to develop in the allograft itself
(277,278).
Key Points: Lymphoma in the Immunocompromised
■ Lymphomas associated with HIV have a propensity to involve
extranodal sites (especially the GI tract, CNS, liver, and bone
marrow) and multiple sites. Most tumors are aggressive with
advanced stage, bulky disease
■ Post-transplant lympoproliferative disorder occurs in 2% to
4% of solid organ and 1% of marrow allograft recipients and
typically causes solitary or multiple lung nodules. In the
abdomen this disorder is characterized by involvement of the
GI tract and liver
POST-TREATMENT EVALUATION
With the advent of FDG PET and now FDG PET/CT, there has
been a paradigm shift in response assessment in lymphoma.
Before the introduction of FDG PET into clinical practice, CT was
the main tool available for this purpose. Cross-sectional imaging
still plays a vital role in monitoring response to therapy during
and at the end of treatment. Once treatment is completed, peri-
odic surveillance studies help in detection of potential relapse.
Where there is clinical evidence of relapse, imaging studies are
performed to evaluate the extent of the disease.
Monitoring Response to Therapy
Achievement of a complete remission following treatment is the
most important factor for prolonged survival in both HL and
(B)
NHL. Thus, final evaluation of response at or within one month
of completion of therapy is critical.
“Complete remission” is diagnosed only when no abnormality is
seen at the site of previously demonstrated disease. The chest radio-
graph is useful in assessing response when there is intrathoracic dis-
ease and is repeated at each monthly visit. Although the chest
radiograph will show response early in the treatment, changes due to
radiotherapy often make the mediastinum difficult to assess. Other
mediastinal changes associated with treatment such as rebound
hyperplasia or thymic cyst formation cannot be reliably identified on
the chest radiograph and therefore response cannot be monitored
reliably. CT therefore remains essential in the monitoring of response
to treatment for mediastinal disease, especially when the chest radio-
graph is indeterminate (279). In patients with intra-abdominal dis-
ease, serial CT is essential in monitoring response. For the purpose of
assessment of response to treatment, it is often necessary to measure
a number of marker lesions before and after therapy. Modern CT
scanners permit accurate reproducible measurements of well defined
nodal masses provided scan parameters (narrow collimation slices,
with overlapping reconstructions) and techniques are optimized.
However, there is significant interobserver variation, which is even
more pronounced with irregular masses or when there is poor
lesion–background contrast, which may occur even with adequate
bowel and vascular opacification (280).
The optimal and exact timing of such scans for reassessment has
not been widely investigated (281,282). In many centers, the prac-
tice is to assess patients fully one month after completion of therapy.
Others favor an interim CT study during initial chemotherapy for
lymphoma after two cycles of chemotherapy; the timing will often
depend on local clinical practice, the availability of resources, and
on whether the patient is participating in a clinical trial. The speed
of modern CT scanners has largely removed the need for limited
scans advocated in the past, and though it has been argued that
routine administration of IV contrast medium is unnecessary for
follow-up scans, in practice, multislice technology allows the acqui-
sition of scans with optimal vascular and parenchymal enhance-
ment throughout the neck, chest, abdomen, and pelvis, facilitating
follow-up of nodal and particularly, extranodal disease.
835
 hematology malignancy
Criteria of Response
International standardized response criteria are essential for clini-
cal research, facilitating data interpretation and comparison of
therapies. A report published in 1999 set out new criteria for
assessment of response in NHL, bringing it into line with those
already in use for HL (283). The International Workshop radio-
logical criteria (IWC) are defined as follows:
• Complete remission (CR): complete disappearance of all
radiographic evidence of disease. Nodes and nodal masses
of disease regressed to <1.5 cm in greatest transverse diam-
eter for nodes >1.5 cm before therapy. Previously involved
nodes 1.1 to 1.5 cm in greatest transverse diameter regressed
to <1 cm in greatest transverse diameter after therapy. The
spleen, if enlarged by CT criteria, must have regressed
• Complete remission, unconfirmed (CRu): where there is
a residual nodal mass >1.5 cm maximum transverse
diameter that has regressed by >75% of sum of products
of greatest diameters (SPD)
• Partial remission (PR): >50% decrease in SPD of largest
nodes/masses. No increase in size of spleen, lymph nodes,
liver. Splenic and hepatic nodules decreased by 50%
• Stable disease (SD): decrease in SPD less than a PR and
no evidence of progressive disease
• Progressive disease (PD): 50% or greater increase from
nadir in the SPD of any previously identified abnormal
node for PRs or non-responders—appearance of any
new lesion during or at the end of therapy
• Relapse from CR or CRu requires: appearance of any new
lesion or increase by 50% or more in the size of previ-
ously involved sites. Fifty percent increase in greatest
diameter of any previously identified node >1 cm in its
short axis or in the SPD of more than one node
Assessment of Residual Masses
Although successfully treated enlarged nodes often return to
normal, in HL and NHL a residual mass of “sterilized” fibrous
(A)
Figure 33.57 A residual mediastinal mass in a patient treated for HL. (A) CT scan. (B) Conventional spin-echo T2-weighted MR image. The residual mass (m) measures
approximately 5 × 5 cm in diameter and has a homogeneous intensity, suggesting that the mass is inactive. A CT-guided core biopsy was obtained. On histological
examination there was no evidence of active HL.
836
tissue can persist. On a chest radiograph such a residual mass may
remain following treatment in 12% to 88% of patients (284). Such
residual masses occur more frequently in patients with bulky
rather than non-bulky disease, in HL and NHL. Residual masses
are seen at CT in up to 20% to 50% of patients in clinical CR after
treatment for NHL (285,286). It is uncertain whether relapse is
more common in patients with residual masses; the literature on
this subject is conflicting (282,287). There is no obvious correla-
tion between the size of the residual mass and the relapse rate.
Determining the nature of such residual masses and excluding the
possibility of active disease by imaging remains a major challenge
in monitoring patients with lymphoma.
Computed Tomography
Using the International Workshop criteria, residual masses at CT
are those that have reduced by up to 75% but which are none-
theless more than 1.5 cm in maximum transverse diameter
(Fig. 33.14). CT cannot distinguish between fibrotic tissue, necro-
sis, and residual active disease on the basis of density alone, hence
the very low specificity and PPV of CT after treatment in every
series published to date. Nevertheless, serial CT performed every
two to three months has been the most widely used method of
determining the true nature of a residual mass. Masses that remain
static after one year are considered to be inactive, whereas any
increase in size is highly suggestive of relapse. Relapse following
satisfactory response to initial treatment occurs in 10% to 40% of
patients with HL and in around 50% of patients with NHL (126).
In HL, relapse usually occurs within the first two years following
treatment and patients are followed up closely during this period,
although CT examinations are not usually required unless clinical
features suggest the possibility of recurrence.
Magnetic Resonance Imaging
There is now substantial data investigating the value of MR in identi-
fying residual active neoplasm within residual masses (71,72,288,289).
In general, a reduction in signal intensity on T2-weighted images
is seen during or following successful treatment (Fig. 33.57).
(B)
 lymphoma
Persistent heterogeneous or recurrent high signal intensity on
T2-weighted sequences following treatment appears to have a
high specificity and PPV for residual active disease (289). False
positives do arise due to inflammatory edema or cyst formation
(117,288,290). However, not surprisingly, the sensitivity for the
detection of active disease is low, as small foci of persistent tumor
within a low signal intensity mass cannot be identified reliably on
T2-weighted images (71,72,290). Furthermore, with increasing
availability of PET/CT, it is likely that this modality will supercede
MR in the assessment of the residual mass.
Functional Imaging
In the past decade, there has been an explosion of interest in the use
of functional imaging (notably, FDG PET) for response assessment
and evaluation of the residual mass. Gallium scintigraphy is no
(A) (B)
(D)
(C)
Figure 33.58 A PET negative residual mass (same patient as in Fig. 33.11C). (A) Axial CT component of PET/CT demonstrates a residual anterior mediastinal mass.
(B) Axial FDG-PET scan. (C) Coronal FDG-PET scan. (D) Fused axial image. There is no significant metabolic activity within the residual mass.
longer the investigation of choice in this setting. Though persistent
positive uptake usually indicates persistent active neoplasm (reflected
in a PPV for relapse double that of CT) (291,292), the value of gal-
lium scanning is limited by both its lower sensitivity and specificity,
by the significant proportion of non-gallium-avid tumors, and by
the imaging characteristics of the isotope (82,291). Furthermore, the
radiation dose imparted is much higher than that from a PET scan.
Indeed, in a recent study of patients with HL and residual mediasti-
nal masses, there was a non-significant trend towards greater accu-
racy with MR compared to Ga-67, with greater predictive powers for
two year progression-free survival (293). For all these reasons, Ga-67
today is not widely used to evaluate the residual mass.
On the other hand, FDG PET has been shown to have a high
predictive value in the differentiation between active tumor and
fibrosis in patients with a residual mass (Figs. 33.58 and 33.59) (80).
837
 hematology malignancy

(A) (B)

(C) (D)

Figure 33.59 A PET-positive residual mass in a patient with primary mediastinal large B cell lymphoma. (A) Pre-treatment axial contrast-enhanced CT scan. (B) Post-
treatment CT component of PET/CT scan demonstrates an irregular residual mass. (C) The axial FDG-PET scan demonstrates a focus of intense metabolic activity
within part of the residual mass. (D) Fused image. The focus of residual disease involves the chest wall. Symmetrical moderate activity around the costo-transverse joints
posteriorly is within brown fat.

Indeed, FDG PET has a high PPV for relapse, with or without a
residual mass at CT, allowing directed biopsies, or consolidative
therapy as appropriate (294–300). There are a few pitfalls in
that small volumes of disease can produce false negative exami-
nations (in around 5%), whereas reactive and inflammatory
changes (for example in the lungs, thymus, and bone marrow)
are causes of false positive examinations. Thus, it is essential
that clinical correlation be made when interpreting FDG PET
results (301). In one study directly comparing Ga-67 and FDG
PET, the latter was more sensitive, and though there were more
false positive findings with FDG PET, these were readily inter-
preted as such when reference was made to the clinical history
and other findings (302).
FDG PET in Response Assessment
Generally, a positive FDG PET scan at the end of therapy strongly
predicts for early relapse (298) for HL and NHL. In one follow-
up study, all PET-positive/CT-negative patients relapsed, whereas
only 5% of PET-negative/CT-positive patients relapsed (303).
Jerusalem and colleagues showed the PPV of FDG PET to be
100%, compared with 42% for CT, in the post-treatment assess-
ment of patients with HL or NHL (297). In a similar study
including 93 patients with NHL, Spaepen et al. demonstrated
the predictive value for progression-free survival (PFS) of FDG
PET at the end of first-line therapy, with a two year PFS of 4%
for patients with a positive FDG PET, compared with 85% for
patients with a negative FDG PET (304). Ultimately, all patients
with a positive PET scan relapsed, but under 50% of relapses
would have been predicted by conventional imaging. Similar
results were reported by the same group in patients with HL, two
year PFS being 0% for patients with a positive FDG PET in com-
parison with 91% for the group with a negative FDG PET (305).
Incorporation of the end-of-treatment FDG PET scan result
into the standard response criteria has a significant impact on
response categorization. In a retrospective study of 54 patients
with DLBCL treated with CHOP, and followed up for 18 months,
Juweid et al. found that the assessment based on IWC and PET
provided a more accurate response classification that correlated
better with clinical outcome than the standard response criteria
(306). Patients with a PR by standard IWC, who were FDG PET
negative, did as well as those who were in CR by IWC and IWC
and PET, indicating superior discriminative ability. The category
CRu was abolished by the inclusion of FDG PET.
As a result of the increasing evidence for the use of FDG PET in
response assessment, an International Harmonization Project was
convened to revise the standard response criteria (307). These
guidelines support the use of FDG PET for end of therapy response
assessment in DLBCL and HL. However, they state that the role

838
 lymphoma
of FDG PET for response assessment of “aggressive” NHL subtypes
other than DLBCL and “indolent” lymphomas is less clear-cut,
and that FDG PET should be used only if overall response rate
and CR rate are important end-points of clinical studies. The
revised criteria specify that patients can be assigned to the CR cat-
egory with a residual mass of any size, provided that it is PET
negative at the end of treatment and was, or can reasonably
expected to have been, FDG PET positive before treatment. The
CRu category is eliminated. For patients with FDG-avid lympho-
mas, a partial response exists where there is residual FDG PET
positivity in at least one previously involved site. The group has
also issued guidance on performance and interpretation of FDG
PET scans (308).
FDG PET in Prognostication
One of the most exciting applications of FDG PET scanning is
in early prediction of response to treatment, which is quite dif-
ferent from assessment of treatment response after completion
of therapy. Prediction of response refers to FDG PET imaging
after one or two cycles of systemic therapy. Early prediction of
response to treatment may be of value in the identification of
patients who are unlikely to respond, allowing early discon-
tinuation of ineffective therapy before toxicity has resulted
(309). Several studies have shown early FDG PET (after 2 or 3
cycles of chemotherapy) in “aggressive” NHL to be a more
accurate predictor of PFS and overall survival than other
known prognostic indictors, such as the IPI, especially for dif-
fuse histologies (294,310). Haioun et al. found that PFS at two
years was 82% for patients with a negative interim FDG PET,
whereas it was 43% for patients with a positive FDG PET (311).
Similar studies of early interim FDG PET in patients with HL
have also shown a strong association between FDG PET result
after two to three cycles and PFS and overall survival (OS)
(312,313). There is some evidence that FDG PET performed
after just one cycle of chemotherapy has high prognostic value
both in DLBCL and HL, but the optimum timing of early
response assessment still needs to be evaluated in larger studies
with longer follow-up (314).
Most of these studies have used qualitative interpretation of
FDG uptake and there is limited data utilizing quantitative
assessment. Calculation of standardized uptake values (SUV) by
normalization of tumor FDG uptake to injected activity and body
weight is the most common method for tumor quantification.
Naumann and colleagues reported that a cut-off of 3.0 for the
SUV was able to differentiate between active lymphoma and ster-
ile residual masses with a sensitivity of 100% and a specificity of
93% (298). The percentage reduction in SUV from baseline may
also be used to differentiate responders from non-responders.
Thus, Torizuka et al. clearly separated responders from the non-
responders using a 60% reduction in the SUV from baseline to
post one to two cycles of chemotherapy (315). At present, there is
no consensus on which method should be used for early predic-
tion of response, and therefore, interim FDG PET should only be
performed as part of a clinical trial.
FDG PET can also be used to predict outcome prior to high-
dose treatments (316). Patients who commence high-dose
therapies with a positive pre-treatment PET scan have a much
poorer prognosis.
Key Points: Functional Imaging
■ Residual masses are seen in up to 50% of patients successfully
treated for HL and NHL
■ Functional imaging with FDG PET distinguishes between
residual disease and sterilized fibrous tissue much more
accurately than anatomical cross-sectional imaging
■ Incorporation of end-of-treatment PET result into the
standardized response criteria for NHL improves correlation
with clinical outcome
■ Early interim PET scans after one to two cycles of treatment
for aggressive NHL can confer important prognostic
information
■ A positive FDG PET scan at completion of therapy predicts
for early relapse and reduced progression-free survival,
regardless of the CT findings
Follow-up and Surveillance
Strategies for follow-up with imaging vary between institutions
and, in addition, in patients with residual masses in HL and NHL,
follow-up depends on the size of the mass, the sites of involvement,
and the extent of disease. It is therefore impossible to define strict
guidelines for each clinical situation.
For patients who attain CR or CRu (i.e., where there is a Ga-67
or a FDG PET-negative residual mass), it has been argued that
routine imaging is desirable to detect asymptomatic early relapse,
so that salvage therapy can be offered. In this situation, CT may be
of limited value, since it may take some time before there is an
appreciable increase in the size of the residual mass.
In one series of patients with NHL who attained CR, only two of
36 relapses were diagnosed before patients were symptomatic, and
only one was identified by imaging alone. This study did not
include functional imaging. Of the relapses, 25% were in new sites
alone, whereas the previous site was involved in the remainder
(317). Front et al. (79) found that Ga-67 scintigraphy indicated
relapse on average seven months before the development of clini-
cal signs or an abnormality on CT and in this setting, the sensitiv-
ity of Ga-67 was 95%. In another study, the quoted sensitivities
and specificities for recurrence were 59% and 72% for CT, and
88% and 100% for Ga-67, respectively (318).
There are other studies suggesting that conventional imaging
follow-up with CT is rarely rewarding. Radford et al. found that
86% of relapses in a cohort of patients with HL were detected as a
result of investigation of new symptoms rather than by routine
follow-up studies (319), and Guadagnolo et al. calculated that
there was very little benefit from routine CT in the surveillance of
asymptomatic patients in CR after treatment for HL (320). In
another series of patients with treated intermediate and high-
grade NHL, only 17% of relapses were detected by routine CT
(13%) or laboratory tests (4%) alone (321).
Given the wealth of comparative data consistently showing a
higher sensitivity for FDG PET in the detection of disease com-
pared to CT, especially at extranodal sites, and the lower radiation
dose (9 mSv vs. 30 mSv), there are theoretical reasons for choosing
PET as a routine surveillance procedure—but there is as yet little
evidence to support the role of PET in this situation. Jerusalem
et al. evaluated FDG PET in the detection of preclinical relapse in
839
 hematology malignancy

(A) (B)

(C)

(D) (E)

Figure 33.60 Relapsed high-grade NHL. (A) Axial CT component of PET/CT scan.(B) Corresponding FDG-PET scan. (C) Fused dataset. There are renal and
adrenal FDG-avid masses as well as a small coeliac axis lymph node which also displays moderate activity. (D) Coronal FDG-PET scan and (E) corresponding
fused dataset demonstrate nodal and extranodal relapse in multiple supra- and infradiaphragmatic nodal groups, the lungs, major viscera and also within the
musculature of the thigh.

a cohort of patients treated for HL (322). In this series, all relapses
were identified by PET before there was any other evidence of
relapse. There was a significant number of false positive scans but
in each of these, a confirmatory scan four to six weeks later was
normal, and there were no false negative studies. In this setting,
FDG PET will only be useful if there is a survival advantage to be
gained from starting salvage therapy sooner rather than later, and
if the rate of false positive studies is acceptably low. However, in
cases of suspected relapse, the development of a positive PET scan
is highly suggestive (Fig. 33.60). There is a need for multicenter
prospective randomized trials to establish the role, if any, of
routine imaging surveillance of asymptomatic patients.
Role of Percutaneous Biopsy
Percutaneous core biopsy using imaging guidance is now
established as a valuable method of determining the nature of
soft tissue masses in lymphoma. The indications for its use
include:
• Defining the nature of a residual mass following
treatment
• Detection of transformation of NHL to a higher grade
(323,324)
• Primary diagnosis in patients who present with unusual
manifestations of disease

840
 lymphoma
Two large studies have demonstrated that core biopsy is sufficient
for management in just under 90%, enabling around 80% to avoid
open surgical biopsy (324,325)
Key Points: Post-Treatment Evaluation
■ Achievement of CR following treatment is the most impor-
tant prognostic indicator in both HL and NHL
■ Relapse following initial treatment occurs in up to 40% of
patients with HL and over 50% of patients with NHL
■ Relapse usually occurs within the first two years following
treatment of HL
■ Residual masses in HL and NHL may contain active malig-
nancy that cannot be detected on anatomical cross-sectional
imaging alone
■ Functional imaging with FDG-PET is more accurate than
CT in early and late assessment of response to treatment
Summary
■ NHL and HL are a heterogeneous diverse group of malig-
nancies that predominantly involves the lymph nodes
■ In HL, most patients present with early-stage malignancy,
whereas in NHL most patients present with advanced disease
■ The incidence of NHL is increasing but the incidence of HL
is stable
■ In NHL, the prognosis varies widely according to tumor
grade and stage at diagnosis
■ HL tends to spread from one lymph node to the next in a
contiguous manner, whereas NHL spreads in a more haphaz-
ard manner
■ Involvement of intrathoracic lymph nodes is more common
in HL than NHL
■ Involvement of retroperitoneal and mesenteric nodes is more
common in NHL than HL
■ Extranodal sites of involvement are more common in NHL
than HL
■ The spleen is involved in 10% of patients with HL as
isolated infradiaphragmatic disease
■ Splenomegaly is an unreliable indicator of splenic lymphoma
■ Primary extranodal lymphoma is almost exclusively seen
in NHL
REFERENCES
1. Reznek RH, Richards MA. The radiology of lymphoma.
Baillière’s Clin Haematol 1987; 1: 77–107.
2. CancerStats—Incidence UK. Cancer Research UK, February
2008.
3. Callender ST, Vaneghan RI. The lymphomas. In: Weatherall
DJ, Ledingham JG, Warrell DA, eds. Oxford Textbook of
Medicine. Oxford: Oxford University Press, 1983: 160–74.
4. Jemal A, Siegel R, Ward E, et al. Cancer Statistics, 2008. CA
Cancer J Clin 2008; 58: 71–96.
5. Ries LA, Kosary CL, Hankey BF, et al. SEER Cancer Statistics
Review, 1973–1996. Bethesda, MD: National Cancer Institute,
1999.
6. Devesa SS, Fears T. Non-Hodgkin’s lymphoma time trends:
United States and international data. Cancer Res 1992; 52:
5432s–5440s.
7. Muir C, Waterhouse J, Mack T, et al. Cancer incidence in
five continents, Vol V. IARC Scientific Publication 42. Lyon:
International Agency for Research on Cancer, 1987.
8. Cartwright R, Brincker H, Carli PM, et al. The rise in inci-
dence of lymphomas in Europe 1985–1992. Eur J Cancer
1999; 35: 627–33.
9. Rabkin CS, Devesa SS, Zahm SH, Gail MH. Increasing incidence
of non-Hodgkin’s lymphoma. Semin Hematol 1993; 30: 286–96.
10. Banks PM. Changes in diagnosis of Non-Hodgkin’s lympho-
mas over time. Cancer Res 1992; 52: 5453s–5455s.
11. International collaboration on HIV and cancer. Highly active
antiretroviral therapy and the incidence of cancer in HIV-
infected adults. J Natl Cancer Inst 2000; 92: 1823–30.
12. Hartge P, Devesa SS. Quantification of the impact of known
risk factors on time trends in non-Hodgkin’s lymphoma
incidence. Cancer Res 1992; 52: 5566s–5569s.
13. Barnes N, Cartwright RA, O’Brien C, et al. Rising incidence
of lymphoid malignancies—true or false? Br J Cancer 1986;
53: 393–8.
14. Glass AG, Karnell LH, Menck HR. The National Cancer Data
Base report on non-Hodgkin’s lymphoma. Cancer 1997; 80:
2311–20.
15. Horwich A. Hodgkin’s disease. In: Horwich A, ed. Oncology:
A Multidisciplinary Textbook. London: Chapman and Hall,
1995: 235–50.
16. Kuefler PR, Bunn PA Jr. Adult T cell leukaemia/lymphoma.
Clin Haematol 1986; 15: 695–726.
17. De la Fouchardiere A, Vandenesch F, Berger F. Borrelia-
associated primary cutaneous MALT lymphoma in a non-
endemic region. Am J Surg Pathol 2003; 27: 702–3.
18. Skibola CF, Curry JD, Nieters A. Genetic susceptibility to
lymphoma. Haematologica 2007; 92: 960–9.
19. Ballerini P, Gaidano G, Gong JZ, et al. Multiple genetic lesions
in acquired immunodeficiency syndrome-related non-
Hodgkin’s lymphoma. Blood 1993; 81: 166–76.
20. Cleary ML, Sklar J. Lymphoproliferative disorders in cardiac
transplant recipients are multiclonal lymphomas. Lancet
1984; 2: 489–93.
21. Filipovich AH, Mathur A, Kamat D, Shapiro RS. Primary
immunodeficiencies: genetic risk factors for lymphoma.
Cancer Res 1992; 52(19 Suppl): 5465s–5467s.
22. Osborne BM. Contextual diagnosis of Hodgkin’s disease and
non-Hodgkin’s lymphoma. Radiol Clin North Am 1990; 28:
669–82.
23. Lukes RJ, Butler JJ. The pathology and nomenclature of
Hodgkin’s disease. Cancer Res 1966; 26: 1063–83.
24. Lukes RJ, Craver LF, Hall TC, et al. Report of the Nomen-
clature Committee. Cancer Res 1966; 26: 1311.
25. National Cancer Institute sponsored study of classifications
of Non-Hodgkin’s lymphomas: summary and description of
a working formulation for clinical usage. The Non-Hodgkin
Lymphoma Pathologic Classification Project. Cancer 1982;
49: 2112–35.
26. Rosenberg SA, Diamond HD, Jaslowitz B, Craver LF. Lym-
phosarcoma: a review of 1269 cases. Medicine 1961; 40: 31–84.
841
 hematology malignancy
27. Rappaport H. Tumors of the hematopoietic system. In: Atlas
of Tumor Pathology. Section 2, Fascicle 8. Washington, DC:
Armed Forces Institute of Pathology, 1966.
28. Cossman J, Uppenkamp M, Sundeen J, Coupland R, Raffeld M.
Molecular genetics and the diagnosis of lymphoma. Arch
Pathol Lab Med 1988; 112: 117–27.
29. Harris NL, Jaffe ES, Stein H, et al. A revised European-
American classification of lymphoid neoplasms: a proposal
from the International Lymphoma Study Group. Blood 1994;
84: 1361–92.
30. Harris NL, Jaffe ES, Diebold J, et al. World Health Organiza-
tion classification of neoplastic diseases of the hematopoietic
and lymphoid tissues: report of the Clinical Advisory Com-
mittee meeting—Airlie House, Virginia, November 1997.
J Clin Oncol 1999; 17: 3835–49.
31. A clinical evaluation of the International Lymphoma Study
Group classification of non-Hodgkin’s lymphoma. The Non-
Hodgkin’s Lymphoma Classification Project. Blood 1997;
89: 3909–18.
32. Armitage JO, Weisenburger DD. New approach to classifying
non-Hodgkin’s lymphomas: clinical features of the major
histologic subtypes. Non-Hodgkin’s Lymphoma Classification
Project. J Clin Oncol 1998;16: 2780–95.
33. Alizadeh AA, Eisen MB, Davis RE, et al. Distinct types of
diffuse large B-cell lymphoma identified by gene expression
profiling. Nature 2000; 403: 503–11.
34. Lister TA, Crowther D, Sutcliffe SB, et al. Report of a commit-
tee convened to discuss the evaluation and staging of patients
with Hodgkin’s disease: Cotswolds meeting. J Clin Oncol
1989; 7: 1630–6.
35. Cabanillas F, Fuller LM. The radiologic assessment of the
lymphoma patient from the standpoint of the clinician.
Radiol Clin North Am 1990; 28: 683–95.
36. Marglin SI, Castellino RA. Selection of imaging studies for
the initial staging of patients with Hodgkin’s disease. Semin
Ultrasound CT MR 1985; 6: 393.
37. Murphy SB. Childhood non-Hodgkin’s lymphoma. N Engl
J Med 1978; 299: 1446–8.
38. Ng YY, Healy JC, Vincent JM, et al. The radiology of non-
Hodgkin lymphoma in childhood: a review of 80 cases.
Clin Radiol 1994; 49: 594–600.
39. Ott G, Katzenberger T, Lohr A, et al. Cytomorphologic,
immunohistochemical and cytogenetic profiles of follicular
lymphoma: 2 types of follicular lymphoma grade 3. Blood
2002; 99: 3806–12.
40. Price CG. Non-Hodgkin’s lymphoma. In: Price CG, Sikora K,
eds. Treatment of Cancer. London: Chapman and Hall, 1995:
881–97.
41. Kennedy BJ, Loeb V Jr, Peterson VM, et al. National survey
of patterns of care for Hodgkin’s disease. Cancer 1985; 56:
2547–56.
42. Hellman S, Mauch P. Role of radiation therapy in the treatment
of Hodgkin disease. Cancer Treat Rep 1982; 66: 915–23.
43. Tubiana M, Henry-Amar M, Carde P, et al. Toward compre-
hensive management tailored to prognostic factors of patients
with clinical stages I and II in Hodgkin’s disease. The EORTC
Lymphoma Group controlled clinical trials: 1964–1987. Blood
1989; 73: 47–56.
842
44. Henry-Amar M. Second cancer after the treatment for
Hodgkin’s disease: a report from the International Database
on Hodgkin’s Disease. Ann Oncol 1992; 3(Suppl 4):
117–28.
45. Chabner BA, Fisher RI, Young RC, DeVita VT. Staging of
non-Hodgkin’s lymphoma. Semin Oncol 1980; 7: 285–91.
46. Bonadonna G, Santoro A, Bonfante V, Valagussa P. Cyclic
delivery of MOPP and ABVD combinations in Stage IV
Hodgkin disease: rationale, background studies, and recent
results. Cancer Treat Rep 1982; 66: 881–7.
47. Canellos GP, Anderson JR, Propert KJ, et al. Chemotherapy
of advanced Hodgkin’s disease with MOPP, ABVD, or MOPP
alternating with ABVD. N Engl J Med 1992; 327: 1478–84.
48. Gupta RK, Lister TA. Hodgkin’s disease. In: Price CG, Sikora
K, eds. Treatment of Cancer. London: Chapman & Hall, 1995:
851–80.
49. Healey EA, Tarbell NJ, Kalish LA, et al. Prognostic factors for
patients with Hodgkin disease in first relapse. Cancer 1993;
71: 2613–20.
50. Desch CE, Lasala MR, Smith TJ, Hillner BE. The optimal
timing of autologous bone marrow transplantation in
Hodgkin’s disease patients after a chemotherapy relapse.
J Clin Oncol 1992; 10: 200–9.
51. Ng AK, Bernardo MP, Weller E, et al. Long-term survival
and competing causes of death in patients with early-stage
Hodgkin’s disease treated at age 50 or younger. J Clin Oncol
2002; 20: 2101–8.
52. Kaufman D, Longo D. Hodgkin’s disease. Crit Rev Oncol/
Hematol 1992; 13: 135–87.
53. Sundeen JT, Cossman J, Jaffe ES. Lymphocyte predominant
Hodgkin’s disease, nodular subtype with coexistent “large
cell lymphoma”. Histological progression or composite
malignancy? Am J Surg Pathol 1988; 12; 599–606.
54. Bastion Y, Sebban C, Berger F, et al. Incidence, predictive fac-
tors and outcome of lymphoma transformation in follicular
lymphoma patients. J Clin Oncol 1997; 15: 1587–94.
55. The International Non-Hodgkin’s Lymphoma Prognostic
Factors Project. A predictive model for aggressive non-
Hodgkin’s lymphoma. N Engl J Med 1993; 329: 987–94.
56. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response
criteria of the Eastern Cooperative Oncology Group. Am J
Clin Oncol 1982; 5: 649–55.
57. Solal-Celigny P. Follicular Lymphoma International Prog-
nostic Index. Curr Treat Option Oncol 2006; 7: 270–5.
58. Dyer MJ. Non-Hodgkin’s lymphoma. In: Horwich A, ed.
Oncology: A Multidisciplinary Textbook. London: Chapman
and Hall, 1995: 251–9.
59. McMillan AK, Goldstone AH. Autologous bone marrow
transplant for non-Hodgkin’s lymphoma. Eur J Haem 1991;
46: 129–35.
60. Fineberg HV, Wittenberg J, Ferrucci JT Jr, et al. The clinical
value of body computed tomography over time and techno-
logic change. Am J Roentgenol 1983; 141: 1067–72.
61. Carroll BA. Ultrasound of lymphoma. Semin Ultrasound
1982; III: 114–22.
62. Beyer D, Peters PE. Real-time ultrasonography—an efficient
screening method for abdominal and pelvic lymphadeno-
pathy. Lymphology 1980; 13: 142–9.
 lymphoma
63. Munker R, Stengel A, Stäbler A, Hillere E, Brehm G. Diagnos-
tic accuracy of ultrasound and computed tomography in the
staging of Hodgkin’s disease. Verification by laparotomy in
100 cases. Cancer 1995; 76: 1460–6.
64. Clouse ME, Harrison DA, Grassi CJ, et al. Lymphangiography,
ultrasonography, and computed tomography in Hodgkin’s
disease and non-Hodgkin’s lymphoma. J Comput Tomogr
1985; 9: 1–8.
65. Magnusson A, Erikson B, Hemmingsson A. Investigation of
retroperitoneal lymph nodes in Hodgkin’s disease. Ups J Med
Sci 1984; 89: 205–12.
66. Steinkamp HJ, Wissgott C, Rademaker J, Felix R. Current
status of power Doppler and color Doppler sonography in
the differential diagnosis of lymph node lesions. Eur Radiol
2002; 12: 1785–93.
67. Neumann CH, Robert NJ, Rosenthal D, Canellos G. Clinical
value of ultrasonography for the management of non-Hodgkin’s
lymphoma patients as compared with abdominal computed
tomography. J Comput Assist Tomogr 1983; 7: 666–9.
68. Reznek RH, Husband JE. The radiology of lymphoma. Curr
Imaging 1990; 2: 9–17.
69. Lee JK, Heiken JP, Ling D, et al. Magnetic resonance imaging
of abdominal and pelvic lymphadenopathy. Radiology 1984;
153: 181–8.
70. Dooms GC, Hricak H, Crooks LE, Higgins CB. Magnetic
resonance imaging of the lymph nodes: comparison with CT.
Radiology 1984; 153: 719–28.
71. Greco A, Jelliffe AM, Maher EJ, Leung AW. MR imaging of
lymphomas: impact on therapy. J Comput Assist Tomogr
1988; 12: 785–91.
72. Hill M, Cunningham D, MacVicar D, et al. Role of magnetic
resonance imaging in predicting relapse in residual masses
after treatment of lymphoma. J Clin Oncol 1993; 11: 2273–8.
73. Nyman R, Rhen S, Ericsson A, et al. An attempt to characterize
malignant lymphoma in spleen, liver and lymph nodes with
magnetic resonance imaging. Acta Radiol 1987; 28: 527–33.
74. Shmidt GP, Wintersperber B, Graser A, et al. High-resolution
whole-body magnetic resonance imaging applications at 1.5
and 3 Tesla: a comparative study. Invest Radiol 2007; 42:
449–59.
75. King AD, Ahuja AT, Yeung DK, et al. Malignant cervica
lymphadenopathy: diagnostic accuracy of diffusion-weighted
MR Imaging. Radiology 2007; 245: 806–13.
76. Weissleder R, Elizondo G, Wittenberg J, et al. Ultrasmall
superparamagnetic iron oxide: an intravenous contrast agent
for assessing lymph nodes with MR imaging. Radiology 1990;
175: 494–8.
77. Bellin MF, Roy C, Kinkel K, et al. Lymph node metastases:
safety and effectiveness of MR imaging with ultrasmall
superparamagnetic iron oxide particles – initial clinical expe-
rience. Radiology 1998; 207: 799–808.
78. Griffiths JR, Tate AR, Howe FA, Stubbs M. Magnetic reso-
nance spectroscopy of cancer: practicalities of multi-centre
trials and early results in non-Hodgkin’s lymphoma. Eur J
Cancer 2002; 38: 2085–93.
79. Front D, Bar-Shalom R, Epelbaum R, et al. Early detection of
lymphoma recurrence with gallium-67 scintigraphy. J Nucl
Med 1993; 34: 2101–4.
80. Newman JS, Francis IR, Kaminski MS, Wahl RL. Imaging
of lymphoma with PET with 2-[F-18]-fluoro-2-deoxy-D-
glucose: correlation with CT. Radiology 1994; 190: 111–16.
81. Front D, Israel O, Epelbaum R, et al. Ga-67 SPECT before
and after treatment of lymphoma. Radiology 1990; 175:
515–19.
82. Gallamini A, Biggi A, Fruttero A, et al. Revisiting the
prognostic role of gallium scintigraphy in low-grade non-
Hodgkin’s lymphoma. Eur J Nucl Med 1997; 24: 1499–506.
83. Hussain R, Christie DR, Gebski V, Barton MB, Gruenewald SM.
The role of the gallium scan in primary extranodal lymphoma.
J Nucl Med 1998; 39: 95–8.
84. Moog F, Bangerter M, Diederichs CG, et al. Lymphoma: role
of whole-body 2-deoxy-2-[F-18]fluoro-D-glucose (FDG) PET
in nodal staging. Radiology 1997; 203: 795–800.
85. Moog F, Bangerter M, Diederichs CG, et al. Extranodal
malignant lymphoma: detection with FDG PET versus CT.
Radiology 1998; 206: 475–81.
86. Wirth A, Seymour JF, Hicks RJ, et al. Fluorine-18 fluorode-
oxyglucose positron emission tomography, gallium-67 scin-
tigraphy, and conventional staging for Hodgkin’s disease and
non-Hodgkin’s lymphoma. Am J Med 2002; 112: 262–8.
87. Kostakoglu L, Leonard JP, Kuji I, et al. Comparison of
fluorine-18 fluorodeoxyglucose positron emission tomo-
graphy and Ga-67 scintigraphy in evaluation of lymphoma.
Cancer 2002; 94: 879–88.
88. Bangerter M, Moog F, Buchmann I, et al. Whole-body 2-[18F]-
fluoro-2-deoxy-D-glucose positron emission tomography
(FDG-PET) for accurate staging of Hodgkin’s disease. Ann
Oncol 1998; 9: 1117–22.
89. Hoh CK, Glaspy J, Rosen P, et al. Whole-body FDG-PET
imaging for staging of Hodgkin’s disease and lymphoma.
J Nucl Med 1997; 38: 343–8.
90. Jerusalem G, Warland V, Najjar F, et al. Whole-body 18F-FDG
PET for the evaluation of patients with Hodgkin’s disease
and non-Hodgkin’s lymphoma. Nucl Med Commun 1999;
20: 13–20.
91. Weihrauch MR, Re D, Bischoff S, et al. Whole-body positron
emission tomography using 18F-fluorodeoxyglucose for ini-
tial staging of patients with Hodgkin’s disease. Ann Hematol
2002; 81: 20–5.
92. Menzel C, Döbert N, Mitrou P, et al. Positron emission tomo-
graphy for the staging of Hodgkin’s lymphoma—increasing
the body of evidence in favor of the method. Acta Oncol
2002; 41: 430–6.
93. Hoffmann M, Kletter K, Diemling M, et al. Positron emission
tomography with fluorine-18-2-fluoro-2-deoxy-D-glucose
(F18-FDG) does not visualize extranodal B-cell lymphoma
of the mucosa-associated lymphoid tissue (MALT)-type.
Ann Oncol 1999; 10: 1185–9.
94. Jerusalem G, Beguin Y, Najjar F, et al. Positron emission
tomography (PET) with 18F-fluorodeoxyglucose (18F-FDG)
for the staging of low-grade non-Hodgkin’s lymphoma (NHL).
Ann Oncol 2001; 12: 825–30.
95. Rodríguez-Vigil B, Gómez-León N, Pinílla I, et al. PET/CT in
lymphoma: prospective study of enhanced full-dose PET/CT
versus unenhanced low-dose PET/CT. J Nucl Med 2006; 47:
1643–8.
843
 hematology malignancy
96. La Fougère C, Hundt W, Bröckel N, et al. Value of PET/CT
versus PET and CT performed as separate investigations in
patients with Hodgkin’s disease and non-Hodgkin’s lymphoma.
Eur J Nucl Med Mol Imaging 2006; 33: 1417–25.
97. Stomper PC, Cholewinski SP, Park J, Bakshi SP, Barcos MP.
Abdominal staging of thoracic Hodgkin disease: CT-
lymphangiography-Ga-67 scanning correlation. Radiology
1993; 187: 381–6.
98. Valette F, Querellou S, Oudoux A, et al. Comparison of
positron emission tomography and lymphangiography in
the diagnosis of infradiaphragmatic Hodgkin’s disease. Acta
Radiol 2007; 48: 59–63.
99. DePena CA, Van Tassel P, Lee YY. Lymphoma of the head and
neck. Radiol Clin North Am 1990; 28: 723–43.
100. Pombo F, Rodriguez E, Caruncho MV, Villalva C, Crespo C.
CT attenuation values and enhancing characteristics of tho-
racoabdominal lymphomatous adenopathies. J Comput Assist
Tomogr 1994; 18: 59–62.
101. Dooms GC, Hricak H, Crooks LE, Higgins CB. Magnetic
resonance imaging of the lymph nodes: comparison with CT.
Radiology 1984; 153: 719–28.
102. Filly R, Bland N, Castellino RA. Radiographic distribution of
intrathoracic disease in previously untreated patients with
Hodgkin’s disease and non-Hodgkin’s lymphoma. Radiology
1976; 120: 277–81.
103. Castellino RA, Blank N, Hoppe RT, Cho C. Hodgkin disease:
contributions of chest CT in the initial staging evaluation.
Radiology 1986; 160: 603–5.
104. Castellino RA, Hilton S, O’Brien JP, Portlock CS. Non-
Hodgkin’s lymphoma: contribution of chest CT in the initial
staging evaluation. Radiology 1996; 199: 129–32.
105. Grossman H, Winchester PH, Bragg DG, Tan C, Murphy ML.
Roentgenographic changes in childhood Hodgkin’s disease.
Am J Roentgenol Radium Ther Nucl Med 1970; 108: 354–64.
106. Jochelson MS, Balikian JP, Mauch P, Liebman H. Peri- and
paracardial involvement in lymphoma: a radiographic study
of 11 cases. Am J Roentgenol 1983; 140: 483–8.
107. Strijk SP. Lymph node calcification in malignant lymphoma.
Presentation of nine cases and a review of the literature. Acta
Radiol Diagn (Stockh) 1985; 26: 427–31.
108. Apter S, Avigdor A, Gayer G, et al. Calcification in lymphoma
occurring before therapy: CT features and clinical correla-
tion. Am J Roentgenol 2002; 178: 935–8.
109. Hopper KD, Diehl LF, Cole BA, et al. The significance of necrotic
mediastinal lymph nodes on CT in patients with newly diag-
nosed Hodgkin disease. Am J Roentgenol 1990; 155: 267–70.
110. North LB, Fuller LM, Hagemeister FB, et al. Importance of
initial mediastinal adenopathy in Hodgkin disease. Am J
Roentgenol 1982; 138: 229–35.
111. Gallagher CJ, White FE, Tucker AK, Malpas JS, Lister TA. The
role of computed tomography in the detection of intratho-
racic lymphoma. Br J Cancer 1984; 49: 621–9.
112. Khoury MB, Godwin JD, Halvorsen R, Hanun Y, Putman CE.
Role of chest CT in non-Hodgkin’s lymphoma. Radiology
1986; 158: 659–62.
113. Hopper KD, Diehl LF, Lesar M, et al. Hodgkin disease: clini-
cal utility of CT in initial staging and treatment. Radiology
1988; 169: 17–22.
844
114. Heron CW, Husband JE, Williams MP. Hodgkin disease:
CT of the thymus. Radiology 1988; 167: 647–51.
115. Wernecke K, Vassallo P, Rutsch F, Peters PE, Potter R. Thymic
involvement in Hodgkin disease: CT and sonographic find-
ings. Radiology 1991; 181: 375–83.
116. Shaffer K, Smith D, Kirn D, et al. Primary mediastinal large-
B-cell lymphoma: radiologic findings at presentation. Am J
Roentgenol 1996; 167: 425–30.
117. Spiers AS, Husband JE, MacVicar AD. Treated thymic lym-
phoma: comparison of MR imaging with CT. Radiology 1997;
203: 369–76.
118. Rodriguez M, Rehn SM, Nyman RS, et al. CT in malignancy
grading and prognostic prediction of non-Hodgkin’s lym-
phoma. Acta Radiol 1999; 40: 191–7.
119. Rehn S, Sperber GO, Nyman R, et al. Quantification of
inhomogeneities in malignancy grading of non-Hodgkin’s
lymphoma with MR imaging. Acta Radiol 1993; 34: 3–9.
120. Rehn SM, Nyman RS, Glimelius BL, Hagberg HE, Sunström JC.
Non-Hodgkin’s lymphoma: predicting prognostic grade with
MR imaging. Radiology 1990; 176: 249–53.
121. Lazzarino M, Orlandi E, Paulli M, et al. Primary mediastinal
B-cell lymphoma with sclerosis: an aggressive tumor with
distinctive clinical and pathological features. J Clin Oncol
1993; 11: 2606–13.
122. Harell GS, Breiman RS, Glatstein EJ, Marshall WH Jr,
Castellino RA. Computed tomography of the abdomen in the
malignant lymphomas. Radiol Clin North Am 1977; 15:
391–400.
123. Castellino RA, Marglin S, Blank N. Hodgkin disease, the
non-Hodgkin’s lymphomas, and the leukemias in the retro-
peritoneum. Semin Roentgenol 1980; 15: 288–301.
124. Kadin MD, Glatstein EJ, Dorfman RF. Clinicopathologic
studies in 117 untreated patients subject to laparotomy
for the staging of Hodgkin’s disease. Cancer 1980; 27:
1277–94.
125. Goffinet DR, Warnke R, Dunnick NR, et al. Clinical and
surgical (laparotomy) evaluation of patients with non-
Hodgkin’s lymphomas. Cancer Treat Rep 1977; 61: 981–92.
126. Rosenberg SA, Kaplan HS. Evidence for an orderly progres-
sion in the spread of Hodgkin’s disease. Cancer Res 1966; 26:
1225–31.
127. Urba WJ, Longo DL. Hodgkin’s disease. N Engl J Med 1992;
326: 678–87.
128. Weinstein JB, Heiken JP, Lee JK, et al. High resolution CT of
the porta hepatis and hepatoduodenal ligament. Radiographics
1986; 6: 55–74.
129. Yang ZG, Min PQ, Sone S, et al. Tuberculosis versus lympho-
mas in the abdominal lymph nodes: evaluation with contrast-
enhanced CT. Am J Roentgenol 1999; 172: 619–23.
130. Hutchings M, Loft A, Hansen M, et al. Position emission
tomography with or without computed tomography in the
primary staging of Hodgkin’s lymphoma. Haematologica
2006; 91: 482–9.
131. Partridge S, Timothy A, O’Doherty MJ, et al. 2-Fluorine-
18-fluoro-2-deoxy-D glucose positron emission tomography
in the pretreatment staging of Hodgkin’s disease: influence
on patient management in a single institution. Ann Oncol
2000; 11: 1273–9.
 lymphoma
132. Kaplan HS. Contiguity and progression in Hodgkin’s disease.
Cancer Res 1971; 31: 1811–13.
133. Cobby M, Whipp E, Bullimore J, et al. CT appearances of
relapse of lymphoma in the lung. Clin Radiol 1990; 41: 232–8.
134. Eisner MD, Kaplan LD, Herndier B, Stulbarg MS. The
pulmonary manifestations of AIDS-related non-Hodgkin’s
lymphoma. Chest 1996; 110: 729–36.
135. MacDonald JB. Lung involvement in Hodgkin’s disease.
Thorax 1977; 32: 664–7.
136. Burgener FA, Hamlin DJ. Intrathoracic histiocytic lymphoma.
Am J Roentgenol 1981; 136: 499–504.
137. Lewis ER, Caskey CI, Fishman EK. Lymphoma of the lung:
CT findings in 31 patients. Am J Roentgenol 1991; 156:
711–14.
138. Jackson SA, Tung KT, Mead GM. Multiple cavitating
pulmonary lesions in non-Hodgkin’s lymphoma. Clin Radiol
1994; 49: 883–5.
139. Isaacson PG, Norton AJ. General features of extranodal
lymphoma. In: Isaacson PG, ed., Extranodal Lymphomas.
London: Churchill-Livingstone, 1994: 1–14.
140. Cordier JF, Chailleux E, Lauque D, et al. Primary pulmonary
lymphomas. A clinical study of 70 cases in nonimmunocom-
promised patients. Chest 1993; 103: 201–8.
141. Peterson H, Snider HL, Yam LT, et al. Primary pulmonary
lymphoma. A clinical and immunohistochemical study of six
cases. Cancer 1985; 56: 805–13.
142. Murray KA, Chor PJ, Turner JF Jr. Intrathoracic lymphopro-
liferative disorders and lymphoma. Curr Probl Diagn Radiol
1996; 25: 78–106.
143. Ooi GC, Ho JC, Khong PL, et al. Computed tomography
characteristics of advanced primary pulmonary lympho-
epithelioma-like carcinoma. Eur Radiol 2003; 13: 522–6.
144. Bae YA, Lee KS, Han J, et al. Marginal zone B-cell lymphoma
of bronchus-associated lymphoid tissue: imaging findings in
21 patients. Chest 2008; 133: 433–40.
145. Dunnick NR, Parker BR, Castellino RA. Rapid onset of pul-
monary infiltration due to histiocytic lymphoma. Radiology
1976; 118: 281–5.
146. Radin AI. Primary pulmonary Hodgkin’s disease. Cancer
1990; 65: 550–63.
147. Cartier Y, Johkoh T, Honda O, Muller NL. Primary pulmo-
nary Hodgkin’s disease: CT findings in three patients. Clin
Radiol 1999; 54: 182–4.
148. Edinburgh KJ, Jasmer RM, Huang L, et al. Multiple pulmo-
nary nodules in AIDS: usefulness of CT in distinguishing
among potential causes. Radiology 2000; 214: 427–32.
149. Celikoglu F, Teirstein AS, Krellenstein DJ, Strauchen JA.
Pleural effusion in non-Hodgkin’s lymphoma. Chest 1992;
101: 1357–60.
150. Bergin CJ, Healy MV, Zincone GE, Castellino RA. MR evalu-
ation of chest wall involvement in malignant lymphoma.
J Comput Assist Tomogr 1990; 14: 928–32.
151. Carlsen SE, Bergin CJ, Hoppe RT. MR imaging to detect chest
wall and pleural involvement in patients with lymphoma:
effect on radiation therapy planning. Am J Roentgenol 1993;
160: 1191–5.
152. North LB, Libshitz HI, Lorigan JG. Thoracic lymphoma.
Radiol Clin North Am 1990; 28: 745–62.
153. Tesoro-Tess JD, Biasi S, Balzarini L, et al. Heart involvement
in lymphomas. The value of magnetic resonance imaging and
two-dimensional echocardiography at disease presentation.
Cancer 1993; 72: 2484–90.
154. Tohno E, Cosgrove DO, Sloan JP. Malignant disease—local
recurrence and metastases. In: Tohno E, Cosgrove DO, Sloan
JP, eds. Ultrasound Diagnosis of Breast Diseases. Edinburgh:
Churchill Livingstone, 1994: 186.
155. Yang WT, Lane DL, Le-Petross HT, Abruzzo LV, Macapinlac
HA. Breast lymphoma: imaging findings of 32 tumors in
27 patients. Radiology 2007; 245: 692–702.
156. Paulus DD. Lymphoma of the breast. Radiol Clin North Am
1990; 28: 833–40.
157. Sabaté JM, Gómez A, Torrubia S, et al. Lymphoma of the
breast: clinical and radiologic features with pathologic cor-
relation in 28 patients. Breast J 2002; 8: 294–304.
158. Thomas JL, Bernardino ME, Vermess M, et al. EOE-13 in
the detection of hepatosplenic lymphoma. Radiology 1982;
145: 629–34.
159. Bonadonna G, Santoro A. Clinical evolution and treatment
of Hodgkin’s disease. In: Wiernik PH, Canellos G, Kyle RA,
Schiffer CA, eds. Neoplastic Disease of the Blood. Edinburgh:
Churchill Livingstone, 1985: 789.
160. Warshauer DM, Molina PL, Worawattanakul S. The spotted
spleen: CT and clinical correlation in a tertiary care center.
J Comput Assist Tomogr 1998; 22: 694–702.
161. Dachman AH, Buck JL, Krishnan J, Aguilera NS, Buetow PC.
Primary non-Hodgkin’s splenic lymphoma. Clin Radiol
1998; 53: 137–42.
162. Daskalogiannaki M, Prassopoulos P, Katrinakis G, et al.
Splenic involvement in lymphomas. Evaluation on serial
CT examinations. Acta Radiol 2001; 42: 326–32.
163. Strijk SP, Wagener DJ, Bogman MJ, de Pauw BE, Wobbes T.
The spleen in Hodgkin disease: diagnostic value of CT. Radi-
ology 1985; 154: 753–7.
164. Strijk SP, Boetes C, Bogman MJ, de Pauw BE, Wobbes T.
The spleen in non-Hodgkin’s lymphoma. Diagnostic value
of computed tomography. Acta Radiol 1987; 28: 139–44.
165. Hess CF, Kurtz B, Hoffmann W, Bamberg M. Ultrasound
diagnosis of splenic lymphoma: ROC analysis of multi-
dimensional splenic indices. Br J Radiol 1993; 66: 859–64.
166. Harisinghani MG, Saini S, Weissleder R, et al. Splenic
imaging with ultrasmall superparamagnetic iron oxide
ferumoxtran-10 (AMI-7227): preliminary observations.
J Comput Assist Tomogr 2001; 25: 770–6.
167. Weissleder R, Elizondo G, Stark DD, et al. The diagnosis of
splenic lymphoma by MR imaging: value of superparamag-
netic iron oxide. Am J Roentgenol 1989; 152: 175–80.
168. Weissleder R, Hahn PF, Stark DD, et al. Superparamagnetic
iron oxide: enhanced detection of focal splenic tumors with
MR imaging. Radiology 1988; 169: 399–403.
169. Rini JN, Manalili EY, Hoffman MA, et al. F-18 FDG versus
Ga-67 for detecting splenic involvement in Hodgkin’s dis-
ease. Clin Nucl Med 2002; 27: 572–7.
170. Kaplan HS, Dorfman RF, Nelsen TS, Rosenberg SA. Staging
laparotomy and splenectomy in Hodgkin’s disease: analysis of
indications and patterns of involvement in 285 consecutive,
unselected patients. Natl Cancer Inst Monogr 1973; 36: 291–301.
845
 hematology malignancy
171. Maher MM, McDermott SR, Fenlon HM, et al. Imaging of
primary non-Hodgkin’s lymphoma of the liver. Clin Radiol
2001; 56: 295–301.
172. Weissleder R, Stark DD, Elizondo G, et al. MRI of hepatic
lymphoma. Magn Reson Imaging 1988; 6: 675–8.
173. Coakley FV, O’Reilly EM, Schwartz LH, Panicek DM,
Castellino RA. Non-Hodgkin’s lymphoma as a cause of
intrahepatic periportal low attenuation on CT. J Comput
Assist Tomogr 1997; 21: 726–8.
174. Richards MA, Webb JA, Reznek RH, et al. Detection of spread
of malignant lymphoma to the liver by low field strength
magnetic resonance imaging. Br Med J (Clin Res Ed) 1986;
293: 1126–8.
175. Weinreb JC, Brateman L, Maravilla KR. Magnetic resonance
imaging of hepatic lymphoma. Am J Roentgenol 1984; 143:
1211–14.
176. Stark DD, Weissleder R, Elizondo G, et al. Superparamagnetic
iron oxide: clinical application as a contrast agent for MR
imaging of the liver. Radiology 1988; 168: 297–301.
177. Brady LW, Asbell SO. Malignant lymphoma of the gastro-
intestinal tract. Erskine Memorial Lecture, 1979. Radiology
1980; 137: 291–8.
178. Dodd GD. Lymphoma of the hollow abdominal viscera.
Radiol Clin North Am 1990; 28: 771–83.
179. Rohatiner A, d’Amore F, Coiffier B, et al. Report on a work-
shop convened to discuss the pathological and staging clas-
sifications of gastrointestinal tract lymphoma. Ann Oncol
1994; 5: 397–400.
180. Dragosics B, Bauer P, Radaszkiewicz T. Primary gastrointesti-
nal Non-Hodgkin’s lymphomas. A retrospective clinicopatho-
logic study of 150 cases. Cancer 1985; 55: 1060–73.
181. Fishman EK, Urban BA, Hruban RH. CT of the stomach:
spectrum of disease. Radiographics 1996; 16: 1035–54.
182. Megibow AJ, Balthazar EJ, Naidich DP, Bosniak MA. Com-
puted tomography of gastrointestinal lymphoma. Am J
Roentgenol 1983; 141: 541–7.
183. Kessar P, Norton A, Rohatiner AZ, Lister RA, Reznek RH. CT
appearances of mucosa-associated lymphoid tissue (MALT)
lymphoma. Eur Radiol 1999; 9: 693–6.
184. Fujishima H, Chijiiwa Y. Endoscopic ultrasonographic
staging of primary gastric lymphoma. Abdom Imaging
1996; 21: 192–4.
185. Raderer M, Vorbeck F, Formanek M, et al. Importance of
extensive staging in patients with mucosa-associated lym-
phoid tissue (MALT)-type lymphoma. Br J Cancer 2000; 83:
454–7.
186. Balthazar EJ, Noordhoorn M, Megibow AJ, Gordon RB. CT
of small-bowel lymphoma in immunocompetent patients
and patients with AIDS: comparison of findings. Am J
Roentgenol 1997; 168: 675–80.
187. Lohan DG, Alhajeri AN, Cronin CG, Roche CJ, Murphy JM.
MR enterography of small bowel lymphoma: potential
for suggestion of histologic subtype and the presence of
underlying celiac disease. Am J Roentgenol 2008; 190:
287–93.
188. Lecuit M, Abachin E, Martin A. Immunoproliferative small
intestinal disease associated with Campylobacter jejuni.
N Engl J Med 2004; 350: 239–48.
846
189. Kim Y, Cho O, Song S, et al. Peritoneal lymphomatosis:
CT findings. Abdom Imaging 1998; 23: 87–90.
190. Reed K, Vose PC, Jarstfer BS. Pancreatic cancer: 30 year review
(1947 to 1977). Am J Surg 1979; 138: 929–33.
191. Webb TH, Lillemoe KD, Pitt HA, Jones RA, Cameron JL.
Pancreatic lymphoma. Is surgery mandatory for diagnosis or
treatment? Ann Surg 1989; 209: 25–30.
192. Shirkhoda A, Ros PR, Farah J, Staab EV. Lymphoma of the
solid abdominal viscera. Radiol Clin North Am 1990; 28:
785–99.
193. Van Beers B, Lalonde L, Soyer P, et al. Dynamic CT in pancre-
atic lymphoma. J Comput Assist Tomogr 1993; 17: 94–7.
194. Prayer L, Schurawitzki H, Mallek R, Mostbeck G. CT in
pancreatic involvement of non-Hodgkin’s lymphoma. Acta
Radiol 1992; 33: 123–7.
195. Charnsangavej C. Lymphoma of the genitourinary tract.
Radiol Clin North Am 1990; 28: 865–77.
196. Reznek RH, Mootoosamy I, Webb JA, Richards MA. CT in
renal and perirenal lymphoma: a further look. Clin Radiol
1990; 42: 233–8.
197. Hartman DS, David CJ Jr, Goldman SM, Friedman AC,
Fritzsche P. Renal lymphoma: radiologic-pathologic correla-
tion of 21 cases. Radiology 1982; 144: 759–66.
198. Heiken JP, Gold RP, Schnur MJ, et al. Computed tomography
of renal lymphoma with ultrasound correlation. J Comput
Assist Tomogr 1983; 7: 245–50.
199. Connor SE, Umaria N, Guest PJ. Case report: extranodal
peripelvic and periureteric lymphoma—demonstration with
CT. Clin Radiol 2001; 56: 422–4.
200. Aigen AB, Phillips M. Primary malignant lymphoma of
urinary bladder. Urology 1986; 28: 235–7.
201. Yeoman LJ, Mason MD, Olliff JF. Non-Hodgkin’s lymphoma
of the bladder—and MRI appearances. Clin Radiol 1991; 44:
389–92.
202. Tasu JP, Geffroy D, Rocher L, et al. Primary malignant lym-
phoma of the urinary bladder: report of three cases and
review of the literature. Eur Radiol 2000; 10: 1261–4.
203. Mostofi FK. Proceedings: Testicular tumors. Epidemiologic,
etiologic, and pathologic features. Cancer 1973; 32:
1186–201.
204. Thurnher S, Hricak H, Carroll PR, Pobiel RS, Filly RA.
Imaging the testis: comparison between MR imaging and
US. Radiology 1988; 167: 631–6.
205. Kim YS, Koh BH, Cho OK, Rhim HC. MR imaging of primary
uterine lymphoma. Abdom Imaging 1997; 22: 441–4.
206. Jenkins N, Husband J, Sellars N, Gore M. MRI in primary
non-Hodgkin’s lymphoma of the vagina associated with a
uterine congenital anomaly. Br J Radiol 1997; 70: 219–22.
207. Glazer HS, Lee JK, Balfe DM, et al. Non-Hodgkin’s lym-
phoma: computed tomographic demonstration of unusual
extranodal involvement. Radiology 1983; 149: 211–17.
208. Ferrozzi F, Tognini G, Bova D, Zuccoli G. Non-Hodgkin’s
lymphomas of the ovaries: MR findings. J Comput Assist
Tomogr 2000; 24: 416–20.
209. Vincent JM, Morrison ID, Armstrong P, Reznek RH. Com-
puted tomography of diffuse, non-metastatic enlargement of
the adrenal glands in patients with malignant disease. Clin
Radiol 1994; 49: 456–60.
 lymphoma
210. Jenkins PJ, Sohaib SA, Trainer PJ, et al. Adrenal enlargement
and failure of suppression of circulating cortisol by dexame-
thasone in patients with malignancy. Br J Cancer 1999; 80:
1815–9.
211. Zimmerman RA. Central nervous system lymphoma. Radiol
Clin North Am 1990; 28: 697–721.
212. Hobson DE, Anderson BA, Carr I, West M. Primary lym-
phoma of the central nervous system: Manitoba experience
and literature review. Can J Neurol Sci 1986; 13: 55–61.
213. Snider WD, Simpson DM, Nielsen S, et al. Neurological com-
plications of acquired immune deficiency syndrome: analysis
of 50 patients. Ann Neurol 1983; 14: 403–18.
214. Jenkins CN, Colquhoun IR. Characterization of primary
intracranial lymphoma by computed tomography: an analy-
sis of 36 cases and a review of the literature with particular
reference to calcification haemorrhage and cyst formation.
Clin Radiol 1998; 53: 428–34.
215. Herman TS, Hammond N, Jones SE, et al. Involvement of
the central nervous system by non-Hodgkin lymphoma: the
Southwest Oncology Group experience. Cancer 1979; 43:
390–7.
216. Kotasek D, Albertyn LE, Sage RE. A five-year experience with
central nervous system lymphoma. Med J Aust 1986; 144:
299–303.
217. Bragg DG, Colby TV, Ward JH. New concepts in the non-
Hodgkin’s lymphomas: radiologic implications. Radiology
1986; 159: 291–304.
218. Chamberlain MC, Sandy AD, Press GA. Leptomeningeal
metastasis: a comparison of gadolinium-enhanced MR
and contrast-enhanced CT of the brain. Neurology 1990; 40:
435–8.
219. Yousem DM, Patrone PM, Grossman RI. Leptomeningeal
metastases: MR evaluation. J Comput Assist Tomogr 1990;
14: 255–61.
220. MacVicar D, Williams MP. CT scanning in epidural lym-
phoma. Clin Radiol 1991; 43: 95–102.
221. Evans C. A review of non-Hodgkin’s lymphomata of the head
and neck. Clin Oncol 1981; 7: 23–31.
222. Robbins KT, Fuller LM, Vlasak M, et al. Primary lymphomas
of the nasal cavity and paranasal sinuses. Cancer 1985; 56:
814–19.
223. Shikhani A, Samara M, Allam C, Salem P, Lenhard R.
Primary lymphoma in the salivary glands: report of five
cases and review of the literature. Laryngoscope 1987; 97:
1438–42.
224. Takashima S, Ikezoe J, Morimoto S, et al. Primary thyroid
lymphoma: evaluation with CT. Radiology 1988; 168: 765–8.
225. Takashima S, Nomura N, Noguchi Y, Matsuzuka F, Inoue T.
Primary thyroid lymphoma: evaluation with US, CT and
MRI. J Comput Assist Tomogr 1995; 19: 282–8.
226. Braunstein EM. Hodgkin disease of bone: radiographic
correlation with the histological classification. Radiology
1980; 137: 643–6.
227. Cooley BL, Higinbotham NL, Groesbeck HP. Primary reticu-
lum cell sarcoma of bone: classification. Radiology 1950; 50:
641–58.
228. Ngan H, Preston BJ. Non-Hodgkin’s lymphoma presenting
with osseous lesions. Clin Radiol 1975; 26: 351–6.
229. Stroszczynski C, Oellinger J, Hosten N, et al. Staging and
monitoring of malignant lymphoma of the bone: comparison
of 67Ga scintigraphy and MRI. J Nucl Med 1999; 40: 387–93.
230. Mengiardi B, Honegger H, Hodler J, et al. Primary lymphoma
of bone: MRI and CT characteristics before and after suc-
cessful treatment. Am J Roentgenol 2005; 184: 185–92.
231. Moog F, Kotzerke J, Reske SN. FDG PET can replace bone
scintigraphy in primary staging of malignant lymphoma.
J Nucl Med 1999; 40: 1407–13.
232. Park YH, Kim S, Choi SJ, et al. Clinical impact of whole-
body FDG-PET for evaluation of response and therapeutic
decision-making of primary lymphoma of bone. Ann Oncol
2005; 16: 1401–2.
233. Castellino RA, Goffinet DR, Blank N, Parker BR, Kaplan HS.
The role of radiography in the staging of non-Hodgkin’s
lymphoma with laparotomy correlation. Radiology 1974;
110: 329–38.
234. Chabner BA, Johnson RE, Young RC, et al. Sequential non-
surgical and surgical staging of non-Hodgkin’s lymphoma.
Ann Intern Med 1976; 85: 149–54.
235. Glatstein E, Guernsey JM, Rosenberg SA, Kaplan HS. The
value of laparotomy and splenectomy in the staging of
Hodgkin’s disease. Cancer 1969; 24: 709–18.
236. Kaplan HS. Essentials of staging and management of the
malignant lymphomas. Semin Roentgenol 1980; 15: 219–26.
237. Linden A, Zankovich R, Theissen P, Diehl V, Schicha H.
Malignant lymphoma: bone marrow imaging versus biopsy.
Radiology 1989; 173: 335–9.
238. Pond GD, Castellino RA, Horning S, Hoppe RT. Non-Hodgkin’s
lymphoma: influence of lymphography, CT, and bone
marrow biopsy on staging and management. Radiology 1989;
170: 159–64.
239. Wang J, Weiss LM, Chang KL, et al. Diagnostic utility of bilat-
eral bone marrow examination: significance of morphologic
and ancillary technique study in malignancy. Cancer 2002;
94: 1522–31.
240. Döhner H, Gückel F, Knauf W, et al. Magnetic resonance
imaging of bone marrow in lymphoproliferative disorders:
correlation with bone marrow biopsy. Br J Haematol 1989;
73: 12–17.
241. Hoane BR, Shields AF, Porter BA, Shulman HM. Detection of
lymphomatous bone marrow involvement with magnetic
resonance imaging. Blood 1991; 78: 728–38.
242. Yasumoto M, Nonomura Y, Yoshimura R, et al. MR detection
of iliac bone marrow involvement by malignant lymphoma
with various MR sequences including diffusion-weighted
echo-planar imaging. Skeletal Radiol 2002; 31: 263–9.
243. Shields AF, Porter BA, Churchley S, et al. The detection of
bone marrow involvement by lymphoma using magnetic
resonance imaging. J Clin Oncol 1987; 5: 225–30.
244. Tsunoda S, Takagi S, Tanaka O, Miura Y. Clinical and prog-
nostic significance of femoral marrow magnetic resonance
imaging in patients with malignant lymphoma. Blood 1997;
89: 286–90.
245. Moog F, Bangerter M, Kotzerke J, et al. 18-F-fluorodeoxy-
glucose-positron emission tomography as a new approach
to detect lymphomatous bone marrow. J Clin Oncol 1998;
16: 603–9.
847
 hematology malignancy
246. Schaefer NG, Stroble K, Taverna C, Hany T. Bone involve-
ment in patients with lymphoma: the role of FGD-PET/CT.
Eur J Nucl Med Mol Imaging 2007; 34: 60–7.
247. Elstrom R, Guan L, Baker G, et al. Utility of FDG-PET scan-
ning in lymphoma by WHO classification. Blood 2003; 101:
3875–6.
248. Carr R, Barrington SF, Madan B, et al. Detection of lym-
phoma in bone marrow by whole-body positron emission
tomography. Blood 1998; 91: 3340–6.
249. Pakos EE, Fotopoulos AD, Ioannidis JP. 18F-FDG PET for
evaluation of bone marrow infiltration in staging of lym-
phoma: a meta-analysis. J Nucl Med 2005; 46: 958–63.
250. Daldrup-Link HE, Rummeny EJ, Ihssen B, et al. Iron-oxide-
enhanced MR imaging of bone marrow in patients with
non-Hodgkin’s lymphoma: differentiation between tumor
infiltration and hypercellular bone marrow. Eur Radiol 2002;
12: 1557–66.
251. Williams MP, Olliff JF. Magnetic resonance imaging in extra-
nodal pelvic lymphoma. Clin Radiol 1990; 42: 264–8.
252. Malloy PC, Fishman EK, Magid D. Lymphoma of bone, mus-
cle, and skin: CT findings. Am J Roentgenol 1992; 159: 805–9.
253. Wotherspoon AC, Ortiz-Hidalgo C, Falzon MR, Isaacson PG.
Helicobacter pylori-associated gastritis and primary B-cell
gastric lymphoma. Lancet 1991; 338: 1175–6.
254. Nakamura S, Aoyagi K, Furuse M, et al. B-cell monoclonality
precedes the development of gastric MALT lymphoma in
Helicobacter pylori-associated chronic gastritis. Am J Pathol
1998; 152: 1271–9.
255. Thieblemont C, Bastion Y, Berger F, et al. Mucosa-associated
lymphoid tissue gastrointestinal and nongastrointestinal
lymphoma behavior: analysis of 108 patients. J Clin Oncol
1997; 15: 1624–30.
256. Vorbeck F, Osterreicher C, Püspök A, et al. Comparison of
spiral-computed tomography with water-filling of the
stomach and endosonography for gastric lymphoma of
mucosa-associated lymphoid tissue-type. Digestion 2002;
65: 196–9.
257. Park MS, Kim KW, Yu JS, et al. Radiographic findings of
primary B-cell lymphoma of the stomach: low-grade versus
high-grade malignancy in relation to the mucosa-associated
lymphoid tissue concept. Am J Roentgenol 2002; 179:
1297–304.
258. Palazzo L, Roseau G, Ruskone-Fourmestraux A, et al. Endo-
scopic ultrasonography in the local staging of primary gas-
tric lymphoma. Endoscopy 1993; 25: 502–8.
259. Sackmann M, Morgner A, Rudolph B, et al. Regression of
gastric MALT lymphoma after eradication of Helicobacter
pylori is predicted by endosonographic staging. MALT Lym-
phoma Study Group. Gastroenterology 1997; 113: 1087–90.
260. Lee HJ, Han JK, Kim TK, et al. Primary colorectal lymphoma:
spectrum of imaging findings with pathologic correlation.
Eur Radiol 2002; 12: 2242–9.
261. King LJ, Padley SP, Wotherspoon AC, Nicholson AG. Pulmo-
nary MALT lymphoma: imaging findings in 24 cases. Eur
Radiol 2000; 10: 1932–8.
262. Lee DK, Im JG, Lee KS, et al. B-cell lymphoma of bronchus-
associated lymphoid tissue (BALT): CT features in 10 patients.
J Comput Assist Tomogr 2000; 24: 30–4.
848
263. Vincent JM, Ng YY, Norton AJ, Armstrong P. CT “angiogram
sign” in primary pulmonary lymphoma. J Comput Assist
Tomogr 1992; 16: 829–31.
264. Burkitt DP. Classics in oncology. A sarcoma involving the
jaws in African children. CA Cancer J Clin 1972; 22:
345–55.
265. O’Connor GT, Rappaport H, Smith EB. Childhood lym-
phoma resembling “Burkitt tumour” in the United States.
Cancer 1965; 18: 411–17.
266. Ziegler JL, Bluming AZ, Morrow RH, Fass L, Carbone PP.
Central nervous system involvement in Burkitt’s lymphoma.
Blood 1970; 36: 718–28.
267. Johnson KA, Tung K, Mead G, Sweetenham J. The imaging of
Burkitt’s and Burkitt-like lymphoma. Clin Radiol 1998; 53:
835–41.
268. World Health Organization Classification of Tumours.
Pathology & Genetics. Tumours of Haematopoietic and
Lymphoid Tissues. Lyon: IARC Press, 2001.
269. Dal Maso L, Francheschi S. Epidemiology of non-Hodgkin’s
lymphoma and other haemolymphopoietic neoplasms in
people with AIDS. Lancet Oncol 2003; 4: 110–19.
270. Radin DR, Esplin JA, Levine AM, Ralls PW. AIDS-related non-
Hodgkin’s lymphoma: abdominal CT findings in 112 patients.
Am J Roentgenol 1993; 160: 1133–9.
271. Jasmer RM, Gotway MB, Creasman JM, et al. Clinical and
radiographic predictors of the etiology of computed
tomography-diagnosed intrathoracic lymphadenopathy
in HIV-infected patients. J Acquir Immune Defic Syndr
2002; 31: 291–8.
272. Cordoliani Y-S, Derosier C, Pharaboz C, et al. Primary
cerebral lymphoma in patients with AIDS: MR findings in
17 cases. Am J Roentgenol 1992; 159: 841–7.
273. O’Doherty MJ, Barrington SF, Campbell M, Lowe J,
Bradbeer CS. PET scanning and the human immuno-
deficiency virus-positive patient. J Nucl Med 1997; 38:
1575–83.
274. Dodd GD III, Ledesma-Medina J, Baron RL, Fuhrman CR.
Posttransplant lymphoproliferative disorder: intrathoracic
manifestations. Radiology 1992; 184: 65–9.
275. Carignan S, Staples CA, Muller NL. Intrathoracic lympho-
proliferative disorders in the immunocompromised patient:
CT findings. Radiology 1995; 197: 53–8.
276. Lim GY, Newman B, Kurland G, Webber SA. Posttrans-
plantation lymphoproliferative disorder: manifestations
in pediatric thoracic organ recipients. Radiology 2002;
222: 699–708.
277. Lee DA, Hartman RP, Trenkner SW, Leone JP, Gruessner R.
Lymphomas in solid organ transplantation. Abdom Imaging
1998; 23: 553–7.
278. Pickhardt PJ, Siegel MJ. Abdominal manifestations of
posttransplantation lymphoproliferative disorder. Am J
Roentgenol 1998; 171: 1007–13.
279. Heron CW, Husband JE, Williams MP, Cherryman GR. The
value of thoracic computed tomography in the detection of
recurrent Hodgkin’s disease. Br J Radiol 1988; 61: 567–72.
280. Hopper KD, Kasales CJ, Van Slyke MA, et al. Analysis of
interobserver and intraobserver variability in CT tumor
measurements. Am J Roentgenol 1996; 167: 851–4.
 lymphoma
281. DeVita VT Jr, Hellman S, Rosenberg SA, eds. Non-Hodgkin’s
lymphomas (Chapter 45.3) and Lymphoma (Chapter 45.6).
In: Cancer—Principles and Practice of Oncology. Toronto:
J B Lippincott Co, 2001: 2339, 2256.
282. North LB, Fuller LM, Sullivan-Halley JA, Hagemeister FB.
Regression of mediastinal Hodgkin disease after therapy:
evaluation of time interval. Radiology 1987; 164: 599–602.
283. Cheson BD, Horning SJ, Coiffier B, et al. Report of an
international workshop to standardize response criteria for
non-Hodgkin’s lymphomas. NCI Sponsored International
Working Group. J Clin Oncol 1999; 17: 1244.
284. Radford JA, Cowan RA, Flanagan M, et al. The significance of
residual mediastinal abnormality on the chest radiograph
following treatment for Hodgkin’s disease. J Clin Oncol 1988;
6: 940–6.
285. Surbone A, Longo DL, Devita VT Jr, et al. Residual abdomi-
nal masses in aggressive non-Hodgkin’s lymphoma after
combination chemotherapy: significance and management.
J Clin Oncol 1988; 6: 1832–7.
286. Lewis E, Bernardino ME, Salvador PG, et al. Post-therapy
CT-detected mass in lymphoma patients: is it viable tissue?
J Comput Assist Tomogr 1982; 6: 792–5.
287. Coiffier B, Gisselbrecht C, Herbrecht R, et al. LNH-84 regimen:
a multicenter study of intensive chemotherapy in 737 patients
with aggressive malignant lymphoma. J Clin Oncol 1989; 7:
1018–26.
288. Nyman RS, Rehn SM, Glimelius BL, et al. Residual mediasti-
nal masses in Hodgkin’s disease: prediction of size with MR
imaging. Radiology 1989; 170: 435–40.
289. Rahmouni A, Tempany C, Jones R, et al. Lymphoma: moni-
toring tumor size and signal intensity with MR imaging.
Radiology 1993; 188: 445–51.
290. Rodriguez M. Computed tomography, magnetic resonance
imaging and positron emission tomography in non-Hodgkin’s
lymphoma. Acta Radiol Suppl 1998; 417: 1–36.
291. Kaplan WD, Jochelson MS, Herman TS, et al. Gallium-67
imaging: a predictor of residual tumor viability and clinical
outcome in patients with diffuse large-cell lymphoma. J Clin
Oncol 1990; 8: 1966–70.
292. Front D, Ben-Haim S, Israel O, et al. Lymphoma: predictive
value of Ga-67 scintigraphy after treatment. Radiology 1992;
182: 359–63.
293. Herman M, Paucek B, Raida L, et al. Comparison of mag-
netic resonance imaging and (67)gallium scintigraphy in the
evaluation of posttherapeutic residual mediastinal mass in
the patients with Hodgkin’s lymphoma. Eur J Radiol 2007;
64: 432–8.
294. Mikhaeel NG, Timothy AR, O’Doherty MJ, Hain S, Maisey
MN. 18-FDG-PET as a prognostic indicator in the treatment
of aggressive non-Hodgkin’s lymphoma—comparison with
CT. Leuk Lymphoma 2000; 39: 543–53.
295. Cremerius U, Fabry U, Neuerburg J, et al. Positron emission
tomography with 18F-FDG to detect residual disease after
therapy for malignant lymphoma. Nucl Med Commun 1998;
19: 1055–63.
296. de Wit M, Bumann D, Beyer W, et al. Whole-body positron
emission tomography (PET) for diagnosis of residual mass in
patients with lymphoma. Ann Oncol 1997; 8(Suppl 1): 57–60.
297. Jerusalem G, Beguin Y, Fassotte MF, et al. Whole-body posi-
tron emission tomography using 18F-fluorodeoxyglucose for
posttreatment evaluation in Hodgkin’s disease and non-
Hodgkin’s lymphoma has higher diagnostic and prognostic
value than classical computed tomography scan imaging.
Blood 1999; 94: 429–33.
298. Naumann R, Vaic A, Beuthien-Baumann B, et al. Prognostic
value of positron emission tomography in the evaluation of
post-treatment residual mass in patients with Hodgkin’s dis-
ease and non-Hodgkin’s lymphoma. Br J Haematol 2001;
115: 793–800.
299. Schöder H, Meta J, Yap C, et al. Effect of whole-body (18)
F-FDG PET imaging on clinical staging and management of
patients with malignant lymphoma. J Nucl Med 2001; 42:
1139–43.
300. Weihrauch MR, Re D, Scheidhauer K, et al. Thoracic positron
emission tomography using 18F-fluorodeoxyglucose for the
evaluation of residual mediastinal Hodgkin disease. Blood
2001; 98: 2930–4.
201. Bakheet SM, Powe J. Benign causes of 18-FDG uptake on
whole body imaging. Semin Nucl Med 1998; 28: 352–8.
302. Van Den Bosche B, Lambert B, De Winter F, et al. 18FDG PET
versus high-dose 67Ga scintigraphy for restaging and treat-
ment follow-up of lymphoma patients. Nucl Med Commun
2002; 23: 1079–83.
303. Zinzani PL, Chierichetti F, Zompatori M, et al. Advantages of
positron emission tomography (PET) with respect to com-
puted tomography in the follow-up of lymphoma patients
with abdominal presentation. Leuk Lymphoma 2002; 43:
1239–43.
304. Spaepen K, Stroobants S, Dupont P, et al. Prognostic value of
positron emission tomography (PET) with fluorine-18 fluo-
rodeoxyglucose ([18F]FDG) after first-line chemotherapy in
non-Hodgkin lymphoma: is [18F]FDG-PET a valid alterna-
tive to conventional diagnostic methods? J Clin Oncol 2001;
19: 414–19.
305. Spaepen K, Stroobants S, Dupont P, et al. Can positron emis-
sion tomography with [(18)F]-fluorodeoxyglucose after
first-line treatment distinguish Hodgkin’s disease patients
who need additional therapy from others in whom addi-
tional therapy would mean avoidable toxicity? Br J Haematol
2001; 115: 272–8.
306. Juweid M, Wiseman GA, Vose J, et al. Response assessment
of aggressive non-Hodgkin’s lymphoma by Integrated Interna-
tional Workshop criteria and fluorine-18-fluordeoxyglucose
positron emission tomography. J Clin Oncol 2005; 23: 4652–61.
307. Cheson BD, Pfistner B, Juweid ME, et al. Revised response
criteria for malignant lymphoma. J Clin Oncol 2007; 25:
579–86.
308. Juweid ME, Stroobants S, Hoekstra OS, et al. Use of positron
emission tomography for response assessment of lymphoma:
consensus of the Imaging Subcommittee of International
Harmonization Project in Lymphoma. J Clin Oncol 2007; 25:
571–8.
309. Kostakoglu L, Coleman M, Leonard JP, et al. PET predicts
prognosis after 1 cycle of chemotherapy in aggressive lym-
phoma and Hodgkin’s disease. J Nucl Med 2002; 43:
1018–27.
849
 hematology malignancy
310. Spaepen K, Stroobants S, Dupont P, et al. Early restaging
positron emission tomography with (18)F-fluorodeoxy-
glucose predicts outcome in patients with aggressive non-
Hodgkin’s lymphoma. Ann Oncol 2002; 13: 1356–63.
311. Haioun C, Itti E, Rahmouni A, et al. [18F]fluoro-2-deoxy-D-
glucose positron emission tomography (FDG-PET) in aggres-
sive lymphoma: an early prognostic tool for predicting patient
outcome. Blood 2005; 106: 1376–81.
312. Hutchings M, Loft A, Hansen M, et al. FDG-PET after
two cycles of chemotherapy predicts treatment failure and
progression-free survival in Hodgkin lymphoma. Blood
2006; 107: 52–9.
313. Gallamini A, Hutchings M, Rigacci L, et al. Early interim
2-[18F]fluoro-2-deoxy-D-glucose positron emission tomo-
graphy is prognostically superior to international prognostic
score in advanced-stage Hodgkin’s lymphoma: a report from
a joint Italian-Danish study. J Clin Oncol 2007; 25: 3746–52.
314. Kostakoglu L, Goldsmith SJ, Leonard JP, et al. FDG-PET
after 1 cycle of therapy predicts outcome in diffuse large cell
lymphoma and classic Hodgkin disease. Cancer 2006; 107:
2678–87.
315. Torizuka T, Nakamura F, Kanno T, et al. Early therapy moni-
toring with FDG-PET in aggressive non-Hodgkin’s lymphoma
and Hodgkin’s lymphoma. Eur J Nucl Med Mol Imaging
2004; 31: 22–8.
316. Becherer A, Mitterbauer M, Jaeger U, et al. Positron emission
tomography with [18F]2-fluoro-D-2-deoxyglucose (FDG-
PET) predicts relapse of malignant lymphoma after high-dose
therapy with stem cell transplantation. Leukemia 2002; 16:
260–7.
317. Weeks JC, Yeap BY, Canellos GP, Shipp MA. Value of follow-up
procedures in patients with large-cell lymphoma who
850
achieve a complete remission. J Clin Oncol 1991; 9:
1196–203.
318. Setoain FJ, Pons F, Herranz R, et al. 67Ga scintigraphy for the
evaluation of recurrences and residual masses in patients
with lymphoma. Nucl Med Commun 1997; 18: 405–11.
319. Radford JA, Eardley A, Woodman C, Crowther D. Follow up
policy after treatment for Hodgkin’s disease: too many clinic
visits and routine tests? A review of hospital records. Br Med
J 1997; 314: 343–6.
320. Guadagnolo BA, Punglia RS, Kuntz KM, Mauch PM, Ng AK.
Cost-effectiveness analysis of computerized tomography
in the routine follow-up of patients after primary treat-
ment for Hodgkin’s disease. J Clin Oncol 2006; 24:
4116–22.
321. Elis A, Blickstein D, Klein O, et al. Detection of relapse in
non-Hodgkin’s lymphoma: role of routine follow-up studies.
Am J Hematol 2002; 69: 41–4.
322. Jerusalem G, Beguin Y, Fassotte MF, et al. Early detection of
relapse by whole-body positron emission tomography in the
follow-up of patients with Hodgkin’s disease. Ann Oncol
2003; 14: 123–30.
323. Whelan JS, Reznek RH, Daniell SJ, et al. Computed tomogra-
phy (CT) and ultrasound (US) guided core biopsy in the
management of non-Hodgkin’s lymphoma. Br J Cancer
1991; 63: 460–2.
324. Pappa VI, Hussain HK, Reznek RH, et al. Role of image-
guided core-needle biopsy in the management of patients
with lymphoma. J Clin Oncol 1996; 14: 2427–30.
325. Ben Yehuda D, Polliack A, Okon E, et al. Image-guided core-
needle biopsy in malignant lymphoma: experience with
100 patients that suggests the technique is reliable. J Clin
Oncol 1996; 14: 2431–4.
 34 Multiple Myeloma
Conor Collins
INTRODUCTION
Multiple myeloma is the second most common form of hematologi-
cal malignancy in the western world after non-Hodgkin’s lymphoma,
accounting for approximately 10% of hematological malignancies
and 1% of all malignancies (1). It is a disease of later life with 98% of
patients aged 40 or older at presentation (median age 70 years) (2).
The etiology is unknown though there is an increased risk in those
who have a past history of radiation exposure.
Multiple myeloma is characterized by uncontrolled proliferation
of plasma cells within the marrow (mature antibody producing B
cells). This leads to disruption of the subtle balance between
osteoblastosis and osteoclastosis within bone by overproduction
of TRANCE (tumor necrosis factor-related induced cytokine) and
inactivation of osteoprotegerin resulting in unrestricted osteo-
clastic activity manifest as lytic deposits. An unwanted secondary
effect is the promotion of further clonal proliferation of myeloma
cells thus augmenting the disease process (3). Multiple myeloma
should not be confused with the condition known as monoclonal
gammopathy of undetermined significance (MGUS). In this disease
the serum paraprotein level is <3 g/dl with no evidence of myeloma
or a related disorder. The risk of MGUS progressing to myeloma
or a related condition is low: 16% at 10 years, 33% at 20 years, and
40% at 25 years (4).
Diagnosis is based on laboratory and radiographic findings and
depends on three abnormal results:
• Bone marrow containing more than 10% plasma cells
(normally no more than 4% of the cells in the bone marrow
are plasma cells)
• Generalized osteopenia and/or lytic bone deposits on
plain film radiography
• Blood serum and/or urine containing an abnormal protein
In about 75% of all cases of multiple myeloma the paraprotein
present (M protein) will correspond with one type of immuno-
globulin. In about 60% of cases an abnormal protein, known as
Bence-Jones protein may also be found in the urine. Measuring the
amount of paraprotein in the blood or urine is of value in the
diagnosis of myeloma and in monitoring the response to treatment.
STAGING
The clinical staging system devised by Durie and Salmon distin-
guishes different patient subgroups in terms of tumor mass and
disease aggression and even now frequently determines manage-
ment ( Table 34.1) (5). Patients with at least two lytic foci are
classified in advanced disease subgroups and aggressive systemic
treatment is usually indicated. Subsequently, the scientific advisers
of the International Myeloma Foundation proposed a new staging
system called “Durie and Salmon PLUS” based on the traditional
Durie and Salmon system integrated by 18F-fluoro-2-deoxyglucose
positron emission tomography (FDG PET) or magnetic resonance
(MR) imaging of the spine (Table 34.2) (6). This system attributes an
equal relevance to both FDG PET and MR imaging of the spine,
which can be used, as suggested by the guidelines, in a flexible fash-
ion. However, this staging system has recently been replaced by one
based entirely on serum β2 microglobulin and serum albumin levels
(Table 34.3) (7). Patient outcome in myeloma may be affected by
abnormalities of chromosome 13 but this does not add to the prog-
nostic power of the new international staging system (7,8). Despite
the new system many physicians still find that information regarding
imaging status influences their management, so the Durie-Salmon
PLUS is a more relevant system for radiologists (Table 34.2).
THERAPY
The International Myeloma Foundation and U.K. Myeloma Forum
(with the support of the British Committee for Standards in
Haematology) should be regarded as the preferred source of
detailed guidance on treatment (6,9,10). Treatment strategy is
directed towards adequate analgesia, rehydration, management of
hypercalcemia and renal impairment, and treatment of infection.
The response categories (complete, near complete, partial, mini-
mal, stable, and progressive) are determined primarily by the level
of M protein present. M protein is the level of monoclonal protein
measured by protein electrophoresis in serum or 24 hour urine.
Changes in M protein should be supported with other evidence of
treatment benefit to confirm response (6).
Chemotherapy is indicated for management of symptomatic
myeloma. High dose therapy using melphalan and prednisolone
can produce complete remission in up to 75% of patients (11,12).
In recent years thalidomide (and its more potent immunomodu-
latory analogue lenalidomide) has been recognized as a valuable
drug for the treatment of myeloma (13–15). A newer class of drug
Bortezomib (a proteasome inhibitor) is effective for treatment of
relapsed refractory myeloma and is superior to dexamethasone in
progression-free and overall survival (16–19). Other new agents
entering clinical trials include conventional drugs (Doxil), cytokines
(Avastin), biological agents (Betathine), and agents such as arsenic
trioxide (15,20,21). Animal studies using the novel recombinant
vesicular stomatitis virus have proved encouraging and point to
the likely direction of future therapies (22).
The most serious morbidity in these patients arises from
destructive bone deposits which cause severe intractable pain and
pathological fractures often resulting in deformity and disability.
Vertebroplasty and kyphoplasty have been performed to alleviate
bone pain from collapsed vertebrae and restore vertebral body height
(23–25). A recently published retrospective review of outcome
data from 67 myeloma patients treated with vertebroplasty
demonstrated significant improvement in rest pain, activity pain,
narcotic use, and mobility (26). The introduction of the bisphos-
phonate group of drugs has transformed this aspect of the disease.
851
 hematology malignancy

Table 34.1 Durie and Salmon Staging System of less than 5% (15,34,35). At present the added benefit of double
for Multiple Myeloma (5) or tandem transplantation versus a single autologous transplant is
not known.
Stagea Criteria Cell Mass
Radiation therapy is reserved for patients with spinal cord com-
I All of the following Low pression secondary to vertebral body collapse associated with a
Hemoglobin >10 g/100 ml <0.6 × 1012 cells per mm2
soft tissue mass or to pathological fractures elsewhere associated
Normal serum calcium <12 mg/100 ml
Normal bone structure or solitary bone with a soft tissue mass. It can be very effective but permanently
lesion only on radiography destroys normal bone marrow stem cells in the treatment field.
Low M component production rates Myeloma is generally considered incurable. It is a slowly pro-
IgG <5 g/100 ml gressing disease with long periods of relative inactivity. Relapse
IgA <3 g/100 ml
occurs in virtually all cases. On current treatment regimens patients
Urine light chain M component on
electrophoresis <4 g/24 hr younger than 70 years can expect a median survival of five years
II Fitting neither stage I nor stage III Intermediate (depending on stage) (11,21). Death results from bacterial infection,
III One or more of the following: High renal insufficiency, and thromboembolism.
Hemoglobin <8.5 g/100 ml >1.2 × 1012 cells per mm2
Serum calcium >12 mg/100 ml
Advanced lytic bone lesion Key Points: General Features
High M component production rates
IgG >7 g/100 ml ■ Multiple myeloma is the second most common form
IgA >5 g/100 ml of hematological malignancy in the Western world after
Urine light chain M component on
non-Hodgkin’s lymphoma
electrophoresis >12 g/24 hr
■ Multiple myeloma is an uncontrolled proliferation of a clone
a
Subclassifications: A, relatively normal renal function [serum creatinine value
of plasma cells
<20 mg/100 ml (175 mol/l)]; B, abnormal renal function [serum creatinine value
>20 mg/100 ml (175 mmol/l)]. ■ Myeloma is characterized by (i) plasma cell proliferation of
the bone marrow, (ii) lytic bone deposits, and (iii) myeloma
protein in the serum or urine
■ Myeloma should not be confused with monoclonal
Table 34.2 Durie and Salmon PLUS Staging System for gammopathy of uncertain significance (MGUS)
Symptomatic Multiple Myeloma (6) ■ The Durie and Salmon PLUS staging system intergrates the
Laboratory findings Imaging findings (including MR and FDG PET) traditional Durie–Salmon staging system with 18F-FDG
Stage I clinical criteria <5 focal spine lesions ± mild diffuse spine disease PET or MR imaging of the spine
Stage II clinical criteria 5–20 focal lesions ± moderate diffuse spine disease ■ Treatment comprises chemotherapy for symptomatic myeloma
Stage III clinical criteria >20 focal lesions ± severe diffuse spine disease and supportive measures to reduce pain, renal impairment,
and infection. Surgery also has a place in the management of
complications such as pathological fractures
Table 34.3 New International Staging System (7)
Stage I Serum β2 microglobuli <3.5 mg/L (average survival 62 mo)
RADIOLOGY AND CROSS-SECTIONAL IMAGING
Serum albumin >3.5 g/dL
Stage II Not I or IIIa (average survival 44 mo)
Stage III Serum β2 microglobulin >5.5 mg/L (average survival 29 mo)
Radiology plays an important role in staging, monitoring treat-
a
ment response, detection of relapse, and assessing complications.
There are two categories for stage II
• Serum β2 microglobulin <3.5 mg/L but serum albumin <3.5 g/dL
The various imaging techniques employed and their associated
Or findings are described more fully below.
• Serum β2 microglobulin 3.5–5.5 irrespective of the serum albumin level.
Conventional Radiography (Skeletal Survey)
Almost 80% of patients with multiple myeloma will have radio-
They bind to the bone at sites of active bone remodeling and can logical evidence of skeletal involvement at diagnosis which is
therefore inhibit myelomatous bone damage, thereby arresting the manifested in four different appearances—solitary deposit (plas-
destructive cycle described above (27,28). These agents (used in macytoma), diffuse skeletal involvement (myelomatosis), gener-
conjunction with cytotoxic chemotherapy) have been found to be alized osteopenia, and sclerosing myeloma (36). Views acquired
superior to chemotherapy alone in decreasing the incidence of should be posteroanterior chest, anteroposterior and lateral
pathological fractures and bone pain and may lead to prolonged views of cervical spine (including an open mouth view), tho-
survival (29–32). Recently published guidelines recommend that racic spine, lumbar spine, humeri, and femora, AP and lateral
bisphosphonate therapy be discontinued after two years in patients views of skull, and AP view of pelvis (Fig. 34.1) (37). Additional
with stable or responsive disease (33). views of any symptomatic area should also be acquired. The
Autologous transplantation has an established place in the treat- most common sites include the vertebrae, ribs, skull, and pelvis
ment of myeloma. It is the treatment of choice for patients aged whereas involvement of the distal bones is unusual. In early stage
under 65 years and can be considered in older age groups (with disease the role of the plain radiograph is limited because
good performance status) carrying a procedure related mortality myeloma deposits are often not visualized (38,39).

852
 multiple myeloma

(A) (B)
Figure 34.1 (A) Conventional radiograph of skull (lateral view) demonstrating multiple lytic deposits. (B) Conventional radiograph of left shoulder demonstrating
multiple lytic deposits in left humerus, clavicle, and scapula.

Sites of involvement include

• Vertebrae in 66% of patients

• Ribs (45%)
• Skull (40%)
• Shoulder (40%)
• Pelvis (30%)
• Long bones (25%)

Myeloma lesions are sharply defined, small lytic areas (average

size 20 mm) of bone destruction with no reactive bone formation.
At post mortem these lesions are due to nodular replacement of
marrow and bone by plasma cells. Although myeloma arises
within the medulla, disease progression may produce infiltration
of the cortex, invasion of the periosteum, and large extraosseous
soft tissue masses. The pattern of destruction may be geographic,
moth-eaten, or permeated. Pathological fractures are common
and the probability of occurrence can be calculated using a scoring
system (Fig. 34.2) (Table 34.4) (40,41).
When the skeletal survey has been obtained any further imaging
should be discussed in the context of a multidisciplinary setting
that includes an appropriately experienced radiologist, hemato-
oncologist, and sometimes the contribution of an orthopedic
surgeon may also be valuable (42). The expertise of the latter is
useful in deciding if surgical stabilization of any bones is required.
A major disadvantage of the skeletal survey is its relatively low
sensitivity, with lytic deposits only becoming visible once 30% of Figure 34.2 Conventional radiograph of proximal left femur (AP view) demon-
strating a large deposit associated with a pathological fracture.
the trabecular bone substance has been lost. Particular difficulty
may arise in the sternum, sacrum, scapulae, and ribs. In addition,
Table 34.4 Scoring System for Diagnosing Impending
accurate assessment of osteopenia is not possible.
Pathological Fractures (41)
Generalized osteopenia may be the only bone manifestation of
myeloma in up to 15% of patients. At post mortem these patients Variable Score
show diffuse replacement of marrow with plasma cells but have 1 2 3
less severe bone resorption when compared with lytic deposits Site Upper limb Lower limb Peritrochanteric
(40). Vertebral body collapse is the usual manifestation of this Pain Mild Moderate Functional
subtype which should not be confused with non-myelomatous Lesion Blastic Mixed Lytic
osteoporosis which occurs in many older patients. Normal bone Size <1/3 diameter 1/3–2/3 diameter >2/3 diameter

853
 hematology malignancy

(A) (B) (C)

Figure 34.3 (A) Technetium-99m disphosphonate isotope bone scan showing photopenic regions affecting mid-right rib (arrow) and lesser trochanter of right femur
(arrow). There is also a recent fracture affecting third right anterior rib. (B) Plain radiograph confirms presence of lytic deposit in lesser trochanter of right femur. (C)
CT demonstrates an expansile myelomatous deposit arising from mid right rib.

surveys are noted in 10% of myeloma patients although this has Table 34.5 Multiple Myeloma Vs. Bone Metastases
not always been associated with improved survival (43).
Radiological features Multiple myeloma Bone metastases
Involvement of intervertebral Yes No
Radionuclide Imaging discs
In multiple myeloma the osteoblastic response to bone destruc- Involvement of mandible Yes No
tion is negligible and the bone scan (using Technetium-99m labeled Involvement of vertebral pedicles No Yes
Associated paraspinal soft tissue Yes No
diphosphonate) is therefore frequently normal or may show areas
mass
of decreased uptake (photopenia) (Fig. 34.3) (Table 34.5). Most Isotope bone scan Frequently negative Frequently positive
studies have shown that the sensitivity of skeletal scintigraphy for
detecting individual deposits ranges from 40% to 60% (44,45).
However, skeletal scintigraphy may be helpful in evaluating areas disease (91% of patients with a positive scan had active myeloma).
not well visualized on plain film radiographs such as the ribs, The semi-quantitative score of diffuse Tc99m-MIBI bone marrow
sacrum, scapulae, and sternum. uptake (based on intensity and extension of uptake) correlates with
Technetium-99m-2-methoxyisobutlisonitrile (Tc99m-MIBI) has the amount of monoclonal component and with the percentage
been shown to be superior to conventional radiography and skeletal of bone marrow plasma cells. These results suggested a potential
scintigraphy in detecting bone and bone marrow involvement role for Tc99m-MIBI in the prognosis and follow-up of patients
(46,47). Alterations in cell metabolism which occur in malignant with multiple myeloma (currently based on measurement of the
cells (including plasma cells) can affect the membrane potential of monoclonal component, skeletal survey, and bone marrow biopsy).
the cell wall and mitochondrion leading to accumulation of Thallium-201 has also been described in multiple myeloma but
Tc99m-MIBI within the cell (48). Different patterns of Tc99m-MIBI due to limitations of the isotope its use has not been widespread
uptake have been described with multiple myeloma (negative, dif- nor has it been shown to be superior to Tc99m-MIBI (50,51). As
fuse, focal, combined focal and diffuse) and semi-quantitative evalu- a result the technique has largely fallen into disuse.
ation of these patterns showed a significant correlation with clinical Positron emission tomography (PET) using the glucose analogue
18
status and stage of the disease (49). A negative scan in a patient with F-fluorodeoxyglucose (FDG) has both the functional and
multiple myeloma indicates early stage disease or post treatment morphological capacity to identify the extent and activity of mul-
remission while the presence of focal uptake and/or intense dif- tiple myeloma for staging and monitoring purposes. The ability of
fuse bone marrow uptake suggests an advanced stage of active PET to perform whole body examinations is a major advantage

854
 multiple myeloma
over conventional imaging techniques. In one series comprising
28 patients, PET was true positive in almost 93% of the radio-
graphically documented osteolytic deposits and demonstrated a
greater extent of disease than plain film radiography in 61% of
patients (52). Another study confirmed its reliability in detecting
active myeloma both within bone and at extramedullary sites and
its ability to differentiate between new active disease and inactive
(treated) sites (53,54). It is extremely useful in the evaluation of
non-secretory myeloma and in identifying patients with a poor
prognosis (residual myeloma post-stem cell transplantation and
extramedullary myeloma). A negative 18F-FDG PET strongly sup-
ports the diagnosis of MGUS (53,55). In a recent study of 49 patients
with plasma cell malignancies only 5% relapsed after a negative
FDG PET scan post therapy (55). The more recently available tech-
nology of PET combined with computed tomography (PET-CT) is
now being used in the assessment of multiple myeloma (Fig. 34.4).
In a small study of 16 patients comparing FDG PET-CT with the
skeletal survey, CT and MR imaging was shown that FDG PET-CT
led to management changes in nine patients but that MR imaging
revealed diffuse bone involvement in five patients not evident on
PET-CT (56). A larger study of 46 patients comparing FDG PET-CT
with MR imaging of spine and pelvis and skeletal survey revealed
that in 30% of patients PET-CT failed to show abnormalities visible
on the MR imaging (57). However, PET-CT identified deposits
outside the spine and pelvis in 35% of patients. Combining both
techniques enabled identification of 92% of medullary and
extramedullary sites of active disease. A further study comparing
FDG PET-CT with Tc99m-MIBI and MR imaging in 33 patients
demonstrated that PET-CT performed better than MIBI in the
detection of focal deposits whereas MIBI was superior in the visu-
alization of diffuse disease (58). MR imaging was comparable to
both techniques in the spine and pelvis in the detection of focal and
diffuse disease. Therefore, in the diagnostic work-up of multiple
myeloma, the ability of MR imaging to accurately detect both focal
and diffuse disease in the spine and pelvis means that it should be
reserved for the evaluation of bone marrow involvement in these
regions. Until whole-body MR imaging with reasonably short
imaging times, good spatial resolution, and standardized sequences
for multiple myeloma becomes widely available, the main draw-
back of MR imaging of spine and pelvis will be the limited field of
(A)
Figure 34.4 (A) CT image from a PET-CT study demonstrating a lytic deposit in posterior right ilium. (B) Fused PET-CT image demonstrates active disease at this site.
view which could lead to understaging of newly diagnosed multiple
myeloma because deposits located outside these regions are inevi-
tably missed. Therefore, in the whole-body evaluation of multiple
myeloma patients at diagnosis, 18F-FDG PET-CT can contribute to
a more accurate assessment of disease, especially in a clinical con-
text highly suggestive of focal involvement of the appendicular
skeleton, such as the presence of bone pain or pathologic fractures
in long bones or in the case of discrepancies between clinical status
and hematological readings. On the other hand, despite the limited
capacity in detecting focal lesions, Tc99m-MIBI still remains the
most rapid and inexpensive technique for whole-body evaluation
and may be an alternative option when a PET facility is not
available. No formal study comparing whole body MR imaging
with PET-CT is yet available although the usefulness of both
techniques in this setting has been acknowledged (59,60).
It is worth remembering that false positive PET scans using
FDG may arise from inflammatory changes due to active infection,
chemotherapy within the previous three to four weeks or radio-
therapy within the previous two to three months (61,62).
A study comparing 18F FDG PET-CT with 11C-Choline
PET-CT in 10 patients demonstrated a higher sensitivity for
11
C-Choline in the detection of myelomatous deposits but the
difference was not significant (63). Increased methionine uptake
has also been demonstrated in plasma cells enabling imaging to
be undertaken using 11C-methionine PET-CT to identify disease
at medullary and extra-medullary sites (64).
Cross-Sectional Imaging
Computed Tomography
A wide range of findings have been described in CT of myeloma.
These include sharp, lytic foci of small and relatively homogenous
size with no sclerotic rim, diffuse faint osteolysis fan angioma-like
appearance due to the presence of thickened vertical trabeculae and
expansile deposits (Fig. 34.4) (65). Myelomatous marrow often
shows an abnormally high attenuation value compared with
normal marrow. Discrete interruption of the cortical contour may
be seen. CT can accurately depict the extent of associated soft tissue
masses and can direct needle biopsy for histological diagnosis. For
detection of small lytic bone deposits of less than 1 cm, narrow
collimation protocols at a high tube current and tube voltage are
(B)
855
 hematology malignancy

(A) (B) (C)

Figure 34.5 Sixty-eight-year-old man with newly diagnosed multiple myeloma, Stage III. (A) Lateral radiograph of lumbar spine [corresponding to multidetector CT
(MDCT) and MR image] shows large osteolytic deposit affecting L5 (arrows). Further deposits larger than 1 cm in diameter in lumbar spine and in T3 and T9 are not
recognizable on conventional radiographs. (B) MDCT image depicts deposits diameter larger than 10 mm in L5 (arrows) as well as in L1–L4, T3, and T9 (arrowheads).
Diffuse osteopenia or deposits with diameters between 5 mm and 1 cm are visible in all vertebrae depicted. (C) Sagittal T2-weighted MR image (TR/TE 2957/120) shows
tumor infiltration of all depicted vertebrae. Lesions larger than 1 cm in lumbar spine (arrowheads), especially in L5 (arrow), are clearly depicted. Source: From Ref. 66.

mandatory, because these parameters determine the resolution
and image noise. Advances in X-ray tube technology with high
heat storage capacities and simultaneous acquisition of multiple
slices per rotation allows scanning time to be shortened signifi-
cantly to less than a minute for a complete body scan. The advent
of multidetector CT (MDCT) provides more detailed information
on the risk of vertebral fractures compared with conventional
radiography and MR imaging (66). In patients who are severely
disabled or who are unable to undergo MR imaging examination
this is a useful alternative imaging technique (67).
A study using MDCT in patients with Stage III myeloma
provided more detailed information on the risk of vertebral
fractures compared with plain film radiography and MR imag-
ing (Fig. 34.5). Upward stage migration occurred in 17% of
patients (66). More recently, a study comparing MDCT (64 ×
0.6 mm collimation) with conventional radiography demon-
strated a significant increase in detection of myelomatous depos-
its in spine, pelvis, and ribs (p < 0.001) necessitating a change in
management in 18% of patients (68). MDCT also allows for
improved imaging of patients with scoliosis due to its ability to
adapt the dataset to the individual patient’s features. As the
degree of osseous infiltration in myeloma has a significant influ-
ence on therapy, it is likely there will be an increasing role for
this technique in patients who are severely disabled or who are
unable to undergo MR imaging examination. As most patients
are elderly, dose considerations are not a major drawback and its
ability to provide high quality images of the ribs, sternum, scap-
ulae, and sacrum in addition to the fact that intravenous con-
trast medium is not necessary makes MR imaging a realistic
alternative in the clinical scenarios outlined above. A large study
comparing whole body low dose unenhanced MDCT in
131 patients with multiple myeloma with conventional hemato-
logical parameters demonstrated that the combination provided
significantly greater diagnostic accuracy compared with labora-
tory testing alone particularly in monitoring patients post-therapy
(69). A study comparing the efficacy of MDCT with MR imaging
and FDG PET for detection of spinal bone marrow involvement
in 10 patients demonstrated that MDCT was superior to FDG
PET overall and to MR imaging in the detection of spinal
deposits less than 5 mm (p = 0.031) (70). Although some
groups use MDCT routinely in the assessment of multiple
myeloma patients, this is not universal practice with others
preferring to use the CT images from an FDG PET-CT examina-
tion in the context of follow-up evaluation (60,66,67,69,71).

856
 multiple myeloma

MDCT has an important role in evaluating suspected spinal
cord compression in cases when MR imaging is contraindicated
(e.g., cardiac pacemaker, intraorbital metallic foreign body), or
impossible due to patient intolerance or when facilities are
unavailable.
Magnetic Resonance Imaging
MR imaging is used routinely in many centers as a diagnostic
technique due to its high sensitivity and its ability to directly
visualize bone marrow. The role of MR imaging (and PET imaging)
is acknowledged by their inclusion in the Durie-Salmon Plus staging
system (6). In this system the number of lytic lesions is counted
leading to possible upstaging and altered therapy (71). In patients
with suspected cord compression MR imaging is the examination
of first choice. Bone deposits have been shown by MR imaging in
about 50% of asymptomatic myeloma patients with normal plain
radiographs. In a recent study of over 600 patients it was shown
that focal deposits detected by MR imaging (but not on skeletal
survey) independently affected survival (72). Complete resolution
of focal lesions visualized on MR imaging also conferred superior
survival. MR imaging can detect bone marrow infiltration in 29%
to 50% of patients with Durie-Salmon Stage I disease and negative
conventional radiographs (73). Nonetheless, the skeletal survey
retains an important role in myeloma and remains on the list of
recommended investigations (Fig. 34.6) (37).
Sagittal studies of the spine enable screening of a high propor-
tion of hematopoietic marrow in a limited time and detection of
any potential threat to the spinal cord. Additional coronal images
of the pelvis and proximal femora enable evaluation of about an
extra one-third of red marrow in an adult. These images may
enable detection of deposits potentially at risk of fracture. Whole
body MR imaging (WB-MRI) can be performed although its

Suspected myeloma or Suspected spinal cord

Soft tissue mass
plasmacytoma compression

CT scan and Radiological skeletal survey Urgent MR/CT scan

consider blopsy and appropriate
clinical management

Lytic lesions
present?

No Ambiguous findings or
Yes unexplained bone pain

Apparently Other evidence of end MRI/CT/PET

Multiple
solitary lesion organ damage (real scan
impairment / high
calcium / BM failure
Risk of fracture? Risk of fracture?

No Yes No Yes No

Urgent
orthopaedic
Generalised osteopenia
review and
appropriate
clinical
management
MRI whole spine to
exclude occult disease

Occult lesions identified and Normal

confirmed to be myelomatous

Systemic Local R/T to index lesion Local Systemic Observation and

therapy and systemic therapy radiotherapy therapy consider bisphosphonates

Figure 34.6 Suggested algorithm for imaging multiple myeloma (37).

857
 hematology malignancy

clinical benefit has not yet been fully evaluated in myeloma
(60,74–76). In one study comparing WB-MRI and the skeletal
survey in 54 patients (47 myeloma, 7 MGUS), WB-MRI correctly
demonstrated marrow deposits in 74% of patients versus 55%
for the skeletal survey (Fig. 34.7) (77). WB-MRI also showed
greater extent of infiltration in 90% of concordant deposits.
The imaging patterns in multiple myeloma can be classified as
normal, focal, diffuse, and variegated (78,79). Others have added
a further classification of combined diffuse and focal infiltration
(80). Normal marrow is present on MR imaging at diagnosis in
50% to 75% of patients with early untreated (Stage I) myeloma
and in about 20% of patients with advanced and treated (Stage III)

(A)

(B)
Figure 34.7 A 58-year-old male with Stage III disease of IgG myeloma. Bone marrow specimen revealed a bone marrow infiltration of 50%. Whole-body MRI and the
radiographic skeletal survery (RSS) were performed within 12 days. (A) The RSS reveals no osteolytic bone lesion of the skull, upper, and lower extremities and pelvis.
Note pinned healed fracture of the right femur. On plain films of the axial skeleton, no diffuse osteoporosis was detected. The thoraco-lumbar spine is characterized by
degenerative change, although a height decrease of the different multiple vertebra at levels T12, L1, and L2 is seen, indicating bone involvement for multiple myeloma
with pathological fractures (arrows). (B) Whole-body MRI shows a combined homogeneous and inhomogeneous pattern, indicating disseminated bone marrow infiltration
(arrows). A homogeneous diffuse bone marrow infiltration of both humeri, the rib cage, and the cervical spine is depicted by whole body MRI. The vertebral bodies of
the thoracic and lumbar spine, which are characterized by morphological changes of the adjacent endplates and a height decrease, exhibit a diffuse inhomogeneous
appearance. Pathological fractures at levels L1 and L2 are depicted with whole body MRI in agreement with the RSS. Diffuse bone marrow infiltration of the sacrum,
pelvis, and femora is also seen on MRI. In the clinical follow-up of 18 months, this patient had a progressive disease. Source: From Ref. 77.

858
 multiple myeloma
disease. Monoclonal plasma cells arrange themselves so as not to
displace the fat cells and the ratio of hematopoietic (and
myeloma) to fat cells in bone marrow does not exceed that of
healthy individuals (81). Hematopoietic marrow in adults
between 40 and 70 years old is composed of approximately 20%
to 25% bone substance, 40% to 45% fat, and 30% to 35% cellular
marrow (82).
Fast and complete assessment can be achieved using a combina-
tion of a T1-weighted sequence and a fat suppression technique
(Fig. 34.8) (73). The focal pattern consists of localized areas of
decreased signal intensity on T1-weighted images and increased
signal intensity on T2-weighted images. Myelomatous deposits
are generally sharply demarcated on a background of an other-
wise normal appearing bone marrow. Homogeneous enhancement
occurs on T1-weighted images following intravenous contrast
injection. Dynamic contrast-enhanced MR imaging has been
shown to correlate with vessel density and paraprotein level (83).
In a recent study using WB-MRI in 23 patients the highest sensi-
tivity and reliability was achieved using a T2-weighted inversion
recovery sequence (84).
The diffuse pattern is characterized by a diffuse and homogeneous
decrease in marrow signal intensity which becomes identical to or
lower than that of adjacent intervertebral discs on a T1-weighted
image and on a T2-weighted image by a diffuse or patchy increase
in signal intensity (Fig. 34.9). Marked enhancement is usually
seen on T1-weighted images following intravenous contrast
medium. The increased contrast between enhancing marrow and
the lower signal intervertebral discs allows more subtle forms of
infiltration to be identified (85).
(A) (B)
Figure 34.8 (A) Sagittal T1-weighted and (B) STIR MR images of lower thoracic
and lumbar spine showing focal and diffuse myelomatous infiltration affecting
multiple vertebrae with marked compression affecting T12.
The variegated pattern is characterized by the presence of multiple
foci of low signal intensity on T1-weighted images, intermediate
to high signal intensity on T2-weighted images, and enhancement
following IV contrast T1-weighted images. This pattern is seen
almost exclusively in an early stage of the disease (86).
These patterns of marrow involvement do not seem to corre-
late with the interstitial, nodular, and diffuse patterns of marrow
infiltration seen at microscopy. However, they show a positive
correlation with some laboratory parameters. Patients with the
normal and variegated patterns tend to have a lower tumor bur-
den than those with the focal and diffuse marrow involvement
patterns. Higher cellularity, higher plasmacytosis, and more
severe signs of bone failure are usually found in patients with the
diffuse pattern (87).
The lack of specificity of the MR imaging patterns should be
noted. The focal and diffuse patterns may be observed in both
metastatic disease from primary solid tumors and in other hema-
tological malignancies, especially lymphoma, and leukemia. Dif-
ferentiation between red marrow hyperplasia secondary to anemia,
infection, malignant or treated marrow infiltration can be
extremely difficult. Normal marrow heterogeneities may mimic
the variegated pattern although in most cases high signal intensity
on T2-weighted images and contrast enhancement help distin-
guish relevant small marrow abnormalities from normal
hematopoietic foci that generally show intermediate signal inten-
sity on T2-weighted images and no contrast enhancement on
T1-weighted images. The advent of diffusion-weighted imaging
promised an effective method for differentiating benign from
malignant compression fractures (88,89). However, only variable
(A) (B)
Figure 34.9 (A) Sagittal T1-weighted MR image of lumbar spine pre-transplantation
demonstrating diffuse abnormal low signal intensity in vertebral bodies. (B) Sagittal
T1-weighted MR image of lumbar spine post-transplantation shows conversion
to normal high signal marrow. Source: From Ref. 131.
859
 hematology malignancy

success has been reported since then and as a result it is not used Table 34.6 MRI Criteria for the Differential Diagnosis of
routinely (90,91). Benign Vs. Malignant Vertebral Fractures (95)
Variable Osteoporotic fractures Malignant fractures
Key Points: Radiological Features Marrow Signal Normal on all sequences Diffusely low on
(old fracture) T1-weighted images
■ Eighty percent of patients have radiological evidence of Band-like low SI adjacent to High or heterogeneous
skeletal disease with four patterns of disease; solitary deposit, fracture (acute) on T2-weighted images
diffuse involvement, generalized osteopenia, and sclerosing Normal SI preserved opposite Round or irreglar foci of
the fractured end plate marrow replacement
myeloma. 66% of patients have vertebral deposits Posterior elements
■ Myeloma lesions are sharply defined, small (20 mm), and involved
lytic. They are only visible when 30% of the trabecular bone Soft tissues/epidural
has been destroyed involvement
■ Osteopenia may be the only manifestation of disease in up to
Contrast Homogenous “return to High or heterogeneous
enhancement normal” SI after injection
15% of patients Vertebral contours Retropulsion of a posterior Convex posterior cortex
■ Conventional bone scintigraphy is frequently normal as the bone fragment (often
osteoblastic reaction around deposits is negligible. Skeletal postero-superior)
scintigraphy may be helpful for evaluating areas difficult to
display on conventional films such as the ribs, sternum,
scapulae, and sacrum
■ PET and PET-CT technology using 18F-FDG has a growing role
in the management of multiple myeloma. It may identify
more extensive disease than on plain radiographs and may
distinguish new active disease and inactive deposits
■ A negative PET scan indicates the diagnosis of MGUS
■ MDCT is a useful imaging tool for the assessment of patients
at risk of vertebral fractures or those with obvious fractures.
It can demonstrate the presence and extent of the soft tissue
component and is able to assess suspected spinal cord
compression. It is a realistic alternative in patients who are
unable to undergo MR imaging
■ MR imaging shows bone abnormalities in 50% of
asymptomatic patients with normal conventional radiography
■ Focal deposits show a low signal intensity on T1 and a high
signal intensity on T2 weighting. Uniform enhancement occurs
after injection of intravenous contrast medium
■ The MR imaging patterns are non-specific and may be
observed in both metastatic disease from primary solid
tumors and other hematological malignancies
■ WB-MRI shows promise but is not yet fully established in
practice
■ Combining MR imaging with FDG PET-CT enables
identification of more than 90% of active medullary and
extramedullary sites

Compression Fractures in Multiple Myeloma
Compression fractures arise from extensive osteoclastic bone
resorption or replacement of bone by a growing plasma cell
tumor mass. Several criteria exist for differentiating benign from
malignant vertebral body compression fractures ( Table 34.6)
(92) (Fig. 34.10). However, these should be applied with
caution to patients with multiple myeloma as normal signal
intensity within a compressed vertebral body on spinal MR
images does not preclude the diagnosis of multiple myeloma.
In a study of 224 vertebral fractures in patients with known
multiple myeloma, Lecouvet et al. found that 67% appeared
benign on MR imaging and 38% of their 37 patients had benign
fractures only at diagnosis (93).
Figure 34.10 Sagittal MRI STIR image of the spine showing malignant vertebral
body compression at T9 and T11 in addition to spinal cord compression at these
sites (arrows).
In patients with osteoporotic or post-traumatic vertebral
compression of recent onset, MR imaging will usually show signal
alteration that parallels one of the endplates, involves less than half
of the vertebral body, does not extend to the pedicles and enhances
homogeneously following intravenous contrast. Diffusion-weighted
MR imaging may also prove to be a useful method to apply to the
differential diagnosis of compression fractures (88).
Patients being treated for multiple myeloma may suffer acute
back pain secondary to vertebral body collapse even after effective

860
 multiple myeloma
chemotherapy. This is due to resolution of the tumor mass that
was supporting the bony cortex. Thirty-five new vertebral com-
pression fractures were discovered on post-treatment MR images
of 29 patients with multiple myeloma in remission (94). In another
study, 131 vertebral compression fractures appeared in 37 patients
with multiple myeloma after the onset of therapy (88). Conversely,
progression of disease may also be responsible for a new compres-
sion fracture and MR imaging may be useful in differentiating
between these two clinical settings. It has been shown that patients
with either normal marrow appearance or less than ten focal
lesions on pre-treatment MR images had significantly longer
fracture-free survival than patients with more than 10 focal lesions
or with diffuse patterns on pre-treatment MR images (87).
Key Points: Compression Fractures
■ Criteria for differentiating benign and malignant vertebral
compression fractures should be applied with caution in
patients with multiple myeloma
■ A normal signal intensity of a compressed vertebral body
does not preclude the diagnosis of multiple myeloma.
■ New compression fractures may arise following treatment as a
result of resolving soft tissue masses which formerly supported
bone. Progression of disease may also result in compression
fractures and MR imaging is helpful in distinguishing these
two different entities
SIDE EFFECTS OF THERAPY AND COMPLICATIONS:
THE ROLE OF RADIOLOGY
Drug Therapy
Infection is the single most dangerous complication for myeloma
patients with the patient most at risk in the first three months of
front-line therapy and is a recognized cause of bone pain in its
own right (6,95). Myeloma is associated with a higher incidence of
infective discitis and cerebritis in part due to cytotoxic therapy
induced immunosuppression associated with corticosteroid therapy
(96–98). Central venous catheters represent a potential source of
bacteremia (99). MR imaging enables early identification followed
by percutaneous needle aspirate using CT to confirm the diagno-
sis and provide information regarding choice of antibiotic (100).
Melphalan is associated with increased risk of pancytopenia,
mucositis, and pulmonary complications (101–104). Conven-
tional radiography and CT scanning are the appropriate imaging
investigations. High doses of corticosteroids may cause spinal
fractures and avascular necrosis of the femoral heads (amongst
other bones). MR imaging is useful for assessing both these condi-
tions. When thalidomide is used in combination with dexametha-
sone it carries a 16% incidence of deep vein thrombosis (DVT)
(105,106). Abdominal discomfort resulting from constipation is
also a well-recognized side effect of thalidomide and can be
readily assessed radiologically using a supine plain radiograph of
abdomen. A reported side-effect is interstitial pneumonitis which
can be identified on high resolution CT (107). The drug Bortezomib
is associated with cytopenia and a decrease in platelet count to
<50,000 mm3 occurs in almost 30% of patients increasing the risk
of hemorrhage (108). This drug has not been associated with an
increased incidence of DVT in trials reported to date (21). Other
reported adverse effects are sensory neuropathy and pseudomem-
branous colitis (109). Chronic bisphosphonate use is associated
with renal damage (monitored with regular serum creatinine
levels) and osteonecrosis of the mandible (110–113). Regular
dental check-ups in association with an orthopantomogram and a
CT scan enable early diagnosis of the latter (114).
Marrow Transplantation
Allogeneic transplant is a high risk procedure with reported
encephalopathic changes (reversible) which may develop as result
of cyclosporin therapy (115). In patients undergoing non-
myeloablative or “mini” allogeneic transplants there is a high risk
of acute (32–39%) and chronic (32–46%) graft versus host disease
in reported series (15). Autologous stem cell transplantation is
also available but it is not curative with a median relapse time of
three years (116). Imaging depends on symptomatology and con-
sists of plain film radiography, CT, and MR imaging as required.
Spinal Cord Compression
Spinal cord compression resulting from vertebral body collapse
may occur in up to 25% of patients and has been described as the
presenting feature in 12% of patients (117–119). Early recogni-
tion of back pain and neurological symptoms is essential. MR is
the imaging investigation of choice (Fig. 34.10). Pathological frac-
tures are common occurring in 50% of patients (40). Fractures of
the tubular bones heal readily with normal amounts of callus but
extensive fractures may require insertion of intra-medullary nails.
Myelofibrosis manifest by diffuse low signal on both T1-weighted
and STIR sequences and amyloidosis manifest by focal areas of
decreased signal on T1-weighted and STIR sequences are other
recognized complications (36).
Osteopenia
In myeloma, osteopenia may be confined to bones where myeloma
is active leaving the remaining bony skeleton unaffected. Insuffi-
ciency fractures may arise in the sacrum, pubic rami, or acetabular
roof with the latter having a characteristic appearance (Fig. 34.11)
(120). Although dual energy X-ray absorptiometry (DEXA) is the
best technique for diagnosing osteoporosis and for fracture risk
assessment no reliable data exists currently to differentiate between
benign osteoporosis and myeloma induced osteoporosis. One
study comprising 30 patients has demonstrated that lumbar
DEXA scans at diagnosis can identify patients at risk from early
vertebral body compression (121). Newer scanners allow esti-
mation of vertebral bone mineral density from a lateral view (with
the patient supine) but accuracy of the analysis is affected if spinal
osteophytes, pre-existing vertebral body compression, or spondy-
losis are present precluding its use routinely. A further complicating
factor is the widespread use of bisphosphonates in symptomatic
myeloma patients.
Patients being treated for multiple myeloma may suffer acute
back pain secondary to vertebral body collapse even after effective
chemotherapy. This is due to resolution of the tumor mass that
was supporting the bony cortex. Thirty-five new vertebral com-
pression fractures were discovered on post-treatment MR images
of 29 patients with multiple myeloma in remission (94). In another
study, 131 vertebral compression fractures appeared in 37 patients
861
 hematology malignancy

(A) (B)
Figure 34.11 A 56-year-old woman with known multiple myeloma and new right groin pain. Pelvic radiograph (A) shows fractures of right superior and inferior pubic
rami. 3D CT image (B) constructed from whole body PET-CT examination data shows fractures of pubic rami and both sacral alae (arrows). These fractures were
considered to be insufficiency fractures through areas of myelomatous foci rather than pathological fractures. Source: From Ref. 60.

with multiple myeloma after the onset of therapy (88). Conversely,
progression of disease may also be responsible for a new compres-
sion fracture and MR imaging may be useful in differentiating
between these two clinical settings. It has been shown that patients
with either normal marrow appearance or less than ten focal
lesions on pre-treatment MR images had significantly longer
fracture-free survival than patients with more than 10 focal lesions
or with diffuse patterns on pre-treatment MR images (87).
The most sensitive and specific imaging technique for the diag-
nosis of avascular necrosis of the femoral head is MR imaging
which is manifest by a characteristic double-line sign on
T2-weighted images (122). This condition may result from high
dose steroid therapy or radiotherapy and its early recognition
before the development of subchondral fractures is important for
the success of conservative management.
difficult to demonstrate due to motion artefact and blood pooling
in addition to proximity of the spleen (126). Unfortunately, this
examination is only available in a few specialist centers.
Key Points: Side Effects of Therapy: The Role
of Radiology
■ Infective discitis is a serious complication, and MR imaging
and CT have a key role in identifying the site of disease and
in guiding needle aspiration
■ High dose steroid therapy may induce avascular necrosis and
spinal fractures are best investigated with MR imaging
RADIOLOGY OF RESPONDING/RELAPSING DISEASE

Renal Impairment The role of radiology in the assessment of treatment response is

Renal impairment is common in myeloma and affects up to half of
all patients at some stage in their illness. This is usually a conse-
quence of amyloisosis rather than plasma cell infiltration (123).
Other possible causes include hypercalcemia, dehydration, hyper-
uricemia, infection or the action of nephrotoxic drugs. Unfortu-
nately several of the drugs that are used to treat myeloma have an
adverse effect on kidney function. Secondary amyloid occurs in
approximately 10% of cases and in the early stages ultrasound
demonstrates enlarged kidneys with increased cortical reflectivity.
Amyloid protein is deposited mainly in the cortex so that corti-
comedullary differentiation is preserved and the pyramids are
normal in size (124). Radiolabeled serum amyloid P component
scintigraphy is a non-invasive and quantitative method for imaging
amyloid deposits though it is less effective in myeloma associated
amyloid than other forms of amyloid (125). Cardiac involvement is
limited and sequential quantification of biological markers of dis-
ease (monoclonal protein levels and bone marrow plasmacytosis)
are usually sufficient to assess response to chemotherapy. The
choice of imaging technique for assessing disease response depends
on the findings from the initial work-up and treatment received.
Conventional Radiography
A repeat skeletal survey is not routinely indicated as lytic bone
deposits often show little evidence of healing radiographically
(manifest by shrinkage or sclerosis) even in those patients achiev-
ing a complete remission (37,71). The addition of bisphosphonate
compounds as antiosteoclast agents leads to bone strengthening
which may further accentuate these features. New or enlarging
deposits signify disease progression. New vertebral body compres-
sion fractures on conventional radiography do not necessarily

862
 multiple myeloma
indicate disease progression as they may arise due to resolution of
the tumor mass formerly supporting the bony cortex. Persistence
of radiological abnormalities should not be considered evidence of
active disease, since they may represent residual osteolysis in the
absence of plasma cell proliferation. There is insufficient evidence
to recommend routine skeletal surveys in untreated asymptomatic
patients in the absence of any evidence of disease progression (37).
If this situation changes the skeletal survey should be repeated with
targeted views of any symptomatic region.
Computed Tomography
Current evidence does not support the use of CT for routine
follow-up assessment. However, in selected cases particularly
those with a substantial soft tissue component it is reasonable to
use CT to monitor treatment response. In these cases there is
disappearance of extra-osseous or extra-medullary masses and
the reappearance of a continuous cortical outline with fatty
marrow content (79). CT should also be considered if there are
persistent unexplained symptoms, concern about a risk of fracture
or lack of response to therapy.
Magnetic Resonance Imaging
There is insufficient evidence to recommend routine MR imaging
for the follow-up of treated disease (37). Interpretation of post-
treatment MR imaging changes can be difficult as there is a wide
spectrum of possible treatment induced changes on MR imaging
depending on the pattern of bone marrow infiltration. Although
MR imaging is more sensitive than the skeletal survey it is often
difficult to differentiate inactive from active disease. Focal marrow
lesions may remain identical or decrease in size (94,127). Changes
in contrast enhancement between the pre- and post-treatment
MR examinations have been studied (128). The lack of lesion
enhancement or only a peripheral rim enhancement seen after
treatment can be indicative of responsive deposits. Other features
suggestive of a good response include decreased signal intensity
on T2-weighted images (73). Local radiation therapy of focal
complex deposits induces a rapid decrease in the soft tissue
extension and appearance of presumably necrotic, avascular cen-
tral areas within the deposit on T1-weighted images with a later
decrease in lesion size (129). In diffuse marrow abnormalities,
increased marrow signal is usually observed on post-treatment
T1-weighted images due to reappearance of fat cells within more
hydrated cellular components (Fig. 34.9). Conversion of a diffuse
to a focal or variegated pattern is also frequent (94). Post-treatment
MR imaging of the bone marrow may provide important informa-
tion for patients with equivocal clinical and laboratory results as
well as for patients with non-secretory myeloma.
In contrast to patients with advanced disease stages treated with
conventional chemotherapy, patients with normal MR findings at
diagnosis have better response to treatment and a longer survival
than those with focal or diffuse marrow abnormalities at MR imag-
ing (85). This feature has not yet been assessed in patients treated
with marrow transplantation. Patients undergoing therapy with
thalidomide have more favorable outcomes (better overall survival
rate and prolonged event-free survival) with normal post-treatment
MR imaging than those with persistent focal deposits (13).
After bone marrow transplantation, the bone marrow generally
has a high signal on T1-weighted images but focal residual deposits
are frequent (130). The prognostic significance of these abnormali-
ties is uncertain as patients with these residual abnormalities did not
always have a poorer outcome than those with normal post-
transplantation MR imaging examinations (36,131). Increased mar-
row cellularity due to marrow stimulating factors and decreased
signal due to marrow hemosiderosis resulting from repeated trans-
fusions may also be present on post-transplantation MR images.
Despite the superiority of MR imaging over conventional radiogra-
phy for spinal and pelvic lesion detection, an MR imaging survey
limited to these areas may be less sensitive than the conventional
skeletal survey which may detect deposits in the skull and rib (132).
In patients with clinical relapse new focal deposits or an increase
in size of deposits previously present can be identified with MR
imaging. Conversion of a normal or variegated pattern to a diffuse
pattern indicates severe relapse on follow-up MR imaging. MR
imaging is also useful in assessing status of leptomeninges as abnor-
mal enhancement representing tumor spread has been reported in
18 out of 1856 treated patients in one series (133). In patients with
a solitary bone plasmacytoma MR screening of the spine and pelvis
will usually reveal radiographically unsuspected deposits in up to
80% of patients thus suggesting true myeloma from the outset. This
finding is associated with a poor response to localized radiotherapy
and an earlier development of systemic disease than in patients with
a negative MR imaging survey (134).
MR imaging has been useful in the assessment of patients fol-
lowing transplantation. The bone marrow evolution index based
on comparison of pre- and post-transplant MR imaging combines
findings related to the number of deposits, deposit size, contrast
enhancement, and marrow background (131). A score of 0, 1, or 2
is given depending on whether there is improvement, stability or
deterioration. A score below 4 had superior treatment response
and was more successful than evaluating each parameter indi-
vidually. However, diffuse or focal marrow changes following
granulocyte colony stimulating factor (GCSF) treatment may
mimic active disease and limit its effectiveness (135).
High levels of serum β2 microglobulin correlate with a poor
prognosis and remain the single most powerful determinant of out-
come (136). No correlation between this finding and appearances
on MR imaging has yet been demonstrated. Long term prospective
studies are required to establish the significance and prognostic
value of the different MR imaging patterns of marrow involvement
and their correlation with various laboratory values particularly in
patients undergoing transplantation.
Functional Imaging
Conventional Scintigraphy
Although abnormal tracer uptake has been shown to indicate
residual activity on conventional skeletal scintigraphy, osteoblas-
tic activity due to healing vertebral body fractures, fractures
elsewhere in bony skeleton, and drug therapy (particularly bis-
phosphonates) will also give rise to increased isotope uptake
(27,28,45). 99mTc-MIBI has been shown to be superior to plain
film radiography and skeletal scintigraphy in detecting bone and
bone marrow involvement (46–48,137). A negative scan in a
patient with multiple myeloma indicates early stage disease or
post-treatment remission while the presence of focal uptake and/
or intense diffuse bone marrow uptake suggests an advanced stage
of active disease (49). A subsequent follow-up study involving
863
 hematology malignancy

22 patients showed a significant correlation between the scinti-

graphic findings and clinical status post-chemotherapy (138).
More recent studies have demonstrated significant correlation
between the extent of disease within bone marrow and serum
β2 microglobulin levels (p = 0.012) in 25 patients (139). A further
study involving 24 patients correlating Tc99m-MIBI with MR
imaging scans and skeletal survey demonstrated no significant
difference between the Tc99m-MIBI scan and MR imaging in pre-
dicting the extension of bone marrow infiltration and was signifi-
cantly better than the skeletal survey (p = 0.021) (140). The
post-treatment Tc99m-MIBI score also correlated significantly
with post-treatment response (p = 0.016). In the largest study
comprising 397 scans, 40% of asymptomatic patients were
upstaged as a result of the Tc99m-MIBI scan (141). Of 168 scans
(A) (B)
performed during follow-up, the specificity of Tc99m-MIBI was
86% in patients demonstrating a complete response. These
results indicate a role for this examination particularly in patients
who are unable to undergo MR imaging or PET-CT. However,
evaluation of the treated patient using this tracer may be compro-
mized if drug resistance is present. If this is manifest as Pgp expres-
sion dual phase imaging (at 10 minutes and four hours following
injection) helps to differentiate but if Bcl-2 is expressed correlation
with other imaging methods is necessary (142). MIBI has also been
found to be predictive of disease relapse (143). Despite the volume
of published work supporting MIBI it is likely to be superseded by
PET-CT in major oncology centers in the coming years.

FDG-PET and PET-CT

Studies have demonstrated its reliability in detecting active
myeloma both within bone and at extramedullary sites and its
ability to differentiate between new active disease and inactive
treated sites (53,144,145). In a study involving 13 patients using
FDG PET, nine of whom had undergone therapy, PET proved
superior to anatomical imaging in identifying sites of active residual
disease (54). Patients showing no abnormal or decreased FDG
uptake demonstrated clinical improvement. In a recent study of
49 patients with plasma cell malignancies only 5% relapsed after a (C) (D)
negative FDG PET post therapy (55). False negative results may Figure 34.12 Axial CT scan (A) from a 57-year-old male post treatment demon-
occur due to limitations with spatial resolution, resulting in strating a residual soft tissue mass within right frontal bone. Fused PET-CT image
deposits less than 0.5 cm not being detected. If relapse is suspected (B) demonstrates no abnormal FDG uptake indicating the absence of active disease.
Sagittal CT image from PET-CT study (C) shows no evidence of lytic deposits.
PET may identify new sites of disease and unsuspected sites of
Sagittal fused PET-CT image (D) demonstrates active focus of myeloma within
extramedullary disease. If FDG uptake is present in medullary or body of sternum.
extramedullary compartment following high dose therapy and
stem cell transplantation then prognosis is adversely affected (53).
GCSF can cause changes mimicking active disease on PET scans
which can last for up to one month following discontinuation of Key Points: Post-Treatment Evaluation
treatment (146). In many centers PET-CT is becoming the imaging
■ Role of radiology in assessment of treatment response is
study of choice for post-transplant patients. Deposits in the range
limited; routine use of conventional radiography, MDCT, or
of 0.5 to 1 cm (SUVmax > 2.5) can be identified (83). FDG PET-CT
MR imaging is not recommended
has an advantage over MR imaging in the post transplantation
■ Sequential analysis of biological markers is more frequently
patient by more accurately reflecting disease status (Fig. 34.12)
employed
(57,147). Given the range of newer therapies now available the
■ A wide spectrum of findings is present on post-treatment
identification of occult active disease may allow for targeted
MR imaging
multimodal therapy. Non-secretory myeloma patients should get
■ Conversion of diffuse to a focal or variegated pattern on MR
PET-CT during their initial staging since PET-CT will be the imaging
imaging is frequent
study of choice after treatment (60). Despite much anecdotal
■ Lack of contrast enhancement on MR imaging can be indica-
evidence for its success, PET is not yet recommended for use in
tive of responsive deposits
routine follow-up in treated myeloma patients (37).

864
 multiple myeloma
■ Focal residual deposits are frequent on MR imaging
following bone marrow transplantation but are not
necessarily associated with a poorer outcome
■ 99mTc-MIBI is superior to plain film radiography and
skeletal scintigraphy in detecting bone and bone marrow
involvement post-treatment
■ FDG PET-CT is now becoming the imaging technique of
choice in treated patients as it can distinguish active disease
from inactive disease
UNCOMMON VARIANTS OF MYELOMA
Extraosseous Myeloma
Clinical manifestations of extraosseous myeloma are rare, occur-
ring in less than 5% of patients with multiple myeloma. Extraosseous
myeloma deposits have been reported at multiple sites with the
breast, lymph nodes, and spleen most frequently involved. It may
also occur in the epidural region causing cord compression (148).
Extraosseous myeloma is more aggressive, occurs in a younger age
group (average age 50 years), and is associated with worse survival
than conventional myeloma (149).
Sclerotic Myeloma
Primary sclerotic manifestations are rare and occur only in 3% of
patients. It may take the form of diffuse osteosclerosis, patchy scle-
rotic areas throughout the skeleton or very small numbers of focal
sclerotic lesions (150).
Summary
■ Multiple myeloma is characterized by the classic triad of
bone marrow infiltration by plasma cells, lytic bone deposits
on conventional radiography (skeletal survey), and the
presence of M protein serum or urine
■ Durie-Salmon PLUS staging system remains the preferred
choice of many oncologists as it combines imaging and
laboratory findings
■ MDCT is a realistic alternative for imaging in severely
disabled patients or those unable to undergo MR imaging
examination
■ FDG PET-CT reliably detects active and inactive myeloma
within bone and at extramedullary sites
■ Improvements in PET-CT technology allow the CT component
of the examination to be used for anatomical assessment of the
bony skeleton
■ No role for routine imaging in the assessment of treatment
response—sequential analysis of biological markers is
preferred
■ Marrow deposits demonstrated on post-transplantation
MR imaging are not necessarily associated with a poorer
outcome
■ Skeletal survey will be superseded by whole body-MRI and
FDG PET-CT
■ Serum beta microglobulin levels remain the single most
powerful prognostic determinant
REFERENCES
1. Cancer Facts and Figures 2007. American Cancer Society, Inc.
Atlanta, Georgia, U.S.A. [Available from: www.cancer.org].
2. Phekoo KJ, Schey SA, Richards MA, et al. A population study
to define the incidence and survival of multiple myeloma in
a National Health Service Region in UK. Br J Haematol 2004;
127: 299–304.
3. Tricot G. New insights into role of microenvironment in
multiple myeloma. Lancet 2000; 355: 248–50.
4. Kyle RA, Rajkumar SV. Monoclonal gammopathies of unde-
termined significance. Hematol Oncol Clin North Am 1999;
13: 1181–202.
5. Durie BG, Salmon SE. A clinical staging system for multiple
myeloma. Correlation of measured myeloma cell mass with
presenting clinical features, response to treatment, and
survival. Cancer 1975; 36: 842–54.
6. Durie BG, Kyle RA, Belch A, et al. Myeloma management
guidelines: a consensus report from the Scientific Advisors
of the International Myeloma Foundation. Haematol J 2003;
4: 379–98.
7. Greipp PR, San Miguel J, Durie BG, et al. International
staging system for myeloma. J Clin Oncol 2005; 23: 3412–20.
8. Facon T, Avet-Loiseau H, Guillerm G, et al. Intergroupe
Francophone du Myélome. Chromosome 13 abnormalities
identified by FISH analysis and serum beta2-microglobulin
produce a powerful myeloma staging system for patients
receiving high dose therapy. Blood 2001; 97: 1566–71.
9. Samson D. Diagnosis and management of multiple myeloma.
Br J Haematol 2001; 115: 522–40.
10. Smith A, Wisloff F, Samson D. Guidelines on the diagnosis
and management of multiple myeloma 2005. Br J Haematol
2006; 132: 410–51.
11. Sirohi B, Powles R. Multiple myeloma. Lancet 2004; 363:
875–87.
12. Barlogie B, Shaughnessy J, Tricot G, et al. Treatment of mul-
tiple myeloma. Blood 2004; 103: 20–32.
13. Barlogie B, Zangari M, Spencer T, et al. Thalidomide in the
management of multiple myeloma. Semin Hematol 2001; 38:
250–9.
14. Cavenagh JD, Oakervee H. Thalidomide in multiple myeloma:
current status and future prospects. Br J Haematol 2003; 120:
18–26.
15. Harousseau JL, Shaughnessy J Jr, Richardson P. Multiple
myeloma. Hematology (Am Soc Hematol Educ Program)
2004: 237–56.
16. Dicato M, Boccadoro M, Cavenagh J, et al. Management of
multiple myeloma with bortezomib: experts review the data
and debate the issues. Oncology 2006; 70: 474–82.
17. Popat R, Joel S, Oakervee H, Cavenagh J. Bortezomib for
multiple myeloma. Expert Opin Pharmacother 2006; 7:
1337–46.
18. Oakervee H, Popat R, Cavenagh JD. Use of bortezomib as
induction therapy prior to stem cell transplantation in front-
line treatment of multiple myeloma: impact on stem cell
harvesting and engraftment. Leuk Lymphoma 2007; 48:
1910–21.
865
 hematology malignancy
19. Morgan GJ, Davies FE, Cavenagh JD, Jackson GH. Position
statement on the use of bortezomib in multiple myeloma. Int
J Lab Hematol 2008; 30: 1–10.
20. Bruno B, Rotta M, Giaccone Let al. New drugs for treatment
of multiple myeloma. Lancet Oncology 2004; 5: 430–42.
21. Morgan GJ, Davies FE. Evolving treatment strategies for
myeloma. Br J Cancer 2005; 92: 217–21.
22. Goel A, Carlson SK, Classic KL, et al. Radioiodide imaging
and radiovirotherapy of multiple myeloma using
VSV(Delta51)-NIS, an attenuated vesicular stomatitis virus
encoding the sodium iodide symporter gene. Blood 2007;
110: 2342–50.
23. Cotten A, Dewatre F, Cortet B, et al. Percutaneous verte-
broplasty for osteolytic metastases and myeloma: effects of
the percentage of lesion filling and the leakage of methyl
methacrylate at clinical follow-up. Radiology 1996; 200:
525–30.
24. Theodorou DJ, Theodorou SJ, Sartoris DJ. Treatment of
osteoporosis: current status and recent advances. Compr
Ther 2002; 28: 109–22.
25. Dudeney S, Lieberman IH, Reinhardt MK, Hussein M.
Kyphoplasty in the treatment of osteolytic vertebral com-
pression fractures as a result of multiple myeloma. J Clin
Oncol 2002; 20: 2382–7.
26. McDonald RJ, Trout AT, Gray LA, et al. Vertebroplasty in
multiple myeloma: outcomes in a large patient series. AJNR
Am J Neuroradiol 2008; 29: 642–8.
27. Conte P, Coleman R. Bisphosphonates in the treatment of
skeletal metastases. Semin Oncol 2004; 31: 59–63.
28. Lipton A. Pathophysiology of bone metastases: how this
knowledge may lead to therapeutic intervention. J Support
Oncol 2004; 2: 205–13; discussion 213–14, 216–17, 219–20.
29. Kanis JA, McCloskey EV. Bisphosphonates in multiple
myeloma. Cancer 2000; 88: 3022–32.
30. Theriault RL, Hortobagyi GN. The evolving role of bisphos-
phonates. Semin Oncol 2001; 28: 284–90.
31. Berenson JR, Hillner BE, Kyle RA, et al. American Society
of Clinical Oncology clinical practice guidelines: the role of
bisphosphonates in multiple myeloma. J Clin Oncol 2002;
20: 3719–36.
32. Durie BG, Jacobson J, Barlogie B, Crowley J. Magnitude of
response with myeloma frontline therapy does not predict
outcome: importance of time to progression in Southwest
Oncology Group Chemotherapy Trials. J Clin Oncol 2004;
22: 1857–63.
33. Kyle RA, Yee GC, Somerfield MR, et al. American Society of
Clinical Oncology 2007 clinical practice guideline update on
the role of bisphosphonates in multiple myeloma. J Clin
Oncol 2007; 25: 2464–72.
34. Barlogie B, Jagannath S, Vesole DH, et al. Superiority of
tandem autologous transplantation over standard therapy for
previously untreated multiple myeloma. Blood 1997; 89:
789–93.
35. Zaidi AA, Vesole DH. Multiple myeloma: an old disease with
new hope for the future. CA Cancer J Clin 2001; 51: 273–85.
36. Angtuaco EJ, Fassas AB, Walker R, Sethi R, Barlogie B.
Multiple myeloma: clinical review and diagnostic imaging.
Radiology 2004; 231: 11–23.
866
37. D’Sa S, Abildgaard N, Tighe J, Shaw P, Hall-Craggs M. Guide-
lines for the use of imaging in the management of myeloma.
Br J Haematol 2007; 137: 49–63.
38. Moulopoulos LA, Dimopoulos MA, Smith TL, et al. Prog-
nostic significance of magnetic resonance imaging in patients
with asymptomatic multiple myeloma. J Clin Oncol 1995;
13: 251–6.
39. Mariette X, Zagdanski AM, Guermazi A, et al. Prognostic
value of vertebral lesions detected by magnetic resonance
imaging in patients with stage I multiple myeloma. Br J
Haematol 1999; 104: 723–9.
40. Kapadia SB. Multiple myeloma: a clinicopathologic study of
62 consecutively autopsied cases. Medicine (Baltimore) 1980;
59: 380–92.
41. Mirels H. Metastatic disease in long bones. A proposed
scoring system for diagnosing impending pathologic frac-
tures. Clin Orthop Relat Res 1989; (249): 256–64.
42. Singh J, Fairbairn KJ, Williams C, et al. Expert radiological
review of skeletal surveys identifies additional abnormalities
in 23% of cases: further evidence for the value of myeloma
multi-disciplinary teams in the accurate staging and treat-
ment of myeloma patients. Br J Haematol 2007; 137: 172–3.
43. Smith DB, Scarffe JH, Eddleston B. The prognostic signifi-
cance of X-ray changes at presentation and reassessment in
patients with multiple myeloma. Haematol Oncol 1988; 6:
1–6.
44. Ludwig H, Kupman W, Sinzinger H. Radiography and bone
scintigraphy in multiple myeloma: a comparative analysis.
Br J Radiol 1982; 55: 173–81.
45. Bataille R, Chevalier J, Rossi M, Sany J. Bone scintigraphy in
plasma-cell myeloma. A prospective study of 70 patients.
Radiology 1982; 145: 801–4.
46. Catalano L, Pace L, Califano C, et al. Detection of focal
myeloma lesions by technetium-99m-sestaMIBI scintigraphy.
Haematologica 1999; 84: 119–24.
47. Alexandrakis MG, Kyriakou DS, Passam F, Koukouraki S,
Karkavitsas N. Value of Tc-99m sestamibi scintigraphy in the
detection of bone lesions in multiple myeloma: comparison
with Tc-99m methylene diphosphonate. Ann Haematol
2001; 80: 349–53.
48. Fonti R, Del Vecchio S, Zannetti A, et al. Bone marrow uptake
of 99mTc-MIBI in patients with multiple myeloma. Eur J
Nucl Med 2001; 28: 214–20.
49. Pace L, Catalano L, Pinto A, et al. Different patterns of
technetium-99m sestamibi uptake in multiple myeloma. Eur J
Nucl Med 1998; 25: 714–20.
50. Ishibashi M, Nonoshita M, Uchida M. Bone marrow uptake
of thallium-201 before and after therapy in multiple myeloma.
J Nucl Med 1998; 39: 473–5.
51. Chun KA, Cho IH, Won KC, et al. Comparison of Tc-99m
sestamibi and Tl-201 uptake in multple myeloma. Clin Nucl
Med 2001; 26: 212–15.
52. Schirrmeister H, Bommer L, Buck AK, et al. Initial results in
the assessment of multiple myeloma using 18F-FDG PET.
Eur J Nucl Med Mol Imaging 2002; 29: 361–6.
53. Durie BG, Waxman AD, D’Agnolo A, Williams CM. Whole
body (18)F-FDG PET identifies high-risk myeloma. J Nucl
Med 2002; 43: 1457–63.
 multiple myeloma
54. Bredella MA, Steinbach L, Caputo G, Segall G, Hawkins R.
Value of FDG PET in the assessment of patients with multi-
ple myeloma. AJR Am J Roentgenol 2005; 184: 1199–204.
55. Adam Z, Bolcak K, Stanicek J, et al. Fluorodeoxyglucose
positron emission tomography in multiple myeloma, solitary
plasmocytoma and monoclonal gammapathy of unknown
significance. Neoplasma 2007; 54: 536–40.
56. Breyer RJ 3rd, Mulligan ME, Smith SE, Line BR, Badros AZ.
Comparison of imaging with FDG PET/CT with other imag-
ing modalities in myeloma. Skeletal Radiol 2006; 35: 632–40.
57. Zamagni E, Nanni C, Patriarca F, et al. A prospective com-
parison of 18F-fluorodeoxyglucose positron emission
tomography-computed tomography, magnetic resonance
imaging and whole-body planar radiographs in the assess-
ment of bone disease in newly diagnosed multiple myeloma.
Haematologica 2007; 92: 50–5.
58. Fonti R, Salvatore B, Quarantelli M, et al. 18F-FDG PET/CT,
99mTc-MIBI, and MRI in evaluation of patients with mul-
tiple myeloma. J Nucl Med 2008; 49: 195–200.
59. Lin C, Luciani A, Itti E, Haioun C, Rahmouni A. Whole body
MRI and PET/CT in haematological malignancies. Cancer
Imaging 2007; 7 Spec No A: S88–93.
60. Mulligan ME, Badros AZ. PET/CT and MR imaging in
myeloma. Skeletal Radiol 2007; 36: 5–16.
61. Mahfouz T, Miceli MH, Saghafifar F, et al. 18F-fluorode-
oxyglucose positron emission tomography contributes to the
diagnosis and management of infections in patients with
multiple myeloma: a study of 165 infectious episodes. J Clin
Oncol 2005; 23: 7857–63.
62. Juweid ME, Cheson BD. Positron-emission tomography
and assessment of cancer therapy. N Engl J Med 2006; 354:
496–507.
63. Nanni C, Zamagni E, Cavo M, et al. 11C-choline vs. 18F-FDG
PET/CT in assessing bone involvement in patients with
multiple myeloma. World J Surg Oncol 2007; 5: 68.
64. Dankerl A, Liebisch P, Glatting G, et al. Multiple Myeloma:
Molecular Imaging with 11C-Methionine PET/CT—Initial
Experience. Radiology 2007; 242: 498–508.
65. Helms CA, Genant HK. Computed tomography in the early
detection of skeletal involvement with multiple myeloma.
JAMA 1982; 248: 2886–7.
66. Mahnken AH, Wildberger JE, Gehbauer G, et al. Multi-
detector CT of the spine in multiple myeloma: comparison
with MR imaging and radiography. AJR Am J Roentgenol
2002; 178: 1429–36.
67. Horger M, Claussen CD, Bross-Bach U, et al. Whole-body
low-dose multidetector row-CT in the diagnosis of multiple
myeloma: an alternative to conventional radiography. Eur J
Radiol 2005; 54: 289–97.
68. Kröpil P, Fenk R, Fritz LB, et al. Comparison of whole-body
64-slice multidetector computed tomography and conven-
tional radiography in staging of multiple myeloma. Eur
Radiol 2008; 18: 51–8.
69. Horger M, Kanz L, Denecke B, et al. The benefit of using
whole-body, low-dose, nonenhanced, multidetector computed
tomography for follow-up and therapy response monitoring
in patients with multiple myeloma. Cancer 2007; 109:
1617–26.
70. Hur J, Yoon CS, Ryu YH, Yun MJ, Suh JS. Efficacy of multide-
tector row computed tomography of the spine in patients
with multiple myeloma: comparison with magnetic reso-
nance imaging and fluorodeoxyglucose-positron emission
tomography. J Comput Assist Tomogr 2007; 31: 342–7.
71. Mulligan ME. Imaging techniques used in the diagnosis,
staging, and follow-up of patients with myeloma. Acta Radiol
2005; 46: 716–24.
72. Walker R, Barlogie B, Haessler J, et al. Magnetic resonance
imaging in multiple myeloma: diagnostic and clinical impli-
cations. J Clin Oncol 2007; 25: 1121–8.
73. Baur-Melnyk A, Buhmann S, Dürr HR, Reiser M. Role of
MRI for the diagnosis and prognosis of multiple myeloma.
Eur J Radiol 2005; 55: 56–63.
74. Schmidt GP, Schoenberg SO, Reiser MF, Baur-Melnyk A.
Whole-body MR imaging of bone marrow. Eur J Radiol 2005;
55: 33–40.
75. Johnston C, Brennan S, Ford S, Eustace S. Whole body MR
imaging: applications in oncology. Eur J Surg Oncol 2006; 32:
239–46.
76. Schmidt GP, Reiser MF, Baur-Melnyk A. Whole-body imag-
ing of the musculoskeletal system: the value of MR imaging.
Skeletal Radiol 2007; 36: 1109–19.
77. Ghanem N, Lohrmann C, Engelhardt M, et al. Whole-body
MRI in the detection of bone marrow infiltration in patients
with plasma cell neoplasms in comparison to the radiologi-
cal skeletal survey. Eur Radiol 2006; 16: 1005–14.
78. Dimopoulos MA, Moulopoulos LA, Datseris I, et al. Imaging
of myeloma bone disease—implications for staging, progno-
sis and follow-up. Acta Oncol 2000; 39: 823–7.
79. Lecouvet FE, Vandeberg BC, Malghem J, Maldague BM.
Magnetic resonance and computed tomography imaging in
multiple myeloma. Semin Musculoskelet Radiol 2001; 5: 43–55.
80. Baur-Melnyk A, Reiser M. [Staging of multiple myeloma
with MRI: comparison to MSCT and conventional radiogra-
phy]. Radiologe 2004; 44: 874–81.
81. Stäbler A, Baur A, Bartl R, et al. Contrast enhancement and
quantitative signal analysis in MR imaging of multiple
myeloma: assessment of focal and diffuse growth patterns in
marrow correlated with biopsies and survival rates. AJR Am
J Roentgenol 1996; 167: 1029–36.
82. Bartl R, Frisch B, Fateh-Moghadam A, et al. Histologic classifi-
cation and staging of multiple myeloma. A retrospective and
prospective study of 674 cases. Am J Clin Pathol 1987; 87:
342–55.
83. Nosàs-Garcia S, Moehler T, Wasser K, et al. Dynamic
contrast-enhanced MRI for assessing the disease activity of
multiple myeloma: a comparative study with histology and
clinical markers. J Magn Reson Imaging 2005; 22: 154–62.
84. Weininger M, Lauterbach B, Knop S, et al. Whole-body MRI
of multiple myeloma: Comparison of different MRI
sequences in assessment of different growth patterns. Eur J
Radiol 2008; 69: 339–45.
85. Lecouvet FE, Vande Berg BC, Michaux L, et al. Stage III mul-
tiple myeloma: clinical and prognostic value of spinal bone
marrow MR imaging. Radiology 1998; 209: 653–60.
86. Van de Berg BC, Lecouvet FE, Michaux L, et al. Stage I
multiple myeloma: value of MR imaging of the bone marrow
867
 hematology malignancy
in the determination of prognosis. Radiology 1996; 201:
243–6.
87. Lecouvet FE, Malghem J, Michaux L, et al. Vertebral com-
pression fractures in multiple myeloma. Part II. Assessment
of fracture risk with MR imaging of spinal bone marrow.
Radiology 1997; 204: 201–5.
88. Baur A, Stäbler A, Bruning R, et al. Diffusion-weighted MR
imaging of bone marrow: differentiation of benign versus
pathologic compression fractures. Radiology 1998; 207:
349–56.
89. Le Bihan DJ. Differentiation of benign versus pathologic
compression fractures with diffusion-weighted MR imaging:
a closer step toward the “holy grail” of tissue characteriza-
tion? Radiology 1998; 207: 305–7.
90. Baur A, Huber A, Ertl-Wagner B, et al. Diagnostic value of
increased diffusion weighting of a steady-state free preces-
sion sequence for differentiating acute benign osteoporotic
fractures from pathologic vertebral compression fractures.
AJNR Am J Neuroradiol 2001; 22: 366–72.
91. Castillo M. Diffusion-weighted imaging of the spine: is it
reliable? AJNR Am J Neuroradiol 2003; 24: 1251–3.
92. Cuénod CA, Laredo JD, Chevret S, et al. Acute vertebral
collapse due to osteoporosis or malignancy: appearance
on unenhanced and gadolinium-enhanced MR images.
Radiology 1996; 199: 541–9.
93. Lecouvet FE, Vande Berg BC, Maldague BE, et al. Vertebral
compression fractures in multiple myeloma. Part I. Distribu-
tion and appearance at MR imaging. Radiology 1997; 204:
195–9.
94. Moulopoulos LA, Dimopoulos MA, Alexanian R, Leeds NE,
Libshitz HI. Multiple myeloma: MR patterns of response to
treatment. Radiology 1994; 193: 441–6.
95. Desikan R, Barlogie B, Sethi R, et al. Infection—an under-
appreciated cause of bone pain in multiple myeloma. Br J
Haematol 2003; 120: 1047–50.
96. Burton CH, Fairham SA, Millet B, DasGupta R, Sivakumaran
M. Unusual aetiology of persistent back pain in a patient
with multiple myeloma: infectious discitis. J Clin Pathol
1998; 51: 633–4.
97. Tung GA, Rogg JM. Diffusion-weighted imaging of cerebri-
tis. AJNR Am J Neuroradiol 2003; 24: 1110–13.
98. Desikan R, Barlogie B, Sawyer J, et al. Results of high-dose
therapy for 1000 patients with multiple myeloma: durable
complete remissions and superior survival in the absence of
chromosome 13 abnormalities. Blood 2000; 95: 4008–10.
99. Bucher E, Trampuz A, Donati L, Zimmerli W. Spondylodisci-
tis associated with bacteraemia due to coagulase-negative
staphylococci. Eur J Clin Microbiol Infect Dis 2000; 19:
118–20.
100. Chew FS, Kline MJ. Diagnostic yield of CT-guided percuta-
neous aspiration procedures in suspected spontaneous infec-
tious diskitis. Radiology 2001; 218: 211–14.
101. Williams L, Beveridge RA, Rifkin RM, et al. Increased pulmo-
nary toxicity results from a 1-day versus 2-day schedule of
administration of high-dose melphalan. Biol Blood Marrow
Transplant 2002; 8: 334–5.
102. Srkalovic G, Elson P, Trebisky B, Karam MA, Hussein MA.
Use of melphalan, thalidomide, and dexamethasone in treat-
868
ment of refractory and relapsed multiple myeloma. Med
Oncol 2002; 19: 219–26.
103. Palumbo A, Bringhen S, Bertola A, et al. Multiple myeloma:
comparison of two dose-intensive melphalan regimens (100
vs 200 mg/m(2)). Leukemia 2004; 18: 133–8.
104. Carlson K, Hjorth M, Knudsen LM. Toxicity in standard
melphalan-prednisone therapy among myeloma patients
with renal failure—a retrospective analysis and recommendations
for dose adjustment. Br J Haematol 2005; 128: 631–5.
105. Osman K, Comenzo R, Rajkumar SV. Deep venous thrombo-
sis and thalidomide therapy for multiple myeloma. N Engl J
Med 2001; 344: 1951–2.
106. Rajkumar SV. Thalidomide: tragic past and promising future.
Mayo Clin Proc 2004; 79: 899–903.
107. Onozawa M, Hashino S, Sogabe S, et al. Side effects and good
effects from new chemotherapeutic agents. Case 2. Thalidomide-
induced interstitial pneumonitis. J Clin Oncol 2005; 23:
2425–6.
108. Kyle RA, Rajkumar SV. Multiple myeloma. N Engl J Med 2004;
351: 1860–73.
109. Moon SJ, Min CK, Lee DG, et al. Pseudomembranous colitis
following bortezomib therapy in a myeloma patient. Acta
Haematol 2007; 117: 211–14.
110. Lugassy G, Shaham R, Nemets A, Ben-Dor D, Nahlieli O.
Severe osteomyelitis of the jaw in long-term survivors of
multiple myeloma: a new clinical entity. Am J Med 2004; 117:
440–1.
111. Vannucchi AM, Ficarra G, Antonioli E, Bosi A. Osteonecrosis
of the jaw associated with zoledronate therapy in a patient
with multiple myeloma. Br J Haematol 2005; 128: 738.
112. Kelleher FC, McKenna M, Collins C, et al. Bisphosphonate
induced osteonecrosis of the jaws: unravelling uncertainty in
disease causality. Acta Oncol 2007; 46: 702–4.
113. Kelleher FC, McKenna M, Collins CD, Crown JP. A potential
anatomic cause of mandibular osteonecrosis in patients
receiving bisphosphonate treatment. Mayo Clin Proc 2007;
82: 134; author reply 134–5.
114. Phal PM, Myall RW, Assael LA, Weissman JL. Imaging find-
ings of bisphosphonate-associated osteonecrosis of the jaws.
AJNR Am J Neuroradiol 2007; 28: 1139–45.
115. Aydin K, Donmez F, Tuzun U, Minareci O, Atamer T. Diffu-
sion MR findings in cyclosporin-A induced encephalopathy.
Neuroradiology 2004; 46: 822–4.
116. Attal M, Harousseau JL. Role of autologous stem-cell trans-
plantation in multiple myeloma. Best Pract Res Clin Haematol
2007; 20: 747–59.
117. Woo E, Yu YL, Ng M, Huang CY, Todd D. Spinal cord
compression in multiple myeloma; who gets it? Aus N Z J
Med 1986; 16: 671–5.
118. Speiss JL, Adelstein DJ, Hines JD. Multiple myeloma pre-
senting with spinal cord compression. Oncology 1988; 45:
88–92.
119. Loughrey GJ, Collins CD, Todd SM, Brown NM, Johnson RJ.
Magnetic resonance imaging in the management of suspected
spinal canal disease in patients with known malignancy. Clin
Radiol 2000; 55: 849–55.
120. Theodorou SJ, Theodorou DJ, Schweitzer ME, Kakitsubata Y,
Resnick D. Magnetic resonance imaging of para-acetabular
 multiple myeloma
insufficiency fractures in patients with malignancy. Clin
Radiol 2006; 61: 181–90.
121. Abildgaard N, Brixen K, Eriksen EF, et al. Sequential analysis of
biochemical markers of bone resorption and bone densitometry
in multiple myeloma. Haematologica 2004; 89: 567–77.
122. Lafforgue P, Dahan E, Chagnaud C, et al. Early-stage avascular
necrosis of the femoral head: MR imaging for prognosis in
31 cases with at least 2 years of follow-up. Radiology 1993;
187: 199–204.
123. Kyle RA. Multiple myeloma: review of 869 cases. Mayo Clin
Proc 1975; 50: 29–40.
124. Subramanyam BR. Renal amyloidosis in juvenile rheumatoid
arthritis: sonographic features. AJR Am J Roentgenol 1981;
136: 411–12.
125. Hawkins PN. Serum amyloid P component scintigraphy for
diagnosis and monitoring amyloidosis. Curr Opin Nephrol
Hypertens 2002; 11: 649–55.
126. Hachulla E, Maulin L, Deveaux M, et al. Prospective and
serial study of primary amyloidosis with serum amyloid P
component scintigraphy: from diagnosis to prognosis. Am J
Med 1996; 101: 77–87.
127. Lecouvet FE, De Nayer P, Garbar C, et al. Treated plasma cell
lesions of bone with MRI signs of response to treatment:
unexpected pathological findings. Skeletal Radiol 1998; 27:
692–5.
128. Rahmouni A, Divine M, Mathieu D, et al. MR appearance of
multiple myeloma of the spine before and after treatment.
AJR Am J Roentgenol 1993; 160: 1053–7.
129. Lecouvet F, Richard F, Vande Berg B, et al. Long-term effects
of localised spinal radiation therapy on vertebral fractures
and focal lesions appearance in patients with multiple
myeloma. Br J Haematol 1997; 96: 743–5.
130. Agren B, Rudberg U, Isberg B, Svensson L, Aspelin P. MR
imaging of multiple myeloma patients with bone marrow
transplants. Acta Radiol 1998; 39: 36–42.
131. Lecouvet FE, Dechambre S, Malghem J, et al. Bone marrow
transplantation in patients with multiple myeloma: prognos-
tic significance of MR imaging. AJR Am J Roentgenol 2001;
176: 91–96.
132. Lecouvet FE, Malghem J, Michaux L, et al. Skeletal survey in
advanced multiple myeloma: radiographic versus MR imaging
survey. Br J Haematol 1999; 106: 35–39.
133. Fassas AB, Muwalla F, Berryman T, et al. Myeloma of the cen-
tral nervous system: association with high-risk chromosomal
abnormalities, plasmablastic morphology and extramedullary
manifestations. Br J Haematol 2002; 117: 103–8.
134. Moulopoulos LA, Dimopoulos MA, Weber D, et al. Magnetic
resonance imaging in the staging of solitary plasmacytoma
of bone. J Clin Oncol 1993; 11: 1311–15.
135. Hartman RP, Sundaram M, Okuno SH, Sim FH. Effect of
granulocyte-stimulating factors on marrow of adult patients
with musculoskeletal malignancies: incidence and MRI find-
ings. AJR Am J Roentgenol 2004; 183: 645–53.
136. Sezer O, Niemöller K, Jakob C, et al. Relationship between
bone marrow angiogenesis and plasma cell infiltration and
serum beta2-microglobulin levels in patients with multiple
myeloma. Ann Haematol 2001; 80: 598–601.
137. Alper E, Gurel M, Evrensel T, et al. 99mTc-MIBI scintigraphy
in untreated stage III multiple myeloma: comparison with
X-ray skeletal survey and bone scintigraphy. Nucl Med
Commun 2003; 24: 537–42.
138. Pace L, Catalano L, Del Vecchio S, et al. Predictive value of
technetium-99m sestamibi in patients with multiple myeloma
and potential role in the follow-up. Eur J Nucl Med 2001; 28:
304–12.
139. Koutsikos J, Grigoraki V, Athanasoulis T, et al. Scintigraphy
with technetium-99m methoxyisobutylisonitrile in multiple
myeloma patients: correlation with the International Staging
System. Hell J Nucl Med 2006; 9: 177–80.
140. Erten N, Saka B, Berberoglu K, et al. Technetium-99m
2-methoxy-isobutyl-isonitrile uptake scintigraphy in detec-
tion of the bone marrow infiltration in multiple myeloma:
correlation with MRI and other prognostic factors. Ann
Hematol 2007; 86: 805–13.
141. Mele A, Offidani M, Visani G, et al. Technetium-99m sesta-
mibi scintigraphy is sensitive and specific for the staging
and the follow-up of patients with multiple myeloma: a
multicentre study on 397 scans. Br J Haematol 2007; 136:
729–35.
142. Pace L, Del Vecchio S, Salvatore M. Technetium 99m sesta-
mibi in multiple myeloma. Radiology 2005; 234: 312–13;
author reply 313.
143. Fallahi B, Saghari M, Fard Esfahani A, et al. The value of
99mTc-MIBI whole body scintigraphy in active and in remis-
sion multiple myeloma. Hell J Nucl Med 2005; 8: 165–8.
144. Jadvar H, Conti PS. Diagnostic utility of FDG PET in multi-
ple myeloma. Skeletal Radiol 2002; 31: 690–4.
145. Orchard K, Barrington S, Buscombe J, et al. Fluoro-
deoxyglucose positron emission tomography imaging for
the detection of occult disease in multiple myeloma. Br J
Haematol 2002; 117: 133–5.
146. Kazama T, Swanston N, Podoloff DA, Macapinlac HA. Effect
of colony-stimulating factor and conventional- or high-dose
chemotherapy on FDG uptake in bone marrow. Eur J Nucl
Med Mol Imaging 2005; 32: 1406–11.
147. Wiesenthal AA, Nguyen BD. F-18 FDG PET/CT staging of
multiple myeloma with diffuse osseous and extramedullary
lesions. Clin Nucl Med 2007; 32: 797–801.
148. Okacha N, Chrif E, Brahim E, et al. Extraosseous epidural
multiple myeloma presenting with thoracic spine compression.
Joint Bone Spine 2008; 75: 70–72.
149. Patlas M, Hadas-Halpern I, Libson E. Imaging findings of
extraosseous multiple myeloma. Cancer Imaging 2002; 2:
120–2.
150. Grover SB, Dhar A. Imaging spectrum in sclerotic myelomas:
an experience of three cases. Eur Radiol 2000; 10: 1828–31.
869
 35 Leukemia
Dow-Mu Koh and Janet E Husband
INTRODUCTION
Leukemias are a group of diverse neoplasms which are derived
from the arrested or aberrant development of a clone of normal
hemopoietic cells. These immature cells proliferate progressively
within the bone marrow replacing normal hemopoietic tissue and
circulate within the peripheral blood becoming deposited in
various organs and tissues, such as the spleen and lymph nodes.
Leukemic cells are incapable of normal function and many of
the clinical features and complications arising from this condition
are a direct result of the failure of normal hemopoietic activity.
There are four major groups of leukemia, categorized according
to the predominant type of proliferating cell:
• Acute myelogenous leukemia (AML)
• Acute lymphoblastic leukemia (ALL)
• Chronic myelocytic leukemia (CML)
• Chronic lymphocytic leukemia (CLL)
A complete classification of the leukemias has become increas-
ingly complex as new methods of discriminating different sub-
types, such as immunophenotyping and cytogenetic studies, have
been developed. Thus the subclassification and characterization
of the leukemias continues to evolve (1,2). Two major classifica-
tion systems are in use: the French-American-British (FAB) clas-
sification system and the World Health Organization (WHO)
classification system. The classification shown in Table 35.1 is
illustrative of the wide-ranging heterogeneity of these diseases,
but a detailed review of the two classification systems is beyond
the scope of this chapter.
While the radiologist working in oncological practice does not
need to have a full understanding of the different subtypes of leu-
kemia, some knowledge of the subtypes is useful as they manifest
different radiological appearances.
There is some overlap between leukemias and lymphomas. How-
ever, in general, ALL is distinguished from lymphomas on the basis
of cellular maturity and by the fact that at least initially lymphomas
mainly involve extramedullary sites. The lymphoblastic lympho-
mas and Burkitt’s lymphoma have features of both leukemia and
lymphoma. Adult T-cell leukemia/lymphoma (ATLL) is a distinct
variety of leukemia/lymphoma that is characterized by lymph-
adenopathy and hepatosplenomegaly and is endemic in certain
parts of the world including Japan and the Caribbean basin.
Myelodysplasia is a syndrome characterized by pancytopenia or
chronic anemia which results from dysfunction of the bone mar-
row. Transformation into acute leukemia may develop during the
course of disease.
Cross-sectional imaging, as well as conventional radiology, has
an important place in the management of leukemia. However, it is
impossible to define strict algorithms for the use of imaging
because the disease is manifested in many different organs and
organ systems and the complications of leukemia are common
870
and diverse. As in other malignant tumors, close liaison between
clinician and radiologist is essential to determine the most appro-
priate use of imaging for individual patient care.
INCIDENCE AND ETIOLOGY
Acute leukemias account for less than 3% of all cancers in the
United States but are a leading cause of cancer death in patients
under the age of 35 years. The estimated number of new cases
of leukemia in the United States in 2008 was 44,270. Chronic
leukemias accounted for 7% more cases than acute leukemias. The
total number of deaths was estimated at approximately 21,700 (3).
Interestingly, mortality from CML has decreased due to improved
treatment outcome using the multi-kinase inhibitor Imatinib.
Subtype New cases (3) Deaths (3)
Acute myeloid leukemia 13,290 8,820
Chronic lymphatic leukemia 15,110 4,390
Chronic myeloid leukemia 4,830 450
Acute lymphocytic leukemia 5,430 1,460
Other leukemias 5,610 6,590
The most common type of leukemia in children under 19 years
of age is ALL. Acute myelogenous leukemia is more common than
ALL in adults. In adults, the most common subtypes of leukemia
are AML and CLL.
In the United Kingdom, the incidence of leukemia in relation to
other cancers and the distribution of subtypes is similar to that in
the United States. There are about 7300 new cases diagnosed annu-
ally and in 2006 there were 4292 deaths in the United Kingdom (4).
Leukemia incidence rates in Great Britain increased slowly until
the end of the 1990s. However, the last few years have started to see
a fall in the incidence rates. The current overall lifetime risk of
developing leukemia is 1.0% in males and 0.8% in females.
More recently, enormous strides have been made in understand-
ing the molecular biology and cytogenetics of leukemia. Various
chromosomal abnormalities have been identified which have
helped to define the subsets of AML and ALL listed in the classifi-
cation (e.g., Philadelphia chromosome-positive). These subsets of
leukemia have various clinical features and different patterns of
response to therapy. This information is used to direct patients to
particular therapeutic regimens and, in the longer-term, may
allow appropriate targeting of new therapies.
While the importance of genetic changes in the development of
the leukemias is well-established, the underlying causes initiating
these changes are largely unknown. Down’s syndrome and certain
other genetic syndromes are linked to leukemia. Excessive exposure
to ionizing radiation (5), chronic exposure to low-dose radiation
in the environment, chemicals, and smoking (6) have now been
established as important causes. It is worth pointing out that many
people with risk factors do not develop the disease, and many patients
diagnosed with leukemia do not have any apparent risk factors.
 leukemia

Table 35.1 Classification of Leukemia CLINICAL FEATURES

Acute
Acute myelogenous leukemia (AML) The replacement of normal hemopoietic cells within the bone
Acute myeloblastic leukemia marrow by an excessive number of abnormal functionless cells is
Acute promyelocytic leukemia responsible for the major clinical features of leukemias:
Acute myelomonocytic leukemia
Acute monoblastic leukemia • Anemia
Acute erythroleukemia
Acute megakaryoblastic leukemia
• Infection
Acute lymphoblastic leukemia (ALL) • Hemorrhage
Pre-B-cell acute lymphoblastic leukemia In acute leukemia, patients usually present with a one month to
Common acute lymphoblastic leukemia
three months history of weight loss, fatigue, bruising, or signs of
Cytoplasmic immunoglobulin (+) ALL
Philadelphia chromosome (+) ALL infection such as fever. In chronic leukemias, the onset of disease
T-cell is more insidious but fever may be observed without an obvious
B-cell infective cause. Occasionally, the diagnosis of chronic leukemia
Acute unclassifiable leukemia (AUL) is made on routine examination of the peripheral blood in an
Chronic otherwise asymptomatic patient.
Chronic myelocytic leukemia (CML)
In all patients, the diagnosis is confirmed by examination of the
Chronic phase of CML
Metamorphosis of CML
peripheral blood and bone marrow biopsy. Immunophenotyping
Accelerated ± myelofibrosis and cytogenetic studies are performed to discriminate between
Lymphoblastic transformation the different subsets of the disease. A majority of patients have
Myeloblastic transformation anemia and thrombocytopenia. The peripheral white cell blood
Megakaryoblastic transformation count may be normal, raised, or reduced but blast cells are seen in
Juvenile chronic granulocytic leukemia
Chronic eosinophilic leukemia
the peripheral blood of almost all the patients.
Chronic lymphocytic leukemia (CLL) Certain clinical features of leukemia are more prevalent in one
B-cell subtype than another, and the frequency of involvement of differ-
T-cell ent organs and sites also varies (Table 35.2) (15).
Hairy cell leukemia In acute leukemias, central nervous system (CNS) involvement
Polymorphocytic leukemia
Plasma cell leukemia
is more common in ALL than AML but is also seen in chronic
Sézary syndromea leukemias. The CNS is resistant to chemotherapy and is therefore
Adult T-cell leukemia/lymphoma termed a ‘‘sanctuary site’’ of disease.
a
Leukemic phase of mycosis fungoides. Hepatosplenomegaly due to leukemia infiltration is seen
in almost all cases but the degree of enlargement is greater in
chronic than in acute leukemias (Fig. 35.1).
Secondary AML may develop after treatment of childhood acute Lymphadenopathy is most frequently seen in CLL and in juve-
leukemia and following therapy for other cancers such as tumors nile CML (Figs. 35.2 and 35.3). It is rare in adult Philadelphia
of the breast and ovary, and Hodgkin’s disease (7–10). chromosome-positive CML. The incidence of enlarged lymph
A human retrovirus (HTLV-1) has been identified as a cause of nodes at presentation in the acute leukemias is as follows:
human T-cell leukemia/lymphoma (ATLL) (11,12). The cumula-
tive risk of an infected individual developing ATLL is estimated to
• Acute lymphoblastic leukemias (50%) (usually T-cell or
B-cell)
be between 0.5% and 5% (13,14).
• Acute monoblastic leukemias (15–20%)
Key Points: General Features • Other subtypes of acute myelogenous leukemia (8%) (16)
Fever is a common feature of all the leukemias whether due to infec-
■ Leukemias are derived from the arrested or aberrant tion or not. In those without documented infection, fever may be
development of a clone of normal hemopoietic cells caused by increased metabolism due to the leukemic process.
■ Various subtypes are recognized which have different clinical
Anemia is present in the majority of patients and is caused by
features, and radiological features, prognosis, and therapeutic inadequate erythrocyte production, bleeding, hypersplenism, or
implications hemolysis.
■ ALL is the most common subtype in childhood
Bleeding is more common in the acute leukemias than in the
■ AML and CLL are the most common subtypes in adults
chronic subtypes and usually takes the form of small petechial
■ Various chromosomal abnormalities have been identified in
hemorrhages. Occasionally, a patient may present with a cata-
the leukemias strophic intracranial hemorrhage.
■ Acute leukemias account for about 3% and chronic leukemias
In the acute leukemias hemorrhage is a major cause of death and
for about 7% of all cancers in the United States morbidity. Hemorrhage results from coagulation defects associated
■ Down’s syndrome is strongly linked with acute leukemia
with the disease, thrombocytopenia, and the effects of chemother-
■ Ionizing radiation, chemicals, and smoking cause leukemia
apy. The acute promyelocytic form of leukemia is particularly prone
■ The human retrovirus (HTLV-1) infection causes human
to hemorrhage and, in one study, intracranial hemorrhage was the
T-cell leukemia/lymphoma cause of death in 60% of patients (17). Another group of patients at

871
 hematology malignancy

particularly high risk of intracranial hemorrhage are those with Patients with intracranial hemorrhage present acutely with
acute leukemia in “blast” crisis. In such patients the excessive num- headaches, seizures, and deterioration of neurological functions.
bers of leucocytes form tiny foci which plug small arterioles and Rarely, intracranial hemorrhage may lead to the diagnosis of acute
destroy the vascular walls, leading to hemorrhage (18). leukemia.
Bone pain is a common presenting feature in children with
ALL, occurring in 25% to 30% of cases, whereas in adults it is
Table 35.2 Organ Involvement by Leukemia Cell Type
only seen in approximately 5% of patients (19,20). Bone pain
(1958–1982) (15)
is characteristically migratory and periarticular (21). It is prob-
Organ/sites AML (%) CML (%) ALL (%) CLLa(%) ably due to lifting of the periosteum by infiltration of leukemic
CNS (sanctuary sites) cells or to the development of bone infarction (22). Mono-
Brain 9 11 14 7 arthralgia or polyarthralgia is not an uncommon presenting
Dura mater 14 14 26 21 feature.
Leptomeninges 12 10 34 8 Abdominal and chest pain are also relatively common and are
Lymphoreticular sites related to a variety of problems. For example, abdominal pain
Liver 41 55 63 83
may result from stretching of the splenic capsule due to its rapid
Lymph nodes 45 59 55 76
Spleen 58 68 70 76 enlargement or from intestinal obstruction due to leukemic
Cardiopulmonary infiltration of the bowel wall. Chest pain may be caused by a large
Pericardium 8 6 11 14 mediastinal mass compressing adjacent structures.
Heart 15 11 21 22 Granulocytic sarcoma (chloroma) is a mass composed of leu-
Pleura 8 5 11 16 kemic cells. These tumors are usually seen in patients with AML
Lungs 28 29 41 41
but may also occur in CML and other myeloprolific disorders
Gastro-intestinal
such as polycythemia rubra vera (23). They consist of myelo-
Esophagus 17 9 16 19
Stomach 11 11 17 11 blasts, promyelocytes, and myelocytes and are most frequently
Large bowel 15 9 20 15 found in the orbits, subcutaneous tissues, paranasal sinuses,
Pancreas 8 6 18 12 lymph nodes, and bones but many other sites have also been
Endocrine described (24). In a series of 728 patients with childhood
Pituitary 9 10 15 20 myelogenous leukemia, Pui et al. found an incidence of 4.7% of
Thyroid 6 3 5 7
granulocytic sarcoma developing at some point during the
Adrenals 15 22 21 33
course of disease. Others have reported an incidence ranging
Genito-urinary
Kidneys 33 38 53 63 from 2.5% to 8% (25,26). Rarely, these tumors may be the pre-
Bladder 7 6 9 8 senting feature of leukemia occurring before the onset of clini-
Prostate 9 5 12 22 cally overt disease (27). They were first described by Burns in
Uterus 11 4 25 14 1811 (28) but it was not until 1853 that the term chloroma was
Gonads (sanctuary sites) coined by King to describe their typical greenish color (29).
Testes 20 16 40 15 However, in 1966, the term chloroma was replaced by granulo-
Ovaries 11 9 21 22
cytic sarcoma because fewer than half of them actually display
Total number of cases 585 204 308 109
the characteristic greenish color.
a
Percentage of all cases examined.

Figure 35.1 A 54-year-old man with acute lymphoblastic leukemia. Coronal and sagittal CT reformats allow the volume of the enlarged spleen to be calculated. Note also
the enlarged portal lymph node (arrowhead) and retroperitoneal lymph nodes (arrows).

872
 leukemia

(A) (B)

(C)

Figure 35.2 A male patient with CLL showing multiple enlarged lymph nodes on CT. (A) in the mediastinum and axillae, (B) in the retroperitoneum, and (C) in the pelvis.

(B)

(A)

(C)
Figure 35.3 In this 24-year-old patient with ALL, there is nodal enlargement seen (A) along the deep cervical chain of lymph nodes in the neck, (B) both axillae, and
(C) within the retroperitoneum. Note also the diffusely enlarged kidneys due to leukemic infiltration.

873
 hematology malignancy
Key Points: Clinical Features
■ The major clinical features of leukemia are anemia, infection,
and hemorrhage
■ CNS involvement is more common in ALL than AML
■ Lymphadenopathy is most frequently seen in CLL
■ Bone pain is a common presenting feature in childhood
leukemia, occurring in about 25% of cases. Bone pain occurs
in only 5% of adults
■ Granulocytic sarcoma is a mass composed of leukemic cells
which occurs most frequently in AML. The incidence ranges
from 2.5% to 8%
■ The most common sites of granulocytic sarcoma are the
orbits, subcutaneous tissues, paranasal sinuses, and bones
STAGING AND TREATMENT
At diagnosis, the leukemias are usually widely disseminated. Con-
sequently, conventional staging using tumor size measurement,
nodal dissemination, and metastatic involvement (TNM classifi-
cation) is inappropriate. Laboratory tests rather than imaging are
used to determine the type of leukemia, which in turn influences
the choice of treatment. However, in clinical practice, the leukemias
are still often classified or staged, because this provides important
prognostic information as well as giving an indication of the
likelihood of response to treatment.
Treatment of acute leukemia aims to induce a remission as
quickly as possible and then to maintain remission. The success of
therapy depends as much on the treatment of non-leukemic-
related problems as on the eradication of leukemia itself.
In the acute leukemias, certain features are important prognos-
tic factors and determine the detailed approach to management.
These include patient age (older patients are less likely to achieve
complete remission) or previous myelodysplasia. Certain cytoge-
netic subtypes have a poorer prognosis. For example, in adult
patients with ALL, the Philadelphia chromosome (a translocation
between chromosomes 9 and 22) can be detected in 20% to 25%
of cases, which is a poor prognostic indicator.
Acute lymphoblastic leukemia (common ALL) is the most success-
fully treated of all the leukemias (30–33). Complete remission can be
achieved in over 90% of children and in up to 80% of adults (30).
IMAGING IN LEUKEMIA
Leukemia is diagnosed and monitored by hematological studies of
the peripheral blood and bone marrow and imaging therefore plays a
lesser role in the diagnosis and staging of this disease than in the lym-
phomas. However, the importance of radiology in the management
of leukemia has increased over the last two decades, mainly due to
the advent of cross-sectional imaging and also to improvements in
therapy. Imaging is used to evaluate the leukemic process itself or to
investigate its complications. Thus the imaging findings in leukemia
can be broadly categorized into two groups, those related to:
• Direct involvement of organs and tissues by leukemic cells
• Indirect involvement of organs and tissues due to
complications
874
In this text, direct and indirect imaging findings will be discussed
in relation to different anatomical sites and organ systems.
Central Nervous System
Direct Involvement by Leukemia
Central nervous system (CNS) involvement is usually seen in
acute leukemia. It may be a manifestation of disease at diagnosis
or may herald relapse in patients believed to be in remission.
At diagnosis, less than 10% of adults with ALL have CNS involve-
ment and it does not appear to be an independent prognostic
indicator (34). The number of patients who relapse with CNS
involvement has been dramatically reduced by the introduction of
CNS prophylactic therapy (35).
Leukemic spread to the CNS is presumed to be by direct infil-
tration from involved bone marrow of the cranium (or vertebrae)
or by the hematogenous route whereby circulating leukemia cells
enter the CNS by migration through spaces in the venous
endothelium (36,37).
The leukemic process may involve the leptomeninges, dura, or
both, and may be diffuse or focal. Meningeal involvement occurs
in up to 10% of patients with acute leukemia and begins in the
superficial arachnoid membrane; leukemic cells then invade the
cerebrospinal fluid (CSF) space and pia mater (38,39). Extradural
(parameningeal) masses (granulocytic sarcoma) may also be
observed in intracranial or intraspinal sites. Involvement of the
brain parenchyma is rare but when it does occur, it probably
results from perivascular extension of the disease across the
Virchow–Robin spaces through the pia–glial membrane (40).
Intracerebral and meningeal granulocytic sarcomas are a rare
occurrence in myelogenous leukemias.
Meningeal and Dural Disease
Symptoms of meningeal involvement of the brain include head-
ache, nausea, vomiting, and lethargy. Signs of intracranial pressure
and cranial nerve palsies may be apparent on clinical examination
(35). Meningeal involvement is diagnosed based on the finding of
leukemic cells within CSF. However, analysis of the CSF is often
negative and several repeat lumbar punctures may be required to
establish the diagnosis of meningeal disease.
Imaging is complementary to lumbar puncture but the detection
of diffuse meningeal involvement with computed tomography
(CT) has been disappointing due to insufficient contrast enhance-
ment of the abnormal meninges (41). CT is more accurate in
carcinomatous meningitis and inflammatory conditions because
the contrast enhancement is usually more intense (40).
Magnetic resonance (MR) imaging is the method of choice for
the detection of intracranial and spinal leptomeningeal disease and
occasionally may demonstrate leukemic infiltration in the presence
of multiple negative cytological analyses (35). The technique is con-
siderably more sensitive than CT, myelography or CT myelography,
and so has replaced these techniques in the investigation of CNS
leukemia (42,43). Although T2-weighted spin-echo sequences may
reveal abnormal signal intensity within the CSF space, meningeal
disease is best demonstrated on gadolinium-enhanced T1-weighted
images. Axial and coronal images of the head and sagittal images
of the spine provide the best imaging planes to survey all the
meningeal surfaces. Leukemic infiltration is seen as abnormal
nodular thickening of the meninges which enhances after injection
 leukemia
(A)
Figure 35.4 (A) and (B) Contrast-enhanced coronal MR images in a nine-year-old boy with AML. There is extensive contrast-enhanced nodual thickening of the
leptomeninges (arrows), representing leukemic infiltration.
of intravenous (IV) contrast medium (Fig. 35.4). Thickening and
enhancement of nerve roots, particularly in the region of the cauda
equina, is shown on MR imaging but may also be demonstrated on
CT myelography. Diffuse dural infiltration is less common than
leptomeningeal disease, but is also seen as thickening and enhance-
ment of the dural surfaces. In patients with leukemia, the observation
of thickened enhancing meninges is not pathognomonic of leuke-
mic infiltration as it may also be seen in other conditions associated
with leukemia such as infectious meningitis, drug reactions, and
meningeal fibrosis following hemorrhage (35).
Parameningeal Disease
Intracranial and spinal parameningeal disease usually takes the
form of a mass of leukemic cells known as granulocytic sarcoma
(chloroma).
The majority of intracranial granulocytic sarcomas are durally-
based lesions and are believed to develop by direct spread from the
bone marrow. The CT and MR imaging appearances of granulo-
cytic sarcomas are variable and they may mimic meningiomas,
other tumors, or abscesses (44,45). For example, Moudden et al.
describe a case of granulocytic sarcoma in ALL mimicking a falx
meningioma (46,47).
On unenhanced CT, intracranial granulocytic sarcomas are
isodense or slightly hyperdense compared to a normal brain but
frequently show intense enhancement following injection of IV
contrast medium (Fig. 35.5) (47,48). On MR imaging, these
lesions may be of high signal intensity on T1-weighted images
and bright on T2-weighting. As with CT, they show intense
contrast enhancement (44).
Spinal granulocytic sarcomas may be paraspinal or intraspinal
(Fig. 35.6). Soft tissue masses in the paravertebral region extend
(B)
into the spinal canal via the intervertebral foraminae (Fig. 35.7)
(49). These masses invade the dura and may cause spinal cord
compression, nerve root compression, and bone destruction.
Although CT may show paravertebral masses and extension
into the spinal canal or discrete intraspinal masses (Fig. 35.7A),
MR imaging is the preferred technique for demonstrating these
lesions because the whole spine can be examined at a single inves-
tigation (Fig. 35.7B). The multiplanar capability of MR imaging is
also an advantage as it allows clear delineation of tumor extent.
Granulocytic sarcomas have a low signal intensity on T1-weighted
images and a relatively high or intermediate signal intensity on
T2-weighted images (49). They often show intense contrast
enhancement.
Key Points: Central Nervous System
■ CNS involvement is usually a manifestation of acute leukemia
■ Approximately 3% of all children with ALL have CNS disease
■ The leukemic process may involve the leptomeninges, dura,
or extradural space
■ Disease may be diffuse or focal
■ Granulocytic sarcomas are usually durally-based lesions
■ MR is the best imaging method for detecting intracranial
meningeal and dural infiltration as well as granulocytic
sarcoma
Indirect Effects of Leukemia
The indirect effects of leukemia on the CNS include vascular
events, infection, and toxic effects related to therapy.
875
 hematology malignancy

(A) (B)

Figure 35.5 Intracranial granulocytic sarcoma. (A) CT of the brain in a 14-year-old boy with relapsed ALL. The mass which probably arises from the left parietal
bone extends both intracranially and into the subcutaneous soft tissues. There is homogeneous intense contrast enhancement. (B) CT of an eight-year-old girl
who relapsed following initial therapy for ALL with a large durally-based lesion in the temporal lobe. Note homogeneous enhancement and surrounding
edema.

(A) (B)

Figure 35.6 A nine-year-old boy who presented with acute back pain and signs of spinal cord compression. (A) T1-weighted sagittal MR image showing an intraspinal
extradural soft tissue mass in the mid-thoracic region (arrows). Note partial collapse of the vertebral body of T5 (arrowhead). A diagnosis of AML with a granulocytic
sarcoma was made on investigation. There is diffuse abnormally low signal intensity throughout the vertebral bodies indicating diffuse leukemic infiltration. (B) Repeat
T1-weighted MR scan six weeks later shows an excellent response to treatment. The granulocytic sarcomatous mass has almost completely resolved (arrows) and the
signal intensity of the bone marrow has increased markedly indicating reduction in bone marrow infiltration. The vertebral body of T5 still shows abnormal signal
intensity posteriorly.

876
 leukemia

(A) (B)

Figure 35.7 An adult male patient who presented with back pain due to a granulocytic sarcoma before clinical manifestation of AML. (A) CT, and (B) T1-weighted coronal
MR image. In (A) a soft tissue mass is seen surrounding the inferior vena cava and obscuring the contour of the aorta. The mass extends posteriorly deep to the right psoas
muscle and enters the spinal canal through the intervertebral foramen (arrow). In (B) the coronal MR image shows the cranio-caudal extent of the mass and clearly delineates
the intraspinal component at the level of L3/L4 and L4/L5 intervertebral foraminae. Tumor surrounds the exit nerve roots. Note normal nerve roots on the left side (arrow).

Vascular Complications • General risks—patient age, atherosclerosis

Hemorrhage. CT or MR imaging is essential in patients suspected
of intracranial hemorrhage. In most cases, CT will be undertaken,
as this is more readily available and generally quicker than MR
examinations. Unenhanced CT will show the classic features of
subarachnoid and/or intracerebral hemorrhage, which includes
the presence of high-density material in the subarachnoid space,
in the brain parenchyma and ventricular system. There may be
mass effect with some surrounding edema. On MR imaging, fresh
blood has high signal intensity on T1 and T2 weighting. Break-
down products of hemoglobin (hemosiderin) may also be present
giving low signal intensity on T2 weighting.
CT and MR imaging are not only valuable for demonstrating
the presence of intracranial hemorrhage but also for excluding
hemorrhage in patients in whom the diagnosis is questionable on
clinical grounds. Furthermore, imaging may show other associ-
ated abnormalities such as sinovenous thrombosis.
Sinovenous Thrombosis. Sinovenous thrombosis, another vascular
complication of acute leukemia, may be related to treatment
with L-asparaginase as well as to leukemic infiltration (41,49).
Both CT and MR imaging are useful non-invasive methods of
detecting sinovenous thrombosis. On CT, postcontrast-enhanced
images may show a low density filling defect within the sinus and,
on precontrast images, the sinus may be abnormally hyperdense.
On MR imaging, loss of the normal signal void is apparent on
T2-weighted sequences and, on postcontrast images, a filling
defect may be observed, as on CT. Gradient-echo or other flow
sensitive techniques such as fast fluid-attenuated inversion
recovery (FLAIR) may also demonstrate sinovenous thrombosis
on MR imaging (41,50). Leukemic infiltration of meninges and
sinus thrombosis may coexist.
Cerebral Infarction. Patients with leukemia are at an increased
risk of cerebral infarction for several reasons, which include: (41)
• Intravascular coagulation
• Sinovenous occlusion
• Tumor emboli
• Septic emboli
• Effects of therapy (17)
As in the diagnosis of intracranial hemorrhage, CT and MR imaging
are valuable for demonstrating the presence of cerebral infarction
and for distinguishing infarcts from other intracranial lesions
such as hemorrhage, infection, and drug-related toxicity.
Infection
In leukemic patients, intracranial infection results from direct
spread of infection from the paranasal sinuses or by the hemato-
genous route. Sinusitis is usually aggressive in immunocompro-
mised patients and infection with organisms such as Aspergillus
results in invasion of local structures and destruction of bone (Fig.
35.8), thereby giving access to the dura, meninges, and underlying
brain parenchyma. Other organisms including bacteria (e.g.,
Klebsiella pneumonii) and viruses are also associated with intra-
cranial infection in leukemia (51). Abscesses may develop and,
whether solitary or multiple, may simulate parenchymal leukemic
deposits (51). On CT, abscesses usually show rim enhancement
with a relatively low-density center; on MR imaging these masses
have a high signal intensity on T2 weighting and a relatively low
signal intensity on T1 weighting. As on CT rim enhancement is
noted following injection of IV contrast medium.
Treatment-Related Complications
There are many neurological complications associated with the treat-
ment of leukemia but such complications are related particularly to
the treatment or prophylaxis of the CNS. Different syndromes and

877
 hematology malignancy

(A) (B)
Figure 35.8 CT in a 53-year-old male patient with relapsed AML showing extensive paranasal sinus infection with Aspergillus. (A) The soft tissue mass occupies the left
maxillary sinus. There is almost complete destruction of the medial wall of the maxillary sinus with extension of the soft tissue mass into the nasal cavity and nasophar-
ynx. There is also destruction of the lateral wall of the maxillary sinus with extension of disease into the pterygoid region. Note enlargement and poor definition of the
lsteral pterygoid muscle (p). (B) The soft tissue mass is also seen extending into the posterior aspect of the left orbit. The left ethmoid sinuses are replaced by soft tissue
and there is destruction of the medial wall of the orbit.

clinical features are associated with particular drugs or radiotherapy.
In general, CNS toxicity can be divided into acute, subacute, and
chronic forms (52).
Acute or subacute neurological complications are more likely to
be reversible than the complications which develop in the longer
term. Patients present with symptoms and signs of raised intrac-
ranial pressure and on examination neurological deficit is com-
mon (53). After bone marrow transplantation for CML, MR
imaging may show acute ventricular enlargement and cortical
atrophy which progress over time (54). On clinical evaluation, it
may be impossible to distinguish CNS leukemic relapse from the
effects of therapy and, in this situation, imaging plays a key role.
Delayed or chronic toxic effects are more likely to be irreversible
and may develop several years after initial treatment.
Radiotherapy neurotoxicity is usually subacute, developing sev-
eral weeks after treatment. It is characterized by drowsiness, nau-
sea, and malaise, as well as somnolence (35). Imaging is not usually
required to reach a definitive diagnosis.
The delayed effects of radiotherapy include cerebral atrophy and
necrosis (52). This results in growth disturbance, intellectual impair-
ment, neuroendocrine problems, and even second cancers (52). MR
shows abnormally high signal intensity in the white matter following
cranial irradiation and may demonstrate abnormalities even in
patients without clinical evidence of toxicity. CT may reveal areas of
low attenuation within the white matter and calcifications. Long-
term survivors of childhood ALL treated with cranial irradiation and
intrathecal methotrexate frequently show abnormalities on MR
imaging. This is more common in patients treated with both modali-
ties than with intrathecal methotrexate alone (55,56). A study reported
by Laitt and colleagues (57) revealed an incidence of significant
abnormalities in the brain on MR imaging in 26% of 35 long-term
survivors. These abnormalities included three tumors (meningioma,
rhabdomyosarcoma, and anaplastic astrocytoma) as well as large
vessel vasculopathy, small cystic infarcts and diffuse white matter
change. Recently, long-term cerebral metabolic changes have been
demonstrated with proton MR spectroscopy (MRS) in patients
treated with intrathecal methotrexate and cranial irradiation prophy-
laxis for ALL. These abnormalities were found in brains with hemo-
siderin and were reflected by decreasing N-acetylaspartate (NAA)/
creatine (Cr) and choline (Cho)/creatine (Cr) from diagnosis (58).
Intrathecal methotrexate may cause acute arachnoiditis and
imaging is not required in the diagnostic work-up. Subacute
neurotoxicity and delayed reactions are characterized by seizures
and other manifestations of motor dysfunction such as paraple-
gia. Imaging may be required to exclude direct involvement of the
CNS by leukemia, for example the presence of a granulocytic
sarcoma. Delayed effects of methotrexate include white matter
ischemia and imaging shows intracerebral calcifications and cerebral
atrophy. Both CT and MR imaging are useful for demonstrating
the extent of these abnormalities.
Disseminated necrotising leucoencephalopathy is more likely to
develop when CNS irradiation is combined with intrathecal metho-
trexate and high-dose methotrexate but may occur without cranial
irradiation (Fig. 35.9) (35,53,59–61). This condition may be fulmi-
nating and rapidly fatal, or less severe leading to chronic neurological
deficit. Leucoencephalopathy affects the white matter of the brain
and is seen on CT as multifocal areas of low attenuation and on MR
imaging as areas of high signal intensity on spin-echo T2-weighted
images. Enhancement of these lesions can sometimes be seen on CT
and MR imaging (61–64). Calcification may also be observed in the
basal ganglia and in the subcortical white matter (61). It may be dif-
ficult to distinguish leucoencephalopathy from underlying disease.
However, on MR imaging, a new focus in the periventricular white
matter, especially the corpus callosum may be considered suspicious

878
 leukemia

(A) (B)

Figure 35.9 Necrotizing leucoencaphalopathy. (A) and (B) T2-weighted axial MR images of the brain showing abnormal high signal intensity in the white matter following
cranial irradiation and methotrexate therapy.

(A) (B)

Figure 35.10 (A) FLAIR axial MR image shows a high signal intensity focus within the posterior corpus callosum (arrow). (B) T1-weighted MR image acquired at the same
level shows no appreciable enhancement (arrow) following intravenous gadolinium contrast administration. The appearance is in keeping with leucoencephalopathy.

of leucoencephalopathy because the periventricular white matter is
highly susceptible to radiation necrosis (Fig. 35.10). Radiation necro-
sis is also more likely to have a nodular or swiss-cheese appearance.
Other drugs such as cytarabine and cyclosporin A are also associated
with severe neurotoxicity (34). Vera et al. (65) investigated SPECT in
the diagnosis of CNS toxicity following therapy with a cytarabine-
containing regimen and found that diffuse heterogeneous low perfu-
sion levels may be the only abnormal feature on imaging.
Neuropsychological disorders developing as a result of treatment of
childhood leukemia are well-recognized (66). Earlier imaging studies,
such as that reported by Harila-Saari et al. (67) showed no significant
correlation between neuropsychological outcome and morphological
MR imaging findings of white matter change, atrophy, old hemorrhage,
and calcifications. However, a subsequent investigation of the long-
term cognitive effects of intrathecal methotrexate and cranial irradia-
tion in a group of 21 children cured of ALL showed that poor
performance was associated with white matter changes in 50% of
cases (68). Furthermore, there was good correlation between the
presence of calcifications and the number of methotrexate injections.
There is now some evidence to suggest that diffusion-tensor imaging
(DTI), an MR imaging technique used to study the diffusivity
and orientation of the white matter tracts in the brain, can
demonstrate potential relationships between changes observed at
DTI and neurocognitive performance (69). Microscopic damage in

879
 hematology malignancy
the normal-appearing white matter, in children treated with cranial
irradiation for pediatric tumors, was reflected as lower diffusion frac-
tional anisotrophy (FA), which were in turn correlated with poorer
IQ scores compared to the age-matched controls (69,70). Thus, DTI
appears to have the potential to quantify the degree of treatment
related damage to the normal brain non-invasively.
Key Points: CNS Complications
■ Hemorrhage is a major cause of death in acute leukemia,
particularly in acute promyelocytic leukemia and patients in
“blast” crisis
■ Sinovenous thrombosis may be demonstrated by MR imag-
ing and CT, but may co-exist with leukemic meningeal
infiltration
■ Cerebral infarction has an increased incidence in patients
with leukemia
■ Intracranial infection usually results from spread of
infection from paranasal sinuses directly by organisms such
as Aspergillus
■ CNS toxicity is related to irradiation, intrathecal methotrexate,
and high-dose methotrexate
■ Disseminating necrotizing leucoencephalopathy affects the
white matter of the brain and is demonstrated on MR imag-
ing as areas of high signal intensity with foci on T2-weighted
images, which have a predilection for periventricular white
matter and may have a nodular or swiss-cheese appearance.
Enhancement of the lesions may be seen
■ Long-term cognitive impairment can result from intrathecal
methotrexate and cranial irradiation. Changes may be
demonstrated on CT and MR imaging
(A)
Figure 35.11 Orbital chloroma in a young man with ALL. (A) Contrast-enhanced CT showing an enhancing mass arising from the superolateral corner of the left orbit, with
displacement of the underlying globe. The appearance is typical for orbital granulocytic sarcoma. (B) CT of the orbits obtained three months later showed progression of
disease.
880
Head and Neck
Direct Involvement by Leukemia
The most important extracranial site of leukemia of the head
and neck region is the orbit. Leukemic deposits may infiltrate
around the optic nerve, often in association with meningeal dis-
ease and the choroid and retina may also be involved by diffuse
infiltration. The orbit is a well-recognized site of granulocytic
sarcoma (chloroma) (45,71,72). On both CT and MR imaging,
intraorbital granulocytic sarcomas enhance with IV contrast
medium and are usually seen as soft tissue masses related to the
intraocular muscles (Fig. 35.11) (24). Granulocytic sarcoma in
the paranasal sinuses may spread by direct extension into the
orbit.
Key Point: Granulocytic Sarcoma
■ The orbit is a common site of granulocytic sarcoma
Indirect Effects of Leukemia
Two major indirect effects of leukemia in the head and neck are
hemorrhage and infection. Infection of the paranasal sinuses may
be extremely aggressive, resulting in intracranial disease as
described above. Imaging with CT or MR may be required to
define the extent of infection extracranially as well as the presence
of meningeal or brain involvement (73).
Intrathoracic Disease
The vast majority of pulmonary abnormalities detected in leu-
kemic patients are due to indirect causes related to complications
(B)
 leukemia
Figure 35.12 Chest radiograph in a four-year-old boy with ALL showing a large
mediastinal mass at presentation.
of therapy, whereas mediastinal abnormalities, although much
less common, are usually the result of nodal involvement. Chest
radiographs play an important role in the assessment of leuke-
mic patients, especially during therapy at the time of immuno-
suppression. High resolution CT (HRCT) of the lungs can also
provide additional useful information in selected cases but
should be used as an adjunct to plain chest radiographs and
not as a substitute investigation (74).
Direct Involvement by Leukemia
Mediastinal lymphadenopathy is a common feature of ALL as well
as CLL (Fig. 35.12). A large anterior mediastinal mass on plain
chest films is a characteristic feature of childhood T-cell leukemia,
and over 50% of patients with adult T-cell leukemia also have
mediastinal disease (Fig. 35.13) (16,75). These large masses may
cause superior vena caval obstruction or tracheal compression.
Hilar lymphadenopathy may also be seen.
Pulmonary leukemic infiltration is only rarely diagnosed on
plain chest radiographs but is found more commonly at autopsy
(76). On a plain chest film, leukemic infiltration appears as dif-
fuse peribronchial infiltration accompanied by septal lines. The
findings are usually indistinguishable from infection or pulmo-
nary edema and therefore the diagnosis is rarely made radio-
logically. In those cases detected while the patient is alive, the
diagnosis is readily made at transbronchial biopsy and bronchial
lavage (77). In a series of 109 patients reported by Green and
Nichols, 30 had autopsy evidence of pulmonary infiltration but
only two of these patients showed evidence of infiltration on
chest radiographs (78). HRCT may show diffuse nodular lesions
along peribronchovascular bundles, but biopsy is required for a
definitive diagnosis (79).
Figure 35.13 CT in a male patient with T-cell leukemia showing bulky heteroge-
neous anterior mediastinal lymphadenopathy, resulting in widening of the
mediastinum.
Indirect Effects of Leukemia
Mediastinal widening may be due to hemorrhage within the medi-
astinum, thrombus within the superior vena cava (usually as a result
of central line insertion) or to mediastinitis (this may be associated
with central line insertion due to an extraluminal placement of a
catheter tip or infection). The cause can be detected on contrast-
enhanced CT and is readily distinguished from lymphadenopathy
(Fig. 35.14).
Pulmonary infection is a major cause of abnormal shadowing
detected on plain chest radiographs in leukemic patients. These
infections result from immunosuppression and may be bacte-
rial, viral, or fungal (Fig. 35.15). The most common organisms
with a predilection for immunosuppressed hosts include cyto-
megalovirus (CMV), Pneumocystis carinii, and fungal infection
by organisms such as Aspergillus and Cryptococcus (80–82). On
occasion, HRCT may be useful in the differential diagnosis of
pulmonary infiltration, for example CT may demonstrate the
rounded lesions of Aspergillus fumigatus not visualized on plain
chest films. Invasive aspergillosis is an increasingly common and
frequently fatal complication in children with hematological
disorders (83). Oropharyngeal and esophageal infection with
Candida albicans is common and results from antibiotic therapy
as well as the impaired immune response (80).
Pulmonary hemorrhage should be considered in the differential
diagnosis of abnormal air space pulmonary shadowing on plain
chest films, particularly if accompanied by hemoptysis. Pulmo-
nary edema may mimic infection and indeed may coexist with an
inflammatory process.
Treatment-related pulmonary damage is important in the dif-
ferential diagnosis of abnormal pulmonary shadowing and chest
symptoms in the leukemic patient.
Drugs cause pulmonary edema and vasculitis. In the early
stages of lung toxicity, plain chest radiographs are usually
normal. Alveolar damage is usually a generalized process at the
lung bases and, in moderate to severe cases, is seen as bilateral
881
 hematology malignancy

(A) (B)
Figure 35.14 (A) and (B) Contrast-enhanced CT in a three-year-old child with massive mediastinal widening due to extrusion of the central line from the left
innominate vein into the mediastinal soft tissues. Note thrombus in the left innominate vein shown as tubular low attenuation (arrows). Thrombus is also present
in the superior vena cava (arrow). The mediastinum is widened and contains generalized increased soft tissue density due to mediastinitis. Central venous line
(black arrow).

(A) (B)

(C) (D)
Figure 35.15 (A) and (B) CT images in a 41-year-old man with ALL prior to treatment showing bilateral axillary lymphadenopathy. The spleen was normal in appear-
ance. (C) CT performed two months after commencing chemotherapy revealed reduction in the axillary lymphadenopathy, but a new mass was visible within the
left upper lobe associated with a small pleural effusion. (D) In addition, multiple low attenuation lesions were also noted within the spleen. Biopsy of the lung mass
confirmed infection with mycobacterium tuberculosis.

abnormal non-specific shadowing both on plain films and on CT.
Such injury may be caused by busulphan, carmustine (BCNU),
and methotrexate. Pulmonary vasculitis leads to infarction and,
in some cases, cavitation may result. Pulmonary vascular dam-
age may occur with busulphan therapy (84).
Chronic graft versus host disease (GVHD) is characterized by
lymphocytic infiltration of the interstitial tissues and bronchial walls.
Bronchiolitis obliterans is also seen (85). Plain chest radiographs
may be normal but abnormal shadowing around peripheral bronchi
may be observed on CT (86).

882
 leukemia
Key Points: Thoracic Manifestations
■ Mediastinal lymphadenopathy is a common feature of ALL
and CLL
■ Mediastinal lymphadenopathy is also seen in T-cell child-
hood leukemia and in adult T-cell leukemia/lymphoma
■ Leukemic infiltration of the lungs is rarely diagnosed
during life. The appearances are often indistinguishable
from infection or pulmonary edema
■ Mediastinal widening may be due to mediastinitis, hemorrhage,
or superior vena caval thrombosis as well as lymphadenopathy
■ Pulmonary infection is a major cause of morbidity in
leukemic patients. Organisms include CMV, P. carinii, and
fungal infections such as invasive pulmonary aspergillosis
Abdomen and Pelvis
Direct Involvement by Leukemia
Hepatosplenomegaly due to diffuse involvement of the liver and
spleen is a frequent manifestation of leukemia (Fig. 35.1). Imaging
is not usually undertaken to evaluate these organs but both CT and
ultrasound (US) will demonstrate hepatosplenomegaly. Focal
lesions within the liver and spleen due to leukemia are rarely seen.
Splenic infarction may be associated with gross splenomegaly. These
lesions appear as an irregular, relatively low-density area within a
massively enlarged spleen on CT and as hypoechoic lesions on US.
Renal involvement in leukemia is common, occurring in approx-
imately 50% of cases at autopsy (16). As in patients with lymphoma,
leukemia may involve the kidneys by:
• Diffuse parenchymal infiltration (bilateral or unilateral)
(Fig. 35.16)
• Discrete renal mass or masses
• Obstruction due to lymphadenopathy at the hilum
In a review of 700 cases of the renal manifestations of non-
Hodgkin’s lymphoma and lymphocytic leukemia by Da’as et al.
(87) no cases of primary renal involvement were found. Acute
renal failure was seen in 83 patients but leukemic infiltration
was shown to be the cause in only five (87).
(A)
Figure 35.16 (A) and (B) CT in a 40-year-old female patient with AML showing bilateral renal infiltration. Both kidneys are enlarged and demonstrate multiple
ill-defined low attenuation areas. Note the presence of small volume retroperitoneal lymph nodes.
US is a useful technique for detecting leukemic infiltration. The
kidneys are diffusely enlarged and show patchy areas of low
echogenicity. On contrast-enhanced CT, the parenchyma shows
an inhomogeneous pattern with areas of diminished density
interspersed with areas of enhancement, findings similar to those
seen in lymphoma (88). Solid renal masses may also be observed
on CT.
The gastrointestinal tract is involved in leukemia in about 25%
of cases (89). Leukemia infiltrates spread through the lamina pro-
pria or submucosa of the bowel wall producing localized areas of
bowel wall thickening. Imaging is seldom required as it is unusual
for such lesions to become clinically manifest. Occasionally, a
granulocytic sarcoma may develop within the bowel wall and may
present as abdominal pain or intestinal obstruction.
As in other anatomical sites, abdominal lymph node involvement
is more commonly seen in the acute lymphoblastic and chronic
lymphocytic leukemias than in the myelogenous leukemias. Multiple
enlarged nodes may be seen within the retroperitoneum, mesentery,
splenic hilum, porta hepatis, and other intra-abdominal and pelvic
sites (Figs. 35.2, 35.16, and 35.17). Nodes are usually discretely
enlarged and, on imaging, the appearances are indistinguishable
from those of non-Hodgkin’s lymphoma.
Other sites of involvement in the abdomen and pelvis include
the prostate gland, uterus, and adrenal glands. The testis and ovary
are sanctuary sites and are therefore relatively resistant to chemo-
therapy (Table 35.2) (15).
Key Points: Abdominal/Pelvic Manifestations
■ Hepatosplenomegaly is a common feature of all the leukemias
■ Splenic infarcts may be demonstrated on imaging
■ Renal involvement is seen in 50% of cases at autopsy
■ Renal involvement may be diffuse or focal
■ Enlarged lymph nodes in the abdomen and pelvis occur in
multiple sites in ALL and CLL
■ The gastro-intestinal tract is involved in approximately 25%
of cases. In the majority of patients the disease is silent
(B)
883
 hematology malignancy
Indirect Effects of Leukemia
The most important indirect effects of leukemia within the abdo-
men and pelvis are GVHD, neutropenic enterocolitis, hemorrhage,
and infection.
Graft vs. Host Disease
Graft versus host disease most commonly affects the skin, gastro-
intestinal tract, and liver. This disease is a major complication of
allogeneic BMT, occurring in about 50% of patients. The phe-
nomenon is a manifestation of graft rejection in which the immuno-
competent donor lymphoid cells react against host antigens. The
Figure 35.17 Contrast-enhanced CT in a 34-year-old man with ALL demonstrat-
ing a mesenteric mass (arrow).
(A)
Figure 35.18 In this 38-year-old man with previous history of an allogenic bone marrow transplant for CML, CT (A) and (B) shows multiple thickened small bowel loops
exhibiting “target sign” (arrows) due to low attenuation edema within the bowel wall adjacent to the enhancing mucosal and serosal surfaces. The CT appearance is suggestive
of graft versus host disease.
884
principal bowel abnormalities are those of lymphocytic infiltration
of the lamina propria, crypt dilatation and necrosis, and focal
micro-abscess formation (90,91). Involvement of the bowel can
be demonstrated on conventional plain abdominal radiographs,
barium studies, and on CT (92).
On plain radiography, air-fluid levels, bowel wall and mucosal
fold-thickening, and ascites may be seen (93). On barium studies,
the small bowel shows thickening and flattening of the mucosal
folds, a rapid transit time, and air-fluid levels (94). Pneumatosis
intestinalis may be observed in severe cases (95). Graft versus host
disease may resolve completely, in which case the abnormal plain
film and barium findings return to normal. CT findings of GVHD
include bowel wall thickening, stenosis of small bowel loops and
edema of the bowel wall. Edema is typically seen as a “target sign”
with decreased attenuation centrally bounded by high attenuation
on both the serosal and mucosal surfaces of the bowel (Fig. 35.18).
In addition, there is usually generalized increased density within
the mesenteric fat (96). These findings are non-specific and may
be seen in other benign and malignant conditions.
Neutropenic Enterocolitis
Neutropenic enterocolitis is a severe complication of intensive che-
motherapy for acute leukemia and is difficult to confidently diagnose
clinically. Patients present with abdominal pain, fever, and diarrhea,
and imaging with US and CT can play a useful role in the diagnosis by
demonstrating bowel wall thickening. Cartoni et al. (97) found that
US was able to determine bowel wall thickening and that the degree of
thickness correlated well with the clinical course and disease outcome.
Patients with bowel wall thickening greater than 10 mm had a signifi-
cantly poorer prognosis than those with lesser degrees of thickening.
Hemorrhage
Occasionally, imaging is required to investigate clinical features
suggestive of intra-abdominal hemorrhage in leukemic patients.
This is usually manifested by acute abdominal pain together with
clinical features of blood loss. Retroperitoneal hemorrhage may
present as acute back pain and, in such patients, CT is the ideal
imaging modality to demonstrate the presence of fresh blood and
the extent of hemorrhage (Fig. 35.19).
(B)
 leukemia

(A) (B)
Figure 35.19 (A) T1-weighted and (B) T2-weighted axial MR images in a 53-year-old man with ALL, presenting with acute right flank pain. The images show a large right
retroperitoneal hematoma, which appears of high signal intensity on both T1- and T2-weighted imaging, indicating the presence of blood within the lesion.

Liver infection is a serious complication of treatment. Candidi-

asis may involve the liver and spleen and is recognized on imaging
as multiple small focal lesions throughout the organ parenchyma.
Diagnosis must be made by biopsy or blood culture in the pres-
ence of abnormal imaging findings. MR imaging is a sensitive
method of identifying these focal liver abnormalities and may also
be used to monitor therapy.

Key Points: Abdominal/Pelvic Complications

■ GVHD is a major complication of allogeneic BMT
■ Acute GVHD most commonly affects the skin, liver, and
gastrointestinal tract
■ Plain radiographs, barium studies, and CT may all show dilatation,
stenosis, and thickening of small bowel loops with air-fluid levels
■ Ascites and pneumatosis intestinalis are seen in severe cases
■ Neutropenic enterocolitis is a serious complication of inten-
sive treatment as it is manifested by bowel wall thickening
■ Intra-abdominal/retroperitoneal hemorrhage may account
for the onset of abdominal pain in leukemic patients
■ Intra-abdominal infection such as cecitis (typhlitis) may
complicate acute leukemia
■ Liver infection with candidiasis can be detected and monitored
with imaging; MR is a sensitive technique to monitor response

Skeletal System
Figure 35.20 Coronal reformatted CT image of the abdomen in a three-year-old Direct Involvement of Leukemia
girl with acute lymphocytic leukemia. Note abnormal thickening of transverse The incidence and radiographic manifestations of skeletal involve-
colon (arrows) due to an infective colitis. ment in leukemia vary with patient age and subtype of the disease.

Radiographic Findings
In children, leukemic infiltration of the long bones produces charac-
teristic appearances on plain radiographs (Fig. 35.21), which include:
Infection
Intra-abdominal infection is an important cause of abdominal • Diffuse osteoporosis
pain in leukemic patients. Infectious cecitis (typhlitis), perirectal • Transverse metaphyseal bands of diminished density
abscesses, and appendicitis may all complicate the clinical pic- • Dense transverse metaphyseal lines of arrested growth
ture of leukemia (Fig. 35.20). CT may be helpful in the manage- • Subperiosteal new bone formation
ment of these patients because hemorrhage may be distinguished • Osteolytic lesions
from infection and the site of infection localized. • Osteosclerotic lesions in less than 2% of patients (20)

885
 hematology malignancy
(A) (B)
Figure 35.21 Plain radiographs of the wrist in a four-year-old boy with ALL. (A)
Anterior/posterior view; (B) lateral view, showing diffuse osteoporosis throughout
the radius and ulna as well as the bones of the wrist. Transverse metaphyseal bands
of diminished density are noted. There is an extensive periosteal reaction on the
distal surfaces of the radius and ulna.
Diffuse osteoporosis is the most common skeletal abnormality in
childhood ALL, occurring in up to 60% of cases, and is most obvi-
ous in the spine.
In adults, osteoporosis and cortical thinning of long bones due
to expansion of the marrow space are common. Other character-
istic features of childhood leukemia such as metaphyseal bands,
are not seen in adults. In adult T-cell leukemia/lymphoma, lytic
bone lesions are common (75). Subperiosteal bone resorption
may be seen in this subtype of leukemia and probably results from
hypercalcemia (75).
In children with acute leukemia presenting with backache, plain
radiographs may show collapse of one or several vertebral bodies (Fig.
35.22A). This is either due to vertebral compression fractures as a result
of osteoporosis or from destruction of bone trabeculae by leukemic
infiltration. With treatment, remodeling of the vertebral body with
reconstitution of the vertebral height may be observed (Fig. 35.22B). A
characteristic but unusual feature is that of a “bone” within a bone (98).
Submetaphyseal bands are seen in approximately 40% of children
and probably represent osteoporosis in the rapidly growing region
of the long bone. They are seen most frequently in the distal femur,
proximal tibia, proximal humerus, and vertebral bodies.
Focal lytic lesions are less common in AML than in ALL (Fig. 35.23)
but may develop in CML during the accelerated growth phase
and, in this group of patients, hypercalcemia may also be evident
(99). Focal lesions are usually permeative and may show cortical
destruction with pathological fracture. In the skull, lucent areas
with a “moth-eaten” appearance may be identified due to leuke-
mic infiltration.In children, widening of the sutures is associated
with underlying meningeal disease. This has been less commonly
observed since the introduction of CNS prophylaxis.
886
(A) (B)
Figure 35.22 Lateral plain radiographs in a four-year-old boy who presented with
back pain due to ALL. (A) At presentation, partial collapse of the lumbar vertebral
bodies is noted. The most severely affected vertebra is L2. (B) Two years later fol-
lowing treatment, there has been remodeling of the bone. Note the thin dense lines
adjacent to the vertebral end-plates giving the appearance of a bone within a bone.
There is still extensive osteoporosis.
Bone is one of the most frequent sites for development of gran-
ulocytic sarcoma. An area of bone destruction is seen on plain
radiographs which may be accompanied by a soft tissue mass. The
lesions are most commonly found in the skull, spine, ribs, and
sternum (100). Unusually, leukemic infiltration may affect the
periosteum and para-osteal soft tissue (Fig. 35.24).
CT is indicated for the evaluation of leukemic masses (granulo-
cytic sarcoma) in various sites, as the technique can define the soft
tissue disease as well as the extent of bone destruction.
Neither radionuclide bone scanning with technetium-99m-
diphosphonate, nor bone marrow imaging with colloid, is required in
the routine management of leukemia (101,102). However, bone scans
may be helpful in patients suspected of harboring occult bone infection.
When MR imaging was first introduced into clinical practice over a
decade ago there was considerable enthusiasm regarding its potential
to evaluate diffuse bone marrow disease. Certainly, diffuse infiltration
of the bone marrow can be elegantly demonstrated on spin-echo
imaging as diffuse abnormally low signal intensity on T1-weighted
images accompanied by intermediate signal intensity on T2-weighted
images. In leukemia, the axial skeleton is mainly involved (Fig. 35.25).
However, MR imaging is non-specific, as both benign and malignant
disorders give similar appearances (Fig. 35.26) (103,104). Clear
advantages of MR imaging are the ability to survey large volumes of
the bone marrow at a single investigation and the high sensitivity of
the technique in detecting bone marrow pathology.
MR imaging may demonstrate changes within the bone marrow in
leukemic patients in response to treatment (Fig. 35.27) and some
authors have used quantitative measurements of T1 relaxation times
to evaluate therapeutic response (105,106). Van de Berg et al. (107)
showed that sequential quantitative MR imaging during therapy for
ALL and AML revealed significant differences in the initial bulk values
of T1 relaxation between these subtypes of leukemia and also in the
changes observed in T1 between the two groups during therapy. As a
 leukemia

(A) (B) (C)

Figure 35.23 A 42-year-old man with ALL. (A) T1-weighted coronal, (B) STIR coronal, and (C) T1-weighted axial MR images showing a focal leukemic deposit replacing
the normal marrow signal within the condyles of the distal left humerus. The mass infiltrates into the adjacent soft tissues.

* * * *

(A) (B)

Figure 35.24 (A) STIR and (B) T1-weighted coronal MR images

through both femur show irregular low T1-signal changes within the
marrow cavity in keeping with bone infarcts (*). In addition there is
abnormal high signal intensity in the periosteum and paraosteal soft
tissue on STIR imaging around the shaft of the upper right femur
(arrows). T1-weighted axial MR image obtained (C) before and (D)
after gadolinium contrast shows abnormal enhancement (arrow) in
(C) (D) the area. Biopsy confirmed leukemic infiltration.

result, these authors suggest that bone marrow imaging with MR may with CLL. Diffusion-weighted imaging may be applied to examina-
be a useful method of predicting response in ALL (107). However, tion of the bone marrow in leukemic patients (109). Measured signal-
Lecouvet et al. (108) have shown that quantitative MR imaging to-noise ratios agreed with an estimate of percentage cellularity and,
failed to identify bone marrow abnormalities in 41% of patients in addition, the signal-to-noise ratios were also dependent on time

887
 hematology malignancy

(A)

(A)

(B)

Figure 35.25 T1-weighted spin-echo MR images in a 21-year-old female with ALL.

(A) Sagittal image of the spine; (B) axial image through the pelvis. The MR exam-
ination shows widespread diffuse abnormal low signal intensity throughout the
vertebral bodies and pelvis, indicating extensive bone marrow infiltration.

(B)
Figure 35.27 MR images in a four-year-old boy with ALL. This is the same
patient as shown in Figure 35.22 T1-weighted sagittal images through the tho-
racic and lumbar spine, (A) before treatment, (B) two years after treatment.
The MR image at presentation shows diffuse abnormal low signal intensity
throughout the vertebral bodies indicating leukemic infiltration. Note that the
signal intensity of the bone marrow is lower than that of the adjacent interver-
tebral discs. There is partial collapse of multiple vertebrae. Two years later the
Figure 35.26 A 50-year-old female patient with myelofibrosis. The spin-echo
signal intensity of the vertebral bodies is higher than the adjacent interverte-
T1-weighted axial MR image of the pelvis shows diffuse abnormal low signal
bral discs. This represents response to treatment.
intensity throughout the iliac bones and sacrum. The appearances are identical to
those of leukemic infiltration.

888
 leukemia
(A)
Figure 35.28 A 10-year-old boy treated three years previously for ALL with CNS relapse. He represented with right leg pain. (A) Plain radiograph of the femora did not
reveal any abnormality. (B) Coronal T1-weighted MR image of the femora showing extensive abnormal low signal intensity throughout the metaphyseal region and
upper diaphysis of the right femur. This represented leukemic relapse.
Figure 35.29 MR image in a 21-year-old male patient following bone marrow
transplant. T1-weighted sagittal image showing typical “bandlike” pattern of
repopulation of bone marrow with areas of low signal intensity adjacent to the
vertebral end-plates. Higher signal intensity centrally represents fat.
(B)
after commencement of treatment (109). Dynamic contrast-en-
hanced MR imaging (DCE-MRI) has also been investigated as a
method of measuring angiogenic activity of bone marrow as a predic-
tor of adverse clinical outcome. Shih et al. (110) have shown that DCE-
MRI proved to be an independent prognostic indicator in 78 patients
with acute myeloid leukemia.
Despite these interesting results, the current role of MR imag-
ing in the evaluation of leukemia is limited as clinical and hema-
tological investigations usually direct patient management.
Although MR imaging seems to have little role in the routine
evaluation of the bone marrow in leukemia, it is useful in patients
suspected of relapse. It is useful for patients believed to be in
remission who present with bone pain (Fig. 35.28), or in patients
at high risk of relapse in whom serial bone marrow biopsies are
negative.
Key Points: Skeletal Involvement
■ Osteoporosis occurs in up to 60% of childhood ALL cases
■ Metaphyseal translucencies are seen in the long bones in
approximately 40% of children with ALL
■ Focal bone lesions are more common in ALL than AML
■ Granulocytic sarcoma in AML occurs most frequently in the
skull, ribs, and sternum
■ MR imaging shows diffuse bone marrow abnormality in
acute leukemia but the appearances are non-specific
■ MR imaging has a valuable role in the detection of leukemic
relapse in patients with bone pain
889
 hematology malignancy

(A) (B)
Figure 35.30 An adult male patient with ALL with avascular necrosis of the femoral head. (A) Coronal T1-weighted MR image, (B) turbo STIR image. The T1-weighted
image shows classic signs of avascular necrosis with irregular areas of low signal intensity within the femoral heads bilaterally. The STIR image shows abnormal high
signal intensity areas within the femoral heads and also in the femoral neck on the right, indicating associated edema.

Indirect Effects of Leukemia

Following therapy with BMT, repopulation of the bone marrow
gives rise to striking appearances with bands of low signal inten-
sity adjacent and bands of high signal intensity central to the ver-
tebral end-plates on MR imaging (Fig. 35.29). These appearances
are related to repopulation of the marrow in the region of the
capillary network which lies adjacent to the vertebral end-
plates (111,112). Treatment with steroids may lead to avascular
necrosis of the femoral head (Fig. 35.30). Bony infarcts may also
be detected on MR imaging. MR is well-established as the best
imaging technique for detecting avascular necrosis and is indi-
cated in all symptomatic patients with normal plain films. As in
other areas of the body, infection is a major hazard in the acute
leukemias and bone pain may represent osteomyelitis as well as
leukemic relapse (Fig. 35.31).

Figure 35.31 Plain film of the right knee in a five-year-old boy with ALL com-
plaining of severe bone pain around the knee joint. There is a destructive lytic
lesion in the lateral aspect of the tibial metaphysis. This was due to osteomyelitis
and was surgically drained.
Summary
■ Acute lymphoblastic leukemia (ALL) is the most common
subtype in childhood
■ Acute myelogenous leukemia (AML) and chronic
lymphocytic leukemia (CLL) are the most common subtypes
in adults
■ Chromosomal abnormalities have been identified in
many of the subtypes of leukemia, which is of prognostic
importance
■ The major clinical features of leukemia relate to anemia,
infection, and hemorrhage

890
 leukemia
■ Bone pain is a common presenting feature in children with
ALL but is rare in adults
■ Granulocytic sarcoma (chloroma) is a mass composed of
precursors of myelocytes. It occurs in AML and in other
myeloprolific disorders
■ Granulocytic sarcoma most commonly involves the orbits
■ In the CNS, leukemia involves the leptomeninges, dura
and, rarely, the brain parenchyma. It may be diffuse or focal
■ Hemorrhage, sinovenous thrombosis and cerebral infarction,
as well as infection, are all indirect effects of leukemia on
the CNS
■ Intrathoracic leukemia usually involves mediastinal and
hilar lymph nodes. Pulmonary complications include
infection, hemorrhage, edema, and graft versus host disease
(GVHD)
■ Diffuse involvement of intra-abdominal organs is common
(liver, spleen, kidneys, gastrointestinal tract, intra-abdominal
lymph nodes)
■ GVHD and neutropenic enterocolitis are important
intra-abdominal complications which can be assessed with
CT and US
■ Skeletal manifestations of childhood leukemia are seen in up to
60% of patients and include osteoporosis, transmetaphyseal
bands, and subperiosteal new bone formation
REFERENCES
1. Caligiuri MA, Ritz J. Immunology. In: Henderson ES, Lister
TA, eds. Leukaemia, 5th edn. Philadelphia: W B Saunders,
1990; 103–30.
2. Garson CM. Cytogenetics of leukemic cells. In: Henderson
ES, Lister TA, eds. Leukaemia, 5th edn. Philadelphia: W B
Saunders, 1990; 131–52.
3. Cancer Facts and Figures 2008. American Cancer Society Inc,
2008. [Available from: http://www.cancer.org].
4. Cancer Research UK Cancer Stats 2008. [Available from:
http://www.cancerresearchuk.org].
5. Preston DL, Kusumi S, Tomonaga M, et al. Cancer incidence
in atomic bomb survivors. Part III. Leukemia, lymphoma and
multiple myeloma, 1950–1987. Radiat Res 1994; 137: S68–97.
6. Sandler DP. Recent studies in leukemia epidemiology. Curr
Opin Oncol 1995; 7: 12–18.
7. Arseneau JC, Sponzo RW, Levin DL, et al. Nonlymphoma-
tous malignant tumors complicating Hodgkin’s disease.
Possible association with intensive therapy. N Engl J Med
1972; 287: 1119–22.
8. Aisenberg AC. Acute nonlymphocytic leukemia after treat-
ment for Hodgkin’s disease. Am J Med 1983; 75: 449–54.
9. Curtis RE, Boice JD Jr, Stovall M, et al. Risk of leukemia after
chemotherapy and radiation treatment for breast cancer. N
Engl J Med 1992; 326: 1745–51.
10. Kaldor JM, Day NE, Pettersson F, et al. Leukemia following
chemotherapy for ovarian cancer. N Engl J Med 1990; 322: 1–6.
11. Robert-Guroff M, Reitz MS Jr, Robey WG, et al. In vitro gen-
eration of an HTLV-III variant by neutralizing antibody.
J Immunol 1986; 137: 3306–9.
12. Kalyanaraman VS, Sarngadharan MG, Nakao Y, et al. Natural
antibodies to the structural core protein (p24) of the human
T-cell leukemia (lymphoma) retrovirus found in sera of leu-
kemia patients in Japan. Proc Natl Acad Sci USA 1982; 79:
1653–57.
13. Weber J. HTLV-I infection in Britain. Br Med J 1990; 301:
71–2.
14. Anonymous. HTLV-1 comes of age. Lancet 1988; 1: 217–19.
15. Barcos M, Lane W, Gomez GA, et al. An autopsy study of
1206 acute and chronic leukemias (1958–1982). Cancer 1987;
60: 827–37.
16. Henderson ES, Afshani E. Clinical manifestation and diagno-
sis. In: Henderson ES, Lister TA, eds. Leukaemia, 5th edn.
Philadelphia: W B Saunders, 1990; 291–359.
17. Graus F, Rogers LR, Posner JB. Cerebrovascular complica-
tions in patients with cancer. Medicine (Baltimore) 1985;
64: 16–35.
18. Freireich EJ, Thomas LB, Frei E, et al. A distinctive type of
intracerebral haemorrhage associated with “blastic crisis” in
patients with leukaemia. Cancer 1960; 13: 146–54.
19. Fernbach DJ. Natural history of acute leukemia. In: Sutow W,
Vietti TJ, Fernbach DJ, eds. Pediatric Oncology, 2nd edn. St
Louis: Mosby, 1977; 291–333.
20. Thomas LG, Forkner CEJ, Frei E. The skeletal lesions of acute
leukemia. Cancer 1961; 14: 608.
21. Hann IM, Gupta S, Palmer MK, et al. The prognostic signifi-
cance of radiological and symptomatic bone involvement in
childhood acute lymphoblastic leukaemia. Med Pediatr
Oncol 1979; 6: 51–5.
22. Nies BA, Kundel DW, Thomas LB, et al. Leucopenia, bone
pain, and bone necrosis in patients with acute leukemia. A
clinicopathological complex. Ann Intern Med 1965; 62: 698.
23. Neiman RS, Barcos M, Berard C, et al. Granulocytic sarcoma:
a clinicopathologic study of 61 biopsied cases. Cancer 1981;
48: 1426–37.
24. Pui MH, Fletcher BD, Langston JW. Granulocytic sarcoma in
childhood leukemia: imaging features. Radiology 1994; 190:
698–702.
25. Muss HB, Moloney WC. Chloroma and other myeloblastic
tumors. Blood 1973; 42: 721–8.
26. Liu PI, Ishimaru T, McGregor DH, et al. Autopsy study of
granulocytic sarcoma (chloroma) in patients with myeloge-
nous leukemia, Hiroshima-Nagasaki 1949–1969. Cancer
1973; 31: 948–55.
27. Krause JR. Granulocytic sarcoma preceding acute leukemia:
a report of six cases. Cancer 1979; 44: 1017–21.
28. Burns A. Observation of the Surgical Anatomy of the Head
and Neck. Edinburgh, Scotland: Thomas Bryce, 1811.
29. King A. A case of chloroma. Monthly J Med Soc 1853; 17: 97.
30. Henderson ES, Hoelzer D, Freeman AI. The treatment of
acute lymphoblastic leukaemia. In: Henderson ES, Lister TA,
eds. Leukaemia, 5th edn. Philadelphia: W B Saunders, 1990;
443–82.
31. Ortega JA, Nesbit ME, Sather HN, et al. Long-term evalua-
tion of a CNS prophylaxis trial–treatment comparisons and
outcome after CNS relapse in childhood ALL: a report from
the Children’s Cancer Study Group. J Clin Oncol 1987; 5:
1646–54.
891
 hematology malignancy
32. de Vries EG, Mulder NH, Houwen B, et al. Combination
chemotherapy for acute lymphocytic leukaemia in 25 adults.
Blut 1982; 44: 151–8.
33. Veerman AJ, Hahlen K, Kamps WA, et al. High cure rate with
a moderately intensive treatment regimen in non-high-risk
childhood acute lymphoblastic leukemia. Results of protocol
ALL VI from the Dutch Childhood Leukemia Study Group.
J Clin Oncol 1996; 14: 911–18.
34. Thomas X, Le QH. Central nervous system involvement in
adult acute lymphoblastic leukemia. Hematology 2008; 13:
293–302.
35. Bleyer WA. Central nervous system leukemia. In: Henderson
ES, Lister TA, eds. Leukaemia, 5th edn. Philadelphia: W B
Saunders, 1990; 733–68.
36. Price RA, Johnson WW. The central nervous system in child-
hood leukemia. I. The arachnoid. Cancer 1973; 31: 520–33.
37. Azzarelli V, Roessmann U. Pathogenesis of central nervous
system infiltration in acute leukemia. Arch Pathol Lab Med
1977; 101: 203–5.
38. Brant-Zawadzki M, Enzmann DR. Computed tomographic
brain scanning in patients with lymphoma. Radiology 1978;
129: 67–71.
39. Enzmann DR, Krikorian J, Yorke C, et al. Computed tomo-
graphy in leptomeningeal spread of tumor. J Comput Assist
Tomogr 1978; 2: 448–55.
40. Pagani JJ, Libshitz HI, Wallace S, et al. Central nervous
system leukemia and lymphoma: computed tomographic
manifestations. Am J Roentgenol 1981; 137: 1195–201.
41. Ginsberg LE, Leeds NE. Neuroradiology of leukemia. Am J
Roentgenol 1995; 165: 525–34.
42. Paakko E, Patronas NJ, Schellinger D. Meningeal Gd-DTPA
enhancement in patients with malignancies. J Comput Assist
Tomogr 1990; 14: 542–6.
43. Sze G, Abramson A, Krol G et al. Gadolinium-DTPA in the
evaluation of intradural extramedullary spinal disease. AJR
Am J Roentgenol 1988; 150: 911–21.
44. Kao SC, Yuh WT, Sato Y et al. Intracranial granulocytic
sarcoma (chloroma): MR findings. J Comput Assist Tomogr
1987; 11: 938–41.
45. Pomeranz S J, Hawkins H H, Towbin R et al. Granulocytic
sarcoma (chloroma): CT manifestations. Radiology 1985;
155: 167–70.
46. Moudden M, El-Moutawakil B, Boulajaj F L, Slassi I, Azhar A.
Granulocytic sarcoma of the brain revealed on vascular
mode. Rev Neurol 2005; 161: 1191–6.
47. Ahn JY, Kwon SO, Shin MS, et al. Meningeal chloroma (gran-
ulocytic sarcoma) in acute lymphoblastic leukemia mimick-
ing a falx meningioma. J Neurooncol 2002; 60: 31–5.
48. Barnett MJ, Zussman WV. Granulocytic sarcoma of the brain:
a case report and review of the literature. Radiology 1986;
160: 223–5.
49. Williams MP, Olliff JF, Rowley MR. CT and MR findings in
parameningeal leukaemic masses. J Comput Assist Tomogr
1990; 14: 736–42.
50. Ho CL, Chen CY, Chen YC, et al. Cerebral dural sinus thrombosis
in acute lymphoblastic leukemia with early diagnosis by fast fluid-
attenuated inversion recovery (FLAIR) MR image: a case report
and review of the literature. Ann Hematol 2000; 79: 90–4.
892
51. Henderson ES. Complications of leukaemia: a selective over-
view. In: Henderson ES, Lister TA, eds. Leukaemia, 5th edn.
Philadelphia: W B Saunders, 1990; 671–85.
52. Mulrooney DA, Dover DC, Li S, et al. Twenty years of
follow-up among survivors of childhood and young adult
acute myeloid leukemia: a report from the Childhood Cancer
Survivor Study. Cancer 2008; 112: 2071–9.
53. Bleyer WA. Neurologic sequelae of methotrexate and ioniz-
ing radiation: a new classification. Cancer Treat Rep 1981;
65(Suppl 1): 89–98.
54. Jager HR, Williams EJ, Savage DG, et al. Assessment of brain
changes with registered MR before and after bone marrow
transplantation for chronic myeloid leukemia. Am J Neuro-
radiol 1996; 17: 1275–82.
55. Packer RJ, Zimmerman RA, Bilaniuk LT. Magnetic resonance
imaging in the evaluation of treatment-related central ner-
vous system damage. Cancer 1986; 58: 635–40.
56. Duffner PK, Cohen ME, Brecher ML, et al. CT abnormalities
and altered methotrexate clearance in children with CNS
leukemia. Neurology 1984; 34: 229–33.
57. Laitt RD, Chambers EJ, Goddard PR, et al. Magnetic reso-
nance imaging and magnetic resonance angiography in long
term survivors of acute lymphoblastic leukemia treated with
cranial irradiation. Cancer 1995; 76: 1846–52.
58. Chan YL, Roebuck DJ, Yuen MP, et al. Long-term cerebral
metabolite changes on proton magnetic resonance spectro-
scopy in patients cured of acute lymphoblastic leukemia with
previous intrathecal methotrexate and cranial irradiation
prophylaxis. Int J Radiat Oncol Biol Phys 2001; 50: 759–63.
59. Rubinstein LJ, Herman MM, Long TF, et al. Disseminated
necrotizing leukoencephalopathy: a complication of treated
central nervous system leukemia and lymphoma. Cancer
1975; 35: 291–305.
60. Pande AR, Ando K, Ishikura R, et al. Disseminated necrotiz-
ing leukoencephalopathy following chemoradiation therapy
for acute lymphoblastic leukemia. Radiat Med 2006; 24: 515–19.
61. Matsubayashi J, Tsuchiya K, Matsunaga T, Mukai K.
Methotrexate-related leukoencephalopathy without radia-
tion therapy: distribution of brain lesions and pathological
heterogeneity on two autopsy cases. Neuropathology 2009;
29: 105–15.
62. Price RA, Birdwell DA. The central nervous system in child-
hood leukemia. III. Mineralizing microangiopathy and
dystrophic calcification. Cancer 1978; 42: 717–28.
63. Ito M, Akiyama Y, Asato R, et al. Early diagnosis of leukoen-
cephalopathy of acute lymphocytic leukemia by MRI. Pediatr
Neurol 1991; 7: 436–9.
64. Bjorgen JE, Gold LH. Computed tomographic appearance
of methotrexate-induced necrotizing leukoencephalopathy.
Radiology 1977; 122: 377–8.
65. Vera P, Rohrlich P, Stievenart JL, et al. Contribution of single-
photon emission computed tomography in the diagnosis and
follow-up of CNS toxicity of a cytarabine-containing regimen
in pediatric leukemia. J Clin Oncol 1999; 17: 2804–10.
66. Buizer AI, de Sonneville LM, Veerman AJ. Effects of chemo-
therapy on neurocognitive function in children with acute
lymphoblastic leukemia: A critical review of the literature.
Pediatr Blood Cancer 2009; 52: 447–54.
 leukemia
67. Harila-Saari AH, Paakko EL, Vainionpaa LK, et al. A longitu-
dinal magnetic resonance imaging study of the brain in sur-
vivors in childhood acute lymphoblastic leukemia. Cancer
1998; 83: 2608–17.
68. Iuvone L, Mariotti P, Colosimo C, et al. Long-term cognitive
outcome, brain computed tomography scan, and magnetic
resonance imaging in children cured for acute lymphoblastic
leukemia. Cancer 2002; 95: 2562–70.
69. Mabbott DJ, Noseworthy MD, Bouffet E, Rockel C, Laughlin
S. Diffusion tensor imaging of white matter after cranial
radiation in children for medulloblastoma: correlation with
IQ. Neuro-oncol. 2006 ; 8: 244–52.
70. Khong P-L, Leung LH, Fung AA, et al. White matter anisot-
ropy in post-treatment childhood cancer survivors: prelimi-
nary evidence of association with neurocognitive function.
J Clinical Oncol 2006; 24: 884–90.
71. Kumar J, Seith A, Bakhshi S, et al. Isolated granulocytic sar-
coma of the orbit. Eur J Haematol 2007; 78: 456.
72. Manabe Y, Hamakawa Y, Sunami K, et al. Granulocytic sar-
coma with orbit, cauda equina, muscle and peripheral nerve
extension but without bone marrow involvement. Intern
Med 2007; 46: 633–5.
73. Lackner H, Sovinz P, Benesch M, et al. Management of brain
abscesses in children treated for acute lymphoblastic leuke-
mia. Pediatr Blood Cancer 2009; 52: 408–11.
74. Lee WA, Hruban RH, Kuhlman JE, et al. High resolution
computed tomography of inflation-fixed lungs: pathologic–
radiologic correlation of pulmonary lesions in patients with
leukemia, lymphoma, or other hematopoietic proliferative
disorders. Clin Imaging 1992; 16: 15–24.
75. George CD, Wilson AG, Philpott NJ, et al. The radiological
features of adult T-cell leukaemia/lymphoma. Clin Radiol
1994; 49: 83–8.
76. Armstrong P, Dyer R, Alford BA, et al. Leukemic pulmonary
infiltrates: rapid development mimicking pulmonary edema.
Am J Roentgenol 1980; 135: 373–4.
77. Berkman N, Polliack A, Breuer R, et al. Pulmonary involve-
ment as the major manifestation of chronic lymphocytic leu-
kemia. Leuk Lymphoma 1992; 8: 495–9.
78. Green RA, Nichols NJ. Pulmonary involvment in leukemia.
Am Rev Resp Dis 1959; 80: 833–44.
79. Kakihana K, Ohashi K, Sakai F, et al. Leukemic infiltration of
the lung following allogenic hematopoietic stem cell trans-
plantation. Int J Hematol 2009; 89: 118–22.
80. Schimpff SC. Infection in the leukaemia patient: diagnosis,
therapy and prevention. In: Henderson ES, Lister TA, eds. Leu-
kaemia, 5th edn. Philadelphia: W B Saunders, 1990; 687–709.
81. DeGregorio MW, Lee WM, Linker CA, et al. Fungal infections
in patients with acute leukemia. Am J Med 1982; 73: 543–8.
82. Olliff JF, Williams MP. Radiological appearances of cytomeg-
alovirus infections. Clin Radiol 1989; 40: 463–7.
83. Crassard N, Hadden H, Pondarré C, et al. Invasive aspergillosis
and allogeneic hematopoietic stem cell transplantation in chil-
dren: a 15-year experience. Transpl Infect Dis 2008; 10: 177–83.
84. Dee P. Drug- and radiation-induced lung disease. In:
Armstrong P, Wilson AG, Hansell DM, eds. Imaging Diseases
of the Chest, 2nd edn. St Louis: Mosby, 1995; 461–84.
85. Chan CK, Hyland RH, Hutcheon MA, et al. Small-airways
disease in recipients of allogeneic bone marrow transplants.
An analysis of 11 cases and a review of the literature. Medi-
cine 1987; 66: 327–40.
86. Graham NJ, Muller NL, Miller RR, et al. Intrathoracic com-
plications following allogeneic bone marrow transplanta-
tion: CT findings. Radiology 1991; 181: 153–6.
87. Da’as N, Polliack A, Cohen Y, et al. Kidney involvement and
renal manifestations in non-Hodgkin’s lymphoma and lym-
phocytic leukemia: a retrospective study in 700 patients. Eur
J Haematol 2001; 67: 158–64.
88. Gore RM, Shkolnik A. Abdominal manifestations of pediat-
ric leukemias: sonographic assessment. Radiology 1982; 143:
207–10.
89. Boggs DA, Wintrobe MM, Cartwright GE. The acute leukae-
mias. Analysis of 322 cases and review of the literature. Med-
icine 1962; 41: 163.
90. Epstein RJ, McDonald GB, Sale GE, et al. The diagnostic
accuracy of the rectal biopsy in acute graft-versus-host dis-
ease: a prospective study of thirteen patients. Gastroenterol-
ogy 1980; 78: 764–71.
91. Slavin RE, Woodruff JM. The pathology of bone marrow
transplantation. In: Somers SC, ed. Pathology Annual. New
York: Appleton-Century Crofts, 1974; 291.
92. Kalantari BN, Mortelé KJ, Cantisani V, et al. CT features
with pathologic correlation of acute gastrointestinal
graft-versus-host disease after bone marrow transplantation
in adults. AJR Am J Roentgenol 2003; 181: 1621–5.
93. Belli AM, Williams MP. Graft-versus-host disease: findings
on plain abdominal radiography. Clin Radiol 1988; 39: 262–4.
94. Fisk JD, Shulman HM, Greening RR, et al. Gastrointestinal
radiographic features of human graft-versus-host disease.
Am J Roentgenol 1981; 136: 329–36.
95. Maile CW, Frick MP, Crass JR, et al. The plain abdominal
radiograph in acute gastrointestinal graft-versus-host dis-
ease. Am J Roentgenol 1985; 145: 289–92.
96. Jones B, Fishman EK, Kramer SS, et al. Computed tomogra-
phy of gastrointestinal inflammation after bone marrow
transplantation. Am J Roentgenol 1986; 146: 691–5.
97. Cartoni C, Dragoni F, Micozzi A, et al. Neutropenic entero-
colitis in patients with acute leukemia: prognostic signifi-
cance of bowel wall thickening detected by ultrasonography.
J Clin Oncol 2001; 19: 756–61.
98. deCastro LA, Kuhn JP, Freeman AI, et al. Complete
remodeling of the vertebrae in a child successfully treated
for acute lymphocytic leukemia (ALL). Cancer 1977; 40:
398–401.
99. Tricot G, Boogaerts MA, Broeckaert-Van Orshoven A, et al.
Hypercalcemia and diffuse osteolytic lesions in the acute
phase of chronic myelogenous leukemia. A possible relation
between lymphoid transformation and hypercalcemia. Can-
cer 1983; 52: 841–5.
100. Van Slyck EJ. The bony changes in malignant hematologic
disease. Orthop Clin North Am 1972; 3: 733–4.
101. Goergen TG, Alazraki NP, Halpern SE, et al. “Cold” bone
lesions: a newly recognized phenomenon of bone imaging.
J Nucl Med 1974; 15: 1120–4.
893
 hematology malignancy
102. Parker BR, Marglin S, Castellino RA. Skeletal manifestations
of leukemia, Hodgkin disease, and non-Hodgkin’s lym-
phoma. Semin Roentgenol 1980; 15: 302–15.
103. Porter BA, Shields AF, Olson DO. Magnetic resonance imag-
ing of bone marrow disorders. Radiol Clin North Am 1986;
24: 269–89.
104. Jones RJ. The role of bone marrow imaging. Radiology 1992;
183: 321–2.
105. Moore SG, Gooding CA, Brasch RC, et al. Bone marrow in
children with acute lymphocytic leukemia: MR relaxation
times Radiology 1986; 160: 237–40.
106. McKinstry CS, Steiner RE, Young AT, et al. Bone marrow in
leukemia and aplastic anemia: MR imaging before, during,
and after treatment. Radiology 1987; 162: 701–7.
107. Van de Berg BC, Michaux L, Scheiff JM, et al. Sequential
quantitative MR analysis of bone marrow: differences during
treatment of lymphoid versus myeloid leukemia. Radiology
1996; 201: 519–23.
894
108. Lecouvet FE, van de Berg BC, Michaux L, et al. Chronic lym-
phocytic leukemia: changes in bone marrow composition
and distribution assessed with quantitative MRI. J Magn
Reson Imaging 1998; 8: 733–9.
109. Ballon D, Dyke J, Schwartz LH, et al. Bone marrow segmenta-
tion in leukemia using diffusion and T(2)-weighted echo
planar magnetic resonance imaging. NMR Biomed 2000; 13:
321–8.
110. Shih TT, Hou HA, Liu CY, et al. Bone marrow angiogenesis
MR imaging in patients with acute myeloid leukemia: peak
enhancement ratio is an independent predictor for overall
survival. Blood 2009; 113: 3161–7.
111. Stevens SK, Moore SG, Amylon MD. Repopulation of
marrow after transplantation: MR imaging with pathologic
correlation. Radiology 1990; 175: 213–18.
112. Tanner SF, Clarke J, Leach MO, et al. MRI in the evaluation of
late bone marrow changes following bone marrow trans-
plantation. Br J Radiol 1996; 69: 1145–51.
 36 General Principles in Pediatric Oncology
David Stringer and Harvey Teo
INTRODUCTION
Children with cancer are a relatively small group within a typical
pediatric-imaging department. However they place the greatest
demand on staff and services. This is because they are often very ill
and have enormous anxieties concerning all medical interactions,
not least radiological. Understandably, the parents are also likely to
be under considerable stress and expect urgent, immediate, safe
radiological investigation with rapid, correct diagnosis. The radiol-
ogist needs to be particularly sensitive to these needs, giving objec-
tive, decisive, and diagnostically accurate reports. Close rapport
with the oncologist is required, not least because he will be under
considerable pressure from the parents to expedite treatment.
It is essential that all modalities are available in the hospital where
investigation and treatment are being undertaken, including:
• Plain radiography
• Ultrasound (US)
• Nuclear medicine
• Computed tomography (CT)
• Magnetic resonance (MR) imaging
• Angiography/interventional facilities
• PET-CT
THE DEPARTMENT
Children with cancer ideally should be investigated and treated in
a department that deals extensively or exclusively with children. In
a busy general hospital it is difficult to give the same attention to
detail and for staff inexperienced in dealing with sick children, the
situation can be very stressful . Hence pediatric hospitals or women’s
and children hospitals with fully trained pediatric staff in all disci-
plines (radiologists, radiographers, sonographers, and nurses) will
undoubtedly give the most comfortable and supportive service.
Special attention should be given to the facilities provided by
the department in order to obtain optimum results from imaging.
General Ambience
The general ambience of a pediatric imaging facility should be
designed to make the child feel secure in what is otherwise a
frightening environment. Hence murals, toys, and other decora-
tions, which can be adequately cleaned, should be readily avail-
able. For older children suitable reading materials should be made
available. It is important to cater to all age groups.
Some manufacturers of major radiology equipment offer spe-
cial ambience programs that can be purchased along with their
major pieces of equipment. Examples of this are mood videos and
electronic wall decorations that can be programmed into the MR
suite which are individually chosen by each child. Multiple televi-
sion sets in strategic locations are also useful for keeping children
entertained whilst waiting for or during studies. A ceiling mounted
television with low sound can help keep a very fretful child quiet
and motionless during US studies. During MR imaging music
should be provided either using earplugs or headphones and if a
CD player is available children can be encouraged to bring their
own music to play during the examination.
Injections
Many radiological examinations require an intravenous (IV) injec-
tion, either for administration of contrast medium or for sedation.
Children with cancer frequently undergo multiple IV injections
during the course of treatment and investigation and many of
these injections consist of cytotoxic materials which make them feel
extremely unwell. Hence these children may develop needle phobia
which renders the whole diagnostic examination more difficult
than in adults. However, with the assistance of staff experienced in
gaining IV access in children, the procedure can be performed in a
calm and controlled environment. Nevertheless some children are
terrified at the prospect of having an injection, usually having had
multiple painful injections in the past and therefore these injections
should be given in a private room with relative sound proofing as
the sound of crying is likely to make other children apprehensive.
The use of a local anesthetic cream prior to an injection may
help to reduce discomfort of needle puncture and in some depart-
ments acupuncture has been reported to be effective in reducing
chemotherapy side effects (1). A butterfly needle system should be
used because the flexible tube reduces the risk of displacement of
the needle as a result of sudden movement. If injection speed is
not important for the particular study, a very small needle of 23 to
27 French Gauge can be used.
By working closely with the pediatric oncology team a schedule
of procedures can be planned for the day and in order to avoid
multiple injections on the same day, it may be appropriate to
insert an IV cannula instead of a butterfly needle.
Cancer treatment reduces children’s immunity and hence great
care should be taken to avoid any possible risk of infection. In
particular if an IV access long line has been inserted and is to
be used for IV contrast administration or sedation then strict
adherence to hospital protocols must be maintained.
Sedation and General Anesthesia for Imaging
Some children are uncooperative either due to their young age or
sometimes due to medical or developmental factors. General
anesthesia (GA) is most often required for MR imaging examina-
tions between the ages of one and seven years, because the long
claustrophobic tube is frightening, the examination takes a long
time and the procedure is noisy. Furthermore diagnostic quality is
impaired because movement degrades the images. Multidetector
CT (MDCT) is much less of a problem than MR imaging studies
and using 64-slice MDCT sedation is only required occasionally.
Nuclear medicine studies also sometimes require sedation.
If sedation or GA is to be performed for an investigation it is
imperative to check with the referring physicians whether any other
895
 pediatrics

tests need to be performed so that these can be combined with the
radiological investigation and carried out under the same anesthetic
procedure. These other tests could include insertion of a long-line,
biopsy, bone marrow aspiration, lumbar puncture, or even just a
venepuncture. GA will require close co-operation between the pedi-
atric anesthetist and MR imaging scheduler. It is best to organize
dedicated general anesthesia days. This makes scheduling for both
the anesthetist and for radiologists much simpler and safer.
In the design of an MR imaging or CT suite an induction and
recovery area should be incorporated so that dedicated nurses or
doctors can easily monitor these patients. Radiographers should
not be responsible for monitoring sedation, firstly because they
are unlikely to be specifically trained in resuscitation of children
and secondly because their expertise should be dedicated to
achieving a high quality diagnostic imaging study.
Sedation generally works well for infants under one year of age
and for selected children of an older age. There are three stages of
sedation—mild, moderate, and deep.
• Mild sedation that does not depress respiratory function,
like Chloral
• A typical moderate sedation agent is Midazolam
• Deep sedation should only be performed by an anesthetist
Mild and moderate sedation should be performed only by those who
are fully trained to give these agents. Pediatric anesthetists with input
from radiologists and nursing staff should develop strict hospital pro-
tocols for sedation during radiology procedures. There should be an
accreditation process for those staff (doctors and nurses) who are
given the responsibility to give and monitor sedation.
include very high frequency linear and sector transducers. These
achieve the best spatial and contrast resolution for the small ana-
tomical structures in children. Color Doppler and spectral Doppler
are essential. All equipment should be cleaned scrupulously
between patients to prevent cross infection, which is particularly
important in these children who are often immunodepressed.
Plain Radiography
Plain radiography gives a low dose of radiation, lower than any
other x-ray modality, but is only of value in musculoskeletal, chest,
and abdominal tumors. It is important to keep the radiation dose
for each study as low as possible, tailoring the dosage to the size
of the child. Adult doses should never be used. Using computed
radiography (CR) it is possible to reduce dosage significantly for
some examinations, for example a scoliosis series, as image quality
to assess fine detail is less important in such examinations.
Nuclear Medicine
Nuclear medicine, particularly utilizing bone scans, is very useful for
the investigation, staging, and follow-up of many tumors (Fig. 36.1).
Acquisition time is relatively long so some patients will need sedation
and providing television programs or music can decrease the need for
sedation. High-resolution collimation must be available. Radiation
doses should be tailored to the size of the child.
Positron emission tomography (FDG PET) is increasingly being
used in pediatric oncology, and is especially useful in detecting

Heat Loss
Young children, particularly infants, lose heat very quickly and
significant medical problems can arise if they are not kept warm.
Blankets and commercially available heating devices should be
used. There are special MR imaging coils which mimic an incubator
that should be used if available.

Equipment and Radiation

Imaging equipment is manufactured by a relatively small number
of companies and is primarily designed for adults. Hence when
purchasing any equipment, it is particularly important to consider
pediatric applications.
X-rays are more harmful to children than adults because they
are rapidly growing and dividing cells are the most sensitive to
radiation damage (2,3). Radiation should be avoided unless abso-
lutely necessary; therefore equipment such as US and MR imaging
are the preferred modalities.

Ultrasound
US is a safe modality using high frequency sound only. It is excel-
lent for the initial evaluation of a palpable mass in the soft tissues
or abdomen and can also be used for routine screening of the
abdomen. Follow-up of some tumors is also possible with US but
the technique is not as reproducible as CT or MR imaging. In the L Posterior R
chest, US has limited value. Also, since most brain tumors arise
Figure 36.1 Seven-year-old boy with neuroblastoma. Posterior image taken during
after fontanelles have closed the technique is of little value in Tc-99m methylenediphosphonate bone scan shows the presence of multiple hot
children with suspected intracranial malignancy. US equipment, spots in the spine, left upper humerus, and medial aspect of the right iliac wing
when purchased, should include pediatric transducers. These (arrows) due to bone metastases.

896
 general principles in pediatric oncology

occult disease in a variety of tumors. This equipment is the most

expensive of all radiology equipment and a high radiation dose is
given. The cost of studies and limited availability make this a less
used modality than CT or MR imaging, but in selected cases, it
can be extremely useful, providing unique information.

Computed Tomography
The need for sedation and general anesthesia is considerably
reduced using CT scanners with a fast acquisition time and there-
fore these are recommended for all pediatric examinations.
There is increased concern in the literature of the risks of CT
radiation in children (2–5). Children, as explained above, are
much more sensitive to radiation and cancer induction and/or
cancer mortality in later life. Hence the benefit of the examination
must always be compared to the risks. In cancer patients requiring
multiple examinations, the risk increases in a linear fashion to the
radiation dose. Estimates of carcinogenesis resulting in death are
possibly as high as one in 1000 CTs. Dose reduction can be
achieved by all of the above methods as well as changing the scan
parameters, reducing mAs and kVp according to patient weight
and altering slice thickness or scan pitch (4,5).
Adult radiation doses and settings should never be used in chil-
dren and each study should be tailored to get the maximum infor-
mation with the least radiation, the ALARA principle (as low as Figure 36.2 Ten-year-old boy presenting with headache. Sagittal T1-weighted
reasonably achievable) (4,5). Detector systems and scan protocols post-contrast MR image shows the presence of a tumor (arrow) in the fourth
should be chosen to minimize radiation dose (4,5). Ideally a ventricle causing hydrocephalus. Histologically this was an ependymoma.
multidetector 64-slice CT scanner with dose modulation technology
should be used as this can give the lowest doses. To screen sensitive
areas such as breast and thyroids, shields can be used. Taking the
scout view with the x-ray tube underneath the patient will reduce Staff
the radiation dose to exposed organs as well. Training and motivation of all staff is extremely important.
Empathetic radiographers, nurses, reception staff, and radiolo-
Magnetic Resonance Imaging gists can reduce anxiety of the patient and parents tremendously
MR imaging is increasingly used for diagnosis and follow-up of thus enabling optimum image quality to be obtained during sub-
cancer as there is no ionizing radiation, but the cost of studies and sequent imaging studies. To successfully image a child requires
general availability of MR imaging remain important considerations. special commitment and those who show aptitude should be
MR imaging is especially good for some specific tumors, particularly selected to be part of the team who perform all pediatric studies in
brain, spinal, bone and soft tissue tumours (Fig. 36.2). a mixed adult and children’s department.
Of all imaging equipment MR is one of the most daunting for a
child. Hence many younger children (usually aged between one
and seven years) will require GA or moderate sedation. To reduce Key Points: General Considerations
the need for sedation or GA, a thorough age appropriate discus- ■ Radiological work-up is best performed in pediatric
sion is necessary and a mock-up of the scanner demonstrated on departments that deal exclusively or extensively with
a teddy bear or similar toy can be most helpful in alleviating fears. children and staff are experienced in cancer imaging
Tapes of the very loud tapping noise that occurs during the scan ■ Fully trained pediatric imaging staff are essential for achieving
process will significantly improve acceptance by the child. Scan successful imaging studies
sequences should be chosen for the shortest time possible that will ■ Facilities for pediatric imaging should be designed to provide
provide the necessary information. Cardiac and respiratory gating a homely child-friendly ambience
may be necessary. ■ Strict protocols for sedation should be in place, prepared in

Fluoroscopy conjunction with the anesthesia department

■ US is an excellent modality for initial investigation of
Fluoroscopy is a rarely required. If needed for any purpose, low
dose techniques, including using the last image hold, pulsed suspected malignancy
■ Dose reduction techniques are critically important, particularly
fluoroscopy, rare earth filters, and short fluoroscopy time without
a grid, will very significantly reduce radiation dose. The tabletop for examining children with CT who will require multiple
should be covered with lead except for the area to be examined. studies during follow-up. 64-slice MDCT offers the most
This reduces radiation to the patient and reduces scatter radiation effective dose reduction technology
■ MR imaging is indicated for brain and spinal tumors as well
to the operators. Preferably, a nurse should be in the room with
the patient and the radiologist in addition to a radiographer. as for bone and soft tissue tumors

897
 pediatrics
Figure 36.3 Ten-year-old girl with Beckwith-Weidemann syndrome on six-monthly ultrasound follow-up for nephroblastomatosis of the right (RT) kidney (arrows)
shown on longitudinal (LS) and transverse (TS) sections. This echogenic lesion in the right kidney has been stable for several years.
ROLE OF IMAGING
The role of imaging in pediatric cancer management includes:
• Screening
• Diagnosis
• Staging
• Follow-up
Screening
There are a few conditions in children that predispose or are asso-
ciated with higher risks of cancer. Examples include:
• Genitourinary malformations (renal ectopia, ureteral
duplication, renal hypoplasia, horseshoe kidney, and
cryptorchidism), sporadic aniridia (Wilms’ tumors)
• Denys-Drash syndrome (male pseudohermaphroditism
and nephritis) (Wilms’ tumor)
• Beckwith-Weidemann syndrome (Fig. 36.3) (embryonal
tumors such as Wilms’ tumor, hepatoblastoma, neuro-
blastoma, rhabdomyosarcoma)
There are also some other rare syndromes, such as Perlman syn-
drome (fetal gigantism, hypotonia, and multiple congenital
abnormalities) and overgrowth syndromes such as congenital
hypertrophy and WAGR syndrome (Wilms’ tumor, sporadic
aniridia, genital malformations, and retardation) which all have a
significantly increased incidence of Wilms’ tumors (6). Hence
regular three- to six-monthly US studies can be used to screen the
kidneys. Unless there is such a predisposing risk, screening is not
otherwise indicated.
Diagnosis
In most instances the radiologist is among the first to diagnose
a tumor. Although the final diagnosis will be histological, many
898
pediatric tumors have sufficiently characteristic appearances to
allow a preliminary diagnosis to be made. In the initial investi-
gation plain films followed by US and/or CT can be very help-
ful. A plain film of the musculoskeletal system is useful if the
suspected tumor is peripheral (Fig. 36.4). A chest radiograph
should be performed in all patients suspected of having a
malignant tumor.
US is the second modality of choice to investigate the abdomen
and soft tissues. Once a malignant tumor is suspected on initial
investigation, a CT or MR imaging study is essential. CT is most
useful in the thorax. In the abdomen both CT and MR imaging
can be used, depending on location and type of tumor suspected.
The aim of the diagnostic work-up is to obtain the maximum
amount of information with the minimum number of tests and
the least radiation dosage.
MR imaging is the modality of choice for examination of:
• Brain
• Spine
• Pelvis
• Bone
• Soft tissues
Investigation is best performed in the center where the tumor
is to be treated. Biopsies should never be performed before the
full imaging work-up has been obtained. For example, if a
biopsy of a suspected osteogenic sarcoma of the knee is per-
formed prior to an MR imaging examination it will not be
possible to determine whether the lesion is operable or inop-
erable because the biopsy will have disturbed the tumor
margins.
Some tumors have a characteristic appearance. For example, the
two most common tumors in the abdomen, neuroblastoma, and
Wilms’ tumor can usually be differentiated on imaging alone (see
chaps. 37 and 38). For example, a neuroblastoma surrounds blood
 general principles in pediatric oncology
Figure 36.4 Six-year-old boy with a left tibial osteosarcoma. The plain radio-
graph of the left tibia shows the presence of an ill-defined destructive lesion in
the metaphysis of the tibia. There is periosteal new bone formation with lifting
of the periosteum giving the typical appearance of “Codman’s triangle”
(arrow). These features are highly suggestive of osteosarcoma, which was
proven histologically.
vessels whereas a Wilms’ tumor displaces them. This is readily
demonstrated on US, CT, and MR imaging.
Biopsy
Biopsy is required for almost all tumors, except some inaccessible
brain tumors. The surgeon often performs the biopsy, but increas-
ingly radiologists are involved in image guidance or undertake the
entire procedure.
If there is more than one tumor, then the most accessible is
biopsied. It is essential that the specimens obtained are of
sufficient size and quality for the pathologist to undertake accu-
rate cytogenetic and immuno-histochemistry studies, that
appropriate storage medium is used and that arrangements are
in place for rapid transport of tissue samples to the pathology
department. Thus close liaison with the pathology department
is essential.
If the radiologist is performing the biopsy then close liaison
with the surgeon is essential to ensure that the region biopsied
and the path of the biopsy needle will not interfere with subsequent
Figure 36.5 One-year-old girl with lung metastases from hepatoblastoma. Axial
CT of the chest, at the level of the carina, shows multiple lung metastases in both
lungs (arrows).
surgical management. Imaging should be performed prior to
biopsy when possible in order to demarcate the tumor as accu-
rately as possible and to define its local extent.
Staging
The order of frequency of pediatric tumors is as follows:
• Leukemia
• Central nervous system
• Lymphoma
• Neuroblastoma
• Renal tumor
• Soft tissue sarcoma
• Bone tumors
• Others
Once a tumor has been detected, localized, and delineated, local
and distant spread needs to be assessed. CT is the modality of choice
for detecting lung metastases (e.g., Wilms’ tumor) (Fig. 36.5) but is
unnecessary for some tumors as lung metastases are very rare, for
example, neuroblastoma.
Follow-up
Imaging is an essential part of follow-up and should be performed
on a regular basis, working closely with the team providing the
patient’s care which includes the oncologist, surgeon, pathologist,
and the patient’s family. Co-ordination by this team approach
gives the best healthcare delivery to the child.
The imaging modality used should be the one which pro-
vides the necessary information with the least discomfort and
risk to the child. This will vary according to the type and
location of each tumor. Ideally the examination should be
performed in the same hospital for each study and where treat-
ment is being given, as this will facilitate good reproducible
comparison between studies to be made by the team that knows
the patient well (Fig. 36.6).
899
 pediatrics
Figure 36.6 Same patient as in Figure 36.5 (hepatoblastoma with lung metastases).
Axial CT of the chest, at the level of the carina, performed one year later after resec-
tion of the primary tumor, and chemotherapy shows complete resolution of the
lung metastases.
Key Points: Role of Imaging
■ Screening should only be performed for children with
congenital syndromes which predispose to malignancy such
as genitourinary malformations
■ Plain films and US provide initial imaging modalities of
choice in a child with suspected malignancy
■ Most pediatric tumors have sufficient characteristic appear-
ances to permit an initial diagnosis although histological
diagnosis is essential
■ CT and MR imaging are required for further evaluation of
suspected malignancy and for staging
■ Imaging should be performed prior to biopsy when possible in
order to demarcate the tumor as accurately as possible
■ The modality used for follow-up should be the one which
will provide the necessary information with the lowest risk to
the child and the least discomfort
INVESTIGATION OF THERAPEUTIC COMPLICATIONS
The short-term effect of chemotherapy and long-term effects of
radiation can result in a number of serious and significant life-
threatening complications which may be acute or chronic. Both
radiation and chemotherapeutic agents can cause acute compli-
cations. These are related to depression of the hematological sys-
tem, particularly with respect to the production of platelets and
white blood cells. Thus hemorrhage and infection as well as other
immunological abnormalities can occur. Strict attention to
hygiene while imaging, cleaning of patient areas and separating
those who are most at risk from others, is essential to prevent
cross infections.
Acute Complications
Infection
Immunosuppression associated with both chemotherapy and
radiation renders these children susceptible to all types of infection,
900
Figure 36.7 Eight-year-old girl with acute myeloid leukemia and shortness of
breath. The chest radiograph shows the presence of bilateral lower lobe infiltrates
(arrows). A porta-cath is noted in situ. Microbiological studies revealed infection
due to cytomegalovirus. Abbreviations: RT, right side
but especially to opportunistic infections. Common sense hygiene
and meticulous attention to detail, such as well-rehearsed hand
washing routines between each patient, can lead to a significant
reduction in this complication. As far as possible during this
period they should be kept away from other patients with known
infections, including staff that have common colds or other minor
ailments.
Various types of infection can occur with the commonest
being pneumonia (Fig. 36.7). The most frequent pneumonias
are viral or bacterial but opportunistic infection also commonly
occurs. The opportunistic infections most frequently seen include
fungal disease, tuberculosis, mycoplasma, and pneumocystis car-
inii pneumonia (7–12). Although, their imaging features have
been described elsewhere, the causative organism cannot be
accurately diagnosed by imaging alone (7–12). In children with
AIDS, atypical tuberculosis may occur giving rise to lymphade-
nopathy (11). In the early stages the diagnosis is difficult to make
but later pulmonary infiltrates develop and these are best visual-
ized by high resolution CT (HRCT) (10,13,14). Pulmonary infil-
trates may appear as mass-like lesions and therefore may be
confused with metastases and furthermore lymphadenopathy
due to tuberculosis may be ascribed to metastatic disease. Clini-
cal correlation and comparison with previous CT studies will
help to distinguish infection from relapsing or progressive cancer.
The diagnosis of tuberculosis should be confirmed by bronchial
lavage or biopsy.
Fungal infection should be suspected in the febrile neutropenic
patient (7–10). Fungal infection often gives rise to unusual radiologi-
cal appearances which may resemble lung metastases. Correlation
with previous chest radiographs or CT as well as clinical correlation
usually make this an easy differentiation due to the typical appear-
ance and speed of change of infective processes. A common fungus is
 general principles in pediatric oncology
aspergillus, which can give arise to mycetoma (fungus ball) or may be
frankly invasive, especially in the severely immunocompromised.
Wedge-shaped areas of consolidation may be seen.
Infection resulting from long intravenous lines is a frequent
cause of pyrexia in neutropenic children. When an infusion is
given through an infected line, clumps of bacteria can become
septic emboli which carry the risk of causing bacterial endocarditis.
The emboli can also cause foci of infection in other organs, such
as the liver, kidneys, and brain.
Other Complications of Intravenous Lines
Intravenous lines may be misplaced, may migrate to the wrong
position, become thrombosed or blocked by debris or even frac-
ture. Great care should be taken in assessing all lines. A single
frontal radiograph may be misleading. Where the line appears in
perfect position on one projection, for example often overlying
the region of the superior vena cava, a lateral view may show that
it is significantly displaced. The radiologist is often the first to
realize there is a line problem either on reporting a follow-up chest
radiograph (if the line is significantly displaced), or when infusing
the line by discovering a resistance to flow. Such an occurrence
should be treated extremely seriously and immediate investigation
should be undertaken with radiography and, if necessary, linogra-
phy (injection of a small amount of contrast fluoroscopically). If
some contrast can be injected then a linogram is the most useful
test, as it will accurately show the correct site of the problem. If the
line is completely blocked then a decision, based on the radiographic
findings, needs to be made as to whether it can be safely removed.
If there is any question that it has perforated a blood vessel or the
heart then further evaluation, usually by CT, is necessary to accu-
rately localize the tip to determine whether it is safe to withdraw
the line blindly or whether an operation is indicated.
Occasionally a thrombosis develops which extends beyond the
line itself into the superior vena cava. Depending on the exact site
of the obstruction, superior vena cava syndrome may ensue with
associated edema of the upper limb and neck. A Doppler study
may exclude this serious complication or occasionally venogra-
phy, MR venography (MRV), and/or MR angiography (MRA) is
necessary to demonstrate the anatomy of the vessels, as well as the
site and extent of obstruction (15,16).
Hemorrhagic Complications
Hemorrhage is a rare complication of treatment even though the
platelet count during treatment is often low. Plain films are useful
for determining the presence of hemorrhage in the chest. US, CT,
and MR imaging are the modalities of choice for investigating
suspected hemorrhage in the abdomen, pelvis, soft tissues, and
brain. Unenhanced studies should be performed because acute
hemorrhage, which has a high attenuation on CT and a high
signal intensity on T1-weighted MR imaging, may be masked by
parenchymal enhancement.
Gastrointestinal Complications
The three main complications of the gastrointestinal tract are:
• Neutropenic enterocolitis
• Pseudomembranous colitis
• Systemic disease - graft versus host disease
Neutropenic Enterocolitis
Neutropenic enterocolitis primarily affects the cecum. In Greek
the cecum is called the typhlos and hence neutropenic enterocoli-
tis is often referred to as typhlitis. It occurs in children who are
immunosuppressed, irrespective of the cause, but is most com-
monly seen in children who have been treated with chemotherapy
for leukemia (17). The classical presentation is that of abdominal
pain, pyrexia, and bloody diarrhea. However the presentation may
be variable with one or more of these symptoms.
Plain radiography is the initial investigation of choice. In children
over one year of age there should always be some fecal shadowing in
the right lower quadrant. Lack of fecal shadowing in a patient, who
is eating normally and is not taking aperients, is abnormal. Hence in
the correct clinical setting, absence of any fecal shadowing in the
right lower quadrant should alert the radiologist to the possibility
of neutropenic enterocolitis. Lack of right iliac fecal bowel gas,
thickened bowel, thumb-printing, or evidence of pneumatosis coli
are diagnostic. There may be evidence of generalized paralytic ileus
secondary to the inflammation. Perforation is rare.
US is a very useful modality, especially as these very sick patients
may need portable studies (18). The US findings include bowel wall
thickening and rigidity with increased blood flow on color Doppler.
Free fluid is often present. US may identify a localized perforation or
an abscess. CT is occasionally indicated for further evaluation of
complex cases (Fig. 36.8) (19,20). Rarely intussusceptions can occur.
Pseudomembranous Colitis
Pseudomembranous colitis is less common than neutropenic
enterocolitis. It is due to overgrowth with Clostridium difficile
and its toxin and is secondary to antibiotic therapy (21). The
radiographic, US, and CT findings are similar to neutropenic
enterocolitis, although with a higher risk of pneumatosis intesti-
nalis and perforation (21–23).
Systemic Disease—Graft Versus Host Disease
Children who have bone marrow transplantation and who
become profoundly neutropenic can suffer an unusual multi-
system abnormality, graft verses host disease (GVHD). Usually the
Figure 36.8 Neutropenic 10-year-old boy with acute lymphoblastic leukemia
undergoing chemotherapy presenting with right-sided abdominal pain. CT shows
a circumferentially thick-walled cecum consistent with neutropenic colitis (arrow).
901
 pediatrics
gastrointestinal tract is the most affected region but the liver and
skin can also be affected. Treatment is conservative unless perfo-
ration or abscess formation occurs. Plain radiography shows a
non-specific dilatation and generalized bowel wall thickening,
confirmed on sonography (24). Pneumatosis intestinalis can
also occur (25,26).
Sonography may show the pneumatosis as a circle of increased
echogenicity within the bowel wall (27), and color Doppler may
show increased blood flow to the bowel. CT or MR imaging are
indicated only for investigating complications and will also
show bowel wall thickening associated with abnormal contrast
enhancement due to increased vascularity of the bowel
wall (28–30).
Lung GVHD, presenting with cough, and bronchospasm gives
an obstructive pattern with hyperinflation. Very high infiltration
leads to a diffuse interstitial pattern and is best confirmed on
HRCT (31). Definite diagnosis is made by biopsy.
Key Points: Acute Complications
■ Acute complications of chemotherapy and radiotherapy
include infection, hemorrhage, and gastrointestinal disorders
■ Immunosuppression renders children susceptible to viral,
bacterial, and opportunistic infections
■ Opportunistic infections are usually due to tuberculosis,
fungal, or Pneumocystis carinii
■ Long IV lines may become infected, misplaced, may migrate, or
become thrombosed. Occasionally a line may fracture
■ Hemorrhage is a rare complication of therapy
■ Neutropenic enterocolitis most commonly occurs in
immunosuppressed children with leukemia
■ Pseudomembranous colitis is secondary to C. difficile
■ Graft versus host disease most commonly affects the
gastrointestinal tract but is a multisystem disorder
Chronic Complications
Increasingly children are being cured of their primary cancer and
more long-term complications are appearing (32–34). Complica-
tions are secondary to irradiation radiotherapy or from chemo-
therapy (32,35). Following radiotherapy the anatomical site of
treatment will determine the complication which in turn will
determine the imaging to be performed.
Chronic complications from therapy affect primarily the fol-
lowing regions:
• Central nervous system
• Musculoskeletal system
• Heart
• Lungs
• Gonads
• Thyroid
• Kidneys
Central Nervous System
Generalized long-term damage to the brain can be caused by
radiotherapy and chemotherapy, even in the absence of treatment
of a primary brain tumor. This occurs particularly in children
with leukemia and leads to cerebral atrophy with loss of cerebral
902
tissue. There is a compensatory non-obstructive dilatation of the
ventricles (see chap. 31).
Sometimes functional neuroendocrine defects can occur fol-
lowing treatment of a primary brain tumor, especially if the tumor
originated close to the pituitary gland. Cranial MR imaging is the
modality of choice for assessing these complications.
Musculoskeletal System
Therapeutic doses of radiation in the primary beam cause damage
to a growing skeleton. Thus unless the whole spine is irradiated, a
short segment scoliosis will occur due to the lack of growth of the
irradiated side of the spine. The face may also become asymmetri-
cal following radiotherapy for craniofacial tumors.
Plain films should be undertaken initially and these will dem-
onstrate most abnormalities. Limb length can be measured by a
scanogram of the hips, knees, and the ankles using a low dose
technique or by three-foot plain film images.
Bone age assessments can be useful when there are growth abnor-
malities (36). If surgery or further detail of any osseous deformity is
required, 3D reconstructions from an unenhanced CT are necessary.
Heart
Radiotherapy can result in a constrictive pericarditis (32). This
only occurs following mediastinal radiation, but this type of
therapy is rarely used today. Cardiac function can be disturbed by
chemotherapy with impairment of left ventricular function.
Echocardiography is the best initial investigation.
Lungs
Both radiotherapy and chemotherapy can cause pneumonitis and
fibrosis which is best demonstrated on HRCT.
Gonadal Effects
Generalized growth failure can also be a result of radiation of the
gonads or as a result of chemotherapy. Bone age assessments can
be useful for assessment of gonadal failure (36). Infertility and
early menopause may result (37). Boys appear to be more likely to
be affected than girls and may present with small testes and ele-
vated gonadotrophins.
Thyroid
The thyroid is sensitive to irradiation and hence can be damaged
with resulting dysfunction. In the long term, this can lead to pal-
pable nodularity that is best evaluated by US.
Kidneys
Acute or chronic nephrotoxicity can occur and may result in
deteriorating renal function or hypertension. Hypertension
should be investigated initially with Doppler sonography to
exclude renal artery stenosis. Further evaluation is done with
Captopril reno-graphy, MRA or angiography. If a major vessel
stenosis is diagnosed then angioplasty can be performed. Radio-
therapy and some chemotherapy agents can cause radiation cystitis
resulting in bladder wall thickening and a small volume bladder,
best evaluated by US.
 general principles in pediatric oncology
Key Points: Chronic Complications
■ Long-term brain injury can result from both radiotherapy
to the brain and from systemic chemotherapy, especially in
leukemia
■ Skeletal growth failure following radiotherapy leads to
asymmetric growth. This complication should be taken into
account when treating areas of the skeleton
■ Radiotherapy and chemotherapy may cause lung pneumonitis
and fibrosis
■ Gonadal failure is more common in boys than girls and may
result from radiotherapy or chemotherapy
■ Renal impairment may result from chemotherapy, and
radiation cystitis may result in a small fibrosed bladder
Summary
■ Ideally children with cancer should be investigated and
treated in a specialist department or unit
■ Special equipment which improves the ambience of the
surroundings should be available for pediatric examinations
■ Cancer treatment reduces a child’s immunity and therefore
great care should be taken to avoid unnecessary infection
when administering IV contrast medium
■ General anesthesia is usually required for MR examinations
between the ages of one and seven years
■ Children are more sensitive to the harmful effects of radiation
than adults
■ US is an excellent method for the initial investigation of a
palpable mass
■ Using CT techniques to reduce radiation dose is critically
important for those children who will expect to undergo
multiple follow-up studies
■ MR imaging is the modality of choice for investigation of tumors
of the brain and spine, and for bone and soft tissue tumors
■ The imaging modality used for follow-up should be the one
which will provide the necessary information with the lowest
risk to the child and the least discomfort
■ Acute complications of cancer therapy include infection,
hemorrhage, and neutropenic enterocolitis
■ Chronic complications of radiotherapy depend on the
anatomical area irradiated and the disturbed function of
adjacent structures and organs
REFERENCES
1. Reindl TK , Geilen W, Hartmann R, et al. Acupuncture against
chemotherapy-induced nausea and vomiting in pediatric
oncology. Interim results of a multicenter crossover study.
Supportive Care Cancer 2006; 14: 172–6.
2. Brenner DJ, Elliston CD, Hall EJ, Berdon WE. Estimated risks
of radiation induced fatal cancer from pediatric CT. AJR Am J
Roentgenol 2002; 176: 289–96.
3. Paterson A, Frush DP, Donnelly LF. Helical CT of the body: are
settings adjusted for paediatric patients? AJR Am J Roentgenol
2002; 176: 297–301.
4. Donnelly LF, Emery KH, Body AS, et al. Minimising radiation
dose for pediatric body applications of single-detector helical
CT: Strategies at a large children’s hospital. AJR Am J Roent-
genol 2002; 176: 303–6.
5. Frush DP. Pediatric CT: practical approach to diminish the
radiation dose. Pediatr Radiol 2002; 32: 714–17.
6. Babyn PS, Seigel MJ. Chapter 9: The kidney and ureter. In:
Seigel MJ, ed. Pediatric Body CT, 2nd edn. Philadelphia:
Lippincott Williams & Wilkins, 2007, 297.
7. Markowitz RI, Kramer SS. The spectrum of pulmonary infec-
tion in the immunocompromised child. Sem Roentgenol
2000; 2: 171–80.
8. Jeanes AC, Owens CM. Chest imaging in the immunocompro-
mised child. Pediatr Respir Rev 2002; 3: 59–69.
9. Donnelly LF. CT of Acute pulmonary infection/trauma. In:
Lucaya J, Strife JL, eds. Pediatric Chest Imaging. Chest Imaging
in Infants and Children. Berlin Heidelberg: Springer-Verlag,
2002: 113–27.
10. Hiorns MP, Screaton NJ, Műller NL. Acute lung disease in the
immunocompromised host. Radiol Clin North Am 2001; 39:
1137–51.
11. Pursner M, Hallet JO, Berdon WE. Imaging features of Myco-
bacterium avium-intracellulae complex (MAC) in children.
Pediatr Radiol 2000; 30: 426–9.
12. John SD, Ramanathan J, Swischuk LE. Spectrum of clinical
and radiographic findings in pediatric Mycoplasma pneumo-
nia. Radiographics 2001; 21: 121–31.
13. Kim CK, Chung CY, Kim JS, et al. Late abnormal findings on
high resolution computed tomography after Mycoplasma
pneumonia. Pediatrics 2000; 105: 372–8.
14. Leong MA, Nachajon R, Ruchelli E, Allen JL. Bronchiolitis
obliterans due to Mycoplasma pneumonia. Pediatr Pulmonol
1997; 23: 375–81.
15. Shinde TS, Lee VS, Rofsky NM, et al. Three-dimensional Gad-
olinium enhanced MR venographic evaluation of patency of
central veins in the thorax: initial experience. Radiology 1999;
213: 555–60.
16. Rose SC, Gomes AS, Yoon HC. MR angiography for mapping
potential central venous access sites in patients with advanced
venous occlusive disease. AJR Am J Roentgenol 1996; 166:
1181–7.
17. Baerg J, Murphy JJ, Anderson R, Magee JF. Neutropenic
enteropathy: a 10-year review. J Pediatr Surg 1999; 34:
1068–71.
18. Cartoni C, Dragoni F, Micozzi A, et al. Neutropenic entero-
colitis in patients with acute leukaemia: prognostic signifi-
cance of bowel wall thickening detected by ultrasonography.
J Clin Oncol 2001; 19: 756–61.
19. Donnelly LF. CT Imaging of immunocompromised children
with acute abdominal symptoms. AJR Am J Roentgenol 1996;
167: 909–13.
20. Horton KM, Corl FM, Fishman EK. CT evaluation of the colon:
inflammatory disease. Radiographics 2000;20: 399–418.
21. Gillett PM, Russell RK, Wilson DC, Thomas AE. C. difficile
induced pneumatosis intestinalis in a neutropenic child.
Archives Dis Child 2002; 87: 85.
22. Ros PR, Buetow PC, Pantograg-Brown L, et al. Pseudomem-
branous colitis. Radiology 1996; 198: 1–9.
903
 pediatrics
23. Zamora S, Coppes MJ, Scott RB, Mueller DL. Clostridium
difficile, Pseudomembranous enterocolitis: striking CT and
sonographic features in a pediatric patient. Eur J Radiol 1996;
23: 104–6.
24. Haber HP, Schlegel PG, Dette S, et al. Intestinal acute graft-
versus-host disease: findings on sonography. AJR Am J Roent-
genol 2000; 174: 118–20.
25. Jones B, Wall SD. Gastrointestinal disease in the immunocom-
promised host. Radiol Clin North Am 1992; 30: 555–77.
26. Yeager AM, Kanof ME, Kramer SS, et al. Pneumatosis intesti-
nalis in children after allogenic bone marrow transplantation.
Pediatr Radiol 1987; 17: 18–22.
27. Goske MJ, Goldblum JR, Applegate KE, et al. The “circle sign”:
a new sonographic sign of Pneumatosis intestinalis—clinical,
pathologic and experimental findings. Pediatr Radiol 1999;
29: 530–5.
28. Donnelly LF, Morris CL. Acute graft-versus-host disease in chil-
dren: abdominal CT findings. Radiology 1996; 199: 265–8.
29. Donnelly LF. CT imaging of immunocompromised children
with acute symptoms. AJR Am J Roentgenol 1996; 167: 909–13.
904
30. Mentzel H-J, Kentouche K, Kosmehl H, et al. US and MRI of
gastrointestinal graft-versus-host disease. Pediatr Radiol 2002;
32: 195–8.
31. Armstrong P, Dee P. AIDS and other forms of immunocompro-
mise. In: Armstrong P, Wilson AG, Dee P, Hansell DM, eds. Imag-
ing of Diseases of the Chest. London: Mosby, 2000: 255–304.
32. Malpas JS. Clinical review: long-term effects of treatment of
childhood malignancy. Clin Radiol 1996; 51: 466–74.
33. Schwartz CL. Long-term survivors of childhood cancer: the
late effects of therapy. The Oncologist 1999; 4: 45–54.
34. Friedman DL, Meadows AT. Late effects of childhood cancer
therapy. Pediatr Clin North Am 2002; 49: 1083–106.
35. Lipscultz SE, Colan SD, Gelber RD, et al. Late cardiac effects
of doxorubicin therapy. New Engl J Med 1991; 324:
808–15.
36. Tanner JM, Whitehouse RH, Marshall WA, et al. In: Assessment
of Skeletal Maturity and Prediction of Adult Height (TW2
Method). London: Academic Press, 1975.
37. Byrne J. Infertility and premature menopause in childhood
cancer survivors. Medical Pediatric Oncology 1999; 33: 24–28.
 37 Wilms’ Tumor and Associated Neoplasms of the Kidney
Rebecca Leung and Kieran McHugh
WILMS’ TUMOR
Incidence and Epidemiology
Wilms’ tumor is one of the most common primary malignant
tumors of childhood and also the most common renal tumor,
accounting for 6% of all pediatric malignancy (1,2). It occurs
mainly in young children with a mean age at diagnosis of three to
four years (2) and 95% are diagnosed by the age of 10 years (1).
There is an equal distribution between the sexes (3). In Europe the
incidence is 10/1,000,000 per year with approximately 900 cases
diagnosed each year (2). The incidence has remained relatively
constant and therefore was once considered an “index” tumor of
childhood. However, there are variations according to ethnicity,
with higher rates reported in the Afro-Caribbean population
(9–12/1,000,000) than in Caucasians (6–10/1,000,000) and the
lowest rates reported among East-Asians (3/1,000,000) (4). These
variations are ethnic rather than geographical, suggesting that
environmental factors do not play an important role. The role of
environmental exposures in utero as a cause of early onset of
Wilms’ tumor in infancy remains unproven (5).
Genetics and Associated Conditions
Only 2% of patients have a family history of Wilms’ tumor (5,6),
while 15% of those with Wilms’ tumor have associated congenital
anomalies (7). The remainder are sporadic. A review of 1905 cases
from the National Wilms Tumor Study (NWTS) carried out
between 1969 and 1981 (8) revealed that the most common
anomalies are cryptorchidism (2.8%), hemihypertrophy (2.5%),
and hypospadias (1.8%). Other conditions include horseshoe
kidney (9), Fanconi anemia (10,11), Beckwith-Wiedemann syn-
drome (9,12) (visceromegaly, macroglossia, omphalocele, and
hyperinsulinemic hypoglycemia), Denys-Drash syndrome (10,13)
(nephropathy, renal failure, and male pseudohermaphrodism),
Soto’s (8) (cerebral gigantism), Bloom’s (8) (immunodeficiency
and facial telangiectasia), Perlman (8,10,14) (autosomal recessive
overgrowth), and Simpson-Golabi-Behmel (10) (X-linked over-
growth) syndromes. Wilms’ tumor is also associated with the spo-
radic form of aniridia (8,15) (absence of ophthalmic iris), with
one-third of patients with sporadic aniridia having Wilms’ tumor
and 1% of Wilms’ tumor patients having aniridia (16). A related
condition is the WAGR complex (10,13) (Wilms’ tumor, aniridia,
genitourinary abnormalities, and mental retardation). Patients
with WAGR have a deletion within the short arm of chromosome
11 at band p13 (11p13 deletion) (17). This chromosome was
subsequently found to be the location of the WT-suppressor gene
(WT1) (18–20). This gene encodes a transcription factor which regu-
lates the expression of growth factors critical to renal and gonadal
development. Inactivation of the WT-1 gene gives rise to the
unregulated growth of Wilms’ tumor. Inactivating point mutations
in the WT1 gene occur in the Denys-Drash syndrome (21,22).
Based on tumor specific loss of heterozygosity (LOH), a further
WT locus, called WT2 was mapped to chromosome 11p15, which
is also shared by Beckwith-Wiedemann syndrome (23,24). Loss of
heterozygosity has also been found at chromosomes 1p and 16q
(25). LOH at these sites has been associated with anaplastic Wilms’
tumor (26) i.e., unfavorable histology, an increased rate of relapse
and greater risk of mortality. Results from the fifth National Wilms
Tumor Study (NWTS-5) have shown that even in children with
favorable histology tumors, LOH on both chromosomes 1p and
16q was correlated with a greater risk of relapse and death (26).
Thus LOH at 1p and 16q has been introduced in the United States
Children’s Oncology Group (COG) protocols as a risk-stratifying
molecular marker and affected children will receive augmented
therapy (25,26).
Pathology
Macroscopic
The majority of Wilms’ tumors are solitary with 7% to 12%
occurring multifocally within one kidney and 5% to 7% bilat-
erally (5,27). Most bilateral tumors present synchronously but
1% to 1.9% present metachronously (5), usually in infants of
less than one year who have already been successfully treated
for a unilateral tumor and whose resected kidney contained
nephrogenic rests.
Typically the tumor is a solid spherical mass that is sharply
demarcated from surrounding renal parenchyma by a fibrous
pseudocapsule (27). On histological sections they have a gray-
white appearance and may have foci of hemorrhage, necrosis,
cysts, and rarely calcifications. Wilms’ tumor can arise anywhere
in the cortex or medulla and may protrude into the calyces and
ureter.
Microscopic
Wilms’ tumor, or nephroblastoma, is derived from the primitive
metanephric blastema and classically consists of three different
cell types: blastemal (small round cells), stromal (spindle, myx-
oid), and epithelial (tubular, glomerular), reflecting different
stages of normal renal development. This coexistence of all three
cell lines is described as a “triphasic” pattern. The proportion of
each cell type may vary between different tumors; some may even
be biphasic or monomorphous. The histological pattern is defined
by the predominant component, which comprises more than two-
thirds of the tumor sample. The histological diversity of these
tumors has led to correlations between different histological sub-
types and prognosis. For example, triphasic tumors, which lack
anaplasia, are regarded as “favorable histology” (28). Approxi-
mately 90% of patients have favorable histology (16). Conversely
the anaplastic type (hyperchromatic cells with large nuclei and
irregular mitotic figures), which accounts for approximately 5%
of Wilms’ tumor (27) and usually occurs in children over two
years (5), defines “unfavorable histology” and is associated with an
905
 pediatrics

increased rate of hematogenous metastasis, poor outcome, and

increased rate of recurrence (16,27,29). The presence of anaplasia
is so far the strongest indicator of adverse outcome (30) and is
judged to be a marker of chemotherapy resistance (29,30). Thus,
even when present in low stage tumors, intensive chemotherapy
is required. Focal anaplasia carries a better prognosis than diffuse
anaplasia (29,30). Clear-cell sarcoma of the kidney and malignant
rhabdoid tumor of the kidney were originally believed to be vari-
ants of Wilms’ tumor and were defined as unfavorable histology.
They are now considered to be distinct tumors in their own right
and will be discussed below.

Clinical Presentation
The clinical presentation of Wilms’ tumor is not tumor specific.
The most common presentation is of the incidental discovery
of an asymptomatic abdominal mass (83%) (31) typically found
by parents whilst bathing or clothing the child. By the time it is
discovered therefore, the mass is large. In one series of
130 patients, detection occurred after coincidental minor
trauma in 10% of cases (32). Up to about one-third of patients
present with a combination of abdominal pain, pyrexia of Figure 37.1 Wilms’ tumor. Abdominal US shows a large heterogeneous solid mass
in the right flank, with a mixture of hyperechoic, hypoechoic, and cystic areas. This
unknown origin, anorexia, malaise, and vomiting (30). Abdominal is abutting the undersurface of the liver (LIV) and on other images the mass was
pain may be secondary to local distension, intratumoral hem- seen to arise from the right kidney.
orrhage, or peritoneal rupture. Other presentations include
hypertension (seen in up to 25%) (30,33) gross or microscopic
hematuria (reported in 10–30%) (7,30,31) which may signify Role of Imaging in Diagnosis
tumor invasion of the renal pelvis (34), coagulopathy (less than Initial investigations include biochemical tests such as a full blood
10%) (30,35), and spontaneous intratumoral hemorrhage (8%) count and differential renal function tests, liver function tests,
(31) which manifests as rapid abdominal enlargement, anemia, coagulation tests, and urinalysis. Radiological investigations play a
hypotension, and fever. Although tumor extends into the renal crucial role in diagnosis, staging, surgical planning, and assess-
vein and inferior vena cava in 6% of patients, this is manifest ment of response to treatment. Due to differences in approach to
symptomatically in only 50% of these cases (36), typically as treatment between the United States and Europe, there are differ-
hepatomegaly, ascites, or congestive heart failure (37). Invasion ences in the approach to imaging, particularly in the choice of
of the renal vein or inferior vena cava may also manifest as a imaging modality at diagnosis. For example, as the International
varicocele, secondary to obstruction of the spermatic vein (5,37). Society of Paediatric Oncology (SIOP) protocol, mainly used in
Paraneoplastic manifestations of Wilms’ tumor include acquired Europe, is based on pre-operative chemotherapy, imaging is
von Willebrand disease (reported in up to 8%) (35,38), tumor- primarily used for diagnosis and initial presumptive staging.
induced glomerulonephritis (3), and erythropoietin and Chemotherapy is commenced on this basis only and not on a
hyaluronidase secretion (3,39). biopsy result, although biopsy is performed routinely in the United
Kingdom. In the National Wilms’ Tumor Study (NWTS) protocol
Key Points: General Features primarily used in the United States, surgery precedes radiotherapy
and chemotherapy; the role of imaging here is to provide ana-
■ Wilms’ tumor is one of the most common childhood tomical information to aid surgical planning.
malignancies
■ Wilms’ tumor is the most common renal tumor of childhood
Ultrasound
■ Wilms’ tumor is predominantly sporadic but is associated
Ultrasound (US) is first line investigation of an abdominal mass.
with congenital syndromes in 15% of cases
At US, the renal origin of a Wilms’ tumor can be confirmed by
■ The most common anomalies associated with Wilms’ are
distortion of the adjacent renal parenchyma. A large (5–10 cm)
cryptorchidism and hemihypertrophy
predominantly solid spherical mass with heterogeneous echotex-
■ The majority of Wilms’ tumors are solitary
ture is seen (Fig. 37.1). There are often anechoic areas reflecting
■ Wilms’ tumor arises from primitive metanephric blastema
hemorrhage, necrosis, or cyst formation (Fig. 37.2). The mass is
and consists of three different cell types
well demarcated from the adjacent renal parenchyma. Invasion of
■ Over 90% of patients have favorable histology
the renal vein and inferior vena cava occurs in 4% to 10% of
■ The most common presentation is of an asymptomatic
cases (40,41); extension into the right atrium occurs rarely. Color
abdominal mass
Doppler US is able to visualize thrombus within the renal vein and
■ Some patients present with non specific abdominal pain,
inferior vena cava better than CT and therefore is regarded as the
pyrexia, and malaise
most reliable method of assessment (Fig. 37.2C) (36). On US,

906
 wilms’ tumor and associated neoplasms of the kidney

(A) (B)

(C)
Figure 37.2 (A) Abdominal US shows a predominantly cystic Wilms’ tumor. The marked cystic nature of this mass makes it unsuitable for biopsy and primary nephrec-
tomy is indicated. (B) Wilms’ tumor in another patient which appears predominantly hyperechoic with a few hypoechoic foci. These may represent areas of necrosis or
hemorrhage. (C) Longitudinal color Doppler US in the same patient demonstrates a patent inferior vena cava (arrow) with no evidence of tumor thrombus.

careful evaluation must also be made of the contralateral kidney,
liver for metastases, and retroperitoneum for lymphadenopathy
(Fig. 37.3B and C).
Computed Tomography and Magnetic Resonance Imaging
Computed tomography (CT) or magnetic resonance (MR)
imaging is usually performed to confirm the US findings and to
provide additional information about local anatomical relation-
ships between the tumor, the great vessels, and retroperitoneal
structures. It also identifies associated anatomical malformations
such as a horseshoe kidney (Fig. 37.4). However, it is notable that
some European centers only perform US, both for diagnosis and
follow-up of these tumors (7).
Metastases occur most commonly in the lungs (10%) (41) fol-
lowed by local para-aortic lymph nodes and liver (2%) (41). It is
extremely rare for brain or bone metastases to occur. CT tends to
be used for the initial evaluation of regional invasion, metastases,
and lymphadenopathy (Fig. 37.3D) since it is more readily avail-
able than MR imaging. Assessment of the lungs for the presence of
pulmonary metastases is also better with CT (Fig. 37.5B).
On CT, the primary tumor is usually well-circumscribed with a
beak or claw of surrounding renal parenchyma (Fig. 37.6A). It is
typically of heterogeneous attenuation, demonstrating a mixture
of hemorrhage, necrosis, cysts, and calcification. Fat is rarely seen
at diagnosis but may develop within the tumor after treatment.
Enhancement following injection of intravenous (IV) contrast
medium is seen but the degree of enhancement is much less than
that of the adjacent normal renal parenchyma.
If US is deemed inadequate for assessment of treatment
response, MR imaging is the preferred imaging modality since CT
exposes the child to ionizing radiation; the rationale of this being
the ALARA principle, i.e., keeping the radiation dose to the child
“as low as reasonably achievable” (42). On MR imaging, the tumor
is a well-circumscribed mass demonstrating low signal intensity
on T1-weighted sequences and usually a high signal intensity on
T2-weighted sequences (Fig. 37.6B and C). The mass enhances
heterogeneously but as with CT, much less than normal renal
parenchyma. Assessment of vascular invasion may also be made
on MR imaging, particularly through the use of magnetic reso-
nance angiography (MRA).

907
 pediatrics

Liver
left

(A) (B)

N
T Tumor thrombus

(C) (D)

(E) (F)
Figure 37.3 Metastatic Wilms’ tumor. (A) Abdominal US shows a large right sided tumor of heterogeneous echotexture. (B) A hepatic metastasis in the same patient (M).
(C) A para-aortic nodal mass (N) with tumor thrombus (T) in the inferior vena cava. (D) Contrast-enhanced CT in the same patient shows the large right-sided Wilms’
tumor with adjacent para-aortic lymph node mass (N), tumor thrombus in the IVC (T), and multiple hepatic metastases. (E) Same CT at a more inferior level shows the
thrombus in the IVC (arrow). (F) Axial fat-suppressed T2-weighted MR image demonstrates the hyperintense Wilms’ tumor and multiple hepatic metastases.

Differential Diagnoses
Encasement and anterior displacement of the great vessels, the
presence of a paravertebral mass or invasion of the spinal canal,
and the presence of calcification on CT are more suggestive of
neuroblastoma than Wilms’ tumor (43).
Other primary renal neoplasms, which may be indistinguishable
from Wilms’ tumor on imaging, include mesoblastic nephroma (in
infants less than one year of age), rhabdoid tumors, clear cell sarcomas
of the kidney, and renal cell carcinomas (44). On CT, classically
rhabdoid tumors are reported to display a peripheral fluid crescent
sign (45) but this is not pathognomonic and is seldom seen. Cases
of predominantly cystic Wilms’ tumor can be sonographically indis-
tinguishable from multilocular cystic nephroma, a benign tumor.
In infants less than six months of age a renal mass is most likely
to be a mesoblastic nephroma (45). In children over seven years of
age other renal malignancies start to predominate.

908
 wilms’ tumor and associated neoplasms of the kidney
Figure 37.4 Contrast-enhanced CT demonstrating a Wilms’ tumor (T) arising
from a horseshoe kidney (K).
(A)
(B)
Figure 37.5 Lung metastases in a Wilms’ tumor patient. (A) PA chest radiograph
shows multiple ill defined opacities, predominantly in the left lower zone. (B)
Chest CT in the same patient more clearly demonstrates multiple bilateral lung
metastases.
(A)
(B)
(C)
Figure 37.6 (A) Contrast-enhanced CT demonstrates a large heterogeneous
mass (T) arising from the right kidney, which is displaced anteromedially with a
beak or claw of renal parenchyma surrounding the mass. The mass shows little
enhancement compared with the adjacent renal parenchyma. (B) Axial fat sup-
pressed T2-weighted MR image at the same level as (A) demonstrating a well-
circumscribed hyperintense mass with displacement of adjacent renal
parenchyma. (C) Coronal fat-suppressed T2-weighted MR image shows that the
mass is separate from the liver (L). The left kidney is normal in appearance.
909
 pediatrics

Chest Imaging in Wilms’ Tumor

There has been controversy for many years regarding the best way
to image the chest in Wilms’ tumor. The traditional method of
screening for lung metastases has been a postero-anterior and lat-
eral plain chest radiograph (CXR) (Fig. 37.5A) (46,47). However,
chest CT is more sensitive than CXR (48–51) and can detect small
volume lesions, termed “CT-only lesions,” or “CXR-negative, CT-
positive disease,” that are not visible on plain films in a small group
of patients (48). Chest CT has become the routine method of
assessing the lungs for pulmonary lesions in North America. How-
ever, since clinical outcomes have traditionally been based on
lesions detected by plain radiography (47), there is some uncer-
tainty as to how patients with CT-only lesions should be treated,
since not all pulmonary nodules are necessarily metasta-
ses (47,48,52). There have been two approaches to treatment of
these lesions: one has been to treat by local stage of the primary
tumor and “ignore” the pulmonary lesions, the rationale being
that small volume lung metastases have a lower tumor burden and
require less intensive chemotherapy (51). For a Stage I or II patient
this typically involves two-drug chemotherapy and no radiother-
apy. The other approach has been to treat as if there were metasta-
ses detected by CXR, resulting in the addition of doxorubicin,
which is cardiotoxic, and whole lung irradiation. This is based on
the premise that the small-volume pulmonary metastases identi-
fied on CT lie at the lower end of a continuum and will eventually
develop into the much larger lesions visible on plain film (53).
Making the assumption that they are metastases may lead to over-
treatment in some cases; conversely, there is potential danger in
disregarding these CT-only lesions. The general consensus from
the NWTS, SIOP, and UKW3 studies has been to advise treatment
of CXR-negative, CT-positive lesions as if lung metastases did not
exist, on the premise that small volume lung metastases respond
well to less chemotherapy. However, there is some limited evi-
dence to suggest that these patients have a higher relapse
rate (47,54). Thus, in the latest SIOP study, chest CT is also now
recommended (7), but a lesion must measure more than 10 mm
to be considered a metastasis, with biopsy confirmation of smaller
nodules being usually impractical.
Key Points: Radiological Diagnosis
■ US is the first line investigation of an abdominal mass
■ US can distinguish between a cystic and a solid mass, assess
vascular invasion, and examine the contralateral kidney
■ Invasion of the renal vein and inferior vena cava occurs in
4% to 10% of cases
■ Color Doppler is the most reliable method of detecting
vascular invasion
■ CT and MR imaging give additional information about local
anatomical relationships between the tumor and adjacent
structures and can assess distant spread
■ Magnetic resonance angiography (MRA) is useful for surgical
planning
■ A wide variety of primary renal neoplasms may have
identical imaging characteristics to Wilms’ tumor
■ Chest CT is more sensitive than plain chest radiography in
detecting small pulmonary nodules and is now recommended
by SIOP
Staging
The most important prognostic factors in Wilms’ tumor are the
histological grade and stage of the tumor (29). Staging criteria are
based on the anatomical extent of the tumor on imaging studies
and on both surgical and pathological findings at nephrectomy;
biological, genetic, or molecular markers are currently not gener-
ally taken into account, although they are expected to be included
in the future (30). The staging system has been progressively
updated as adverse prognostic features have been identified. There
are currently two major staging systems in use: a pre-chemotherapy,
surgery based system developed by the National Wilms Tumor
Study Group (NWTS), now called the Children’s Oncology Group
(COG), in the United States, and a post-chemotherapy based sys-
tem developed by the International Society of Pediatric Oncology
(SIOP). The staging protocols are summarized in Tables 37.1 and
37.2. Due to differences in surgical timing, the histological classi-
fication and formal staging given by these two protocols is not

Table 37.1 Staging According to SIOP

Stage Criteria
I Tumor limited to kidney or surrounded by fibrous pseudocapsule if outside the normal contours of the kidney; tumor does not breach outer surface
of renal capsule. Tumor is completely resected
Tumor may protrude into pelvic system but does not infiltrate their walls
No involvement of vessels of renal sinus
Intrarenal vessels may be involved
II Tumor extends beyond kidney or penetrates through renal capsule and/or through fibrous pseudocapsule into perirenal fat, but is completely resected
Tumor infiltrates renal sinus and/or invades blood and lymphatics outside renal parenchyma, but is completely resected
Tumor infiltrates adjacent organs or vena cava, but is completely resected
Surgical (wedge) biopsy has been performed prior to preoperative chemotherapy or surgery
III Incomplete excision of tumor, which extends beyond resection margins
Abdominal lymph node involvement
Tumor rupture before or during surgery (irrespective of other criteria for staging)
Tumor has penetrated the peritoneal surface
Tumor thrombi evident at resection; margins of vessels or ureter transected or removed at surgery
IV Hematogenous metastases (to lung, liver, brain, etc.) or lymph node metastases outside the abdomen or pelvis
V Bilateral renal tumors at diagnosis. Each side is substaged using the above classification

910
 wilms’ tumor and associated neoplasms of the kidney

Table 37.2 Staging According to NWTS/COG

Stage % of pts Criteria
I 43% Tumor limited to kidney or surrounded by fibrous pseudocapsule if outside the normal contours of the kidney; tumor does not breach
outer surface of renal capsule. Tumor is completely resected
Tumor may protrude into pelvic system but does not infiltrate their walls
No involvement of vessels of renal sinus
Intrarenal vessels may be involved
II 23% Tumor extends beyond kidney or penetrates through renal capsule and/or through fibrous pseudocapsule into perirenal fat, but is
completed resected
Tumor infiltrates renal sinus and/or invades blood and lymphatics outside renal parenchyma, but is completely resected
Tumor infiltrates adjacent organs or vena cava, but is completely resected
Surgical (wedge) biopsy has been performed or there was tumor spillage before or during surgery that is confined to the flank and does
not involve the peritoneal surface
III 23% Residual tumor is present and confined to the abdomen
Any one of: Abdominal lymph node involvement
Tumor has penetrated through the peritoneal surface
Tumor implants found on the peritoneal surface
Gross or microscopic tumor remains postoperatively
Tumor is nonresectable due to local infiltration into vital structures
Tumor spill before or during surgery
IV 10% Hematogenous metastases (lung, liver, bone, brain, etc.) or lymph node metastases outside the abdomen or pelvis
V 5% Bilateral renal tumors at diagnosis. Each side is substaged using the above classification

directly comparable. The NWTS/COG classification is based on
favorable and unfavorable histology and the presence or absence
of anaplasia. The SIOP classification, which has recently been
revised as a result of the SIOP 9 and 93-01 trials and studies, strat-
ifies patients who have undergone pre-operative chemotherapy
into low, intermediate, and high-risk histology on the basis of
their nephrectomy pathological findings (55,56). According to
this classification, the “blastemal” type is defined as the survival of
large amounts of blastema following pre-operative chemotherapy
and is believed to confer an adverse outcome. Conversely, tumors
with epithelial or stromal predominance after pre-operative
chemotherapy have a favorable outcome. Anaplasia, whether focal
or diffuse, is regarded as “unfavorable” and “high-risk” by both
NWTS and SIOP classification schemes.
Treatment
Primary surgical resection followed by adjuvant chemotherapy and
radiotherapy as indicated, based on the extent of disease defined at
surgery remains the mainstay of treatment for Wilms’ tumor in
North America (NWTS/COG). This approach enables as much
information as possible about prognostic factors to be gathered at
the time of surgery, in order to tailor an individual’s therapy. Due to
the large size and central location of Wilms’ tumors, total nephrec-
tomy is performed. Biopsy of adjacent or regional lymph nodes is
important because nodal involvement upstages from II to III,
although radical lymph node dissection is unnecessary (29,30), as
there is no evidence that it alters the outcome (5). Biopsy of nodes
at the level of the renal vessels is obligatory, regardless of size (29,57).
Extension of tumor into the renal vein must be determined before
vessel ligation (37). Surgical exploration of the contralateral kidney
is no longer recommended (57,58), as CT or MR imaging now pro-
vides sufficient sensitivity in excluding contralateral disease (37).
The only indications for pre-operative chemotherapy under NWTS
are for patients with bilateral tumors, tumors in a solitary kidney,
tumors with inferior vena caval extension above the hepatic veins,
and tumors found to be unresectable at surgery (3).
Nephron-sparing surgery such as polar hemi-nephrectomy, wedge
resection or enucleation is controversial, as it carries the risk of leav-
ing nephrogenic rests in the unresected portion of the kidney (30).
At present, such procedures are only indicated for those patients
with a solitary kidney, bilateral Wilms’ tumor, renal insufficiency,
disorders affecting the contralateral kidney, and those at risk of
multiple neoplasms such as Beckwith-Wiedemann syndrome (30).
According to the SIOP 2001 protocol (July 2004) the contraindica-
tions to partial nephrectomy are: pre-operative tumor rupture or
biopsy, tumor-infiltrating extrarenal structures, intra-abdominal
metastases or lymph nodes on pre-operative imaging, renal vein or
IVC thrombus, tumor involving more than one-third of the kidney,
multifocal tumor, central location, calyceal involvement, hematuria,
and little experience with the surgical procedure (59).
In Europe (SIOP and UKW3 trials), staging and histological
diagnosis are delayed until surgery, which occurs several weeks
after clinical and imaging diagnosis. Pre-operative chemotherapy
is used to shrink the size of the tumor to facilitate surgery and
improve the chance of resectability. It has also been shown to
reduce the incidence of per-operative tumor rupture or spillage
[from 20% in primary surgical resection to 6% with pre-operative
chemotherapy in the NWTS-4 trial (60)] by inducing fibrosis,
thereby rendering the capsule less friable. Reducing the size also
downstages the tumor which then requires less intensive adjuvant
chemotherapy and avoids radiotherapy in the majority of patients.
The recent UKW3 trial carried out by the United Kingdom Chil-
dren’s Cancer Study Group (UKCCSG) shows a more favorable
stage distribution, reduction in surgical complications and reduced
overall treatment burden in patients who undergo neoadjuvant
chemotherapy as opposed to immediate nephrectomy (61). Pro-
spective data gave a morbidity rate of 7% in the groups treated by
the SIOP approach compared with 10% in the NWTS groups (61).
The pre-operative chemotherapy approach also allows for in vivo
assessment of histological response to chemotherapy.
One disadvantage of the delayed surgical approach is that if a
tumor demonstrates the typical imaging and clinical features of

911
 pediatrics
Wilms’ tumor, neoadjuvant chemotherapy may be commenced
without a histological diagnosis. This may result in the alteration
of the tumor histology and the loss of accurate staging informa-
tion. Of particular concern is the risk of missing diffuse anaplasia.
The approach of omitting pre-operative biopsy also results in 1%
of children with a benign renal lesion, such as mesoblastic neph-
roma, receiving chemotherapy, including actinomycin D, which
carries a 3% risk of hepatotoxicity (62). Conversely, patients with
highly malignant tumors such as rhabdoid tumor or clear cell sar-
coma, which respond to intensive chemotherapy, go unrecognized
and are therefore under-treated. Thus, during the UKW3 trial,
immediate biopsy was recommended prior to treatment with pre-
operative chemotherapy. The results of this study show that 12%
of “Wilms’ tumors” diagnosed on the basis of imaging studies
were found to have other diagnoses on biopsy, with 1% of children
having a non-malignant lesion (62). There was also no evidence
from the trial to suggest that percutaneous biopsy increases the
risk of needle track tumor recurrence (62), although biopsy in
COG trials is actually considered local spill and automatically
upstages a tumor to Stage III disease.
Current chemotherapy regimens are based on three first line
drugs: dactinomycin (actinomycin-D), vincristine, and doxorubi-
cin (37). Four second line drugs: cyclophoshamide, ifosfamide,
carboplatin, and etoposide are used in patients who have relapsed
or have a poor response to first line chemotherapy (37). Different
treatment algorithms depend on the stage and grade of the tumor.
Studies on the relationship between chemotherapy and radio-
therapy have enabled both dose reduction and narrowing of the
indications for radiotherapy without compromising the survival
rates. The current indications for radiotherapy are therefore:
• Stage III—positive lymph nodes and/or diffuse peritoneal
spillage
• Stage II–IV—diffuse anaplasia
• Stage IV—metastatic disease (usually pulmonary)
according to NWTS protocol
• Residual lung metastases after chemotherapy and
metastatectomy in SIOP (3)
Key Points: Staging and Therapy
■ The most important prognostic factors in Wilms’ tumor are
the histological grade and stage of the tumor
■ Staging criteria are based on the anatomical extent of the
tumor on imaging and on both surgical, and pathological
findings at nephrectomy
■ There are two major staging systems in use: a pre-chemotherapy,
surgery based system (NWTS/COG), and a pre-operative
chemotherapy based system (SIOP)
■ Surgical resection of the primary tumor (usually total
nephrectomy) is performed either before or after treatment
with chemotherapy and radiotherapy depending upon local
protocols
■ Nephron-sparing surgery is considered in patients with a
solitary kidney, abnormalities of the contralateral kidney, or
risk of multiple tumors
■ Different chemotherapy and radiotherapy treatment
algorithms depend on the stage and grade of the tumor
912
Role of Imaging in Biopsy
In the SIOP protocol, diagnosis has been traditionally based on
the characteristic imaging features of a Wilms’ tumor. Biopsy was
not recommended as it was generally believed to increase the risk
of flank relapse; possibly upstaging the tumor to Stage III. As
mentioned previously, however, there are dangers to treating a
child without a histological diagnosis and as a result of the
UKW3 study (62), pre-chemotherapy biopsy has been routinely
adopted. During this study, patients amenable to primary nephre-
ctomy were randomly assigned to either immediate surgery then
chemotherapy, or immediate biopsy followed by six weeks of pre-
operative chemotherapy. The results of the study showed that
there was complete concordance between biopsy and nephrec-
tomy diagnoses in 99.5% of cases (62). Of 182 children who
underwent percutaneous cutting needle biopsy, 20% had a subse-
quent fall in hemoglobin and 19% had local pain. One child
required emergency nephrectomy due to massive intra-tumoral
bleeding, one had tumor rupture which was not thought to be
biopsy related, and one developed a needle track recurrence eight
months following biopsy (62).
The traditional method of obtaining histology has been through
open surgical biopsy. Percutaneous US or CT-guided biopsy, how-
ever, improves the diagnostic yield compared to blind biopsy (63),
and is technically safer as it is able to direct the operator away
from large tumor vessels. It also enables sampling of appropriate
areas within the tumor mass (63): viable tumor is present periph-
erally whilst necrotic areas are often centrally located, thus there is
more potential for sampling error in blind biopsies. A posterior
approach is preferred thereby avoiding peritoneal dissemina-
tion. The morbidity associated with percutaneous biopsy is
small. Microscopic hematuria and mild flank pain are relatively
common occurrences after percutaneous biopsy, and are gener-
ally not considered to be significant complications (62). There is
a 20% risk of bleeding post-core-needle biopsy, but the inci-
dence of massive tumor bleeding or lethal tumor rupture is
rare (62,63). Arterio-venous fistula has been reported in 2% to
8% of renal biopsies but only in one case of biopsied Wilms’
tumor (64). Needle-track recurrence has been reported in only
three Wilms’ tumor cases in the literature, including the one
reported from the UKW3 trial (62,65,66). Thus the concern with
tumor recurrence by this procedure is likely to be unfounded,
given the large number of percutaneous biopsies now performed
in many centers.
Role of Imaging in Treatment
Radiological follow-up during neo-adjuvant chemotherapy for
localized disease consists of abdominal sonography and plain
chest radiograph every three months (67). For patients with lung
metastases (Stage IV disease), a chest radiograph is performed at
six weeks and then at 12 weeks to confirm response to treatment.
Thereafter three-monthly chest radiographs and abdominal
sonography is recommended during treatment (67).
In the SIOP protocol, since Response Evaluation Criteria In
Solid Tumors (RECIST) has not been validated for pediatric
Wilms’ tumors, the response to treatment is assessed by measur-
ing the tumor size at diagnosis, usually by the largest diameter in
three planes, and using that as a comparison during subsequent
 wilms’ tumor and associated neoplasms of the kidney

follow-up studies (68). The guidelines for tumor measurement

Key Points: Role of Imaging in Biopsy, Treatment,
according to the NWTS/COG also include maximal tumor
and Follow-up
dimensions in three planes (41). These measurements must be
made on the same imaging modality throughout treatment and ■ Percutaneous US or CT-guided biopsy improves the diagnostic
follow-up, be it with CT or MR imaging. In addition to reduc- yield, is technically safer and carries a lower morbidity
tion in size, change in tumor characteristics such as necrosis may compared with blind biopsy
indicate response. ■ There is a 20% risk of hemorrhage following biopsy but this
is rarely severe
■ Radiological follow-up during treatment for localized disease
Role of Imaging in Follow-up
Most Wilms’ tumor recurrences arise in the lung (58%) and abdo- consists of chest radiography and abdominal sonography
men (29%) and rarely in bone, brain, and mediastinum (46). every three months
■ Measurement of the maximum diameter of the tumor in
Ninety percent of relapses occur during the first four years after
diagnosis (47). The overall relapse rates for all patients enrolled on three planes should be made to assess treatment response
■ Ninety percent of relapses occur during the first four years
NWTS and SIOP studies is 17% to 24% (3). The use of multi-
agent intensive salvage regimes has improved the survival from after diagnosis
■ The main aim of long-term follow-up is to monitor the growth
relapsed Wilms’ from less than 30% (69) just 20 years ago to 50%
to 60% (70). Local relapse is defined as recurrence in the original of the remaining kidney, blood pressure, and renal function
tumor bed, retroperitoneum, abdomen, or pelvis.
A higher risk of local recurrence is seen in patients with: Bilateral Disease
• Lymph node involvement Wilms’ tumors are bilateral in 5% to 7% of patients (5,72), with 5%
• Unfavorable histology to 6% occurring synchronously (30,73). Bilateral Wilms’ tumor are
• Tumor spillage classified as Stage V disease. They are more frequent in girls and
• Incomplete tumor removal children of a younger mean age of 2.5 years than those with unilat-
• Absence of lymph node sampling during surgery (57) eral disease (73). They are associated with nephrogenic rests (in
90% of synchronous and 94% of metachronous bilateral Wilms’
Good prognostic factors for relapse include an initial diagnosis of
tumors) (33,74), congenital anomalies, and predisposing syndromes
Stage I or II, initial two chemotherapy agent treatment, no radio-
(5). Patients with unilateral tumors who subsequently develop
therapy, favorable histology, and longer time from diagnosis to
contralateral disease share the same associations as synchronous
relapse (30). The recommended imaging protocol under SIOP for
bilateral disease, but the risk is higher in infants younger than one
post-treatment surveillance is summarized in Table 37.3. Those
year of age at the time of diagnosis (73). The 10-year survival rate in
patients who survive relapse-free for more than three years after
patients with bilateral synchronous disease is approximately
diagnosis are unlikely to develop recurrent disease (71). Therefore
70% (37,75), and 50% for bilateral metachronous disease (75). How-
the main aim of long-term follow-up is to monitor the growth of
ever, there is a high incidence of renal failure (76). The overriding
the remaining kidney, blood pressure, and renal function well into
aim, therefore, is to preserve renal function without compromising
adulthood.
the cancer therapy. Bilateral synchronous disease is one group of
patients in whom there is a consensus between both SIOP and
NWTS regarding optimum management: pre-operative chemother-
apy after biopsy confirmation to decrease the tumor volume, then
Table 37.3 Recommended Imaging Follow-up After Treatment reassessment of tumor to evaluate feasibility of nephron-sparing
for Wilms’ Tumor surgery (76). A useful imaging modality in this situation may be
positron emission tomography (PET) to detect viable post-chemo-
Region Imaging modality Frequency therapy tumor (73). As a minimum, multiplanar MR imaging or CT
Chest X-ray 1st year every 3 months should be performed to assess to extent of the bilateral tumors and
2nd year every 6 months proximity to the surrounding anatomy (77). Surgeons find that
3rd to 5th years every 12 months contrast-enhanced CT with good definition of the arterial anatomy
If initally stage IV lung:
1st and 2nd years every 2–3 months
is particularly useful for bilateral tumors (Fig. 37.7). The imaging of
3rd and 4th years every 6 months bilateral disease is similar to that of unilateral disease, although each
5th year every 12 months kidney is staged separately. Intraoperative sonography may also be
Abdomen/pelvis US At end of treatment helpful to determine the intrarenal extent of the tumor (78).
1st and 2nd years every 6 months
3rd to 5th years every 12 months
If nephrogenic rests, local Stage Nephroblastomatosis and Nephrogenic Rests
III and/or high risk histology: Nephrogenic rests are remnants of renal embryonal tissue which arise
1st and 2nd years every 3 months from incomplete induction of the metanephric blastema into mature
3rd to 5th years every 6 months
renal parenchyma. They are regarded as precursor lesions to Wilms’
6th to 10th years every 12 months
tumor and were found to co-exist with 41% of Wilms’ tumors in
Source: Adapted from Nephroblastoma Clinical Trial and Study Protocol, the National Wilms Tumor Study (79), although it is estimated that
SIOP 2001.
only 1% undergo malignant transformation (35,80). Two distinct

913
 pediatrics

(A) (B)
Figure 37.7 Bilateral Wilms’ tumors. (A) Contrast-enhanced CT of the same patient as in Figure 37.3 shows a synchronous lesion in the posterior aspect of the contra-
lateral kidney (arrow), in addition to hepatic metastases. This lesion could be either another Wilms’ tumor or a focus of nephroblastomatosis—only a biopsy could
establish the pathological diagnosis. (B) Axial T1-weighted post-gadolinium enhanced MR image in another patient shows bilateral synchronous tumors.

categories of nephrogenic rests have been identified: perilobar
nephrogenic rests (PLNR), which occur later on in nephrogenesis at
the periphery of the renal lobe and are associated with an older age at
diagnosis, hemihypertrophy and Beckwith-Wiedemann syndrome,
and intralobar nephrogenic rests (ILNR) which occur early in neph-
rogenesis and are associated with a younger age at diagnosis, WAGR,
Denys-Drash syndrome, and bilateral disease (34). Multifocal or
diffuse nephrogenic rests are termed “nephroblastomatosis.”
The clinical course of nephroblastomatosis is highly variable;
lesions may remain stable over many years or proliferate. Imaging
plays an important role in recognizing these lesions due to the risk of
developing Wilms’ tumor. Microscopic nephrogenic rests are not vis-
ible on imaging. In one study, macroscopic nephrogenic rests were
found to be better resolved by MR imaging and CT (to 0.5 cm) than
by US (to 0.8 cm), although this was not by high-resolution US (81).
On US, diffuse nephroblastomatosis is shown as a homogeneous
and hypoechoic rim in the periphery of the kidney, which pre-
serves its renal shape but causes an increase in its size. The appear-
ances on sonography may be similar to those of leukemia or
lymphoma (Fig. 37.8A). Isolated macroscopic nephrogenic rests
appear on US as isoechoic or slightly hypoechoic nodules which
cause a local bulge or lobulated renal contour.
On unenhanced CT and MR imaging nephroblastomatosis is
very similar in attenuation and intensity to normal renal paren-
chyma and is only made conspicuous after contrast enhancement,
where normally enhancing renal parenchyma is clearly different
from non-enhancing nephroblastomatosis (Fig. 37.8B and C). On
CT, isolated nephrogenic rests are iso- or slightly hyperdense to
renal cortex and do not enhance. On MR imaging, so-called dor-
mant, sclerotic nephrogenic rests are typically homogeneously
hypointense on T1-weighted, and T2-weighted or STIR sequences,
and do not enhance post-Gadolinium (Fig. 37.8C). These are
thought to have a low malignant potential (81,82). Hyperplastic
rests are hyperintense on T2-weighted and STIR sequences and
are considered to have a higher malignant risk (81,82).
Differentiation of nephroblastomatosis from Wilms’ tumor
on percutaneous biopsy is often inconclusive as they have similar
histological characteristics and there are potential sampling errors.
Imaging characteristics are also very similar, although nephro-
genic rests tend to be less than 2 cm in size and of ovoid or lenticu-
lar shape, while Wilms’ tumors are usually greater than 3 cm and
spherical (83). However, any criteria based on these observations
is unreliable (83).
The management of nephroblastomatosis and nephrogenic rests
remains controversial. There is currently no specific treatment for
nephrogenic rests apart from close radiological surveillance for the
development of Wilms’ tumor. The role of chemotherapy in
attempting to halt or slow the progression of nephroblastomatosis
is unclear. It has been suggested that there may be some benefit in
treating diffuse nephroblastomatosis for up to one year with vin-
cristine and actinomycin-D (84). Small focal areas of nephroblas-
tomatosis still present at the end of chemotherapy require
surveillance with MR imaging for at least one year.
Key Points: Bilateral Disease and
Nephroblastomatosis
■ Wilms’ tumors are bilateral in 5% to 7% of patients and are
classified as Stage V disease
■ Bilateral tumors are associated with nephrogenic rests,
congenital anomalies, and predisposing syndromes
■ There is a high incidence of eventual renal failure with bilateral
disease, therefore nephron-sparing procedures are indicated
■ Nephrogenic rests are regarded as precursor lesions to Wilms’
tumor
■ Nephroblastomatosis may have similar imaging and
histological characteristics to Wilms’ tumor
■ Foci of nephroblastomatosis show homogeneous non-
enhancement with contrast administration on CT and MR
imaging, while Wilms’ tumors show heterogeneous
enhancement
■ There is no specific treatment for nephroblastomatosis
■ Small focal areas of nephroblastomatosis still present at the
end of chemotherapy require initial surveillance with MR
imaging for at least one year

914
 wilms’ tumor and associated neoplasms of the kidney

(A) (B)

(C)
Figure 37.8 Nephroblastomatosis. (A) US shows an enlarged left kidney (Lt.K) with complete distortion of the normal architecture and replacement by multiple soft
tissue masses. [Spleen (SPL)] The right kidney showed similar appearances. (B) Contrast-enhanced CT demonstrates bilaterally enlarged kidneys containing multiple
non-enhancing soft tissue masses. There is a thin rim of normal enhancing renal parenchyma. (C) Axial T1-weighted post-gadolinium MR image, performed one year
later after chemotherapy treatment, demonstrates improved appearances with multiple small residual non-enhancing lesions in both kidneys.

Complications and Late Effects of Treatment
The success of Wilms’ tumor treatment has improved patients’
long-term survival into adulthood and this has enabled the late
effects of treatment to be studied. These effects are defined as those
absent or unrecognized at the end of therapy. Acute toxicity is usu-
ally caused by the immunosuppression induced by chemotherapy.
Following unilateral nephrectomy in childhood the remaining
kidney shows compensatory hypertrophy, and one year later the
glomerular filtration rate (GFR) and effective renal plasma flow
are 90% of normal (85). Children who receive both surgery and
chemotherapy also have close to normal renal function. The addi-
tion of radiation significantly reduces renal function to about
73% of normal GFR. Renal failure is rare among unilateral Wilms’
tumor survivors (85), although the incidence appears to be
increased in those with Wilms’ tumor and aniridia, and also in
those with intralobar nephrogenic rests on long-term follow-up
(86). Adjuvant chemotherapy and radiotherapy may also cause
both acute and chronic damage to organs such as the heart, lungs,
liver, bones, and gonads. The cardiotoxicity of doxorubicin can
cause cardiac failure even many years following treatment. Whole
lung irradiation can cause pneumonitis, and restrictive lung dis-
ease and can also affect cardiac function. Abdominal irradiation
and the chemotherapeutic agent actinomycin-D are hepatotoxic
and can cause hepatic veno-occlusive disease (VOD) which con-
sists clinically of the triad of hepatomegaly, ascites, and icterus.
VOD can be fatal, and is usually treated with supportive measures
and the withholding of chemotherapy until the patient has clini-
cally recovered. Trunk irradiation can cause the late effects of sco-
liosis and soft tissue underdevelopment but asymmetric skeletal
effects are now largely preventable by symmetric radiotherapy
doses across the midline. Osteochondromas are common in the
ribs or scapulae in patients who have had chest irradiation (87). A
high incidence of infertility, spontaneous miscarriages, and intra-
uterine growth retardation has been found in girls where the
uterus and ovaries were within the radiation field (88). Along with
an inherent predisposition towards developing other malignan-
cies, both chemotherapy and radiotherapy can induce secondary
malignant neoplasms (SMNs). Types of SMNs encountered include
bone and soft tissue sarcomas, lymphoma, breast carcinoma,
gastro-intestinal tumors, melanoma and acute leukemias (89).
Role of Imaging in Surveillance
US is the preferred modality for the purposes of surveillance (90), as
CT carries the risk of ionizing radiation and MR imaging the need

915
 pediatrics
Table 37.4 Conditions with Risk of Developing Wilms’ Tumor
in Excess of 5%
Gene Phenotype WT risk
WT1 WAGR syndrome High >20%
Denys-Drash syndrome
Frasier syndrome
Familial WT
Aniridia
Isolated WT
BRCA2 Fanconi anemia High >20%
Some childhood cancers
BUB1B Mosaic variegated aneuploidy High >20%
Unknown Perlman syndrome High >20%
11p15 Beckwith-Wiedemann syndrome Moderate 5–20%
Some hemihypertrophy cases
GPC3 Simpson-Golabi-Behmel syndrome Moderate 5–20%
Source: Adapted from Ref. 90 on behalf of the Wilms’ Tumor Surveillance
Working Group.
for sedation in young children. Regular surveillance of children
thought to be at increased risk (in the order of 10–30%) of develop-
ing Wilms’ tumor, for example, those with Wilms’ tumor-related
congenital syndromes, has become widespread practice (91). Rec-
ommendations for such surveillance approved by the Children’s
Cancer and Leukaemia Group (CCLG) include offering screening
to those at greater than 5% risk of developing Wilms’ tumor via
three to four-monthly renal sonography up to the age of five to
seven years (90). Specifically, surveillance should continue until five
years of age for all those conditions except for proven Beckwith-
Wiedemann syndrome, Simpson-Golabi-Behmel syndrome, and
some familial Wilms’ tumors where it should continue until seven
years of age as the risk of developing Wilms’ tumor is considered to
be high (>20%) (90). Table 37.4 summarizes the conditions and
syndromes associated with a greater than 5% risk of Wilms’ tumor.
Long term follow-up is also important in patients with known
nephrogenic rests or nephroblastomatosis due to the risk of devel-
oping Wilms’ tumor. Attention should also be paid to the contra-
lateral kidney in patients with previous unilateral nephrectomy
for Wilms’ tumor. Even though the risk of contralateral, metachro-
nous relapse is low, the risk is increased if nephrogenic rests were
identified at initial diagnosis or if the patient was less than one
year of age at the time of diagnosis (74). Early detection of pri-
mary or metachronous tumor occurring in pre-existing nephro-
blastomatosis will facilitate nephron-sparing surgery. Clues to the
malignant transformation of a lesion include rapid increase in
size, the appearance of a nodular lesion or heterogeneity within a
lesion (73). In such cases the patient should proceed to surgery, as
percutaneous biopsy is unhelpful.
Prognosis
The treatment of Wilms’ tumor is one of the most significant suc-
cess stories in pediatric oncology. The prognosis for most children
diagnosed with Wilms’ tumor is excellent, with no significant differ-
ence in relapse-free survival between the two treatment approaches
of primary surgical resection and pre-operative chemotherapy (38).
The four-year survival rate is 86% to 96% for Stages I to III, up to
916
83% for Stage IV, and 70% for Stage V (7). However, the four-year
survival rate for diffuse anaplastic disease is 45% for Stage III and
only 7% for Stage IV tumors (7). The two-, five-, and ten-year sur-
vival rates for bilateral synchronous Wilms’ tumor are 83%, 73%,
and 70% respectively (91). The long-term survival of patients with
relapse/recurrence is about 50% to 60% (70).
Key Points: Late effects, Surveillance, and Prognosis
■ Adjuvant chemotherapy and radiotherapy may cause both
acute and chronic damage to organs such as the heart, lungs,
liver, bones, and gonads
■ Long-term survivors are prone to developing secondary
malignant neoplasms
■ US is the preferred modality for the purposes of surveillance
■ Screening is recommended in individuals who have a >5%
risk of developing Wilms’ tumor
■ The prognosis for most children diagnosed with Wilms’
tumor is excellent
OTHER RENAL NEOPLASMS OF CHILDHOOD
Clear Cell Sarcoma of the Kidney
Clear cell sarcoma of the kidney (CCSK) is a primitive mesenchy-
mal tumor which comprises 4% of all renal tumors of child-
hood (7,45). The peak age of incidence is similar to that of Wilms’
tumor and there is a male preponderance (7). CCSK has not been
reported with Wilms’ tumor associated conditions nor have there
been any reports of bilateral tumors (16,45). The clinical presen-
tation is most often of an abdominal mass and the imaging
appearances are very similar to those of Wilms’ tumor (Fig. 37.9).
CCSK has a propensity to metastasize to bone, with 23% develop-
ing bone metastases compared to 0.3% of all other patients
enrolled in the UKW3 study. Hence, once the diagnosis is made,
99mTc-MDP bone scintigraphy is indicated to stage the tumor.
Appearances may be either of reduced (osteolytic) or increased
(osteoblastic) isotope uptake (16). However, relapse is more
commonly seen in the lungs or central nervous system (7). The
relapse and mortality rates in CCSK are higher than in Wilms’
tumor. The four-year relapse-free survival rate in CCSK treated
with a combination of vincristine, adriamycin, and actinomycin-
D on the NWTS-3 trial was 71%. The current long-term survival
is about 60% to 70% (45).
Rhabdoid Tumor of the Kidney
Rhabdoid tumor is the most aggressive malignant pediatric renal
tumor with the worst prognosis of all the primary childhood
renal tumors. The tumor is unrelated to rhabdomyosarcoma or
Wilms’ tumor and may be of neural crest origin. It occurs almost
exclusively in young children, accounting for 1% to 2% of all
childhood renal neoplasms, with most cases diagnosed in infancy
(7). Clinical presentation may be that of hematuria, but due to
the aggressive nature of the tumor, symptoms are often related to
metastatic disease.
There is a known association between rhabdoid tumors and syn-
chronous, or metachronous primary central nervous system neo-
plasms (7,16,45). Hence cranial CT or MR imaging is recommended
 wilms’ tumor and associated neoplasms of the kidney

(A) (B)

(C)
Figure 37.9 Clear cell sarcoma of the kidney (CCSK). (A) Abdominal US shows a large, well-defined, left sided mass which is of heterogeneous echotexture. (B) Abdom-
inal US in another patient with CCSK demonstrating small hypoechoic areas within a mass which may represent necrosis or hemorrhage. (C) Contrast-enhanced CT in
the same patient demonstrates imaging characteristics that are indistinguishable from those of Wilms’ tumor.

in all patients. Brain lesions have a propensity for the posterior
fossa, and include primitive neuroectodermal tumor (PNET),
ependymoma, and cerebellar and brainstem astrocytomas. On
imaging, rhabdoid tumors are indistinguishable from Wilms’
tumors (Fig. 37.10). However, if present, the characteristic feature
of subcapsular fluid collections manifest as the peripheral fluid
crescent sign can point to the correct diagnosis (7,16,45).
Rhabdoid tumors require more intensive chemotherapy, but
despite this, the prognosis is poor and the tumor metastasizes early
to lungs, liver, brain, and bone. The four-year relapse-free survival on
a combination of vincristine, adriamycin, and actinomycin-D was
23.1% in the NWTS-3, with four-year overall survival of only 25%.
Renal Cell Carcinoma
Renal cell carcinoma is rare in the first two decades of life, with
less than 1% of all cases occurring in pediatric patients (7).
However, there are increasing numbers of cases reported in chil-
dren (92), some of whom are associated with hereditary cancer
syndromes, such as von Hippel-Lindau disease (93). In this syn-
drome tumors tend to be multiple and present at a younger age
(93). The mean age at presentation is nine years (7), which is the
main differentiating feature between renal cell carcinoma and
Wilms’ tumor. Clinical presentation is typically of a palpable
mass or flank pain, with hematuria occurring less frequently.
The gross morphology can be indistinguishable from that of
Wilms’ tumor: both are solid intrarenal masses with variable
amounts of necrosis, hemorrhage, calcification, and cystic degen-
eration. Renal cell carcinomas have a higher frequency of calcifi-
cation (25%) than Wilms’ tumor (9%) (33). In addition, the
calcifications in renal cell carcinoma tend to be ring-like (7),
which are unusual in Wilms’ tumor. Both tumors distort the adja-
cent renal architecture and form a pseudocapsule. However, renal

917
 pediatrics

(A) (B)

(C)
Figure 37.10 Rhabdoid tumor of the kidney. (A) Abdominal US demonstrates a mass (M) arising from the left kidney (K), which compresses the adjacent renal paren-
chyma. (B) Contrast-enhanced CT shows imaging characteristics that are typical for a renal neoplasm and thus essentially similar to those of a Wilms’ tumor. Note the
unfused neural arch indicating that this is an infant or young toddler. (C) Axial T1-weighted post-gadolinium MR image shows a left sided rhabdoid tumor (T) with
multiple hepatic metastases.

(A) (B)
Figure 37.11 Renal cell carcinoma in an adolescent patient with von Hippel-Lindau disease. (A) Longitudinal abdominal US demonstrates an ill-defined heterogeneous
mass in the upper pole of the left kidney (arrow) (B) Contrast-enhanced CT reveals multiple ill-defined and heterogeneously enhancing lesions in the left kidney. Note
a previous right sided nephrectomy has been performed for contralateral renal cell carcinoma.

918
 wilms’ tumor and associated neoplasms of the kidney
cell tumors tend to be smaller in size than Wilms’ at diagnosis and
therefore less easily identifiable at US and better detected on CT
or MR imaging, where they show similar imaging characteristics
to Wilms’ tumor (Fig. 37.11) (45). Local and regional lymph node
spread, in the absence of distant metastases, does not appear to be
a poor prognostic factor in children, unlike in adults. Metastases
to the lungs, liver, bone, or brain occur in 20% of patients at
diagnosis (45). Renal cell carcinoma is more likely than Wilms’
tumor to manifest bilaterally and metastasize to bone. The overall
survival rate is approximately 64% (45). The tumor is not particu-
larly chemosensitive and the best results have been obtained from
radical nephrectomy and regional lymphadenectomy, with
nephron-sparing surgery for bilateral disease.
Mesoblastic Nephroma
So-called congenital mesoblastic nephroma (CMN) is the most
common solid renal tumor presenting in the neonatal period. It
was historically thought to represent a congenital Wilms’ tumor,
but was recognized as a distinct entity in 1967 (16,45). Ninety per-
cent of cases present within the first year of life, most frequently as
a large, palpable abdominal mass (45). Other symptoms may
include hematuria, hypertension, vomiting, and jaundice. The
mass is infiltrative with ill-defined margins and no capsule, but is
histologically benign. Imaging appearances may be indistinguish-
able from a Wilms’ tumor. As CMN is the most likely renal mass in
the first six months of life, most collaborative oncology groups
advise against biopsy before six months and advocate primary
nephrectomy in this setting. The tumor is usually successfully
treated by nephrectomy alone. However, metastases are rare but
can occur to lungs, brain, and bone. Therefore close monitoring
for one year after surgery is recommended (45).
Key Points: Other Renal Neoplasms of Childhood
■ Clear cell sarcoma of the kidney (CCSK) is a primitive mes-
enchymal tumor which comprises 4% of all renal tumors of
childhood
■ Imaging appearances of CCSK are similar to Wilms’ tumors
■ CCSK has a propensity to spread to bone
■ Rhabdoid tumor is the most aggressive childhood renal tumor
and accounts for 1% to 2% of all renal tumors of childhood
■ Renal cell carcinoma is rare and may be associated with
hereditary cancer disorders
■ Mesoblastic nephroma is the most common renal tumor
presenting in the neonatal period
■ Mesoblastic nephroma is histologically benign but metastases
can occur
FUTURE DIRECTIONS IN IMAGING
FDG PET
The experience of 18FDG PET-CT in childhood cancers is limited,
being used in Hodgkin’s lymphoma and sarcomas but untried in
Wilms’ tumor (73). Since Wilms’ tumor, particularly the more
aggressive anaplastic type, is presumed to be FDG-avid (94), there
is a theoretical role for this technique in, for example, the targeted
biopsy of viable and biologically aggressive tissue. Monitoring of
the biological treatment response of the primary tumor as well as
of FDG-positive lung metastases might also be possible.
Quantitative MR Imaging
Diffusion-weighted imaging (DWI) is being increasingly used in
body MR imaging, particularly in the detection, characterization,
and subsequent monitoring of neoplastic disease. Studies have
shown that there is a correlation between cellularity and apparent
diffusion coefficient (ADC) values with high cellularity associated
with low ADC and low cellularity with high ADC values (95) (see
chap. 65). Thus quantitative MR imaging has the potential to eval-
uate treatment response and has the advantage over other meth-
ods of not utilizing ionizing radiation.
Contrast-Enhanced Ultrasound
US evaluation of renal and other tumors following the admin-
istration of IV contrast medium has been shown to improve
the accuracy of their detection and characterization in adults
(96). The role of this imaging technique in children is as yet
unproven because these contrast media are unlicensed for use
in children.
Summary
■ Wilms’ tumor is one of the most common renal tumors of
childhood
■ Wilms’ tumor is associated with congenital syndromes in
15% of cases
■ The majority of Wilms’ tumors are solitary; bilateral tumors
occuring in 5% to 7% of patients
■ The most common presentation is of an asymptomatic
abdominal mass and over 90% of patients have favorable his-
tology
■ US can distinguish between a cystic and a solid mass, assess
vascular invasion, and examine the contralateral kidney
■ CT and MR imaging give additional information and chest
CT is now recommended by SIOP for detecting pulmonary
metastases
■ There are two major staging systems in use: a pre-
chemotherapy, surgery based system (NWTS/COG), and a
preoperative chemotherapy based system (SIOP).
■ Ninety percent of relapses occur during the first four years
after diagnosis
■ Nephroblastomatosis may have similar imaging and
histological characteristics to Wilms’ tumor
■ The prognosis for most children diagnosed with Wilms’
tumor is excellent
■ US is the preferred modality for the purposes of surveillance
and screening is recommended in individuals who have a
>5% risk of developing Wilms’ tumor
■ Clear cell sarcoma of the kidney comprises 4% of renal
tumors of childhood, rhabdoid tumors account for about
1% and renal cell carcinomas are very rare
■ Mesoblastic nephroma tumors usually present during the
first year of life and are histologically benign
919
 pediatrics
REFERENCES
1. Kaste SC, Dome JS, Babyn PS, et al. Wilms tumour: prognostic
factors, staging, therapy, and late effects. Pediatr Radiol 2008;
38: 2–17.
2. Mitry E, Ciccolallo L, Coleman MP, Gatta G, Pritchard-Jones
K. EUROCARE Working Group. Incidence of and survival
from Wilms’ tumour in adults in Europe: data from the
EUROCARE study. Eur J Cancer 2006; 42: 2363–8.
3. de Camargo B, Pritchard-Jones K. Nephroblastoma. In: Voute
PA, Barrett A, Stevens MCG, and Caron HN, eds. Cancer in
Children: Clinical Management, 5th edn. Oxford University
Press, 2005: 321–36.
4. Fukuzawa R, Reeve AE. Molecular pathology and epidemiol-
ogy of nephrogenic rests and Wilms tumors. J Pediatr Hematol
Oncol 2007; 29: 589–94.
5. Grundy PE, Green DM, Coppes MJ, et al. Renal tumors. In:
Pizzo PA, Poplack DG, eds. Principles and Practice of Paediat-
ric Oncology. Philadelphia: Lippincott Williams and Wilkins,
2003: 865–93.
6. Hartman DJ, MacLennan GT. Wilms tumor. J Urol 2005; 173:
2147.
7. McHugh K. Renal and adrenal tumours in children. Cancer
Imaging 2007; 7: 41–51.
8. Breslow NE, Beckwith JB. Epidemiological features of Wilms’
tumor: results of the National Wilms’ Tumor Study. J Natl
Cancer Inst 1982; 68: 429–36.
9. Mesrobian HG, Kelalis PP, Hrabovsky E, et al. Wilms tumor in
horseshoe kidneys: a report from the National Wilms Tumour
Study. J Urol 1985; 133: 1002–3.
10. Scott RH, Stiller CA, Walker L, Rahman N. Syndromes and
constitutional chromosomal abnormalities associated with
Wilms tumour. J Med Genet 2006; 43: 705–15.
11. Reid S, Renwick A, Seal S, et al. Biallelic BRCA2 mutations are
associated with multiple malignancies in childhood including
familial Wilms tumour. J Med Genet 2005; 42: 147–51.
12. Weksberg R, Shuman C, Smith AC. Beckwith-Wiedemann syn-
drome. Am J Med Genet C Semin Med Genet 2005; 137: 12–23.
13. Royer-Pokora B, Beier M, Henzler M, et al. Twenty-four new
cases of WT1 germline mutations and review of the literature:
genotype-phenotype correlations for Wilms tumor develop-
ment. Am J Med Genet A 2004; 127A: 249–57.
14. Henneveld HT, van Lingen RA, Hamel BC, Stolte-Dijkstra I,
van Essen AJ. Perlman syndrome: four additional cases and
review. Am J Med Genet 1999; 86: 439–46.
15. Francois J, Coucke D, Coppieters R. Aniridia-Wilms’ tumour
syndrome. Ophthalmology 1977; 174: 35–9.
16. White KS, Grossman H. Wilms’ and associated renal tumors
of childhood. Pediatr Radiol 1991; 21: 81–8.
17. Riccardi VM, Sujansky E, Smith AC, Francke U. Chromosomal
imbalance in the Aniridia-Wilms’ tumor association: 11p
interstitial deletion. Pediatrics 1978; 61: 604–10.
18. Call KM, Glaser T, Ito CY, et al. Isolation and characterization
of a zinc finger polypeptide gene at the human chromosome
11 Wilms’ tumor locus. Cell 1990; 60: 509–20.
19. Gessler M, Poutska A, Cavenee W, et al. Homozygous deletion
in Wilms tumours of a zinc-finger gene identified by chromo-
some jumping. Nature 1990; 343: 774–8.
920
20. Bonetta L, Kuehn SE, Huang A, et al. Wilms tumor locus on
11p13 defined by multiple CpG island-associated transcripts.
Science 1990; 250: 994–7.
21. Coppes MJ, Huff V, Pelletier J. Denys-Drash syndrome: relat-
ing a clinical disorder to genetic alterations in the tumor sup-
pression gene WT1. J Pediatr 1993; 123: 673–8.
22. Pelletier J, Bruening W, Kashtan CE, et al. Germline mutations
in the Wilms’ tumour suppressor gene are associated with
abnormal urogenital development in Denys-Drash syndrome.
Cell 1991; 67: 437–47.
23. Koufos A, Grundy P, Morgan K, et al. Familial Wiedemann-
Beckwith syndrome and a second Wilms’ tumor locus both
map to 11p15.5. Am J Human Genet 1989; 44: 711–19.
24. Ping AJ, Reeve AE, Law DJ, et al. Genetic linkage of Beckwith-
Wiedemann syndrome to 11p15. Am J Hum Genet 1989; 44:
720–3.
25. Driscoll K, Isakoff M, Ferrer F. Update on pediatric genitouri-
nary oncology. Curr Opin Urol 2007; 17: 281–6.
26. Grundy PE, Breslow NE, Li S, et al. Loss of heterozygosity
for chromosomes 1p and 16q is an adverse prognostic
factor in favourable-histology Wilms tumor: a report from
the National Wilms Tumor Study Group. J Clin Oncol 2005;
23: 7312–21.
27. Hartman DJ, MacLennan GT. Wilms tumor. J Urol 2005; 173:
2147.
28. Beckwith JB, Palmer NF. Histopathology and prognosis of
Wilms’ tumor. Cancer 1978; 41: 1937–48.
29. Kaste SC, Dome JS, Babyn PS, et al. Wilms tumour: prognostic
factors, staging, therapy, and late effects. Pediatr Radiol 2008;
38: 2–17.
30. Kalapurakal JA, Dome JS, Perlman EJ, et al. Management of
Wilms’ tumour: current practice and future goals. Lancet
Oncol 2004; 5: 37–46.
31. Halperin EC. Wilms’ tumor. In: Halperin EC, Constine LS,
Tarbell NJ, and Kun LE, eds. Pediatric Radiation Oncology,
4th edn. Philadelphia: Lippincott Williams & Wilkins, 2005:
379–421.
32. Miller RC, Sterioff S, Jr, Drucker WR, et al. The incidental
discovery of occult abdominal tumors in children following
blunt abdominal trauma. J Trauma 1996; 6: 99–106.
33. Lonergan GJ, Martinez-Leon MI, Agrons GA, Montemarano
H, Suarez ES. Nephrogenic rests, nephroblastomatosis, and
associated lesions of the kidney. Radiographics 1998; 18:
947–68.
34. Niu CK, Chen WF, Chuang JH, et al. Intrapelvic Wilms’ tumor:
report of 2 cases and review of the literature. J Urol 1993; 150:
936–9.
35. Leung RS, Liesner R, Brock P. Coagulopathy as a presenting
feature of Wilms tumour. Eur J Pediatr 2004; 163: 369–73.
36. Ritchey ML, Kelalis PP, Breslow N, et al. Intracaval and atrial
involvement with nephroblastoma: review of National Wilms
Tumor Study-3. J Urol 1988; 140: 1113–18.
37. Gommersall LM, Arya M, Mushtaq I, Duffy P. Current chal-
lenges in Wilms’ tumor management. Nat Clin Pract Oncol
2005; 2: 298–304.
38. Coppes MJ, Zandvoort SW, Sparling CR, et al. Acquired von
Willebrand disease in Wilms’ tumor patients. J Clin Oncol
1992; 10: 422–7.
 wilms’ tumor and associated neoplasms of the kidney
39. Lin RY, Argenta PA, Sullivan KM, Stern R, Adzick NS. Urinary
hyaluronic acid is a Wilm’s tumor marker. J Pediatr Surg 1995;
30: 304–8.
40. Lall A, Pritchard-Jones K, Walker J, et al. Wilms’ tumor with
intracaval thrombus in the UK Children’s Cancer Study Group
UKW3 trial. J Pediatr Surg 2006; 41: 382–7.
41. Brisse HJ, Smets AM, Kaste SC, Owens CM. Imaging in unilat-
eral Wilms tumour. Pediatr Radiol 2008; 38: 18–29.
42. Slovis TL, ed. The ALARA (as low as reasonably achievable)
concept in pediatric CT intelligent dose reduction. Multidis-
ciplinary conference organized by the Society of Pediatric
Radiology 2001. Pediatr Radiol 2002; 32: 217–313.
43. Scott DJ, Wallace WH, Hendry GM. With advances in medical
imaging can the radiologist reliably diagnose Wilms’ tumours?
Clin Radiol 1999; 54: 321–7.
44. Panuel M, Bourliere-Najean B, Gentet JC, et al. Aggressive neuro-
blastoma with initial pulmonary metastases and kidney involve-
ment simulating Wilms’ tumor. Eur J Radiol 1992; 14: 201–3.
45. Lowe LH, Isuani BH, Heller RM, et al. Pediatric renal masses:
Wilms’ tumor and beyond. Radiographics 2000; 20: 1585–603.
46. Grundy P, Breslow N, Green DM, et al. Prognostic factors for
children with recurrent Wilms’ tumor: results from the Sec-
ond and Third National Wilms’ Tumor Study. J Clin Oncol
1989; 7: 638–47.
47. Grundy P, Perlman E, Rosen NS, et al. Current issues in Wilms’
tumor management. Curr Probl Cancer 2005; 29: 221–60.
48. Owens CM, Veys PA, Pritchard J, et al. Role of chest computed
tomography at diagnosis in the management of Wilms’ tumor:
a study by the United Kingdom Children’s Cancer Study
Group. J Clin Oncol 2002; 20: 2768–73.
49. Wootton-Gorges SL, Albano EA, Riggs JM, et al. Chest radiog-
raphy versus chest CT in the evaluation for pulmonary metas-
tases in patients with Wilms’ tumor: a retrospective review.
Pediatr Radiol 2000; 30: 533–7.
50. Ditchfield MR, De Campo JF, Waters KD, Nolan TM. Wilms’
tumor: a rational use of preoperative imaging. Med Pediatr
Oncol 1995; 24: 93–6.
51. D’Angio GJ, Rosenberg H, Sharples K, et al. Position paper:
imaging methods for primary renal tumors of childhood:
costs versus benefits. Med Pediatr Oncol 1993; 21: 205–12.
52. Ehrlich PF, Hamilton TE, Grundy P, et al. The value of surgery
in directing therapy for patients with Wilm’s tumor with pul-
monary disease. A report from the National Wilms’ Tumor
Study Group (National Wilms’ Tumor Study 5). J Pediatr Surg
2006; 41: 162–7.
53. Attard-Montalto SP, Kingston JE, Eden OB, Plowman PN. Late
follow-up of lung function after whole lung irradiation for
Wilms’ tumour. Br J Radiol 1992; 65: 1114–18.
54. McHugh K, Pritchard J. Problems in the imaging of three com-
mon pediatric solid tumours. Eur J Radiol 2001; 37: 72–8.
55. Delemarre JF, Sandstedt B, Harms D, Boccon-Gibod L, Vujanić
GM. The new SIOP (Stockholm) working classification of
renal tumours of childhood. International Society of Paediat-
ric Oncology. Med Pediatr Oncol 1996; 26: 145–6.
56. Vujanić GM, Sandstedt B, Harms D, et al. Revised Interna-
tional Society of Paediatric Oncology (SIOP) working classifi-
cation of renal tumors of childhood. Med Pediatr Oncol 2002;
38: 79–82.
57. Shamberger RC, Guthrie KA, Ritchey ML, et al. Surgery-related
factors and local recurrence of Wilms tumor in National
Wilms Tumor Study 4. Ann Surg 1999; 229: 292–7.
58. Ritchey ML, Shamberger RC, Hamilton T, et al. Fate of bilat-
eral renal lesions missed on preoperative imaging: a report
from the National Wilms Tumor Study Group. J Urol 2005;
174: 1519–21.
59. de Kraker J, Graf N, van Tinteren H, et al. Reduction of post-
operative chemotherapy in children with stage I intermediate-
risk and anaplastic Wilms’ tumour (SIOP 93-01 trial): a
randomised controlled trial. Lancet 2004; 364; 1229–35.
60. Ritchey ML, Shamberger RC, Haase G, et al. Surgical compli-
cations after primary nephrectomy for Wilms’ tumour: report
from the National Wilms’ Tumor Study Group. J Am Coll Surg
2001; 192: 63–8.
61. Mitchell C, Pritchard-Jones KP, Shannon R, et al. and for the
United Kingdom Cancer Study Group. Immediate nephrec-
tomy versus preoperative chemotherapy in the management
of non-metastatic Wilms’ tumour: results of a randomised
trial (UKW3) by the UK Children’s Cancer Study Group. Eur
J Cancer 2006; 42: 2554–62.
62. Vujanić GM, Kelsey A, Mitchell C, Shannon RS, Gornall P. The
role of biopsy in the diagnosis of renal tumours of childhood:
results of the UKCCSG Wilms tumor study 3. Med Pediatr
Oncol 2003; 40: 18–22.
63. Dykes EH, Marwaha RK, Dicks-Mireaux C, et al. Risks and
benefits of percutaneous biopsy and primary chemotherapy
in advanced Wilms’ tumour. J Pediatr Surg 1991; 26: 610–12.
64. Coppes MJ, Anderson RA, Mueller DL, et al. Arteriovenous
fistula: a complication following renal biopsy of suspected
bilateral Wilms’ tumor. Med Pediatr Oncol 1997; 28: 455–61.
65. Lee IS, Nguyen S, Shanberg AM. Needle tract seeding after
percutaneous biopsy of Wilms tumor. J Urol 1995; 153: 1074–6.
66. Aslam A, Foot AB, Spicer RD. Needle track recurrence after
biopsy of non-metastatic Wilms tumour. Pediatr Surg Int
1996; 11: 416–17.
67. Duncan A, on behalf of the United Kingdom Children’s Can-
cer Study Group. UKCCSG Radiology Imaging Guidelines,
June 2001.
68. Barnacle AM, McHugh K. Limitations with the response eval-
uation criteria in solid tumours (RECIST) guidance in dis-
seminated pediatric malignancy. Pediatr Blood Cancer 2006;
46: 127–34.
69. Miser JS, Tournade MF. The management of relapsed Wilms
tumour. Hematol Oncol Clin North Am 1995; 9: 1287–302.
70. Dome JS, Liu T, Krasin M, et al. Improved survival for patients
with recurrent Wilms tumour: the experience at St Jude Chil-
dren’s Research Hospital. J Pediatr Hematol Oncol 2002; 24:
192–8.
71. Pritchard-Jones K. Controversies and advances in the man-
agement of Wilms’ tumour. Arch Dis Child 2002; 87: 241–4.
72. Petruzzi MJ, Green DM. Wilms tumour. Pediatr Clin North
Am 1997; 44: 939–52.
73. Owens CM, Brisse HJ, Olsen OE, Begent J, Smets AM. Bilateral
disease and new trends in Wilms tumour. Pediatr Radiol 2008;
38: 30–9.
74. Merchant SA, Badhe PB. Nephroblastomatosis—pathological
and imaging characteristics. J Postgrad Med 1995; 41: 72–80.
921
 pediatrics
75. Ahmed HU, Arya M, Tsiouris A, et al. An update on the
management of Wilms’ tumour. Eur J Surg Oncol 2007; 33:
824–31.
76. Montgomery BT, Kelalis PP, Blute ML, et al. Extended fol-
lowup of bilateral Wilms tumor: results of the National Wilms
Tumor Study. J Urol 1991; 146: 514–18.
77. Hoffer FA. Magnetic resonance imaging of abdominal masses
in the pediatric patient. Semin Ultrasound CT MR 2005; 26:
212–23.
78. Berenyi P, Pinter J, Szokoly V. Intraoperative sonography in
organ preserving operations of kidney tumours. Z Urol Neph-
rol 1990; 83: 419–24.
79. Beckwith JB, Kiviat NB, Bonadio JF. Nephrogenic rests, neph-
roblastomatosis, and the pathogenesis of Wilms’ tumor. Pedi-
atr Pathol 1990; 10: 1–36.
80. Perlman E, Dijoud F, Boccon-Gibod L. Nephrogenic rests and
nephroblastomatosis. Ann Pathol 2004; 24: 510–15.
81. Rohrschneider WK, Weirich A, Rieden K, et al. US, CT and
MR imaging characteristics of nephroblastomatosis. Pediatr
Radiol 1998; 28: 435–43.
82. Gylys-Morin V, Hoffer FA, Kozakewich H, Shamberger RC.
Wilms tumour and nephroblastomatosis: imaging character-
istics at gadolinium-enhanced MR imaging. Radiology 1993;
188: 517–21.
83. Subhas N, Argani P, Gearhart JP, Siegelman SS. Nephrogenic
rests mimicking Wilms’ tumour on CT. Pediatr Radiol 2004;
34: 152–5.
84. Beckwith JB. New developments in the pathology of Wilms
tumour. Cancer Invest 1997; 15: 153–62.
85. Bailey S, Roberts A, Brock C, et al. Nephrotoxicity in survivors
of Wilms’ tumours in the North of England. Br J Cancer 2002;
87: 1092–8.
922
86. Breslow NE, Takashima JR, Ritchey ML, Strong LC, Green
DM. Renal failure in the Deny-Drash and Wilms’ tumor-
aniridia syndromes. Cancer Res 2000; 60: 4030–2.
87. Walker DA, Dillon M, Levitt G, et al. Multiple exostosis (osteo-
chondroma) and Wilms’ tumour—a possible association. Med
Pediatr Oncol 1992; 20: 360–1.
88. Green DM, Whitton JA, Stovall M, et al. Pregnancy outcome
of female survivors of childhood cancer: a report from the
Childhood Cancer Survivor Study. Am J Obstet Gynecol 2002;
187: 1070–80.
89. Carli M, Frascella E, Tournade MF, et al. Second malignant
neoplasms in patients treated on SIOP Wilms tumour studies
and trials 1, 2, 5 and 6. Med Pediatr Oncol 1997; 29: 239–44.
90. Scott RH, Walker L, Olsen OE, et al. Surveillance for Wilms
tumour in at-risk children: pragmatic recommendations for
best practice. Arch Dis Child 2006; 91: 995–9.
91. Metzger ML, Dome JS. Current therapy for Wilms’ tumor.
Oncologist 2005; 10: 815–26.
92. Kawashima A, Glockner JF, King BF Jr. CT urography and MR
urography. Radiol Clin North Am 2003; 41: 945–61.
93. Leung RS, Biswas SV, Duncan M, Rankin S. Imaging features
of von Hippel-Lindau disease. Radiographics 2008; 28: 65–79.
94. Wegner EA, Barrington SF, Kingston JE, et al. The impact of
PET scanning on management of paediatric oncology patients.
Eur J Nucl Med Mol Imaging 2005; 32: 23–30.
95. Humphries PD, Sebire NJ, Siegel MJ, Olsen OE. Tumors in
pediatric patients at diffusion-weighted MR imaging: appar-
ent diffusion coefficient and tumor cellularity. Radiology
2007; 245: 848–54.
96. Ascenti G, Mazziotti S, Zimbaro G, et al. Complex cystic renal
masses: characterization with contrast-enhanced US. Radiol-
ogy 2007; 243: 158–65.
 38 Neuroblastoma
Marilyn J Siegel
INTRODUCTION
Neuroblastoma is the most common extracranial solid malignant
tumor of childhood. It has a spectrum of locations and degrees of
histopathologic differentiation resulting in a diversity of clinical
and biologic features (1–3). With the exception of infants under
the age of one year, the prognosis of children with neuroblastoma
is generally poor. Tumor stage is an extremely important indicator
of patient outcome and imaging therefore plays a crucial role in
the determination of stage prior to treatment.
EPIDEMIOLOGY
Neuroblastoma accounts for 8% to 10% of all childhood cancers
(1). The prevalence is about one case per 7000 live births and
there are approximately 800 newly diagnosed cases of neuroblas-
toma in the United States annually (1–3). In the United Kingdom,
recent data indicates a rate of 8.4 per million for all ages 0 to
14 years (4). Thus in the United Kingdom, the expected annual
number of new cases of neuroblastoma is between 75 and 80.
Neuroblastoma is the most common cancer of infancy. The
median age at diagnosis of children with neuroblastoma is approxi-
mately 19 months (1). Approximately 36% of patients are infants;
89% are under five years; and 98% are under 10 years of age. Boys
are affected slightly more often than girls with a male-to-female
ratio of 1.1:1 (1).
GENETICS OF NEUROBLASTOMA
In a subgroup of patients, neuroblastoma exhibits an autosomal
dominant pattern of inheritance, possibly related to an abnormal-
ity in the short arm of chromosome 16 (16p12-13) (5,6). In this
subset, the median age at diagnosis is nine months and there is an
increased prevalence of bilateral adrenal or multifocal primary
tumors. In addition, there are data suggesting that genes associ-
ated with the genesis of other tumors of neural crest origin, such
as neurofibromatosis type 1 and Hirschsprung disease, may be
involved in the initiation or progression of neuroblastoma (1).
PROGNOSTIC FACTORS
Certain biochemical, biologic, and histologic markers are
predicators of outcome in children with neuroblastoma
( Table 38.1). These markers help to define specific subgroups
of patients with widely divergent natural histories and survival
rates ( Table 38.2).
Biochemical markers include serum levels of lactate dehydro-
genase, ferritin, and neuron-specific enolases (1,7,8). In general,
low levels of any of these serum markers predict a good outcome,
whereas high serum levels are associated with a poorer prognosis.
Urinary catecholamine levels are not predictive of outcome.
However, high homovanillic acid (HVA) and low vanillylmandelic
acid (VMA) serum levels have been associated with shortened
survival (1).
Biologic markers with prognostic value include amplification of
the N-myc oncogene (9–12), the amount of tumor cell DNA (11,12)
and karyotype (1,13–15). Up to 30% of children with neuroblastoma
present with N-myc amplification in tumor cells (greater than 10
copies of a segment of DNA termed N-myc oncogene). N-myc
amplification and diploid karyotype (normal or near-normal
DNA content) are associated with aggressive tumor behavior and
poor prognosis, regardless of tumors stage. Partial deletions of
chromosome 1 and 11 and gains of chromosome 17 are other
poor prognostic signs.
Histopathologic prognostic factors include tumor stromal con-
tent, degree of mitosis (16–18), and level of nerve growth factor
tyrosine kinase receptors (Trk) expression (11,19). A stroma-rich
tumor matrix, low mitotic activity, and a high level of expression
of nerve growth factor TrkA correlate highly with favorable out-
come. High expression of TrkB is seen with unfavorable neuro-
blastoma (11). Selected prognostic factors are summarized in
Table 38.1.
PATHOLOGY
Neuroblastoma arises from primitive sympathetic cells, which
are derived from the embryonic neural crest, and is one of the
small, round blue-cell tumors of childhood. There are three
histopathologic patterns of neuroblastoma, which correlate with
the degree of tumor differentiation: neuroblastoma, ganglio-
neuroblastoma, and ganglioneuroma (1–3). Neuroblastoma is
composed of small round cells with scant cytoplasm and hyper-
chromatic nuclei, often arranged in clusters resembling rosettes.
Ganglioneuroblastoma contains rests of neuroblasts along with
mature or maturing ganglion cells. Ganglioneuroma is fully dif-
ferentiated and is composed of mature ganglion cells and
Schwann cells. Neuroblastoma and ganglioneuroblastoma are
usually grouped together (and referred to as neuroblastoma) for
purposes of staging and reporting survival statistics as well as
imaging features.
Macroscopically, neuroblastomas average 6 to 8 cm in size and
often are hemorrhagic. Areas of stroma are often interposed
between areas of hemorrhagic tissue, giving the tumor a lobular
appearance. Areas of hemorrhage, necrosis and calcification are
common on cut section (3). Distinguishing neuroblastoma from
other small, round blue-cell tumors of childhood, including Ewing
sarcoma, primitive neuro-ectodermal tumor, rhabdomyosarcoma,
leukemia, and lymphoma, can be difficult on routine light micros-
copy and often requires the adjunctive use of electron microscopy
or immunohistochemistry.
923
 pediatrics

Table 38.1 Selected Biologic Prognostic Factors (20), post-natal screening programs (1,21–25), physical examination,
or imaging studies obtained for other indications.
Biologic parameter Adverse finding
Tumor cell features Screening Programmes
N-myc oncogene >10 copies Neuroblastoma in situ has been described in fetuses (21–23).
Chromosomal ploidy Near diploid
Postnatal clinical and radiological follow-up has demonstrated
Chromosome 17 q Gain
Chromosome 1p36 Deletion
spontaneous resolution in virtually all cases, confirming the
Chromosome 11q14–22 Deletion benign nature of these antenatal tumors.
Histopathologic markers Post-natal screening programs have been introduced in Canada,
TrkA Absent or low expression Europe, and Japan (24–28). The basis of urine catecholamine popu-
TrkB High expression lation screening programs is that early detection of neuroblastoma
Shimada histopathology Unfavorable
Biochemical marker
will decrease the prevalence of advanced stage disease in children
Serum lactate dehydrogenase >1500 U/L older than one year of age. These screening studies increased detec-
Serum neuron-specific enolase >100 ng/mL tion of neuroblastoma in infants less than one year of age without
Serum ferritin >142 ng/mL decreasing the incidence of advanced stage disease and the mortal-
Urine VMA:HVA ratio <1 ity from neuroblastoma in older children. Those patients in whom
Abbreviations: HVA, homovanillic acid; VMA, vanillylmandelic acid. neuroblastomas were identified generally had lower stages of
Source : From Refs. 1, 44. disease and virtually all of the tumors were biologically favorable.

Table 38.2 Biologic and Clinical Subtypes of Neuroblastoma Symptoms due to Primary Tumor
Neuroblastoma can arise anywhere along the sympathetic chain,
Feature Type 1 Type 2 Type 3 from the neck to the pelvis. Approximately two-thirds occur in the
N-myc oncogene Normal Normal Amplified abdomen and 50% to 75% of these arise in the adrenal medulla. The
DNA ploidy Hyperdiploid/ Near diploid Near diploid remaining abdominal tumors arise from sympathetic paraspinal
triploid
ganglia. Less common sites of origin are the posterior mediastinum
Chromosome 17q gain Rare Common Common
Chromosome 1p loss Rare ±Present Common (10–15%), neck (5%), and pelvis (5%). In approximately 1% of chil-
Chromosome 11q loss Rare Common Rare dren, a primary tumor cannot be found. The sites of origin also vary
TrkA expression High Low or absent Low or absent with patient age. Infants have more cervical and thoracic tumors,
TrkB expression Truncated Low or absent High (full length) whereas older children have more primary adrenal tumors (3).
Age (yr) Usually <1 Usually ≥1 Usually 1–5 The clinical presentation varies depending on the site of tumor
Stage Usually 1, 2, 4S Usually 3, 4 Usually 3, 4
5-yr survival (%) 95 40–50 25
and extent of disease (1–3,29). Tumors occurring in the abdomen
are more likely to be symptomatic than those arising in the chest.
Source: From Refs. 1, 44. Abdominal disease is likely to result in a palpable abdominal mass
or abdominal pain. Sudden increase in abdominal size can result
Key Points: Incidence, Prognosis, Pathology from spontaneous hemorrhage into the tumor. Large abdominal
tumors can compress the kidney or encase or stretch the renal
■ Neuroblastoma is the most common extracranial malignant artery, activating the renin-angiotensin system and causing hyper-
tumor of childhood tension. Pelvic tumors can result in sciatic nerve palsy, urinary and
■ Eighty-nine percent of tumors occur under five years of age fecal incontinence, neuropathic bladder, leg weakness or nerve
and the prognosis is generally poor root injury, and lower extremity edema resulting from compres-
■ Approximately two-thirds of tumors occur in the abdomen, sion of venous and lymphatic drainage (30).
50% to 75% in the adrenal medulla Primary posterior mediastinal tumors often are an incidental
■ Prognosis depends on multiple variables: clinical (patient age, finding on chest radiographs obtained to evaluate respiratory symp-
tumor stage), biochemical (lactate dehydrogenase, ferritin, toms or trauma. High thoracic and cervical neuroblastomas can be
neuron-specific enolase), biologic (tumor cell DNA, loss associated with dysphagia, stridor, or Horner syndrome (unilateral
of chromosome 1p, N-myc oncogene amplification), and ptosis, pupillary constriction, and anhydrosis) (31). Occasionally,
histopathologic (stromal content, degree of mitosis, level of thoracic tumors result in superior vena cava syndrome.
nerve growth factor expression) Paraspinal tumors can result in scoliosis, back pain, urinary or fecal
■ Urinary catecholamine levels are not predictive of patient retention, and peripheral neurologic deficits due to neural foraminal
outcome invasion and nerve root or cord compression. The neurologic mani-
■ There are three histopathologic types of neuroblastoma: festations are usually related to the level and extent of tumor invasion
neuroblastoma, ganglioneuroblastoma, and ganglioneuroma in the spinal canal and include radicular pain and subacute or acute
paraplegia as well as bladder or bowel dysfunction (1).

CLINICAL PRESENTATION Symptoms due to Distant Disease

At least 70% of patients with neuroblastoma will have dissemi-
Most children with neuroblastoma are symptomatic. The tumor, nated disease at the time of diagnosis, including 70% of infants
however, can be detected incidentally on antenatal ultrasonography and 85% of children older than one year of age (1). Metastatic

924
 neuroblastoma
extension occurs via lymphatic and hematogenous routes. In
infants under 12 months of age, metastases are predominantly to
the skin, liver, bone marrow, and lymph nodes. Metastases to the
skin or subcutaneous tissue cause non-tender, bluish, mobile nod-
ules (“blueberry muffin baby”), while metastases to the liver can
present as hepatomegaly. In neonates the enlarging liver can cause
severe respiratory compromise and compression of the inferior
vena cava with resultant ascites, anasarca, and renal failure.
In children older than one year of age, metastases are to cortical
bone, bone marrow, lymph nodes, and liver. Long bone and bone
marrow metastases may cause migratory or recurrent bone pain
or a palpable mass. These symptoms are often confused with leu-
kemia, juvenile rheumatoid arthritis, or osteomyelitis (32). Meta-
static disease to the sphenoid bone or retrobulbar soft tissues can
result in proptosis and ecchymosis, creating a characteristic “rac-
coon eye” appearance. Metastatic lesions to the dura or brain can
present with findings of increased intracranial pressure, such as
widened cranial sutures, or focal neurologic signs. Non-specific
signs and symptoms, including fever, irritability, weight loss, and
anemia, are also common findings.
Paraneoplastic Syndromes
Several paraneoplastic syndromes have been associated with local-
ized and disseminated neuroblastoma, including opsoclonus-
myoclonus syndrome, intractable diarrhea, and flushing associated
with hypertension. These findings have been attributed to meta-
bolic and immunological disturbances associated with the
tumor. The opsoclonus-myoclonus syndrome, also referred to as
myoclonic encephalopathy of infants, is characterized by acute
cerebellar and truncal ataxia and random eye movements (“danc-
ing eyes”) (33,34). It occurs in up to 4% of patients with newly
diagnosed neuroblastoma. Conversely, up to 50% of children with
this syndrome may have neuroblastoma (1). The primary tumor is
most commonly found in the posterior mediastinum (50% of
cases), but it may be found anywhere along the sympathetic chain.
The majority of patients with opsoclonus-myoclonus syndrome
have favorable outcomes with respect to their tumor. However,
most have long term neurologic deficits that can progress even after
removal of the tumor (33,34). These deficits are presumably due to
antineural antibodies against the primary tumor that cross-react
with neural cells in the cerebellum or elsewhere in the brain (34).
Intractable watery diarrhea associated with hypokalemia and
dehydration is a result of tumor secretion of vasoactive intestinal
peptide (VIP). Flushing in combination with hypertension is
thought to be a manifestation of very high levels of catecholamines.
Most patients with tumor-related diarrhea and hypertension
have histologically mature tumors (either ganglioneuroma or
ganglioneuroblastoma) and favorable outcomes (35,36). Surgical
resection of the tumor leads to resolution of symptoms.
METHODS OF DIAGNOSIS
An unequivocal pathological diagnosis can be made based on
tissue sampling and light microscopy, electron microscopy, or
immunohistology. A diagnosis can also be established by the com-
bination of a bone marrow aspirate or biopsy that shows unequiv-
ocal tumor cells and increased serum or urinary catecholamines
Table 38.3 INSS Staging System for Neuroblastoma
Stage Definition
1 Localized tumor with complete resection, with or without
microscopic residual disease; representative ipsilateral lymph
nodes negative for tumor microscopically
2A Localized tumor with incomplete gross excision; representative
ipsilateral nonadherent lymph nodes negative for tumor
microscopically
2B Localized tumor with or without complete gross excision, with
representative ipsilateral non-adherent lymph nodes positive for
tumor. Enlarged contralateral lymph nodes must be negative
microscopically.
3 Unresectable unilateral tumor infiltrating across the midline, with
or without regional lymph node involvement; or localized
unilateral tumor with contralateral regional lymph node
involvement; or midline tumor with bilateral extension by
infiltration (unresectable) or by lymph node involvement.
4 Any primary tumor with dissemination to distant lymph nodes,
bone, bone marrow, liver, skin, and/or other organs (except as
defined for stage 4S)
4S Localized primary tumor (as defined for Stage 1, 2A, or 2B), with
dissemination limited to skin, liver, and/or bone marrow. Bone
marrow involvement should be minimal (<10% of total nucleated
cells identified as malignant on bone marrow biopsy or on marrow
aspirate). Limited to infants less than one year of age.
or metabolites. Percutaneous biopsy of the primary tumor or liver
metastases in children with advanced disease (Stages 3, 4, or 4S) is
an alternative to open biopsy for diagnosis and determination of
prognostic information (37).
STAGING
The most widely used staging system for neuroblastoma is the Inter-
national Neuroblastoma Staging System (INSS) (Table 38.3)
(38,39). This classification takes into account radiological find-
ings, surgical resectability and lymph node and bone marrow
involvement. Regional disease is divided into Stages 1, 2, and 3,
based on whether the tumor extends across the midline or is resec-
table, and on regional lymph node status. Distant disease in all
patients ≥12 months is Stage 4 disease. In infants <12 months,
widespread disease is characterized as Stage 4S (“special”), which
is defined as a small tumor (Stage 1 or 2), rare (<10%) tumor cells
in bone marrow, and no distant osseous metastases.
TREATMENT
Based on clinical factors of patient age at diagnosis, INSS stage
and selected biologic factors (tumor histopathology, chromo-
somal ploidy, and N-myc amplification status), patients are
grouped into low-, intermediate-, and high-risk categories for
treatment planning (1). The goal is to reduce chemotherapy treat-
ment in low- and intermediate-risk patients and to increase the
intensity of chemotherapy in high-risk patients.
Treatment of Low-Risk Disease
Patients included in this group are: all patients with INSS Stage 1
disease; patients with INSS Stage 2 disease (except patients older
925
 pediatrics

than one year at diagnosis with N-myc amplification and unfavor-

PRIMARY NEUROBLASTOMA: IMAGING
able Shimada pathology); and infants with 4S disease that have
tumors with hyperdiploidy, favorable Shimada and no N-myc CHARACTERISTICS
amplification (1). Treatment of low-risk neuroblastoma consists
Imaging of neuroblastoma requires diagnosis of the primary
of surgical resection of the primary tumor (40,41).
tumor along with evaluation of the extent of local and distant dis-
ease. The multiple sites of origin and varying patterns of metasta-
Treatment of Intermediate-Risk Disease ses make assessment of disease dependent on a multitude of
Included in this group are: INSS stage 3 patients younger than one imaging studies (44).
year with no N-myc amplification; INSS stage 3 patients older
than one year with no N-myc amplification and favorable Imaging Studies
Shimada pathology; Stage 4 infants with no N-myc amplification; Plain Radiographs
and nonamplified stage 4S patients with either unfavorable Plain radiography is an insensitive method of diagnosing neuro-
Shimada histopathology or tumor diploidy (or both) (1). Treatment blastoma. However plain radiographs undertaken to investigate
of intermediate-risk disease consists of combination chemotherapy unrelated clinical features may reveal unsuspected tumor in the
including carboplatin, etoposide, cyclophosphamide, and doxo- neck, chest, or abdomen, or evidence of metastatic disease. Occa-
rubicin. Once the tumor decreases sufficiently in volume, delayed sionally plain radiographs are obtained to further evaluate an
surgical resection may be performed. abnormality shown on other imaging studies.
Plain radiographic findings include a posterior retroperitoneal,
Treatment of High-Risk Disease thoracic, or cervical mass (Fig. 38.1) and enlargement of the inter-
Patients included in this group are: INSS Stage 4 patients older vertebral foramina or erosion of the pedicles due to intraspinal
than one year at diagnosis; any INSS Stage 3 patients with extension of tumor. The tumor may contain calcifications.
N-myc amplification; INSS Stage 3 patients older than one year
at diagnosis with unfavorable Shimada pathology; INSS Stage Ultrasonography
2 patients with N-myc amplification and unfavorable Shimada The evaluation of patients with palpable abdominal masses,
pathology; and INSS Stage 4S patients with N-myc amplifica- including neuroblastoma, usually begins with sonography.
tion (1). Treatment of high-risk disease has included intensive
induction and consolidation chemotherapy, local radiotherapy
to prevent relapse in primary tumor sites, 13-cis retinoic acid,
and targeted radiotherapy with 131I-metaiodobenzylguanidine
(MIBG) or 131I-labelled monoclonal antibodies (1,30,42–44).
Surgical resection following treatment may also have an important
place in management.
Occasionally, neuroblastoma will spontaneously regress. Sponta-
neous regression occurs most commonly in infants. Neuroblastoma
cells also may differentiate into more benign ganglion cells, either
spontaneously or after chemotherapy (1).
When disease recurs, it may be in the primary tumor site
with extension into surrounding tissues or in other areas of the
body. Bone and bone marrow relapses are common sites of
relapse.

Key Points: Clinical Features, Staging, Treatment

■ The majority of tumors arise in the abdomen and 50% to
75% of these occur in the adrenal gland. Most children are
symptomatic at presentation with abdominal pain and/or a
palpable mass
■ At least 70% of patients have disseminated disease at the time
of diagnosis. Metastases are predominantly to the skin, liver,
bone marrow, and lymph nodes
■ Paraneoplastic syndromes are associated with neuroblastoma
■ Pathological diagnosis is made on tissue sampling and light
microscopy, electron microscopy, and immunohistology
■ The International Neuroblastoma Staging System (INSS) is
now the most widely used staging classification
■ Treatment is based on an assessment of risk and includes
Figure 38.1 Right adrenal neuroblastoma in a two-year-old girl. Abdominal radio-
surgery, combination chemotherapy and radiotherapy
graph shows a large right paraspinal mass (arrows) displacing bowel gas to the left.

926
 neuroblastoma

(A) (B)

Figure 38.2 Suprarenal neuroblastoma in a 15-month-old girl. (A) Transverse longitudinal sonogram of the left upper quadrant shows a homogeneous echogenic left
suprarenal mass (arrows) anterior to the left kidney (LK), posterior to the pancreas (PANC), and lateral to the aorta (A). (B) Color Doppler sonogram shows minimal
vascularity within the tumor (arrows).

Sonography is an excellent study to confirm the presence of an

abdominal or pelvic mass and its site of origin. Neuroblastoma
appears either as a suprarenal or paraspinal mass (Fig. 38.2). The
tumors are echogenic. They may be homogeneous or heteroge-
neous, containing focal echogenic areas secondary to calcification
and hypoechoic areas, secondary to hemorrhage, necrosis, cystic
change, or some combination thereof (45–47). Doppler sonography
may show increased peripheral or central tumor vascularity.
In newborns, neuroblastomas may appear predominantly
cystic or anechoic, corresponding to hemorrhage, degenerative
change in the tumor or, in some cases, clusters of microcysts in
the tumor cells (Fig. 38.3) (48,49). Unfortunately, this imaging
appearance is non-specific and can mimic adrenal hematoma,
another common lesion of the neonate. Differentiation requires
demonstration of metastatic disease or positive laboratory stud-
ies (i.e., urinary catecholamine analysis) or serial sonographic
examination. The generally excellent prognosis of neuroblas-
toma in this age group makes observation rather than surgery a
reasonable alternative. Figure 38.3 Neonatal adrenal neuroblastoma. Longitudinal sonogram views
through the left upper quadrant of a one-week-old boy show a complex suprarenal
Computed Tomography mass (arrows), with hypoechoic areas, representing hemorrhage and cystic change.
After the presence of a mass has been confirmed by sonography or
plain radiography, patients undergo further imaging with either
computed tomography (CT) or magnetic resonance (MR) imaging Magnetic Resonance Imaging
to determine the extent of disease and guide staging. On CT, neu- On MR imaging, neuroblastoma appears as an extrarenal or
roblastoma appears as a homogeneous or heterogeneous soft- paraspinal mass which is iso-, hypo-, or hyperintense to surround-
tissue mass in a suprarenal or paraspinal location (Figs. 38.4 and ing soft tissues on T1-weighted spin-echo images and hyperin-
38.5) (44,49–51). The tumor enhances less than that of surround- tense on fat-suppressed T2-weighted or STIR sequences (52,53).
ing tissues after administration of IV contrast material. At CT, The margins may be smooth, irregular, or lobulated. Heterogene-
approximately 85% of abdominal and 50% of thoracic neuroblas- ity is common due to hemorrhage, necrosis, or calcification.
tomas demonstrate calcification (Fig. 38.6). Hemorrhage results in variable signal intensity, dependent on the

927
 pediatrics

(A)
(A)

(B)

(B)
Figure 38.4 Adrenal neuroblastoma. (A) Axial CT and (B) coronal reformation in
a three-year-old girl shows a large soft-tissue mass (arrows) with calcifications in
the right suprarenal area. The tumor displaces the right kidney (K) posteriorly and
inferiorly. There is no midline extension.
Figure 38.5 Sympathetic ganglion neuroblastoma. (A) Axial CT and (B) coronal
reformation in a two-year-old girl shows a soft-tissue mass (arrows) with coarse
calcifications in the paraspinal location. The tumor displaces the left kidney (K)
superiorly and laterally.

age of the blood. Necrotic foci usually appear hypointense on

T1-weighted sequences and hyperintense on T2-weighted
sequences, while tumor calcification has low signal intensity on
both pulse sequences. Most neuroblastomas enhance after admin-
istration of IV gadolinium chelate agents (Fig. 38.7).

Additional Findings of Primary Abdominal Tumors

Adrenal masses commonly displace the kidney inferiorly and
laterally (Fig. 38.4). Neuroblastomas originating from ganglion
cells displace the kidney superiorly and laterally (Fig. 38.5).
Occasionally, the kidney is displaced anteriorly and medially.
Aggressive neuroblastoma may invade the kidney and simulate
Wilms’ tumor (54,55). Renal atrophy can be the result of infarc-
tion due to encasement or compression of the renal vessels by Figure 38.6 Calcified thoracic neuroblastoma, eight-month-old girl. Coronal CT
the primary tumor, surgical trauma, chemotherapy, or radiation shows a well circumscribed mass in the right paraspinal region (white arrows) with
therapy. calcification. The tumor invades the spinal canal (black arrow).

928
 neuroblastoma

(A) (B)

(C)

Figure 38.7 Thoracic neuroblastoma, 14-month-old girl. (A) Coronal T1-weighted MR image of the chest demonstrates a large left paraspinal neuroblastoma that is
isointense with soft tissues. (B) On the fat-suppressed T2-weighted MR image, the tumor is hyperintense compared with subcutaneous fat. (C) Heterogeneous enhance-
ment is noted on the fat-suppressed T1-weighted MR image following administration of gadolinium chelate.

Additional Findings of Extra-abdominal Neuroblastomas

Pelvic Neuroblastoma
Pelvic tumors are typically presacral in location and are situated
behind the rectum and bladder. Erosion of the sacrum and bony
pelvis and extension of tumor into the lateral pelvic sidewalls,
sacral foramina, and sciatic notches may be commonly observed
(Fig. 38.8).

Thoracic Neuroblastoma
Thoracic neuroblastoma is almost always paravertebral and may
be associated with rib and vertebral body erosion and scoliosis.

Cervical Neuroblastoma
The mass seen in cervical neuroblastoma is usually well demar-
cated in the parapharyngeal space, displacing the carotid and
jugular anteriorly (Fig. 38.9) (56–59). Extension through the Figure 38.8 Pelvic neuroblastoma. CT in a two-year-old boy shows a presacral mass
skull base into the infratemporal fossa may be seen on CT and (black arrows) displacing the rectum (R) and bladder (B) anteriorly. The tumor
MR imaging. invades the obturator muscles bilaterally and the spinal canal (white arrow).

929
 pediatrics
Figure 38.9 Cervical neuroblastoma in a one-year-old girl with neck swelling.
Axial proton-density MR image shows a large right neck mass (M) surrounds the
common carotid artery (arrow) and extends into the right parapharyngeal space
(arrowheads). The right internal jugular vein is compressed and not seen. Source:
From Ref. 59.
Key Points: Primary Neuroblastoma, Imaging
Characteristics
■ Ultrasonography is used predominantly to confirm the pres-
ence of a mass lesion; CT and MR imaging are used to stage
the disease
■ In newborns, neuroblastomas are often cystic
■ On CT approximately 85% of abdominal tumors and 50% of
thoracic tumors show calcification
■ Most neuroblastomas enhance on CT and MR imaging after
administration of IV contrast material
■ Aggressive neuroblastomas may invade the kidney and
simulate Wilms’ tumor
■ Pelvic tumors are usually presacral and thoracic tumors are
almost always paravertebral in location
Local Disease Extent: Imaging Characteristics
The presence or absence of midline extension, vascular encase-
ment, regional lymph node enlargement, and intraspinal exten-
sion need to be determined since these factors can affect surgical
planning, staging, and prognosis.
Midline extension is defined as tumor extending to or beyond
the pedicle contralateral to the primary tumor. Midline extension
is important because it alters staging and upgrades the disease to
Stage 3 (Fig. 38.10).
Vascular encasement is defined as tumor surrounding at
least three-fourths of the circumference of one or more major
abdominal arteries or veins, including the aorta, superior
mesenteric artery and vein, inferior vena cava, or right or left
renal artery and vein (Fig. 38.11). Vascular encasement can be
930
Figure 38.10 Midline extension. Coronal CT shows a large mass with calcification
arising in the right suprarenal area and crossing the midline (arrows).
a contraindication to total surgical resection because of the
risk of loss of vital structures or significant postoperative
morbidity. Complications have been reported in 5% to 25% of
patients with neuroblastoma related to surgical resection of
the primary abdominal tumor at diagnosis (60). Commonly
encountered complications related to vascular encasement
include nephrectomy, operative hemorrhage, and injury to
renal or mesenteric vessels.
Lymph node involvement is defined as discrete masses separate
from the main tumor mass. The extent of nodal disease is impor-
tant because it alters stage. Ipsilateral nodes correspond to a Stage
2 disease. Contralateral nodal disease indicates Stage 3 disease
(Fig. 38.12).
Intraspinal extension of neuroblastoma is defined as a mass
within the spinal canal (with or without cord displacement) that
is contiguous with the main tumor mass (Fig. 38.13) (61).
Intraspinal extension of neuroblastoma associated with spinal
symptoms requires either urgent treatment with chemotherapy
and steroids or a laminectomy alone or in combination with
radiation therapy to reduce cord compression prior to tumor
resection or debulking.
Ultrasonography has limited value in demonstrating involve-
ment of retroperitoneal and retrocrural nodes and extension
into the spinal canal. The choice of CT versus MR imaging for
determining local extent has been the subject of continuing
debate. Unfortunately, there are no large prospective series that
compare MR imaging and CT in neuroblastoma for staging
accuracy. CT with contrast enhancement can reliably demon-
strate the primary tumor and it is superior to MR imaging in
demonstrating calcification. A prospective multicenter study of
children with newly diagnosed neuroblastoma found that overall,
 neuroblastoma
(A)
(B)
Figure 38.11 Midline extension. (A) CT in a 12-month-old boy shows a mass arising
in the left adrenal gland, crossing the midline and encasing the aorta (A), superior
mesenteric artery (white arrow), and hepatic artery (black arrow). (B) At a lower
level, the tumor encases the left renal artery (arrowhead) and the aorta (A). The right
renal artery and vein (open arrow) and the left kidney are pushed laterally. The renal
arteries may be sufficiently compressed to cause hypertension. Extensive vascular
encasement can be a contraindication to early surgical resection.
Figure 38.12 Contralateral lymphadenopathy. CT in three-year-old boy shows a
left adrenal tumor (T) with calcification and an enlarged contralateral necrotic
lymph node (arrow) displacing the inferior vena cava anteriorly (C).
(A)
(B)
Figure 38.13 Intraspinal extension. (A) Coronal T1-weighted gadolinium-enhanced
MR image in an eight-month-old girl (same patient as Fig. 38.6) shows an enhancing
mass within the right lateral aspect of the chest cavity with tumor extension through
the neural foramina (arrow) into the spinal canal of the upper thoracic spine. (B) CT
in a two-year-old girl shows a left paravertebral tumor (T) with neural foraminal inva-
sion (arrow), with marked thecal sac (open arrow) displacement toward the right.
CT and MR had statistically similar, but relatively poor perfor-
mance for assessing features of local disease (62). However a
major limitation of the study was that it was designed to evaluate
distant not local disease and the prevalence of local disease was
relatively low. The positive predictive values (PPV) and negative
predictive values (NPV) for CT in detection of tumor extension
across the midline were 73% and 83%, respectively. For MR
imaging, corresponding PPV and NPV were 81% and 79%. PPV
and NPV for CT in detection of local nodes were 20% and 95%,
respectively. For MR imaging, corresponding PPV and NPV
were 19% and 99%, respectively.
931
 pediatrics

Key Points: Local Disease Extent

■ Midline tumor extension, vascular encasement, regional
lymph node enlargement, and intraspinal extension are
important features of local tumor spread
■ Midline extension is defined as tumor extending to or beyond
the pedicle contralateral to the primary tumor. This feature
upstages the tumor
■ Vascular encasement and intraspinal extension affect surgical
management but do not affect stage
■ Lymphadenopathy is defined as a tumor mass separate from
the primary mass and upstages disease
■ Intraspinal tumor is defined as a mass within the spinal canal
(with or without cord displacement) that is contiguous with
the main tumor mass
■ CT and MR imaging are both useful for determining extent of
local tumor spread and appear to provide similar accuracy Figure 38.14 Hepatic metastases. Five-year-old boy with Stage 4 neuroblastoma
who presented with an enlarging abdomen and worsening abdominal pain. CT
shows multiple low attenuation hepatic metastases.
Distant Disease: Imaging Characteristics
Detection of distant metastases upstages the tumor to a Stage 4 or
4S. Neuroblastoma metastasizes to liver, distant nodes, cortical
bone, and bone marrow. Lung and intracranial metastases are rare.

Hepatic Metastases
Hepatic metastases occur in 5% to 10% of children with neuro-
blastoma. Two common patterns of hepatic metastases have been
described; focal metastases, typically seen in older children, and
diffuse infiltration, usually occurring in infants with Stage 4S dis-
ease. Focal lesions tend to be well-defined and they may be single or
multiple (Fig. 38.14). They are equally well recognized on CT and
MR imaging. Diffuse infiltration can be difficult to detect on CT
and may be easier to recognize on MR imaging, especially on
T2-weighted sequences, where hyperintense masses can be seen
throughout the liver.

Distant Nodal Metastases

Distant nodes are those that are outside the cavity of origin of (A)
the tumor. Evaluation of the chest, abdomen, and pelvis,
regardless of the site of primary disease, is performed in all
patients with neuroblastomas to increase detection of distant
nodal involvement. A common site of distant nodal spread is
the supraclavicular region (63).

Skeletal and Bone Marrow Metastases

Skeletal metastases occur in 50% to 60% of patients at diagnosis,
mostly in patients older than one year of age. These can involve
cortical bone or bone marrow.

Plain Radiographs
While plain radiographs are not routinely used in the detection of
bony metastases, the initial presentation in some patients may be
bone pain, prompting skeletal radiographs. Thus, recognition of
the conventional radiographic features is important. Skull radio- (B)
graphic findings include sutural diastasis secondary to dural
Figure 38.15 Metastatic neuroblastoma. (A) Lateral skull radiograph shows diffuse
involvement, focal lytic defects, periosteal reaction (“sunburst” poorly defined lytic lucencies throughout the calvarium, consistent with diffuse
appearance), and foci of sclerosis (Fig. 38.15). Metastatic disease metastatic disease. (B) Frontal radiograph in another patient shows cranial sutural
to long bones may manifest as metaphyseal lucencies, periosteal widening due to dural metastases.

932
 neuroblastoma

(A) (B)

Figure 38.16 Osseous metastases. (A) Frontal radiograph of the left distal femur in a two-year-old boy shows multiple lytic areas in the femoral metaphysis. (B) Frontal
radiograph of the left humerus shows metaphyseal lucencies and a permeative appearance in the diaphysis, representing diffuse marrow infiltration.

reaction, or sclerotic foci (Fig. 38.16). In both appendicular and

axial skeleton, there may be a generalized reduction in bone den-
sity and a mottled trabecular or permeative pattern due to diffuse
marrow infiltration (Fig. 38.16B).

Computed Tomography
CT is not a primary study for confirming skeletal metastases.
However, metastases may be seen on CT when the primary tumor
is evaluated and in some instances, there may be unsuspected
findings on scans obtained for evaluation of other clinical prob-
lems. Metastases are most frequently destructive lesions (Fig.
38.17) but occasionally sclerotic lesions may be seen. Associated
findings include periosteal new bone and a soft-tissue mass.

Skeletal Scintigraphy
Scintigraphy with 99mTc-dimercaptophosphonate (MDP) is
known to be superior to the conventional skeletal survey in the
detection of cortical bone metastases. MDP is taken up by cells
active in bone metabolism. The sensitivity of 99mTc-MDP is about
90%, compared to a sensitivity of 35% to 70% for the radiographic
skeletal survey (64,65). Metastases appear either as focal areas of
increased radiopharmaceutical accumulation (Fig. 38.18) or Figure 38.17 Osseous metastasis. CT in a two-year-old boy shows a destructive
rarely, as photopenic or cold lesions. Asymmetrical metaphyseal lesion in the left femoral metaphysis (arrow).
uptake is typical. Common sites of metastases are the skull, facial
bones, orbits, ribs, and vertebral bodies. Increased tracer activity
can also be seen in the primary tumor, but this has no clinical to 131I MIBG because of lower radiation dose to the patient, better
significance. image resolution, greater sensitivity for disease detection, and
shorter time to scanning following tracer administration. In
MIBG Scintigraphy patients with neuroblastoma, abnormal activity can be seen in
Metaiodobenzylguanidine (MIBG) has become the study of choice the primary tumor and in bone, bone marrow, and soft tissue
for imaging skeletal metastases (66–72). MIBG, an analogue of metastases (Fig. 38.19). The sensitivity of 123I MIBG for tumor
catecholamine precursors, is taken up by catecholamine-producing detection in bone, bone marrow, and lymph nodes is 90% to
tumors. MIBG can be labeled with 123I or 131I. 123I MIBG is preferable 95% (69,71). Absence of MIBG activity has been reported in more

933
 pediatrics

mature tumors and also in very poorly differentiated tumors.

Causes of false-negative MIBG scans include non-visualization of
lesions due to intense radiotracer uptake in normal liver, myocar-
dium, salivary glands, intestines, and thyroid (44). Several rare
tumors may also show MIBG uptake, potentially resulting in false-
positive scans. These include neuroendocrine tumors, pancreatico-
blastomas, neuro-ectodermal tumors, pheochromocytomas,
carcinoid tumors, and medullary thyroid carcinomas (69). How-
ever, these lesions are extremely uncommon in the pediatric pop-
ulation and MIBG activity in a child is virtually specific for
neuroblastoma (69,71,73). The specificity of MIBG for neuroblas-
toma in the appropriate clinical context is greater than 95% (74).

Magnetic Resonance Imaging

MR imaging can be performed as a dedicated study for evalua-
tion of localized bone pain or as whole-body imaging for detec-
tion of distant metastases (62,75–82). Typically, metastatic
disease produces low signal intensity on T1-weighted sequences
P and high signal intensity on T2-weighted and fat suppressed
A o
n images (Fig. 38.20). The sensitivity of MR imaging for detect-
s
t t ing marrow involvement is between 85% and 100% (62,77,79,82).
MR imaging can show abnormalities not detected by bone
Figure 38.18 Metastatic neuroblastoma, bone scintigraphy. Anterior and posterior marrow biopsy (62).
bone scintigrams after injection of Tc-99m MDP in a three-year-old girl show
Two morphologic patterns of bone marrow involvement have
abnormal osseous uptake in multiple vertebral bodies, several ribs, right humeral
head and proximal diaphysis, and bilateral proximal femoral and tibial metaphyses. been described: focal and diffuse (82). The diffuse form of marrow
infiltration is invariably associated with cortical destruction (84%
of cases) and commonly (>75% of cases) leaves residual signal

L Post R
R Ant L

R Ant L L Post R

R Ant L L Post R

(A) (B)
Figure 38.19 Metastatic neuroblastoma, I-123 MIBG. (A) Anterior and posterior scintigrams obtained 24 hours after injection of I-123 MIBG demonstrate increased
uptake in a right posterior mediastinal neuroblastoma (arrows). There is expected I-123 MIBG activity in the salivary glands, liver, myocardium, and urinary bladder.
Normal skeleton/marrow does not demonstrate MIBG activity. (B) I-123 MIBG in another patient shows increased tracer uptake throughout the skeleton consistent with
diffuse osseous/marrow metastases. There also is uptake in the left adrenal primary (arrow).

934
 neuroblastoma
Figure 38.20 In this patient with metastatic neuroblastoma, coronal fat-suppressed
T2-weighted MR image shows abnormally bright signal indicative of diffuse
marrow infiltration. By comparison, normal red marrow would have signal intensity
similar to that of muscle on fat-suppressed images.
abnormalities after chemotherapy. The focal form of disease is
rarely associated with cortical involvement (16% of cases), but if
present it virtually always disappears after chemotherapy.
Indium-111 Pentetreotide Scintigraphy
Indium-111 pentetreotide (octreotide), a radiolabeled somatosta-
tin analogue, has an affinity for binding to the somatostatin recep-
tors in neuroblastomas (Fig. 38.21) (83–85). Scans are more
frequently positive in undifferentiated tumors and in tumors
associated with elevated urinary catecholamines. Pentetreotide
may be picked up in MIBG-negative tumors (86,87) and vice
versa. The sensitivity of pentetreotide for detection of the primary
tumor varies from 65% to 100% (88–90). In small series, patients
with receptor-positive tumors had 100% one-year survival, while
those with receptor-negative tumors had less than 60% one-year
survival (88,89). The usefulness of octreotide for staging distant
disease is still to be determined.
Positron Emission Tomography
In contrast to the dependence primarily on anatomic imaging
features, positron emission tomography (PET) exploits the meta-
bolic characteristics of tissue for the detection of disease. The
metabolic activity of neuroblastoma is usually evaluated by
utilizing 2-[fluorine-2418]-fluoro-2-deoxy-D-glucose (FDG)
(Fig. 38.22) (91–93), or less commonly 11Chydioxyephedrine
(HED) (94). FDG uptake is directly proportional to tumor burden
Figure 38.21 Metastatic neuroblastoma, octreotide scan. Posterior bone scintigram
(left panel) and Indium-111 pentetreotide scintigram (right panel) demonstrate
multifocal osseous metastases from neuroblastoma. Normal activity seen in the
spleen, kidneys, and liver on the octreotide study.
and to tumor-cell proliferation. Most neuroblastomas and their
metastases avidly concentrate FDG prior to chemotherapy or
radiation therapy. The uptake after therapy is variable. These
agents may also be useful for imaging tumors that do not concen-
trate MIBG. A limitation of PET scanning is the poor visualiza-
tion of lesions in the cranial vault, because of the normally high
physiologic FDG activity in the brain. Causes of false-positive
scans include physiologic uptake in bowel, thymus, urinary tract,
normal adrenal gland, hyperactive bone marrow, and sites of
inflammation.
Intracranial Metastases
Intracranial involvement is generally confined to the dura and
leptomeninges. Parenchymal disease is usually attributed to direct
extension from adjacent skull or dural disease (95,96). Isolated
parenchymal brain metastases from extracranial neuroblastoma
without associated calvarial or dural involvement are rare. When
present these lesions are generally solid and show heterogeneous
contrast enhancement on CT and MR imaging; on occasion, hem-
orrhagic and cystic metastases may also been seen (97). Cerebral
metastatic disease is usually seen at the time of relapse, rather than
at the time of diagnosis.
Metastases to the skull and orbit have been reported in up to
25% of cases of neuroblastoma, often being the first evidence of
the primary tumor (98). CT or MR imaging can show sutural
widening, calvarial new bone formation, and tumor extension
into the soft tissues of the scalp or through the inner table of the
935
 pediatrics

(A)

(B)

Figure 38.22 PET imaging with F-18 fluorodeoxyglucose (FDG). (A) Metastatic neuroblastoma in an eight-year-old boy. FDG-PET with corrected attenuation image
(left), unenhanced CT (middle) and CT fusion image (right) show focus of increased FDG uptake within the right internal iliac chain, consistent with metastatic disease.
(B) In another patient FDG-PET with corrected attenuation image (left), unenhanced CT (middle) and CT fusion image (right) show increased FDG uptake within a left
adrenal neuroblastoma, representing the primary tumor. There was no evidence of metastatic disease.

Figure 38.24 Thoracic metastases. CT shows multiple pulmonary metastases.

Figure 38.23 Calvarial metastases. CT shows widening of the coronal sutures

(arrows), irregular calvarial new bone formation, and epidural spread of tumor
(arrowheads). Source: From Ref. 99.
skull (Fig. 38.23). When there is sphenoid bone involvement, the
tumor can extend into the orbits and cause proptosis.
Thoracic Metastases
Pulmonary and/or pleural involvement are rare initial com-
plications of neuroblastoma, occurring in less than 3% of
children (54). More commonly, thoracic disease is seen at the
time of relapse. Pulmonary involvement can result from
hematogenous or lymphatic spread or from direct extension.
On CT, parenchymal metastases appear as either single or
multiple small nodules (Fig. 38.24) or large parenchymal
masses. Pleural disease may manifest as either an effusion or
as pleural masses.

936
 neuroblastoma

recommended at the end of treatment, before and after surgical

Key Points: Distant Disease
■ Distant metastases upstages disease to Stage 4 or 4S
■ Hepatic metastases occur in up to 5% to 10% of children
■ Distant nodal metastases are defined as those occurring
outside the body cavity of the origin of the primary tumor
■ Supraclavicular node involvement is a common site of nodal
spread
■ Skeletal metastases occur in 50% to 60% of children at
diagnosis
■ MIBG 123I is the method of choice for detecting skeletal
metastases and distant metastases can also be identified in
the primary tumor, bone marrow, and soft tissue sites
■ MR imaging is useful for assessing localized skeletal pain or
as a screening study for skeletal metastases
■ The role of Indium-111 pentetreotide (octreotide) in the
detection of metastases has not yet been established
■ Most primary neuroblastomas and their metastases take up
FDG avidly on PET scanning
■ Intracranial metastases are usually the result of direct spread
from skull or dural lesions
■ Pulmonary disease is most frequently seen at the time of
relapse
procedures, before stem cell transplantation, and as clinically
indicated (1).
Key Points: Follow-up
■ Measurement of response requires monitoring change in the
primary tumor and in the metastases
■ The International Neuroblastoma Response Criteria (1993)
require that the primary tumor, lymph nodes, and liver
metastases are monitored using CT and/or MR imaging, and
distant metastases are assessed using MIBG, Tc-99m bone
scans, and bone marrow biopsies
■ Complete response indicates disappearance of all disease
sites. A very good partial response indicates a 90% to 99%
volume reduction of primary tumor and resolution of all
metastases
■ Response is assessed at approximately four months after
initiation of chemotherapy
■ Further evaluation is recommended at the end of treatment,
before and after surgical procedures, before stem cell
transplantation, and as clinically indicated

RESPONSE TO TREATMENT
Summary
■ Neuroblastoma is the most common extracranial malignant
The International Neuroblastoma Response Criteria (INRC) were
tumor of childhood, accounting for 8% to 10% of all child-
established in 1988 and subsequently modified in 1993 (38,39).
hood cancers
Response to treatment consists of response of the primary tumor
■ Serum markets (lactate dehydrogenase, ferritin, and neuron-
and also of the metastatic sites. The INRC requires that the pri-
specific enolases) provide important prognostic information.
mary tumor lymph nodes, and liver metastases be evaluated by
Urinary catecholamine levels are not predictive of outcome
CT and/or MR imaging and that distant metastases be evaluated
■ The majority of children present with clinical symptoms or
using MIBG scans, Tc-99m bone scans, and bilateral iliac crest
signs, most commonly an abdominal mass or abdominal pain
marrow aspirates and trephine biopsies. Because of the difficulties
■ Paraneoplastic syndromes are associated with both local and
in making accurate measurements of a tumor with an irregular
disseminated disease
shape, volume (three-dimensions rather than the product of the
■ The International Neuroblastoma Staging System is now the
two largest diameters) has been suggested to assess response.
most widely used for staging
A complete response (CR) indicates complete disappearance of
■ Treatment is based on an assessment of risk and includes
all primary and metastatic disease. A very good partial response
surgery, combination chemotherapy, and radiotherapy
(VGPR) indicates a 90% to 99% volume reduction in the primary
■ There are no large prospective series comparing CT with MR
tumor with resolution of pre-existing metastatic disease and no
imaging for local staging accuracy. However, MR imaging is
new bone lesions. The only exception to this is that there can be
the preferred technique for showing intraspinal extension
residual abnormality on technetium bone scintigraphy attribut-
■ Ultrasonography is an excellent screening tool for detection
able to incomplete healing of the bone at sites of previous metas-
of abdominal tumor, but it is seldom used to demonstrate
tases. The MIBG scan should be negative at all metastatic sites. A
the full extent of a large tumor
partial response (PR) indicates a 50% to 90% reduction in both
■ Imaging is vital in the detection of distant metastases. These
the primary tumor and all measurable metastatic sites. No
are chiefly to bone and/or bone marrow, occurring in over
response (NR) indicates a less than 50% reduction of some or all
half the children with neuroblastoma
measurable lesions, but no increase of greater than 25% in any
■ Tc99m-labelled MDP and MIBG remain the techniques of
existing lesion and no new lesions. Progressive disease (PD) indi-
choice for the detection of bone metastases
cates the presence of a new lesion; increase of any measurable
■ The International Neuroblastoma Response Criteria (1993)
lesion by greater than 25%; or conversion of marrow from nega-
require that the volume of the primary tumor, the liver and
tive to positive (38,39).
lymph nodes are evaluated by CT and/or MR imaging, and
Most tumors that are going to respond to treatment do so by
that metastases are evaluated with MIBG scans and Tc99m
three to four months and therefore, it is recommended that
MDP bone scans., and that the bone marrow is assessed by
evaluations for response be performed at approximately four
bilateral iliac crest marrow aspirates and trephine biopsies
months from the initiation of chemotherapy. Further evaluation is

937
 pediatrics
REFERENCES
1. Brodeur GM, Maris JM. Neuroblastoma. In: Pizzo PA, Poplack
DG, eds. Principles and Practice of Pediatric Oncology, 5th edn.
Philadelphia: Lippincott Williams & Wilkins, 2006; 933–70.
2. Gurney JG, Davis, Severson RK, Fang JY, Ross JA, Robison LL.
Trends in cancer incidence among children in the U.S. Cancer
1996; 78: 532–41.
3. Lonergan GJ, Schwab CM, Suarez ES, Carlson CL. Neuroblas-
toma, ganglioneuroblastoma and ganglioneuroma: radiologic-
pathologic correlation. Radiographics 2002; 22: 911–34.
4. Spix C, Pastore G, Sankila R, Stiller CA, Steliarova-Foucher E.
Neuroblastoma incidence and survival in European children
(1978-1997): Report from the Automatic Childhood Cancer
Information System project. Eur J Cancer 2006; 42: 2081–91.
5. Maris JM, Weiss MJ, Mosse Y, et al. Evidence for a hereditary
neuroblastoma predisposition locus at chromosome 16p12-13.
Cancer Res 2002; 62: 6651–8.
6. Maris JM, Matthay KK. Molecular biology of neuroblastoma.
J Clin Oncol 1999; 17: 2264–79.
7. Berthold F, Trechow R, Utsch S, Zieschang J. Prognostic fac-
tors in metastatic neuroblastoma. A multivariate analysis of
182 cases. Am J Pediatr Hematol Oncol 1992; 14: 207–15.
8. Zeltzer PM, Marangos PJ, Evans AE, Schneider SL. Serum
neuron-specific enolase in children with neuroblastoma:
relationship to stage and disease course. Cancer 1986; 57:
1230–4.
9. Bordow SB, Norris MD, Haber PS, Marshall GM, Haber M.
Prognostic significance of MYCN oncogene expression in
childhood neuroblastoma. J Clin Oncol 1998; 16: 3286–94.
10. Brodeur GM, Seeger RC, Schwab M, Varmus HE, Bishop JM.
Amplification of N-myc in untreated human neuroblastomas
correlates with advanced disease stage. Science 1984; 224:
1121–4.
11. Brodeur GM. Neuroblastoma: biologic insights into a clinical
enigma. Nat Rev Cancer 2003; 3: 203–16.
12. Look AT, Hayes FA, Shuster JJ, et al. Clinical relevance of
tumour cell ploidy and N-myc gene amplification in child-
hood neuroblastoma: A Pediatric Oncology Group study.
J Clin Oncol 1991; 9: 581–91.
13. Attiyeh EF, London WB, Mosse YP, et al. Chromosome 1p and
11q deletions and outcome in neuroblastoma. N Engl J Med
2005; 353: 2243–53.
14. Caron H, van Sluis P, de Kraker J, et al. Allelic loss of chromo-
some 1p as a predictor of unfavourable outcome in patients
with neuroblastoma. N Engl J Med 1996; 334: 225–30.
15. Maris JM, White PS, Beltinger CP, et al. Significance of chro-
mosome 1p loss of heterozygosity in neuroblastoma. Cancer
Res 1995; 55: 4664–9.
16. Joshi VV, Cantor AB, Altshuler G, et al. Recommendations for
modification of terminology of neuroblastic tumours and
prognostic significance of Shimada classification. A clinico-
pathologic study of 213 cases from the Pediatric Oncology
Group. Cancer 1992; 69: 2183–96.
17. Shimada H, Ambros IM, Dehner LP, et al The International
Neuroblastoma Pathology Classification (the Shimada system).
Cancer 1999; 86: 364–72.
938
18. Shimada H, Stram DO, Chatten J, et al. Identification of sub-
sets of neuroblastomas by combined histopathologic and
N-myc analysis. J Natl Cancer Inst 1995; 87: 1470–6.
19. Nakagawara A, Arima-Nakagawara M, Scavarda NJ, et al.
Association between high levels of expression of the TRK gene
and favourable outcome in human neuroblastoma. New Engl
J Med 1993; 328: 847–54.
20. Lukens JN. Neuroblastoma in the neonate. Semin Perinatol
1999; 22: 263–73.
21. Granata C, Fagnani AM, Gambini C, et al. Features and out-
come of neuroblastoma detected before birth. J Pediatr Surg
2000; 35: 88–91.
22. Ho PT, Estroff JA, Kozakewich H, et al. Prenatal detection of
neuroblastoma: a ten-year experience from the Dana-Farber
Cancer Institute and Children’s Hospital. Pediatrics 1993; 92:
358–64.
23. Erttmann R, Tafese T, Berthold F, et al. 10 years’ neuroblas-
toma screening in Europe: preliminary results of a clinical and
biological review from the Study Group for Evaluation of
Neuroblastoma Screening in Europe (SENSE). Eur J Cancer
1998; 34: 1391–7.
24. Nishi M, Miyake H, Takeda T, et al. Mass screening of neuro-
blastoma in Sapporo City, Japan. Am J Pediatr Hematol Oncol
1992; 14: 327–31.
25. Nishihira H, Toyoda Y, Tanaka Y, et al: Natural course of neu-
roblastoma detected by mass screening: a 5-year prospective
study at a single institution. J Clin Oncol 2000; 18: 3012–17.
26. Woods WG, Tuchman M, Robison LL, et al. Screening for
neuroblastoma is ineffective in reducing the incidence of
unfavourable advanced stage disease in older children. Eur J
Cancer 1997; 33: 2106–12.
27. Woods WG, Tuchman M, Robison LL, et al. A population-
based study of the usefulness of screening for neuroblastoma.
Lancet 1996; 348: 1682–7.
28. Yamamoto K, Hayashi Y, Hanada R, et al. Mass screening and
age-specific incidence of neuroblastoma in Saitame Prefec-
ture, Japan. J Clin Oncol 1995; 13: 2033–8.
29. Abramson SJ. Adrenal neoplasms in children. Radiol Clin
North Am 1997; 35: 1415–53.
30. Cruccetti A, Kiely EM, Spitz L, et al. Pelvic neuroblastoma:
low mortality and high morbidity. J Pediatr Surg 2000; 35:
724–8.
31. Abramson SJ, Berdon WE, Ruzal–Shapiro C, Stolar C, Garvin J.
Cervical neuroblastoma in eleven infants – a tumour with
favourable prognosis. Clinical and radiologic (US, CT, MRI)
findings. Pediatr Radiol 1993; 23: 253–7.
32. Applegate K, Connolly LP, Treves ST. Neuroblastoma present-
ing clinically as hip osteomyelitis: a “signature” diagnosis on
skeletal scintigraphy. Pediatr Radiol 1995; 25: S93–S96.
33. Koh PS, Raffensperger JG, Berry S, et al. Long-term outcome
in children with opsoclonus-myoclonus and ataxia and coin-
cident neuroblastoma. J Pediatr 1994; 125: 712–16.
34. Mitchell WG, Snodgrass SR. Opsoclonus-ataxia due to child-
hood neural crest tumours: a chronic neurologic syndrome.
J Child Neurol 1990; 5: 153–8.
35. Tiedemann K, Pritchard J, Long R, Bloom SR. Intractable diar-
rhoea in a patient with vasoactive intestinal peptide-secreting
 neuroblastoma
neuroblastoma. Attempted control by somatostatin. Eur
J Pediatr 1981; 137: 217–19.
36. Mendelsohn G, Eggleston JC, Olson JL, et al. Vasoactive intes-
tinal peptide and its relationship to ganglion cell differentia-
tion in neuroblastoma. Lab Invest 1979; 41: 144–9.
37. Hoffer FA, Chung T, Diller L, et al. Percutaneous biopsy for
prognostic testing of neuroblastoma. Radiology 1996; 200:
213–16.
38. Brodeur GM, Seeger RC, Barrett A, et al. International criteria
for diagnosis, staging and response to treatment in patients
with neuroblastoma. J Clin Oncol 1988; 6: 1874–81.
39. Brodeur GM, Pritchard J, Berthold F, et al. Revisions of the
international criteria for neuroblastoma diagnosis, staging
and response to treatment. J Clin Oncol 1993; 11: 1466–77.
40. Perez CA, Matthay KK, Atkinson JB, et al. Biologic variables in
the outcome of stages I and II neuroblastoma treated with
surgery as primary therapy: a children’s cancer group study.
J Clin Oncol 2000; 18: 18–26.
41. Weinstein JL, Katzenstein HM, Cohn SL. Advances in the
diagnosis and treatment of neuroblastoma. Oncologist 2003;
8: 278–92.
42. Matthay KK, Villablanca JG, Seeger RC, et al. Treatment of
high-risk neuroblastoma with intensive chemotherapy,
radiotherapy, autologous bone marrow transplantation, and
13-cis retinoic acid. N Engl J Med 1999; 341: 1165–73.
43. Pashankar FD, O’Dorisio MS, Menda Y. MIBG and somatosta-
tin receptor analogs in children: current concepts on diagnostic
and therapeutic use. J Nucl Med 2005; 46: 55S–61S.
44. Kushner BH. Neuroblastoma: a disease requiring a multitude
of imaging studies. J Nucl Med 2004; 45: 1172–88.
45. Berdon WE, Ruzal-Shapiro C, Abramson SJ, Garvin J. The
diagnosis of abdominal neuroblastoma: relative roles of ultra-
sonography, CT and MRI. Urol Radiol 1992; 14: 252–62.
46. Siegel MJ. Adrenal glands, pancreas and retroperitoneum. In:
Siegel MJ, ed. Pediatric Sonography, 3rd edn. Philadelphia:
Lippincott Williams & Wilkins, 2002; 476–527.
47. Cassady C, Winters WD. Bilateral cystic neuroblastoma: imag-
ing features and differential diagnosis. Pediatr Radiol 1997; 27:
758–9.
48. Hugosson C, Nyman R, Jorulf H, et al. Imaging of abdominal
neuroblastoma in children. Acta Radiol 1999; 40: 534–42.
49. Teoh SK, Whitman GJ, Chew FS. Neonatal neuroblastoma.
AJR Am J Roentgenol 1997; 168: 54.
50. Siegel MJ. Adrenal glands, pancreas, and other retroperitoneal
structures. In: Siegel MJ, ed. Pediatric Body CT, 2nd edn.
Philadelphia: Lippincott Williams & Wilkins, 2008; 323–60.
55. Rosenfield NS, Leonidas JC, Barwick KW. Aggressive neuro-
blastoma simulating Wilms tumour. Radiology 1988; 166:
165–7.
56. Casselman JW, Smet MH, Van Damme B, Lemahieu SF. Pri-
mary cervical neuroblastoma: CT and MR findings. J Comput
Assist Tomogr 1988; 12: 684–6.
57. Herman TE, Siegel MJ. Cervical neuroblastoma, stage IV-S.
J Perinatol 2001; 21: 470–2.
58. Goldberg RM, Keller IA, Schonfeld SM, Mezrich RS, Rosenfeld
DL. Intracranial route of a cervical neuroblastoma through
skull base foramina. Pediatr Radiol 1996; 26: 715–16.
59. Siegel MJ, Coley BD. Neck. In: Siegel MJ, Coley BD, eds. The
Core Curriculum: Pediatric Imaging. Philadelphia: Lippincott
Williams & Wilkins, 2006: 12.
60. Nitschke R, Smith EI, Shochat S, et al. Localized neuroblas-
toma treated by surgery: a Pediatric Oncology Group study.
J Clin Oncol 1988; 6: 1271–9.
61. Siegel MJ, Jamroz GA, Glazer HS, Abramson CL. MR imaging
of intraspinal extension of neuroblastoma. J Comput Assist
Tomogr 1986; 10: 593–5.
62. Siegel MJ, Ishwaran H, Fletcher BD, et al. Staging of neuro-
blastoma by imaging: report of the Radiology Diagnostic
Oncology Group. Radiology 2002; 223: 168–75.
63. Abramson SJ, Berdon WE, Stolar C, Ruzal-Shapiro C, Garvin J.
Stage IVN neuroblastoma: MRI diagnosis of left supraclavicular
“Virchow’s” nodal spread. Pediatr Radiol 1996; 26: 717–19.
64. Heisel MA, Miller JH, Reid BS, Siegel SE. Radionuclide bone
scan in neuroblastoma. Pediatrics 1983; 71: 206–9.
65. Howman-Giles RB, Gilday DL, Ash JM. Radionuclide skeletal
survey in neuroblastoma. Radiology 1979; 131: 497–502.
66. Gelfand MJ. Meta-iodobenzylguanidine in children. Semin
Nucl Med 1993; 23: 231–42.
67. Gelfand MJ, Elgazzar AH, Kriss VM, Masters PR, Golsch GJ.
Iodine-123-MIBG SPECT versus planar imaging in children
with neural crest tumours. J Nucl Med 1994; 35: 1753–7.
68. Gordon I, Peters AM, Gutman A, et al. Skeletal assessment in
neuroblastoma. The pitfalls of iodine-123-MIBG scans. J Nucl
Med 1990; 31: 129–34.
69. Howman Giles R, Shaw PJ, Uren RF, Chung DK. Neuroblas-
toma and other neuroendocrine tumours. Semin Nucl Med
2007; 37: 286–302.
70. Parisi MT, Greene MK, Dykes TM, et al. Efficacy of metaiodo-
benzylguanidine as a scintigraphic agent for detection of neu-
roblastoma. Invest Radiol 1992; 27: 768–73.
71. Paltiel HJ, Gelfand MJ, Elgazzar AH, et al. Neural crest tumours:
I-123 MIBG imaging in children. Pediatr Radiol 1994;