HEAD AND NECK MANAGEMENT

OF THE CANCER PATIENT

 Developments in Oncology

FJ Cleton and JWIM Simons, eds.: Genetic Origins of Tumour Cells. 90-247-2272-l.
J Aisner and P Chang, eds.: Cancer Treatment and Research. 90-247-2358-2.
BW Ongerboer de Visser, DA Bosch and WMH van Woerkom-Eykenboom, eds.: Neuro-
oncology: Clinical and Experimental Aspects. 90-247-2421-X.
K Hellmann, P Hilgard and S Eccles, eds.: Metastasis: Clinical and Experimental Aspects.
90-247-2424-4.
HF Seigler, ed.: Clinical Management of Melanoma. 90-247-2584-4.
P Correa and W Haenszel, eds.: Epidemiology of Cancer of the Digestive Tract. 90-247-2601-
8.
LA Liotta and IR Hart, eds.: Tumour Invasion and Metastasis. 90-247-2611-5.
J Banoczy, ed.: Oral Leukoplakia. 90-247-2655-7.
C Tijssen, M Halprin and L Endtz, eds.: Familial Brain Tumours. 90-247-2691-3.
FM Muggia, CW Young and SK Carter, eds.: Anthracycline Antibiotics in Cancer. 90-247-
2711-1.
BW Hancock, ed.: Assessment of Tumour Response. 90-247-2712-X.
DE Peterson and S Sonis, eds: Oral Complications of Cancer Chemotherapy.
0-89838-563-6.
R Mastrangelo, DG Poplack and R Ricardi, eds.: Central Nervous System Leukemia. Preven-
tion and Treatment. 0-89838-570-9.
A Polliack, ed.: Human Leukemias. Cytochemical and Ultrastructural Techniques in Diagno-
sis and Research. 0-89838-585-7.
W Davis, C Maltoni and S Tanneberger, eds.: The Control of Tumor Growth and its Biologi-
cal Bases. 0-89838-603-9.
APM Heintz, CT Griffiths and JB Trimbos, eds.: Surgery in Gynecological Oncology. 0-
89838-604-7.
MP Hacker, EB Douple and I Krakoff, eds.: Platinum Coordination Complexes in Cancer
Chemotherapy. 0-89838-619-5.
MJ van Zwieten. The Rat as Animal Model in Breast Cancer Research: A Histopathological
Study of Radiation- and Hormone-Induced Rat Mammary Tumors. 0-89838-624-l.
B Lowenberg and A Hogenbeck, eds.: Minimal Residual Disease in Acute Leukemia. 0-89838-
630-6.
I van der Waal and GB Snow, eds.: Oral Oncology. 0-89838-631-4.
BW Hancock and AM Ward, eds.: Immunological Aspects of Cancer. 0-89838-664-0.
KV Honn and BF Sloane, eds.: Hemostatic Mechanisms and Metastasis. 0-89838-667-5.
KR Harrap, W Davis and AN CaJvert, eds.: Cancer Chemotherapy and Selective Drug De-
velopment. 0-89838-673-X.
VD Velde, JH Comelis and PH Sugarbaker, eds.: Liver Metastasis. 0-89838-648-5.
DJ Ruiter, K Welvaart and S Ferrone, eds.: Cutaneous Melanoma and Precursor Lesions.
0-89838-689-6.
SB Howell, ed.: Intra-Arterial and Intracavitary Cancer Chemotherapy. 0-89838-691-8.
DL Kisner and JF Smyth, eds.: Interferon Alpha-2: Pre-Clinical and Clinical Evaluation.
0-89838-701-9.
P Furmanski,JC Hager and MA Rich, eds.: RNA Tumor Viruses, Oncogenes, Human Cancer
and AIDS: On the Frontiers of Understanding. 0-89838-703-5.
JE Talmadge, IJ Fidler and RK Oldham: Screening for Biological Response Modifiers:
Methods and Rationale. 0-89838-712-4.
JC Bottino, RW Opfell and FM Muggia, eds.: Liver Cancer. 0-89838-713-2.
PK Pattengale, RJ Lukes and CR Taylor, eds: Lymphoproliferative Diseases: Pathogenesis,
Diagnosis, Therapy. 0-89838-725-6.
F Cavalli, G Bonadonna and M Rozencweig, eds.: Malignant Lymphomas and Hodgkin's
Disease. 0-89838-727-2.
L Baker, F Valcriote and V Ratanatharathom, eds.: Biology and Therapy of Acute Leukemia.
0-89838-728-0.
J Russo, ed.: Immunocytochemistry in Tumor Diagnosis. 0-89838-737-X.
RL Ceriani, ed.: Monoclonal Antibodies and Breast Cancer. 0-89838-739-6.

11
HEAD AND NECK
MANAGEMENT
OF THE CANCER
PATIENT

Edited by
Douglas E Peterson
UNIVERSITY OF MARYLAND AT BALTIMORE

E George Elias
UNIVERSITY OF MARYLAND AT BALTIMORE

Stephen T Sonis
HARVARD SCHOOL OF DENTAL MEDICINE

"
~

Martinus Nijhoff Publishers

a member of the Kluwer Academic Publishers Group
BOSTON DORDRECHT LANCASTER
 DISTRIBUTORS

for the United States and Canada: Kluwer Academic Publishers, 101 Philip Drive,
Assinippi Park, Norwell, MA, 02061, USA
for the UK and Ireland: Kluwer Academic Publishers, MTP Press Limited, Falcon
House, Queen Square, Lancaster LAI IRN, UK
for all other countries: Kluwer Academic Publishers Group, Distribution Centre, P.O.
Box 322, 3300 AH Dordrecht, The Netherlands
Library of Congress Cataloging in Publication Data

Library of Congress Cataloging-in-Publication Data

Main entry under title:
Head and neck management of the cancer patient.
(Developments in oncology)
Includes bibliographies and index.
1. Head-Cancer. 2. Neck-Cancer. 3. Cancer-
Treatment-Complications and sequelae. I. Peterson,
Douglas E. II. Elias E George. III. Sonis,
Stephen T. IV. Series. [DNLM: 1. Head and Neck
Neoplasms-therapy. WI DE998N/WE 707 H4318]
RC280.H4H387 1985 616.99'491'06 85-13684
ISBN-13: 978-1-4612-9411-5 e-ISBN-13: 978-1-4613-2289-4
DOl: 10.1007/978-1-4613-2289-4

© 1986 by Martinus Nijhoff Publishing, Boston.

Softcover reprint of the hardcover I st edition 1986
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, mechanical, photocopying,
recording, or otherwise, without the prior written permission of the publishers.
Martinus Nijhoff Publishing, 101 Philip Drive, Assinippi Park, Norwell, MA, 02061, USA
 CONTENTS

Contributing authors Vll

Preface Xl

1. INTRODUCTION 11. Initial detection and evaluation:

extraoral neoplasms 179
1. Cancer, its complications, and the by Allen D Hillel and Charles W Cummings
head and neck 3
by Stephen T Sonis 12. Diagnostic radiology for head and
neck neoplasms with emphasis on
2. Pathology of malignancy 17 computerized tomography 191
by John L Giunta by Alfred L Weber and James V Manzione

3. Biology and biochemistry of 13. Neoplasms of the salivary

metastatic cells 45 glands 201
by James E Talmadge, Lance A Liotta, and by Marvin P Fried
Robert R Kohn
14. Nonmucosal neoplasms of the
II. PRINCIPLES OF MANAGEMENT maxillofacial region 231
by Leonard B Kaban and Robert Chuong
4. Principles of surgical oncology 71
by E George Elias 15. Surgical management of head and
neck neoplasia 255
5. Principles of radiation therapy 77 by E George Elias
by Nancy J Tarbell and Ralph R Weichselbaum
16. Radiotherapeutic management of head
6. Principles of chemotherapy 83 and neck neoplasia 275
by Paul L Weiden by Daphne Y Tong

7. Principles of immunology 101 17. Chemotherapeutic management of

by Crispian Scully head and neck neoplasia 299
by MuhyiAI-SaTTaf
8. Principles of bone marrow
transplantation 129 18. Assessment of success of treatment of
by Joel M Rappeport head and neck neoplasia 331
by R Kim Davis and Stanley M Shapshay
9. Principles of infection
management 141 IV. HEAD AND NECK COMPLICATIONS
by James C Wade OF CANCER THERAPY

19. Oral complications associated with

III. DIAGNOSIS AND MANAGEMENT OF hematologic neoplasms and their
HEAD AND NECK NEOPLASIA
treatment 351
10. Initial detection and evaluation: by Douglas E Peterson
intraoral neoplasms 163
by Douglas E Peterson, C Daniel Overholser,
Jr, Stewart A Bergman, and Todd Beckerman
VI CONTENTS

20. Head and neck neurologic 24. Standards for nursing care of the oral
complications of malignancy 363 cavity 479
by N Simon Tchekmedyian and Richard S by Lisa T Williams, Noel E Slotke,Jane Daly,
Kaplan and Douglas E Peterson

21. Head and neck complications of bone 25. Psychosocial effect of cancer on the
marrow transplantation 401 patient and the family 503
by Mark M Schubert, Keith M Sullivan, and by Nathan Schnaper and Tamar Koren Kellner
Edmond L Truelove
26. Nutrition in the patient with
22. Oral complications of radiation compromised oral function 509
therapy 429 by E George Elias and Deborah L McCaslin
by Peter B Lockhart
Appendix: Staging of head and neck
V. SUPPORTIVE CARE neoplasia 517

23. Prosthetic management 453 Index 521

by John Beumer III, Louis G De Paola, and
Robert] Leupold
 CONTRIBUTING AUTHORS
Muhyi Al-Sarraf, M.D.
Division of Oncology, Wayne State University
and Harper-Grace Hospitals
3990 John R Street
Detroit, Michigan 48201, USA
Todd Beckerman, D.D.S., M.S.
Associate Professor
Department of Oral Pathology
Baltimore College of Dental Surgery
Dental School
University of Maryland
Baltimore, Maryland 21201, USA
Stewart A Bergman, D.D.S., M.S.
Associate Professor
Department of Oral Surgery
Baltimore College of Dental Surgery
Dental School
University of Maryland
Baltimore, Maryland 21201, USA
John Beumer III, D.D.S., M.S.
Professor and Chairman
Removable Prosthodontics
School of Dentistry
Center for the Health Sciences
University of California
Los Angeles, California 90024, USA
Robert Chuong, D.M.D., M.D.
Instructor of Oral and Maxillofacial Surgery
Harvard School of Dental Medicine
and
Assistant in Surgery
Children's Hospital
and
Junior Surgeon
Brigham and Women's Hospital
Boston, Massachusetts, 02115, USA
Charles W Cummings, M.D.
Professor and Chairman
Department of Otolaryngology
University of Washington
School of Medicine
Seattle, Washington 98195, USA
Jane Daly, R.N., D.D.S.
Resident, Department of Oral and
Maxillofacial Surgery
Washington Hospital Center
Washington, D.C., USA 20010
R Kim Davis, M.D.
Assistant Professor of Surgery
Division of Otolaryngology
Head and Neck Surgery
University of Utah
College of Medicine
Salt Lake City, Utah 84112, USA
Louis G De Paola, D.D.S., M.S.
Assistant Professor
Department of Oral Diagnosis
Baltimore College of Dental Surgery
Dental School
University of Maryland
and
Consultant
University of Maryland Cancer Center
Baltimore, Maryland 21201, USA
E George Elias, M.D., Ph.D.
Professor of Surgery and Oncology
Director of Surgical Oncology
University of Maryland School of Medicine
Baltimore, Maryland 21201, USA
Marvin P Fried, M.D.
Assistant Professor
Department of Otolaryngology
Harvard Medical School
Boston, Massachusetts 02215, USA
John L Giunta, D.M.D., M.S.
Professor
Department of Oral Pathology
Tufts School of Dental Medicine
1 Kneeland Street
Boston, Massachusetts 02111, USA
VII
Vlll CONTRIBUTING AUTHORS

Allen D Hillel, M.D. Assistant Professor

Assistant Professor Department of Oral Medicine and
Department of Otolaryngology RL-30 Oral Pathology
BB-1165 University of Washington Hospital Harvard School of Dental Medicine
Seattle, Washington 98195, USA Boston, Massachusetts 02115, USA

Leonard B Kaban, D.M.D., M.D. James V Manzione, D.M.D., M.D.

Professor and Chief Department of Radiology
Oral and Maxillofacial Surgery Balboa Hospital
University of California, San Francisco San Diego, California, USA 92134-5000
San Francisco, California 9414 3, USA
Deborah L McCaslin, R.D., M.B.A.
Richard S Kaplan, M.D., E.A.C.P. District Director
Associate Professor of Oncology Home Nutritional Support-A Healthdyne
University of Maryland Cancer Center Company
and 8920 Route 108
Assistant Professor of Medicine Columbia, Maryland 21045, USA
University of Maryland School of Medicine
Baltimore, Maryland 21201, USA C Daniel Overholser, D.D.S., M.S.D.
Professor and Chairman
Tamar Koren Kellner, B.A. Department of Oral Diagnosis
Research Assistant Baltimore College of Dental Surgery
Private Practice of Group Therapy for Cancer Dental School
Patients and Families University of Maryland
Baltimore, Maryland 21210, USA and
Associate Professor
Robert R Kohn, Ph.D. Program of Oncology
Institute of Pathology University of Maryland
Case Western Reserve University School of Medicine
Cleveland, Ohio 44106, USA Baltimore, Maryland 21201, USA

RobertJ Leupold, D.M.D., M.A. Douglas E Peterson, D.M.D., Ph.D.

Professor and Chairman Associate Professor
Department of Removable Prosthodontics Department of Oral Diagnosis
Baltimore College of Dental Surgery Baltimore College of Dental Surgery
Dental School Dental School
University of Maryland University of Maryland
Baltimore, Maryland 21201, USA and
Associate Professor
Lance A Liotta, Ph.D. Program of Oncology
Laboratory Chief of Pathology University of Maryland
Building 10 School of Medicine
National Cancer Institute Baltimore, Maryland 21201, USA
National Institutes of Health
Bethesda, Maryland 20205, USA Joel M Rappeport, M.D.
Assistant Professor of Medicine
Peter B Lockhart, D.D.S. Harvard Medical School
Program Director and
General Practice Residency Clinical Director
Brigham and Women's Hospital Bone Marrow Transplant Program
75 Francis Street Brigham and Women's Hospital
and Children's Hospital Medical Center
Boston, Massachusetts 02115, USA
 CONTRIBUTING AUTHORS ix

Nathan Schnaper, M.D. Associate Professor

Head Department of Oral Medicine and Oral
Division of Psychiatry Pathology
University of Maryland Cancer Center Harvard School of Dental Medicine
University of Maryland Hospital Boston, Massachusetts 02115, USA
Baltimore, Maryland 21201, USA
Keith M Sullivan, M.D.
Mark M Schubert, D.D.S., M.s.D. Assistant Professor
Assistant Professor Department of Medicine
Department of Oral Medicine University of Washington School of Medicine
University of Washington and
School of Dentistry Assistant Member
University of Washington Fred Hutchinson Cancer Research Center
and Seattle, Washington 98104, USA
Director
Oral Medicine Supportive Services James E Talmadge, Ph.D.
Fred Hutchinson Cancer Research Center Head
Seattle, Washington 98114, USA Preclinical Screening Laboratory
National Cancer Institute-Frederick Cancer
Crisp ian Scully, B.Sc., B.D.S., M.B., B.S., Ph.D., Research Facility
F.D.S., MRCPath P.O. BoxB
Professor of Stomatology and Head of Frederick, Maryland 21701, USA
University Department of Oral Medicine
and Oral Surgery Nancy J Tarbell, M.D.
Bristol Dental School and Hospital Instructor in Radiation Therapy
Lower Maudlin Street Department of Radiation Therapy
Bristol BS 1 2LY, United Kingdom Harvard Medical School
50 Binney Street
Stanley M Shapshay, M.D. Boston, Massachusetts 02115, USA
Department of Otolaryngology
Lahey Clinic N Simon Tchekmedyian, M.D.
41 Mall Road Clinical Associate
Burlington, Massachusetts 01805 Medical Oncology
and University of Maryland Cancer Center
Assistant Professor Baltimore, Maryland 21201, USA
Department of Otolaryngology
Boston University Daphne Y Tong, M.D.
School of Medicine Department of Radiation Therapy
Boston, Massachusetts, USA 02118 Group Health Hospital
200 15th Avenue East
Noel E Slotke, R.D.H., M.S. Seattle, Washington 98112
Faculty,J ohns Hopkins University School of and
Medicine Clinical Associate Professor
Division of Dentistry and Oral and Maxillofacial University of Washington
Surgery School of Medicine
Baltimore, Maryland 21205, USA Seattle, Washington 98195, USA

Stephen T Sonis, D.M.D., D.M.Sc. Edmond L Truelove, D.D.s., M.S.D.

Chief Associate Professor and Chairman
Division of Dentistry Department of Oral Medicine
Brigham and Women's Hospital University of Washington School of Dentistry
75 Francis Street Seattle, Washington 98195, USA
and
x CONTRIBUTING AUTHORS

James C Wade, M.D. Clinical Associate Professor of Medicine

Associate Professor Division of Oncology
Head University of Washington
Section of Infectious Disease School of Medicine
University of Maryland Cancer Center Seattle, Washington, 98195
22 South Greene Street and
Baltimore, Maryland 21201, USA Affiliate Investigator in Medical Oncology
Fred Hutchinson Cancer Research Center
AlfredL Weber, M.D. Seattle, Washington 98104, USA
Chairman
Department of Radiology Lisa T Williams, B.S., R.D.H.
Massachusetts Eye and Ear Infirmary Dental Hygienist
243 Charles Street University of Maryland Cancer Center
Boston, Massachusetts 02114, USA University of Maryland Hospital
and
Ralph R Weichselbaum, M.D. Instructor
Associate Professor Department of Oral Diagnosis
Department of Radiation Therapy Baltimore College of Dental Surgery
Harvard Medical School Dental School
50 Binney Street University of Maryland
Boston, Massachusetts 02115, USA Baltimore, Maryland 21201, USA

Paul L Weiden, M.D., F.A.C.P.

Section of Hematology-Oncology
The Mason Clinic
1100 Ninth Avenue
P.O. Box 900
and
 PREFACE
This book presents in a comprehensive way cur-
rent advances in the management of neoplasia
and associated complications of the head and
neck. A broad range of clinical considerations is
discussed following overviews of relevant basic
biologic issues and the roles of various disci-
plines. Each chapter has been structured to
"stand by itself"; at the same time, obvious rela-
tionships with other chapters have been noted.
We are pleased that this book represents, in our
opinion, a truly multidisciplinary approach to
the clinical care of the patient with head and neck
cancer involvement and/or its complications.
Today's complex treatments in oncology re-
quire a comprehensive approach to effect a posi-
tive result for the cancer patient whose facial
appearance and function are compromised. We
trust that physicians, dentists, nurses, dental
hygienists, and individuals in the supportive ser-
vices involved in the management of the cancer
patient will find this book beneficial.
Xl
I. INTRODUCTION
 1. CANCER, ITS COMPLICATIONS,
AND THE HEAD AND NECK

Stephen T. Sanis

Few diseases are as complex in their biology,
physiology, pathology, or management as can-
cer [1, 2]. In addition, the disease concurrently
has extensive psychological impact on patients.
Consequently, the diagnosis and management
of malignant disease requires an understanding
not only of the process, but also of its ramifica-
tions. Because of its complexity, treatment of
cancer is usually best accomplished by a team of
individuals working for the patient.
Cancer should be thought of as a collective
term used to describe a large number of dif-
fering diseases that are similar in that their
fundamental pathology is abnormal cellular
growth. Cancers are, however, frequently dis-
similar in their biology, etiology, epidemiology,
symptoms, and clinical course. Thus, their
treatments are varied; while some malignancies
are responsive to radiotherapy, others are
radioresistant. Similarly, while chemotherapy is
of significant benefit in some cancers such as
leukemia or lymphoma, its usefulness in other
tumors, such as colorectal cancers, seems
equivocal [3].
Significance
Unfortunately, cancer is common; excluding
non melanotic skin cancers, there are over
800,000 new cases annually in the United States
[1]. Approximately 66 million individuals
(about one-third of Americans now living in the
United States) will develop cancer. While the
prognosis for patients with cancer continues to
improve, the disease still has a high mortality;
approximately 60% patients with cancer die of
their illness [4]. In the United States, this
numerically translates to approximately 400,000
deaths per year, the second largest number fol-
lowing heart disease (table 1-1). Cancer is also
the second leading cause of death in children
between the ages of 1 and 14 and the most
frequent killer of individuals between the ages
of 15 and 34. If the current projections of the

TABLE \-1. Mortality profiles for leading causes of death in the United States (1978)

Death rate %
per 10,000 Total
Rank Cause of death No. population deaths

1 Heart disease 729,510 300.4 37.8

2 Cancer 396,992 169.9 20.6
3 Cerebrovascular disease 175,629 70.8 9.1
4 Accidents 105,561 45.8 5.5
5 Pneumonia and influenza 58,319 23.6 3.0
6 Chronic obstructive lung disease 50,488 12.2 2.6
7 Diabetes mellitus 33,841 14.2 1.8
8 Cirrhosis of liver 30,066 13.4 1.6
9 Arteriosclerosis 28,940 11.1 1.5
10 Suicide 27,294 11.6 1.4

Peterson et ai., HEAD AND NECK MANAGEMENT OF THE CANCER PATIENT.

© 1986. Martinus NijhofJ Publishing. All rights reserved. 3
4 1. INTRODUCTION

American Cancer Society are correct, cancer most common sites of malignancy in men
deaths in the United States will exceed 500,000 (figure 1-1 and table 1-2) [4]. The breast is the
by the year 2000. most frequent site of cancer in women, followed
Cancer elicits a high economic as well as hu- by the colon/rectum and uterus. Cancers of the
man cost. The cost of diagnosis, research, and lung have demonstrated a strikingly significant
treatment of malignant diseases is extensive. The increase in terms of mortality. The increase in
complexity of the disease, its often protracted age-adjusted death due to lung cancer between
course, the requirement of technologically ad- 1951-53 to 1976-78 is dramatic, with a 172%
vanced instrumentation for accurate diagnosis increase in men and a 256% increase in women.
and longitudinal assessment, and the frequent Cancers do not affect all racial or ethnic
need for multimodality therapy all contribute to groups equally. Cancers in American blacks are
the direct economic impact of cancer [5, 6]. Lost increasing at a significantly faster rate than that
hours from work and the need for supportive of whites [7]. The age-standardized cancer
services are additional expenses that arise mortality increased 26% in blacks between 1950
secondary to the disease. to 1974 as compared with only 5% in whites.
Certain tumor types have shown a predilection
for ethnic groups. For example, nasopharyngeal
Epidemiology cancers are 20-30 times more frequent in
Age, sex, geographic location, and race all bear Chinese than in other groups. Jewish women
on the incidence of cancer, as well as associated tend to have cervical cancer more often than
mortality [7]. The frequency and mortality of other groups.
cancer increase with age. The elderly are at
highest risk for developing malignancies; cancer
accounts for 60% of deaths in individuals over Etiology
age 65. Between ages 45 and 64, 34% of deaths The etiology of the various types of cancer is
are due to malignancy. Under age 45, cancer ac- not well established, although epidemiologic
counts for 6% of deaths. and demographic data strongly suggest an
Taken as a group, cancers tend to be more environmental cause in about 80% of cases.
common in women than in men. However, this This etiology strongly overshadows a genetic
trend is now undergoing change, probably as a influence and is borne out by a number of
consequence of the increase in number of men examples. While stomach cancer is relatively
with lung cancer and the decrease in number of uncommon in the United States, it is frequent
women developing cervical cancer. in Japan. Conversely, while carcinoma of the
The lung, prostate, and colon/rectum are the breast is the leading malignancy in American
women, it is rare in Japan. When native Japanese
move to the United States, however the cancer
TABLE 1-2. Estimated new cases and deaths for major trend becomes that of the American rather
sites for cancer (1984) than of the Japanese experience. Geographic
prevalence has been noted for a variety of other
Site No. of cases Deaths cancers including cancers of the skin, bronchus,
esophagus, nasopharynx, and prostate.
Lung 139,000 121,000
Colon-rectum 130,000 59,000 Carcinogenesis is thought to occur by a mul-
Breast 116,000 38,000 tiphase process [8, 9]. In the first phase, the
Prostate 76,000 25,000 genetic structure is rapidly and irreversibly altered.
Urinary 57,000 19,000 Once this occurs, a second, long-lasting stage
Uterus 55,000- 10,000 occurs during which transformed cells undergo
Oral 27,000 9,000 changes to first become microscopic clones of
Pancreas 25,000 23,000 tumor cells and then clinically-detected tumors.
Leukemia 24,000 17,000 Thus, tumor development can be affected by
Ovary 18,000 12,000 two processes: direct alteration of cellular ge-
Skin 18,000b 7,000
netic material (such as by viruses, chemicals,
a Not counting carcinoma in situ. and radiation) with resultant neoplastic trans-
b Estimated new cases of nonmelanoma about 400,000. formation, and epigenetic influences, which
From Cancer Facts and Figures (American Cancer Society, 1984). promote tumor growth following its induction.
 1. CANCER, ITS COMPLICATIONS, AND THE HEAD AND NECK
CANCER INCIDENCE BY SITE AND SEX t
SKIN SKIN
ORAL
ORAL
BREAST
LUNG
LUNG
COLON &
RECTUM COLON &
RECTUM
PANCREAS PANCREAS
PROSTATE
OVARY
UTERUS
URINARY
URINARY
ALL OTHER 120% I 115%1 ALLOTHER
tExcluding non-melanoma skin cancer and carCinoma in situ.
FIGURE 1-1. Estimates of cancer incidence and
deaths by site and sex in 1984, From Cancer Facts and
Figures (American Cancer Society, 1984),
Regardless of etiology, it thus appears that
carcinogenesis requires a number of steps before
cancer develops. However, the evidence for the
multistep theory is largely circumstantial. First,
in humans there generally appears to be a long
latent period between exposure to carcinogen
and the development of malignancy. Second,
more than one agent (co-carcinogen) is fre-
quently required to produce malignancy. A
recent study, for example, demonstrated the de-
velopment of a local oral malignancy in an area
of chronic irritation following the parenteral
injection of a carcinogen [10]. These results sug-
gest a synergistic effect between the carcinogen
and local irritation. It is clear that the frequency
and speed with which a cancer develops de-
pends largely on the dose of carcinogen expo-
sure.
A large number of chemicals have been rec-
ognized as being carcinogenic (table 1-3).
Seemingly, this list grows daily. While some
chemicals appear to act by direct contact, others
may require metabolic conversion to become
carcinogenic. Highest on the list of significant
carcinogens must be cigarette smoke. Addi-
tionally, while many animal studies suggest viral
5
CANCER DEATHS BY SITE AND SEX
~SKIN
/~ORAL
i~.:~.":...........
:":'~
18%:I
18%
BREAST
LUNG
OVARY
UTE RUS
URINARY
ALL OTHE A 120% I 119% I ALL OTHER
etiology for some malignancies, there is evi-
dence for a significant role for viruses in certain
human cancers. For example, human T-cell
leukemia virus is the probable etiologic agent of
adult T-cell leukemia [11, 12]. An association
between Burkitt's lymphoma and Epstein-Barr
virus has been well documented in African
populations [13].
Modification of host resistance has also been
implicated as influencing cancer development
[14]. Specifically, defects in the ability of the im-
mune system to recognize newly transformed
cells that manifest tumor specific antigens have
been proposed to explain the escape of tumor
cells from immune surveillance. Subsequently,
clinical neoplasia develops. Evidence for this
theory is derived from the observed increased
frequency of malignancies in chronically im-
munosuppressed patients (i.e., renal allograft
recipients who develop lymphomas) and the
finding of increased susceptibility to both
spontaneous and induced tumors in immuno-
deficient laboratory animals.
Diagnosis
Diagnosis of malignancy has been traditionally
based on the histologic demonstration of abnor-
mal cells. Malignant cells share a number of his-
6 I. INTRODUCTION

TABLE 1-3. Chemicals recognized as carcinogens in tologic characteristics (see chapter 2). Obvious-
human subjects ly, such evalution is predicated upon examining
cells microscopically, utilizing biopsy.
Chemical Site of cancers Since prognosis and early detection are close-
Chemical mixtures ly related, methods for screening populations at
Soots, coal tars, oils Skin lungs, scrotum risk for certain cancers have been extensively
Cigarette smoke Lungs, esophagus, proposed. One of the first screening techniques
bladder developed utilizes cytologic smears. This tech-
Industrial chemicals (occupational hazards) nique (the Papanicolaou test or Pap smear) has
2-Naphthylamine Urinary bladder been widely used to screen for carcinoma of the
Benzidine (aniline dye Urinary bladder cervix; this test has been performed routinely in
precursors) the United States since the 1940s. While the fre-
4-Aminobiphenyl Urinary bladder quency of cervical cancer has decreased, it is dif-
Chloromethyl methyl Lungs ficult, however, to attribute this finding solely
ether to increased screening activity.
Nickel compounds Lungs, nasal sin uses Similar techniques can be used to screen for
Chromium compounds Lungs oral cancer (see chapter 10). Cytologic screening
Asbestos Lungs, pleura, techniques require the scraping of a suspected
peritoneum
Arsenic compounds Skin, lungs lesion and the smearing of cells onto a glass
Isopropyl oil Nasal sinuses slide. After fixation and staining, a pathologist
Vinyl chloride Liver (angiosarcoma) or technician then examines the smear and
Benzene Leukemia assesses cellular morphology. Cytologic screen-
ing methods thus offer the advantage of ease of
Drugs
N, N-bis (2-chloroethyl)- Urinary bladder administration, low cost, and speed. The major
2-naphthylamine disadvantages seem to be associated with need
Bis-(2-chloroethyl Lungs for accessibility to tissue and occurrence of false-
sulfide) (mustard gas) negative results; studies have demonstrated as
Immunosuppressive drugs Reticulosarcoma, all high as a 15% false-negative rate for smears of
sites (?) oral carcinomas [15].
Diethylstilbestrol Vagina Radiographic techniques are routinely used
Phenacetin Renal pelvis for both the diagnosis and screening of sus-
Steroid contraceptives Benign hepatomas pected malignant disease. For example, the use
Polycyclic hydrocarbons Skin of mammography (coupled with self-adminis-
in ointment tered clinical examination) has resulted in a
Naturally occurring compounds significant improvement in the prognosis for
Betal nuts Buccal mucosa breast cancer [16]. However, in addition to risks
Aflatoxins (a mold Liver incurred by radiation, such diagnostic meth-
product) ods are technologically intensive and hence ex-
Ionizing radiations pensive. These disadvantages must be weighed
Radar Bronchus against the cost benefit of early detection and
x-Ray, radium All sites treatment of disease.
Ultraviolet Skin Fairly recently, the use of tumor markers has
Thorium, Thorotrast Bone, reticuloen- attained a role in the screening for and monitor-
dothelial system ing of certain malignancies [17]. The basis for
Potent carcinogens in animals to which human these assays is that unique markers are produced
populations are exposed by certain cancers; further, these markers are
Sterigmatocystin Liver detectable, usually in patient's serum or blood.
Cycasin Liver Oncofetal antigens were among the first de-
Safrol Liver scribed. Specifically, carcinoembryonic antigen
Pyrrolizidine alkaloids Liver
Nitroso compounds (CEA) has been found to be associated with a
Esophagus, liver,
kidney, stomach number of gastrointestinal, lung, and breast
cancers. Increased titers of CEA may indicate
From Beeson, et al. (eds.): Cecil Textbook of Medicine (Phil- the presence of such a malignancy or the recur-
adelphia, W.B. Saunders, 1979). rence of treated disease [18]. A number of
 1. CANCER, ITS COMPLICATIONS, AND THE HEAD AND NECK
other tumor markers exist, including alpha-
fetoprotein for hepatic and testicular cancers.
Clearly, the appeal of such markers is that
their identification may provide a rapid, cost-
effective, and accurate technique to screen for . (figure 1-3). In reviewing five-year cancer sur-
cancers and to subsequently monitor the effec-
tiveness of therapy.
Treatment and Prognosis
Treatment for cancer has become increasingly
. sophisticated as more knowledge has been
gained regarding cancer biology. Simultaneous-
ly, successes in therapy are now reported in
malignancies that, not long ago, were uniformly
fatal (figure 1-2). Whereas the overall five-
year survival was less than 20% for patients
diagnosed and treated for cancer in the 1930s,
38% of patients treated today have an overall
expectation of surviving at least five years.
Given death due to other causes, this ratio im-
proves to 46% when only malignancy as a cause
of death is considered. The three-year disease-
100r-------------------------------,
90
80 1950-54[B] 1970·73
70
50
50
40
30
20
COLON-
RECTUM
PROSTATE
Adjusted fornormill life expectancy.
Source: Biometry Branch,National Cancer Institute
FIGURE 1-2. Five-year cancer survival rates trends
for selected sites from 1950-1954 to 1970-1973.
From Cancer Facts and Figures (American Cancer
Society,1984).
7
free survival for patients with acute lymphocytic
leukemia is almost 50%.
Prognosis is most often related to degree
of cancer dissemination at time of diagnosis
vival rates, the importance of early detection
and treatment becomes clear; the cure rate for
localized cancers ranges from 50% to 80% as
compared with only 5% to 20% for patients
with distant metastases.
The form of therapy is dictated by the pros-
pective tumor behavior locally, its metastatic
potential, and the toxicity of a given therapy
weighed against its potential benefit. Currently,
the three main modalities of cancer treatment
are surgery, chemotherapy, and radiotherapy.
Specific considerations of each of these are
discussed in detail in subsequent chapters. Im-
munotherapy has been used with some forms of
cancer, but is still not considered to be a con-
ventional form of treatment.
Medical Problems due to Cancer
Medical problems due to cancer can be general-
ly grouped into three major categories (table
1-4). First, problems may arise because of the
direct impingement of primary or secondary
malignant disease on normal tissue or organ sys-
tems. For example, an expanding tumor may
cause circulatory distress by obstructing major
blood vessels; functional myelosuppression
may occur because of marrow invasion by
malignant cells. In the head and neck, expanding
tumor may cause functional alterations of the
tongue by inhibiting motion; the lesion may
also cause erosion of the wall of a carotid artery.
The second major group of medical problems
caused by cancer is that due to the production
of physiologically active products by the tumor.
The most obvious examples are the synthesis of
endogenous hormones by proliferating tumor.
In the head and neck region, one observes in-
creased parathormone production with clinical
manifestations of hyperparathyroidism in the
patient with carcinoma of the parathyroids. In
BREAST UTERUS
non-head-and-neck sites, examples include
Cushing's syndrome due to excess adrenocorti-
cotropic hormone production in patients with
adrenal neoplasms and the over production of
insulin in individuals with islet cell tumors of
the pancreas. Production of these and other
hormones may result in a number of syndromes
(table 1-4).
00

WHITE BLACK

13%
47%
STOMACH
6%
33%
COLON- 59%
RECTUM 20%
6%L
LUNG 24%
3%

46% • • • • • • • • • • • •
LARYNX

49%
BREAST 79%
35%
61%liii
l iiiiiiiiiiiiiiiiiiiiiiiiiiiiiitiiiiiiiiiiiii~
UTERUS, 78%
CERVIX
35% 1-1 iiiiiiiiiiiiiiiiiiiiiiiiiiiiiitiiiiiiiiiiiii~
45% -
UTERUS, 69%
CORPUS 18%
34% 1;;;;;1
iiiiiiiiiiiiiiiiiiiiiiiiiiii;;'
OVARY -81%

19% 1-1
iiiiiiiiiiiiiiiiiiiiiiiiiiii~
51% . .
PROSTATE 66%
39% 33%
42% 39%liiiil iiiiiiiiiiiiiiiiiiiiiiii~iiiiiiiiiiii~
KIONEY 72 62%
22
21% I I'
54% 32%
BLADDER 67% 50%
12% 6%
~~~~~~N'S 63%

LEUKEMIA 15%
MULTIPLE 19%
MYELOMA :[
_ ALLSTAGES !%f.:..<:i4 LOCALIZED c=J SPREAD
* Adjusted for normal life expectancy Source: Biometry Branch, National Cancer Institute

FIGURE 1-3. Five-year cancer survival rates for selected sites by race, From Cancer Facts and Figures (American Cancer ~ociety, 1984).
!ABLE 1-4. Examples of common medical problems Syndromes due to excess
III cancer endogenous hormones
Cortisol Carcinoma of the adrenals
I. Those secondary to involvement with Cushing's syndrome
of organ systems Insulin Islet cell cancer of the pancreas
Obstruction and its with hypoglycemia
consequences Parathormone Carcinoma of the parathyroids
Ureters Azotemia with hyperparathyroidism
Blood vessels Superior vena caval Catecholamines Pheochromocytoma with
obstruction hypertension
Intestine Perforation, fistulas, pain Syndromes due to presumed
Bronchus Atelectasis, distal infection (but not identified)
Biliary excretory Obstructive jaundice humoral products
ducts Cerebellar
Lymph vessels Lymphedema, malabsorp- degeneration
tion Sensorimotor
Organ failure secondary polyneuropathies
to metastases Hypertrophic
Liver Hepatic coma, hypoglycemia osteoarthropathy
Heart Cardiac arrhythmias, Migratory throm-
tamponade bophlebitis
Skeleton Myelophthisic anemia, Dermatomyositis
fractures, pain
Lungs Pneumothorax, respiratory III. Those secondary to treatment
failure Infections
Endocrine organs Diabetes insipidus, myxedema Leukopenia Chemotherapy
Anatomic cavities Ascites, pleural effusion Immuno- Chemotherapy
Central nervous Increased intracranial pres- suppressIOn
system sure, cord compression Tuberculosis Prolonged corticosteroids
Organ failure due to primary neoplasm Infections due Catheters
to invasive
Blood cells Acute leukemia with infection procedures
Lymph nodes Hodgkin's disease with anergy Systemic infec- Immunotherapy
Pancreas Exocrine deficiency with tion with BCG
steatorrhea
Metabolic disorders
II. Those secondary to physiologically Hypercalcemia Sex steroids in breast
active tumor products cancer
Hyperuricemia Tumor lysis syndrome
Syndromes secondary to ectopic Osteoporosis Oophorectomy
hormone production
Adrenocortico-tropic Bronchogenic carcinoma Fluid and electolyte
hormone with Cushing's syndrome disorders
Parathormone Hypernephroma with ectopic Edema, hyper- Sex steroids, corticosteroids
hyperparathyroidism tension, heart
Antidiuretic Oat cell carcinoma of the failure
hormone lung with the inappropriate Metabolic alka- Vomiting due to radio-
antidiuretic hormone losis therapy, chemotherapy
Gastrin Non-beta cell carcinoma of H yperchloremic Ureterosigmoidostomy
the pancreas with the acidosis and
Zollinger-Ellison syndrome hypokalemia
Human chorionic Carcinoma of the testis with Hyponatremia, Inappropriate fluid and
gonadotropin gynecomastia water intoxica- electrolyte therapy
Melanocyte- Carcinoma of the thymus or tion
stimulating pancreas with hyperpig- Weight I~ss and Chemotherapy,
hormone mentation anoreXIa radiotherapy
Bt2 and folate Gastrectomy and small
deficiencies bowel resections
Steatorrhea Vagotomy
9
10 I. INTRODUCTION

TABLE 1~4. (Continued) and hormonal alteration. In the head and neck
region, surgical resection of tumor may produce
Emotional and behavioral serious aesthetic and functional problems (see
disorders chapters 15 and 23). Hormonal alterations can
Depression Prolonged corticosteroids
Psychotic Amitriptyline (Elavil)
result from adrenalectomy and oophorectomy
behavior in the patient with breast cancer.
Radiotherapy may also produce a wide varie-
Hematologic disorders ty of side effects. Of those that affect the head
Thrombocyto~ Chemotherapy
and neck, the most common are those related to
penia, leuko~
penia, bleeding
xerostomia due to alterations of salivary gland
Disseminated Chemotherapy function. Subsequent osteoradionecrosis due to
intravascular secondary infection may also be noted among
coagulation patients receiving radiotherapy to the head and
neck (see chapters 16 and 22).
Endocrine disorders
Adrenal Adrenalectomy
Of the problems associated with the adminis-
insufficiency tration of cancer chemotherapy, bone marrow
Diabetes in~ Hypophysectomy suppression results in those of most serious
sipidus consequence. The non-tumor-specific inhibi-
Diabetes mellitus Pancreatectomy tion of cell division results in myelosuppression
Cardiorespiratory disorders
with its associated leukopenia and thrombocy-
Respiratory Pneumonectomy topenia. Thus, the patient's ability to deal effec-
insufficiency tively with infection places him at risk for sepsis
Pneumonitis, Radiotherapy, chemotherapy [19]. The oral cavity is an important portal of
pulmonary entry for microorganisms since it harbors
fibrosis numerous bacteria and fungi. In fact, the oral
Myocardial Doxorubicin cavity is the most frequenty identifiable source
insufficiency (adriamycin) of sepsis in granulocytopenic cancer patients
Pericardial Radiotherapy [20]. The importance of the mouth as a source
effusion of infection in myelosuppressed cancer patients
Second primary cancer is discussed in detail in chapter 19.
Acute leukemia Chemotherapy A variety of other secondary effects also
in Hodgkin's occur as a consequence of cancer therapy, not
disease the least of which are the psychological
Squamous cancer Radiotherapy
ramifications of treatment due to disfigurement,
of the skin
functional alterations, and discomfort. No part
IV. Miscellaneous of the body has more impact on this aspect of
cancer care than does the head and neck. A pa-
Anxiety and depression incident to tient's ability to function and be accepted within
cancer and its attendant circumstances
society can be severely altered after resective
Pain
surgery of the head and neck. The importance
From Beeson et al. (eds.), Cecil Textbook of Medicine (W.B. Saud- of reconstructive and rehabilitative care cannot
ers, Philadelphia, 1979). be overemphasized, and is discussed in chapters
23 and 24.
The third category of medical problems that
are consequences of cancer is that related to
treatment; these complications are probably the
most frequent and most important with respect
Animal Models of Head and Neck
to the head and neck. As previously discussed, Malignancy
current therapy for malignant disease includes Animal models are essential for the study of
surgery, radiotherapy, and chemotherapy. Each the pathogenesis of disease and its clinical be-
of these modalities may result in significant havior as well as to serve as tools to investigate
iatrogenic problems for the patient. techniques of treatment. Thus, the development
Surgical therapy plays three major roles in the of a model for intraoral squamous cell carcino-
treatment of cancer: diagnosis, tumor resection, ma in hamsters by Salley in 1954 [21] was an
 1. CANCER, ITS COMPLICA nONS, AND THE HEAD AND NECK
FIGURE 1-4. Clinical appearance of hamster buccal
cheek pouch before (a) and after application of
DMBA (b). DMBA was applied over a period of 12
weeks. Photograph courtesy of Dr. Gerald Shklar.
important contribution to investigations of
these tumors. Hamsters were selected as an
experimental model as their cheek pouches
provide a large mucosal surface area. A 0.5%
solution of the potent chemical carcinogen
dimethylbanzathracene (DMBA) in mineral oil
was painted onto the surface of cheek pouches
three times weekly for twelve weeks. Longitu-
dinal histologic evaluation demonstrated a
three-part sequence of carcinogenesis, character-
ized by hyperkeratosis, dysplasia, and ulti-
mately locally invasive epidermoid carcinoma
(figures 1-4 and 1-5).
Because of its limited lymph supply, the ham-
ster cheek pouch was originally considered an
immunologically privileged site. However, a
large number of studies have consistently de-
monstrated the sensitivity of the cheek pouch
model to systemic modification of the immune
system. Immunosuppression caused by the
administration of cortisone acetate (2.0 mg,
thrice weekly) resulted in more rapid dyspla-
sia, larger tumors, and more local invasion than
did mucosal treatment with DMBA alone
11
[22]. The administration of the antimetabolite
methotrexate had similar effects [23].
Woods [24J and Guinta and Shklar [25J found
that the administration of antilymphocyte serum
(ALS) profoundly enhanced hamster cheek
pouch carcinogenesis. This finding supported
earlier hypotheses since ALS was a known
inhibitor of immune function. These studies
were also in agreement with those demon-
strated in a variety of non oral animal tumor
models.
Conversely, substances known to potentiate
or enhance immune function have been used
successfully to delay carcinogenesis in the ham-
ster cheek pouch model. Nonspecific stimu-
lation of cell-mediated immunity (CMI) by
Bacillus Calmette-Guerin (BCG) is well es-
tablished. When BCG was given to hamsters
(simultaneously) with DMBA application, a sig-
nificant retardation of carcinogenesis was noted
[26]. Parallel findings were reported when leva-
misole, an antihelminthic with the ability to
stimulate CMI, was administered with DMBA
[27]. The retinoid 13-cis-retinoic acid has also
been shown to delay the development of cheek
pouch carcinomas, a finding attributed to its
immunoenhancing properties [28, 29].
However, comparison of this animal model
12 I. INTRODUCTION
with the human condition must be qualified,
since the behavior of hamster cheek pouch car-
cinoma differs from that of the human. Whereas
cervical lymph metastasis is a common occur-
rence in the patient with intraoral tumor, its
spontaneous occurrence in the hamster model is
rare. However, a recent study by Safour et al.
[30] reported a 53% occurrence of hamster
cheek pouch metastatic carcinoma in which
surgical manipulation of tumor was performed.
Given the limitations of the hamster model of
induced carcinoma, the recent development of a
transplantable oral cancer model by Meng et al.
[31] was important because it overcame two sig-
nificant drawbacks of the cheek pouch model.
First, it permitted study of tumor cells of single
tumor origin over long periods of time. Second,
it resulted in tumor cells that were more ana-
plastic than those noted in the primary tumor.
By using immunologically-suppressed neonatal
hamsters, allogeneic tumor cells could be suc-
cessfully passaged until the alloantigens were no
longer able to elicit rejection phenomenon.
In this model, a cell suspension from minced
tumor obtained from adult DMBA cheek pouch
tumors in Syrian hamsters was injected in-
traperitoneally (i.p.) into neonatal Syrian ham-
sters. Simultaneously, and for two subsequent
FIGURE 1~5. Histologic appearance of hamster
buccal pouch carcinoma induced by DMBA. Note
local invasion, hyperkeratosis, and dysplastic cells.
Photograph courtesy of Dr. Gerald Shklar.
weeks, rabbit anti-hamster lymphocyte serum
was injected i.p. three times weekly. Tumors
that developed were then transferred to addi-
tional animals. The authors found that, after
the third generation (passage), tumors would
"take" and grow in nonneonatal (seven-day)
animals. They also noted that tumors were more
anaplastic than the primary tumor and were
histologically stable.
While the hamster buccal cheek pouch model
has been the most extensively studied, two
other models for head and neck carcinoma have
also been examined. Although cancer of the
tongue is a common intraoral site in humans, an
animal model eluded investigators until 1973
when Fujita and colleagues [32, 33] described a
model in hamsters. This model was further
modified by Marefat and Shklar [34], who in-
duced lingual carcinomas by painting the lateral
border of the tongue with a 0.5% solution of
DMBA in acetone. By 12 weeks after applica-
tion, the tongue demonstrated gross evidence of
leukoplakia and histologic findings of dysplasia
and hyperkeratosis. By 14 weeks, small papil-
 1. CANCER, ITS COMPLICATIONS, AND THE HEAD AND NECK 13

lary epidermoid carcinomas were present that

increased in size and became increasingly
anaplastic over the subsequent two weeks
(figures 1-6 and 1-7). At 18 weeks, although
local tumors were extensive, there was no evi-
dence of distant metastases.
The second model utilizes the rat, which
has long served as an experimental model for
salivary gland tumors [35, 36]. The study by
Cataldo et al. on experimental submaxillary
gland tumors in rats [37] provides a good de-
scription of the technique for tumor induction
and histologic and histochemical characteristics
of tumors.
After surgical exposure of the submaxillary
glands, a 5-mg pellet of powdered DMBA was
placed into the body of glandular tissue. The
incisions were then closed. Beginning three
months after DMBA implantation, swelling and
nodular masses became present in some rats. A
four-phase sequence was used to describe the
development of tumor: a degenerative phase, a
proliferative phase, a metaplastic phase, and a
FIGURE 1-6. Clinical appearance of tongue following malignant neoplastic phase. Of the tumors that
application of DMBA: top, six weeks; and bottom, resulted, epidermoid carcinomas and adenocar-
12 weeks. Photograph courtesy of Dr. Gerald Shklar. cinomas were most common. This model has
been used successfully to study modification of
FIGURE 1-7. Histologic appearance of DMBA in salivary gland carcinogenesis by a number of
acetone-induced lingual carcinoma. Note more ana- systemic influences [38-41].
plasia of lesion as compared with buccal pouch
tumors. Photograph courtesy of Dr. Gerald Shklar.
14 1. INTRODUCTION
Animal models have also been used to investi-
gate the role of chronic irritation in the develop-
ment of oral carcinomas. Konstantinidis and
colleagues [10] found that, when local irritation
was applied to the mucosa by a wire affixed to a
rat's molar, the systemic administration of car-
cinogen resulted in the development of a local
oral tumor in proximity to the local irritation.
While the models described have permitted
extensive research to have been performed rela-
tive to oral and salivary gland carcinogenesis,
the behavior of tumors induced in these models
differs in many ways from their human counter-
parts. Furthermore, an inbred model to permit
more sophisticated immunologic studies is still
needed.
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 2. PATHOLOGY OF MALIGNANCY
John L. Giunta
This chapter reviews general principles and con-
cepts of the complex group of diseases called
cancer, with emphasis on findings at the level
of the light microscope. Classifications, charac-
teristics of epithelial tumors, grading, staging,
metastasis, and the development of neoplasia are
discussed; however, factors governing growth,
altered cell membrane function, and other prop-
erties of the cancer cell, its biochemistry, and
the immunology of cancer are not covered.
Stress is placed on head and neck tumors,
using examples of surgical pathology. For the
specific pathology of head and neck tumors, the
reader is referred to other chapters in this book
as well as some of the excellent books and arti-
cles on the subject [1-14].
Tumors of the head and neck include a widely
diverse group of cancers in the oral cavity,
oropharynx, hypopharynx, larynx, pharynx,
nose, and paranasal sinuses. They comprise
about 5% of all malignancies. If skin tumors
and melanomas are included, the incidence of
malignancy in this area almost doubles. Table
2-1 lists the estimated new cases and deaths of
head and neck cancers for 1983 [15].
The term neoplasia designates a new, uncon-
trolled growth of tissue arising from host cells
TABLE 2-1. Estimated new cases of cancer and estimated deaths-, 19.83
Category Total
All cancers 855,000 (440,000)
Lip 4,600 (175)
Tongue 4,900 (2,000)
Salivary (700)
Floor 9,800 (525)
Other (1,550)
Pharynx 7,800 (4,200)
Melanoma 17,400 (7,100)
Skin 400,000 annually
a. Estimated deaths are in parentheses.
Peterson et al., HEAD AND NECK MANAGEMENT OF THE CANCER PATIENT.
© 1986. Martinus NijhoJf Publishing. All rights reserved.
that usually presents clinically as a swelling or
tumor. Neoplasms are classified morphological-
ly according to the cell or tissue of origin. More
important, however, is the classification accord-
ing to the expected behavior related to the mor-
phologic pattern. Thus, a tumor is designated
benign if it will not invade local tissues and will
not produce distant metastases. The exceptions
are those benign tumors, located in strategic
locations, which on occasion cause pressure or
obstruction, or those producing an endocrine
capable of interfering with homeostasis. A
malignant tumor by contrast is so designated
because it can invade locally, can produce dis-
tant metastases and can endanger life.
The term cancer is a synonym for any malig-
nant tumor regardless of cellular origin. A carci-
noma is a cancer that arises from an epithelial
cell. A sarcoma is a cancer that arises from a
connective tissue cell. This classification is sim-
plistic, however, for there are those tumors that
are intermediate in their behavior. Examples are
the basal cell carcinomas of the skin and the
ameloblastomas of the jawbones. Both have a
similar histology and both are locally aggres-
sive, slow-growing lesions that behave in-
termediate between being benign and malignant
Male Female
422,500 (238,500) 432,500 (201,500)
4,100 (150) 500 (25)
3,200 (1,400) 1,700 (600)
(450) (250)
5,800 (400) 4,000 (125)
(1,000) (550)
5,500 (2,900) 2,300 (1,300)
8,500 (4,200) 8,900 (2,900)
17
18 1. INTRODUCTION
in that, despite their aggressiveness, they do not
metastasize.
Table 2-2 offers a classification of tumors
based on tissue of origin that may be diagnosed
in the head and neck. The complexity of tissues
in this area yields a variety of neoplasms. Such
diversity is a challenge to the pathologist as
the patterns of tumors of this area are highly
variable and complex. Nonetheless, most of the
malignancies are squamous cell carcinomas.
The biologic distinction between a benign
and a malignant neoplasm is ultimately based on
its clinical behavior. Morphologically, however,
generalizations can be made. A benign tumor is
nodular or circumscribed, often is encapsulated,
grows slowly and orderly, and is composed of
cells very closely resembling those in the host
tissue from which it has arisen. By contrast, a
malignant tumor infiltrates the tissue from
which it arises, is not encapsulated, and can give
rise to metastases, both locally and at great dis-
tances from the site of origin (this is the hall-
mark of malignancy). The cells may be atypical
of the tissue of origin, vary in size and shape,
and have nuclei that are hyperchromatic, en-
larged, and have irregular outlines and promi-
nent nucleoli. The chromatin pattern may be
abnormal, and mitoses may be increased and
abnormally configured. Malignant cells may be
in lymphatic and blood vessels.
The problem that arises in the surgical path-
FIGURE 2-1. Adenoid cystic carcinoma (cylindroma)
of salivary gland. Hyperchromatic basaloid cells are
uniform and regular with no mitoses. They form
cylindrical structures characteristic of this malignan-
cy. This is classified malignant by its behavior rather
than its morphology.
ology of malignancy is that not all tumors ad-
here to the criteria as enumerated. Exceptions
abound [8]. Some malignant tumors are slow
growing, circumscribed, resemble the parent
tissue of origin very closely, and have few or no
mitotic figures. Adenoid cystic carcinoma of
salivary duct origin is an example (figure 2-1).
Morphologically, it is benign with regular, non-
mitotic, basaloid cells; behaviorally, it is ma-
lignant in that most patients are dead of their
disease at the 20-year follow-up. By contrast,
capillary hemangiomas in children (figure 2-2)
may have many obvious but regular mitoses, yet
are benign and often regress at puberty. Thus,
mitoses, per se, may not be diagnostic of malig-
nancy unless they are abnormal. Mitotic activity
may be normally high, particularly in rapidly
growing tissue and in tissue with a high turn-
over rate. For example, the squamous papilloma
is a benign tumor arising from epithelium with
a normally high mitotic index; it often has an
alarmingly high number of mitoses (figure 2-3).
On the other hand, there is significance to a
single mitosis in a cartilagenous tumor, especial-
ly when noted in conjunction with binucleated
 2. PATHOLOGY OF MALIGNANCY 19

TABLE 2-2. Classification of some primary neoplasms in the head and neck

Cell or tissue of origin Benign Malignant (cancer)

1. Epithelium Carcinoma
Squamous Papilloma Squamous cell carcinoma
Verrucous carcinoma
Basal cell carcinoma
Respiratory Papilloma Nasopharyngeal carcinoma
Inverted papilloma
Glandular Adenoma Adenocarcinoma
Salivary duct Pleomorphic adenoma Malignant pleomorphic
adenoma
Pigment cells Pigmented nevus Melanoma
Tooth Ameloblastoma Malignant ameloblastoma
2. Connective tissue
Fibrous Fibroma Fibrosarcoma
Adipose Lipoma Liposarcoma
Cartilage Chondroma Chondrosarcoma
Bone Osteoma Osteosarcoma
Neural-nerve Neuroma Neurosarcoma
Schwann cell Schwan noma Malignant Schwannoma
(Neurilemoma) (Malignant neurilemoma)
Combined Neurofibroma Neurofibrosarcoma
Vascular Angioma Angiosarcoma
Blood vessels Hemangioma Hemangiosarcoma
Lymph vessels Lymphangioma Lymphangiosarcoma
Cystic hygroma
Glomus cells Glomus tumor
Pericytes Hemangiopericytoma Malignant hemangiopericytoma
Granular cells Granular cell tumor Alveolar soft-part sarcoma
Blood forming Lymphoma, leukemia, myeloma
Tooth Odontogenic fibroma
Muscle
Smooth Leiomyoma Leiomyosarcoma
Skeletal Rhabdomyoma Rhabdomyosarcoma
Histiocyte Fibrous histiocytoma Malignant fibrous histiocytoma

3. Mixed-epithelial and
connective tissue
Tooth Odontoma
Ameloblastic fi broma Ameloblastic fibrosarcoma
Tumor-like lesions
Fascia Nodular faciitis
Lymph node and
epithelium Lymphoephithcliallesion
Nasal mucosa Nasal polyp
Giant cells Giant cell tumors
Odontogenic and
nonodontogenic Aneurysmal bone "cyst"
epithelium Cysts of jaws
Granulation tissue Pyogenic granuloma
Fibrous Fibromatosis (aggressive)
20 l. INTRODUCTION

FIGURE 2-2. Hemangioendothelioma. There is a

central normal mitotic figure (arrow). These lesions
are compactly cellular. Mitotic figures alone are not
indicative of malignancy.

FIGURE 2-3. Portion of a papilloma of oral mucosa.

The proliferative spinous and basal epithelial cells re-
semble normal squamous epithelium (well differenti-
ated), but there are numerous mitoses and some
cellular atypia despite the fact that this lesion was
benign.
 2. PATHOLOGY OF MALIGNANCY
FIGURE 2-4. Verrucous carcinoma of the oral cavity,
featuring prominent hyperplasia of spinous cells, in-
vaginations of surface plugged with keratin (rounded
areas) and broad, nodular rete ridges.
chondrocytes; such criteria lead to a diagnosis
of chondrosarcoma. For smooth muscle tumors
of the uterus, the mitotic index is more prog-
nostic than the grade of the tumor; even a mod-
erate number of mitoses suggests a leiomyosar-
coma.
Besides morphologic exceptions, clinical his-
tory or pattern is important [7, 8]. For example,
the usual squamous cell carcinoma offers no
problem in diagnosis unless it is sufficiently
poorly differentiated and does not resemble
epithelium. However, a verrucous carcinoma of
the oral mucosa is usually so well differentiated
that an incisional biopsy specimen may be inter-
preted as benign epithelial hyperplasia or a papil-
loma (figures 2-4 and 2-5). For this low-grade
malignancy, the clinical history, including size,
presence/absence of exophytic growth, and/or
local infiltration, is most important in rendering
a proper diagnosis. Schneiderian papillomas of
the nose are microscopically endophytic, mim-
icking malignancy. Position is important and, if
occurring on the lateral wall versus the medial
wall, such a lesion is associated with squamous
cell carcinomas [3]. Finally, the cylindrical cell
papilloma of the nose and paranasal sinuses may
be confused with an adenocarcinoma [3].
21
The morphology of tumors and their be-
havior, unfortunately, do not fit neatly into the
simplistic classifications as outlined. Tumors
derived from similar cells of origin but from
different areas may look alike histologically, but
may behave differently (figure 2-6). For exam-
ple, a squamous cell carcinoma of the lower lip
may be morphologically similar to one on the
lateral border of the tongue or the floor of the
mouth; however, the behavior will be markedly
different at each site. The lip carcinoma has an
excellent prognosis, as it rarely metastasizes;
however, carcinomas of the tongue and floor
have only a fair prognosis since they may have
already spread to regional lymph nodes at the
time of diagnosis. In general, as size increases
and location becomes more posterior, risk of
dissemination increases and the prognosis de-
creases.
As there can be variations in behavior of
tumors with similar morphology, there can be
variations of tumors at the same site. Such varia-
tions have led to subclassifications of malignan-
cies. In some instances, a subclassification has
clinical significance. For example, the salivary
gland malignancies are primarily adenocarcino-
mas. However, their subclassification by mor-
phology has proved to be important. As already
indicated, the adenoid cystic carcinoma (cylin-
droma), despite its bland morphology, is truly
malignant when followed for a long time. By
22 I. INTRODUCTION
contrast, it differs markedly in behavior from an
adenocarcinoma not otherwise subclassified.
Most patients with adenocarcinoma are dead of
their disease before the five-year follow-up ver-
sus the 20-year period for cylindromas. Recent-
ly, another adenocarcinoma of salivary gland
origin has merited subclassification. Resembling
its morphologic counterpart in the breast, the
lobular adenocarcinoma of the salivary gland
does not behave aggressively, requires only con-
servative surgical removal, and does not recur
[16]. Similarly, liposarcoma of the myxoid type
has a better prognosis than the pleomorphic
type; it ~as a longer clinical course and rarely
metastasizes.
Besides an accurate diagnosis, the histo-
pathology can reveal other information of clin-
ical importance. Features to be noted are the
depth of invasion, type of growth pattern (i.e.,
expanding versus infiltrative border), the pre-
sence of vascular invasion and/or of perineural
involvement, the number of mitoses, the degree
of differentiation (grade of the tumor), and the
distance of the tumor from the margins.
Likewise, the histologic depth of dermal inva-
sion in a melanoma has prognostic significance.
The deeper the invasion, the less favorable is
the prognosis. In addition, the level of invasion
is highly correlated with the clinical height of
the lesion such that a "raised" tumor is most
likely to have a deep level of invasion and a
FIGURE 2-5. Verrucous carcinoma; high power of 4.
The cells are so well differentiated that there arc few
abnormalities except for the hyperplasia. Clinical
characteristics aid in diagnosis.
poorer prognosis than a "nonraised" tumor [17].
Perineural invasion, a common feature of the
adenoid cystic carcinoma (figure 2-7), infers
tumor spread and a poor prognosis. However,
perineural invasion is not always ominous.
o Region al
80 El
• Estimated
'0
deaths/new cases
50
30
LIP TONG U E MOUTH
FIGURE 2-6. Bar graph comparing and contrasting
by percent the extent that carcinomas of the lip,
tongue, mouth, and pharynx have spread versus
being localized at time of diagnosis combined with
the percent of estimated deaths divided by the esti-
mated new cases at these sites.
 2. PATHOLOGY OF MALIGNANCY 23

FIGURE 2-7. Perineural lymphatic invasion in an

adenoid cystic carcinoma of salivary gland. This may
indicate direct extension of tumor and a poor prog-
nOSIS.

FIGURE 2-8. Perineural arrangement of well-

differentiated squamous cells with keratinization in a
keratoacanthoma. This is not significant relative to
behavior of this spontaneously regressive lesion.
24 I. INTRODUCTION
It has been noted in the keratoacanthoma, a
"self-healing" low-grade tumor that does not
metastasize (figure 2-8) [18].
Evaluation
The most common and accurate method of di-
agnosing tumors is the biopsy [7, 19]. Most
areas in the head and neck are accessible for the
removal of tissue to be examined microscopical-
ly. The incisional biopsy is most commonly
used unless the lesion is sufficiently small to be
removed totally with margins at the first biopsy.
One should incise into the tumor and avoid
necrotic areas. Punch biopsies are very useful in
removing adequate tissue. Once removed, the
specimen should be preserved in saline and
placed as soon as possible into the preferred
fixative, depending on the type of laboratory
examination necessary. In most instances, neu-
tral buffered 10% formalin is preferred for
routine examination by light microscopy of
most tissues. Needle aspiration is useful for in-
accessible areas and for lymph node biopsies.
Caution should be exercised in biopsying
lymph nodes in the neck unless the primary is
known. It is now generally felt that an inci-
sional biopsy of a malignancy in the oral cavity
will not contribute to the spread of the tumor
in contrast to biopsies in the peritoneum.
In the uterine cervix and in the oral cavity,
exfoliative cytology is useful despite some false
negatives. Abnormal cells at or near the surface
may be scraped from suspicious lesions with a
tongue blade, spread on a glass slide, and fixed
with hair spray. When stained by the Papa-
nicolaou method, the variously differentiated
epithelial cells may be noted as well as abnormal
cel~s. Malignant or dysplastic cells have charac-
teristic changes (figure 2-9). Any suspicious or
positive findings for cancer cells require that a
follow-up biopsy be performed.
Grading and Staging
Grading and staging are two different ways of
evaluating malignant tumors [10, 12-14, 19].
Grading refers to the degree of cellular dif-
ferentiation similar to the tissue of origin. Staging
refers to the clinical, and the confirmed patho-
logic, extent of spread of the malignancy at the
time of diagnosis. Both may have prognostic
value, although there are times when grading
has little significance to the eventual outcome.
Since metastasis is the hallmark of malignancy,
clinical and pathologic staging may have more
FIGURE 2-9. Oral cytologic smear of a proven
epidermoid carcinoma. Clearly abnormal cancer cell
with reversal of nuclear-cytoplasmic ratio; hyper-
chromatic nucleus is noted (arrow). The other cells
are normal squames. The squame to the right of
cancer cell is keratinized and has no nucleus.
 2. PATHOLOGY OF MALIGNANCY
FIGURE 2-10. Well-differentiated epidermoid
(squamous cell) carcinoma. The tumor has many
areas with well-formed keratin (keratin pearls, black-
ened zones). It is connected to the surface and is in-
vading the connective tissue and undermining hyper-
plastic epithelium at right.
value because it addresses, the spread of the
tumor.
Grading is an assessment by the pathologist
of the extent that the malignant cells appear like
the parent cells (differentiated) or unlike the
parent cells (undifferentiated or anaplastic).
Generally, the system is used for carcinomas,
but is also applied to sarcomas. Regarding car-
cinomas, there may be a numerical or a non-
numerical system. In the numerical system,
four grades are used. Grade I tumors resemble
the parent tissue very closely (figures 2-10 to
2-13). The cells are well-differentiated. In a
squamous cell carcinoma, the cells are clustered,
have obvious attachments, and produce varying
quantities of keratin. Comparatively, Grade IV
tumors do not resemble epithelial tissue (figure
2-14). The cells are poorly differentiated or ana-
plastic. There may be little clustering, no observ-
able attachments, bizarre cell forms, and no
observable evidence of keratin formation. Grades
II and III are intermediate (figure 2-15). On
the other hand, many pathologists use terms for
grading rather than numbers. Thus, a tumor
may be well differentiated, moderately differ-
25
entiated, or poorly differentiated (undifferenti-
ated; anaplastic). Or, it may be low, moderate,
or high grade, corresponding to grades I, II-III,
or IV, respectively. Because many tumors vary
in their differentiation, grading is according to
the least differentiated area. The ultimate grade
is made after the whole tumor is sampled.
Sarcomas should also be graded. However, it
can be difficult to be consistent in establishing
grades for sarcomas and there may be more
overlapping of the grades than with carcinomas
[14]. It is of interest that a poorly differentiated
carcinoma may have a spindled pattern similar
to a sarcoma (figures 2-16, 2-17). In the head
and neck, there are a variety of spindle cell
lesions, some neoplastic, others reactive [6]. Sar-
comatoid carcinomas, nodular fasciitis, and
fibrosarcoma may resemble one another. Spe-
cial chemical stains, electron microscopy, and
other diagnostic means often are needed to
determine the cellular composition.
The prognostic value of grading is variable. In
general, the more undifferentiated a tumor is,
the more likely that it is rapidly growing and
has spread at the time of diagnosis. Thus, the
prognosis is poorer for an anaplastic carcino-
ma than for a well-differentiated one. Well-
differentiated carcinomas, as in the tongue,
however, have likely spread at diagnosis and
also have a poor prognosis despite the state of
differentiation (figure 2-6). On the other hand,
26 1. INTRODUCTION

FIGURE 2-11. Well-differentiated epidermoid car-

cinoma; higher power of figure 2-10. Keratin is at
left. The cells are recognized as spinous cells in a
haphazard configuration.

FIGURE 2-12. Well-differentiated epidermoid car-

cinoma; high power, figure 2-10. Features are
hyperchromatism, reversal of nuclear-cytoplasmic
ratio, prominent nucleoli, pleomorphism, loss of
polarity, lack of cellular cohesion, and a tripolar
mitotic figure (arrow).
 2. PATHOLOGY OF MALIGNANCY 27

FIGURE 2-13. Well-differentiated epidermoid car-

cinoma. Sheets of benign-looking spinous cells with
peripheral palisaded basal cells invading connective
tissue.

FIGURE 2-14. Poorly differentiated epidermoid car-

cinoma. 'There is no keratin formation. Intercellular
connections cannot be seen. 'There is vacuolization
and nucleoli are prominent.
28 I. INTRODUCTION

FIGURE 2-15. Moderately differentiated epidermoid

carcinoma. The cells are gathered like spinous cells
and are pleomorphic with loss of polarity. There is
less keratinization and more anaplasia.

FIGURE 2-16. Spindle cell carcinoma of tongue. These

spindle-shaped anaplastic cells were proven to be
epithelial by immunohistochemical peroxidase stains
for keratin and by finding tonofilaments by electron
microscopy.
 2. PATHOLOGY OF MALIGNANCY 29

FIGURE 2-17. Sarcoma of oral mucosa. High density

of prominent pleomorphic spindle-shaped nuclei. The M refers to the presence or absence
There is mitotic activity (arrow) and some collagen
formation. of distant metastases. Mo signifies no known
metastases; M \ that distant metastases are pres-
ent at specified sites.
grading seems important for chondrosarcomas, The combination of TNM categories is used
since the five-year survival rate for a low-grade to arrive at a "clinical" stage grouping. If all
malignancy is almost 80% in contrast to a rate suspicious tissues are examined pathologically,
of 20% for a high-grade malignancy. however, a more accurate staging is reached.
Staging of cancer differs from grading in that
it is based on the clinical extent of spread of the
cancer rather than on the histopathology. The
TABLE 2-3. Possible primary sites for tumors of the
TNM classification system adopted by the head and neck
American Joint Committee on Cancer Staging is
generally used [20]. T (tumor) refers to the size Oral cavity Oropharynx
of the tumor at the primary site or to the extent Lip Base of tongue
of local spread. Because of anatomic differences, Anterior .;-'3 of tongue Tonsil
the T category varies for each primary tumor at Floor or mouth Soft palate
each site. Table 2-3 lists the possible primary Gingivae Pharyngeal walls
sites for head and neck tumors. Some sites are Retromolar area
Buccal mucosa Hypopharynx
more accessible for measurement than are
Hard palate Pyriform sinus
others. Thus, for example, a T\ category for the Postcricoid area
oral cavity is a measurement, where the greatest Others Posterior wall
diameter of the primary tumor is 2 cm or less. Nasopharynx
For comparison, a T\ category for the hypo- Posterosuperior and Larynx
pharynx or maxillary sinus is not a measure- lateral walls Supraglottis
ment, but a finding that the tumor is confined to Paranasal sinuses False cords
its site of origin. Ethmoid Epiglottis
The N refers to regional lymph node involve- Sphenoid Glottis
ment at the clinical level. No means there are no Maxillary True cords
Nasal cavity Commissures
clinically positive nodes. N3 means there are
Subglottis
massive lymph nodes.
30 I. INTRODUCTION
TABLE 2-4. Staging: Staging TNM classification of
squamous cell carcinomas, upper aerodigestive tract
(except primary salivary gland tumors)
Stage I T\ No Mo
Stage II T2 No Mo
Stage III T3 No Mo
T\> T2 or T3 N\ Mo
Stage IV T4
AnyT
AnyT
This is called surgical or pathologic staging.
Table 2-4 shows the stage grouping for all
squamous cell carcinomas of the upper aero-
digestive tract [20].
This staging system, based on the best esti-
mate of the extent of disease before treatment, is
most useful. for developing a prognosis. For a
given tumor, the prognosis is closely related to
its clinical stage. Thus, a stage II carcinoma of
the tongue has a better prognosis than one with
stage IV. Carcinomas of the nasal cavity, para-
nasal sinuses, and larynx usually have an omi-
nous prognosis due to their advanced clinical
staging. In the sinuses, for instance, the tumors
manifest only after invasion has occurred [4].
Spindle cell neoplastic lesions of the head and
neck, though rare, can be very deadly. Their
prognosis is also based on size, location, and in-
vasion, i.e., clinical staging. Interestingly, those
spindle cell neoplasms that are superficial are
not life threatening [6].
The staging system is also useful in develop-
ing a treatment plan and evaluating its results.
Both radiation and surgical therapy offer a good
likelihood of a cure for stage I and stage II
epidermoid carcinomas of the head and neck.
However, the results for advanced (stages III
and IV) cancer in these sites are unsatisfactory.
Failures are due to recurrent, persistent disease
or to distant metastases. Studies have shown
that the risk of recurrence in stages III and IV
was almost 40% even when surgical margins
were satisfactorily free of tumor. In patients
with a clinically negative neck (no palpable
nodes), treated only for their primary cancer of
the tongue, 38% developed metastases in the
neck. The incidence increased to 77%, however,
in patients with stage III disease. Consequently,
studies utilizing elective radiation of the clini-
cally-negative neck have shown it to be effective
in eliminating subclinical foci of metastatic dis-
ease and In preventing subsequent metastases
[21].
Spread of Tumors
Benign tumors do not spread, but remain local-
ized. As they expand they compress adjacent
tissues and can cause atrophy of contiguous
structures. On expanding, they may cause a
collagenous capsule to form around them. How-
ever, extent of capsulization may be thick, thin,
or nonexistent. If a benign tumor is functional,
as in production of a hormone, it may create an
effect at a distant site. Examples are a pituitary
adenoma causing growth of the hands, feet, and
mandible by eliciting growth hormone, and a
parathyroid adenoma causing lytic lesions of
bones by elaborating parathormone.
Malignant tumors spread by several means
and may develop at a distant site (metastasis).
The process of metastasis is a series of interre-
lated steps, dependent on the properties of the
tumor cells and the response of the host, in
which cells of a malignant neoplasm disseminate
from the primary site to a distant site and then
develop into a secondary deposit [7,11-13,22].
Metastasis begins locally by direct invasion of
the stromal tissue of the host through mechani-
cal pressure, enzymatic activity by tumor or
inflammatory cells, and increased motility of
tumor cells. The malignant cells can penetrate
lymphatic or blood vessels. There they can
grow or they can embolize as single cells or as
groups of cells. In the vessel, they must avoid
defense mechanisms of the host, e.g., natural
killer cells. After successful embolization, the
tumor cells can invade distant organs by initially
adhering to capillary endothelial cells or to ex-
posed basement membrane of the capillary bed.
Next they infiltrate the distant organ tissue by
enzymatic activity. Then, by developing a
vascular network and by evading local host de-
fenses, the growth of the metastasis can ensue.
This process can be repeated, including dissemi-
nation from the metastatic site. The process for
a metastatic cell to survive is arduous and
appears to be selective rather than random [22].
The presence of cells within a blood vessel does
not mean that there will be a metastasis. Rather,
a selection of a subpopulation of cells from the
original tumor, but with characteristics for
enabling their survival, is necessary to develop a
metastasis [22, 23].
Vascular spread is via lymphatics, veins,
 2. PATHOLOGY OF MALIGNANCY
Carcinoma
UNormal" Dysplasia in situ
-.-.-.-.-;
.......
;,.•.•~. ......
...
;:.;-;.;.;.-
'-
-------------- ..
N eoplast ic
change
----------.,,7~'''(--------.-· ---)
Node
~·D ~
f- ()
Penetration Arrest
Prol iferation
(Metastasis)
Secondary organ
FIGURE 2-18. The development of a squamous cell
carcinoma and a metastasis. Features are invasion,
spread by lymphatics and blood vessels, and steps
progressing to a secondary neoplasm (metastasis).
and arteries. Generally, carcinoma invades the
lymph channels and sarcoma invades the veins.
However, both carcinomas and sarcomas can
eventually thus reach the systemic circulation.
Some carcinomas, such as thyroid, metastasize
via veins (figure 2-18).
Carcinoma invades the lymphatic vessels and
embolizes to lymph nodes (figure 2-19), lodg-
ing first in subcapsular sinuses, which act as a
temporary barrier. Eventually, the carcinoma
invades the node and carcinoma cells may reach
the main venous vessels by way of the thoracic
duct or venous supply of the lymph node. Thus,
palpation of lymph nodes draining a primary
site is important in staging and in prognosis.
Unfortunately, there is a poor correlation with
the size of a node and the spread of cancer. For
example, the experienced examiner may be
relatively accurate in palpating cervical nodes,
depending on the primary tumor. With primary
melanoma and lymphadenopathy, the nodes are
highly likely to be positive for melanoma. But,
if the primary is a verrucous carcinoma or a
carcinoma of the lower lip, then an enlarged
node is due more likely to inflammation than to
metastatic spread.
31
Carcinoma
(Epidermoid)
• • :.1F
.. .
~;~:,
........
•4!...':~
Basement
-If:.'-~ membrane
••
...--Invasion
• • - ..- Tumor
cell death
Capi Ilary
Tr ansport
lO,o ......
Embolization
The sites of metastases vary and are not predi-
cated on the richness of vascularity [12]. For ex-
ample, the spleen, despite its abundant lymph
drainage and blood supply, is rarely involved
with metastases. The same is true of skeletal
muscle. Periosteum, though well vascularized,
is similar to cartilage in that it serves as a barrier
to invasion. Thus, parosteal sarcomas may be
contained; indeed, they have a better prognosis
than endosteal osteosarcomas.
The most common site for metastases of most
malignancies is the liver. The lung is a frequent
site for sarcomas, but carcinomas from the
kidney, breast, and thyroid are also typical.
There are preferred sites for metastases by some
tumors. Cancers of the breast commonly spread
to the bones or brain; colonic cancers dissemi-
nate to the liver [23]. Bone is a common site for
carcinomas but not sarcomas. For example, car-
cinomas of the breast, prostate, thyroid, colon,
and the lung frequently metastasize to the
oral cavity (figure 2-20). It is not unusual that
the metastatic focus is the first sign of malignant
disease.
In the head and neck, metastases to lymph
nodes are common. A thorough palpation by an
experienced clinician is necessary for all tumors
in this region; positive findings will reflect on
the prognosis and even on diagnosis since most
nodal metastases from an unknown primary
32 I. INTRODUCTION
FIGURE 2-19. Intralymphatic nests of poorly differ-
entiated squamous cell carcinoma of esophagus.
. survival, accounting for a large percentage of
tumor are found in the neck. Many occult
tumors are discovered only by inspection of the
neck nodes [24, 25]. In fact, the location of cer-
vical adenopathy is the most useful parameter
for predicting the eventual histopathology of
an occult carcinoma. For example, multiple
supraclavicular and posterior cervical positive
nodes are frequently due to lymphoma or to a
metastasis from below the clavicle and account
for one-third of the occult primaries. Two-
thirds of the occult tumors occur in the head
and neck. Nasopharyngeal carcinoma usually is
asymptomatic until it presents as a metastatic
node, most often in the posterior cervical region
beneath the ear.
The significance of metastasis relates directly
to the survival of the patient. If a tumor is local-
ized at discovery, it is more amenable to treat-
ment and hopefully to cure. Cure in cancer is
measured in years of survival, usually by five-
year increments. An example of the significance
of the spread of malignancy at time of diagnosis
related to the prognosis is seen in figure 2-6.
Epidermoid carcinomas of the lip are usually
localized and do not metastasize. They have an
excellent prognosis with little chance of affect-
ing survival. By contrast, in the more posterior
oral areas, the carcinomas spread and metasta-
size to a much higher degree. This spread affects
deaths; almost 50% of patients with cancer of
the pharynx die of their disease [15].
Development of Neoplasia
Current concepts in carcinogenesis state that
development of neoplasia is a multistep process
whereby various factors chiefly act on target
cell chromosomes. Three events that are impor-
tant are initiation, promotion, and progression
(figure 2-21). In initiation, a low dose of true
carcinogen may cause genetic change. Viruses,
chemicals, and ionizing radiation may induce
a cell or cells to be potentially neoplastic. A
promoting agent, repeatedly applied, enhances
the genetic changes and leads to the prolifera-
tion of cells and the development of a tumor.
The classic experiments by Berenblum [26]
support these concepts. In these studies, chem-
ical carcinogen, a polycyclic hydrocarbon, was
applied once to the skin of a mouse. Then,
croton oil, an irritant but not a carcinogen,
was applied repeatedly for weeks, after which
time a benign tumor appeared. Without the pre-
treatment by the carcinogen or follow-up treat-
ment by the irritant, a co-carcinogen, no tumors
appeared. Thus, the true carcinogen was the
initiator; the irritant was the promoting agent
or enhancer.
Human correlates to this animal model exist.
Phorbol esters are tumor promoters that playa
 2. PATHOLOGY OF MALIGNANCY 33

FIGURE 2-20. Metastatic adenocarcinoma of colon

to oral mucosa. Glandlike structures resembling
primary tumor of colon are nested in submucosa.
The overlying epithelium is intact and in no way
resembles the tumor.
FIGURE 2-21. Generalized diagram on the develop-
ment of neoplasia incorporating Pierce's concept of
the involvement of cells of renewal and the concept of
progression. The three basic steps are initiation,
promotion, and progression. If a differentiated cell at
mitosis has nuclear change, then a benign tumor re-
sults. If a stem or reserve cell has nuclear change, then
a malignant tumor results.

VI
cot
.oJ
@--~)CB
-~~
Q.
Init ialion
o Stem Potential

~ ~
W cell cell
Z ____ -;;:ss\O(\
----t)
Initiation
0 -------4)
Promotion
.: \,t o

BENIGN
Differentiated
cell
----------------TIME--------------------~)
34 1. INTRODUCTION
role in human cancer [27]. Recently, it has been
shown that the phorbol esters may also damage
the genetic material, in addition to that caused
by the initiating agent [28]. They may bind to
the inner aspect of the cell membrane and cause
the production of activated forms of oxygen
that can damage DNA. Alternately, they may
bind to cells and, by phosphorylating cellular
proteins, affect the production of a factor that
induces cellular growth, leading to proliferation
[29].
According to Pierce's concept [30], cancer is
the pathology of cells involved in tissue mainte-
nance and renewal. The cells involved are the
stem or reserve cells. The outcome depends on
the stage of differentiation of the targeted stem
cell. If carcinogenesis is superimposed on a post-
mitotic or differentiated stem cell, then a benign
tumor will form. If carcinogenesis is super-
imposed on a mitotic or undifferentiated stem
cell, then a malignant tumor will form. The neo-
plastic potential increases with time as long as
the promoting agent is applied (figure 2-21).
Thus, in the uterine cervix and in the oral cavity,
with time there may be a progression from pre-
invasive dysplasia to invasive carcinoma. It is
emphasized, however, that this occurs through
the poorly understood phase of progression
[27]. Progression implies a decisive change in
the cells whereby they acquire invasive prop-
erties. It also infers that some altered cells may
not change further and that there are other fates
for the dysplastic lesions. There can also be the
development of a malignancy without ever
having a premalignant phase.
Even benign tumors, over several years, can
transform into malignant tumors. By acquiring
genetic alterations, the benign tumor may pro-
gress to malignancy because the genetic altera-
tions are a permanent and irreversible qualitative
change. An example is the pleomorphic adeno-
ma. This common lesion of salivary glands is
slowly growing and may reach considerable size
over many years. In a small percent of cases,
there may be a sudden spurt of growth that his-
tologically correlates with a carcinoma arising in
an otherwise benign tumor.
It has been shown that a malignant tumor is
composed of a heterogeneous group of stem
cells and well-differentiated cells [22, 23]. At the
electron microscopic level, the stem cells them-
selves show varying degrees of differentiation.
In an epidermoid carcinoma, undifferentiated
stem cells would give rise to malignant cells.
Eventually, even those cells differentiate and
form keratin. Sometimes keratin levels seem
high and other times they are lowered. Im-
munohistochemical stains for keratin have been
produced to show the presence of keratin in
poorly differentiated epidermoid carcinomas
[31]. Electronmicroscopic studies are also use-
ful in identifying the cell of origin in undiffer-
entiated tumors. For epidermoid carcinomas,
tonofilaments within the cytoplasm and desmo-
somes are diagnostic indicators.
There is evidence that a rearrangement of
genetic material represents a common step in
the development of malignancy. Through the
technique of high-resolution banding for look-
ing at chromosomes, it has been shown that
malignant cells of most tumors have chromo-
somal defects [32]. Cancer cells are abnormal in
karyotype and phenotype. Translocations of
genetic material occur in many leukemias and
lymphomas. Specific band deletions are noted in
several carcinomas. In a few tumors, there is
trisomy resulting in extra gene dosage. There
are three recognized chromosomal alterations
leading to malignancy. The first is genomic
rearrangement such that a stem cell becomes
a malignant cell. The second is an alteration of
the control of the steps of cellular proliferation
and differentiation of committed stem cells. The
third is a nonrandom secondary defect, seen
during tumor evolution, that enhances tumor
aggressiveness. In fact, large chromosomal
change is associated with lethality and invasive-
ness.
Genetic configuration or alteration may
result in neoplastic transformation. Oncogenes
(oncogenic genes) have been noted in over 20
animal cancer viruses. Also found in humans,
oncogenes are found in various human cancers
and on specific human chromosomes [32].
There are recent reports that the oncogene of
simian sarcoma virus is very closely related to a
human gene coding for platelet-derived growth
factor. This provides evidence that the oncogene
may contribute to malignant transformation of
cells by inappropriately producing a product
that normally stimulates cell growth. Thus, the
virus can "turn on" a cellular gene that was
active only in embryogenesis, when rapid cell
division was necessary. But, if reactivated later
in life, the expression of that gene could inap-
propriately transform a cell into a cancerous
one. Significant to this hypothesis, cancer cells
often behave like immature, undifferentiated
 2. PATHOLOGY OF MALIGNANCY 35

FIGURE 2-22. Focus of early invasive epidermoid

carcinoma between hyperplastic epithelium of oral
mucosa.

FIGURE 2-23. Two other separate foci of early

carcinoma from tissue adjacent to figure 2-22.
36 I. INTRODUCTION

FIGURE 2-24. Well-differentiated epidermoid carino-

rna at right next to moderately dysplastic epithelium
with a focal zone of inflammatory cells. Frequently,
dysplasia is noted adjacent to oral carcinomas.

FIGURE 2-25. Normal squamous epithelium of oral

mucosa. The basal cell layer (with mitoses), spinous
cell layer, and parakeratotic surface layer are well
oriented over connective tissue.
 2. PATHOLOGY OF MALIGNANCY
cells. In Burkitt's lymphoma (strongly associated
causally with the Epstein-Barr virus), there
are defective chromosomes, 8 and 14, with a
translocation of oncogene material next to a
break in the chromosome. By a mechanism still
unknown, the rearrangement of chromosomal
material may activate the oncogene that may
trigger or enhance malignant growth.
Most cancers result from the proliferation of
a single transformed cell. Superimposed on the
monoclonal group of cells are mutations that
occur through evolution of the tumor. Ulti-
mately, most tumors are apparently heter-
ogeneous [22]. Indeed, metastases are heter-
ogeneous. Even at the light-microscopic level,
one can note that a single cancer is composed of
a mixture of cells. These cells have different
properties. The subpopulation of cells vary in
their ability to spread, to react to drug therapy,
and to provoke immune responses.
Although most cancers are originally uni-
cellular, some are initially multicellular, as evi-
denced by the appearance of multifocal tumors.
In the head and neck, there is an incidence of
FIGURE 2-26. Mild epithelial dysplasia of oral mu-
cosa. There is hyperchromatism, reversal of nuclear-
cytoplasmic ratio, and loss of polarity in and about
basal cell region. The upper layers are not affected.
There is a dense focal infiltrate of lymphocytes and
plasma cells beneath the epithelium. This pattern
could be mistaken for lichen planus.
37
10% of multiple primary squamous cell carci-
nomas [33]. They are geographically separate
and do not represent a metastasis. The prog-
nosis is poor, in that the five-year survival rate
of patients with multiple tumors is 9%. Such
multifocal occurrence supports the ideas of
field cancerization and "condemned" mucosa
(figures 2-22 and 2-23). Certainly several
mucosal sites are being affected at once by
factors contributing to malignancy.
The concept of a possible progression from a
precancerous lesion (dysplasia) to an in situ
condition to an invasive carcinoma must be con-
sidered as well. This is true for the natural his-
tory of development of cancer in the uterine
cervix [34] and is strongly suggested for cancers
of the mucous membranes of the head and neck.
In a retrospective study of oral carcinomas [35]
where there was adjacent epithelium, epithelial
dysplasia was noted next to the carcinoma in
75% of the cases (figure 2-24). Studies of pa-
tients with oral dysplasia or carcinoma in situ
who were not treated after biopsy show that a
large percent do develop invasive cancers.
Epithelial dysplasia is an abnormal growth
of the epithelium with a disarray of cells with
varying undifferentiated characteristics. There
is hyperchromatism, loss of polarity, reversal
of nuclear-cytoplasmic ratio, mitotic activity,
(often in the spinous cell layer), and sometimes
abnormal mitoses. All characteristics of malignan-
38 1. INTRODUCTION
cy are present except for invasion. Dysplasia is
mild if the changes occur about the basal cell
layer (figures 2-25 and 2-26), moderate if they
involve the basal and the spinous cell layers, and
severe if the entire thickness·of epithelium is in-
volved (figure 2-27). The term carcinoma in situ
is applied when the entire thickness of epithe-
lium, including the surface layer, shows atypical
changes . These criteria are used for carcinoma
of the uterine cervix where this continuum of
change is called cervical intraepithelial neoplasia
(stage 0 carcinoma). In the cervix, as the dif-
ferentiation decreases, the risk of progression
toward carcinoma increases [34]. However,
similar criteria may not be useful for other
mucous membrane dysplasias. Not infrequently
in the oral cavity, there may be anaplasia in the
deeper epithelial layers, but the surface layer
may still show maturation and differentiation.
Similar findings are true of Bowen's disease of
the skin. Also typical of oral dysplasia is the fre-
quent finding of "drop-shaped" rete ridges
(figure 2-28). Although it is helpful in diagnos-
ing dys'pl~si~, the.re are times when the "drops"
may mimiC mvaslOn.
As previously indicated, epithelial dysplasia
has several possible fates. There may be a pro-
gression to a malignant lesion; within dysplasia
FIGURE 2-27. Severe epithelial dysplasia or carcinoma
in situ. Atypical cells extend through all layers of
epithelium. However, there is no invasion into con-
nective tissue. Note bandlike round cell infiltrate next
to the atypical epithelium, a feature of oral dysplasia.
or carcinoma in situ the cells can acquire inva-
sive properties. There may be continued growth
or spread of the dysplasia, or the dysplasia may
simply persist. Some dysplastic lesions have
been removed totally (the margins of the re-
sected specimen being free of dysplasia) only to
find that there is a regrowth of dysplasia at the
resection site. This can be easily explained on the
basis that the clinician removed the end result of
the process, but the etiologic factors remain to
induce new changes. Lastly, the dysplasia may
regress. The exact fate, though, is not predict-
able and epithelial dysplasia is best considered
to be a premalignant condition. In addition, a
finding of dysplasia on the biopsy may indicate
that there is an associated carcinoma either
deeper in the specimen or at the edge of the
biopsy site.
There are circumstances where benign lesions
may mimic dysplasia. One example is lichen
planus. Both lichen planus and dysplasia charac-
teristically have infiltrates of immunologic cells
immediately subjacent to the epithelium. Dys-
plasia may have more plasma cells among the
lymphocytes than lichen planus, but since this
finding is not universal, there can be confusion.
Certainly there are cases of mild to moderate
 2. PATHOLOGY OF MALIGNANCY
FIGURE 2-28. Moderate to severe epithelial dys-
plasia. There are "drop-shaped" rete ridges filled
with atypical cells. The atypical cells almost extend to
the surface. Note the thinness of epithelium in areas
and extension of vessels close to surface. Clinically,
this lesion was erythroplakia.
dysplasia that have been misdiagnosed as lichen
planus and vice versa.
The clinical appearance of dysplasia is as vari-
able as its histology. From the histology, one
may see a keratinized surface indicating the le-
sion would be white (leukoplakia). Often, the
epithelium is thinned or the subepithelial capil-
laries are very close to the surface such that the
clinical lesion would be reddened (erythropla-
kia). Nonspecific lesions that are red and white
should be considered cancerous until proven
otherwise. Of the two clinical lesions, erythro-
plakia is either premalignant or malignant 90%
of the time. By contrast, leukoplakia does not
have a high malignant potential and has been
overstressed. On biopsy, 90% of keratotic
white lesions show hyperkeratosis without
dysplasia; 10% show dysplasia or malignancy.
Even clinically, only 4% of patients with leuko-
plakia that has been followed for many years
have developed a carcinoma. Nonetheless, many
epidermoid carcinomas are associated with
a white, keratotic lesion. Actinic keratosis is
a white lesion occurring on sun-exposed lips
or skin. Although considered a premalignant
lesion, only a small percent of cases develop into
39
a carcinoma. Interestingly, those carcinomas are
low grade and rarely metastasize.
In the nasal cavity, paranasal sinuses and the
larynx, 85%-90% of carcinomas are derived
from metaplastic epithelium [4]. Metaplasia re-
fers to the reversible substitution of one type of
adult cell for another type of adult cell. Through
reserve cells adapting to an abnormal environ-
mental change, e.g., tobacco, the epithelium can
change from a respiratory type, with its goblet
cells and other protective characteristics, to a
mature squamous epithelium that is not normal
to the area. Metaplasia is different from dyspla-
sia in that it is definitely reversible. However,
the constant turnover of the epithelium requires
an increase in mitotic activity. Exposure of the
cells to carcinogens in the mitotic phase can
predispose those cells to nuclear change and
eventual carcinogenesis.
In distinguishing neoplastic change, one must
beware that there are many lesions that can re-
semble malignant lesions [8]; yet, despite their
ominous appearance, their behavior is benign.
For example, pseudoepitheliomatous hyper-
plasia may be seen as a reactive process to an
underlying granular cell tumor of the tongue
(figure 2-29). It may resemble an invasive car-
cinoma of the tongue (figure 2-30) such that a
misdiagnosis may lead to unnecessary surgery.
Another condition is necrotizing sialometaplasia.
This benign, spontaneously healing condition
40 I. INTRODUCTION

FIGURE 2-29. Pseudo epitheliomatous hyperplasia of

epithelium in granular cell tumor of tongue. This is
benign epithelial hyperplasia that can be mistaken for
malignancy.

FIGURE 2-30. Well-differentiated epidermoid carci-

noma of tongue. Compare this pattern of invasion
with figure 2-29.
 2. PATHOLOGY OF MALIGNANCY 41

FIGURE 2-3\. Active proliferating granulation tissue.

Note the large bizarre spindle-shaped cells that re-
semble malignant cells. Scattered inflammatory cells
aid in diagnosis.

FIGURE 2-32. Squamous odontogenic tumor. Well-

differentiated islands of spinous epithelium sur-
rounded by flattened basal cells in a fibrous stroma.
This may resemble ameloblastoma, or invasive or
metastatic carcinoma. None of the cells is atypical
and the lesion is benign.
42 I. INTRODUCTION
mimics cancer both clinically and microscopi-
cally. Actively proliferating granulation tissue
may have bizarre cells and a pattern mimicking
malignancy (figure 2-31) or tissue that has been
irradiated previously for cancer. Similarly, the
squamous odontogenic tumor (figure 2-32) is a
benign, nonaggressive odontogenic neoplasm,
clinically resembling periodontal disease, whose
microscopic pattern can be mistaken for ame-
loblastoma or even for invasive or metastatic
squamous cell carcinoma.
Epidemiologic studies have linked the major
causes of cancer to long-term exposure to en-
vironmental factors, such as chemicals, ionizing
radiation, and viruses. The immune system is
definitely involved and may even playa role as a
co-carcinogen. Patients with head and neck can-
cers have a: depression of their cellular immun-
ity. Both the numbers of T cells and their func-
tion are decreased even in the early stages of
malignancy [36].
Ionizing radiation is well recognized as a
factor in carcinogenesis. The greater the sun ex-
posure to the skin, the greater is the risk of
developing a carcinoma. Even therapeutic radia-
tion is implicated. Postradiation sarcomas may
develop several years after treatment for benign
or malignant conditions. In a study of 143 pa-
tients who were treated with radiation to the
head and neck for benign conditions, it was
found that the thyroid, parathyroid, and sali-
vary glands can develop malignancies with a
latent period of up to 30 years [37].
The carcinogens of the upper aerodigestive
tract are mainly chemical, with radiation and
viruses likely playing some role. Tobacco, as in
lung cancer, is the major factor. Co-carcinogens
or promoters are ethanol, chronic sepsis, mal-
nutrition, irritation, immunosuppression, and
genetics (family risks). Squamous cell carcino-
ma, the primary cancer of the head and neck, is
strongly associated with long-term tobacco and
alcohol usage. If the patient continues to smoke
after treatment, the risk for recurrence is great.
Some carcinomas are associated with occupa-
tional hazards. There is an increased incidence
among nickel workers and woodworkers. For
nasopharyngeal carcinoma, there is a genetic
predisposition in that it is 25 times more
predominant in Chinese descendants. In addi-
tion, the Epstein-Barr virus plays a major causal
role in nasopharyngeal carcinoma as well as in
Burkitt's lymphoma [38].
References
1. Batsakis JG: Tumors of the head and neck: clini-
cal and pathological considerations. Baltimore,
Williams and Wilkins 1979.
2. Batsakis JG, Regezi JA: The pathology of head
and neck tumors: salivary glands, part 1. Head
Neck Surg 1:59-68,1978.
3. Batsakis JG: The pathology of head and neck
tumors: nasal cavity and paranasal sinuses, part 5.
Head Neck Surg 2: 410-419,1980.
4. Batsakis JG, Rice DH, Solomon AR: The patho-
logy of head and neck tumors: squamous and
mucous gland carcinomas of nasal cavity, para-
nasal sinuses, and larynx, part 6. Head Neck Surg
2:497-508,1980.
5. BatsakisJG, Solomon AR, Rice DH: The patho-
logy of head and neck tumors: neoplasms of
cartilage, bone and the notochord, part 7. Head
Neck Surg 3:43-57,1980.
6. Batsakis JG, Rice DH, Howard DR: The patho-
logy of head and neck tumors: spindle cell lesions
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Head Neck Surg 4 :499-513, 1982.
7. ,Silverman S: Oral cancer. New York, American
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8. Rosai J, Ackerman LV: The pathology of
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9. Rosai J, Ackerman LV: The pathology of
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10. Rosai J, Ackerman LV: The pathology of
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12. Cawson RA, McCracken AW, Marcus PB:
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14. Enzinger FM, Weiss SW: Soft tissue tumors. St
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15. Cancer statistics: CA 33:9-10,1983.
16. Freedman PD, Lumerman H: Lobular carcinoma
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19. Scully RE, Binder SC, Legg MA: Pathological
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principles. In: Cancer manual, 6th edn. Boston,
American Cancer Society, 1982, pp. 29-36.
20. Baker HW: Staging of cancer of the head and
neck: oral cavity, pharynx, larynx, and paranasal
sinuses. CA 33:130-133,1983.
21. Vikram B, Farr HW: Adjuvant radiation therapy
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22. Fidler lJ, Hart IR: Biological diversity in
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23. Marx J: Tumors: a mixed bag of cells. Science
215:275-277, 1982.
24. Johnson JT, Newman RK: The anatomic loca-
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carcinoma. Otolaryngol Head Neck Surg 89:54-
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25. Batsakis JG: The pathology of head and neck
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head and neck, part 10. Head Neck Surg 3:409-
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26. Bereblum I: The carcinogenic action of 9, 10-
dimethyl-1, 2-benzanthracene on the skin and
subcutaneous tissue of the mouse, rabbit, rat, and
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33. Gluckman JL, Crissman JD, Donegan JO: Mul-
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 3. BIOLOGY AND BIOCHEMISTRY
OF
METASTATIC CELLS
James E. Talmadge
Lance A. Liotta
Robert R. Kahn
There have been remarkable and continuing
advances in the techniques for the diagnosis and
treatment of primary neoplasms; however, the
growth of tumor cells in organs distant to the
primary tumor remains responsible for most
deaths from cancer. Conventional therapy may
be effective when primary neoplasms are de-
tected before metastasis has occurred, but there
is increasing evidence that metastasis occurs in
most patients prior to the time of diagnosis.
There are several reasons for our inability to
control the growth of metastases. One problem
is the delivery of effective levels of cyto"toxic
agents to the metastasis without host toxicity,
but the most formidable obstacles are the heter-
ogeneous nature of cancers, as well as the
diversity among metastases and their response
to therapeutic agents. Improved treatment of
metastases will be achieved only when the under-
lying pathobiology of the metastatic process
is better understood.
Cancer metastasis is the result of a sequence
of events involving interaction between the
malignant tumor cells and their host. The pro-
cess is a continuum, but can be divided arti-
ficially into five steps: (1) growth of the primary
tumor, followed by invasion of cells from the
primary tumor into the surrounding tissue to
Research sponsored by the National Cancer Institute,
HODS, under contract NOl-23910 with Program Re-
sources, Inc. The contents of this publication do not neces-
sarily reflect the views or policies of the Department of
Health and Human Services, nor does mention of trade
names, commercial products, or organizations imply en-
dorsement by the US Government.
Peterson et ai., HEAD AND NECK MANAGEMENT OF THE CANCER PATIENT.
© 1986. Martinus NijhoJf Publishing. All rights reserved.
gain access into the blood and/or lymphatic
vessels, (2) release of tumor cells or emboli into
the circulation, (3) arrest of emboli in distant
organs, (4) tumor cell invasion (extravasation)
into the organ parenchyma and the multiplica-
tion of tumor cells, and (5) growth of vascular-
ized stroma into the new tumor focus. The
whole process may then be repeated.
Primary Tumor Invasion
The mammalian organism is organized into a
number of tissue compartments separated by
two types of extracellular matrix: basement
membranes and interstitial stroma. During the
complex process of invasion, tumor cells must
traverse these matrix barriers as they cross tissue
boundaries. Following the transition from in
situ to invasive carcinoma, tumor cells penetrate
the epithelial basement membrane and enter the
underlying interstitial stroma (figure 3-1). After
traversing the stroma, tumor cells gain access to
lymphatics and blood vessels for further dis-
semination. Tumor cell intravasation or extra-
vasation requires the penetration of the suben-
dothelial basement membrane of the capillary or
venule. In the organ where metastases are initi-
ated, tumor cells that have extravasated must
migrate through the perivascular interstitial
stroma before tumor colony growth occurs in
the organ parenchyma. Therefore, tumor cell
penetration of extracellular matrix occurs at
multiple stages in the metastatic cascade. In-
vestigation of the biochemical interactions of
tumor cells with the matrix may provide insight
45
46 I. INTRODUCTION
into the mechanism of tumor invasion.
The tumor can biochemically modify the
extracellular matrix in the following ways:
1. Destruction of matrix components associated
with invasion. Matrix degradation is prob-
ably restricted to localized regions where
active invasion is taking place. Such matrix
destruction may be caused by proteinases
elaborated by tumor cells and/or host cells.
Marked disorganization or frank loss of the
basement membrane is a general finding dur-
ing the transition from benign to malignant
epithelial neoplasms [1, 2].
2. Accumulation of matrix components (so-
called scar or schirrous reaction) by host cells
in response to the presence of the tumor.
Desmoplasia is the term applied to the
phenomenon of excessive accumulation of
connective tissue associated with breast,
bowel, and prostate cancers [3, 4].
3. Synthesis of matrix components by tumor
cells. Matrix components synthesized by a
tumor cell are generally of the same rype pro-
BASEMENT
MEMBRANE
DEGRADATION
FIGURE 3-1. Scheme of invasion. During the process
of invasion, tumor cells must penetrate the basement
membrane (EM). The tumor cells attach to the ex-
posed BM in part via attachment factors such as lami-
nin, fibronectin, and proteoglycans. Next, the BM is
degraded by local proteolysis, which may involve
several different proteases. Tumor cell locomotion
then allows the cells to move into the interstitial
stroma, where they may then invade vascular BM or
lymphatics.
duced by the normal cell counterpart [5, 6].
The actual amount of matrix produced by the
tumor cells is frequently much less than that
produced by the normal counterpart [5, 7].
The fact that tumors are histologically heter-
ogeneous is well known to any pathologist [8].
Some zones may be poorly differentiated,
anaplastic, and invasive, whereas other zones
of the same tumor may be composed of regular
cells forming differentiated structures such as
pseudoducts. Tumors are heterogeneous with
regard to a number of phenotypic properties,
including metastatic propensity [8]. Therefore,
for a given tumor, one of the above three types
 3. BIOLOGY AND BIOCHEMISTRY OF METASTATIC CELLS
of matrix modification may predominate, or all
three may take place simultaneously in different
regions of the same tumor.
Three-step Hypothesis
The host extracellular matrix is a mechanical
barrier that does not normally contain preexist-
ing passageways for cells. In the interstitial stro-
ma and bone, the spacing of the collagen fibers
is at least two orders of magnitude less than the
diameter of a cell. The basement membrane is a
tough distensible structure that is impermeable
to colloidal carbon. The insoluble nature [9-11]
of the basement membrane is in part due to the
unique arrangements of type-IV collagen mole-
cules, which are interconnected at their end re-
gions to form a hexagonal network. The matrix
becomes focally permeable to cell movement
only during specific conditions such as normal
tissue remodeling, wound healing, inflamma-
tion, and neoplasia. Cellular infiltration of the
matrix undoubtedly depends on multiple fac-
tors, including cell motility, character of the
specific tissue matrix, chemotactic factors, and
cell-cell interactions [12]. Since it is unlikely
that cell motility alone can provide mechanical-
ly the means to penetrate many matrix barriers,
it has been postulated that such penetration is
facilitated by the local release of hydrolytic
enzymes that solubilize the matrix [13-25].
The sequence of biochemical events during
tumor cell invasion of extracellular matrix can
be divided into three steps. The first stage is
tumor cell attachment to the matrix. Attach-
ment may be mediated by specific glycopro-
teins such as laminin or fibronectin [26-36] or
through tumor cell plasma membrane receptors.
Following attachment, the tumor cell secretes
hydrolytic enzyme (or induces host cells to
secrete enzymes), which can locally degrade the
matrix (including degradation of the attachment
glycoproteins). Such enzymes may be mem-
brane-bound or secreted. Matrix degradation
most likely takes place in a highly localized re-
gion close to the tumor cell surface, where the
amount of active enzyme outbalances the natu-
ral protease inhibitors in the serum and in the
matrix itself [37,38]. The third stage of invasion
is tumor cell locomotion into the region of the
matrix modified by proteolysis. The direction
of the locomotion may be influenced by chemo-
tactic factors. The chemotactic factors derived
from serum or local parenchyma may in part
47
influence the organ specificity of metastases.
Continued invasion of the extracellular matrix
may take place by cyclic repetition of these
three events.
Histologic Evidence for Collagen
Degradation during Tumor Invasion
Histopathologic studies of human tumor inva-
sion reveal a marked local alteration in the col-
lagen adjacent to the invading neoplastic cells.
Morphologic studies were carried out on
human tumor specimens that had been fixed in
formalin, imbedded in paraffin, and sectioned at
5 or 811m. Specimens in which the tumor was
invading collagenous connective tissue were
studied for changes in the collagen adjacent to
the neoplastic cells; for this purpose, Van
Gieson and Mallory'S azan connective tissue
stains were employed. It was informative to
study basal cell carcinoma because in these
lesions the carcinoma penetrated the dense col-
lagen of the dermis and, in many cases, changes
in collagen were not obscured by an inflamma-
tory exudate or necrotic debris. Also, collagen
adjacent to the neoplasm could be compared
with that adjacent to hair follicles at the same
depth in the dermis. With one basal cell carcino-
ma, alternate sections were examined by mi-
croradiography utilizing a soft x-ray apparatus.
In the x-ray image thus obtained, the degree of
whiteness at any point is directly proportional
to the dry mass at that point, enabling one to
determine variations in collagen concentration
at different sites within the section.
Microscopic examination of carcinomas pene-
trating preexisting collagenous tissue revealed
many altered foci in collagen adjacent to neo-
plastic cells. Collagen fibers at these sites became
thin, separated, and less intensely stained. Ex-
amples of these changes are shown in figures
3-2A and 3-3A. Pleural and peritoneal surfaces
were trimmed away; a microradiogram of the
basal cell carcinoma (figure 3-3B) indicates that
the collagen adjacent to the carcinoma, in addi-
tion to being fibrillar and loose, is composed of
fibers that have a lower density than the col-
lagen slightly farther from the cancer. Altered
collagen adjacent to the carcinoma can be com-
pared with the dense collagen adjacent to a hair
follicle at the same depth in the dermis (figure
3-3C and D). The hypocellularity of the altered
connective tissue indicates that the collagen is
48 I. INTRODUCTION
not being newly formed, a process that could
also result in thin, loose, pale staining fibers.
When cancer invades cartilage, the main protein
of which is collagen, there appears to be simply
a disappearance of cartilage substance (figure
2B).
Example Demonstration of
Collagenase Activity in Human
Tumors
Extracts of human neoplastic and nonneoplastic
tissue were studied for collagenase activity using
native tendon collagen as the substrate. Young
collagen and old collagen were used as sub-
strates. Adult malignant tumors and organs were
obtained at autopsy or as surgical specimens and
stored at -20°C until used. Nonneoplastic
tissue was trimmed from the tumors and, when
possible, only firm, homogeneous neoplastic
tissue was employed. Crude extracts of the tis-
sues were prepared by adding equal volumes of
cold mammalian Ringer's solution, buffered at
pH 7.4, and homogenizing the tissues at appro-
ximately SOC with a ground-glass homogenizer.
The resulting suspensions were centrifuged at
4000 rpm for 20 min at 6°C. The supernates
FIGURE 3-2. (A) Adenocarcinoma of colon invading
collagen of serosa. Note altered collagen adjacent
to the neoplastic cells. Mallory's azan; X 128. (B)
Squamous cell carcinoma of bronchus destroying
bronchial cartilage. Mallory's azan; x 80.
were decanted and readjusted to pH 7.4 before
use.
Substrates were prepared from central ten-
dons of the diaphragm, obtained from autopsies
in which diaphragms were not involved in any
disease process. Pleural and peritoneal surfaces
were trimmed away and the remaining collagen
mats were stored at -60°C. The tendons were
then minced while frozen and ground to fine
suspensions in pH 7.4 mammalian Ringer's
solution at approximately SOC in a ground-glass
homogenizer. Volumes of the suspensions were
adjusted so that final concentrations were 20 mg
of tendon per milliliter.
For the determinations of collagenase activ-
ity, aliq uots of the tissue extracts were mixed
with aliquots of the tendon suspensions and the
mixtures were incubated at 37°C for 24 h. Ali-
quots of each tissue extract were incubated, in
triplicate, with suspension aliquots of two ten-
dons from individuals under 30 years of age and
with two from individuals over 60 years of age.
Rlanks for each tendon suspension were incu-
 3. BIOLOGY AND BIOCHEMISTRY OF METASTATIC CELLS
FIGURE 3-3. (A) Basal cell carcinoma invading col-
lagen of dermis. Note altered collagen at junction of
cancer and dermis. Van Gieson; x128. (B) Micro-
radiogram of cancer-dermis junction in section
adjacent to that of A. Darkness of fibers next to the
carcinoma indicates a decreased concentration of
collagen. x320. (C) Hair follicle in same section, at
same depth in dermis as cancer in A, showing dense
collagen immediately adjacent to the cells. Van
Gieson; x320. (D) Microradiogram of hair follicle of
C in adjacent section, confirming density of collagen.
bated with 0.5 ml Ringer's solution. Following
incubation, the mixtures were centrifuged at
2200 rpm for 10 min and the supernates were
discarded. Precipitates were washed with 1 ml
Ringer'S solution, after which centrifugation
was repeated and the supernates were discarded.
The precipitates were hydrolyzed and their col-
lagen content was determined by the hydroxy-
proline content. By considering collagen con-
49
tent of the tendon suspension blanks as 100%,
the percentage of collagen in each tendon
suspension that was solubilized by each tissue
extract was calculated.
Percentages of collagen solubilized by ex-
tracts of cancers and nonneoplastic tissues are
shown in table 3-1. Of the nonneoplastic tis-
sues, rather consistent collagen-digesting ability
was noted in extracts of blood cells, kidney,
and spleen. The extract of lung showed activity
toward two of the substrates, while the extract
of pancreas was anomalous in showing consid-
erable activity toward one substrate and none
toward the other three. Extracts of gastric
mucosa, colon, and liver had no collagenase
activity.
As a group, the cancer extracts showed great-
er collagen-digesting ability than those of non-
neoplastic tissue (significant at the p < 0.05
50 I. INTRODUCTION

TABLE 3-1. Percentages of collagen digested by extracts of cancerous and noncancerous tissue a

Age of tendon substrate (years)

Tissue extracted 6 11 14 15 18 60 65 72 80

Noncancerous
Lung 7.3 0 13.0 0
Spleen 7.1 7.0 0 5.3
Gastric mucosa 0 0 0 0
Colon 0 0 0 0
Liver 0 0 0 0
Pancreas 16.0 0 0 0
Kidney 7.9 7.1 9.6 7.9
Blood cells (ca. 3/4 WBC, '14 RBC by vol) 16.0 18.0
Cancerous
Lymphosarcoma in lung 0 4.0 5.7 12.0
Undifferentiated carcinoma
of lung, metastasis in lymph node 0 0 7.6 5.9
Adenocarcinoma of breast 0 36.0 0 18.0
Squamous cell carcinoma of mouth 34.0 20.0 16.0 15.0
Squamous cell carcinoma in 2.6 0 6.4 7.6
lymph node primary
undetermined
Adenocarcinoma of stomach 11.0 0 9.0 12.0
Adenocarinoma of stomach, metastasis 0 0 0 0
in lymph node
Adenocarcinoma of colon 0 0 5.3 5.0
Adenocarcinoma of rectum, metastasis 12.0 26.0 16.0 17.0
in liver
Adenocarcinoma of pancreas, metastasis 0 5.7 4.5 0
in liver
Squamous cell carcinoma of cervix, 0 9.0 5.5 14.5
metastasis in liver
a Eachvalue is the average of three determinations. When values of collagen exposed to extracts overlapped those of blanks, percentage digestion
was considered those of blanks. By analysis of variance, p :::: o.s for difference between digestion by cancerous and noncancerous tissue.

level). The stomach carcinoma metastatic to a
lymph node was the only one to show no activ-
ity and the breast carcinoma was anomalous in
demonstrating marked activity toward two of
the substrates and no activity toward the other
two. Data for four of the cancers (lymphosarco-
ma, carcinomas of colon and lung, and carcino-
ma in lymph node with undetermined primary)
indicate that the two old collagen substrates
were digested more extensively than the young
collagen substrates by the extracts. Only one,
the oral carcinoma, had more activity toward
the young substrates than toward the old sub-
strates. These data demonstrate that human
tumors contain significant amounts of collagen-
ase. A number of investigators have made
similar observations [13-25]. Numerous studies
have been conducted in an attempt to charac-
terize tumor-associated collagenases. Dresden et
al. [15] were the first to identify and partially
characterize a neutral protease derived from hu-
man neoplasms that cleaved type-I collagen.
Collagenase capable of cleaving type-I collagen
had been extracted from a variety of tumor tis-
sues. McCroskery et al. [39] purified a collagen-
ase from transplantable rabbit V2 carcinoma,
and Biswas et al. [40] demonstrated that the
tumor transplantation site may alter collagenase
activity. Wirl reported an increase in collagenase
activity associated with chemical carcinogenesis
of mouse skin [41, 42], while Abramson et al.
[43], Hashimoto et al. [16], Kuettner et al. [18],
Paranjpe [44], and Yamanishi et al. [45, 46]
identified collagenase activity in human tumors.
Collagenases that degrade interstitial collagens
I, II, and III have been partially purified and
characterized from tumor tissue by a number of
investigators [13-46]. Metal ion requirements,
 3. BIOLOGY AND BIOCHEMISTRY OF METASTATIC CELLS
pH optima, and chemical inhibitor susceptibil-
ity of the tumor-derived enzymes are similar to
classic vertebrate collagenase first described by
Gross and coworkers [47, 48]. Vertebrate
collagenases that degrade collagens I, II, and III
are calcium- and zinc-dependent enzymes that
function at neutral pH. These enzymes charac-
teristically produce a single cleavage in the col-
lagen molecule at 25°C, producing i and ~ size
(75% of the way from N terminus) triple helical
fragments. Vertebrate collagenase can attack
either individual collagen molecules in solution
or reconstituted insoluble collagen fibers.
Furthermore, this protease will degrade cross-
linked collagen fibrils, but at a slower rate than
fibrils with no cross-links [49]. Animal and hu-
man tumor collagenases produce a ~: t cleavage
of the collagen molecule and are inhibited
by metal-chelating agents and serum antipro-
teinases. The molecular weight of collagenases
degrading collagen type I derived from non-
neoplastic tissue ranges from 33,000 to 80,000,
depending on the tissue source. Tumor-derived
collagenases exhibited the same range of mo-
lecular weights. Woolley et al. [50] obtained
collagenase from human carcinomas and mela-
nomas. These proteases were shown to cross-
react immunologically with antibodies to col-
lagenase produced by rheumatoid synovium.
Therefore, tumor collagenases have many simi-
larities with collagenases produced by normal
tissues. Nevertheless, differences have been
noted between collagenase derived from tumors
compared with collagenase derived from normal
tissue. Woolley et al. [50] showed that two prep-
arations of human gastric carcinoma collagen-
ase were more resistant in inhibition by two
types of serum antiproteinases. This difference
may relate in part to the affinity constants for
binding of each enzyme to the inhibitor. We can
speculate that the antiprotease resistance of
tumor collagenase enhances its biologic activity.
Collagenases Specific for Basement
Membrane Collagens
More than six types of genetically and bio-
chemically distinct collagen types [5] have
been identified. These types of collagen differ
markedly in their susceptibility to proteases [5,
19, 51, 52]. Collagen types IV and V, which are
associated with the basement membrane, are not
susceptible to attack by classic vertebrate col-
lagenase, which cleaves collagens I, II, and III
51
[5, 19]. A separate family of collagenolytic en-
zymes was identified, which degrades collagen
types IV and V [53, 54]. A type-IV collagenoly-
tic metalloproteinase was identified and purified
from highly metastatic tumor cells [19, 20, 55].
A separate metalloproteinase was identified in
tumor cells that degraded type-V collagen [54].
The purified tumor type-lV-degrading metal-
loproteinase has a molecular weight of about
62,000, appears as a doublet on gel electropho-
resis, exists in a latent form, and has inhibitor
susceptibility and physiochemical properties
similar to those of classic vertebrate collagen-
ase. It produces specific cleavage fragments of
type-IV collagen at 25°C, with a major cleavage
site at a region approximately one-third of
the way from one end of the molecule. Even
though this protease does not degrade collagens
I, II, III, and V or native elastin, it is still uncer-
tain whether type-IV collagen is its only sub-
strate.
Separate metalloproteinases that degrade col-
lagens IV and V are not unique to tumor cells or
inflammatory cells. They are also produced by
normal involuting epithelial duct cells and other
tissues [56]. Such proteases are likely to playa
role in the selective physiologic turnover of
basement membranes during normal tissue re-
modeling. Collagen types 1, 2, and 3, found in
cartilage, are resistant to type-IV collagenase or
elastase. Collagen types 1 and 2 are cleaved by
type-V collagenase, whereas type-3 collagen is
cleaved by the classic type-I collagenase.
Correlation of Collagenase Activity
with Tumor Biologic Behavior
Invasion and metastases is a complex multistep
process. Undoubtedly, there are many neces-
sary biochemical properties that the malignant
tumor cell must possess to enable it to traverse
host cellular and matrix barriers, to survive in
a hostile environment, and to resist host immu-
nologic defenses. It would seem unlikely that
one biochemical property such as collagenase
production will quantitatively correlate with
metastatic propensity. This is because the be-
havior of tumor cells ultimately depends on the
net balance of its various properties. A tumor
cell with high protease activity may have re-
duced motility or high immunogeniciry. The
net result will be that the tumor cell will have
low metastatic potential. Even in the face of
such a complex situation, a number of investiga-
52 1. INTRODUCTION
tors have attempted to quantitatively correlate
tumor collagenase activity with biologically
agressive behavior.
The results of these studies have shown that
the collagenase activity of malignant tumor tis-
sue is consistently higher than in the corre-
sponding benign tissue. This is true for both
animal and human tumors [15, 16, 57]. Indeed,
collagenase activity of head and neck carcino-
mas [43] and bladder carcinomas was found to
correlate with clinical aggressiveness.
Considering that basement membranes are
traversed by tumor cells at many stages in the
metastatic process, it is reasonable to postulate
that type-IV collagenolytic (basement mem-
brane degrading) metalloproteinases will facili-
tate this process. A variety of tumor cells with
known metastatic behavior in vivo were com-
pared for the type-IV collagenolytic activity.
All the highly metastatic tumor cells were con-
sistently elevated in the amount of type-IV col-
lagenolytic activity [55], while normal fibro-
blasts or NIH 3T3 cells lacked enzyme activity.
In this study, metastatic sarcomas were shown
to contain significant type-IV collagenolytic
activity. For a series of tumor cells derived from
the same parent, a quantitative relationship ex-
isted between the amount of type-IV collage-
nolytic activity and the metastatic rate [55]. This
is not unexpected, since the outcome of the
metastatic process is dependent on many com-
plex tumor host factors, as mentioned above.
Nonetheless, degradation of the extracellular
matrix through collagenase and other matrix-
degrading proteases may be necessary but not
sufficient for tumor invasion to take place.
Cell Source of Collagenase
Although collagenases have been extracted from
both human and animal tumors, the cell source
of the collagenase is still questionable. Any
tumor mass is a heterogeneous mixture of both
tumor cells and host cells such as fibroblasts,
myofibroblasts, residual parenchyma, endothe-
lial cells, macrophages, and granulocytes. All of
these types of host cells are potentially capable
of producing collagenases or other proteases
that degrade noncollagenous matrix compo-
nents. Cultured tumor cell lines free of contam-
inating host cell such as sarcomas, carcinomas,
and melanomas have also been shown to pro-
duce collagenases. Even though tumor cells
have the potential to produce collagenases in
vitro, tumor cells do not necessarily produce
collagenases in vivo. Consequently, investiga-
tors have used antibodies to collagenase in an
attempt to judge the cell source and distribution
of this enzyme in vivo. Woolley [58] produced a
monospecific antibody to human rheumatoid
synovial collagenase. The antibody reacted only
with the active and not the latent collagenase.
Tumor collagenases showed cross-reactivity
with the antibody when used with cryosections
of human tumors. The immunoreactivity was
found to localize in melanoma and gastric carci-
noma regions where invading clusters of tumor
cells were present. The fluorescence was associ-
ated both with the tumor cell cytoplasm and the
adjacent connective tissues. Many regions of the
tumor section did not exhibit fluorescence.
Barsky et al. [59] studied the distribution of
immunoreactivity to type-IV collagenase in
human breast carcinoma frozen sections. Using
monospecific antibodies and the immunoperox-
idase technique, 100% of 25 malignant tumors
were positive and no (0/20) benign lesions were
positive. However, the pattern of immunoreac-
tivity in the individual malignant tumors ex-
hibited very heterogeneous distribution. In some
tumors, only 10% of the cells were positive.
These were usually localized at the perimeter of
the invasion front. In other tumors, the major-
ity of tumor cells exhibited positive staining. It
can therefore be postulated that tumor collagen-
ase is present in a heterogeneous distribution
associated with zones of active invasion. In vivo
tumor cells may "switch on and off" their col-
lagenase production. Alternatively, the tumor
cell population may be heterogeneous, contain-
ing subpopulations of cells that produce high
levels of collagenase.
Tumor Desmoplasia
Desmoplasia was first recognized to be asso-
ciated with malignant tissues by the ancient
Greeks, who used the term schirrous, meaning
hard or rocklike, to describe the appearance and
feel of many cancers [60]. Desmoplasia refers to
the formation of excessive extracellular matrix
surrounding invasive tumor cells. Desmoplasia
is neither a sine qua non nor a pathognomonic
sign of malignancy [60]. Some invasive tumors
like melanoma are seldom associated with a des-
moplastic response, whereas other tumors such
as infiltrating ductal breast carcinoma are almost
always associated with a marked desmoplastic
 3. BIOLOGY AND BIOCHEMISTRY OF METASTATIC CELLS
reaction. A few benign tumors (e.g., desmo-
plastic trichoepithelioma) are associated with a
similar increase in extracellular matrix [61]. In
certain carcinomas, i.e., schirrous breast car-
cinoma, it is the desmoplastic response and not
the neoplastic cells per se that is responsible for
the diagnostic "lump" on clinical examination.
Desmoplastic tumors exhibit a characteristic
hard gritty appearance on gross inspection.
The source and etiology of this increase in ex-
tracellular matrix have been poorly understood
and some controversy has arisen concerning the
cell or cells responsible for this matrical
increase. AI-Adnani et al. proposed that the in-
vasive tumor cells synthesized and secreted the
extracellular matrix [62]. In contrast, Jackson
and Orr argued that the desmoplastic response
is not newly synthesized matrix at all, but is,
instead, collapse of preexisting matrix [4]. In
contradiction to both these hypotheses, Barsky
et al. [59] and Iozzo et al. [63], each studying
extracellular matrix of a different tumor, con-
cluded that this matrix was synthesized by host
cells. In the former study, type-V collagen, a
collagen type not normally detected in normal
breast or fibrocystic disease, was found in in-
creased amounts in desmoplastic breast carcino-
ma and was localized to the stroma away from
the invasive tumor cells. In the latter study,
proteoglycan content consisting of increased
chondroitin-4- and 6-sulfate glycosaminoglycan
was altered in the matrix of colon carcinoma;
autoradiographic analysis revealed the source of
the sulfated proteoglycan to be the host stromal
cells and not the tumor cells.
In addition to the changes in the chemical
composition of the extracellular matrix of desmo-
plasia, cellular alterations have also been noted.
Seemayer and coworkers noted a markedly
increased number of myofibroblasts in the
stroma of desmoplastic breast carcinoma [64].
These cells are not normally present in breast
stroma, although they have been seen in orga-
nizing wounds and hypertrophic scars [65]. The
presence of myofibroblasts together with the
chemical alterations of the extracellular matrix
in the desmoplastic response to tumor invasion
suggests a possible link between these observa-
tions. Invasive tumors may elicit factors that
stimulate the formation or recruitment of
myofibroblasts, within the host stroma of
which, in turn, elaborate type-V collagen, pro-
teoglycan, elastin, or some other protein is
found in increased amounts in desmoplasia.
53
Such desmoplastic factors may be derived
directly from the tumor cell or may be derived
from products of matrix degradation by tumor
cells.
The characterization of the components of
the desmoplastic response and the mechanism
of their formation may allow us to understand
the biologic function of this response. Some
investigators have drawn analogies between
the desmoplastic response and an organizing
wound [66]. This hypothesis is based mainly
on the presence of certain substances like fibrin
in the matrix of both desmoplastic tumors
and wounds. However, there are differences
between healing wounds and tumor desmo-
plasia. Myofibroblasts do appear in organizing
wounds, but their appearance is usually tran-
sient rather than sustained as it is in desmoplasia
[65]. Furthermore, inflammatory cells and
granulation tissue appear as central features of
wounds, whereas in tumor desmoplasia the cen-
tral feature is clearly dense collagen and elastin.
The role of the desmoplastic response in limit-
ing the tumor invasive processes is not clear.
The desmoplastic matrix may be an attempt by
the host to "wall off" the invading tumor. This
may benefit the tumor by reducing access by
host immune cells.
Tumor Cell Heterogeneity
The concept of tumor cell heterogeneity, within
both human and animal tumors, is now well
established [67]. At the time of tumor diagnosis,
most human neoplasms are composed of sub-
populations of cells expressing distinctly differ-
ent phenotypes. This cellular diversity within
individual tumors represents the most formid-
able obstacle to the development of a new
approach to the therapy of neoplasia. Histologic
studies have long demonstrated morphologic
differences among cells within the same tumors
and represent the first observations of tumor
heterogeneity [68-70]. Tumor cell populations
within a primary neoplasm can be heter-
ogeneous in their sensitivity to cytostatics, as
demonstrated with cells from rat hepatomas
[71], methylcholanthrene-induced murine sar-
comas [72], murine lung carcinomas [73, 74],
murine melanomas [75-77], and mammary
tumors [78, 79]. Tsuruo and Fidler [76]
examined the in vitro sensitivity to various
chemotherapeutic agents of tumor cells from a
number of parent tumors, both rodent and hu-
54 1. INTRODUCTION
man, their in vitro cloned population, as well as
spontaneous metastases from these tumor lines.
Their findings demonstrated that differences in
tumor cell sensitivity to chemotherapy agents or
radiotherapy [80-84] exist among the cells
populating parent tumors that were cloned in
vitro as well as between the parent lines and
their metastatic subpopulations. A recent study
from Nicolson's laboratory using a rat mam-
mary carcinoma also demonstrated that the
same tumor cells from within a neoplasm can
vary in their sensitivity to radiotherapy [82],
chemotherapy [78], and hyperthermia [85].
Tumors have also been shown to be composed
of cells heterogeneous with regard to antigeni-
city and immunogenicity [86-104]. These varia-
tions can profoundly influence success of spe-
cific immunotherapy. In a recent study, Olsson
and Ebbesen [105], using a number of AKR
murine lymphomas, demonstrated that vaccina-
tion procedures against polyclonal tumors failed
to protect against tumor challenge because only
the dominant subclone was restricted in growth.
The minor subpopulations that did not consti-
tute a sufficient antigenic mass within the vac-
cine to stimulate an immune response were able
to proliferate following the vaccination and
eventually become the dominant population. In
other tumor systems, the successful stimulation
of a host immune response to tumor cells bear-
ing strong antigens has been found to result in
the emergence of tumor cell variants lacking the
antigen. For example, Reading et al. [106] ana-
lyzed a number of in vivo and in vitro selected
murine RAWl17 lymphosarcoma cell lines (and
clones derived from these cell lines) for their
metastatic properties and cell surface antigeni-
city and found that the ability to metastasize to
the liver was inversely correlated with their
expression of the antigenic RNA tumor virus
envelope glycoprotein GP70, as determined by
competitive radioimmunoassay. In this system,
successful metastasis apparently requires escape
from host immune surveillance via antigen dele-
tion of the highly metastatic lymphosarcoma
cells. Within other metastatic systems such as
the B16 melanoma, however, there appears to
be no relationship between metastasis and viral
antigens such as GP70 [107]. Other tumor mod-
els may have certain antigens that are increased
on metastatic cells. Shearman and Longenecker
[108] reported an increase in cellular antigen
content that directly correlated with the ability
of Marek's disease virus-transformed chick lym-
phoma cells to metastasize to the liver. Their
system examined a cell surface antigen, detect-
able with monoclonal antibody, whose level in-
creases directly with the ability to colonize to
the liver. There is, therefore, no simple rela-
tionship between the display of cell surface
antigens, antigenicity, and metastatic potential
when one examines a number of tumor models.
Cells within individual tumors have also been
shown to differ with regard to their growth rate
both in vitro and in vivo [109-115]' Tumor cell
populations can differ in the expression or pro-
duction of markers of differentiation, including
but not limited to appropriate pigmentation
[114, 116, 117], hormone receptors [118-126],
cell products and specialized biosynthetic en-
zymes [127-134], and various cell surface re-
ceptors for lectins [112, 135-138]. The subpop-
ulations within a tumor can also differ on the
basis of DNA content or karyotype as well as
the presence or absence of different marker
chromosomes within the various tumor cell
populations [113, 120, 128, 139-148]. Indeed,
heterogeneity has been demonstrated at the
gene level in a study utilizing a DNA probe
directed against murine mammary tumor
virus (MuMTV), which demonstrated a cellular
heterogeneity in the location and copy number
of the specific gene in strain GR mouse mam-
mary tumors [149, 150]. This is in accordance
with the heterogeneous expression of MuMTV-
coded genes within individual mammary tumors
[151]. Studies on the differential response of
balb/C mammary tumor subpopulations to
inducers of murine MTV gene expressions also
suggest that differences in the regulation of
MuMTV correlate with tumor subpopulation
heterogeneity [99].
The possibility that cells with differing
metastatic capabilities might coexist within the
same parental tumor was first suggested in 1939
by Koch [152], who isolated a highly metastatic
subline from the Ehrlich carcinoma tumor by
serially transplanting lymph node metastases.
The definitive demonstration of metastatic
heterogeneity within a parental tumor was
based on an adaptation of the classic fluctuation
analysis by Luria and Delbruck [153]. It was
reasoned"that, if a tumor was populated by cells
with uniform metastatic capaciry, isolated
clones from that tumor would produce equal
numbers of metastases whereas, if the tumor
was populated by cells with divergent metastatic
potential,. different clones would contain cells
 3. BIOLOGY AND BIOCHEMISTRY OF METASTATIC CELLS
with the capability of producing varying num-
bers of metastases [67]. An established cell cul-
ture of the B16 melanoma was divided into two
portions: one portion was maintained as a mass
culture, while the other portion was cloned to
produce several cell lines, each one established
from an individual cell. Equal numbers of
tumor cells, in single-cell suspension, from each
of the cloned lines and from the parental tumor
were injected into syngeneic mice. The animals
injected with the uncloned parental cell line
from mass culture all exhibited similar numbers
of lung metastases. In contrast, the cloned sub-
lines differed markedly from the parental tumor
line grown as a mass culture, as well as among
themselves in the number of metastases pro-
duced. Control subcloning experiments demon-
strated that this variability was not induced by
the process of cloning per se. Therefore, it is
clear that populations of cells with differing
metastatic potential can preexist within the orig-
inal tumor. Although B16 melanoma is a well-
established tumor line that has been maintained
by repeated passage in syngeneic hosts or cell
culture for many times the lifespan of its natural
host, the metastatic diversity observed within
this tumor is not an artifact caused by its
longevity. Comparable data have been observed
with another murine melanoma of recent origin
[116]. Furthermore, clonal variation in metas-
tatic properties is not unique to melanomas.
Comparable extensive heterogeneity with re-
gard to malignant metastatic properties has been
described in clones isolated from tumors of di-
verse histologic origins from mice [99, 113, 116,
154-158], rats [159, 160], chickens [161], and
hamsters rt621. In these studies, tumor cell
populations with differing metastatic pheno-
types isolated from primary tumors or cultured
'tumor cell lines were as heterogeneous as those
reported by Fidler and Kripke in 1978 using
B16 melanoma [67].
Nowell [142] has proposed that the genera-
tion of cell variants is an inevitable and fun-
damental feature of progressive tumor growth.
He proposed that tumor progression occurs via
a series of multiple but independent changes
in cellular properties, resulting in the rapid gen-
eration of clonal subpopulations with heter-
ogeneous phenotypes. At any time during pro-
gression, the number of subpopulations in a
tumor, and the extent of their phenotypic di-
versity, is dependent on the selection pressures
encountered during tumor growth. Selection
55
pressures could be either natural (e.g., assault by
host defense mechanisms; limiting nutritional
conditions) or exogenous (chemotherapy, radio-
therapy, hormonal therapy, or immuno-
therapy). Nowell's concept of tumor progression
also proposed that, as successive clonal subpop-
ulations emerged, they would display increased
genetic instability. This, together with the
selection pressures imposed by the host and/or
therapy, would increase the emergence of new
subpopulations of tumor cells with enhanced
metastatic capacities.
Recently this hypothesis was examined by
Cifone et al. [115]; they examined the metastatic
stability of several tumor lines with different
capacities for spontaneous and experimental
metastasis. Concomitantly, the rates of muta-
tion to ouabain resistance and/or 6-thioguanine
resistance of paired metastatic and nonmetastatic
cloned lines isolated from four different neo-
plasms was determined. Poorly metastatic and
highly metastatic clones were isolated from the
UV-2237 fibrosarcoma [163] and were culti-
vated in vitro for 72 or 60 days, respectively.
Simultaneously, both clones were also grown
subcutaneously in syngeneic mice. Then, cell
cultures were established from these solid
tumors and, one week later, subclones were iso-
lated. The ability of these subclones to form ex-
perimental metastases was compared with that
of subclones derived from clones grown in cul-
ture and to that of subclones isolated and frozen
when parent clones were initially established.
The patterns of behavior of all the subclones
derived from the poorly metastatic clone were
remarkably similar to that of the parent clone,
regardless of whether the subclones were derived
at the time of isolation or after 72 days of con-
tinuous growth in vitro or in vivo. In contrast,
after 60 days of cultivation in vitro or in vivo,
the metastatic behavior of the subclones derived
from the highly metastatic clone differed con-
siderably from that of the parent clone, suggest-
ing that the metastatic phenotype of the highly
metastatic clone was unstable. This rapid gen-
eration of diversity may have been caused in
part by increased genetic instability.
The rates of spontaneous mutation resulting
in resistance to ouabain or to 6-thioguanine
were determined for cells of the two UV-2237
fibrosarcoma clones using the fluctuation assay
of Luria and Delbruck [153]. The mutation rate
to ouabain resistance was threefold higher and
to 6-thioguanine was 4.6-fold higher in clones
56 1. INTRODUCTION
with high metastatic potential as compared with
clones with low metastatic potential. Similar
results were found when these studies were
extended to three other tumor systems. In
these studies with UV-2237 fibrosarcoma, K-
1735 melanoma, and SF-19 fibrosarcoma (spon-
taneous in origin), the increase in the rate of
spontaneous mutation to ouabain resistance
(4.6-, 7.0- and 5.8-fold, respectively) correlated
with the degree of metastatic capacity.
These results are in accord with the hypothe-
sis that tumor progression could occur as a re-
sult of acquired genetic alterations. However,
the evolution of metastatic heterogeneity did
not progress in a unidirectional manner (some
subclones were less metastatic than the parent
clone); therefore, the results are not incompati-
ble with Nowell's hypothesis [142]. These re-
sults suggest that benign (nonmetastatic) tumors
may have a lower mutational rate and may be
less heterogeneous than malignant (metastatic)
tumors, which are extremely heterogeneous
with perhaps a high mutational rate.
The Selective and Clonal Nature
of Metastasis
The preexistence of metastatic variants with-
in the primary tumor does not address the
question of whether the process of metastasis
is selective or whether the cells populating
metastatic foci represent a random assortment
of the cells contained within the primary neo-
plasm. If the process of metastasis is selective, as
has been suggested by previous studies, direct
evidence to support this contention would be
the demonstration that cells populating spon-
taneous metastases would be demonstrably
more metastatic than the cells within the paren-
tal neoplasm. This observation is obviously
dependent upon an initial tumor population
(parental tumor) being unselected and heter-
ogeneous with respect to metastatic potential as
well as the assumption that the metastatic
process per se exerts a selective pressure on
the tumor cells.
The initial studies from our laboratory to
address this question used three metastatic
variants of B16 melanoma [164]. These variants
were used to minimize those variables that
would be introduced by using tumor models of
varying biologic characteristics. The malignant
melanoma B16-F1 is an unselected tumor cell
line that metastasizes poorly following in-
travenous injection (experimental metastasis) or
footpad injection (spontaneous metastasis). The
B16-F10 tumor was selected ten times for its
ability to colonize the lungs following in-
travenous injection [165]. This tumor is highly
metastatic when examined in an experimental
metastases assay and is moderately metastatic in
the spontaneous metastases assay. The B16-BL6
tumor line was selected in vitro for its invasive
ability: it is moderately metastatic in an assay of
experimental metastasis and demonstrates a
high incidence of spontaneous metastases
following intrafootpad implantation [166].
The experimental design was as follows. The
tumor lines were implanted into the footpads of
syngeneic mice and, when the tumor reached a
1- to 1.2-cm diameter, the tumor-bearing leg in-
cluding the popliteal lymph node was resected.
Several weeks later, when a few mice in each
group appeared listless, the entire group was
killed. From each group, several well-isolated
pulmonary metastases were surgically excised
and established in cultures as individual cell
lines. The metastatic potential of the cells in the
parental tumor and their respective spontaneous
metastases were then examined utilizing assays of
both experimental and spontaneous metastases.
We found that tumor cells harvested from the
spontaneous metastases of the poorly metastatic
tumor cell line (B16-F1) had significantly more
metastatic potential following intravenous in-
jections than an equal number of cells from the
parental line. This increase in experimental
metastasis was also observed with tumor cell
lines from the spontaneous metastases obtained
from mice bearing the B16-BL6 tumor variant.
However, the increase in metastatic potential
of the cell lines from the spontaneous metastases
of B16-BL6 tumors was less than that observed
with the tumor cells from the spontaneous
metastases of the poorly metastatic B16-F1
tumor. In contract, tumor cells from the spon-
taneous metastases of the B16-F10 tumor line,
which had been previously selected for its abil-
ity to form lung colonies, did not exhibit an
increased lung-colonizing potential compared
with the parental tumor. This latter observation
was not attributable to the number of lung
colonies involved since the injection of fivefold
fewer tumor cells gives similar results, i.e., the
lung-colonizing potential of the tumor cells of
spontaneous metastases was comparable to that
of tumor cells from the parental tumor although
the total number of tumor foci was lower.
 3. BIOLOGY AND BIOCHEMISTRY OF METASTATIC CELLS
Subsequent studies from our laboratory using
the malignant melanoma of recent origin
(K1735), the ultraviolet-radiation-induced fibro-
sarcoma (UV-2237) and a cloned subline (clone
40), the Lewis lung carcinoma (3LL), and
the reticulum cell sarcoma of ovarian origin
(M5076) have confirmed these observations
[167]. Recently Pollack and Fidler [168] used
three-week-old nude mice to investigate
whether these animals, which lack functional T-
lymphocytes and express low levels of NK cells,
could provide a model to select metastatic
subpopulations from heterogeneous allogeneic
melanomas. Three-week-old nude mice received
an intravenous injection of a single-cell suspen-
sion of either the B16 or K-1735 malignant
melanoma cell line. From these mice, individual
pulmonary metastases were harvested and their
metastatic potential was assessed in both nude
mice and normal syngeneic mice. In every case,
the cells from the metastases colonized the lungs
with significantly higher efficiency than did cells
from the parental tumor. A continuation of
these studies by Kouslaski (unpublished results)
in nude mice, using a similar strategy, found
that lung colonies from the human melanoma
cell line (A375) contained a subpopulation of
tumor cells with an increased metastatic poten-
tial, which could be selected fo,r by experimental
metastases.
Neri et al. [169], in a study similar to ours
[164, 167], using the rat 13762 mammary carci-
noma, examined the selective or random nature
of metastasis. Tumor cells from the resected
parental mammary adenocarcinoma, following
subcutaneous injection into the mammary
footpad of syngeneic rats, metastasize at a very
low frequency to the lymph nodes and lungs.
However, cell lines from the rare individual
secondary tumor sites were inevitably metasta-
tic from a subcutaneous site within 23 days of
transplantation.
A study [170] using a herpes virus hominis
type II induced tumor line from a Syrian hams-
ter also confirmed the selective nature of metas-
tasis. The parent tumor exhibited a low level of
spontaneous metastasis from a primary sub-
cutaneous tumor site. Tumor lines established
from lung foci had an increased metastatic
potential, however, such that all animals in-
jected with cells from metastases developed
secondary foci within 40 days after the resection
of the primary tumor.
In a recent study, Poste et al. [171] examined
57
the metastatic properties of tumor cell lines
established from individual metastatic lesions
that were obtained after the intravenous injec-
tion of various B16 melanoma variants. They
found that cells populating the individual
metastases were inevitably metastatic. In con-
trast, the tumor cells within the parent tumor
included many nonmetastatic variants, Poste et
al. [171] concluded that subpopulations isolated
from different metastases from the same host
differ markedly in their metastatic ability and
that cells with either high or low metastatic
potentials, but not nonmetastatic cells, could be
recovered from metastases.
The conclusion that metastasis is a selective
process does not infer that it does not also have
a random component. Subpopulations of tumor
cells with metastatic capabilities do not always
complete the metastatic process to form a
secondary tumor foci; indeed, they rarely com-
plete the metastatic process. During the metas-
tatic process, tumor emboli are exposed to
vascular turbulence, to the monocytic cell host
defense system, and to natural killer cells, as
well as to other detrimental conditions that on
a random basis prevent the development of
secondary foci. There is, therefore, a random
element to metastases whereby not all cells (in-
deed less than 0.1 % of cells) with a metastatic
phenotype survive to form secondary nodules.
Nontheless, a tumor cell cannot form a metasta-
tic foci if it does not express all the attributes
needed to complete the metastatic process
within the constraints imposed by the host.
Two questions with important implications
for the design of cancer therapies are whether
metastases are clonal in origin and whether
multiple metastases in a host originate from the
same progenitor cell. If metastases arose from a
common progenitor, then a treatment modality
directed against one metastasis is likely to be
effective ,!gainst all other secondary growths as
well. Alternatively, if different cancer metas-
tases originate from different metastatic pro-
genitor cells, then their response to therapy is
likely to be heterogeneous. We examined these
questions in a study patterned after the classic
study by Becker et al. [172], which demon-
strated the pluripotential nature of bone marrow
stem cells. In our experiments, cells from a
metastatic variant of K-1735 melanoma (K-1735
Met-2) were exposed to x-radiation, which ran-
domly induces chromosomal breaks and re-
arrangements. A certain number of these breaks
58 I. INTRODUCTION
and rearrangements (if not lethal) resulted in
centric fusion chromosomes and would provide
marker chromosomes. We reasoned that if all
the tumor cells populating a single spontaneous
metastasis, which arose from a primary tumor
of x-irradiated tumor cells, exhibited the same
chromosomal rearrangements, the metastasis
would have been derived from one tumor cell. If
the tumor cells populating an individual spon-
taneous metastasis exhibited multiple chromo-
somal rearrangements, however, then the metas-
tasis would have arisen from more than one
progenitor cell. Obviously, the demonstration
of a multiple tumor cell origin of metastases
would be predicated on the stable expression of
the various marker chromosomes [173].
In these experiments, cells from K-1735 Met-
2 melanoma were exposed to 650 roentgens of
x-radiation and then injected into the footpads
of syngeneic C 3 H mice. When the tumors had
reached a diameter of approximately 1 cm, the
tumor-bearing leg was resected at midfemur to
include the popliteal lymph node. When several
of the mice appeared listless, they were necrop-
sied and well-isolated spontaneous metastases
were placed individually into primary culture.
We performed a chromosome analysis on at
least 100 spreads of each line from a spon-
taneous metastasis. In ten of 21 of these lines, all
the chromosomes were telecentric and, there-
fore, these metastases were not informative. In
the other 11 lines, single or multiple marker
chromosomes (submetacentric, metacentric, mi-
nute) were observed. In eight of these lines, uni-
que patterns of chromosomes were found in most
spreads, suggesting that each metastasis origin-
ated from a single cell. In the remaining three
lines, the pattern of markers varied, suggesting
a bimodal or multimodal origin. However,
G-banding analysis by Wolman indicated that
these variations probably represented evolution
within the individual metastases. Subsequent
experiments following a similar methodology
have confirmed this initial observation. These
studies indicate that many secondary tumor
nodules originate from single cells or the prog-
eny of single cells. Because the metastases each
exhibit a unique pattern of marker chromo-
somes, the data also indicate that different
metastases originate from different progenitor
cells. These findings provide an explanation for
the biologic diversity of multiple metastases
proliferating within the same host. These ex-
periments, however, do not resolve the question
of whether metastases arose as a consequence of
individual cells surviving in the bloodstream or
whether homogeneous clumps survived in the
circulation.
Previous studies have shown that tumor
emboli composed of cellular aggregates, either
homotypic (tumor cells) or heterotypic (host
cells), are rapidly arrested in the first capillary
bed encountered and have a better rate of sur-
vival compared with single cells [174]. In both
instances, this results in a higher frequency of
metastases compared with the circulation of a
similar number of single cells. The rapid rate of
arrest is a physical phenomenon associated with
a larger size, while the prolonged survival of
tumor cell emboli is believed to be due to the
"protection" afforded against host effector cells,
natural killer cells, and monocytes, as well as
the turbulence of the circulation. Therefore, if
tumor emboli are better able to metastasize, it
would appear possible that metastases could
develop composed in part by a progenitor cell
population that by itself was unable to complete
the metastatic cascade, but was able to when
associated with an embolus-containing metasta-
tic competent cells. We therefore designed ex-
periments to address the following questions:
do tumor emboli that survive the many steps of
metastasis consist of single cells or cell aggre-
gates of monoclonal origin, and do metastatic
competent cells provide a suitable environment
within cellular aggregates whereby metastatic
compromised or metastatic incompetent cells
could survive and proliferate within the
metastatic focus? In this collaborative study
with Fidler, we formed heterotypic cellular
aggregates of either a single population of
metastatic tumor cells containing a marker
chromosome, several metastatic tumor cell
populations with different characteristic marker
karyotypes, or heterogeneous cellular aggre-
gates composed of metastatic competent tumor
cells and benign tumor cells each with different
marker karyotypes. This study took advantage
of cell variants that we developed with stable
marker chromosomes. The size and extent of
cellular aggregation were confirmed by audio-
graphic studies using admixed radiolabeled and
unlabeled cell populations. In this study, the
metastatic variant K-1735 Met 2 X21 (chromo-
some mode of 42 and a ~ arm length ratio sub-
metacentric chromosome) was admixed with
the metastatic parent tumor population, K-1735
Met 2 (chromosome mode of 44, without a
 3. BIOLOGY AND BIOCHEMISTRY OF METASTATIC CELLS 59

I
In Vitro Clones
If

I Individual Spontaneous
Metastases

I 1

~
~ ....- • ~~~
Metastatic
Polenllal
..,~
~ ~~
" $,1.-
(fItt ~
~

t
~
00
00
o
~00
00
o
~
o
00
00 8 0
00
00 8 0
00
00 ~
00
00
o

Sensitivity to
Chemotherapeutic
Agent

FIGURE 3-4. Scheme of experimental design to deter-

mine how rapidly metastases of clonal origin develop
intralesional heterogeneity with respect to metastatic
potential and sensitivity to cytostatic agents.
marked chromosome), or K-1735 clone 26, a
nonmetastatic tumor variant (chromosome
mode of 54, without marker chromosomes).
These heterotypic or homotypic cellular aggre-
gates of an individual tumor population were
injected intravenously into the lateral tail vein of
syngeneic mice and, 21-24 days later, isolated
metastatic foci were individually established in
tissue culture and karyotyped. The karyotypes
of the metastases obtained from mice injected
with either K-1735 Met 2 or K-1735 Met 2 X21
emboli (11/11 and 10/10, respectfulIy) stably
expressed the appropriate karyotypes. The mice
injected with K-1735 clone 26, the nonmetasta-
tic variant, did not develop metastatic foci. All
of the metastases examined from mice injected
with the cellular aggregates of the metastatic vari-
ant K-1735 Met 2 X21 and the benign tumor
cell line K-1735 clone 26 (9/9) expressed the
karyotype characteristic of K-1735 Met 2 X21
in every spread examined (at least 70 per tumor
line). In contrast, the karyotypes of the cells
from the metastases of mice injected with cellu-
lar aggregates of K-1735 Met 2 and K-1735 Met
2 X21, both metastatic variants, were composed
of characteristic spreads of one (K-1735 Met 2,
4/12 and K-1735 Met 2 X21, 8/12) or the other
metastatic line. We conclude from this study
that, although cellular aggregates are arrested
more rapidly and result in an increased metas-
tatic frequency, only a single tumor cell from
within the embolus survives to form the metas-
tatic foci. Therefore, not only is the metastatic
process clonal in origin [173], but also the
metastatic foci appeared to arise from a single
cell that is likely to have been only one of sever-
al within the tumor embolus. In addition, at
least within this tumor model, a tumor cell lack-
ing metastatic properties is unlikely to be aided
in the metastatic process by other cells that ex-
press metastatic properties and are found within
the same tumor emboli.
Poste et al. [175] undertook a study that util-
ized biochemical markers to determine whether
tumor cells bearing stable experimental metas-
60 I. INTRODUCTION
tases were clonal or multicellular in ongm.
Syngeneic mice were given intravenous injec-
tions of aliquots of wild-type BI6-FI0 cells
admixed with equal aliquots of TFT' and Oua'
BI6-FI0 variants, and individual lung metas-
tases were established in culture. Five clones
from each of the 22 metastases obtained from
three animals were isolated and tested for resis-
tance to TFT' or Oua'. Of 22 lesions, 19 were
populated by cells with the same drug sensitiv-
ity, while two metastases that yielded cells with
different drug sensitivities were identified, sug-
gesting to the authors a poly clonal origin of the
metastases. One of the metastases expressed
cells with either a wild-type or a Oua' pheno-
type, while the others were composed of both
TFT' and Oua' cells. This latter metastasis,
discounting the possibility of a coalescence of
metastatic modules, would very probably be of
polyclonal origin. Nonetheless, this study
further suggests that a polyclonal event during
metastases is a very rare occurrence and that
most metastases are both clonal in origin and of
single-cell origin.
The demonstration that spontaneous metas-
tases result from the clonal expansion of highly
specialized cells and that cells of metastases
demonstrate a high rate of spontaneous mutation
[176] compared with nonmetastatic tumorigenic
cells suggests that clonal metastases may rapidly
become heterogeneous. We were interested,
therefore, in investigating whether rapid tumor
evolution and progression could occur within
a clonal metastasis. If so, this finding would
provide a rational explanation for the observed
heterogeneity within and among metastases.
The demonstration of clonal origin metastases
[173, 175] provided the experimental basis for
this study (figure 3-4). The experimental metas-
tatic potential was examined for the cells from
the original, demonstrable, clonal origin, X-
met-21 line (parent); ten in vitro isolated
clones; the X-met-21 line after growth in vivo
for 60 days; and seven individual spontaneous
lung metastases from the X-met-21 primary
tumors. Six of ten clones differed significantly
from the parent tumor in their capacity to pro-
duce lung tumor colonies, while the metastatic
potential of the X-met-21 population did not
change after subcutaneous growth for 60 days
(p = 0.45) compared with X-met-21 cultured
line. However, cells from six of seven spon-
taneous metastases from mice bearing the X-
met-21 tumor differed significantly in their
metastatic potential from the X-met-21 line
growing at a primary site. The cells from the
cloned lines and from spontaneous metastases
differed greatly in their ability to produce ex-
perimental metastases (p = 0.0001, Kruskal-
Wallis test, Chi-square approximation).
In another set of experiments, we used an in
vitro colony-forming inhibition assay to deter-
mine the relative sensitivity of tumor cells from
the parent line, tumor cells from the cloned
lines, and spontaneous metastases to various
chemotherapeutic drugs. The study used the
chemotherapeutic drugs amsacrine (AMSA),
adriamycin (ADR), bleomycin (BLEO), and
vincristine (VCR). Statistical analysis of the
differences in drug sensitivity revealed that the
following numbers of clones and metastases
differed significantly from the parent tumor
line: for AMSA, five of ten clones and two of
seven metastases; for VCR, one of ten clones
and three of seven metastases; for ADR, seven
of ten clones and four of seven metastases; and
for BLEO, six of ten clones and three of seven
metastases. This variability was reproducible
and was not caused by artifacts associated with
the cloning or selection procedures. This con-
clusion is based on a study in which five sub-
clones isolated from a benign clone of K-1735
melanoma were not distinguishable from the
parent clone in their response to cytotoxic
drugs. In contrast to this diversity in metastatic
potential and drug sensitivity, all cells examined
expressed the unique submetacentric chromo-
some marker, suggesting that its expression was
very stable.
In the study of clonal origin by Poste and
coworkers [171], the metastatic properties of
several tumor cell clones isolated from indi-
vidual B16 melanoma pulmonary metastases at
different stages during the evolution of metasta-
sis were investigated. They found that during
the early stages of metastatic growth following
intravenous injection of tumor cells, the ma-
jority of metastatic lesions contain cells with
indistinguishable metastatic phenotypes (intra-
lesional clonal homogeneity). In contrast, the
progressive growth of metastatic lesions was
accompanied by the emergence of variant
tumor cells with altered metastatic properties
within clonal homogeneous lesions (intralesion-
al heterogeneity).
In summary, distinct differences in metastatic
properties and drug sensitivity were found in
most of the in vitro and in vivo isolated clones;
 3. BIOLOGY AND BIOCHEMISTRY OF METASTATIC CELLS
however, the marker chromosomes appear to be
expressed in an extremely stable manner both in
vitro and in vivo. These intralesional differences
could not be attributed to in vivo fusion of
tumor cells with one another or with normal
host cells, since tetraploid karyotypes were only
rarely observed. It appears, therefore, that the
progressive growth of metastases results in the
rapid development of biologic intralesional
heterogeneity .
Conclusion
The previous discussion demonstrates the mul-
tifacted nature of the metastatic process and the
complex interrelationship between the host and
the tumor as a whole as well as individual tumor
cells. Although advantage may be made of our
present understanding of the metastatic process
to limit or prevent invasion, arrest, and extra-
vasation, this approach must, by its very nature,
by viewed as "prophylaxis." Although ther-
apeutic protocols based on preventing metas-
tases may be utilized prior to or during surgery
or to prevent tertiary metastases, most patients
at diagnosis have preexisting metastases and, as
such, these "prophylactic" approaches are li-
mited.
The heterogeneity of tumors, regardless of
their origin, has important implications for the
study and treatment of metastases. For example,
cells obtained from a primary tumor are not
necessarily representative of cancer cells popu-
lating metastases or even cells in different re-
gions of the same primary tumor. Thus, ex-
perimental efforts must be concentrated on the
identification of the tumor cell phenotypes that
permit malignant cells to metastasize. In addi-
tion, the test systems for new therapeutic agents
or modalities must address the problem of
tumor cell heterogeneity. More effort must be
devoted to testing the efficacy of combination
therapies with the objective of circumventing
the problem of cellular diversity within tumors.
The short-term therapeutic goal must be to
choose the optimal combination of antitumor
agents and to determine the sequence of admin-
istration that will be most effective against a
particular tumor. By limiting the number of
cellular phenotypes within a tumor, we may be
able to improve our therapeutic protocols by a
combination of anticancer drugs, in conjunction
with other adjunct therapeutic modalities, that
will destroy all of the subpopulations of tumor
61
cells. Clearly, the only successful treatment of
metastatic disease will be one that circumvents
the different phenotypes of tumor cells within
individual metastases of a patient and probably
will require multiple therapeutic agents and
modalities.
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158. Tsuruo T, Yamori T, Naganuma K, Tsukagoshi
S, Sakurai Y: Characterization of metastatic
clones derived from a metastatic variant of
mouSe colon adenocarcinoma 26. Cancer Res
43:5437,1983.
159. Talmadge JE, Starkey JR, Davis WC, Cohen
AL: Introduction of metastatic heterogeneity
by short-term in vivo passage of a cloned trans-
formation cell line. J Supramol Struct 121 :227,
1979.
160. Welch DR, Neri A, Nicolson GL: Comparison
of 'spontaneous' and experimental metastasis
using rat 13762 mammary adenocarcinoma
metastatic cell clones. Invasion Metastasis 3 :65,
1983.
161. Shearman PJ, Longenecker BM: Selection for
virulence and organ-specific metastasis of
herpes virus-transformed lymphoma cells. Int J
Cancer 25:363,1980.
162. Enders JF, Diamondopoulous GT: A study of
variation and progression in oncongenicity in an
 3. BIOLOGY AND BIOCHEMISTRY OF METASTATIC CELLS
SV 40-transformed hamster heart cell line and
its clones. Proc R Soc Lond [Bioi] 171 :431,
1969.
163. Kripke ML, Gruys E, Fidler IJ: Metastatic
heterogeneity of cells from an ultraviolet light-
induced murine fibrosarcoma of recent origin.
Cancer Res 38 :2962, 1978.
164. Talmadge JE, Fidler IJ: Cancer metastasis is
selective or random depending on the parent
tumor population. Nature 297:593,1982.
165. Fidler IJ: Selection of successful tumor lines for
metastasis. Nature [New Bioi] 242:148, 1973.
166. Hart IR: Selection and characterization of an in-
vasive variant of the B16 melanoma. Am J
PathoI97:587,1979.
167. Talmadge JE, Fidler IJ: Enhanced metastatic
potential of tumor cells harvested from spon-
taneous metastases of heterogeneous murine
tumors. J Nat! Cancer Inst 69:975, 1982.
168. Pollack VA, Fidler IJ: Use of young nude mice
for selection of subpopulations of cells with in-
creased metastatic potential from nonsyngeneic
neoplasms. J Nat! Cancer Inst 69:137, 1982.
169. Neri A, Welch D, Kawaguchi T, Nicolson GL:
Development and biologic properties of malig-
nant cell sub lines and clones of a spontaneous
metastasizing dlt mammary adenocarcinoma. J
Nat! Cancer Inst 68:507,1982.
170. Walker JR, Rees RC, Teale D, Potter CW:
Properties of a herpes virus-transformed
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teristics of sublines of high and low metastatic
potential. Eur J Cancer Clin Oncol 18:1017,
1982.
171. Poste G, DoIIJ, Brown AE, TzengJ, Zeidman
I: A comparison of the metastatic properties of
B 16 melanoma clones isolated from cultured cell
lines, subcutaneous tumors and individual lung
tumors. Cancer Res 42:2770, 1982.
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colonies derived from transplanted mouse
marrow cells. Nature 197:452, 1963.
173. Talmadge JE, Wolman SR, Fidler IJ: Evidence
for the clonal origin of spontaneous metastases.
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174. Nicolson GL, Brunson KW, Fidler IJ: Specific-
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II. PRINCIPLES OF
MANAGEMENT
 4. PRINCIPLES OF SURGICAL
ONCOLOGY
E. George Elias
As a general rule, surgery and radiation therapy
are utilized for local and regional control of
cancers, while chemotherapy, hormonal therapy,
and immunotherapy are used for systemic
control.
Surgery remains the most effective ther-
apeutic modality for solid tumors; therefore,
the responsibilities of the oncology surgeon are
many. He/she is called upon to establish the
diagnosis, resect for cure, or palliate the pa-
tient. He is responsible for preparing the patient
and planning and conducting the surgery, as
well as providing postoperative care and long-
term follow-up. This individual is also respon-
sible for management of surgical emergencies.
The surgeon who has a major interest in cancer
patients should be knowledgeable in the natural
history of the disease, including its etiology and
epidemiology, and playa role in prevention and
early detection. He should be capable of accu-
rate staging of the disease and be aware of the
prognostic factors, the response to various ther-
apeutic approaches, and the morbidity and
mortality of various kinds of treatment. Besides
his technical skills and sound judgment, the
surgical oncologist should realize that surgery
alone may not be the only treatment in the
modern therapeutic approach, and adjuvant
therapy consisting of radiation therapy, che-
motherapy, hormonal manipulations, and/or
immunology may be required. Although most
of these programs are initiated 2-4 weeks post-
operatively, some are applied a few weeks prior
to definitive surgery.
The surgical oncologist is a member of a mul-
tidisciplinary team that is responsible for cancer
control [1]. Therefore, he should be aware of
the available controlled clinical trials that search
for the best treatment to obtain better survival
Peterson et ai., HEAD AND NECK MANAGEMENT OF THE CANCER PATIENT.
© 1986. Martinus NijhoJ! Publishing. All rights reserved.
and cure rates. He should offer such ap-
proaches, and discuss these with the patient. In
most instances, it is his responsibility to suspect
and histologically document recurrences.
The surgical approach to a cancer patient
should be clear and well-defined: seeking cure
to save life, and restoring both function
and cosmesis, respectively [2, 3]. Ability to
achieve these goals varies from patient to
patient; for example, the standard surgical
approaches alone, in the majority of tumors,
have reached a plateau in cure rates With the
advancement in technology, however, new sur-
gical approaches are now available, including
computerized tomographic (CT) scanning and
sonography which make early detection of
some primary tumors and recurrences amen-
able to early surgical extirpation. Also, blood
element transfusion (e.g., of platelets and
white cells) permits operation on patients with
severe thrombocytopenia and leukopenia. En-
teral and parenteral alimentation supports the
patient who undergoes massive resections and
requires long periods of rest or dysfunction of
the gastrointestinal tract. Hickman catheters
allow one to utilize continuous or intermittent
systemic and organ infusion with chemother-
apy, and facilitate prolonged parenteral nutri-
tion. The development of perfusion pumps and
hyperthermia allows us to utilize hyperthermic
limb perfusion for melanoma and sarcoma.
New generations of antibiotics support surgical
drainage and control of infection in the im-
munosuppressed patient and reduce the inci-
dence of postoperative morbidity and mortality.
In summary, the major role of cancer surgery
is to eliminate the site of the primary tumor as
well as regional lymph nodes. It also has some
role in curing clinically established metastases,
71
72 II. PRINCIPLES OF MANAGEMENT
and a very limited role for micrometastases.
Recent technological advances have enhanced
surgical management of neoplasia.
Prevention and Early Detection
Some hereditary, congenital, and autoimmune
diseases predispose to future development of
cancer. Familial polyposis of the colon, unde-
scended testicle, and ulcerative colitis are excel-
lent examples of this fact. Early surgical in-
tervention can prevent subsequent development
of cancers in these patients. On the other hand,
the development of one cancer, such as medul-
lary carcinoma of the thyroid gland, may signify
the possibility of other tumors in the same pa-
tient and other members of the family. In addi-
tion, some acquired conditions, such as leuko-
plakia, can be a precancerous condition; even if
the lesion is completely excised, the patient
should be closely observed for the development
of similar lesions or squamous cell carcinoma.
Erythroplakia or erythroplasia is to be consid-
ered squamous cell carcinoma, even if the
biopsy is negative for tumor; the lesion should
be managed by local excision and close follow-
up. Although the end result of a disease process
can be removed by surgical elimination of a
tumor, one must realize that it is liable to recur
unless the underlying causes are identified and
eliminated. Patients with small squamous cell
carcinomas of the oral cavity that are well con-
trolled should be observed, not only for recurr-
ences, but for the development of new primaries
at different sites within the head and neck re-
gion. The effect of tobacco and/or alcohol
should be repeatedly emphasized to the patient.
Psychological and social help may be required
in the majority of these patients.
Early diagnosis is of utmost importance in
improving survival. While the family physician
plays a major role in early detection, it is the
dentist who is equally responsible for diagnos-
ing or at least suspecting head and neck tumors.
A good history and physical examination,
including inspection and palpation of the oral
cavity, oropharynx and the neck by the dentist
are the best methods of early detection of these
tumors.
The decision to remove an organ or part of
an organ for prophylaxis/prevention requires
consideration of several factors: the presence
or absence of symptoms, statistical evidence of
future cancer, the risk from surgery, and the
postoperative functional impairment and altera-
tion in appearance.
Major prophylactic surgery in the absence
of histologic proof of malignancy may be
appropriate in certain conditions (e.g., prophy-
lactic lymphadenectomy in patients who pre-
sent with locally advanced disease at the pri-
mary site, with no clinical evidence of enlarged
regional lymph nodes). Furthermore, patients
. who present with enlarged regional lymph
nodes after resection of their primary tumor
should undergo therapeutic lymphadenectomy
without prior biopsy of such lymph nodes.
Such an approach is logical for two reasons: the
chances that these lymph nodes are harboring
cancer are high, and the biopsy may result in
tumor spillage in the surgical field. In addition,
a negative biopsy does not rule out the presence
of cancer in the remaining tissue, except if it is
an excisional biopsy.
Diagnosis
Once a lesion is suspected, the next step is to
establish the diagnosis prior to planning any
management (see chapters 10 and 11). It is
essential to obtain tissue for histopathologic
examination, identifying the cell type and, if
possible, the grade of differentiation. Several
biopsy techniques are now available, name-
ly, aspiration, needle, incisional, and excisional.
Some of these have certain limitations that
should be considered prior to their application.
These are usually performed under local anes-
thesia; however, general anesthesia may be re-
quired.
Aspiration biopsy is the utilization of a thin
needle to aspirate cells and occasional small
fragments of tissue for cytologic examination. It
has multiple limitations; namely, not all tumors
can be diagnosed cytologically and there is a fair
percentage' of error in differentiating a malig-
nant condition from degenerating and inflam-
matory cells. More importantly, most of the
hospitals lack cytologists, and such smears are
referred to a pathologist who may not have the
experience in cytology. On the other hand,
needle aspiration can be utilized in deeply
seated regions that would otherwise require
major surgical intervention.
Needle biopsy has changed from the intro-
duction of the large-core needle to the tru-cut
needle that obtains an excellent core of tissue for
pathologic rather than cytologic examination.
 4. PRINCIPLES OF SURGICAL ONCOLOGY
However, this technique may not be useful for
all head and neck tumors. For example, sarco-
mas, bone tumors and, to some extent, lympho-
mas may not be amenable for diagnosis by this
method.
Incisional biopsy involves removal of a wedge
of tissue that contains normal and suspected
malignant cells. It gives the pathologist the
ability to differentiate a metastatic lesion from
a primary one where changes can be seen at
the interface between the normal and malignant
tissues. However, occasionally a well differ-
entiated tumor cannot be distinguished from a
benign lesion; in these cases, complete excision
is required to obtain multiple sections through-
out to establish the diagnosis, e.g., liposarcoma.
Excisional biopsy indicates complete removal
of the tumor. As mentioned before, it allows the
pathologist a thorough examination for sites of
invasion, especially in case of well-differentiated
sarcomas. If excisional biopsy is performed,
however, exact mapping of .the site is essential
for future planning of curative surgery. Fur-
thermore, the surgeon should take into con-
sideration the placement and the extent of his
surgical incision, placing it within the site of
future curative surgical approach. Some lesions
(e.g., dermal) require excision whether benign
or malignant. Such lesions can be excised with
little risk and with minimal change in function.
In any of the above types of biopsies, there
is no reason to obtain frozen sections unless
definitive surgery is to follow immediately.
Frozen sections can be notoriously unreliable in
some cases such as lymphomas and soft-tissue
sarcomas. In general, therefore, the surgeon
must wait for the permanent sections to plan the
surgery. Occasionally, however, the surgeon
must decide, based on his intraoperative
findings and without histologic documentation,
to proceed with radical surgery. This situation
frequently arises in carcinoma of the pancreas.
Full surgical exploration involving multiple
organ biopsies may be required on occasion not
only for diagnosis but also for staging, e.g.,
in lymphomas. Patients with suspected metas-
tases may require histologic proof of such
metastases and their extent. This is of absolute
necessity in establishing the extent of disease,
upon which the type of therapy will be planned.
Curative Surgery
Prior to undertaking any elective surgery, the
73
patient must be thoroughly evaluated and pre-
pared. A complete blood count with indices,
white cell differential, and actual, not estimated,
platelet count must be obtained. Serum electro-
lytes, blood urea nitrogen, serum creatinine,
fasting blood sugar, serum total protein, albu-
min, calcium, phosphorus, uric acid, and liver
function tests including serum bilirubin, trans-
aminases, and lactic dehydrogenase are essen-
tial. In addition, preoperative staging is com-
pleted by obtaining chest x-ray, liver and bone
scans, and tumor markers, depending on the
type of tumor.
The patient is then prepared for surgery, de-
pending on the finding. For example, the patient
may require nutritional support, correction of
his/her hypovolemia, improvement of kidney
function by hydration, blood and plasma trans-
fusion, pulmonary physiotherapy, correction of
acid-base balance, digitalization of a cardiac
condition, etc. Careful preoperative preparation
will reduce postoperative morbidity and mor-
tality.
There are a few conditions, such as an acute
myocardial infarction, that are contraindica-
tions to surgery. On rare occasions, the patient
may be in very poor condition and may not be
a candidate for radical surgery. In such cases,
a less destructive surgery may be indicated,
such as electrocoagulation, fulguration, or cryo-
surgery.
Curative surgery is one in which all gross
tumor is removed. It is the major local-regional
therapeutic modality that has been proven to
have a major impact in cancer control. While
small primary lesions can be cured by wide local
excisions, radical resections may be requirefi for
larger and more invasive lesions. Such radical
resections may include regional lymphadenec-
tomy that is performed not only to eradicate
potential or actual regional metastases, but also
to accurately stage the disease. In continuity
or en bloc resection of the primary tumor and
regional lymph nodes has been recently ques-
tioned as has the role of elective or prophylactic
regional lymph node dissection in patients
with no clinical evidence of regional lymph
node metastases. It appears that, in the major-
ity of cancers for example, including cutaneous
melanoma [4] and breast carcinoma [5], such
approaches do not affect survival. However,
lymphadenectomy has to be performed for
technical reasons, as in cutaneous melanoma
overlying the regional lymph node area or in
74 II. PRINCIPLES OF MANAGEMENT
head and neck cancers; the primary resection
may thus violate the upper neck region. Clearly,
however, patients who have regional lymph
node metastases should undergo therapeutic
lymphadenectomy.
If regional lymphadenectomy has to be
carried out, this should be done in accurate
and standard planes to insure en bloc lymph
node resection. The surgeon has to tailor the
procedures to the patient's needs and the nat-
ural behavior of their tumor.
It should be kept in mind that the pathologic
staging of the disease is the most important fac-
tor in establishing the prognosis in cancer pa-
tients. Therefore, it is the responsibility of the
surgeon to orient the pathologist to the surgical
specimens and give him accurate clinical in-
formation. It is then the surgical pathologist's
task to obtain detailed description that includes
the actual size of the primary and its location,
clearance of margins and depth of the tumor
areas, total number of lymph nodes removed,
number of involved lymph nodes by tumor,
amount of tumor involvement in lymph nodes,
and the size and location of these lymph nodes.
This thoroughness is of utmost importance for
accurate staging of the disease by the tumor
registry. Additionally, based on such accurate
information, further therapy or observation
will be planned by the physician and the tumor
board, and meaningful survival data can be
obtained and correlated to tumor type, site,
stage, and the treatment given.
Surgery of the primary site should be directed
to prevent tumor implantation and must include
resection of the surrounding tissues with safety
margins. Histologic documentation of absence
of tumor at the margins and depths of the
resected specimen at the time of surgery must
be obtained by frozen section. At the time of re-
section, and occasionally at a later date, such
surgical defects must be closed with adjacent
tissues or reconstructed by flaps or grafts for
functional and cosmetic reasons. Therefore, the
surgical oncologist must be capable of carrying
out most of the reconstructive procedures.
The follow-up of the patient is of utmost im-
portance. This must be carried out periodically
by physical examination, blood testing, and
chest x-rays. Other tests should be performed as
needed; for example, as noted previously, CT
scanning has facilitated the evaluation of deep
areas that cannot be detected clinically. Tumor
markers can be utilized for early detection of
recurrence that may render themselves ame-
nable to surgical extirpation. The surgeon
should be aware of the systemic manifestations
of dissemination, such as the development of
hypercalcemia, antidiuretic hormone syndrome,
and other manifestations of metastases.
Palliative Surgery
Patients with unresectable cancer may be can-
didates for a variety of palliative approaches
designed to improve the quality of life. Such
surgery will include debulking of the tumor;
this has been proven to be beneficial in certain
neoplasms such as ovarian cancer [6]. In this
type of procedure, the surgeon removes as
much as possible of gross tumor, leaving
minimal disease for the chemotherapy that will
follow. For example, while single liver metas-
tases or even multiple liver metastases located at
one lobe from large bowel cancer are amenable
to surgical extirpation, multiple metastases
throughout the liver can be managed by hepatic
artery ligation and intrahepatic infusion of che-
motherapy. Multiple lung metastasis from sar-
comas or colorectal carcinoma can be resected.
Such approaches have resulted in prolongation
of active and productive life.
Another type of palliative surgery is the treat-
ment of complications that arise from the dis-
ease or its treatment, such as perforations and
bleeding in the gastrointestinal tract secondary
to lymphoma of the gastrointestinal tract. Per-
foration and bleeding can be the direct result of
either the progressive lymphoma or secondary
to massive slough of the tumor following radia-
tion therapy or chemotherapy. In addition, per-
forations may lead to abscess formation that re-
quires incision and drainage. Occasionally, this
surgery must be performed as an emergency in
the cancer patient who is usually immunosup-
pressed and has a leukopenia and/or throm-
bocytopenia.
Other indications for palliative surgery exist.
Amputation may be required to eliminate pain,
infection, and odor for fungating large tumors
of the extremities. Bowel obstruction secondary
to disease or irradiation must be surgically
removed, bypassed, or a proximal stoma
performed. Locally advanced tumor may be
managed by repeat fulguration or cryosurgery.
Bone necrosis or fistula formation may require
palliative resection to eliminate pain and odor,
and may improve function.
 4. PRINCIPLES OF SURGICAL ONCOLOGY
Sepsis is a common complication in patients
with advanced and metastatic disease and in
leukemic patients who are receiving chemother-
apy. In these patients, the source of infection
should be identified and eliminated by surgical
drainage and antibiotics. The surgeon should be
knowledgeable of chemotherapeutic agents and
their side effects if he is to operate on patients
receiving such therapy. He may also be called
upon to carry out splenectomy in an immuno-
suppressed patient who is receiving chemother-
apy, to either improve the hematologic picture
or for symptomatic splenomegaly. In such
cases, absolute hemostasis is essential. The
availablility of the Hickman catheter makes it
possible for the surgeon to have venous access
to infuse systemic as well as regional chemo-
therapy for a prolonged period of time. It
also allows access to sample the patient's blood
without repeated puncturing of the skin,
especially in those patients who have difficult
peripheral veins.
Surgical Emergencies
These can be divided into three main categories:
inflammatory, hemorrhagic, and obstructive.
The surgeon has to deal with such emergencies
acutely as most of these patients are immuno-
suppressed, leukopenic, thrombocytopenic,
and/or malnourished. The inflammatory lesions
can vary from a major emergency, such as acute
abdomen, to a relatively minor situation, such
as paronychia or dental abscess, that may result
in septicemia if not efficiently treated. Hemor-
rhagic lesions can vary from slow retroperi-
toneal hemorrhage, which may mimic acute
abdomen and require no surgical intervention,
to severe gastrointestinal bleeding or carotid
75
blowout that will require immediate surgical
control. The obstructive diseases can be related
to bowel or airway obstructions. These can be
due to benign conditions such as adhesions
from previous surgery or strictures from ir-
radiation, or it may be due to malignancies,
secondary to recurrence or metastases.
The surgeon must handle such emergencies
and keep in mind the possible postoperative
complications that include embolism, infection,
dehiscence, and dysfunction. He should be
skilled in preventing some complications and be
capable of early management of other such
sequelae.
References
1. Elias EG: The surgical oncologist. Surg Gynecol
Obstet 150:83-84,1980.
2. Rosenberg SA: Principles of surgical oncology.
In: De Vita VT Jr, Hellman S, Rosenberg SA (eds)
Cancer: principles and practice of oncology.
Philadelphia, JB Lippincott, 1982, pp 93-102.
3. Schrock TR: Principles of surgical oncology. In:
Carter SK, Glatstein E, Livingston RB (eds) Prin-
ciples of cancer treatment. New York: McGraw-
Hill, 1982, pp 53-57.
4. Elias EG, Didolkar MS, Goel IP, Formeister JF,
Valenzuela LZ, Pickren JL, Hebel JR: Deeply
invasive cutaneous malignant melanoma. Surg
Gynecol Obstet 153:67-70, 1981.
5. Fisher B, Wolmark N: New concepts in the man-
agement of primary breast cancer. Cancer 36:627-
632, 1975.
6. Griffith CT, Fuller AF: Intensive surgical and
chemotherapeutic management of advanced ovar-
ian cancer. Surg Clin North Am 58:131-142,
1978.
 5. PRINCIPLES OF RADIATION
THERAPY
Nancy J. Tarbell
Ralph R. Weichselbaum
In this chapter, we delineate general principles
of radiation biology and physics and highlight
their importance and applicability to the clinical
situation, especially as related to the manage-
ment of head and neck malignancies. A com-
bination of the application of physical concepts
as well as natural history of malignant disease is
essential for optimal therapeutic results.
Radiation Physics
The physical characteristics of ionizing radia-
tion vary with the energy of the machine;
these energy differences are of major impor-
tance in optimizing radiation treatment. Radia-
tion energies between 50 and 140 k V are
termed superficial radiation, and orthovoltage is
designated between 140 and 500 kV. Orthovolt-
age and superficial machines yield an advantage
in the treatment of skin or other superficial
tumors because the maximum dose is delivered
to the skin and the dose falls off rapidly below
the surface. Radiation energies of greater than
500 k V are termed supervoltage radiation.
Clinically important advantages are seen when
radiation reaches 500 kV because, above this
energy, there is reduced absorption in bone, less
damage to skin at portal entry, and reduced
scatter of radiation into other tissues. Super-
voltage radiation is also of great importance
in treating tumors deep in the body because
the maximum dose occurs below the skin. The
percent of radiation at any specific depth,
compared with the maximal dose, increases as
the energy increases and produces a therapeu-
tic advantage. Supervoltage radiation should
be employed in the curative treatment of car-
cinoma of the oropharynx and oral cavity.
For a given dose to a soft tissues of the oral
Peterson et ai., HEAD AND NECK MANAGEMENT OF THE CANCER PATIENT.
© 1986. Martinu, NiJhoff Publishing. All rights reserved.
cavity, the osteocytes and vascular structures
of the mandible absorb less than one-half as
much energy from supervoltage as from an
orthovoltage beam.
In addition to photon machines, radioactive
isotopes are sometimes used. Intracavitary
irradiation refers to radiation applied closely to
tumors by hollow containers and loaded with
radioactive isotopes. In the head and neck re-
gion, this is especially applicable in tumors of
the antrum, sinuses, and nasal cavity. Interstitial
radiation refers to the application of removable
sources that are inserted directly into the tumor,
such as radium 226, cobalt 60, or iridium 192, or
nonremovable sources such as radon or radioac-
tive gold. These techniques are employed in the
treatment of carcinomas of the tongue, tonsil,
oral cavity, and metastatic neck nodes.
Treatment planning is essential for optimal
radiotherapy delivery. This involves localiza-
tion of the target volume utilizing both physical
examination and diagnostic x-ray procedures.
For the head and neck region, tomograms, com-
puterized tomographic (CT) scans, soft-tissue
films of the neck, and contrast radiography all
may be used to aid in accurate localization. Such
treatment planning ensures that the tumor re-
ceives an optimal dose while the normal tissues
receive as little dose as possible. Immobilization
devices such as head straps and bite blocks, as
well as frequent checks of portal films to com-
pare with the original planning films, all help to
ensure the reproducibility of the daily treat-
ments [1-3].
Biologic Aspects of Radiation
Therapy
Ionizing radiation is radiation that, during
77
78 II. PRINCIPLES OF MANAGEMENT
absorption, causes the ejection of an orbital
electron. This leaves free radicals that cause
chemical changes due to the breakage of the
chemical bonds and thus produces biologic
effects. Charged particles such as electrons or
protons are directly ionizing with sufficient
energy to break the chemical bonds. X-rays,
gamma rays, and neutrons are indirectly ioniz-
ing; that is, they do not themselves disrupt
chemical bonds but produce secondary elec-
trons with high kinetic energy that breaks these
bonds. Neutrons interact with nuclei of atoms
of the absorbing material and impart kinetic
energy to fast-recoil protons or other nuclear
fragments that then exert a biologic effect [1-3].
Linear Energy Transfer
Linear energy transfer (LET) refers to the ener-
gy transferred per unit length of radiation in the
absorbing material. Differences in LET account
for the fact that, although different types of
radiation usually produce qualitatively similar
effects initially (ionization), there are marked
quantitative differences as well as different
biologic end effects. Equal doses of different
types of ionizing radiation do not produce equal
,,
n generations of progeny and then all generations
, ,
co
.e
" ,
u logarithmically (see figure 5-1). The Do is the
~ dose necessary to reduce the surviving fraction
co
co
»
» to a survival level of 0.37. The extrapolation
.
~
"
<II
CJ
2 4 6
Gro,. (·100 Rod.)
FIGURE 5-1. An idealized radiation survival curve.
The fraction of surviving cells is plotted on a loga-
rithmic scale against dose on a linear scale. The dose-
response curve for sparsely ionizing radiations has an
initial shoulder followed by a straight portion.
biologic effects. To compare radiations, the rela-
tive biologic effectiveness (RBE) is commonly
used. RBE is the dose ratio of different average
LET beams required to produce the same biolog-
ic effect. In radiation biology, the RBE of some
test radiation is compared with 250-kV x-rays,
which are employed as the standard. The RBE is
the ratio of the dose of 250-kV x-rays to the test
radiation required for an equal biologic effect.
Even for a given total dose or dose per fraction,
however, the RBE varies with the biologic sys-
tem and with the end point studied. The RBE
for many cellular systems has been known to
increase with increasing LET, peaking at about
100 kV/m and then decreasing. Sparse ioniza-
tion is less efficient than densely ionizing radia-
tion because more than one particle must pass
through the cell to be activated. Very densely
ionizing radiation is also inefficient because it
deposits more than enough energy in a critical
site so that the energy must be considered
wasted. Thus, there appears to be an optimal
LET (density of ionization) [1-4].
Cell Survival Considerations
The radiobiologic definition of death is an in-
ability to reproduce [3, 5]. Some cells may take a
long time to express lethality by division, and
irradiated cells may actually give rise to several
may die [5, 6]. Furthermore, until cell division
occurs and lethality is expressed, cells may
appear morphologically intact. Survival curves
plot the fraction of surviving cells against the
dose of irradiation with survival plotted semi-
in the straight line portion of the curve by 0.63
number (n) is a measure of the width of the ini-
tial shoulder. The Dq is the dose at which the
straight portion of the survival curve, extrapo-
lated backward, intersects with the line where
the survival fraction is unity [3, 7].
Concepts of Radiocurability
and Radiosensitivity
Radiosensitivity refers to the innate sensitivity
of the cells to radiation. The term refers to the
Do or the slope of the straight-line portion of
the radiation survival curve for cells that die a
reproductive death.
 5. PRINCIPLES OF RADIATION THERAPY
M The cell cycle is divided into mitosis (M) fol-
(Mitosis)
S (DNA Synthetic
Phase)
FIGURE 5-2. The cell cycle. G t and G 2 are "gaps" or
periods of apparent inactivity in the cell cycle.
Radiocurability is a clinical term and refers
to whether a tumor is cured by a maximal toler-
able dose of radiation. Radioresponsiveness re-
fers to the clinical appearance of tumor regres-
sion after radiation, but not to whether a tumor
is radiocurable. This may be a function of the
radiosensitivity or simply a function of the
active cell kinetics of the tumor. Some examples
of radiocurable tumors are carcinoma of the
larynx, cervix, prostate, and breast, in addition
to seminoma and others. For example, carcino-
ma of the prostate is characterized by a relative-
ly slow cell renewal system and thus rates of re-
gression are not meaningful. In fact, ultimate
local control rates for early prostate cancer are
extremely high. The surgeon must not be misled
by position biopsies obtained early after irradia-
tion or by a slow regression rate of the tumor.
Thus, the concept of divisional death explains
why some radiocurable tumors do not appear
radioresponsive. Since cells do not die after irra-
diation until they face mitosis, some tumors that
rapidly proliferate will regress rapidly but will
also regrow rapidly. An example of such a
tumor is small cell carcinoma of the lung,
which regresses rapidly after delivery of rel-
atively low doses (3000-3500 cGy), yet up to
50% of these lesions fail locally even with rel-
atively high doses (5500-6000 cGy). Therefore,
smal!" cell carcinoma of the lung is radiorespon-
sive, but not necessarily radiocurable.
79
Cell Cycle Effects
lowed by G 1 , a period of DNA synthesis (S),
and G b after which mitosis occurs again (figure
5-2). The lethal effects of radiation are cell cycle
specific, and the effects of radiation at different
stages in the cell cycle can be studied using
synchronized populations of cells. This may
vary from cell line to cell line although there are
some generalizations [3, 4]:
1. Cells are generally more sensitive near or at
mitosis.
2. If G 1 is appreciable in length, a resistant
period is evidenced early, followed by a de-
cline in survival toward S; the end of G 1 may
be as sensitive as M.
3. In most cell lines, resistance rises during S to
a maximum in the latter part of S, and this is
usually the most resistant part of the cycle.
4. In most cell lines, Gz is as sensitive as M [3, 8,
9).
Repair
After cells are irradiated, one of four events is
possible:
1. No damage may have occurred in the critical
target in the cell.
2. Damage may have occurred in all critical
targets and the cell may be killed.
3. A cell may have some of its critical targets
damaged and, given time, these may be
repaired. This is referred to as sublethal
damage repair (SLDR) and the amount of
sublethal damage a cell can accumulate is
expressed as the extrapolation number of
the survival curve (n).
4. Cells may repair lethal damage under certain
post-radiation conditions; this is referred
to as potentially lethal damage repair
(PLDR) [7, 10, 11).
Determinants of Radiocurability
It is unlikely that there is a consistent difference
in the intrinsic sensitivity between normal and
malignant tissue. However, differences in the
repair of sublethal and/or potentially lethal
radiation damage may vary from tumor to
tumor type and may explain some of the differ-
ences in clinical radiocurability [11).
Other factors may alter cellular radiosensi-
80 II. PRINCIPLES OF MANAGEMENT
..
(
I
c:
Air 100% O2
o
'""
.
II:
>
.."
II: I
10 20 30 40 50 760
FIGURE 5-3. Relative radiosensitivity as a function of
oxygen pressure. This diagram is idealized from re-
sults of experimental data.
tlVlty and/or the repair of radiation damage.
For example, it is well known that the center of
tumors is necrotic and that there may be a sig-
nificant number of hypoxic cells around this
necrotic center. It has been further shown that
hypoxia (figure 5-3) makes cells more resistant
to ionizing radiation since molecular oxygen is
necessary for free-radical formation [12, 13]. If
hypoxic tumor cells are more resistant than
well-aerated cells, this may unfavorably alter
the therapeutic ratio. The use of electron-affined
agents that are specific for radioresistant hypox-
ic cells is an important area of research in clini-
cal radiotherapy [3, 12, 13]. These studies have
progressed from development in radiation
chemistry to clinical examination. Such drugs
are considered radiation sensitizers; one example
is the nitro imidazole misonidazole, which is
efficient in killing hypoxic tumor cells in
experimental systems and is presently under
clinical investigation [14, 15]. The use of high-
LET radiation (densely ionizing neutrons, pi
mesons), which is not as dependent as sparsely
ionizing radiation on molecular oxygen for the
production of free radicals, is also currently
under clinical investigation to circumvent the
problem of hypoxic cells [16]. Reoxygenation of
tumors may also be an important determinant
of radiocurability. It has been postulated that the
oxygenated cells are killed and previously hypo-
xic cells migrate to the periphery of a tumor
where they become better oxygenated [17].
Differential repopulation between normal and
malignant tissue also may be a determinant of
radiocurability since it has been postulated that
normal tissues may repopulate more efficiently
than tumors. This fact reemphasizes techniques
in treatment planning and interstitial implanta-
tion to maximize tumor dose while minimizing
normal tissue dose. In the process of irradiating
cancers of the oral cavity and oropharynx,
changes are produced in the salivary glands,
mandible, teeth, and neighboring soft tissue,
and protection of these structures can enhance
the therapeutic ratio as well as enhance tumor
cell kill.
Sulfhydryl compounds may be protective
against the effects of ionizing radiation, and in-
vestigation of compounds such as cysteine and
its analogues continues. These sulfhydryl com-
pounds probably protect by reacting with free
radicals in competition with oxygen. Thus, cer-
tain normal tissues such as salivary glands might
be protected against the effects of radiation if
selective uptake of sulfhydryl-containing com-
pounds can be obtained.
Time-Dose Relationships in
Radiotherapy
As the practice of radiation therapy evolved, it
became clear that radiation produced a more
effective therapeutic ratio when small doses
were given each day 'as opposed to one large,
single dose. The final effects of radiation in both
normal and malignant tissues depend on:
1. The total dose.
2. Fraction size or dose of radiation per session.
3. Time and days over which radiation is deliv-
ered.
4. Volume of treatment irradiated.
Although sophisticated mathematical formulas
have been developed to equate fractionation
schemes, experience plays the most important
role in the development of this concept [18]. It
must be pointed out that the ultimate limiting
normal tissue effects are not usually the acute
effects of radiation (i.e., mucositis), but rather
the long-term effects on the vasculoconnective
tissue and possibly the nonvascular mesen-
chymal and epithelial cells [19, 20]. Acute radia-
tion effects depend largely on the rapidly pro-
liferating cell renewal tissues. In particular, the
skin and oropharyngeal mucosa in tumors of
the head and neck. The length of time over
which the radiation is given greatly influences
 5. PRINCIPLES OF RADIATION THERAPY
these acute effects. Late effects differ in this
regard and frequently limit the total dose given
in clinical radiotherapy. Necrosis, fibrosis, and
damage to specific organs such as the spinal
cord are examples of late complications that
limit the total dose of radiation used.
In making therapeutic determinations, the
clinical radiation oncologist must balance the
probability of cure against the potential con-
sequences of treatment and thus these biologic
concepts are valuable in the treatment of malig-
nant disease. Patients might elect a therapeutic
modality that produces a lesser cure rate, but
preserves function, that is, sexual function,
voice, cosmesis, etc. Certainly when cure rates
are equal or close to equal, nonmutilating ther-
apy must be given preference. The end results in
neoplastic disease are not analyzed by survival
alone, but by a detailed analysis of the pattern of
failure and by the complications.
Tumor Size as the Determinant
of Radiocurability Control
of Subclinical Disease
An important concept in clinical radiation ther-
apy is that subclinical (microscopic) disease is
controlled with lower doses than is grossly de-
tectable cancer. The probability of local control
for a variety of carcinomas increases as a func-
tion of dose. This is especially true in the head
and neck region. Most patients with subclinical
disease are controlled with doses of 5000 cGy.
For example, patients with carcinoma of the
oral cavity and oropharynx may have an inci-
dence of developing metastatic cancer in lymph
nodes from 40% to 80% even when the neck is
negative to initial clinical examination. How-
ever, 5000 cGy in five weeks may diminish the
probability of development of lymph node
metastasis to 2%-5% [21]. This concept is sup-
ported by both clinical data and by previously
stated biologic data. For example, small micro-
scopic disease is much less likely to have hypoxic
and/or necrotic centers. Also, radiation kills a
fixed proportion of cells and, the less cells
present, the higher is the probability of local
control. This concept may be extended to
gross clinical cancer and is supported by the
fact that early-stage tumors such as TI lesions,
regardless of site or histology, are more curable
than advanced T3 or T4lesions [21].
Clinical and biologic observations have led to
81
consideration of conservative surgery combined
with moderate doses of irradiation. The ad-
vantage of such an approach is to employ non-
mutilating surgery with moderate doses of
irradiation that are adequate to control disease
without a high likelihood of complications.
Radiation can be given before or after
surgery. Both preoperative and postoperative
irradiation have value and the choice is fre-
quently based on the specific clinical situation.
In large, unresectable cancers, preoperative irra-
diation is generally used. Postoperative irradia-
tion is often advantageous because the exact
margins of the tumor have been defined by the
surgery and the treatment volume can therefore
be more limited.
References
1. Buschke P, and Parker R: Radiation therapy in
cancer management. New York, Grune and
Stratton, 1972.
2. Johns HE, Cunningham JR: Physics of radiolo-
gy. Springfield IL, CC Thomas, 1969.
3. Hall EJ: Radiobiology for the radiologist, 2nd
edn. Hagerstown MD, Harper and Row, 1978.
4. Zirkle RE: The radiobiological importance of
linear energy transfer. In: Hollander A (ed)
Radiation biology, voll. New York, McGraw-
Hill, 1954, pp 315-350.
5. Puck TT, Marcus PI: Action of x-rays on
mammalian cells. J Exp Med 103:653-666, 1956.
6. Thompson LH, Suit HD: Proliferation kinetics
of x-irradiated mouse L-cells studied with time
lapse photography. Int] Radiat Bioi 15:347-362,
1966.
7. Elkind MM, Sutton H: Radiation response of
mammalian cells grown in culture. 1. Repair of
x-ray damage in surviving Chinese hamster cells.
Radiat Res 13:556-593, 1960.
8. Sinclair WK, Morton RA: X-ray sensitivity dur-
ing the cells generation cycle of cultured Chinese
hamster cells. Radiat Res 29:450-474,1966.
9. Sinclair WK: Cyclic x-ray responses in mamma-
lian cells in vitro. Radiat Res 33:620-643,1968.
10. Little JB, Hahn GM, Frindel F, Tubiana M: Re-
pair of potentially lethal radiation damage in vit-
ro and in vivo. Radiology 106:689-694, 1973.
11. Weichselbaum RR, Nove J, Little JB: Response
of human rumor cells in vitro. In: Meyn RE,
Withers HR (eds), Radiation biology in cancer
research. New York, Raven, 1980, pp 345-351.
12. Wright EA, Howard-Flanders P: The influence
of oxygen on the radiosensitivity of mammalian
tissue. Acta RadioI48:26-32, 1957.
13. Thomlinson RH, Gray LH: The histologic struc-
ture of some human lung cancer and possible im-
82 II. PRINCIPLES OF MANAGEMENT
plications for radiotherapy. Br J Cancer 9:539-
549, 1955.
14. Adams GE: Chemical radiosensitization of
hypoxic cells. Br Med Bull 29:48-53, 1973.
15. Adams GE, Disch S, Fallow JF, Thomlinson RE:
Hypoxic cells in radiotherapy. Lancet 186-188,
1976.
16. Catterall M: The treatment of advanced cancer
by fast neutrons from the Medical Research
Council cyclotron at the Hammersmith Hospit-
al, London. Eur J Cancer 10:343-347, 1974.
17. Van Putten LM: Tumor reoxygenation during
fractionated radiotherapy: studies with a trans-
plantable osteosarcoma. Eur J Cancer 4:173-182,
1968.
18. Ellis F: Dose, time, and fractionation in clinical
hypothesis. Clin RadioI20:1-7, 1969.
19. Withers HR, Peters LJ, Kogelnick HD: The
pathobiology of late effects of radiation. In:
Meyn RE, Withers H (eds) Radiation biology in
cancer research. New York, Raven, 1980, pp
439-448.
20. Hopwell JW: The importance of vascular damage
in the development of late radiation effects in
normal tissue. In: Meyn RE, Withers H (eds)
Radiation biology in cancer research New York,
Raven, 1980, pp 439-448.
21. Fletcher GH: Textbook of radiotherapy. Phil-
adelphia, Lea and Febiger, 1973.
 6. PRINCIPLES OF CHEMOTHERAPY
Paul L. Weiden
Chemotherapy properly refers to the use of any
chemical of known composition in the therapy
of any illness. The term was originally defined
by Paul Erhlich at the beginning of this century
in the treatment of parasitic and other infectious
diseases. In general usage today, however,
chemotherapy has come to refer specifically to
the treatment of malignant disease with anti-
neoplastic drugs. Some drugs of wide use (e.g.,
hormones) are occasionally included while
others, albeit of more restricted use (e.g., biolo-
gic response modifiers) are generally excluded.
In this chapter, we present some principles
of chemotherapy, beginning with a review of
relevant tumor cell biology, considering the
pharmacology and types of chemotherapeutic
agents and concluding with a discussion of some
FIGURE 6-1. Diagrammatic representation of the cell
cycle discussed in the text. Cells in cycle are in G h S,
G 2, or M phase; cells not in cycle are either resting in
Go or proceeding to differentiate and eventually to
die.
Peterson etal.~ HEAD AND NECK MANAGEMENT OF THE CANCER PATIENT.
© 1986. Marttnus Nijho/f Publishing. All rights reserved.
clinical aspects of the use of chemotherapy in
treatment of human neoplasia.
Tumor Cell Biology
THE CELL CYCLE
The cell cycle of both normal and neoplastic
cells is generally divided into four stages (figure
6-1). After a cell has been formed by division, it
enters the G 1 phase or first "gap." Initially
thought to be an inactive period, the G 1 phase is
now recognized to be a period of active RNA
and protein synthesis, especially of the enzymes
necessary for DNA synthesis. During the next,
or S, phase DNA synthesis takes place, resulting
in a doubling of cellular DNA content. There
then follows a second gap, or G 2 phase. This
also was initially considered to be a quiescent
period, but is now recognized to be a period
of RNA and protein synthesis required to
construct a mitotic apparatus and begin cell
Differentiation
83
84 II. PRINCIPLES OF MANAGEMENT

TABLE 6-1. Classification of chemotherapeutic agents in relation to dependence of activity on cell cycle and
proliferative state

Class Description Characteristics Examples

Cell-cycle-nonspecific Kill in all phases of cell cycle Nitrogen mustard

independent of proliferative Nitrosureas
state (i.e., active in GO, G1,
S, G2, and M)
II Cell-cycle-specific Most active against cells in one G1-Enzymes (e.g., asparaginase)
phase-specific portion of cell cycle (i.e., S -Antimetabolites
active in G 1, S, G2, or M) G2-Some antibotics (e.g.,
bleomycin) and etoposide
M -Spindle cell inhibitors
III Cell-cycle-specific Kill in all phases of cell cycle, Alkylating agents, including cy-
phase-nonspecific but effectiveness less in non- clophosphamide, chlorambucil,
dividing (GO) cells melphalan, busulfan, dacar-
bazine, and cisplatin
Antibiotics, including doxorubi-
cin, daunomycin, and dactin-
omycin

division. Finally the cell enters the mitotic, or M
phase which, although of briefest duration,
consists of spindle formation, separation of
chromosomes, and actual cell division.
Many human tumor cell cycle times have
been measured: 90% of the values are between
15 and 120 h, with a modal value of about 48 h
[1]. Cells not actively dividing or preparing to
divide are not considered to be in the cell cycle,
but in a resting, or GO, phase. Thus, viable cells,
whether in vitro or in vivo, can either be quies-
cient (i.e., in GO) or cycling (i.e., in G), S, G2> or
M). Additionally, some cells may have exited
from the cell cycle to differentiate and possibly
to die.
Knowledge of the cell cycle is helpful in
understanding the activity and use of many
chemotherapeutic agents (table 6-1). Some
agents-generally designated as class I-appear
to be effective whether cells are resting or in
cycle. These cell-cycle-nonspecific agents in-
clude nitrogen mustard and the nitrosoureas. In
experimen tal animals, these agents show little
differentiation between normal marrow and
malignant lymphoma cells. On the other hand,
agents that are most active against cells in only
one phase of the cell cycle are termed cell-cycle-
specific phase-specific drugs. Finally, drugs that
are effective while cells are in cycle, but are not
dependent on their being in a particular phase,
have been termed cell-cycle-specific phase-
nonspecific drugs. These include most of the
alkylating agents and antitumor antibiotics. In
experimental models, drugs of this class showed
the greatest differential in killing of lymphoma
versus normal marrow cells [2].
It is important to stress that these distinctions
and classifications are not absolute but rather
are relative and intended to be of help in under-
standing and designing chemotherapy pro-
grams. For example, cell-cycle specific phase-
specific agents would be unlikely to be effective
against cell populations with a slow turnover or
a high percentage of dormant cells. Rather, cell-
cycle-nonspecific agents would be preferred
for such slow-growing tumors. Moreover, if a
phase-specific agent were used, a higher dose
would be less likely to kill more cells (since only
those cells in a sensitive phase would be killed)
than would prolonged or repeated exposure to
the drug (to allow more cells to enter the sensi-
tive phase of the cell cycle).
GOMPERTZIAN GROWTH
The growth rate of a tumor, or the population-
doubling time, is influenced not primarily by
the length of the cell cycle, but rather by the
growth fraction and the rate of cell loss or
death. The growth fraction refers to that frac-
tion of cells in the cell cycle at any time. Initial-
ly, a tumor population may be in a lag phase
during which there is little growth as cells be-
come adapted to their environment and prepare
to enter into cycle. There next follows an ex-
 6. PRINCIPLES OF CHEMOTHERAPY
ponential or log phase of growth characterized
by high-growth fraction, little cell loss, and
short population doubling. As cell number and
tumor size increase (generally to macroscopic,
detectable size), the growth fraction declines,
cell loss increases, cell cycle time may lengthen,
and population-doubling time increases. Ulti-
mately, tumor size may nearly stabilize (plateau
phase). Presumably many factors, including
limitation of nutrients and oxygen, increase of
inhibitory metabolites, and cell-cell interac-
tions account for this limitation of growth. This
pattern of biologic growth is described mathe-
matically by an equation derived by Benjamin
Gompertz and is hence known as Gompertzian
growth. Recent data confirm that both experi-
mental and human tumors have Gompertzian
growth kinetics (3). This pattern is not unique
to neoplastic tissues, however, and, for example,
also describes well the growth curve of fetus to
infant to child to adult.
This pattern of tumor growth does have im-
plications for tumor therapy. A small microscop-
ic tumor or few residual malignant cells would
be expected to be growing logarithmically with
a high proportion of cells in cell cycle, and thus
would be particularly susceptible to cell-cycle-
specific phase-specific drugs. A larger tumor
with few cells in cycle and a long doubling
time might respond better to cycle or
phase-nonspecific drugs. Furthermore, if a large
tumor burden could be decreased by other
modalities (e.g., by surgery or radiation), che-
motherapy might be more effective because a
higher percentage of cells would be expected to
be in cell cycle.
LOG CELL KILL HYPOTHESIS
In a series of elegant studies employing LI210
leukemia in mice, Skipper demonstrated that
chemotherapeutic agents under controlled con-
ditions kill a constant proportion of malignant
cells, not a constant number [4]. Thus, a given
drug and dose might reduce a tumor cell
population by "3 logs" from 109 to 106 cells,
i.e., by 999 million cells, or from 103 to 100 cells,
i.e., 999 cells. The assumption that this fraction-
al cell kill observed in experimental studies is
also present in man is generally termed the log
cell kill hypothesis. This hypothesis implies that
since only a proportion of tumor cells are killed
with a given treatment, repeated doses, even of
the most effective chemotherapy, must be em-
85
ployed to eradicate a tumor. This is particularly
true if one considers cell recovery and growth
that are likely to occur between doses of che-
motherapy. Actually, strict adherence to the
hypothesis dictates that the last tumor cell
cannot be killed with chemotherapy, but that
other mechanisms, for example, host defenses
or immunotherapy, would be necessary.
Among the assumptions of the log cell kill
hypothesis are that all cells in a tumor cell
population are equally sensitive to the drug(s)
used and that drug sensitivity does not change
during the course of therapy. Recently, Goldie
and Coldman have emphasized, however, that
spontaneous development of drug resistance in
cancer cell populations is probable and that the
likelihood of there being drug-resistant cells in
any tumor varies directly with tumor size [5).
When combined with the characteristics of
Gompertzian growth discussed above, these
considerations emphasize that the chance of erad-
icating a tumor with chemotherapy is greatest
when the tumor size is small, i.e., when growth
is logarithmic and resistant cell populations
have not had a chance to appear.
Pharmacology of Chemotherapeutic
Agents
SELECTIVITY OF CHEMOTHERAPEUTIC
DRUGS
It has been possible to exploit a unique feature
of bacterial metabolism, cell wall synthesis, to
develop a wide array of antibiotics that exhibit a
marked degree of selective toxicity for bacterial
cells compared with their toxicity for mamma-
lian cells. Unfortunately there are no compara-
ble unique biochemical pathways in cancer cells
compared with normal cells. This has led to the
general misconception that cancer chemother-
apeutic drugs fail to exhibit selective toxicity.
Although differences between malignant and
normal cells are largely quantitative rather than
qualitative, a population of cancer cells general-
ly does have a higher growth fraction and is
therefore usually more susceptible to many che-
motherapeutic agents. Additional factors may
contribute to selective toxicity of some agents
in given settings, including variations in drug
absorption, distribution, metabolism, antagon-
ism, and excretion. The net result of all such
factors contributes to determination of the
therapeutic index of a given drug, that is, the
86 II. PRINCIPLES OF MANAGEMENT
ratio of the dose which results in therapeutic
effectiveness to that which results in unaccep-
table toxicity.
DRUG DELIVERY, DISTRIBUTION, AND
METABOLISM
Various chemotherapeutic drugs can be ad-
ministered by a wide variety of routes. Oral
administration is generally used for longer-
term, lower-dose therapy. Intravenous therapy is
perhaps the most common, chosen either to
assure adequate absorption, to prevent local
tissue reactions, or to increase the peak dose
achieved. Intraarterial administration can be
utilized to achieve a high local drug concentra-
tion, e.g., in the liver or in an extremity. Blood
flow to an extremity can be isolated and the
limb perfused, thus achieving large local con-
centrations of drug. If the hepatic artery is
infused with a drug metabolized in the liver
(e.g., floxuridine), systemic drug concentrations
may be very low in spite of high local drug con-
centrations. Local concentration may also be
improved by intracavitary administration, e.g.,
into the pleural or peritoneal space. Proper
selection of the route of administration is one of
the critical factors in maximizing the effective-
ness and therapeutic ratio of any given drug.
Drug distribution is another factor that may
profoundly influence the results of chemother-
apy. One aspect of this involves distribution
into the brain, i.e., across the so-called blood-
brain barrier. Failure of most chemotherapeutic
agents to penetrate this barrier, thereby permit-
ting cancer cells in the brain to grow unchecked,
led to recognition of the brain as a "sanctuary
site." This can be overcome by direct adminis-
tration of drugs across the blood-brain barrier
by intrathecal or intraventricular administra-
tion. Alternatively, drugs can be selected which,
by virtue of their relative ionization, molecular
size, and lipid solubility, cross the blood-brain
barrier, e.g., the nitrosureas, procarbazine, and
cytosine arabinoside. Protein binding, active
transport,. and drug accumulation are other
aspects ot drug distribution that may signif-
icantly affect drug activity. For example, accu-
mulation of methotrexate in ascitic or pleural
fluid, thereby delaying its excretion, may great-
ly enhance its observed activity.
Drug metabolism, including both drug acti-
vation and inactivation, is clearly another
important consideration. Some drugs are inac-
tive as administered and require biotransforma-
tion into an active form. This is true of many
antimetabolites and of cyclophosphamide.
Cyclophosphamide requires transformation by a
reaction localized primarily in hepatic micro-
somes. Thus, direct instillation of this drug into
the pleural space or infusion into a limb in order
to achieve a high local concentration of active
drug would be inappropriate. Impairment of the
usual routes of drug elimination or catabolism
must also be considered in drug and dose selec-
tion. Of particular note as examples of these in-
teractions are the critical role of renal function
in determining the activity of methotrexate, a
drug eliminated essentially entirely by renal ex-
cretion, and of hepatic function in determining
the activity of doxorubicin (adriamycin), vin-
cristine, and vinblastine, drugs eliminated pri-
marily by hepatic conjugation and biliary excre-
tion.
Drug interactions may occur in patients re-
ceiving chemotherapeutic agents, just as they do
in other patients receiving multiple medications.
A variety of mechanisms may be involved, in-
cluding direct chemical or physical interaction,
alteration of drug absorption, transport, recep-
tor binding, or metabolism or induction of drug
resistance. Such interactions may be beneficial
and therefore specifically intended as part of a
combined drug regimen: for example, one drug
might increase the intracellular concentration of
another, reduce metabolic inactivation of an
active drug or bypass the metabolic effects of
another drug. An example of the latter would be
reversal of the methotrexate-induced inhibition
of folate metabolism by leucovorin (citrovorum
factor). Another specifIc drug interaction that is
particularly important in patients receiving
chemotherapy involves allopurinol, a potent
xanthine oxidase inhibitor, which is frequently
administered to prevent uric acid nephropathy.
Inhibition of xanthine oxidase, however, also
markedly decreases metabolism of mercapto-
purine, a purine analogue and antimetabolite.
Thus, when administered with allopurinol, the
dose of mercaptopurine must be be significantly
reduced to avoid unexpectedly severe toxicity.
DRUG RESISTANCE
Drug resistance is a term used either to de-
scribe the general problem of tumor growth in
the face of chemotherapeutic agents or, more
narrowly, to refer to specific biochemical altera-
tions in cell metabolism leading to ineffective-
ness of one or more chemotherapeutic drugs.
 6. PRINCIPLES OF CHEMOTHERAPY
Resistance can either be present initially before
exposure to a given drug (referred to as natural
or de novo resistance) or emerge after initial re-
sponsiveness (acquired resistance). Resistance
may be based simply on cell population kinet-
ics; that is, many cells may be in a resting state
(GO), thus rendering them insensitive to cell-
cycle-specific agents and relatively less sensitive
to most other chemotherapeutic agents. Poten-
tial strategies to overcome resistance related to
cell kinetics might include reduction of tumor
bulk with surgery or radiotherapy or use of
agents relatively effective against resting cells.
Alternatively, resistance to chemotherapeutic
agents may be related to inadequate drug deliv-
ery secondary to poor absorption, increased ex-
cretion, binding or catabolism, poor transport
into certain compartments, or drug interactions
leading to inadequate blood levels. Resistance
related to these considerations could be over-
come simply by more effective drug delivery,
whether by increasing the dose administered or
by changing the route of administration, con-
current drug therapy, etc. Finally, resistance
may be the result of biochemical alterations
in drug metabolism. Several mechanisms of
biochemical drug resistance have been well
characterized, including insufficient drug activa-
tion, accelerated drug inactivation, increased
concentration of a target enzyme, decreased re-
quirement for a specific metabolic product, in-
creased utilization of an alternative biochemical
pathway, or rapid repair of a drug-induced le-
sion. Strategies for overcoming such biochemi-
cal causes of resistance obviously differ, depend-
ing on the specific nature of the biochemical
mechanism.
Two considerations regarding drug resistance
have been of particular importance in the emer-
gence of modern principles of chemotherapy.
First, drug-resistant cell lines may emerge dur-
ing treatment with a given agent, perhaps even
at an accelerated rate since many chemother-
apeutic agents are also mutagenic. In most ex-
perimental systems, drug resistance is relatively
specific. Thus, the likelihood of a given cell
simultaneously becoming resistant to two unre-
lated agents is represented by the product of the
likelihood of becoming resistant to each agent.
Hence if 1 in 106 cells becomes resistant to drug
A and a like number to drug B, only 1 in 10 12
cells (i.e., 106 X 10 6 ) will become resistant to
both agents simultaneously. This consideration,
analogous to the appearance of antibiotic-
87
resistant bacteria during the course of a treated
infection, constitutes a major rationale for the
use of combination chemotherapy.
Second, the likelihood of a specific drug-
resistant cell being present spontaneously in a
given population is related to the inherent
mutation rate of that tumor population. By the
mathematical model of Goldie and Coldman,
this likelihood in turn varies directly with
tumor mass; i.e., the larger a tumor population,
the more likely it already contains drug-
resistant cells. This again emphasizes a major
advantage of initiating chemotherapy when the
tumor population is small, e.g., immediately af-
ter surgery, as an adjuvant treatment modality.
EFFECTS OF DRUG DOSE AND SCHEDULE
Both drug dose and schedule have been shown
to be of critical importance in the successful
treatment of experimental tumors. As a general
rule, the effectiveness of a given drug can be
related to the product of drug concentration
multiplied by drug exposure time, i.e., C X T [6].
This concept implies that drug effectiveness
could be increased either by increasing dose or
duration of exposure. While generally appli-
cable, this principle is less valid for the anti-
metabolites where increasing dose is less likely
to be beneficial than is increased duration of
exposure, i.e., time to permit all cells to enter S
phase. Thus, for individual drugs, specific fac-
tors (e.g., mechanism of action or drug absorp-
tion, transport, distribution, biotransformation,
excretion, or interactions) may critically affect
the C X T function.
For many tumors and drugs, it is possible to
demonstrate a steep dose-response curve; for
small changes in drug dose, large changes in
therapeutic response are seen [7]. There are now
several examples of human tumors, including
lymphoma, small cell lung cancer, and acute
leukemia, that confirm this observation first
made in animal observations. Increasing doses
of ineffective drugs are not likely to result in
therapeutic benefit, but even small decreases in
the dose of effective agents in an attempt to
reduce toxicity may result in decreased clinical
benefit.
Based on observations of apparent benefit in
children with acute lymphoblastic leukemia,
maintenance chemotherapy (relatively low-dose,
long-term drug administration) has been used
in the treatment of other malignancies includ-
ing Hodgkin's and non-Hodgkin's lymphomas
88 II. PRINCIPLES OF MANAGEMENT
and testicular carcinoma. Recent observations
indicate, however, that chemotherapy mainte-
nance confers no benefit on patients with these
malignancies who have achieved documented
complete remission with high-dose, intermit-
tent chemotherapy regimens. This suggests that
use of maximal doses of chemotherapy over a
short period of time may provide optimal ther-
apeutic benefit.
As suggested above, scheduling of drug ad-
ministration can be critical for both therapeu-
tic and toxic effect. For example, cytarabine, a
rapidly catabolized antimetabolic, is virtually
inactive if given by widely spaced bolus ad-
ministration, but is' highly effective if given
frequently or by continuous infusion. Similar-
ly for methotrexate, the duration of exposure
above a critical blood level is generally of
greater importance than the dose of drug ad-
ministration. In contrast, cyclophosphamide, a
relatively phase-nonspecific alkylating agent
is maximally effective when given on a high-
dose intermittent schedule. Thus, for each che-
motherapeutic agent, the optimal schedule of
administration must be determined to achieve
maximal clinical effectiveness.
RATIONALE FOR COMBINATION
CHEMOTHERAPY
The use of chemotherapeutic agents in com-
bination evolved from frustration with the
results achieved using effective drugs singly in
sequence, promising results observed with com-
bination drug therapy in some resistant infec-
tious diseases (e.g., tuberculosis), and early
attempts to design drug combinations based on
biochemical rationale. In spite of such theoreti-
cal considerations, however, the development of
the most effective drug combinations has been
l~rgely empiric and based on clinical observa-
tion.
Nevertheless, it is possible to identify a num-
ber of reasons that combinations of drugs are
generally more effective than single agents.
Among the more important of these are the
following:
1. Prevention of drug resistance (a) by provid-
ing a broader range of activity which is more
likely to encompass all cells in a given malig-
nant cell population and (b) by making it less
likely that a new clone of cells, resistant to
two or more agents simultaneously, will
emerge (see the section Drug resistance).
2. Cytotoxicity to both resting and dividing
cells can be provided by combining drugs.
active in different phases of the cell cycle (see
table 6-1).
3. Enhancement of biochemical effect by select-
ing agents that affect different biochemical
pathways, or perhaps even more effectively,
different steps in a single pathway leading to
a critical metabolite.
4. Favorable drug interactions can be utilized,
for example, to increase the penetration of
one drug into malignant cells or sanctuary
sites, to affect the metabolism of a drug, or to
bypass the toxic effect of a drug.
These considerations and reflection upon the
effective drug combinations that have been de-
veloped have led to the recognition of several
"principles of combination chemotherapy" that
may serve to guide the development of new
effective combinations:
1. Each drug should be active individually
against the tumor. Addition of inactive drugs
for theoretical biochemical reasons has
generally not been helpful, and may be det-
rimental if only toxicity is added.
2. Whenever possible, drugs with different
dose-limiting toxicities should be selected.
Again, however, addition of ineffective drugs
with different toxicities serves no useful pur-
pose.
3. Drugs should be used in their optimal dose
and schedule. Combinations in which dose
or dose rate have had to be substantially re-
duced in order to use more than one drug are
often no better than a single agent used opti-
mally.
4. Inclusion of agents with different mechan-
isms of action is generally preferred, both to
enhance antitumor effect and to minimize the
possibility of drug resistance.
In spite of the clear superiority of drug com-
binations in treating some diseases and the
theoretical attractiveness of the concept, new
drug combinations should not be accepted as
standard therapy for any malignancy without
critical clinical evaluation, preferably in proper-
ly controlled clinical trials.
DRUG TOXICITY
As a group, cancer chemotherapeutic agents are
notorious-to both patients and physicians-
 6. PRINCIPLES OF CHEMOTHERAPY
for the frequency and severity of expected side
effects at usual therapeutic doses. While some of
this reputation is not justified, it is true that the
usefulness of most agents is limited by toxic
reactions in normal cells or organs, thus lower-
ing the therapeutic index. Some familiarity with
the side effects of these agents is therefore criti-
cal. Patients must be carefully monitored during
therapy so that problems can be recognized
promptly and therapy modified appropriately.
Generally guidelines for the recognition,
evaluation, and grading of toxicity have been
adopted and are helpful in managing individual
patients as well as in assessing and reporting the
results of clinical trials. Representative toxicity
criteria from the Eastern Cooperative Oncology
Group (ECOG) are detailed in table 6-2. Sever-
ity can be graded as 0 (none) through 4 (life-
threatening) for each of the organ systems as
listed. The more common of the acute toxicities
deserve brief comment:
1. Gastrointestinal toxicity. Nausea and
vomiting are frequently seen hours to a few
days after administration of drugs. Strictly
speaking, this represents not gastrointestinal
toxicity, but rather activation of an emesis trig-
ger zone in the central nervous system. Various
antiemetic regimens have been devised in an
attempt to suppress chemotherapy-induced
emesis, more recently with considerable success
[8]. The gastrointestinal tract itself, however, is
significantly affected by many chemotherapeu-
tic agents, presumably because of the rapid turn-
over time of its mucosal surfaces. Stomatitis,
esophagitis, and enteritis can occur.
2. Myelosuppression. The marrow, like the
gastrointestinal tract, consists of rapidly divid-
ing cells. Thus, granulocytopenia, thrombocy-
topenia, and anemia are observed to varying de-
grees after chemotherapy and, in fact, generally
represent the most important, dose-limiting
toxicity associated with chemotherapy. Anemia
can usually be corrected without problems by
transfusions as needed. Marked thrombocy-
topenia can usually be tolerated without spon-
taneous bleeding but, below 10,000-20,000
platelets/ ILl, platelet transfusion support is re-
quired and, if not adequate, life-threatening
hemorrhage may occur. Granulocyte counts be-
low 500/1-11 are associated with significantly in-
creased risk of life-threatening infection. Thus,
patients with marked granulocytopenia must be
managed with special vigor and aggressiveness
89
of antibiotic administration and infrequently
with granulocyte transfusions or ultraisolation
technique. In addition to acute myelotoxicity
occurring 7-15 days after drug administration,
some drugs cause delayed myelosuppression
(4-6 weeks after administration) or cumulative
toxicity that may lead to severe or prolonged
pancytopenia.
3. Immunosuppression. Many chemother-
apeutic agents suppress circulating lymphocyte
counts and, to varying extents, also suppress
both humoral and cellular immunity. Since
many malignancies are also associated with im-
munosuppression, it may be difficult to distin-
guish between the immunosuppressive effects of
underlying disease and therapy. Nevertheless,
additional suppression of host defense via im-
munosuppression is an important and frequent
toxicity of chemotherapy.
Other toxicities that are less frequent or associ-
ated only with selected drugs are not reviewed
in detail here. Some examples of these include
skin reactions, alopecia, hepatic toxicity, pul-
monary toxicity (especially fibrosis related to
bleomycin), neurotoxicity (especially neuro-
pathy after vinca alkaloids), cardiac toxicity
(especially related to anthracyclines), genito-
urinary toxicity (including uric acid nephro-
pathy, renal damage, or hemorrhagic cystitis
related to cyclophosphamide), and anaphylaxis
(especially after asparaginase). This listing is
certainly not all-inclusive, as a wide variety of
other, less frequent complications have been
described. The physician administering these
agents must be aware of these and of the poten-
tial for as yet unrecognized complications of
cancer chemotherapy.
The potential for long-term delayed com-
plications of chemotherapy is becoming more
pertinent as these drugs are used more often as
adjuvant chemotherapy following potentially
curative surgery and as more patients become
long-term survivors after curative chemother-
apy. Any organ that manifests acute toxicity
may fail to recover completely following cessa-
tion of chemotherapy and, for example, long-
term marrow, cardiac, hepatic, pulmonary, or
renal impairment may be observed. With some
drugs, cumulative toxicity may, in fact, be most
important, including, for. example, anthracy-
cline cardiac toxicity, bleomycin pulmonary
toxicity, and vinca alkaloid neurotoxicity.
~
o

TABLE 6-2. Toxicity' criteriab used by the Eastern Cooperative Oncology Groupe. d

0 2 3 4

Leukopenia WBC X 103 ;;,:4.5 3.0-<4.5 2.0-<3.0 1.0-<2.0 <1.0

Neut x 103 ;;':1.9 1.5-<1.9 1.0-<1.5 0.5-<1.0 <0.5
Thrombo- Pit X 103 ;;,:130 90-<130 50-<90 25-<50 <25
cytopenia
Anemia Hgbg% ;;,:11 9.5-10.9 <9.5
Hct% ;;,:32 28-31.9 <28
Clinical Sxofanemia Req transfusions
Hemor- None Minimal Mod-not debilitating Debilitating Life-threatening
rhage
Infection None No active Rx Requires active Rx Debilitating Life-threatening
GU BUNmg% ",20 21-40 41-60 >60 Symptomatic uremia
Creatinine ",1.2 1.3-2.0 2.1-4.0 >4.0
Proteinuria Neg 1+ 2+-3+ 4+ CObst uropathy
Hematuria Neg Micro-cult-positive Gross-cult-positive Gross + clots
Urinary tract infection should be graded under infection, not G U.
Hematuria resulting from thrombocytopenia is graded under hemorrhage.
Hepatic SGOT <1.5 x nl 1.5-2 x normal 2.1-5 X normal >5 X normal
Alkphos <1.5 X nl 1.5-2 X normal 2.1-5 X normal >5 X normal
Bilirubin <1.5 X nl 1.5-2 X normal 2.1-5 X normal >5 X normal
Clinical Precoma Hepatic coma
Viral hepatitis should be recorded as infection rather than liver toxicity.
N&V None Nausea N & V controllable Vomiting intractable
Diarrhea None No dehydration Dehydration Grossly bloody
Pulm PFT Nl 25%-50% decrease in >50% decrease in Dco
DcoorVC orVC
Clinical MildSx ModerateSx Severe Sx-intermittent Assisted vent or con-
O2 tinuous O 2
 Pneumonia is considered infection and not graded as pulmonary toxicity unless felt to be resultant from pulmonary changes directly
induced by treatment.
Cardiac N1 ST -T changes Atrial arrhythmias MildCHF Severe or refract CHF
N1 Sinus tachy > 11 0 at Unifocal PVCs Multifocal PVCs Ventric tachy
rest
Pericarditis Tamponade
Neuro PN None DecrDTRs AbsentDTRs Disabling sens loss Resp dysfunction 2° to
weakness
Mild paresthesias Severe paresthesias Severe PN pain
Mild constipation Severe constipation Obstipation Obstipation req surg
Mild weakness Severe weakness Paralysis-confining pt
Bladder dysfunct to bed/wheelchair

CNS None Mild anxiety Severe anxiety Confused or manic Seizures

Mild depression Mod depression Severe depression Suicidal
Mild headache Mod headache Severe headache Coma
Lethargy Somnolence Cord dysfunction
Tremor Confined to bed due
Mild hyperactivity to CNS dysfunct
Skin & N1 Transient erythema Vesiculation Ulceration
mucosa Pigmentation, atrophy Subepidermal fibrosis Necrosis
Stomatitis None Soreness Ulcers-can eat Ulcers-cannot eat
Alopecia None Alopecia-mild Alopecia-severe
Allergy None Transient rash Urticaria Serum sickness Anaphylaxis
Drug fever <:;38°C Drug fever >38°C Bronchospasm-req
(<:;100.4°F) (>100.4°F) parenteral meds
Mild bronchospasm
Fever <:;37SC <:;38°C (<:;100.4°F) >38°C (>100.4°F) Severe c chills Fever c hypotension
(>40°C)
Fever felt to be caused by drug allergy should be graded as allergy.
Fever due to infection is graded under infection only.
Local tox None Pain Pain + phlebitis Ulceration
a The toxicity grade should reflect the most severe degree occurring during the evaluated period, not an average.
bWhen two criteria are available for similar toxicities, e.g., leukopenia, neutropenia, the onc resulting in the more severe toxicity grade should be used.
cToxicity grade=5 if that toxicity caused the death of the patient.
dAbbreviations used include: Neut, neutrophils; PIt, platelets; N+V, nausea and vomiting; PFT, pulmonary function tests; Deo, diffusion capacity; ve, vital capacity; PN, peripheral
nerves; DTRs, deep tendon reflexes.

~
92 II. PRINCIPLES OF MANAGEMENT

When considering long-term toxicity, gonadal Chemotherapeutic Agents

dysfunction, including sterility, is common,
especially after alkylating agent therapy, and
recovery only variable, especially in adults.
Perhaps of greatest concern in terms of delayed
toxicity is the risk of second neoplasms. Many
chemotherapeutic drugs are clearly mutagenic,
teratogenic, and carcinogenic in vitro or in ex-
perimental animals. Therefore, an apparent in-
crease in the frequency of second malignancies
in successfully treated patients with Hodgkin's
disease, multiple myeloma, and ovarian cancer
is alarming and, perhaps appropriately, begin-
ning to affect drug choice and indications for
therapy. Nevertheless, it is important to con-
sider the risk-benefit ratio and to recognize
that, in most circumstances, the benefits of
chemotherapy far outweigh the potential risk of
a drug-related second malignancy.
A large number of types of chemotherapeutic
agents have been developed and more are in
various stages of testing for efficacy and toxicity
prior to general availability. A complete discus-
sion of these agents, their metabolism, toxicity,
indications, and unique features is beyond the
scope of this chapter. A brief outline, however,
is presented in table 6-3. The classification
scheme utilized divides these drugs in part by
their mechanism of action (alkylating agents,
antimetabolites, hormonal) and in part by their
source (antibiotics, plant alkaloids). In some
instances, classification becomes somewhat
arbitrary, but nevertheless useful. Some aspects
of this classification and characterization of in-
dividual drugs are further amplified below.

TABLE 6-3. Classification and selected characteristics of some antineoplastic agents'

Toxicity

Drug Route Marrow N+V Alopecia Other Comments

Alkylating agent
Cyclophos- i.v., p.o. ++ + + Cystitis, water Requires activation
phamide retention by hepatic micro-
somal enzymes
Melphalan p.o.,l.v. ++ +
Busulfan p.o. ++ Pulmonary fibro-
sis, hepatoto-
xicity
Chlorambucil p.o ++
BCNU I.V. ++ ++ + Pulmonary Enters CNS; delayed
(carmustine) fibrosis myelosuppression
CCNU p.o. ++ + + Pulmonary fibro- Enters CNS; delayed
(lomustine) sis, renal failure myelosuppression
Streptozotocin l.v. + + Renal failure,
hyperglycemia
Cisplatin (CDDP) l.V. + ++ Renal failure,
neuropathy,
ototoxicity
Dacarbazine l.v. + ++ Flu-like syndrome
(DTIC)
Antimetabolites
Methotrexate i.v.,p.o., ++ + Mucositis, renal Effect markedly en-
i.m.,i.t. failure at high hanced if renal
dose function impaired
or ascites/pleural
fluid
5-fluorouracil I.V.,1.a. ++ + Diarrhea, mucosi-
tis, hyperpig-
mentation
TABLE 6-3. (Continued)

6-Mercaptopurine p.o. ++ + Cholestasis

6-Thioguanine 1.v. ++ + Cholestasis,
Cytosine arabino- 1.v. ++ + Cholestasis, Can enter CNS
side mucositis
Hydroxyurea p.o.,i.v. ++ +
Antibiotics
Dactinomycin I.V. ++ ++ + Mucositis
Doxorubicin I.V. ++ ++ ++ Cardiomyopathy
Daunorubicin l.V. ++ ++ + Cardiomyopathy
Mithramycin 1.v. + ++ Renal, coagulation
system, hepatic
Mitomycin l.V. ++ + Renal, pulmonary Cumulativ~ myelo-
suppreSSiOn
Bleomycin i.v., s.C., + Pulmonary, skin,
l.m. fever
Plant alkaloids
Vincristine 1.v. + Neuopathy, in-
appropriate
ADH
Vinblastine 1.v. ++ + + Mucositis, myalgia
Etoposide (VP-16) 1.v. ++ + + Neuropathy
Miscellaneous
Asparaginase l.v. + Pancreatitis, Enzyme
clotting abnor-
malities, hyper-
glycemia,
anaphylaxis,
rash, pneumo-
nitis
Procarbazine p.o. ++ + Rash, pneumonitis Enters CNS, can
cause depression
or antabuse-like
reaction
Hexamethy- p.o. ++ Neurotoxicity
lenamine
o,p'-DDD p.o. ++ Diarrhea, skin,
CNS depression
Hormonal
Corticosteroid p.o.,l.v., Cushingoid
l.m. features,
electrolyte!
fluid!glucose
imbalance, GI
bleeding,
osteoporosis,
mental changes
Estrogen! p.o"i.v" + Fluid retention
progestin! l.m.
androgen
Tamoxifen p.o. Estrogen antagonist
Aminoglute- p.o. Rash Steroid synthesis in-
thimide hibitor
aIV, intravenous; p.o., oral; i.m., intramuscular; i.t., intrathecal; i.a., intraarterial; s.c., subcutaneous; N::: V, nausea and vomiting; ADH,
antidiuretic hormone; and, eNS central nervous system.

93
94 II. PRINCIPLES OF MANAGEj.,1Er-.;T
ALKYLA TING AGENTS
The alky lating agents are a large, diverse
group of highly reactive compounds that have
the ability to substitute alkyl groups for the
hydrogen atoms of many organic compounds.
Nucleic acids, especially DNA, are the critical
target compounds responsible for the cytotoxic
effect of these agents. Alkylation produces
breaks in the DNA molecule, thus interfering
with DNA replication and transcription of
RNA. As a class, because they interact with
preformed molecules, the alkylating agents
are not phase specific and some are cell cycle
nonspecific (classes I and III, table 6-1).
There are, however, marked differences in the
pharmacology, toxicity, and clinical usefulness
of the various alkylating agents. In fact, six
different types of alkylating agents are recog-
nized [9]. Drug resistance to one type of alkyla-
tor tends to predict resistance to another drug
of that type, but not necessarily to alkylating
agents of another type. Furthermore, the nitro-
sureas, dacarbazine, and cisplatin all appear to
have mechanisms of action in addition to their
ability to alkylate nucleic acids.
ANTIMET ABO LITES
The antimetabolites are a group of low molecu-
lar weight compounds that are structural ana-
logues of normal metabolites required for cell
function and replication and, more specifically,
for nucleic acid synthesis. There are three ways
in which these agents or their biotransformed
active products exert their effects: (a) by sub-
stituting for a normal metabolite, when the
product containing the substitute molecule is
functionally inadequate; (b) by competing
with a normal metabolite for the occupation
of the catalytic site of a key enzyme; or (c) by
competing with a normal metabolite that acts
at a noncatalytic site to alter the function of a
key enzyme. Because of their primary effect on
DNA synthesis, these agents are largely cell
cycle specific phase specific (class II, table 6-1)
and their effectiveness is often critically depen-
dent on schedule of administration.
ANTIBIOTICS
The clinically useful antitumor antibiotics are all
produced in culture by various strains of the soil
fungus Streptomyces. All produce their effect by
binding to and thereby damaging DNA: dactin-
omycin and the anthracyclines (doxorubicin
and daunorubicin) intercalate between DNA
base pairs and thus inhibit DNA-dependent
DNA and RNA synthesis, bleomycin causes
DNA strand scission, mitomycin cross-links
DNA and impairs replication, and mithramycin
complexes to DNA, thereby blocking RNA
synthesis. In general, the kinetics of their cyto-
toxic effect is that of cell-cycle-specific phase-
nonspecific (class III) agents.
PLANT ALKALOIDS
Two of the most used chemotherapeutic agents,
vincristine and vinblastine, are derived from the
periwinkle plant. Both are inhibitors of micro-
tubular protein formations and thus interfere
with the development of the mitotic spindle,
resulting in metaphase arrest. Although difficult
to classify, both are generally regarded as cell-
cycle-specific phase-specific. In spite of their
many similarities, these two agents have differ-
ent antitumor and toxic effects and are generally
not cross resistant. Etoposide (VP-16) is the
first of a new group of active drugs derived from
the mayapple plant (a Podophyllum species).
This drug has no effect on microtubules, but
rather arrests cells in the G2 phase, though its
precise mechanism of action remains unknown.
Guidelines for Administering
Chemotherapy
Cancer chemotherapeutic agents are potent
drugs, capable of inducing severe toxicity,
including fatality. Their use must therefore
be judicious and appropriate, guided by the
following general principles:
1. Chemotherapy should be administered
only if the diagnosis of malignancy has been
established histologically. Benign tumors or in-
fectious diseases can be mistaken for malignant
conditions. Thus, histologic proof of malignan-
cy is required in all but the most exceptional
circumstances, e.g., a tumor of the midbrain or
life-threatening superior vena cava syndrome. A
"therapeutic trial" of chemotherapeutic agents
to establish a diagnosis is unwarranted. Fur-
thermore, clinical and pathologic diagnoses
must be consistent; if not, additional informa-
tion should be sought before initiating chemo-
therapy.
2. The extent of the malignancy must be ade-
quately determined before initiating chemother-
apy for two reasons. First, knowledge of the
true extent of disease may alter the therapeutic
 6. PRINCIPLES OF CHEMOTHERAPY
plan. For example, the presence of metastatic
disease following surgery might change the goal
of therapy from "adjuvant" to "therapeutic."
One or more staging systems have been de-
scribed for most cancers, based in part on the
natural history and mode of spread of a given
malignancy, prognostic implications of disease
extent, and usefulness in therapeutic decisions.
Thus the clinician should be certain that
sufficient clinical and laboratory investigations
have been performed to stage adequately a given
tumor in order to be certain that the chosen
therapy is appropriate.
Second, it is critical to establish objective
markers of the tumor prior to initiating che-
motherapy, if at all possible, so that response to
therapy can be assessed accurately and quantita-
tively. Whenever possible, tumor dimensions
should be measured and recorded using a
tumor's longest dimension and its perpendicular
TABLE 6-4. Response criteria for cancer
chemotherapy
Complete Complete disappearance of all
response (CR) signs and symptoms of
malignancy
-persistence of response for at
least one month is generally
also required
-whether determined clinical-
ly or pathologically (by re-
biopsy) should be specified
Partial response Decrease of 50% or more in
(PR) the product of the largest di-
ameter and its perpendicular
diameter of all measurable
lesions
-generally must persist at
least one month
-no new lesions may appear
-performance status must not
decrease
Stable disease (SD) Decrease of less than 50% or
increase of less than 25 % in
the diameter product of
measurable lesions
Progressive disease Increase of more than 25 %
(PD) in the diameter product
of measurable lesions or
development of new lesions
-significant weight loss or de-
crease in performance status
95
diameter. If several lesions exist, all should be
measured, either by physical or radiologic ex-
amination. Some tumors secrete products that
can be measured to quantitate tumor response,
e.g., monoclonal immunoglobulin in myeloma
and gonadotropin in testicular carcinoma.
When tumor size is measured, response can be
measured objectively using criteria such as listed
in table 6-4. Some tumors, however, can not be
quantified accurately (tumor is apparent but
without clearly measurable borders, e.g., a pleu-
ral effusion or paramediastinal mass), and are
then described as "evaluable" for response, but
not "measurable." Whenever subjective im-
provement is all that the clinician may have to
assess response to therapy, the result is often
uncertainty and one must make decisions with
inadequate information. Hence, it is critically
important to measure carefully tumor extent
prior to initiating therapy so that response can
be objectively measured.
3. Before administering chemotherapy, the
clinician must be familiar both with the malig-
nancy to be treated (extent, natural history,
likely sites of progression, complications, ex-
pected responses to therapy) and with the che-
motherapeutic agents to be utilized, including
uncommon as well as expected toxicities. Fur-
thermore, adequate facilities must be available,
not only to monitor for potential toxicity as
well as for response, but also to provide ade-
quate support to respond immediately and ag-
gressively to any side effects of chemotherapy,
including thrombocytopenia with bleeding,
leukopenia with infection, diarrhea with dehy-
dration, mucositis with aspiration, etc. Failure
to adhere to this principle may cause problems
either because toxicity is inadequately rec-
ognized and treated or because the malignancy
is ~n~dequately treated for fear of potential
toxIcity.
4. The overall clinical status of a patient with
cancer is an important predictor of ability to
tolerate therapy, especially chemotherapy, re-
sponse to that therapy, and of survival. Clinical
status is a composite of age, nutritional status,
extent of disease (malignant and other), prior
therapy, and marrow, liver, lung, and kidney
function and reserve. The best single measure of
this is the performance status, an expression of
the level of activity of which a patient is capable.
This is a measurement, independent of the
anatomic extent or histologic characteristics of
the malignancy, of how much the cancer has
96 II. PRINCIPLES OF MANAGEMENT
affected the patient. Two performance statuses
are in general use, one first described by David
Karnofsky (table 6-5) and a simplified version
used by the major cooperative clinical trials
groups (table 6-6). The better the performance
status of patients, the better they tolerate ther-
apy, the more likely they are to respond and, in
general, the longer they survive. Thus, the dis-
tribution of patients by performance status is of
critical importance in assessing a therapeutic
regimen or comparing clinical trials.
Clinical Trials
Because cancer chemotherapy is a relatively new
and rapidly developing arena, the design and
conduct of clinical trials on the one hand and
their interpretation on the other hand are
critical to an understanding of the field. Before
introduction of a new agent for clinical trial,
however, extensive animal testing is undertaken.
The first set of clinical trials, called phase I, is
intended to determine toxicity in man and
establish the maximally tolerated dose or sche-
dule of administration of agents that appear
potentially useful based on animal testing. Such
trials are generally performed in patients with
advanced cancer, but who might conceivably
benefit from the drugs tested. Initial doses are
low, based on animal experience, and then esca-
TABLE 6-5. Karnofsky performance status scale
Functional capability
Able to carty on normal activity; no special care is
needed
Unable to work; able to live at home; cares for most
personal needs; a varying amount of assistance is
needed
Unable to care for self; requires equivalent of institu-
tional or hospital care
lated as tolerated. At the completion of phase-I
testing, phase-II trials are undertaken to iden-
tify tumor types for which the new agent
appears promising and to identify more chronic
or cumulative toxicity. Promising drugs are
then tested in phase-III trials. These trials are
generally randomized or otherwise prospective-
ly controlled and are intended to determine one
or more of the following:
1. The effects of treatment relative to the natural
history of the disease (i.e., a "no treatment'
control arm).
2. Whether a new treatment is more effective
than the standard therapy.
3. Whether a new treatment is equally as effec-
tive as the standard therapy but associated
with less morbidity, mortality, cost, or com-
plexity.
Many drugs or treatment approaches appear to
achieve improved result compared with past
experience or historical controls when first
tested in phase-II trials. Unfortunately, many
variables in addition to the treatment being
tested may influence the outcome of such a trial,
e.g., patient performance status, stage of disease,
supportive therapy, and diagnostic acumen. For
these reasons, a randomized, prospective phase-
III trial is generally required to prove the supe-
Level of activity
100% Normal; no complaints, no evidence of disease
90% Able to carry on normal activity; minor signs
of symptoms of disease
80% Normal activity with effort, some signs or
symptoms of disease
70% Cares for self; unable to carry on normal activ-
ity or to do active work
60% Requires occasional assistance, but is able to
care for most of own needs
50% Requires considerable assistance and frequent
medical care
40% Disabled; requires special medical care and
assistance
30% Severely disabled; hospitalization is indicated,
although death not imminent
20% Very sick; hospitalization necessary; active
supponive treatment necessary
10% Moribund; fatal processes progressing rapidly
0% Dead
 6. PRINCIPLES OF CHEMOTHERAPY
TABLE 6-6. Simplified performance status scale
Grade Level of activity
o Fully active, able to carry on all predisease
performance without restriction (Kar-
nofsky 90-100)
Restricted in physically strenuous activity,
but ambulatory and able to carry out
work of a light or sedentary nature,
e.g., light house work, office work
(Karnofsky 70-80)
2 Ambulatory and capable of all self-care,
but unable to carry out any work activi-
ties; up and about more than 50% of
waking hours (Karnofsky 50-60)
3 Capable of only limited self-care, confined
to bed or chair more than 50% of wak-
ing hours (Karnofsky 30-40)
4 Completely disabled. Cannot carry on
any self-care; totally confined to bed or
chair
5 Dead
riority of a new drug or treatment approach.
Randomization is but one statistical method,
however, of trying to assure comparability of
treatment groups, and other methods may be
equally appropriate to control a clinical trial
prospectively and adequately. More recently,
statistical methods employing multifactorial
analysis have been used in an attempt to com-
pare a current experimental group with a his-
torical control group [10]. Thus, the design
and interpretation of clinical trials have been
actively evolving during the era of cancer che-
motherapy. It is critical that questions regarding
experimen tal design and statistical analysis be
considered whenever one attempts to interpret
the chemotherapy literature.
Present and Future Directions of
Chemotherapy Management and
Research
Certainly the development of new chemother-
apeutic agents that are either more effective or
less toxic or both remains a major hope for
improving the results of chemotherapy in the
treatment of malignant disease. Alternatively
(or additionally), it may be possible to improve
results by more effective administration of
97
agents currently available. Three potential
approaches will be specifically discussed.
OPTIMAL TIMING OF CHEMOTHERAPY
Classically, surgery and radiotherapy were
treatment modalities employed with curative
intent in early stages of cancer, while chemo-
therapy was relegated to a palliative role in
patients with recurrent or advanced disease not
appropriate for curative therapy. Not surpris-
ingly, in such circumstances, toxicity was often
high and benefit generally limited. Subsequent-
ly, chemotherapy has been found to be effective
and potentially curative in several malignancies,
including gestational choriocarcinoma, some
lymphomas and acute leukemias, testicular car-
cinoma, and some pediatric tumors. At the same
time, increased understanding of the natural his-
tory and response to therapy of carefully staged
cancers now enables the clinician to predict which
patients will respond relatively poorly to local
treatment modalities (surgery and radiotherapy)
or have a high likelihood of developing metas-
tatic disease. Principles of cell growth, tumor
kinetics, and sensitivity to chemotherapy dis-
cussed above, failure of chemotherapy to eradi-
cate advanced disease in spite of some effective-
ness (i.e., partial responses), and the ability to
predict the presence of occult metastatic disease
led to the use of chemotherapy as adjuvant ther-
apy, i.e., after apparently curative surgery or
radiotherapy. While adjuvant therapy appears
to contribute to disease-free and overall survival
in some cancers, its precise role remains to be
established. Certainly the use of adjuvant che-
motherapy in cancers that respond only mar-
ginally to chemotherapy without carefully per-
formed, prospectively controlled clinical trials
demonstrating benefit should be avoided. We
can anticipate that the future will bring greater
understanding of adjuvant chemotherapy in-
cluding which chemotherapy to use for which
cancers for what period of time.
Just as chemotherapy may be more effective
against metastatic disease if used earlier as ad-
juvant therapy, it may be more effective against
locally advanced disease if used as initial ther-
apy, that is, before surgery or radiotherapy as
part of a "combined modality" initial treatment
approach. Potential reasons for greater effec-
tiveness of chemotherapy as initial therapy are
listed in table 6-7. In fact, impressive clinical
responses have been observed with initial che-
motherapy in several cancers, including cancers
98 II. PRINCIPLES OF MANAGEMENT
TABLE 6-7. Rationale for initial chemotherapy, i.e.,
chemotherapy before surgery or radiotherapy
I. Greater effectiveness
1. Better drug delivery because tumor vascular-
ity not impaired by surgery or radiotherapy
2. Patient's clinical performance and nutritional
status may be better
3. Smaller tumors may be more rapidly grow-
ing and therefore more susceptible to
chemotherapy
4. Earlier chemotherapy means tumor is less
likely to have spontaneously generated drug-
resistant cells
II. More optimal order of therapy
1. By reducing tumor volume, initial chemother-
apy may convert an incurable lesion into one
curable using surgery and/or radiotherapy
2. Metastatic foci may be treated earlier without
jeopardizing the treatment of the primary
tumor
3. The response of the tumor to a given chemo-
therapy regimen may be assessed
of the head and neck (see chapters 10 and 11),
esophagus, anus, and breast. The contribution
of this approach to long-term disease control
and survival, in spite of the attractive rationale
and impressive responses, remains uncertain
pending the results of randomized clinical trials.
Nevertheless, one might anticipate further def-
inition of the optimal timing of chemotherapy
with respect to other treatment modalities to be
one direction of future clinical investigation.
REGIONAL CHEMOTHERAPY
Regional chemotherapy represents one
approach to augmenting the effectiveness of
chemotherapy by increasing the C X T (concen-
tration X time) against the tumor tissue while
sparing normal tissue. The only such approach
of generally accepted value is instillation of
drugs into the central nervous system through
lumbar puncture or an Ommaya reservoir. In-
stillation of drugs into the pericardial, pleural,
or peritoneal space is another example of
regional chemotherapy; the latter approach is
receiving renewed attention in the treatment
of ovarian cancer [11]. Intraarterial therapy has
been employed with variable results, primarily
in the treatment of hepatic (primary or metas-
tatic) and head and neck cancers. Recently de-
veloped, totally implantable pumps capable of
administering long-term infusion chemotherapy
have reawakened interest in this approach [12]
and will undoubtedly be the subject of future
clinical investigations.
IN VITRO SCREENING FOR EFFECTIVE
DRUGS
The development of in vitro tests predictive of
in vivo response to chemotherapeutic agents
would be a major advance permitting more
rational and individual selection of drugs in the
treatment of malignancy, just as in vitro sensi-
tivity testing plays a critical role in antibacterial
therapy today. Clonogenic cancer cells can be
detected by plating with growth factors on soft
agar, permitting tumor cell colonies to form
[13]. By comparing growth with and without
chemotherapeutic drugs, it is possible to estab-
lish tumor-drug sensitivity profiles. In spite of
the theoretical attractiveness of this approach,
many problems remain: (a) in vitro tumor col-
ony growth is slow, requiring 3-6 weeks for in-
terpretation of results; (b) most tumors cannot
be grown consistently; (c) plating efficiency is
low, limiting the number of drugs that can be
tested; and (d) although lack of in vitro sensitiv-
ity generally predicts lack of in vivo response, in
vitro sensitivity is only a fair predictor of in vivo
clinical responsiveness. Nevertheless, the tech-
nique has promise and, as the pool of active
drugs that might be employed expands and in
vitro techniques improve, the value of this
approach will hopefully increase.
References
1. Tubiana M, Malaise EP: Growth rate and cell
kinetics in human tumours: some prognostic and
therapeutic implications. In: Symington T, Car-
ter RL (eds) Scientific foundations of oncology.
Chicago, (Year Book), 1976, pp 126.:..136.
2. Bruce WR, Meeker BE, Valeriote FA: Compari-
son of the sensitiviry of nonnal hematopoietic
and transplanted lymphoma colony-fonning
cells to chemotherapeutic agents administered in
vivo. J Nat! Cancer Inst 37:233-245,1966.
3. Laird AK: The dynamics of tumour growth. Br J
Cancer 28:490-502,1966.
4. Skipper HE: Reasons for success and failure in
treatment of murine leukemias with the drugs
now employed in treating human leukemia. In:
Cancer chemotherapy, vol 1. Ann Arbor MI,
University Microfilms International, 1978, pp 1-
166.
5. Goldie JH, Coldman AJ: A mathematical model
for relating the drug sensitivity of tumors to the
spontaneous mutation rate. Cancer Treat Rep
 6. PRINCIPLES OF CHEMOTHERAPY
63:1727-1733,1979.
6. Mellett LB: The constancy of the product of con-
centration and time. In: Sartorelli AC, Johns DG
(eds) Antineoplastic and immunosuppressive
agents, part I. New York, Springer-Verlag, 1974,
p 330.
7. Frei E III, Canellos GP: Dose: a critical factor in
cancer chemotherapy. Am J Med 69:585-594,
1980.
8. Sallan SE, Cronin CM, Zelen M, et al.: Anti-
emetics in patients receiving chemotherapy for
cancer. N Engl J Med 302:134-138,1980.
9. Calabresi P, Parks RE Jr: In Goodman LS,
Gilman A (eds) The pharmacological basis of
therapeutics, 5th edn. New York, Macmillan,
1975, pp 1254-1268.
99
10. Breslow N, Powers W: Are there two logistic
regressions for retrospective studies? Biometrics
34:100-105,1978.
11. Dedrick RL, .1y1yers CE, Bungay PM, et al.:
Pharmacokinetic rationale for peritoneal drug
administration in treatment of ovarian cancer.
Cancer Treat Rep 62:1-11, 1978.
12. Balch CM, Urist MM, Soong SJ, et al.: A
prospective phase II clinical trial of continuous
FUDR regional chemotherapy for colorectal
metastases to the liver using a totally implantable
drug infusion pump. Ann Surg 198:567-573, 1983.
13. Salmon SE, Hamburger A W, Soehnlen B, et a!.:
Quantitation of differential sensitivity of human-
tumor stem cells to anticancer drugs. N Engl J
Med 298:1321-1327,1978.
 7. PRINCIPLES OF IMMUNOLOGY
Crisp ian Scully
The increasing complexity of immunology has
resulted in a widening of the gulf between
research findings and their application in clini-
cal practice. Therefore, a brief synopsis of
fundamental immunology is given here [1]
before discussing the immunology of the more
common head and neck malignant tumors, with
particular reference to oral squamous cell carci-
noma.
Fundamental Immunology
The immune system basically consists of leuko-
cytes and their products in the bloodstream,
lymph, tissue, and organs of the reticuloen-
dothelial system. Immune reactions primarily
are defensive in nature and are characterized by
memory and specificity. The body mounts im-
mune responses to nonhost material (antigen)
that is recognized as foreign by cells of the mac-
rophage lineage. These cells process antigens
and present them to lymphocytes, which re-
spond in a variety of ways.
Lymphocytes originate mainly in the bone
marrow. Although lymphocytes appear mor-
phologically to constitute a homogeneous
population of cells, some pass to the thymus
and therein are modified to become T lym-
phocytes, or T cells, the lymphocytes respon-
sible for cell-mediated immune reactions. T
cells are involved in protection against infection
with virus and fungi and in graft rejection. T
cells can be distinguished from other lympho-
cytes by various cell surface markers. Many of
the lymphocytes that are not processed by the
thymus have other markers that distinguish
them as B-lymphocytes, the lymphocytes re-
sponsible for humoral immunity, important
in defense against many bacterial infections.
Although there are two main effector arms to
the immune system-the humoral and cellular
immune systems-these systems are inter-
dependent.
Peterson et al., HEAD AND NECK MANAGEMENT OF THE CANCER PA TIENT.
© 1986. Martinus Nijhoff Publishing. All rights reserved.
Some lymphocytes appear to bear neither the
markers of T nor of B cells and therefore are
termed null cells (K cells).
Humoral Immunity
The B cell system (non thymic derived) provides
the primary defense against the common bacte-
rial pathogens, especially the pyogenic organ-
isms such as streptococci, pneumococci, and
Haemophilus inJluenzae. Immunoglobulin
(antibody) molecules are secreted following the
differentiation of the B cell into a plasma cell.
Antibody can bind to its specific antigen.
The immunoglobulins are large molecular
weight proteins previously classed as gammag-
lobulins on the basis of their electrophoretic
mobility. They form a heterogeneous collection
of five main classes (and many subclasses)
named IgM, IgG, IgA, IgD, and IgE. Each im-
munoglobulin consists of heavy chains (11, Y, ex,
etc.) and light chains (k or 1\).
IgM
IgM is a macroglobulin that is produced early
in the immune response, is predominantly re-
stricted to the bloodstream, and can very effec-
tively activate the complement system (a system
of proteins important in immune defenses).
IgG
IgG is the predominant serum immunoglob-
ulin and is also distributed throughout the
extracellular fluids. IgG is especially responsible
for protection against Gram-positive pyogenic
bacteria and some viruses. IgG can activate
complement and also is involved in opsonic
activity making microorganisms more suscep-
tible to phagocytosis by macrophages and
neutrophils (polymorphonuclear neutrophilic
leukocytes ).
IgG crosses the placenta to confer some
degree of immunity to the fetus.
101
102 II. PRINCIPLES OF MANAGEMENT
IgA
IgA is the predominant immunoglobulin in the
various body secretions including saliva and
tears; it is present as secretory IgA (sIgA),
a dimer consisting of two molecules linked
by a J chain, and is secreted with a "secre-
tory piece" synthesized by local epithelial cells.
The secretory piece is required for transport of
IgA into secretions and confers resistance on the
sIgA to proteolytic enzymes.
sIgA plays an important role in the protection
of mucous surfaces against a wide spectrum of
antigens by inhibiting their adherence to sur-
faces. Serum IgA is of unknown function and is
mainly monomeric, although some sIgA is also
present in serum.
IgE
IgE is present in trace amounts in serum, where
its function is unclear. Immediate-type hyper-
sensitivity reactions are mediated by IgA anti-
body that binds to mast cells (and basophils),
causing the release of their vasoactive amines if
specific antigen contacts the IgE antibody.
IgD
IgD is present in trace amount in serum and is
also found on the surface of many B cells. The
function of IgD is unclear.
Complement
B cells react, via their antibody production,
with the system known as the complement
system. Complement consists of a number of
plasma proteins that exist under normal cir-
cumstances in inactive form.
Complement can be activated to participate in
a chain reaction analogous to the clotting cas-
cade. IgG and IgM antibodies bound to specific
antigen activate the early components of the
classic complement sequence. The components
are numbered numerically in order of their ac-
tion from C1 to C9, with the exception of C4,
which acts second in the sequence. An activated
component is designated Cx while, when a
component is split into fragments, these are
designated Cxa or Cxb, etc. Complete activa-
tion results in the final production of lytic
products (C9) and the liberation of fragments
that are chemotactic to leukocytes (C3a, C5a,
and C567), promote inflammation (C3a), and
opsonize antigens (C3b).
A second, or alternative,. pathway of comple-
ment activation differs in being activated by
microbial products (not antigen-antibody in-
teractions) and by not involving components
C1, C4, or C2. The alternative pathway of com-
plement activation liberates the same various
active complement fragments as the classic
pathway and affords a defense mechanism in-
dependent of specific antibody production. It
is thus capable of acting in the infant who has
yet to produce antibodies.
Phagocytosis
Specific antibodies are secreted by plasma cells
in response to an antigenic challenge and are
defensive by virtue of binding to antigen and
thereby:
1. promoting the phagocytosis of the antigen
(opsonization ),
2. activating complement and hence promoting
cytolysis (and opsonization with comple-
ment fragments), and
3. eliciting antibody-dependent cellular cytotox-
icity (ADCC) by various leukocytes.
B lymphocyte activity therefore is intimately
associated with that of the phagocytes, the mac-
rophages, and neutrophils. Both these phago-
cytes bear surface receptors for IgG and for
complement component C3, bind to antigens
coated (opsonized) with antibody and/or
complement, and then ingest and destroy the
antigens.
Cellular Immunity (Cell-mediated
Immune Responses)
The T lymphocyte system is responsible for
the development of delayed hypersensitivity
reactions, graft rejection, and protection against
virus, fungi, and some bacterial pathogens such
as mycobacteria. T lymphocytes may also be
defensive against tumor development.
By their release of soluble chemical mediators
(lymphokines), T cells influence the activity of
many other cells such as the macrophage. T cells
may also become effector cells: for example, kil-
ler or cytotoxic T cells (Tc) are capable of direct
cytotoxicity against certain antigens. However,
not all cytotoxic lymphocytes are necessarily
derived from T cells and some, such as natural
 7. PRINCIPLES OF IMMUNOLOGY
killer (NK) cells, appear to be important in
tumor immunology.
T cells are necessary for B cells to respond to
many antigens, and for B cell maturation. The
helper or inducer T cell (Th) is necessary for
cooperation with B cells in antibody produc-
tion, while the suppressor T cell (Ts) is capable
of inhibiting antibody production.
Identification of Leukocyte
Populations
Band T lymphocytes are morphologically
similar, but it is possible to delineate Band T
cells, lymphocyte sub populations, and mac-
rophages by virtue of the type of markers
present on their surfaces. Cytochemistry may
also be of value in identification of leukocytes.
B-CELL MARKERS
B cells usually carry immunoglobulins on their
surface that can be stained by fluorescein-
labeled anti-immunoglobulins. The B cell also
has a receptor for the complement component
C3 that can be detected by incubating lympho-
cytes with sheep erythrocytes (E) coated
with antibody (A) and complement (C). The
antibody- and complement-coated erythrocytes
bind to B cells and form clusters or rosettes,
known as EAC rosettes. The B cell also carries
a surface receptor for the Fc portion of im-
munoglobulin, which can be detected by stain-
ing with fluorescein-labeled heat-aggregated
IgG. Monoclonal antisera (see below) are now
available for detection of B cells.
T CELLS
T cells form rosettes with sheep erythrocytes in
the absence of antibody or complement, these
rosettes being termed E rosettes. Different T
cell subpopulations appear to form E rosettes
under different conditions. Monoclonal antisera
are now available for identification of T
lymphocytes and T cell subpopulations.
MONOCLONAL ANTISERA
More precise identification (and isolation) of
lymphocytes, lymphocyte subpopulations, and
other leukocytes is now possible with the
advent of monoclonal antisera produced by
hybridoma technology.
103
Tests of Bcell and T cell Function
IN VIVO TESTS
In vivo tests of B cell function measure either
the affector or effector pathways of humoral
immunity. The antibody response to immuni-
zation with specific antigens, such as typhoid
vaccine or the bacteriophage <l>x 174, or the
measurement of the titers of naturally-occurring
isohemagglutinins, are tests of the affector and
effector pathways. In general, however, tests of
B cell function are restricted to the measure-
ment of immunoglobulin concentrations by im-
munodiffusion or nephelometry, and mitogenic
responses.
T cell function is determined in vivo by the
ability to manifest a delayed hypersensitivity
reaction to the intradermal injection of a variety
of antigens. However, a negative test might
reflect not only defective effector, but also
defective affector function. Candida albicans,
streptokinase-streptodornase (SK-SD), mumps,
and Trichyphyton antigens are normally used,
since they are ubiquitous antigens to which
most patients will have been exposed at some
earlier data (recall antigens); they should
give therefore a positive reaction. Sensitization
of the skin with the primary antigen dinitro-
chlorobenzene (DNCB) will also test the afferent
limb of the delayed hypersensitivity response
since patients should develop hypersensitivity
that can be demonstrated on retesting 2-3
weeks later.
IN VITRO TESTS
The ability of lymphocytes to react to antigens
or to substances termed mitogens by synthesiz-
ing new DNA and transforming into large lym-
phoblasts is the basis of the lymphocyte trans-
formation test (L TT) or lymphoproliferative
response. Lymphocytes are separated from
heparinized blood and cultured in vitro. Specific
antigens or nonspecific mitogens are then added
and the cells undergoing transformation deter-
mined by labeling the newly synthesizing DNA
with, e.g., tritiated thymidine, and counting
radioactivity.
Mitogens are often plant lectins that induce
transformation of many lymphocytes. The
usual mitogens used are phytohemagglutinin
(PHA), which stimulates mainly T cells;
pokeweed mitogen (PWM), which stimulates
mainly B cells; and concanavalin A (Con A),
104 II. PRINCIPLES OF MANAGEMENT
which stimulates both Band T cells. However,
none of the mitogens specifically stimulates
only T or only B cells.
Many fewer lymphocytes (mainly some T
cells) transform under antigenic than under
mitogenic stimulation-only those cells car-
rying memory of previous exposure to that
specific antigen will undergo transformation.
A good in vitro correlate of in vivo T cell
reactivity is the measurement of the antigen-
induced release of the lymphokine MIF (mac-
rophage migration inhibition factor). This test is
performed by analyzing the ability of factors
liberated by stimulated lymphocytes to inhibit
the migration of macrophages.
The mixed lymphocyte reaction or culture
(MLR or MLC) is a measure of the ability of
lymphocytes to respond to the transplantation
antigens (human leukocyte antigens, HLA) that
are involved in graft rejection. Lymphocytes are
mixed with autologous lymphocytes that have
been treated by irradiation or mitomycin to pre-
vent proliferation. The ability of the untreated
lymphocytes to proliferate in response to anti-
gens on the added (or stimulator) treated cells is
then measured. This is mainly a test of T cell
function.
Measurement of the production of immuno-
globulins in response to PWM stimulation
is a measure mainly of B cell activity, but is
not simply a reflection of B cell activity since
macrophages and T cell cooperation are also re-
quired.
Immunogenetics
That most individuals differ antigenically is
clearly demonstrated in the immunologic re-
jection response that occurs when grafts (allo-
grafts) are attempted between individuals of the
same species who are not identical twins. In
contrast, where individuals are genetically iden-
tical (syngeneic) or where the graft is within the
one individual (autograft), there is no rejection
of the graft. Grafts between species (xenografts)
are rapidly rejected.
The antigens primarily responsible for graft
rejection (transplantation antigens) are the ABO
blood group antigens and, more importantly,
the antigens found on most tissues (especially
leukocytes) that are HLA. These antigens are
determined by a complex of genes called the
major histocompatibility complex (MHC),
which also controls a large array of biologic
phenomena, including (a) immune responsive-
ness, (b) development and susceptibility to
disease, and (c) cell interactions.
The disease relationship of particular HLA
types may be related to the fact that located
within the MHC are also immune response
(Ir) genes that control responses mediated by
T -lymphocytes and determine susceptibility to
diseases.
Immunologic Aspects of Carcinoma
in the Head and Neck
Tumor immunology is a relatively recent
science (reviewed by Oettgen and Hellstrom
[2]) that began with the demonstrations that
chemically-induced malignant tumors (sarcomas)
expressed antigens that would result in the re-
jection of tumor grafts transplanted to geneti-
cally identical animals. Each chemically-
induced tumor had individually distinct anti-
gens (tumor-associated transplantation anti-
gens, T ATA; or tumor-specific transplantation
antigens, TSTA).
Tumor-associated antigens were also shown
to develop in virally-induced experimental
tumors, but these antigens were not individually
distinct in most instances: virus-specified
components or viral components at the cell
surface appear to be responsible for this Im-
munogenicity.
Tumor cells are different antigenically from
their normal progenitors. However, whether
tumors are sufficiently immunogenic, that is,
capable of initiating an immune response, is less
clear. Tumor-associated antigens by and large
have proved on further investigation to be dif-
ferentiation antigens (antigens characteristic of
some normal cells at some stage of develop-
ment) rather than antigens restricted to malig-
nant cells. Such differentiation antigens, or fetal
antigens, are termed oncofetal antigens (figure
7-1).
The appearance of fetal antigens in tumors
suggests that, during carcinogenesis, there is
"retrogenetic expression"-a reactivation of
genes that are normally expressed only in fetal
life and are suppressed in the adult. The biologic
role of the fetal antigens seems to be in recogni-
tion mechanisms whereby the fetal cells become
integrated into organized tissues. Many of the
antigens have similarities to blood group anti-
gens and have a significant carbohydrate com-
 7. PRINCIPLES OF IMMUNOLOGY
NORMAL CELL
C )
.,00••• n'; ....
,
00 • •
- ""Histocompatibility antigens'
_ " 82 microglobulin
MALIGNANT CELL
Neoontigens (Tumor associoted transplantotion antigens)
Antigens Antigens lost
(Blood t,lroup ontigens
~
HLA ontigens: 132m)
COncofetol
antigens)
FIGURE 7-1. Some antigen changes in malignancy.
ponent. They are present at an early fetal age
and reappearance as oncofetal antigens in the
adult may mean that they are then recognized as
foreign by the host.
Oncofetal antigens are emerging as measur-
able biochemical entities that playa role in the
diagnosis of some tumors, and may prove useful
in monitoring treatment.
TUMOR-ASSOCIATED ANTIGENS IN HEAD
AND NECK CARCINOMA
Among the changes associated with malignant
neoplasia are not only changes in cellular anti-
gens, including the reappearance of some fetal
antigens (oncofetal antigens) and the appearance
of new antigens (TATA), but also the loss of
s?me other antigens [3].
Oral Squamous Cell Carcinoma. Carci-
noembryonic antigen (CEA), one of the earliest
oncofetal antigens described, reappears in chem-
ically-induced oral carcinoma in animals and in
oral carcinoma in humans [4]. Serum levels of
CEA are increased in patients with head and
neck carcinoma, particularly in smokers [5, 6]
but, unfortunately, assay of CEA is insufficient-
ly specific to be of use in the diagnosis.
Tumor-associated antigens have been de-
scribed and characterized in head and neck
carcinoma [7, 8] but have received remarkably
little attention.
~2 microglobulin, a small molecular weight
constituent of cell surface histocompatibility
105
antigens (HLA), is lost from the tumor cell sur-
face in oral carcinoma [9] and increased in the
serum [10]. Other antigens such as the blood
group isoantigens A and B [11-16] and recep-
tors for the lectin Ricinus communis [17] are also
lost from the tumor cell surface. Blood group
isoantigens A, B, and H(O) are lost increasingly
with the degree of dysplasia in potentially
premalignant lesions of the oral mucosa [18],
and changes in the distribution of larninin [19]
keratin antigens are seen in oral premalignant
lesions [20, 21].
Salivary Gland Neoplasms. CEA is found
in various salivary tumors (both benign and
malignant) is related mainly to the formation of
well-differentiated ductal tissue and is absent
from anaplastic carcinomas [22-24]. CEA is,
however, also found in normal and inflamed
salivary tissue [25]. Alpha-fetoprotein, how-
ever, is not demonstrable in salivary tumors [24].
Keratin and actin antigens are demonstrable in
normal salivary tissue and may eventually prove
valuable in the differential diagnosis of salivary
tumors [21, 26].
IMMUNOGENETICS AND TUMORS
Genetic susceptibility to viral leukemogenesis
in mice has been recognized for some 20 years,
the mechanism probably involving the major
histocompatibility complex through related
immune-response genes [27].
Hodgkin's disease was the first reported asso-
ciation of an HLA specificity with a malignant
tumor in man, but there are now several re-
corded associations of various malignant tumors
with particular HLA specificities [28]. It is
possible that the closely related immune-
response genes are responsible for such associa-
tions.
Ih micro globulin is released in small quanti-
ties into the serum in normal individuals and
in increased amounts in patients with oral carci-
noma, but not in premalignant lesions [10].
The increased release of P2 microglobulin may
reflect changes in cell recognition associated
with neoplasia. In this respect, it is interesting to
note that there is an association of HLA-A8
with oral carcinoma [29] and that in other
tumors the onset of malignancy is associated
with the loss of some cell surface HLA [30].
A study of genetic markers in patients with
head and neck carcinoma has revealed a sig-
nificantly increased prevalence of the immuno-
106 II. PRINCIPLES OF MANAGEMENT
globulin allotypic marker Km [1] (a marker of
kappa immunoglobulin light chains) over con-
trols, but no difference in the prevalence of the
other allotypic markers A2m and Gm [31]. One
possible explanation for the finding of the in-
creased prevalence of the Km [1] allotype is that
it represents an association with an immune-
response gene.
IMMUNOLOGIC SURVEILLANCE AND
MALIGNANT TUMORS
There is clear evidence of influence of the im-
mune system on the development of malignancy
(table 7-1); however, it is unclear whether a
tumor develops because of a failure of recogni-
tion mechanisms or a breakdown of the immune
or other responses. There is even some evidence
that immune responses might actually stimulate
oncogenesis [32].
The concept of "immunologic surveillance,"
which postulates that the host recognizes a
tumor as foreign and then mounts a protective
immune response against the tumor [33], now
appears to be an oversimplification; protection
may be related at least partially to natural killer
cells.
NATURAL KILLER CELLS
Natural killer (NK) cells are a class of effector
lymphocytes that can kill a variety of tumor
(and other) cells. NK cells are present in normal
individuals without prior immunization, their
activity is increased by interferon [34] and by
interleukin 2 [35], and they are sometimes cited
as involved in natural cell-mediated cytotoxicity
(NCMC).
Evidence that NK cells are involved in the
rejection of transplantable tumors is derived
mainly from correlations of NK activity with
tumor resistance; high NK activity in T cell-
deficient mice and nude mice is associated with
tumor resistance and reduced NK activity is
associated with aging and tumor susceptibility
(reviewed by Roder and Haliotis [36]). Fur-
thermore, NK-deficient mice (beige mice) and
patients with reduced NK cells in the Chediak-
Higashi syndrome, Wiskott-Aldrich syndrome,
ataxia telangiectasia, common variable immuno-
deficiency, and those on immunosuppressive
therapy suffer from an increased incidence of
tumors [36] as discussed below.
It is unclear, however, whether NK cells pro-
tect only against lymphoid tumors, or whether
they also provide resistance against other neo-
plasms.
Evidence for the Influence of
the Immune Response on
Malignant Disease
INCREASED INCIDENCE OF MALIGNANT
DISEASE WITH AGING
Cancer may occur at any age, but the risk of
developing most neoplasms, including oral
carcinoma, rises with increasing age. Aging is
associated with a decline in cell-mediated im-
mune reactivity as shown by impaired skin-
delayed hypersensitivity reactions to DNCB
and tuberculin [37-39] and by impaired lymph-
ocyte proliferation in response to mitogens
such as PHA [40]. It has been proposed that the
increased incidence of malignancy associated
with aging may be a consequence of these
impaired immune responses [41], but there is
little firm evidence for this; as noted above,
NK cell activity decreases with age and might
explain these phenomena.
INCREASED INCIDENCE OF NEOPLASIA
IN ANIMALS WITH PRIMARY
IMMUNODEFICIENCIES
Neonatally thymectomized animals, which
have impaired cell-mediated immune response,
undergo a significant increase in the develop-
ment of polyoma-virus-induced neoplasia [42,
43]. However, strains of mice that congenitally
lack a thymus (nude mice) appear not to de-
TABLE 7-1. Circumstantial evidence for host defen-
sive mechanisms against tumors
1. High prevalence of latent malignant disease de-
tected at routine autopsies
2. The occasional regression of primary malignant
neoplasms in the absence of treatment
3. The regression of metastases that occasionally
follows resection of the primary neoplasm
4. The reappearance clinically of metastases after
extremely long latent intervals
5. The infrequency of metastases compared with the
very large number of tumor cells that "seed"
from a malignant neoplasm
6. The relationship between the prognosis in malig-
nant disease and aspects of cellular immunity;
prognosis is improved where there is a dense
cellular infiltrate in relation to the tumor, and
where cell-mediated immune mechanisms are
intact
7. Immunodeficient patients show a predisposition
to develop certain malignant tumors
 7. PRINCIPLES OF IMMUNOLOGY
velop more spontaneous neoplasia than do nor-
mal mice [44]. This observation has been used as
an argument against the concept of immuno-
logic surveillance and might be explained by
NK cell activity.
INCREASED INCIDENCE OF NEOPLASIA
IN IMMUNOSUPPRESSED AND
IMMUNODEFICIENT PATIENTS
Patients iatrogenically immunosuppressed to
inhibit allograft rejection are predisposed to de-
velop malignant neoplasms, predominantly of
the lymphoid system [45]; there is also an in-
creased incidence of skin carcinoma, including
cancer of the lip [46-48]. However, no data are
available showing an increased incidence of oral
carcinoma in immunosuppressed patients. An
extensive review of recipients of renal allografts
did not demonstrate a change in incidence of
oral cancer [49, 50]. Patients with primary
immunodeficiencies, however, occasionally
develop oral tumors [51]. Those with acquired
immunodeficiency syndrome (AIDS), and
others with various immunodefective states
may develop oral Kaposi's sarcoma and oral
carcinoma as well as non-Hodgkin's lymphoma
and Burkitt's lymphoma (reviewed by Scully
et al. [52]).
IMPROVED PROGNOSIS WHERE THERE IS A
PRONOUNCED MONONUCLEAR CELL
INFILTRATE RELATED TO THE TUMOR
In many malignant neoplasms, the prognosis
appears improved when there is a dense mono-
nuclear cell infiltrate related to the neoplasm.
This suggests that the immune response is
defensive.
There is usually a mononuclear cell infiltrate
beneath dysplastic oral epithelium [53], the den-
sity of the infiltrate being greater where there
is marked epithelial atypia [54, 55]. Several
workers have reported that the prognosis in oral
carcinoma is improved where there is a dense
mononuclear cell infiltrate in relation to the
tumor [56-60]. It is interesting that lymphocyte
cytotoxicity is also increased in patients with
head and neck carcinoma where there is a strong
mononuclear cell infiltrate related to the tumor
[61]. The mononuclear cell infiltrate consists
largely of T lymphocytes and is probably the
expression of a cell-mediated immune reaction
to the tumor [62].
The prognosis in head and neck carcinoma
also appears to be related to the reactivity in re-
107
gionallymph nodes [63], since, in carcinoma of
the larynx, the prognosis is better where the
lymph nodes show sinus histiocytosis rather
than where there is hyperplasia of lymphoid
nodules [64]. In oral carcinoma, the prognosis is
best where the regional lymph nodes show a
lymphocyte predominance pattern. The prog-
nosis is also improved where nodes are "active"
and show an expanded inner cortex or increased
number of germinal centers [65, 66]. Interest-
ingly, the improved prognosis in head and neck
carcinoma with active lymph nodes is seen
regardless of the stage or grade of the tumor [65,
66].
Studies of the cell populations of regional
lymph nodes in patients with head and neck car-
cinoma have suggested an increase in the con-
tent of B-lymphocytes (as determined by their
surface immunoglobulin, complement receptor,
and immunoglobulin receptor), although cells
with T-lymphocyte characteristics and capable
of normal lymphoproliferative and MLR are
also present [67, 68]. However, the nodallym-
phocytes appear to be unable to mediate ADCC
[69, 70]. Presumably there are, therefore,
changes in T-lymphocyte subpopulations as
discussed below.
Immunologic Abnormalities
Associated with Head and
Neck Cancer
The most obvious demonstrable immunologic
abnormality in patients with head and neck can-
cer is a depression in cell-mediated immune re-
sponses (table 7-2) that is more profound than
in those with carcinomas of the breast, bladder,
or bronchus [71] or those with melanomas or
sarcomas [72-75]. It is difficult to establish
whether the defect in cell-mediated immunity in
head and neck cancer is primary, or is secondary
to the tumor; however, that the cellular re-
sponses remain depressed after surgical treat-
ment of the tumor in patients with head and
neck cancer [74, 76-78] but recover in patients
with adenocarcinomas, melanomas, or sarcomas
[77, 78] might suggest that the immune defect
in those with head and neck carcinoma is a
primary event. However, there can be other
explanations for these observations.
Several defined exogenous factors may be at
least partially responsible for the decrease in im-
mune reactivity in patients with head and neck
carcinoma. These factors particularly include
108 II. PRINCIPLES OF MANAGEMENT
TABLE 7-2. Immunologic changes in patients with
cancer of the head and neck
1. Cell-mediated immunity
a. Delayed hypersensitivity reactions impaired
b. T -lymphocyte numbers reduced
c. T-lymphocytc responses to mitogens and some
antigens reduced
d. Immune complexes or suppressor cells may be
implicated
2. Humoral immunity
a. B-lymphocyte numbers normal
b. B-lymphocyte responses normal
c. Serum IgG, IgM, IgD normal; IgA and IgE
increased
3. Others
a. Various serum glycoproteins increased
b. Serum carcinoembryonic antigen increased
c. Serum ~2 micro globulin increased
d. 132 microglobulin lost from neoplastic tissue
e. Blood group isoantigens A and B lost from
neoplastic tissue
alcohol (especially if there is liver damage [79-
83]), malnutrition [84], smoking [85], chemo-
therapy [86], anesthesia and surgery [87-89],
and radiotherapy [90-92]. Many studies have
failed to take these various factors into account,
however, when discussing the immunologic
changes. Furthermore, it should always be re-
membered that the demonstration of associa-
tions or correlations of various factors does not
necessarily indicate etiologic relationships.
CELL-MEDIATED IMMUNITY
Tissue-specific cell-mediated immune responses
have been demonstrated in patients with oral
carcinoma [93]. Most aspects of cell-mediated
immunity appear to be impaired in patients with
head and neck carcinoma [94].
In Vivo Tests of Cell-mediated Immu-
nity. Skin-delayed hypersensitivity reactions to
DNCB are impaired or absent in 36%-70%
of patients with head and neck carcinoma
compared with 5% of controls [72, 95, 96].
Reactivity to DNCB is increasingly impaired
(i.e., there is anergy) as the tumor advances
[97-99], particularly when there are lymph
node metastases [77, 92, 100] or multiple pri-
mary tumors [90]. Although this relationship
between impaired DNCB reactivity and extent
of carcinoma has been questioned [72, 73, 98], it
now appears that there may be a correlation in
early (stage I and stage II) but not in advanced
tumors [101]'
Since Eilber and Morton [102] showed in
1970 a strong correlation of a positive DNCB
response with a good prognosis, there have been
many attempts to relate DNCB reactivity to the
prognosis in patients with carcinoma of the
head and neck. The same group showed that
some 80% of patients with inoperable carcino-
ma of the head and neck were anergic to DNCB.
Further, 94 % of anergic patients who were sub-
jected to operation developed a recurrence
within one year, compared with a recurrence in
only 12% of DNCB-reactive patients [103]. In
another study, patients reactive to DNCB
showed a better response to radiotherapy than
those anergic to DNCB; of those with better
than a 75 % regression of tumor following
radiotherapy, 95% were DNCB reactive,
whereas in those with a 25% regression, 40%
were anergic to DNCB [104]. The survival at six
months after treatment was also greater in
DNCB-reactive than anergic patients [105].
Two years postoperatively, 91% of DNCB-
reactive patients were still tumor-free while
only 55% of DNCB-anergic patients were free
of tumor at this time [106]. However, it is
not universally accepted that DNCB reactivity
always correlates with the prognosis in head
and neck cancer [74]; DNCB reactivity is not
an invariable predictor of treatment success
[107]. There are various techniques for testing
for DNCB reactivity and, to be as reliable as
possible, such testing must be standardized and
the results always compared with closely-
matched controls.
Delayed hypersensitivity reactions to various
antigens to which the patient is likely to have
been exposed previously (recall antigens) may
also be impaired in patients with head and neck
carcinoma. Indeed, skin reactivity to purified
protein derivative of tuberculin (PPD) is a bet-
ter predictor of short-term survival than is the
reactivity to DNCB [97]. Most patients with
head and neck carcinoma react to at least one of
a battery of common recall antigens such as
PPD, mumps antigen, candidal antigens, or
streptokinase-streptodornase (SK-SD) antigens
[108]. However, 45% of patients with carcinoma
of the head and neck are anergic to one or more
recall antigen compared with similar anergy in
only 8% of controls [109]. Anergy to recall
antigens is a feature particularly of advanced
tumors ot the head and neck [99,110] and is not
 7. PRINCIPLES OF IMMUNOLOGY
invariable in less advanced tumors [103, 111].
Anergy to recall antigens, like other features of
defective cell-mediated immunity, appears to
occur earlier in patients with head and neck
carcinoma than in those with sarcoma or mela-
noma.
. In summary, the prognosis in patients with
carcinoma of the head and neck appears best
where in vivo testing reveals intact cell-
mediated immune responses. In patients reac-
tive to both DNCB and PPD, there is an 83%
one-year survival, whereas, in those anergic to
both DNCB and PPD, there is only a 29%
one-year survival [112].
In Vitro Tests of Cell-mediated Immunity.
In vitro tests of cell-mediated immunity
confirm that there are impaired responses in
patients with head and neck carcinoma. T-
lymphocyte numbers, usually measured by E
rosettes (T-rosette-forming cells, T.RFC), may
be reduced in patients with head and neck [108,
110,113-115] and oral cancer [116-122]. The
T-lymphocyte count as a percentage of the total
lymphocyte count is also reduced in head and
neck carcinoma, particularly as the tumor
advances [123].
Further examination of leukocyte numbers
has shown a reduction in the lymphocytes that
form rosettes following incubation at 29°C for 1
h (29°T.RFC), particularly where there are no
lymph node metastases [92]. Lymphocytes
forming rosettes following incubation at 37"C
for 15 min (active T.RFC) may also be reduced
in patients with head and neck carcinoma
[18]. Lymphocytes forming rosettes at 20°C
(20"T.RFC), in contrast, appear to increase in
early but are reduced in patients with advanced
tumors [122]. It has been suggested that the
20"T.RFC are surveillance cells [118] involved
in the recognition of, and protection against,
neoplastic cells. It is clear that there is a need
for further studies of subpopulations of T-
lymphocytes in patients with head and neck
carcmoma.
Survival does not appear to correlate with the
T-lymphocyte count [97, 116, 117, 124, 125],
although it has been reported that a percentage
reduction in the lymphocytes that can be sepa-
rated on a Ficoll-Hypaque density-gradient
centrifugation is a good predictor of survival
[126]. The reasons for the depression in T-
lymphocyte numbers are unclear, but it is in-
teresting that this depression parallels a rise in a
109
serum glycoprotein, (X2 HS glycoprotein [121].
Leukocyte function has been shown to be
impaired on in vitro testing of leukocytes from
patients with head and neck carcinoma. Lymph-
okine production is reduced, as shown by
impaired production of leukocyte migration
inhibition factor (LIF) in response to SK-SD
[127] and leukocyte adherence is inhibited
[128].
T-lymphocyte function as assessed by the
lymphoproliferative response is impaired in pa-
tients with head and neck carcinoma. Lympho-
cyte transformation is impaired in response
both to PHA [73, 77, 92, 94, 97, 98, 108, 113,
115,117,119,125,129-133] and to Con A [97,
117, 125]. The lymphocyte transformation in
response to PHA is more profoundly depressed
in patients with poorly-differentiated [92] or
large tumors [97, 129] in the head and neck
than in well-differentiated or small tumors.
Some have reported no relationship of these im-
paired cell-mediated immune responses to the
clinical stage of the tumor [92], but others have
shown a relationship [123]. Similar controversy
exists concerning the prognostic value of the
PHA response [125, 134, 135] although, in
advanced tumors, there is a better survival in
those who show significant lymphocyte reactiv-
ity to PHA [125, 135] or Con A [125].
Lymphocyte transformation in response to
the antigens herpes simplex virus type I and
Candida albicans may also be reduced in oral
carcinoma [133, 136].
The MLR is reduced in 47%-67% of patients
with head and neck carcinoma [94, 130, 137,
138]. This impairment may correlate with the
clinical stage [75] and prognosis [137]. Fur-
thermore, the MLR may be reduced in those
patients who have apparently normal T-lym-
phocyte numbers and mitogenic responses
[130], suggesting that there may be more subtle
or varied defects in cell-mediated immunity in
head and neck carcinoma than formerly sup-
posed. This finding supports the concept of
changes in T-lymphocyte subpopulations. The
decrease in lymphocyte reactivity seems to be
caused by a serum suppressor [73, 113, 132],
possibly an Ct globulin [139] such as Ct2 HS
glycoprotein [121]. Plasma exchange may be of
therapeutic value [140].
Peripheral blood lymphocytes from patients
with head and neck carcinoma may show more
cytotoxicity in vitro for squamous cell carcino-
ma cell lines than do lymphocytes from normal
110 II. PRINCIPLES OF MANAGEMENT
donors [141-143]. This is particularly valid if
the donor of the lymphocytes has a marked
plasma cell infiltrate in his tumor [61]. How-
ever, lymphocytes from patients with carcinoma
in the head and neck have reduced cytotoxic
activity for other cell lines such as HeLa cells
[142], other tumors, or normal fibroblasts [143].
These changes in lymphocyte behavior may
well be related to alterations in lymphocyte
biochemistry [109,144,145].
Monocyte numbers, but not function, are
also reduced in head and neck carcinoma [146]
but NK cell function is normal [94].
HUMORAL IMMUNITY
Changes in humoral immunity in patients with
head and neck carcinoma are less profound and
less well defined than are the defects of cell-
mediated immunity. Some have reported a re-
duction in B-Iymphocyte numbers [97, 110]
with intact mitogenic responses to PWM [57];
others have found increased B-cell numbers in
those with lymph node involvement [94, 125]
and reduced responses to PWM [119]. There
appear to be good antibody responses to some,
but not all, antigens [108]. However, defects
may be related to the T-cell disturbances.
Patients with head and neck carcinoma may
have serum concentrations of IgA [108, 147-
155] higher than in other carcinomas and raised
IgE [154-156], usually with normal levels of
IgG, IgM, and IgD [148-150, 154, 157, 158].
Concentrations of IgA and IgG are increased in
the mixed saliva of patients with oral carcinoma
[150, 159, 160]. This is probably a result of
exudation from the serum, since the IgA and
IgG levels are normal in parotid saliva [149].
Raised levels of serum IgA appear to indicate
a poor prognosis in carcinoma of the head and
neck, levels being higher in more advanced
tumors or in the presence of metastases [161,
162]. IgA may act by suppressing various com-
ponents of the immune reaction such as leuko-
cyte chemotaxis [163, 164], lymphocytotoxicity
[165], and antibody-dependent cellular cytotox-
icity [166]. However, raised serum IgA levels
may simply reflect underlying problems such as
liver disease [167] or malnutrition [168] and
might have little or no effect on immunocompe-
tence in patients with head and neck carcinoma.
In contrast, the prognosis in carcinoma of the
head and neck may be improved where serum
levels of either IgD or IgE are increased [155].
The raised IgA and IgE levels may reflect
changes in cell-mediated immunity or the pro-
duction of both immunoglobulins being regu-
la~ed by T-Iymphocyte activity [169,170]. They
might also be related, for example, to associated
liver disease [Ill].
That a humoral response to head and neck
carcinoma probably occurs is shown by the
localized accumulation beneath the tumor of
plasma cells [172,173], many of which stain for
IgG or IgA [55]. Deposition of IgG and the C3
complement component on the tumor cells of
squamous cell carcinoma of the head and neck
[174, 175] also indicates that an immune re-
sponse has occurred, although there is no evi-
dence that the IgG is deposited as antibody
directed against possible tumor-associated anti-
gens. The immunoglobulin deposit may repre-
sent immune (antigen-antibody) complexes,
since circulating immune complexes have been
detected in about 75% of patients with head and
neck carcinoma [94, 120, 176-179].
The humoral immune response may not
necessarily be protective; immune complexes
may be responsible, at least partially, for im-
paired cell-mediated immune responses. For ex-
ample, in patients with head and neck carcino-
ma, the immune complex levels correlate with
impaired cellular immune responses [120] and,
in other patients, immune complexes appear to
alter lymphoproliferative responses [180-182].
Furthermore, there is a reduction in cells with
receptors for the Fc fragment of immunoglobu-
lin in patients with head and neck carcinoma
[ll]. This phenomenon may be caused by
blockage of these receptors by immune com-
plexes. The humoral immune responses may
therefore enhance tumor formation by the pro-
duction of blocking factors in the serum [183]
that can either be antibody [184] blocking the
recognition by the host of tumor-associated
antigens, or immune complexes that might
block cell-mediated immune responses [185].
Other humoral factors in head and neck can-
cer that might influence cell-mediated immune
responses include immune-reactive proteins
(IRP), particularly certain serum glycoproteins
such as haptoglobin, Ot acid glycoproteins, and
Ott antitrypsin [121]. The serum levels of these
glycoproteins are correlated with anergy to
DNCB and impaired lymphoproliferative re-
 7. PRINCIPLES OF IMMUNOLOGY
sponses to PHA; the levels of other proteins
such as prealbumin and «2 HS glycoprotein fall
where there is anergy [186]. The serum concen-
trations of most of these glycoproteins increase
as the tumor extends but the «2 HS glycoprotein
concentrations fall [121]. The «2 globulins in
particular appear to impair the various cell-
mediated immune responses in vivo [187, 188]
and in vitro [189-192].
However, it is now evident that, while
humoral factors may suppress cell-mediated
immune responses, there are also leukocytes
that suppress cell-mediated immune responses
in patients with head and neck carcinoma [96,
138J. Precisely how such suppressor cells act is
unclear, but in some other malignant states (e.g.,
Hodgkin's disease), suppressor cells appear to
influence the cell-mediated immune responses
by release of prostaglandins [193].
Serum Markers in Head and
Neck Carcinoma
Several components that appear or are increased
in the serum in patients with head and neck car-
cinoma have been discussed above.
CEA appears and levels of IgA and IgE,
various immune-reactive proteins, and 132 micro-
globulin increase where there is head and neck
cancer. As noted previously, there is some evi-
dence that these markers may be of prognostic
value.
Changes in the serum levels of various
enzymes have also been shown in patients
with carcinoma of the head and neck. Levels
of dipeptidyl peptidase are reduced [194], but
nucleic-acid-metabolizing enzymes (including
ribonuclease [195], deoxyribonucleases [196],
and thymidine kinase [197]) are increased as
are lysozyme levels [146]. None of the serum
markers is specific and further work is needed
to evaluate their use in monitoring treatment.
I mmunovirology
It is nearly half a century since the viral etiology
of some oral neoplasms was first revealed
with the demonstration of the viral induction
of benign oral papillomas in rabbits and dogs
[198, 199]. Gross isolated a virus from a murine
parotid tumor [200]; the virus produced tumors
in many organs if injected into newborn mice.
111
This virus was therefore termed "polyoma"
virus [201]. Polyoma virus was subsequently
shown in animals to produce tumors in the head
and neck, including oral neoplasms similar to
the ameloblastoma [202].
In humans, there are associations between a
few viruses and neoplasms [203]: for example,
DNA viruses that are known to be oncogenic
include adenoviruses [204, 205], papovaviruses
[206], and herpesviruses [207, 208]. The import-
ance of viruses in some tumors has recently
been confirmed by the demonstration of viral
oncogenes.
Oncogenes are genes responsible for the
tumorigenic properties of viruses. Cellular in-
fection with some RNA viruses includes a phase
of integration into the DNA of the infected cell
during which they cause some normal genes
(protooncogenes) to become oncogenes (re-
viewed by Robertson [209, 210]).
The suggestion that tumor-associated chro-
mosomal translocations might result in the
transport of a quiescent protooncogene into a
chromosome region of high transcriptional
activity has been confirmed in the translocation
associated with Burkitt's lymphoma [210].
Viruses and Tumors in the Head
and Neck
Of the four herpesviruses that infect man, there
is increasing evidence implicating Epstein-Barr
virus (EBV), cytomegalovirus (CMV), and
herpes simplex (HSV) in the development of
some neoplasms. Each has been implicated in
tumors that may involve the head and neck
[211]. Therefore, the evidence for herpesvirus
oncogenesis is discussed briefly here, with men-
tion of the role of other viruses in head and neck
neoplasms.
EPSTEIN-BARR VIRUS
Burkitt's Lymphoma. Burkitt's lymphoma
characteristically involves the head and neck
region. EBV was first found in explants of
Kenyan Burkitt's lymphoma [212] following
the search for an infectious agent suggested by
the unique geographic distribution of African
Burkitt's lymphoma. However, herpes virus
particles are not seen in tumor biopsy material
112 II. PRINCIPLES OF MANAGEMENT
from Burkitt's lymphoma [213-215]; therefore
tissue culture presumably releases a block that
inhibits expression of latent EBV.
Of course, most infections with EBV are sub-
clinical or cause infectious mononucleosis-a
usually self-limiting disease. However, EBV
causes B cell lymphoproliferation that may, in
rare instances, be fatal. Why EBV infection in
certain circumstances should be other than
self-limiting is unclear, but might be related to
characteristics of the particular strain of EBV
[216, 217], a host cell chromosomal anomaly
such as an 8-14 translocation [218, 219], or
impaired host immune status [220, 221].
The initial response to EBV infection is the
production of IgM and then IgG antibodies to
viral capsid antigen (VeA), followed by the
appearance of antibody to early antigens (EA).
Antibodies to membrane antigens (MA) then
appear, but antibodies to nuclear antigens
(EBNA) appear only after weeks or months of
EBV infection [222]. The presence of IgM anti-
VeA in the absence of anti-EBNA therefore
suggests acute infection with EBV, whereas the
converse, (the absence of IgM anti-yeA in the
presence of anti-EBNA) suggests chronic infec-
tion [222].
Serum antibodies directed against these EBV
antigens are present both in patients with Bur-
kitt's lymphoma and in unaffected individuals,
but the titers of most of these antibodies are
higher in the patients with Burkitt's lymphoma
[223-225].
Antibodies to veA are indicative of early in-
fection and, if present in high titer before the
onset of Burkitt's lymphoma, imply a high risk
of developing a lymphoma [226]; this suggests
that the individuals more likely to develop the
tumor have a heavy early exposure to the virus
or an abnormal response to the virus [227].
In Burkitt's lymphoma, anti-EBNA are pre-
sent with very high titers of IgG anti-yeA;
anti-MA and anti-EA also appear [222].
Neither EBV nor VeA are detectable in
tumor biopsies from Burkitt's lymphoma. The
first direct evidence of viral-specific material in
these tumors was provided by the discovery of
MA on the surface of freshly-biopsied tumor
cells [228] and the demonstration of EBNA in
at least 90% of cells from African Burkitt's
lymphoma [229]. DNA from EBV is almost in-
variably detectable in biopsies from African
Burkitt's lymphoma [229, 230], but not in
non-Burkitt lymphomas [231] even though the
latter patients have serologic evidence of past
infection with EBV. Further evidence for an
oncogenic role of EBV is afforded by the dem-
onstration of the ability of EBV to transform
B-lymphocytes in vitro [232] and the induction
of tumors in primates by EBV [233].
These studies demonstrate that the EBV
genome is present in the tumor cells in African
Burkitt's lymphoma and that the genome is ex-
pressed, since specific proteins are synthesized.
EBV infection alone would appear to be insuf-
ficient for tumor production, however, since
many apparently normal individuals are in-
fected with EBV with no untoward conse-
quences.
Klein has proposed a three-step model of
oncogenesis: the first step is the induction of
poly clonal B-cell immortalization by EBV; the
second step, promotion mediated by environ-
mental factors such as holoendemic malaria
(which stimulates further proliferation of B
cells); and third, chronic B-cell proliferation
[234]. During the latter stage, the specific
chromosome defect (a reciprocal 8-14 trans-
location) appears to occur randomly; clones
with the chromosome anomaly may proliferate
selectively to produce the lymphoma, in some
way evading host defense mechanisms. Im-
paired host defenses may predispose to com-
plications of EBV infection [235].
Secondary immunodeficiencies are common,
particularly as a consequence of iatrogenic im-
munosuppression following organ transplants.
It is interesting, therefore, to examine the evi-
dence for EBV infection and malignancy in such
patients. There is reactivation of EBV [236] and
an increased incidence of malignant lymphoma
in immunosuppressed renal allograft patients
[237], including those immunosuppressed with
cyclosporin A [238, 239]. The etiology of the
lymphomas in immunosuppressed patients is
unclear; however, EBV has now been impli-
cated with the demonstration of rising serum
titers of anti-VeA [240] and tissue presence of
EBNA [241] in patients with lymphomas, com-
plicating treatment with cyclosporin A.
EBV infection may cause damage to B lymph-
ocytes sufficient to activate immune responses
and result in a graft-versus-host-like reaction of
immunoblastic lymphadenopathy [242] which
may become a malignant immunoblastic sarco-
ma [243]. Several cases of immunoblastic sarco-
ma concurrent with infectious mononucleosis
have now been reported in immunosuppressed
 7. PRINCIPLES OF IMMUNOLOGY
recipients of renal allografts [236].
Lymphomas also complicate some patients
with primary immunodeficiencies. Ataxia
telangiectasia, for example, is associated with
abnormal immune responses to EBV. These
patients have a predisposition to develop lym-
phomas [244].
B cell lymphomas have also been reported to
complicate EBV infection in children with var-
ious other immune defects [245] including the
x-linked lymphoproliferative syndrome [246].
Patients with impaired immune responses to
EBV, such as occurs in the x-linked lympho-
proliferative syndrome (Duncan's disease) may
develop, if exposed to EBV, a spectrum of
disorders. These range from fatal infectious
mononucleosis to acquired hypogammaglobu-
linemia following infectious mononucleosis, or
lymphoma [247-249].
Nasopharyngeal Carcinoma. It was soon
appreciated that EBV was associated not only
with Burkitt's lymphoma and infectious mono-
nucleosis but also with nasopharyngeal carcino-
ma [250]. Epidemiologic studies have shown a
high incidence of nasopharyngeal carcinoma,
particularly in those of southern Chinese origin
[251, 252]. The role of genetic factors has been
established with the demonstration of familial
clustering of cases [251,253,254] and the asso-
ciation with certain HLA haplotypes particu-
larly A2 and a new antigen, Singapore-2, in
Chinese patients [254,255]. No association with
HLA types has been demonstrated in Tunisian
patients with nasopharyngeal carcinoma [256].
Eskimos also have a high incidence of naso-
pharyngeal carcinoma [257].
Environmental factors are also at play, since
the incidence of nasopharyngeal carcinoma in
Chinese immigrants to the USA is lower than
that in the country of origin, but is not as low as
in non-Chinese populations in the USA [258,
259]. Interestingly, a family study has shown
IgA deficiency in several relatives of a family
with nasopharyngeal carcinoma and Burkitt's
lymphoma, suggesting that the immune defect
might be implicated in tumor development. The
serology in nasopharyngeal carcinoma is some-
what similar to that of Burkitt's lymphoma
[222], with very high titers of IgG anti-VCA
and anti-MA but with high anti-EBNA and the
presence of IgA anti-VCA. Furthermore, the
anti-EA of nasopharyngeal carcinoma patients
is of a different type (anti-D) than that found in
113
Burkitt's lymphoma (anti-R). Anti-VCR and
anti-EA of the IgA class may be predictive of
the development of nasopharyngeal carcinoma
[260].
EBV DNA has now repeatedly been shown
to be present in tumor tissue from nasopharyn-
geal carcinoma [261-267], but only in undiffer-
entiated tumors [267]. Contrary to the results
with Burkitt's lymphoma, in nasopharyngeal
carcinoma EBV DNA has been demonstrated in
the epithelium rather than lymphoid tissues
[262]. It is also found in tumors from widely
differing geographic areas. EBNA has also been
detected in nasopharyngeal carcinoma [268,
269], again in the epithelium rather than lym-
phoid tissue [263].
If, as appears likely, EBV plays an etiologic
role in undifferentiated nasopharyngeal carcino-
ma, the same questions must be asked as in the
case of Burkitt's lymphoma with regard to the
relative rarity of the tumor in the face of the
ubiquity of the virus.
Salivary Gland Tumors. Preliminary evidence
from the demonstration of EBV antigens in
human parotid tumors suggests an association
with EBV [257].
CYTOMEGALOVIRUS
Seroepidemiologic studies suggest an associa-
tion of CMV with Kaposi's sarcoma [270-
275]. Patients with European Kaposi's sarcoma
have raised titers of serum-neutralizing and
complement-fixing antibodies to CMV [272].
A herpesvirus has been demonstrated in the
tumor tissue [276]. CMV DNA has now been
detected in biopsies of Kaposi's sarcoma, adding
further weight to this association [274, 277]. A
group at particular risk from Kaposi's sarcoma
appears to be male homosexuals, who may be
immunocompromised (AIDS) and susceptible
to CMV infections [52, 278]. It is of interest that
Kaposi's sarcoma has affected the oral cavity in
several patients immunosuppressed iatrogeni-
cally or in association with immunologic dis-
orders such as myelomatosis or lymphomas
[52].
The isolation of CMV from tumors might
imply invasion by virus of tumor cells in an
immunocompromised host, but the ability of
CMV to transform hamster cells in vitro [279]
provides some support for an oncogenic role of
this virus.
114 II. PRINCIPLES OF MANAGEMENT
HERPES SIMPLEX VIRUS
Herpes simplex virus has been implicated in
cervical carcinoma and, more recently, in oral
carcinoma. There is little evidence for the
involvement of herpes simplex virus type I
(HSV) in head and neck, and possibly oral, car-
cinoma. Serum antibodies to nonvirion antigens
of HSV are specifically increased in patients
with head and neck carcinoma [129, 280]; also,
soluble membrane antigens from lip carcinoma
react with this antibody, implying immunologic
identity of the tumor-associated antigen with
the nonvirion antigen of HSV [281]. Titers of
serum IgA antibodies (but not IgG antibodies)
to HSV are increased in patients with head and
neck carcinoma [282, 283], but the titer of IgA
antibodies appears to be independent of the
total serum IgA levels. These findings indicate
that the rise in serum IgA levels cannot wholly
be accounted for by the HSV antibodies. The
IgM class of antibodies to HSV 1 is increased in
untreated oral cancer [284].
Higher titers of neutralizing antibodies to
HSV have been found in patients with advanced
oral carcinoma than in controls [285]. Also,
titers of HSV antibodies are greater in long-term
than in short-term survivors from oral carcino-
ma, though titers of other antibodies (to measles
virus) do not correlate with survival. In this
study, however, HSV antibody titers are com-
parable between controls who smoked and pa-
tients with early oral carcinoma. Antibodies to
other HSV tumor-associated antigens are found
in patients with head and neck cancer [129, 286,
287] and the titer of such antibodies parallels the
cell-mediated immune defect [129]; these data
suggest that the virus might either cause the im-
mune defect or be associated with it. Lymph-
ocyte transformation to HSV is reduced in pa-
tients with oral carcinoma [133, 136], possibly
because of the presence of serum-blocking fac-
tors such as immune complexes [288]. The re-
cent demonstration of RNA complimentary to
HSV DNA in tumor tissue from human oral
carcinoma [289, 290] is the strongest evidence
to date for an association of HSV with oral car-
cinoma. Despite the conflicting evidence in
relation to the association of virus with oral
carcinoma it is possible they may play some
role in the multifactorial process.
Serum IgA antibodies to HSV1-induced anti-
gens are also increased in smokers, though to a
lesser degree than in those with head and neck
carcinomas. This suggests that cigarette smok-
ing predisposes to mucosal HSV infection r2911.
Systemic factors often associated with oral car-
cinoma, such as alcohol abuse and liver disease;
might act by impairing host immune responses,
although there is little evidence that responses
to HSV are impaired. Further support for the
oncogenic role of HSV is provided by the
observation that HSV 1 is capable of the trans-
formation of hamster cells in vitro [292].
The distinction between an etiologic associa-
tion of a virus with a tumor and a secondary
(passenger) association is crucial, but difficult
to establish. The regular presence of the viral
genome or viral products in a tumor, irrespec-
tive of geography, however, is regarded as fairly
conclusive evidence of viral oncogenesis [293].
These criteria are well-fulfilled in relation to the
association of EBV with African Burkitt's
lymphoma and undifferentiated nasopharyngeal
carcinoma, and possibly also with CMV and
Kaposi's sarcoma. Recent studies indicate that
HSV can not be the sole etiologic agent in oral
squamous cell carcinoma since HSV DNA is
also found in other tissue [294]'
If herpes virus do plays an etiologic role in
these tumors, one must still explain why such
ubiquitous agents are only rarely productive of
tumors. Host genetic constitution and immune
status, environmental factors, and the possible
existence of variant oncogenic strains of the
viruses may be important in this respect.
PAPILLOMAVIRUS
Papillomaviruses have been implicated in hu-
man oral focal epithelial hyperplasia, condylo-
ma acuminatum, papillomas and carcinomas but
no etiologic relationship has been shown r2951.
POLYOMA VIRUS
Polyoma virus has been implicated in murine
salivary gland tumors [296], but there appears to
be little evidence of an association in man [297].
Despite the conflicting evidence in relation to
the association of virus with oral carcinoma it is
possible they may play some role in the multi-
factional process.
Immunotherapy
VACCINES
Since many tumors bear tumor-associated anti-
gens, the possibility arises that patients might
be able to be immunized with these antigens.
Attempts at the preparation of such tumor vac-
cines have been made for a number of years, but
with little success; this is largely because of
 7. PRINCIPLES OF IMMUNOLOGY
the difficulties in defining cell surface antigens
before monoclonal antibodies become available.
The early vaccines were prepared from
irradiated, cultured autologous or allogeneic
tumor cells that gave only occasional serologic
responses. These disappointing results may be
related to a number of factors such as weak
immunogenicity, form of presentation of the
antigens, and host immunoregulatory factors
that govern responses to antigens [298].
IMMUNOTOXINS
Immunotoxins are toxins conjugated to anti-
bodies that are designed to react with tumor cell
antigens and localize the toxin activity at the
tumor cell. Immunotoxins using plant toxins
such as ricin are effective in killing rodent leuke-
mic cells but have yet to be developed as safe
for human use; there are many problems re-
lated to pharmacokinetics, cross-reactive anti-
gens, and tumor cell heterogeneity. . terferons have antiviral and immunoregulatory
Immunotoxins directed not against the tumor
cell, but against suppressor T-lymphocytes
(Ts), may be effective in stimulating immune
responsiveness in situations where there is im-
munodeficiency related to Ts hyperreactivity
[299].
- The therapeutic potential of monoclonal anti-
bodies is extremely exciting since it might
be possible to label, with a drug, toxin, or
radionuclide, a monoclonal antibody to a tumor
and inject it intravenously. Thus, when the anti-
body accumlates selectively in the tumor, it
could (depending on the label) locate the tumor
or be tumoricidal.
NONSPECIFIC IMMUNOTHERAPY
An alternative form of immunotherapy is the
nonspecific approach designed to potentiate
general immunologic reactivity. Exogenous
agents such as bacterial adjuvants (bacillus
Calmette-Guerin [BCG] and Corynebacterium
parvum), bacterial toxins, tumor-necrotizing
factor, and levamisole have all been assessed
with only variable success, because of poor trial
design [299]. Endogenous mediators such as
interferon, interleukin 2, and cryoprecipitate
may prove of some benefit.
Bacterial Adjuvants. BCG and C. parvum
have adjuvant activity, i.e., they nonspecifi-
cally stimulate immunologic reactivity on a
global basis. The overall results of clinical
trials in cancer therapy have led to some disen-
chantment with these adjuvants but there may
115
be some value in head and neck cancer [300].
Tumor-necrotizing Factor. Tumor-necrotiz-
ing factor (TNF) is a small molecular weight
glycoprotein released by macrophages that has
tumor-killing activity in vitro and tumor-
necrotizing activity in vivo in mice. The activity
in TNF has now been identified as being inter-
leukin 1, which induces maturation of T- and
B-lymphocytes and release of interleukin 2 by T
cells [300].
Levamisole. Levamisole is an immunomod-
ulatory drug that has been of equivocal value
in immunotherapy, in part because of its po-
tentially adverse reactions on leukocytes [300].
Interferon. Interferons are a group of proteins
produced mainly by leukocytes but also by
cells such as fibroblasts and epithelial cells. In-
effects; they also affect cell growth and dif-
ferentiation.
Deficiency of interferon is associated with
many immunodeficiency states and, in the pre-
sent context, is common in patients with the
secondary immunodeficiencies produced as a
consequence of the chemotherapy used to pre-
vent graft rejection. Interferon production is
particularly depressed in recipients of bone
marrow transplants. Recurrent or severe viral
infections and possibly tumor production may
be related to depressed interferon production in
such individuals.
Interferon levels are reduced also in various
malignant diseases, particularly hematopoietic
malignancies. There have been some promising
results in the treatment of these with exogenous
interferon [300].
Interleukin 2. Th cells produce a factor known
as interleukin 2 (T-cell growth factor) that
causes the proliferation of other subpopulations
of T-lymphocytes. Interleukin 2 has shown
promise as an immunotherapeutic agent, but is
still in the very early stages of development
[300].
Cryoprecipitate. Normal plasma has anti-
tumor activity that appears to have several
characteristics in common with fibronectin.
Plasma cryoprecipitate contains large amounts
of fibronectin as well as factor VIn and has
proved as active in antitumor activity as whole
plasma. However, the mechanism is unclear.
116 II. PRINCIPLES OF MANAGEMENT
TABLE 7-3. Immunotherapy in head and neck cancer
1. Passive immunity
Thymosin
2. Active immunity
a. Nonspecific
Bacillus Calmette-Guerin (BCG)
Corynebacterium parvum
Levamisole
Transfer factor
Interferon
Interleukin 2
h. Specific
Tumor vaccines
Cryoprecipitate is currently undergoing human
trials as an antitumor agent [300].
Immunotherapy in Head and
Neck Carcinoma
In view of the occurrence of immune defects in
patients with head and neck carcinoma, the pos-
sibility of stimulation of the immune response
by immunotherapy has obvious attractions
[301]. Immunotherapy can achieve passive im-
munity, for example, by the administration of
various humoral factors; it can produce a
nonspecific stimulation of active immunity, or
may .possibly produce active tumor-specific
immunity [302-305] (table 7-3).
Since defective cell-mediated immunity is the
most profound immune defect in patients with
head and neck carcinoma, there have been
attempts recently to stimulate cell-mediated
immune responses by the administration of
various thymic factors such as thymosin. Ad-
ministration of thymosin improved the delayed
hypersensitivity responses, the MLR [306], and
Iymphokine (UF) production in response to
SK-SD [127] in patients with head and neck car-
cinoma. At present, however, the little available
evidence suggests that thymosin is of minimal
clinical benefit [306, 307]; it should be noted
that, however, thymosin has only been re-
ported to have been ·used in patients with rel-
atively intact cell-mediated immune responses.
A cautionary note has recently been struck on
the use of thymosin since it appeared to impair
the Iymphokine production in control subjects
[127]; therefore, it might be suitable for use
only in those patients with head and neck
carcinoma with the most significantly reduced
cell-mediated immune responses.
The success of immunotherapy with attenu-
ated Mycobacterium tuberculosis (BCG) in pa-
tients with head and neck carcinoma has been
somewhat equivocal. Although BCG enhances
cell-mediated immune responses nonspecifically
(i.e., it has an adjuvant effect [116, 308]), it
appears not to significantly improve the survival
of patients with head and neck carcinoma over
the survival the appropriate controls. This
observation is valid whether the BCG is used
alone [124, 309], with chemotherapeutic drugs
[310-313], levamisole [119], or with an auto-
logous tumor vaccine [314-316].
The good response in 62% of a group of 32
patients with head and neck carcinoma on a
combined regime of BCG plus methotrexate
and isoniazid [317, 318] was unfortunately not
obtained in a controlled trial. The improved
survival of patients who were treated with
BCG and a combined chemotherapeutic regime
(bleomycin, adriamycin, CCNU, Oncovin, and
nitrogen mustard) over those treated with che-
motherapy alone [308] was probably due to a
number of drug-related deaths in the latter
group. Although it may enhance lymphocyte
transformation in response to PHA [106] and
may cause a transient reduction in suppressor
cells [138], immunotherapy with other micro-
bial adjuvants such as C. parvum [96, 138,319,
320], has little or no impact on the rates of
recurrence or survival of patients with head
and neck cancer [321, 322]. Administration of
microbial antigens directly into the tumor,
although producing some leukocytic response
when BCG is used [323] or when C. parvum is
used [324], appears to be of little value. Ad-
juvant treatment using mumps antigens is also
of little value in the treatment of head and neck
cancer [325].
Nonspecific stimulation of immune responses
using levamisole appears to be of minimal clin-
ical value in patients with head and neck malig-
nancies [326, 327] although some studies have
suggested that the recurrence rate might be re-
duced [158, 328, 329]. This benefit seems most
marked in patients with advanced malignant
disease (stage IV) who have significantly im-
paired cell-mediated immune responsiveness
[327]. These findings have not been confirmed
in other studies, however, despite evidence that
the drug enhances immune reactivity [3261-
Levamisole should certainly be used with ex-
treme caution in view of the possible adverse
reactions and the demonstration that, where
cell-mediated immune responses are only mar-
 7. PRINCIPLES OF IMMUNOLOGY
ginally impaired (stage I or II), the recurrence
rate of head and neck cancer appeared increased.
Immunomodulation induced by thymosin
[330], and interferons [331-333] hopefully may
fulfill their early promise.
Attempts to induce specific active immunity
against carcinoma in the head and neck have
been limited. Intradermal immunization with
autologous tumor vaccine, using tissue from
oral carcinoma, increased lymphoproliferative
reactivity without any obvious clinical benefit
[334]. Tumor cells treated with neuraminidase
to break down surface glycoproteins and reveal
other antigens have been used to immunize pa-
tients with advanced head and neck cancer, but
the results have shown no benefit [314] or were
inconclusive [315, 316].
Other methods of immunotherapy are at ear-
lier stages of development and modalities such
as transfer factor-a product of lymphocytes-
have yet to be evaluated fully [335]. Ad-
vances in immunology are so rapid that it may
not be long before more uniformly effective im-
munotherapy is available.
Immunology in Relation to Other
Treatment Modalities
It is well recognized that, in the case of some
malignant neoplasms such as the nephroblasto-
ma, metastases occasionally regress after exci-
sion of the primary tumor. This phenomenon
has been regarded as further evidence for the
role of the immune response in protection
against malignant neoplasms.
A rise in titer of antibodies against TSTA may
follow surgical excision of a malignant neo-
plasm, but the response is greater following
cryosurgery [336]. Furthermore, in animal
models, immunity to subsequent challenge with
tumor is also greater after cryosurgery than
after excision [337]. These preliminary observ-
ations must be confirmed, particularly since
there is no good evidence that cryosurgery is
more effective than surgery in terms of the ulti-
mate prognosis [338]. There is also no signif-
icant correlation in the case of other tumors be-
tween the incidence of tumor regression and
serum antibody titers to tumor antigens [339].
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1972.
 8. PRINCIPLES OF BONE MARROW
TRANSPLANTATION
Joel M. Rappeport
The era of bone marrow transplantation was
introduced with the interesting reports from
Jacobsen and his coworkers, who described the
protective effects of both splenic shielding and
intravenous infusion of bone marrow in lethally
irradiated mice [1, 2]. These experiments were
stimulated by an interest in radiation biology
developed during the Manhattan Project.
Although the mechanism of protective effect
was initially uncertain, later studies demon-
strated through genetic markers that this effect
was the result of engraftment of hematopoietic
cells. The first potential benefit of bone marrow
transplantation as a therapeutic modality was
demonstrated in mice by Barnes and Loutit,
who lethally irradiated leukemic mice and
rescued them with bone marrow infusions, re-
sulting in mice with normal hematopoiesis [3].
Thomas et at. showed that large amounts of
marrow could be safely infused intravenously
into man [4]. Multiple attempts were made begin-
ning in 1957 to perform human bone marrow
transplantation in patients with leukemia, lym-
phomas, and a variety of other malignancies as
well as aplastic anemia.
With the exception of a dramatic infusion of
bone marrow into six victims of an irradiation
accident reported by Mathe et aI., the early re-
sults were unsuccessful and only helped to de-
lineate the problems [5]. Most transplantation
was attempted in terminally ill patients who did
not survive long enough for engraftment to
occur. In those patients in whom engraftment
did occur, a recurrence of the malignancy or fat-
al graft versus host disease (GVHD) resulted in
death; most early transplants were carried out
between individuals who were not histocom-
patible. Beginning with the initial description
by Dausset of a human leukocyte antigen
(HLA), the HLA-A, -B, and mixed lymphocyte
Peterson etal., HEAD AND NECK MANAGEMENT OF THE CANCER PATIENT.
© 1986. Martinus NijhoJf Publishing. All rights reserved.
loci were defined during the 1960s [6]. More re-
cently, two closely linked loci HLA-C and -DR
have been described.
Before the definition of the human histocom-
patibility locus, however, successful bone mar-
row transplants were carried out between iden-
tical twins. Robins and Noyes were the first to
report complete recovery from aplastic anemia
following an identical twin (syngeneic) trans-
plant [7]. Although Thomas and coworkers
attempted syngeneic bone marrow transplanta-
tion in four patients with end-stage acute lym-
phoblastic leukemia, all four relapsed within
three months [8]. In the 1970s, the Seattle group
performed syngeneic transplants in 34 patients
with both acute lymphoblastic and acute non-
lymphocytic leukemia. Although recurrent
leukemia was the principal cause of death, eight
patients remained in complete remission from
29 to 103 months [9]. These studies were an im-
portant incentive in continued pursuits of bone
marrow transplantation as a therapeutic mod-
ality.
In 1968, two groups reported the correction
of severe combined immunodeficiency by trans-
plantation from histocompatible donors [10,
11]. With the definition of the histocompati-
bility locus, allogeneic transplants between his-
tocompatible nontwin sibling donors began to
be performed successfully. In 1972, Thomas
and coworkers reported the first successful
allogeneic bone marrow transplants for severe
aplastic anemia [12]. In a series of 100 patients
with end-stage leukemia who underwent bone
marrow transplantation from allogeneic donors
after conditioning with cyclophosphamide and
total body irradiation, 13 patients had pro-
longed disease-free survival [13]. Following
these initial triumphs, efforts were made to
improve the overall success. Results III severe
129
130 II. PRINCIPLES OF MANAGEMENT
aplastic anemia improved to 50% with early
transplantation [14]. Similar results were noted
in acute nonlymphocytic leukemia in first
remission [15]. Successful extensions of the
application of marrow transplantation to a
number of congenital hematologic diseases have
been reported including the Wiskott-Aldrich
Syndrome, Kostmann's disease, and osteopet-
rosis [16-18]. Major efforts currently include
continued study of the pathophysiology and
control of the GVHD reaction. These include
therapeutic manipulations to physically elimin-
ate the putative mature T cell, monoclonal anti-
body elimination of the T cell, or control of the
reaction through the use of potent immunosup-
pressive agents such as cyclosporin [19-21].
Patient Selection
Selection of patients should include those for
whom the procedure represents a physiological-
ly rational therapy, and for whom other ther-
apeutic options are limited. In severe aplastic
anemia as defined by Li et al. in 1972, the sur-
vival rate is approximately 20% if the patient
receives supportive therapy alone or in conjunc-
tion with androgens [22]. Reports of improved
survival with bone marrow transplantation has
made this the therapy of choice in situations in
which a suitable donor could be identified.
However, more recent encouraging reports of
the use of antilymphocyte globulin or high-dose
corticosteroids have made the choice of trans-
plantation less certain [23]. Although the pa-
tients treated with immunosuppression alone
are not threatened by GVHD, their hematolo-
gic improvement may only be partial, and the
long-term outcome has yet to be determined.
Uncertainty also exists in the utility of mar-
row transplantation in leukemia. Whereas the
survival rate in bone marrow transplantation in
patients with acute nonlymphocytic leukemia in
first remission in 50%-60%, many of these
patients are less than the age of 18 where
chemotherapy has had similar results [24].
In general, the survival rate decreases and the
incidence of chronic GVHD increases as the
patient's age approaches 40. On the other
hand, patients in second remission have little
likelihood of long-term survival. In this setting,
marrow transplantation offers less success than
in first remission, but substantially more than
chemotherapy. The results in relapse and late or
partial remission continue to be poor.
In acute lymphoblastic leukemia (ALL), most
recent studies involve bone marrow transplanta-
tion in second remission. The results, although
better than in relapsed ALL, are still disappoint-
ing [25]. Various centers are investigating the
use of transplantation in poor-prognosis ALL
in first remission.
Encouraging results have been reported in
patients with stable-phase chronic myelogen-
ous leukemia. Initial attempts at transplanting
patients with chronic myelogenous leukemia
in blast crises were extremely disappointing.
However, it was rational to attempt to correct
this disorder of the pluripotent stem cell by
transplantation. Thus, attempts were made to
cure this disorder in the stable phase utilizing
either normal syngeneic or allogeneic donors
[26, 27]. This situation presents a dilemma.
Although marrow transplantation offers the
opportunity to cure this ultimately fatal disease,
one is faced with the possibility of short-term
death from complications of the therapy.
Attempting to cure chronic myelogenous leu-
kemia may shorten the life of any individual
patient.
- The rarer genetic hematologic and immu-
nologic disorders have not in general been
amenable to treatment, and have certainly not
been curable by conventional methods. Some
of these disorders, including severe combined
immunodeficiency and Kostmann's syndrome,
have a rapidly fulminant course. Other diseases,
such as the Wiskott-Aldrich syndrome and
osteopetrosis, have a progressive downhill
course that may result in death within a few
years. Therefore, the greatest experience with
bone marrow transplantation has been in these
and related disorders. Successful cures of these
disorders have been affected by marrow trans-
plantation. On the other hand, thalassemia and
the hemoglobinopathies have a more protracted
natural course, and hence there has been reluc-
tance to put the patient at the immediate risk
of transplantation. There is, however, a small
but growing experience of transplantation for
thalassemia [28, 29]. Finally, with growing
evidence that tissue macrophages are of hem-
atopoietic origin, exploratory attempts have
been made in correcting some of the enzyme-
deficiency disorders [30].
Donor Selection
Selection of a marrow transplant donor is largely
determined by compatibility at the histocompat-
ibility locus, which in man is a series of closely-
 8. PRINCIPLES OF BONE MARROW TRANSPLANTATION
linked genetic loci on the short arm of the sixth
chromosome. As noted previously, this is
known as the HLA region. The importance of
this region in marrow transplantation is related
not only to the problem of graft rejection, but
also the graft-versus-host reaction. In human
marrow transplantation, a syngeneic donor is an
identical twin. An allogeneic transplant is one
between a donor and recipient who are identical
at the HLA region, but are not otherwise gene-
tically identical. For all practical purposes, given
the number of alleles, these donors are siblings
in whom the chance of sharing both parental ha-
plotypes is 25%. A haploidentical donor is one
who shares one haplotype with the recipient.
The HLA-A, -B, -C, and -DR are identified by
serologic typing with sera from multiparous
females. The HLA-D locus is identified through
the mixed lymphocyte culture.
If a normal identical twin is available, this
represents the best choice of donor since the
risk of GVHD is, at most, minimal. However,
only a small number of patients will have an
identical twin. The most widely utilized donor
is the HLA-matched sibling with whom there is
identity at the HLA region. Given a choice be-
tween otherwise-matched donors, most centers
would opt for a same-sexed donor since there
is suggestive evidence that the incidence of
GVHD is greater between sex-mismatched
donors and recipients.
Given the size of the American family, the
chances of identifying an HLA-identical sibling
donor are approximately 40%, leaving 60% of
patients who might derive benefit from a trans-
plant without a matched donor. Particularly in
the genetic disorders, there is some chance that
parents may share a common haplotype, and
thus a phenotypically identical parental donor
might be identified. Some attempt has been
made by the Seattle team to use donors who are
haploidentical on one chromosome and only
partially identical on the other chromosome.
This has been of little value in aplastic anemia,
but some success has been achieved in leukemic
recipients [31). In an attempt to truly enhance
the donor pool, two avenues of investigation are
being pursued. The first is to identify phenotyp-
ically identical unrelated donors. The data that
are evaluable at present are limited and equivo-
cal [32-34). The other route is the elimination of
the mature T-Iymphocyte from haploidentical
bone marrows. It is thought that the GVHD
reaction is at least initiated by this cell. Trials are
underway to remove the mature T-lymphocyte
131
physically by lectins or by monoclonal anti-
bodies [19,20). Early results, at least in patients
with severe combined immunodeficiency, have
been encouraging.
ABO incompatibility has not proven in mar-
row transplantation to be a cause of donor ineli-
gibility. Minor incompatibility differences such
as transplantation from an 0 donor into an A
recipient have been overcome without difficulty
[35). When a major incompatibility exists, as in
an A donor being transplanted into an 0 recip-
ient, the preexistent isohemagglutinin must be
eliminated by plasma exchange or absorption of
the antibody. These transplants are made pos-
sible by virtue of the fact that the preparatory
therapy eliminates the host immune system,
and the engrafted marrow provides an immune
system compatible with the donor blood type.
The donor must otherwise be of good health
and be able to undergo anesthesia safely. The
donor or, if a minor, an appropriate advocate
must be capable of giving informed consent.
Other than ethical issues, age is of no con-
sideration, and donors have been as young as
five or six months.
Preparation of the Recipient
Proper chemoirradiation preparation of the recip-
ient is necessary in order to achieve a success-
ful outcome. Four major considerations must be
satisfied. The first is an evaluation of the status
of the hematopoietic and immunologic systems
in the recipient before transplantation. Second,
the aims of what is to be engrafted must be con-
sidered and, third, the cumulative toxicity of
prior therapy must be evaluated. Finally, con-
sideration should be given to the genetic rela-
tionship between the donor and the recipient.
Infants with severe combined immunodefi-
ciency have, by virtue of their condition, no
immune system and thus do not usually need
immunosuppressive therapy. Transplantation
without preparation in a majority of cases will
result in lymphoid reconstitution, with hema-
topoiesis remaining recipient in origin.
In aplastic anemia, on the other hand, there is
an absence of hematopoiesis with a relatively in-
tact immune system. With a syngeneic transplant,
no conditioning is necessary in at least 50%
of cases. When an allogeneic transplant is to be
performed, however, large doses of immuno-
suppressive drugs must be administered. The
usual therapy includes cyclophosphamide 50 mg/
kg for four days. Despite this preparation, graft
132 II. PRINCIPLES OF MANAGEMENT
rejection is not uncommon in patients sensitized
to minor histocompatibility antigens through
multiple transfusions [36]. In the setting of
significant pretransplant transfusions, added
immunosuppression is needed and may include
anti thymocyte serum and procarbazine in addi-
tion to the cyclophosphamide [37J.
Leukemia presents a different problem. In
this setting, there is both a relatively intact im-
mune system as well as the presence of active
hematopoiesis that produces an abnormal
product-the leukemic cell. The major objec-
tive is the complete elimination of recipient
hematopoiesis as well as complete immunosup-
pression. The three major classes of agents with
an antihematopoietic stem cell effect include
irradiation, busulfan, and nitrosourea. Most
preparatory regimens for leukemic patients
include lethal doses of total body irradiation in
combination with cyclophosphamide in order
to administer both an antihematopoietic stem
cell preparation as well as potent immunosup-
pression. Some exploratory studies have been
undertaken to evaluate the use of busulfan in-
stead of irradiation [38, 39]. Despite the use of
these agents, recurrent leukemia represents a
potential problem, the incidence of recurrence
depending both on the type of leukemia as well
as the remission status of the patient pretrans-
plant. With the exception of busulfan, prepara-
tory programs utilizing drug alone have had lit-
tle success. Adding other drugs to the regimen
in an attempt to prevent recurrence is limited by
toxicity to nonhematopoietic tissues such as the
gastrointestinal tract, lung, liver, and heart.
In the hematopoietic genetic diseases, both
immunosuppression and destruction of the
pluripotent hematopoietic stem cell must simi-
larly be accomplished. Space must be provided
for engraftment of the normal donor cells.
Failure to irradicate adequately the hemato-
poietic stem cell will result in persistence of the
underlying disorder [16].
Procurement of Marrow
and Engraftment
Bone marrow is widely dispersed through the
marrow cavity, particularly in the central
skeleton. The anterior and posterior iliac crests
are the most accessible and hence the usual sites
of harvest [40]. Bone marrow is harvested in the
operating room utilizing either general or spi-
nal anesthesia. In order to limit dilution by
peripheral blood, 150-400 aspirations are per-
formed for most adult recipients. Attempts are
made to obtain 10 cc bone marrow/kg body
weight of the recipient. The marrow is stored in
tissue culture media and heparin and, after
filtration to eliminate marrow particles, is
administered intravenously to the recipient.
The hematopoietic stem cells settle primarily
in the marrow cavity after traversing the lungs
for as yet unexplained reasons. The spleen and
liver may also be sites of hematopoietic engraft-
ment. Unlike solid organ transplants, which be-
gin to function immediately, the hematopoietic
stem cells must proliferate and mature, a process
that may take weeks. The patient must be sup-
ported hematopoietically during this period of
hematopoietic reconstitution. Although a few
nucleated red cells may be seen by one week and
may represent early evidence of engraftment,
2-4 weeks or longer may be required before
adequate levels of granulocytes, platelets, and
erythrocytes are achieved. Proof of engraftment
is determined primarily by erythrocyte antigen
and chromosomal karyotype differences be-
tween donor and recipient. When appropriate,
the presence of previously absent cells is sugges-
tive evidence of engraftment. During this early
granulocytopenic period, bacterial infection
must be prevented and, if present, must be treated
with adequate antibiotics and perhaps granulo-
cyte transfusions. Frequent platelet transfusions
may be necessary to prevent life-threatening
hemorrhage. Since preexistent platelet anti-
bodies may persist in the early posttransplant
course, HLA-compatible platelet transfusions
may be indicated. The marrow donor may be a
source of these HLA-matched platelets. To pre-
vent accidental engraftment, all blood products
must be irradiated.
Graft Rejections
Nonengraftment or graft rejection may poten-
tially be mediated through a number of pro-
cesses. Obviously, administration of inadequate
numbers of hematopoietic stem cells will result
in failure of engraftment. Despite the presence
of adequate stem cells, a hostile marrow mi-
croenvironment may prevent engraftment. A
newly-engrafted marrow may be extremely
sensitive to pharmacologic agents that under
normal situations might have only a mild effect
 8. PRINCIPLES OF BONE MARROW TRANSPLANTATION
on hematopoiesis.
Failure of engraftment may occur because of
inadequate antihematopoietic stem cell treat-
ment resulting in a return of the recipient's own
disordered hematopoiesis. This situation occurs
most frequently in the genetic hematopoietic
disorders and resistant leukemia. With the rec-
ognition of the difference in antihematopoietic
stem cell properties of chemotherapeutic agents
as well as earlier transplantation in leukemic pa-
tients, this problem has become less frequent.
Similarly, immunologic rejection and graft fail-
ure "results from inadequate immunosuppres-
sive preparation. This situation occurs almost
exclusively in patients with aplastic anemia, and
results from sensitization to minor non-HLA
transplantation antigens. Earlier marrow trans-
plantation prior to extensive transfusions has
decreased this risk [41]. More potent immuno-
suppressive regimens for patients at high risk
for sensitization has also decreased immuno-
logically-mediated graft rejection [37].
Nonengraftment is a highly lethal situation.
Although second and even third graft attempts
have been successful, they are rare and usually
limited to small children with congenital im-
munologic or hematologic disorders. Substan-
tial periods of time may pass before graft rejec-
tion or nonengraftment is recognized. During
this period as well as the time required for
subsequent engraftment, the patient is at high
risk of acquiring an opportunistic infection.
Additional preparatory therapy may also fur-
ther the risk of life-threatening damage to non-
hematopoietic tissues. Careful attention to the
preparatory regimen hopefully will decrease the
risk of nonengraftment in the future.
Graft-versus-Host Disease
Success in marrow transplantation is primarily
limited by the development of GVHD and
its consequences (see chapter 21). GVHD is
thought to be initiated by the expansion of
mature donor T-lymphocytes that contaminate
the marrow infusion. Although the sequence of
the entire reaction is still unclear, presumably
the mature T-lymphocytes recognize histocom-
patibility differences between donor and recip-
ient. In the case of HLA-identical pairs, minor
non-HLA antigenic differences are recognized.
In animal experiments, the more disparate the
donor and recipient, the more severe the reac-
133
tion; hence the current dependence on HLA-
identical donors in human transplantation. The
fact that mild GVHD-like reactions have been
noted in identical twin and even autologous
transplants suggests the possibility of other
pathophysiologic contributions to the reaction
[42]. In these cases, the reaction is presumably
not due to recognition of antigenic differences,
but is instead due to an immunoregulatory dis-
turbance because of a lack of adequate numbers
or function of suppressor T cells [43]. Other
factors that may influence both the incidence
and severity of GVHD may include the micro-
biologic status of the recipient. An attempt at
achieving a gnotobiotic status may decrease
both the severity and mortality associated with
GVHD [44].
Clinically, two types of reactions are noted.
The first is an acute syndrome beginning as ear-
ly as 7-10 days and usually manifesting itself
by five or six weeks after transplant. The chron-
ic syndrome may manifest itself by 8-9 weeks
after transplant or as late as 1 year after marrow
infusion [45, 46]. In both syndromes, the
organs primarily affected are the skin, the
gastrointestinal tract, and the liver. Other
organs, such as the eyes, oropharynx, and bone
marrow, may also be involved. In acute GVHD,
the dermatologic manifestations may vary from
a mild diffuse erythematous rash to a severe tox-
ic epidermal necrolysis syndrome. Massive di-
arrhea may accompany this disorder. Hepatic
manifestations are primarily hepatocellular in
nature.
Mild forms of GVHD are not usually associ-
ated with either morbidity or mortality, while
more severe manifestations may be associated
with death. The incidence of acute GVHD in
recipients of allogeneic marrow transplants may
vary from 50% to 80%, depending upon the
sensitivity of diagnosis [47]; 40% of those de-
veloping severe acute GVHD may succumb to
this disorder. Death is usually due to electrolyte
imbalance, hemorrhage or, most commonly,
opportunistic infections.
Attempts to prevent or ameliorate GVHD
have included many manipulations. Identifica-
tion of an HLA-identical donor and minimiza-
tion of peripheral blood contamination of the
marrow infusion are standard steps. Prophy-
lactic utilization of posttransplant methotrexate
or cyclophosphamide have been developed by
the Seattle and Baltimore teams, respectively
[48, 49]. In the setting of tenuously engrafting
134 II. PRINCIPLES OF MANAGEMENT
marrow, attention to chemotherapy dosage is
necessary. Although initially administered for
14 weeks, the length of time necessary for
maximum benefit from methotrexate has been
questioned [50]. In a randomized study utiliz-
ing prophylactic methotrexate, antithymocyte
globulin, and prednisone, the incidence of
acute GVHD was less than in patients receiv-
ing methotrexate alone [51]. However, no sig-
nificant difference in survival was noted.
Of extreme biologic interest is the fact that
the acute GVHD may spontaneously subside.
On the other hand, a fulminant progressive
syndrome may be seen in which therapeutic
intervention is necessary. Both antithymocyte
serum and high-dose prednisone are capable of
terminating this disorder. Despite these efforts,
up to 40% of severely affected patients may suc-
cumb.
Chronic GVHD IS a more enigmatic
syndrome in terms of its pathophysiology.
Whether it is a distinct syndrome or an exten-
sion of acute GVHD is as yet unclear [45]. The
more severe the acute GVHD syndrome, the
more likely is the development of chronic
GVHD. On the otherhand, chronic GVHD
may develop de novo or after an interval in
which no clinical evidence of acute GVHD is
observed. One interesting observation is that
the incidence is greater the older the marrow
recipient. Clinically, chronic GVHD is different
from acute GVHD. Dermatologic manifesta-
tions are reminiscent of scleroderma with a
brawny, sclerodermatous and often ulcerating
dermatitis. Hepatic involvement is primarily
obstructive. Gastrointestinal manifestations in-
clude malabsorption, mucosal atrophy of both
the large and small bowel, and esophageal stric-
tures. Severe keratoconjunctivitis resulting in a
sicca syndrome and damage to the corneas is
frequent. A buccal mucositis with either partial
or complete xerostomia may hinder adequate
nutrition [52, 53]; the mucositis after marrow
transplant often is a multifactorial problem with
contributions from both infection and chemo-
radiation as well as GVHD. A variety of auto-
immune immunologic abnormalities have also
been noted in a small percentage of patients. A
serious prognostic factor has been accompany-
ing thrombocytopenia, the etiology of which is
unclear. Patients with normal numbers of
platelets in the setting of chronic GVHD have a
better survival than patients with thrombocy-
topenia [54].
In patients with chronic GVHD, the resulting
contractures, light sensitivity, and wasting from
malnutrition may seriously modify life style.
Death in this setting is often due to opportunis-
tic infection.
Attempts at therapy of chronic GVHD have
in general had limited success. Short courses of
anti thymocyte serum and prednisone have been
unsuccessful. The combination of corticoste-
roids and azathioprine have resulted in 40%-
50% of patients having clinical improvement,
and in some cases complete clinical resolution
[55] Attempts to totally abrogate the GVHD
syndromes are under study. These include the
elimination of mature T cells from the infused
marrow and involve physical separation as well
as immunologic removal by monoclonal anti-
bodies [19,20]. The potent immunosuppressive
agent cyclosporin is also being evaluated, but in
addition to its own toxicity, renders the patient
immunosuppressed for long periods of time
[56].
Opportunistic Infections
Infectious diseases account for a considerable
amount of the morbidity and mortality associ-
ated with marrow transplantation (see chapter
21). The patient's preexistent condition and
treatment may have rendered him colonized
with potential opportunistic organisms. Even at
the current time, when patients undergo trans-
plantation earlier and in a more stable con-
dition, the patient may be infected at time of
transplant. Preparatory therapy may, in addi-
tion to rendering the patient neutropenic, dis-
turb the integrity of both the skin and gastro-
intestinal tract. Also, immunosuppressive ther-
apy produces complete immunologic paralysis.
Although reconstitution of the hematopoietic
system with return of granulocytes to protective
levels occurs within a few weeks, the newly-
engrafted immune system may take months to
years to mature and may never completely recon-
stitute. Responses to viral infections may be pri-
mary in nature [Years posttransplant] [57]. This
situation is made worse by the presence of
GVHD and attempts to treat the condition [58].
Finally, GVHD may also disrupt the dermal
and gastrointestinal integrity, increasing suscep-
tibility to infection. Thus, all of the biologically
protective mechanisms become compromised
during the course of marrow transplantation.
In considering a patient for transplantation,
 8. PRINCIPLES OF BONE MARROW TRANSPLANTATION
the infectious disease status of the patient must
be carefully considered. Transplantation of a
leukemic patient in remission who has an active
infection should be delayed until the infection is
adequately treated. The dilemma of whether or
not to proceed with the transplant is most
marked in the infected aplastic anemia patient.
Since the patient is granulocytopenic, treatment
of the infection may be impossible until there is
hematologic reconstitution, which is the reason
for the marrow transplant. On the other hand,
the necessary immunosuppression and time
necessary for engraftment may make the situa-
tion worse. Granulocyte transfusions before
transplant may sensitize the patient to minor
transplantation antigens, leading to graft rejec-
tion. Thus, an infected aplastic patient should
not be excluded from an attempt at transplanta-
tion if the infection can be adequately con-
trolled by appropriate measures.
Successful engraftment can be achieved in
previously infected patients. Recent prior viral
infections with viral hepatitis or cytomegalo-
virus (CMV) are cause for concern, but do not
necessarily add to the risk. For the candidate
without apparent infection, complete evaluation
of occult infections and sources of infection
should be performed before transplantation.
This should include radiologic evaluation of
the lungs and sinuses and surveillance cultures.
Dental evaluation and corrective measures
should be performed.
The infectious risk after bone marrow trans-
plant can be evaluated in terms of the time from
transplantation, since the risks differ. During
the early posttransplant period (the first 30
days) the patients are neutropenic. In addition,
they have recently received lethal chemoirrad-
iation therapy to ablate the cellular immune
response. Dermatologic and gastrointestinal
toxicity may be manifested. Indwelling in-
travenous and bladder catheters may be neces-
sary. However, during this early period, ade-
quate levels of preexistent antibodies will still
be present.
Almost all patients will be febrile during gran-
ulocytopenia. In many instances, no infectious
agent will be detected and the fever may resolve
with a rising granulocyte count; acute GVHD
is frequently associated with fever. Most
documented infections during this interval are
caused by bacteria with both gram-negative and
gram-positive organisms being identified. Of
interest is an increasing incidence of coagulase-
135
negative Staphylococcus sp. bacteremias that
may be related to increased use of indwelling
catheters [59]. Fungal infections occur during
this time period; Candida and Aspergillus sp.
are most commonly involved. In most centers,
the incidence of documented fungal infections
appears to be decreasing. This decrease may be
due to both better clinical condition of patients
as well as the empiric use of amphotericin in
persistently granulocytopenic febrile patients.
The most frequent viral infection during the
early posttransplant period is herpes simplex
and the most frequent clinical expression is
gingivostomatitis.
Various measures have been used to prevent
infections during the granulocytopenic period.
These may vary from single rooms with mask
and gloves to elaborate isolation in laminar flow
rooms with skin decontamination and gastroin-
testinal sterilization. The efficacy of the latter
procedure is still under investigation. Although
sterile isolation for patients undergoing trans-
plantation for aplastic anemia has resulted in de-
creasing both the incidence of bacterial infection
and the severity of GVHD, the overall survival
has not improved [60]. In any evaluation of the
applicability of isolated protection, the degree
of adherence to the procedure as well as the
degree of sterility achieved must be taken in-
to consideration. Prophylactic antibiotics have
been of limited value. Prophylactic granulocyte
transfusions, in addition to being of little value,
increase the risk of CMV infection.
With the establishment of hematopoietic en-
graftment and the onset of acute GVHD, the
scope of the infectious complications begins to
change. Bacterial and fungal infections continue
to be a problem because of the loss of continuity
in skin and gastrointestinal mucosa. The major
impairment during this period is continued im-
munodeficiency that is more severe and pro-
longed in the setting of GVHD. The most
serious infections between the time of engraft-
ment and four months after transplant are
caused by viruses; 40%-50% of recipients of
allogeneic marrow transplants will develop in-
terstitial pneumonias, with at least half of these
succumbing to severe hypoxemia. The incidence
of interstitial pneumonia is higher in patients
conditioned with total body irradiation, older
patients, and patients with severe GVHD [61,
62]. The pathogenesis of the majority of the
pneumonias is often not clear even after lung
biopsy; hence they are labeled idiopathic.
136 II. PRINCIPLES OF MANAGEMENT
The possibility of radiation or chemotherapy
damage has been entertained [63]. Since the
utilization of prophylactic trimethoprim-
sulfamethoxazole, Pneumocystis carinii has
markedly decreased as a cause of pneumonia.
The most common organisms isolated from the
lung have been CMV, although herpes simplex,
varicella zoster, and adenovirus have also been
isolated. Fungal infections appear to be uncom-
mon unless the patient has severe GVHD or is
receiving severe immunosuppression. The high
incidence of CMV may be secondary to both
activation of latent infection as well as transfu-
sion of exogenous virus in blood products [64].
The lung may be the primary target of these
infections because of alveolar macrophage
dysfunction. Although most transplant centers
appear to have similar incidences of interstitial
pneumonia, the incidence of etiologic agents
appears to vary. The prophylactic use of acyclo-
vir has been of little long-term use [65] and
current studies are evaluating the prophylactic
administration of interferon. Judicious use of
blood products as well as the identification of a
CMV -negative donor population may decrease
the incidence of CMV infections. Acyclovir or
adenine arabinoside are of use in established
herpes simplex or varicella zoster infections, but
of no value in CMV.
Virus may cause other clinical syndromes.
CMV or Epstein-Barr virus hepatitis may
occur. Diarrheal syndromes secondary to rota-
virus, adenovirus, or Coxsackievirus may occur.
Asymptomatic viral isolation or seroconversion
have also been frequently noted.
Late infectious complications after marrow
transplant are related to the presence or absence
of chronic GVHD [66]. Varicella zoster occurs
in most at risk patients who had varicella prior
to transplant. Activation of this latent virus
occurs as the pretransplant antibody disappears
and usually manifests itself as a localized
cutaneous syndrome. Cutaneous dissemination
does occur and less frequently pneumonia,
hepatitis, and encephalitis are seen. For the pa-
tient without chronic GVHD, other infections
are not common, but antibody responses to
viral infections are primary in nature. Tetanus,
pneumococcal, and poliomyelitis vaccinations
should be considered, but live viruses should
not be given.
The course in the patient with chronic
GVHD is, however, quite different. The de-
structive effects of chronic GVHD may result
in skin and gastrointestinal tract bacterial infec-
tions and sepsis. Recurrent bacterial infections
of the respiratory tract may lead to progressive
pulmonary insufficiency. The patient is at
particular risk for encapsulated bacterial infec-
tions and attention should be paid to the high
incidence of pneumococcus [67]. In the setting
of chronic GVHD and immunosuppressive
therapy, consideration should be given to both
prophylactic antibiotics as well as gamma-
globulin replacement.
Chemoirradiation Toxicity
The preparatory therapy for marrow trans-
plantation is predicated on the principle that
hematopoietic protection is effected by engraft-
ment of the infused marrow. Failure of engraft-
ment after preparation is ultimately fatal. Other
early manifestations of radiation toxicity in-
clude gastrointestinal upset, parotitis, cardiac
failure, and mucositis. Pneumonias occur more
frequently in recipients of total body irradia-
tion. In an attempt to limit these effects, low
dose rates are administered, and some centers
are exploring administration of fractionated
total body irradiation. Long-term effects in-
clude sterility and cataract formation. High-
dose busulfan trials are underway to determine
whether this agent can therapeutically replace
irradiation as an antihematopoietic stem cell
agent with less resultant toxicity. Although
gastroin testinal side effects appear to be less,
comparison of long-term effects has yet to be
determined. It must be kept in mind, however,
that agents with similar therapeutic effects are
likely to have similar toxicity. The other major
agent used in marrow transplantation prepara-
tion is cyclophosphamide. In addition to gas-
trointestinal, hematopoietic, and immunosup-
pressive effects, the drug may be associated with
cardiomyopathy, inappropriate antidiuretic
hormone, and, not infrequently, bladder toxic-
ity with massive hemorrhage.
Other agents may also cause complications.
Antithymocyte serum is a heterologous biologic
and may be associated with serum sickness or
anaphylaxis. Posttransplant methotrexate may
cause mucositis, but in many cases the mucositis
is multifactorial. Recent use of cyclosporin has
been associated with renal failure and an in-
creased incidence of secondary lymphoprolif-
erative syndromes. Careful consideration must
be given to the use of drugs after transplant
because of the precarious nature of the newly
engrafted marrow.
 8. PRINCIPLES OF BONE MARROW TRANSPLANTATION
Conclusion
Although bone marrow transplantation was
conceived as physiologic, rational therapy in
the 1950s, it was only in the 1970s that the tech-
nology advanced to a clinically applicable stage.
During the past decade, improving results have
been reported in a number of hematopoietic dis-
eases including aplastic anemia and leukemia
and severe combined immunodeficiency. Ap-
plication of marrow transplantation has been
successfully extended to genetic hematopoietic
disorders. Improved success has in part been
due to earlier use of marrow transplantation,
but herein lies the dilemma faced by the practi-
tioner. The unsolved problems of GVHD and
the opportunistic infections may shorten the in-
dividual patient's survival. Should the patient
successfully traverse the iatrogenic difficulties
associated with the procedure, however, long-
term survival and cure are possible. The lack of
an appropriate donor may prevent the availabil-
ity of marrow transplantation for many patients
who might benefit from the procedure. The
complexity of the procedure dictates that it be
performed in centers with experienced person-
nel and dedicated complete facilities. Despite
these unsolved problems, marrow transplanta-
tion has moved from the experimental to the
clinical arena.
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 9. PRINCIPLES OF INFECTION
MANAGEMENT
James C. Wade
A compromised host is an individual who, be-
cause of a dysfunction or deficiency in one or
more of the basic infection defense mechanisms,
is at increased risk of developing an infection.
Infections that occur in the compromised host
are frequently nosocomial (hospital-associated),
although the recognition of reactivation of
previously latent or dormant infections (Myco-
bacteria tuberculosis, Pneumocystis carin ii,
herpes group viruses, etc.) is increasing. The diag-
nosis of infection in the patient with cancer, a
frequently encountered compromised host, is
viewed as challenging and often as an unsolvable
problem. Once the individual patient's pre-
disposing factors for infection are identified,
however, the problem often becomes reason-
ably straightforward. The understanding of
these predisposing factors for infection allows
for earlier diagnosis, an awareness of the un-
usual presentations of infection, an intelligent
approach to early empiric therapy and, of great
importance, the development of an effective
program for infection prevention [1, 2].
Predisposing Factors
The patient's underlying disease is a critical
variable in determining the types of infections
that may occur, but, even among patients with
the same underlying tumor diagnosis, the infec-
tions observed will vary, depending on other
predisposing factors (table 9-1). There are sig-
nificant differences in the frequency or type of
infections that occur in the adult with acute
nonlymphocytic leukemia who is undergoing
initial induction versus maintenance chemother-
apy or a similar patient who has received a mar-
row transplant. There are six major conditions
that predispose the patient with cancer to infec-
tion: granulocytopenia (usually in association
Peterson etal.• HEAD AND NECK MANAGEMENT OF THE CANCER PATIENT.
© 1986. Martin"s Nijhof[ Publishing. All rights reserved.
TABLE 9-1. Predisposing factors (or: what makes the
host compromised?)
Granulocytopenia
Mucosal or integumentary alterations
Cellular immune dysfunction
Humoral immune dysfunction
Obstruction to natural passages
CNS dysfunction
Iatrogenic procedures
Hospital acquisition of pathogens
with damage to the normal anatomic mucosal
barriers that normally limit the penetration of
microorganisms), cellular immune dysfunction,
humoral immune deficiencies, obstruction of
natural passages, central nervous system dys-
function, and various iatrogenic procedures
such as intravascular or urinary catheters.
Infections Associated
with Granulocytopenia
Granulocytopenia by itself is usually not a
primary cause of infection. In most instances,
other factors interact in the presence of granu-
locytopenia to increase the risk of infection.
Damage to anatomic barriers, particularly the
skin, mucosal membranes of the alimentary can-
al, and the mucociliary escalator of the respira-
tory tract, is a factor that increases the infection
risk. However, shifting patterns of microbial
colonization secondary to the underlying dis-
ease state and the acquisition of potential
pathogens from the hospital environment are
also critical.
It is well established that the incidence and
severity of infection rises dramatically as the
absolute granulocyte count decreases [3] (figure
9-1). Although granulocyte counts of less than
141
142 II. PRINCIPLES OF MANAGEMENT
li--ll. AD idections
o--a Severe infections
...--. Bacleremias
GRANULOCYTE COUNT
(censper/Jil
FIGURE 9-1. Incidence of infection in acute nonlym-
phocytic leukemia during induction therapy.
1000/1l1 usually define the "granulocytopenic·
state," a substantial increase in the risk of infec-
tion really does not begin until the granulocyte
count has dropped below SOD/Ill. Essentially all
severe infections, gram-negative bacteremias,
or episodes of disseminated candidiasis occur
when the granulocyte count is less than 100/lll,
yet the extent of marrow reserve or the ability
of the marrow to maintain an adequate level of
granulocytes in the presence of an ongoing in-
fection is critical, and probably more important
with regard to severity and outcome of infection
than is the granulocyte level at the initiation of
the infection.
SITES
The sites of infection are localized to regions of
damaged anatomic barriers that allow for easy
entry of otherwise relatively nonpathogenic
organisms (figure 9-2 and table 9-2). The ali-
mentary canal is the principal site of infection
and includes exacerbation of previously chronic
periodontal disease, pharyngitis, esophagitis
localized to primarily the distal third of the
esophagus, colitis, and perianal lesions. Infec-
tions along the respiratory tract are essentially
limited to sinusitis and pneumonia, whereas in-
fections of the skin occur in the axillae, groin, or
at areas of direct damage due to venipuncture,
intravenous cannulation, bone marrow aspira-
tion, or fingersticks. In addition, there are bac-
FIGURE 9-2. Site of infection in granulocytopenic
cancer patients.
teremias of unknown origin, some of which are
presumed to relate to bacterial translocation
along the intestinal wall. A group of infections
are infusion related and occur secondary to the
placement of intravascular catheters or infusion
of products that are contaminated with bacterial
or viral (hepatitis Band non-A/non-B, cyto-
megalovirus) pathogens. These predominant
infection sites are readily explained: acute per-
iodontitis, which at some centers has been rec-
ognized to cause approximately 20% of febrile
episodes, occurs as a result of acute exacerbation
of previously unrecognized chronic periodontal
disease [5]. Esophagitis occurs in the distal
esophagus secondary to chemotherapy-induced
mucosal damage that is exacerbated by gastric
acid reflux from the stomach occurring during
periods of chemotherapy-induced vomiting.
The primary role of viral reactivation with
agents such as herpes simplex virus has also
been recently suggested as important in the de-
velopment of significant esophageal mucosal
disruption [6]. Perianal lesions occur particular-
ly in patients with acute monocytic or myelo-
monocytic leukemia and can reach an incidence
of 33% among patients who do not receive
alimentary tract decontamination [7]. Patients
with a history of hemorrhoids are most fre-
quently affected because of the predisposition of
 9. PRINCIPLES OF INFECTION MANAGEMENT
TABLE 9-2. Sites and pathogens of infection in granu-
locytopenic patients
Alimentary canal
Periodontitis
Pharyngitis
Esophagitis
Colitis
Perianal lesions
Respiratory tract
Sinusitis
Pneumonitis
Skin
Local trauma
Gram-negative bacilli
Escherichia coli
Klebsiella pneumoniae
Pseudomonas aeruginosa
Gram-positive cocci
Staphylococcus aureus
Staphylococcus epidermidis
Yeastslfungi
Candida spp.
Torulopsis glabrata
Aspergillus fumigatuslf/avus
those hemorrhoids to develop small mucosal
tears. The high pressures developed in the pro-
cess of defecation and the diarrhea frequently
experienced by these patients exacerbate this
process. Sinusitis seems to develop in patients
with a previous history of sinus infections,
perhaps suggesting a tendency toward obstruc-
tion of the sinus ostia. Pneumonia results from
damaged ciliary function and a reduced tra-
cheobronchial secretion of mucus. These al-
terations in the normal clearance mechanisms
allow for organisms, normally aspirated during
sleep, to establish infection that is then un-
checked because of the absence of granulocytes
or pulmonary macrophages. The axillae are
common sites of infection because of the warm,
moist environment that allows for the growth of
organisms in an area that has been damaged by
shaving or in an area where normal hair follicles
have been occluded by antiperspirants. Infec-
tion at areas of direct damage to the skin, such
as bone marrow aspiration sites and finger-
sticks, occurs because these areas of damage heal
slowly, and the number of organisms necessary
to induce infection in the individual who is gra-
nulocytopenic is substantially less than in the
normal host.
143
Bacterial translocation is a term used to define
the movement of bacteria across the intact in-
testinal epithelium into the mesenteric lymph
nodes and possibly beyond to cause systemic
infection [8]. This process is well recognized
with Salmonella typhi in the production of
typhoid fever. However, data are now accumu-
lating from animal experimentation to show
that certain aerobic gram-negative organisms,
principally Escherichia coli, Klebsiella pneumo-
niae, and Pseudomonas aeruginosa, can also
translocate across the normal alimentary canal
mucosa under at least the following conditions:
during suppression of the anaerobic flora of the
intestinal tract or during suppression of cellular
immune function. It is therefore possible that
many episodes of so-called bacteremia of un-
known origin have their origin in the intestinal
tract and occur as a result of bacterial transloca-
tion in the absence of specific mucosal epithelial
damage.
Although not related to granulocytopenia per
se, patients who are granulocytopenic are those
frequently managed with long-term indwelling
right atrial catheters and who must receive
multiple blood product transfusions and fluid
infusions, with the associated infection com-
plications.
PATHOGENS
The most common causes of infection in the
granulocytopenic patient are the aerobic gram-
negative rods, especially Escherichia coli, Kleb-
siella pneumoniae, and Pseudomonas aeruginosa
[4]. At the University of Maryland Cancer Cen-
ter, during a recent two-year period, there were
206 bacteremias of which about 60% were
caused by gram-negative bacilli, but more than
90% of those gram-negative bacteremias were
caused by the three organisms previously noted.
Despite colonization with other gram-negative
bacilli, patients who are granulocytopenic rarely
develop infection or bacteremia with such
organisms. Bacteroides fragilis, an anaerobic
gram-negative rod that is known to cause infec-
tion in many other settings, along with other
anaerobes are uncommon causes of bacteremic
infection during periods of granulocytopenia.
Gram-positive aerobic organisms such as Staphy-
lococcus au reus and Staphylococcus epidermidis
cause most of the gram-positive infections and
both commonly cause bacteremias [9, 10]. The
principal yeasts and fungi are Candida species
(especially C. albicans and C. tropicalis), Toru-
144 II. PRINCIPLES OF MANAGEMENT
lopsis glahrata, Aspergillus (especially A. fumi-
gatus and A. f!avus), and mucormycoses [11-
14]. Petriellidium hoydii and Trichosporon spp.,
although uncommon, can cause pneumonitis
and disseminated infection in such patients [15,
16].
Infections in the granulocytopenic patient are
caused by the organisms that are colonizing at
or near the site of anatomic damage [17]. This
explains why aerobic gram-negative bacilli are
the predominant pathogen in perianal lesions. It
also suggests that E. coli, P. aeruginosa, and K.
pneumoniae (or at least certain strains) are in-
herently more likely to invade than are other
aerobic gram-negative rods or their associated
stool anaerobic counterparts. These same aero-
bic gram-negative rods (E. coli, P. aeruginosa,
and K. pneumoniae) also cause infection at sites
where one typically does not expect to find such
colonization. However, illness of any type
causes changes in mucosal epithelium binding
sites and, as a result, the patterns of coloniza-
tions shift. The oral cavity of a normal healthy
adult is colonized with gram-positive and gram-
negative aerobic cocci and an anaerobic flora
that only rarely includes Bacteroides fragilis.
During any severe infection, the oral epithelial
cells are altered and begin to preferentially bind
aerobic gram-negative rods. Thus, even in the
absence of the use of antimicrobial agents, the
oral cavity will begin to show colonization with
gram-negative bacilli. This helps to explain why
pharyngitis, esophagitis, and pneumonitis are
caused principally by gram-negative bacilli
rather than organisms considered to be "normal
oral flora." Skin infections are usually thought
of as being caused by staphylococci and strep-
tococci, but, again, the granulocytopenic pa-
tient has a shift in the colonizing microbial flora
of the skin and, despite good personal hygiene,
some areas of the skin, such as the axillae and
groin, will be found to be colonized with gram-
negative bacilli. Thus, it should not be surpris-
ing that more than 60% of skin infections are
caused by gram-negative rods [18]. Perhaps the
major exceptions to this rule are fingersticks,
which are usually infected with Staphylococcus
aureus (usually associated with nasopharyngeal
colonization) or catheter exit sites where the
major cause of infection is still due to Staphylo-
coccus sp.
Microbial patterns can be further shifted by
the use of local or systemic antibiotics that may
predispose toward colonization with resistant
gram-negative rods, Corynebacterium, or yeasts
and filamentous fungi. Some cancer chemothera-
peutic agents, such as methotrexate, dauno-
rubicin, and cytarabine, have been shown to have
antibacterial activity against some of the non-
pathogenic aerobic gram-positive cocci. Perhaps
this effect allows for a further increase in col-
onization by gram-negative bacilli and other
potentially pathogenic organisms. Finally, the
mucosal damage secondary to chemotherapy
produces a necrotic debris that serves as an ideal
growth media for many organisms. This is
opposed to the normal state where living cells,
assisted by enzymatic and other activities of
saliva and other bacteriocidal fluids, resist the
invasion of microbes.
It is important to recognize that about 50%
of the infections that occur in the granulocy-
topenic patient are due to organisms that have
been acquired from the local environment [17].
Because of the change in epithelial binding sites,
many organisms with which the patient comes
in contact on a daily basis will now colonize
rather than pass through the alimentary canal.
The organisms acquired in the hospital are more
likely to be resistant to standard antimicrobial
agents and perhaps are more virulent. The major
sources for newly acquired organisms include
food, especially green leafy vegetables, toma-
toes, unpasteurized fruit juices, water supplies
(especially with the use of faucet aerators),
direct contact between staff members and pa-
tients, and inhalation of airborne organisms
(especially filamentous fungi and some viruses)
[19].
INFLAMMATORY RESPONSE
The absence or near absence of granulocytes
substantially limits the inflammatory response,
which in turn affects both diagnosis and prog-
nosis [20]. There are very few early signs and
symptoms of infection except for fever. A pa-
tient with an early pneumonitis may have little
more than a sense of shortness of breath and a
mild cough; examination usually reveals few, if
any, rales; there is no sputum production and
the chest x-ray may be negative for the first 24-
48 h. This all occurs because of the lack of an
adequate inflammatory process. Meanwhile, the
infection may rapidly progress, with early bac-
teremia developing. Similarly, the patient with
an exacerbation of periodontal disease may have
no specific symptoms to suggest the source de-
spite the presence of a fairly extensive "celluli-
 9. PRINCIPLES OF INFECTION MANAGEMENT
tis" involving attached gingiva and alveolar mu-
cosa. A perianal lesion may develop initially as
little more than a complaint of pain with defeca-
tion plus associated fever and chills. A careful
rectal examination will usually show a focal area
of tenderness, but erythema and induration are
usually absent. A bone marrow aspiration site
may be somewhat swollen, erythematous, and
tender to touch, but in no way appears to be a
significant abscess nor a major area of cellulitis
despite the presence of fever, shaking chills, and
positive blood cultures substantiating the rapid
spread of this local process to a systemic infec-
tion.
It is this ability of an otherwise minor appear-
ing and localized infection to progress rapidly
to a systemic bacteremia that makes the need for
early diagnosis and prompt empiric therapy
critical [21]. Indeed, the patient with a gram-
negative bacteremia who is not treated prompt-
ly will usually die within 24-48 h unless anti-
microbial therapy is initiated within the first
few hours. Similarly, a gram-negative pneumo-
nia viith or without an associated bacteremia
will progress rapidly in the absence of granu-
locytes to involve multiple lobes. Although
antibiotics given late may kill the pathogens,
the patient may nevertheless succumb to res-
piratory insufficiency secondary to the exten-
sive pulmonary damage.
Granulocytopenia has a major prognostic
effect on the progression and ultimate course of
disseminated candidiasis and filamentous fun-
gus infections. For example, Candida esophagi-
tis progresses to dissemination usually when the
granulocyte count is less than 100/1..11, but this
same setting ensures that the diagnosis of
dissemination will be fraught with difficulty
because of the absence of additional inflamma-
tory signs and symptoms [22].
DIAGNOSTIC APPROACH
Fever is the first sign of infection and often the
only sign during the first hours or even days of
infection in the granulocytopenic patient [20].
Fever that is almost universal despite the ab-
sence of granulocytes occurs because endoge-
nous pyrogen is produced not by polymorpho-
nuclear leukocytes, but by other phagocytic
cells including the fixed macrophages of the
liver, spleen, and lungs. Endogenous pyrogen
is also produced by some leukemic cells and
by some Reed-Sternberg cells, and this may
help to explain the presence of fever due to dis-
145
TABLE 9-3. Occurrence of infection in setting of
granulocytopenia and new fever
Microbiologically documented
With bacteremia 20%
Without bacteremia 20%
Clinically documented 20%
Possible (equivocal) infection 20%
Not infected 20%
eases like leukemia or lymphoma.
The development of new fever in the granu-
locytopenic patient represents infection in at
least 60% of patients (table 9-3) [23]. About
20% will have a bacteremia and about 50% of
these will be caused by gram-negative bacilli.
Another 20% will have a microbiologically
documented, but nonbacteremic, infection and
a further 20% will have a clinically documented
infection (i.e., the site of infection has been de-
fined but the pathogen is not clearly recog-
nized). An additional 20% will have fever and
some equivocal signs and symptoms that will
make the clinician suspicious that fever was
indeed caused by infection, but proof will be
inadequate. Finally, about 20% of patients
will be found, in retrospect, to have had a non-
infectious cause for the fever.
The basics of an initial evaluation include a
very careful history and physical examination
that emphasizes the subtle symptoms and signs
of inflammation that may be present with the
most common sites of infection in the granu-
locytopenic patient [21]. Thus, significance
should be given to the patient who has throat
discomfort with tenderness to palpation in the
submandibular areas even if pharyngeal erythe-
ma is absent; to the patient who has minimal but
new pain with swallowing; to the patient who
has a sense of fullness in the maxillary sinus or
nose; to the patient who has pain and discom-
fort with defecation, etc. The initial history and
physical examination is frequently negative and
thus must be repeated at least daily until either a
site of infection is determined or until there is
adequate proof that fever was not due to an in-
fectious cause. A chest x-ray should be obtained
immediately and should be compared with a
baseline x-ray. Pneumonitis may not be recog-
nized on x-ray for a few days, however, and
therefore the x-ray examination should be repeat-
ed at least daily until the source of infection is
determined. Urinary tract infections are uncom-
mon except in the patient with a catheter or a
146 II. PRINCIPLES OF MANAGEMENT
history of recurrent urinary infections. Never-
theless, it is an important site that should not be
overlooked and the physician should personally
examine a clean caught specimen for the pres-
ence of bacteriuria (pyuria will not occur in the
absence of granulocytes). Blood cultures should
be obtained from two separate venipunctures.
Preferably, no cultures should be taken through
indwelling catheters, but if one is taken from the
catheter, the second must be taken from a prop-
er peripheral venous puncture. Two cultures are
always necessary because it both increases the
yield for detecting bacteremia and a second cul-
ture is necessary to establish the clinical impor-
tance of an isolate such as a diphtheroid, Bacil-
lus sp. or Staphylococcus epidermidis [10]. Cul-
tures should also be obtained from any obvious
site of infection and this may necessitate aspira-
tion of the skin lesion after the cellulitis has
been injected with preservative-free saline,
biopsy of a skin lesion, transtracheal aspiration,
bronchoscopy, or esophagoscopy. Biopsy is an
important adjunct to these diagnostic proce-
dures; adequate platelet support must therefore
be obtained.
Cultures should also be taken of the nose,
gingiva, or throat and rectum for surveillance
(or inventory) of the organisms that are current-
ly colonizing the patient [24, 25]. The labora-
tory must understand that gram-negative bacilli,
Staphylococcus sp., yeast, and fungi and any
organisms appearing in pure growth must be
identified and that antimicrobial susceptibility
patterns need to be obtained for these organ-
isms. These cultures can be especially useful if a
specific infecting pathogen is not detected, yet
there is a site of infection and the patient is not
doing well. Colonization at the site of infection
with an organism resistant to one of the anti-
microbials being used can lead to an intelligent
adjustment of the antibiotics. It can be useful
to know which patients are colonized with S.
aureus so that antibiotics that are effective for
this organism can be used. Surveillance culture
data may also be useful later when one is con-
sidering the possible need to add amphotericin
-B or other antifungal agents to the antimicrobial
regimen [11, 12,25]. In short, although surveil-
lance cultures cannot make a diagnosis, they
can prove to be especially helpful for the pa-
tient with a "clinically documented" or "possi-
ble infection" in whom the correct approach
to therapy is sometimes difficult to define.
Special techniques for diagnosing viral ill-
nesses are usually not initially necessary in the
granulocytopenic patient because the majority
of infections are caused by bacteria and some
fungi. The exceptions are gingivitis, pharyn-
gitis, and esophagitis where herpes simplex
virus or cytomegalovirus may cause infection,
or gastroenteritis caused by enteric viruses
that may occasionally lead to mini epidemics
within an institution [26-29]. The other com-
mon viral illness that occurs among granu-
locytopenic patients is non-A/non-B hepatitis
[30]. This infection, often initially manifested
by fever, occurs as a result of multiple blood
product transfusions. This is not related to
granulocytopenia per se, nor is it exacerbated
by the granulocytopenic state, but patients
who are granulocytopenic are often the same
ones who require blood product transfusions.
SPECIAL CONSIDERATIONS
The diagnosis of the etiologic agent of a
pneumonia occurring in the granulocytopenic
patient is fraught with difficulties [31]. One
must be concerned about the possibility of car-
diogenic or noncardiogenic pulmonary edema,
hemorrhage, drug toxicity (e.g., bleomycin,
methotrexate, busulfan, nitrosoureas), tumor
(e.g., lymphangitic spread of carcinoma), radia-
tion pneumonitis, or infection. For the reasons
described previously, pneumonias early in the
patient's course of granulocytopenia are usually
caused by bacteria. However, one cannot be
certain of etiology; other possibilities include
the unlikely viral infection, possible filamentous
fungal infection (especially if the patient has had
previous systemic antimicrobics), the unlikely
infection associated primarily with cellular im-
mune deficiency (e.g., tuberculosis, Nocardia,
Cryptococcus, etc.), or a noninfectious cause.
Thus, etiology must be determined. Initial
empiric therapy should not await an invasive
pulmonary procedure, although these proce-
dures should be performed promptly. An inva-
sive procedure is essential if blood cultures re-
turn negative, the patient's infection progresses
or does not begin to improve, or if there are
specific epidemiologic reasons (a long period
of granulocytopenia punctuated by multiple
courses of antibiotics, etc.) or other factors that
suggest an infection not caused by the common
bacteria. There is great controversy as to what
diagnostic procedure is most appropriate, be
that transtracheal aspiration, bronchoscopy
with or without biopsy, or open-lung biopsy
 9. PRINCIPLES OF INFECTION MANAGEMENT
[32, 33]. Each of these procedures has its
definite advantages and disadvantages. For the
patient who is granulocytopenic, there is no
clear-cut correct approach and, to a great degree,
the choice of procedure should depend upon
the skill of specific staff members to perform the
individual procedures. But it must be recalled
that simply obtaining a specimen of tissue by
whatever technique is of little value if there is
not an organized system for specimen handling
and evaluation. The assistance of the pathology,
cytology, and microbiology laboratories is a ne-
cessity.
Esophagoscopy with biopsy is an invaluable
technique for establishing the etiologic diag-
nosis of esophagitis [34]. Radiographs may
demonstrate the so-called classic cobblestone
appearance of Candida esophagitis, but it
should be recalled that an x-ray film does not
make an etiologic diagnosis, and that any of
the common causes of esophagitis can produce
the same radiographic appearance, i.e., gram-
negative bacilli, herpes simplex virus, cyto-
megalovirus, or Candida sp. Esophagoscopy
with scrapings is not sufficient; a biopsy is
necessary to establish the definitive etiologic
agent (e.g., viral inclusions, invasion by Candi-
da). Esophagitis is frequently polymicrobial
and, with the choice of therapy ranging from
antibacterial antibiotics to antivirals to anti-
fungal agents, an intelligent therapeutic deci-
sion becomes impossible without a definitive
pathogen.
Diarrhea, a common problem among granu-
locytopenic patients, is often due to antibiotics,
the effect of chemotherapeutic agents and, to a
less degree, an infectious agent. Nevertheless,
the concern is always present that an epi-
sode of diarrhea with associated fever may be
caused by a bacterium capable of producing
bacteremia. Infection caused by Salmonella,
Campylobacter, or Shigella sp. is reasonably
uncommon, but a recent report has suggested
that viral causes of diarrhea, in the form of
miniepidemics within a ward, may be relatively
common [29]. Although no specific antiviral
therapy is available for rotavirus, atypical
adenovirus, coxsackie virus, and other enteric
virus, knowledge of the etiologic agent can act
as some reassurance against the need for other
forms of therapy. The most practical approach
to diagnosis appears to be the use of an enzyme-
linked immunosorbent-type assay to detect
viral antigens coupled with viral isolation.
147
Antibiotic-associated colitis caused by Clostri-
dium difficile, at least in its most fulminant
form, appears to be rather uncommon, but a
number of recent reports have indicated that C.
difficile may be prevalent in stool cultures from
granulocytopenic patients, suggesting that the
potential for toxin-induced diarrhea is real.
Therefore, it is appropriate to test for C. difficile
toxin in the stool of patients with more than
transient diarrhea.
THERAPY
Empiric therapy for the febrile, neutropenic
patient must be (a) prompt, (b) empiric, (c)
bacteriocidal, (d) broad in spectrum, (e) given
as a combination of agents, and (f) given in-
travenously and in full dosage [21].
The need for prompt institution of therapy is
due to the rapid and high mortality rate of pa-
tients with gram-negative bacteremia [35, 36].
The need for prompt therapy makes the use of
empiric antibacterial regimens clear. Recom-
mendations for specific regimens are given
below, but it is emphasized that an antibiotic
combination must be chosen that is most
appropriate for the specific patient in a specific
institution. It is necessary to know what organ-
isms are most likely to be colonizing the patient
and what the likely susceptibility patterns will
be. Knowledge of this type can be obtained with
serial surveillance cultures, but, in their absence,
it becomes critical to have continually updated
information on the susceptibility patterns of
organisms frequently recovered from the area of
the hospital where the patient is being treated.
It is obvious that bactericidal rather than bac-
teriostatic antibiotics are important. The agents
should have a broad spectrum of activity so
as to "cover" the great majority of hospital
pathogens. This has required the combination
of two or three antibiotics to ensure coverage of
most gram-negative rods, especially P. aerugi-
nasa, K. pneumoniae, and E. coli plus S. aureus
and other gram-positive cocci. The use of anti-
biotic combinations also appears to slow the
emergence of resistant bacterial strains. An
equally important reason for the use of anti-
biotic combinations is the need for two active,
bactericidal agents with· preferably synergistic
action, when treating the patient who has a
circulating granulocyte count of less than 100
granulocytes/ill, an aplastic marrow, and a
gram-negative rod bacteremia. It is this group of
patients, although a minority of all neutropenic
148 II. PRINCIPLES OF MANAGEMENT
patients who receive empiric antimicrobial ther-
apy, who have the highest mortality and for
whom the synergistic combination of agents has
proven necessary [37-39].
SPECIFIC SUGGESTIONS
Most standard combinations employ an amino-
glycoside [40]. This is done because the amino-
glycosides have a broad spectrum of activity
against almost all gram-negative rods including
E. coli, K. pneumoniae, and P. aeruginosa, plus
activity against gram-positive cocci, such as S.
aureus. The disadvantages of the aminoglyco-
sides are their potential for nephrotoxicity and
ototoxicity, the need for monitoring of serum
levels to ensure appropriate dosing, their poor
soft-tissue penetration, and bacteriostatic activ-
ity in the absence of polymorphonuclear leuko-
cytes. The most commonly used aminoglyco-
side has been gentamicin. Tobramycin has the
advantage of somewhat greater activity against
P. aeruginosa with slightly less activity against
Serratia marcescens. Amikacin has no greater
intrinsic activity, but its use is necessary at
those institutions where a high incidence of
gentamicin- or tobramycin-resistant pathogens
exists. All three of these aminoglycosides appear
to be equally efficacious for susceptible prgan-
isms although differences in the frequency of
nephrotoxicity have been reported [41]. A
semisynthetic penicillin, such as carbenicillin
or ticarcillin, has frequently been added to the
amino glycoside to produce synergistic activity
against P. aeruginosa and perhaps E. coli with
added activity against gram-positive cocci [40].
Alternatively, a cephalosporin, such as cepha-
lothin or cefazolin, has been added to the ami-
noglycoside to give added activity with frequent
synergy against K. pneumoniae and E. coli plus
excellent activity against S. aureus [40]. Unfor-
tunately, the first combination does not provide
additive activity against Klebsiella and the latter
combination does not have added activity
against Pseudomonas so that a three-drug com-
bination of an aminoglycoside plus a penicillin
plus a cephalosporin (e.g., gentamicin, carbeni-
cillin and cephalothin) has often been recom-
mended [40]. 'i'his combination has been accept-
able as initial empiric antimicrobial therapy of
the febrile, neutropenic patient, although review
of the many published studies using a three-
drug combination fails to show an advantage for
the three-drug combination over those contain-
ing two antibiotics [40].
Another approach is to use trimethoprim-
sulfamethoxazole (TMP-SMZ) in combination
with either an aminoglycoside or an antipseudo-
monal penicilline. Clinical results have been
very good and toxicities with trimethoprim-
sulfamethoxazole are minimal [42, 43]. How-
ever, these combinations should probably be
avoided in centers where trimethoprim-
sulfamethoxazole is being used as prophylaxis
and resistant strains may be the cause of infec-
tion.
Recently, a series of new semisynthetic
penicillins, notably azlocillin, mezlocillin, and
piperacillin, have been introduced, each with a
much broader spectrum of activity than carbe-
nicillin or ticarcillin. Thus, a combination of
one of these newer penicillins plus an amino-
glycoside gives double coverage against the great
majority of infecting organisms; synergy has
been demonstrated in most cases [44-46]. Con-
current to the introduction of the new penicil-
lins has been the introduction of a new group
of cephalosporin and cephalosporinlike com-
pounds, including cefotaxime, cefoperazone,
moxalactam, and ceftazidime [47-49]. These
agents, unlike the previous available cepha-
losporins, are active against P. aeruginosa,
although their activity against S. aureus and
other gram-positive cocci is substantially less
than that of their cephalosporin ancestors.
When a newer cephalosporin is combined with
an aminoglycoside, there is, as with the newer
penicillin-aminoglycoside combinations, dou-
ble coverage of a very broad spectrum of organ-
isms, with synergy against most. Each of these
combinations has the disadvantage of producing
hypokalemia as a result of the~-lactam com-
pound, and ototoxicity and nephrotoxicity as a
result of the amino glycoside [44, 47].
It has become apparent that many patients,
because of improved survival from their under-
lying disease, are returning to the hospital mul-
tiple times because of the occurrence of fever
and infection during periods of neutropenia. As
a result, there is an increased susceptibility to
renal toxicity and ototoxicity for these patients.
To avoid this potential toxicity and the need for
monitoring serum amino glycoside levels, it may
be useful to consider a double ~-lactam com-
bination of antibiotics. Combinations such as
cephalothin plus ticarcillin have been found use-
ful in the past, but have had the disadvantage
that, with a Klebsiella infection, only cepha-
lothin was active, and similarly, for a Pseudo-
 9. PRINCIPLES OF INFECTION MANAGEMENT
monas infection, only ticarcillin was active [40].
With the new generation of penicillins and
cephalosporins, it is possible to combine either
azlocillin, mezlocillin, or piperacillin with one
of the new cephalosporins such as moxalactam
or cefotaxime or cefoperazone and have a com-
bination with double coverage of almost all
organisms. Great care must be taken in choos-
ing such a combination, however, because some
double J3-lactam combinations not only do not
produce synergy but can be antagonistic [50,
51]. For example, any of the new penicillins plus
cefoxitin or occasionally cefomandole are anta-
gonistic for P. aeruginosa, Enterobacter, Serra-
tia, and some Proteus sp. Other combina-
tions such as piperacillin plus moxalactam or
ceftazidime have been extensively studied in vit-
ro and demonstrate synergy with no antagon-
ism [52, 53]. Clinical trials using the latter double
J3-lactam antibiotic combinations have dem-
onstrated good efficacy with no renal toxicity or
ototoxicity [49, 54, 55].
With the advent of these new very broad
spectrum antibiotics, the question has been
frequently raised as to whether to use a single
broad-spectrum antibiotic for empiric therapy
[48, 56]. Such an approach should be discour-
aged because of the need for double-agent
coverage for the patient with gram-negative
bacteremia with persistent and profound granu-
locytopenia. In addition, there is usually in-
adequate time to make adjustments to antibio-
tics later if the wrong decision is made initially.
Although a single antibiotic may prove more
than adequate for the great majority of patients,
it would seem more prudent to initiate therapy
with an antibiotic combination; the unneeded
antibiotic can then be discontinued if possible
after a few days of therapy once the suscepti-
bility studies are available and the patient's
clinical course has been determined.
GRANULOCYTE TRANSFUSIONS
The use of granulocyte transfusions has been
controversial since their introduction about 20
years ago. Although the controversy relates to
demonstrated efficacy, the reasons for this
debate are three [57]. First, it has been almost
impossible to gather the needed numbers of
patients from the appropriate subgroups so that
a definitive comparative trial can be done.
Second, it is impossible to replace the equivalent
number of granulocytes that the normal bone
marrow can make during the course of infec-
149
tion. Third, granulocyte transfusions have been
associated with significant side effects. Most
notable has been the concern about whether a
pneumonia will be made worse by the infusion
of granulocytes, whether the concurrent use of
amphotericin-B will lead to pulmonary toxicity,
or whether transfusions of leukocytes will lead
to alloimmunization and hence poor response
to future platelet transfusions.
Many trials of granulocyte transfusions have
been performed in recent years and, although
there is some controversy as to their usefulness,
it cannot be denied that the normal body re-
sponse to bacterial infection is the migration of
polymorphonuclear leukocytes to the site of in-
fection. It is clear that granulocyte transfusions
are not needed for the great majority of infec-
tions that develop in the neutropenic patient,
but where granulocyte transfusions appear to be
most useful has been among patients with per-
sistent (greater than 1-2 weeks), profound (less
than 10011L1) granulocytopenia with a serious
infection (pneumonia or bacteremia) caused by
a gram-negative bacillus. The following recom-
mendations seem appropriate: granulocyte
transfusions should be given at the very earliest
evidence of a serious infection in a patient with
profound granulocytopenia and an aplastic mar-
row, which is unresponsive to what are believed
to be appropriate antibiotics. The decision to
administer granulocyte transfusions can usually
be made in the first 24-48 h; once the decision is
made, granulocyte transfusions should begin
immediately utilizing the greatest number of
leukocytes possible. In patients known to be
alloimmunized to random donor platelet trans-
fusions, it will be necessary to obtain an HLA-
compatible donor, for to do otherwise will
result in little benefit from the transfusion
and probably substantial side effects. It is not
clear whether or not' granulocyte transfusions
are useful in the treatment of fungal infections
such as disseminated candidiasis or Aspergillus
pneumonia. However, both of these infections
are clearly life-threatening with poor response
rates. Consequently, the use of granulocyte
transfusions in such infections would seem
rational in the patient with profound, persistent
granulocytopenia.
HYPERIMMUNE GLOBULIN OR PLASMA
There is some evidence to suggest that the use of
plasma that contains a high titer of antibody
against the common core antigen of gram-
150 II. PRINCIPLES OF MANAGEMENT
negative bacilli may be useful in the treatment of
severe infections caused by gram-negative bacil-
li [58]. This work remains investigational and
plasma for this purpose is not generally avail-
able. Recently, gamma-globulin preparations
for intravenous administration have been made
commercially available, and it will be of interest
to monitor the results of studies to determine
whether the use of intravenous gamma globulin
will add to the efficacy of antibiotic therapy.
PERSISTENT FEVER AND
PERSISTENT GRANULOCYTOPENIA
A major concern for the clinician dealing with
the febrile, granulocytopenic patient is what to
do with the patient with persistent granulocy-
topenia who has persistence of fever following
the administration of empiric antibiotic therapy.
The questions relate to whether the initial anti-
biotic should be continued or discontinued,
whether an additional antibacterial antibiotic
should be added, whether an antifungal agent
such as amphotericin-B should be added, or
whether polymorphonuclear leukocyte transfu-
sions should be administered [59]. Clearly,
there is no single correct answer applicable to all
patients. However, the first step should be to
repeat carefully the history and physical ex-
amination, to repeat the chest x-ray, and to re-
view the results of the original cultures with the
microbiology laboratory. More often than not,
such a careful review will reveal an infection
site, if in fact one exists. Yet, other causes of
fever must be considered: blood product trans-
fusions, a history of fever with the underlying
tumor, or drug fever from compounds such as
cytarabine or from the empiric antibiotics them-
selves. If after careful review no specific cause
for fever can be found, and the patient appears
well, it is reasonable to discontinue antibiotic
therapy [60]. Any deterioration should mandate
the reinstitution of antibiotics, but, if the patient
is likely to remain granulocytopenic for a pro-
longed period of time, the continued use of anti-
bacterial antibiotics is likely to predispose
toward the selection of resistant gram-negative
rods, yeast, or fungi. Alternatively, there may
be subtle evidence in addition to fever that sug-
gests that an infection is indeed present. These
data, plus data from surveillance cultures that
may show yeasts in the stool or filamentous
fungi in the nose in a patient who has been
granulocytopenic for a prolonged period of
time and who has had multiple recent courses of
antibiotics, may suggest the need for institu-
tion of amphotericin-B therapy [14]. Converse-
ly, the finding of resistant gram-negative rods
may suggest the need for modification of the
antibacterial antibiotics. In sum, this group of
patients, few in number yet most complex to
treat, require individualization of therapy.
PERSISTENT GRANULOCYTOPENIA WiTH
FEBRILE RESPONSE
Some patients, like the ones just described, who
have persistent granulocytopenia and have no
specific evidence of infection on history or
physical examination have a "febrile response."
This raises the question as to whether the pa-
tient was infected and, if so, whether antibiotics
should be continued [61]. The critical step is to
repeat the history and physical examination, re-
view all culture data, and repeat the chest x-ray.
If no specific evidence of infection can be deter-
mined, yet it would appear that the patient has
had a favorable response to antibiotic therapy, it
would seem reasonable to continue the antibio-
tics for a total of 7-10 days or at least until the
patient has been afebrile for 5-7 days, although
the actual appropriate duration of therapy is still
unsubstantiated [61]. If at that time the granulo-
cyte count remains very low, one must decide
whether to continue antibiotic therapy. There
is some evidence to suggest that this is an
appropriate decision [61], but it must be bal-
anced against the potential risk of predisposing
toward fungal infection [23]. My personal
approach is to discontinue antibiotics and
observe the patient very carefully.
FUNGAL INFECTIONS
The fungal infections that occur during granu-
locytopenia can be divided into those caused by
yeasts, such as Candida and Torulopsis glabrata,
and those caused by filamentous fungi, especial-
ly Aspergillus.
Candidiasis frequently begins as a localized
mucosal infection in the pharynx or the distal
esophagus. When localized, it can perhaps be
treated topically, but data for the efficacy of
ketoconazole in the setting of tissue invasion are
minimal and so one should use intravenous
amphotericin-B. The disadvantage of ampho-
tericin-B, of course, is its multitude of side
effects, including fever, shaking chills, nausea,
anorexia, and nephrotoxicity. Disseminated
candidiasis is a life-threatening, rapidly fatal dis-
ease and can be exceedingly difficult to detect in
its earliest stages. Blood cultures are frequently
 9. PRINCIPLES OF INFECTION MANAGEMENT
nonrevealing because the absolute numbers of
circulating yeasts in the blood are usually very
low, yet postmortem examination will demon-
strate involvement of liver, spleen, kidneys,
adrenals, lungs, and other organs despite re-
peatedly negative blood cultures [11]. A single
positive blood culture for Candida in a granu-
locytopenic patient should be considered
adequate evidence of disseminated candidiasis
and the patient should be treated immediately
with full-dosage intravenous amphotericin-B.
Additional clues to suggest dissemination in the
absence of positive blood cultures would be
evidence of esophagitis, presence of Candida
at multiple surveillance culture sites, persistent
fever despite antibacterial antibiotics, the occa-
sional development of biopsy-positive skin
lesion, or the rare development of endophthal-
mitis. Amphotericin-B is the drug of choice
to which 5-fluorocytosine or rifampin may be
added because of their proven synergistic
activity in animal models [62].
Torulopsis glabrata is a yeast that has charac-
teristics that resemble both Cryptococcus
neoJormans and Candida albicans. This may
help one to recall that T. glabrata, unlike Can-
dida species, tends to be a primary invader of
the lung of neutropenic patients. This is a site
from which dissemination can occur. Unlike
Candida, T. glabrata does not produce pseudo-
hyphae so that one can demonstrate organ
invasion only by histologic section. Torulopsis
glabrata must always be treated with ampho-
tericin B even for localized infections as it is
resistant to the imidiazoles, e.g., ketoconazole
or miconazole.
The filamentous fungi that cause the greatest
percentage of infections in neutropenic patients
are Aspergillus species. Most centers report A.
Jumigatus to be the most common pathogenic
species, but A. flavus has been seen with in-
creasing frequency in recent years, and in at
least some institutions has appeared to be
associated with environmental sources [14, 63].
The most common site of Aspergillus infection
is the lung with the upper respiratory passages,
especially nasal turbinates or sinuses, frequently
involved [64]. From the respiratory sites, essen-
tially any organ can become involved, but the
gastrointestinal tract and the central nervous
system are the two most frequent extrapulmo-
nary sites. Factors predisposing to infection
with Aspergillus include corticosteroid admin-
istration, and prolonged granulocytopenia with
151
associated broad-spectrum antimicrobial admin-
istration [64]. Antibiotics appear to have their
major effect by suppressing the normal flora of
the upper airways, thus allowing colonization
by environmentally present airborne spores of
Aspergillus species [14]. As a result, an early di-
agnostic clue is the presence of pathogenic spe-
cies of Aspergillus in cultures of the anterior
nares or the observation of necrotic lesions high
on the nasal turbinates. Biopsy of these lesions
will usually reveal the characteristic branched
septated hyphae of Aspergillus. This finding in
the presence of an otherwise unexplained
pulmonary infiltrate should lead to initiation of
therapy with amphotericin B.
Pulmonary infiltrates caused by Aspergillus
may be single or, more commonly, multiple and
may involve multiple lobes. A common pattern
of pulmonary infiltration is a wedge-shaped in-
filtrate that results from the propensity of A.
Jumigatus and flavus to invade large vessels,
leading to thrombosis and distal infarction. The
infection can progress slowly or rapidly, and
death is usually due either to respiratory insuf-
ficiency or to massive hemoptysis.
Appropriate treatment requires the use of
amphotericin-B in a dose of 0.6 mg/kg/day.
There is no data that 5-fluorocytosine, although
active in vitro, is useful in these patients. Mico-
nazole and ketoconazole are not active against
these organisms. There is convincing evidence
from animal models that either 5-fluorocytosine
or rifampin combined with amphotericin B is
synergistic, and combination therapy is recom-
mended for treating invasive aspergillosis [62].
There is no data on the use of granulocyte trans-
fusions, but they may be appropriate since it is
known that these infections tend to occur in pa-
tients with aplastic marrows; in vitro studies
have shown that polymorphonuclear leukocytes
destroy the hyphae of Aspergillus by encircle-
ment and direct damage by lysosomal enzymes
[65].
Mucormycosis is less common than aspergil-
losis, but follows a similar pattern as invasive
Aspergillus infections although a more aggres-
sive course is frequent and treatment is rarely
successful. Unlike the diabetic patient in whom
the most common infection is craniofacial in
distribution, the leukemia patient with granu-
locytopenia is much more likely to have a pul-
monary infection. Surgical debridement appears
more important in the management of infec-
tions caused by mucormycosis than those due to
152 II. PRINCIPLES OF MANAGEMENT

Aspergillus. Petriellidium boydii is a rare cause
of filamentous fungus infection in the granu-
locytopenic patient and, on usual histologic
preparations, cannot be distinguished from
Aspergillus [15]. However, identification of
this organism from Aspergillus in culture is im-
portant because, unlike A. flavus or fumigatus,
P. boydii is not sensitive to amphotericin B but
is susceptible to miconazole.
Infections Associated with
Cell-mediated Immunity
Defects in cell-mediated immunity, such as
those found in patients with Hodgkin's disease
or the child with acute leukemia who is receiv-
ing long-term maintenance therapy, predispose
toward infections with the following organisms
(table 9-4) [66]: bacteria-Listeria monocy-·
togenes, Salmonella spp., Nocardia asteroides,
Mycobacteria (typical and atypical), and Legio-
nella pneumophilia; viruses-varicella zoster
virus, cytomegalovirus, and herpes simplex vi-
rus, adenovirus, and Epstein-Barr virus; fungi-
Cryptococcus neoformans, Histoplasma capsula-
tum, and Coccidioides immitis; protozoa-
Toxoplasma gondii and Pneumocystis carmll;
and helminth-Strongyloides stercoralis.
Cellular immunity is important in host-graft
rejection as well as the defenses against virus,
fungi, and bacteria that are obligate intracellular
pathogens. The medical literature is confus-
ing as to the frequency of infections caused by
these organisms. Other than reactivation of
tuberculosis and herpes simplex virus and
the development of varicella zoster virus and
cytomegalovirus infection, most of these or-
ganisms infrequently cause infection, even in
the immunocompromised patient. It is in
this patient population, however, that these
infections are most likely to occur and, should
they occur, are most likely to be widespread
and life-threatening. These pathogens as a
group tend to cause four general patterns of
infection: pneumonia, central nervous system
infection, hepatitis and alimentary canal infec-
tion (table 9-5) [66].
TABLE 9-5. Clinical infectious sites of common
pathogens in patients with cellular immune
deficiency

Lung
Mycobacterium tuberculosis
Atypical mycobacteria
TABLE 9-4. Common pathogens: cellular immune Nocardia asteroides
dysfunction Legionella pneumophilia
Bacteria Cryptococcus neoformans
Listeria monocytogenes Histoplasma capsulatum
Salmonella Coccidioides immitis
Mycobacterium tuberculosis Cytomegalovirus
Atypical mycobacteria Varicella zoster virus
Nocardia asteroides Herpes simplex virus
Legionella pneumophilia Pneumocystis carinii
Strongyloides stercoralis
Fungi
Cryptococcus neoformans Central nervous system
Histoplasma capsulatum Listeria monocytogenes
Coccidioides immitis Nocardia asteroides
Cryptococcus neoformans
Viruses Varicella zoster virus
Cytomegalovirus Toxoplasma gondii
Herpes simplex
Varicella zoster Liver
Epstein-Barr virus Cytomegalovirus
Adenovirus Toxoplasma gondii
Strongyloides stercoralis
Protozoa
Pneumocystis carinii Alimentary tract
Toxoplasma gondii Salmonella
Cytomegalovirus
Helminths Herpes simplex virus
Strongyloides Strongyloides stercoralis
 9. PRINCIPLES OF INFECTION MANAGEMENT
Pneumonitis tends to be caused by Listeria
monocytogenes, Mycobacteria, Nocadia, Legion-
ella pneumophilia, the three yeasts mentioned
above, varicella zoster virus and cytomegalo-
virus, Pneumocystic carinii, Toxoplasma gondii,
and Strongyloides stercoralis. Therefore, the
finding of pneumonitis alone may not be of
much diagnostic value, although the specific
clinical-epidemiologic setting along with other
findings should narrow the possibilities further.
For example, Listeria is likely to be concurrent-
ly associated with pleural effusion, septicemia,
meningitis, or all three; M. tuberculosis is fre-
quently associated with evidence of old scarring
in the lung apices, and varicella zoster pneumo-
nitis almost never occurs in the absence of con-
current cutaneous dissemination. Nonetheless,
these infections are frequently polymicrobial
and the identification of one pathogen could be
misleading regarding the true pathogens.
Central nervous system pathogens include
Listeria monocytogenes causing a meningoen-
cephalitis, Norcardia asteroides causing local-
ized mass lesions, Cryptococcus neoformans
causing an encephalitis followed by meningitis,
Toxoplasma gondii causing mass lesions, men-
ingoencephalitis, or both, and varicella zoster
virus causing meningoencephalitis.
Infections along the alimentary canal include:
Salmonella, which causes an enteritis in patients
with bowel tumors; cytomegalovirus-induced
esophagitis, small bowel inflammation or
colitis; herpes simplex virus-induced distal eso-
phagitis; or enterocolitis due to infection by
Strongyloides stercoralis.
Those organisms that have a predominance
for skin manifestations include varicella zoster
virus-induced chickenpox or "shingles," herpes
simplex virus lesions, usually near the mouth,
nose, or perineum, and the secondary skin
manifestations of many organisms including
Nocardia, Cryptococcus, or Histoplasma.
The list of organisms that tend to cause infec-
tion in the setting of cellular immune deficiency,
and the fact that many different organisms can
be associated with any given clinical picture such
as pneumonitis or enteritis, require that inten-
sive diagnostic procedures (frequently invasive,
with associated tissue biopsy) be performed
promptly so that the correct therapy can be in-
stituted. Obviously, the approach to treatment
of these infections varies widely, depending
upon the etiologic agent. Epidemiologic consid-
erations in association with the clinical picture
153
and initial diagnostic clues can assist in design-
ing a rational approach to empiric therapy.
Infections caused by M. tuberculosis, herpes
simplex virus, and P. carinii can now be effect-
ively prevented through the use of isoniazid,
acyclovir, and TMP-5MZ, respectively [67, 68].
Epidemiologic considerations are important for
prophylaxis of infections such as Legionella,
Strongyloides, and the fungal infections that are
seen among patients with cellular immune de-
ficiency.
Infections Associated with Humoral
Immune Deficiency
Patients who have defects in humoral immunity
(multiple myeloma, chronic lymphocytic leuke-
mia) tend to have infections for which antibody
is the major means of infection prevention, i.e.,
Streptococcus pneumoniae, Hemophilus in/luen-
zae, and (rarely) Neisseria meningitidis [69].
Antibody production against S. pneumoniae is
depressed following bone marrow transplanta-
tion and these patients tend to have an increased
risk of pneumonococcal infection [70]. Patients
who have had a splenectomy for any cause,
including trauma or as a diagnostic procedure
(staging laparotomy for, e.g., Hodgkin's dis-
ease) are at an increased risk of infection with
these same organisms. Although pneumococcal
bacteremia appears to be quite unusual even in
the splenectomized patient with Hodgkin's dis-
ease, it is important to recall that a very small
but real percentage of patients may develop
the "overwhelming pneumococcal sepsis syn-
drome." This has been reported sporadically in
adults in whom an overwhelming septicemia
without apparent origin of infection leads to
the patient's demise in a matter of a day or
less. The syndrome mimics the Waterhouse-
Friderichsen syndrome described with mening-
ococcal sepsis and has also been seen occasional-
ly as a result of Hemophilus in/luenzae sepsis
in splenectomized patients. Therefore, patients
who have had a splenectomy should be advised
that the sudden onset of fever and chills should
prompt immediate medical attention and physi-
cians should be aware that immediate hospita-
lization with institution of intravenous ampicil-
lin (to cover S. pneumoniae, H. in/luenzae, and
N. meningitidis) is appropriate except in those
settings where ~ -lactamase-positive H. in/luen-
zae are prevalent (in which case, chlorampheni-
color moxalactam should be effective).
154 II. PRINCIPLES OF MANAGEMENT
Infections Associated with
Obstruction of Natural Passages
Any lesion that partially obstructs a natural pas-
sage, be that a bronchus, biliary duct, ureter or
urethra, eustachian tube, or sinus ostia, may
lead to infections, such as pneumonia, ascending
cholangitis, urinary tract infection, otitis, or
sinusitis. Obstructions are the most common
causes of infection in patients with solid tumors
or lymphomas. The organisms causing infection
will be those colonizing the patient at or near
the site so that pneumonitis is likely to be
caused by normal mouth flora unless the patient
has been on broad-spectrum antimicrobials or
has been hospitalized for prolonged periods.
Ascending cholangitis is likely to be caused by
enteric gram-negative bacilli, group-D strepto-
cocci, and anaerobes, and urinary tract infection
is also likely to be caused by aerobic gram-
negative rods colonizing the stool. Although
antimicrobial therapy is important, the critical
issue for resolution of these infections is the
alleviation of the obstruction.
Infections Associated with Central
Nervous System Dysfunction
Major abnormalities associated with central ner-
vous system dysfunction that lead to infection
are diminution or loss of the gag reflex with
development of aspiration pneumonitis or
impaired micturition with residual urine and
secondary urinary tract infection. These are
usually very difficult infections to resolve
because of persistence of the neurologic deficit.
Pneumonia is therefore a common cause of
death in patients with primary or metastatic
brain tumors.
Iatrogenic Procedures
INFECTIONS ASSOCIATED
WITH PROCEDURES
Infection morbidity and mortality are common-
ly associated with invasive procedures. An in-
dwelling urinary catheter is the most common
source of nosocomial infection in the general
hospital population, and this is no exception for
the patient with cancer. Not only will catheter
avoidance dramatically reduce the incidence of
urinary tract infection, but it will substantially
reduce the incidence of bacteremia. The associa-
tion of bacteremia and, to a lesser extent, funge-
mia with an indwelling intravascular catheter is
well known. The relatively simple procedures of
utilizing a butterfly-type needle when a venous
catheter is not absolutely essential (i.e., most of
the time) and changing the catheters every 2-3
days when they are in fact indicated will reduce
the frequency of these catheter-associated bac-
teremias. Respiratory assist units are also associ-
ated with nosocomial infection because gram-
negative bacilli are capable of colonizing and
multiplying in a nebulizer from which they can
be forcibly blown into the patient's tracheo-
bronchial tree. Proper attention to cleaning and
maintenance of respiratory assist equipment
will reduce the frequency of such necrotizing
pneumonia.
INFECTIONS ASSOCIATED
WITH INFUSIONS
One of the most common iatrogenic causes of
infection is related to blood and blood product
administration, with resultant non-A/non-B
hepatitis and, less frequently, infections caused
by type-B hepatitis, cytomegalovirus, Epstein-
Barr virus, or Toxoplasma gondii. Less common
are infections associated with contamination
of physiologic fluids, such as the nationwide
epidemic of Enterobacter bacteremia ten years
ago that was related to contamination during
manufacturing of intravenous fluids. Rarely,
gram-negative bacteria can contaminate plate-
lets or other blood products.
Infection Prevention
As with diagnosis and its therapy, infection
prevention first requires recognition of the fac-
tors that predispose to infection. A specific
approach to infection prevention can then be di-
vided into four categories: First, improve the
patient's damaged host defense mechanisms
wherever possible; second, reduce the frequen-
cy of invasive procedures that will further com-
promise the patient's ability to defend against
microbial invasion; third, reduce the acquisition
of potential pathogens; and, fourth, reduce the
numbers of potential pathogens already col-
onizing the patient [71].
BOLSTER HOST DEFENSES
Unfortunately, little can be done to improve the
patient's own host defense mechanisms other
than instituting rapid and effective treatment to
 9. PRINCIPLES OF INFECTION MANAGEMENT
induce total remission of the underlying cancer
with consequent restitution of normal bone
marrow function and restoration of the normal
mucosal integrity. The influenza vaccine may be
useful, not because influenza is more common
in cancer patients, but because the infected pa-
tient may be more likely to develop a superim-
posed serious bacterial pneumonia. At this time,
there are no other useful vaccines and it should
be recalled that attenuated live viral vaccines,
e.g., measles, rubella, mumps, and oral polio,
should be avoided. Currently under study is a
live, attenuated varicella zoster virus vaccine. It
appears to be effective prophylaxis. Further
studies will be required to define its safety and
effectiveness.
REDUCE INVASIVE PROCEDURES
Butterfly needles should be used for peripheral
venous access, changed every 48 h, and inserted
with proper skin preparation. Urinary catheters
should be avoided if at all possible. Venipunc-
tures, fingersticks, and bone marrow aspirations
should be performed with critical attention to
skin cleansing and should be followed by a few
minutes of local pressure to hasten clot forma-
tion and lessen blood extravasation into tissues,
which will reduce the ideal growth media for
the invading microorganisms.
REDUCED ORGANISM ACQUISITION
The major routes of organism acquisition in
order of importance are the hands of medical
and paramedical staff, food, water, and air. The
most basic infection prevention technique is
handwashing by staff members. A 15-s wash
with regular soap under running water is suf-
ficient to remove most transient organisms.
Food is the second most common source of ac-
q uired organisms, especially green leafy vege-
tables, tomatoes, and fresh fruit that are heavily
colonized with gram-negative bacilli [19]. A
low-microbial-content diet can be prepared by
any hospital dietary service by simply using
only fully cooked foods, pasturized liquids, and
foods and beverages certified as "commercially
sterile" such as most canned vegetables, meats,
sodas, and some fruit juices. Salads and fresh
fruits should be avoided during the patient's
granulocytopenic period.
Water supplies from city sources have rel-
atively few viable organisms, but faucet aera-
tors may introduce large numbers of hydrophil-
ic gram-negative bacilli such as P. aeruginosa or
155
Serratia marcescens. A simple approach is to
either remove the faucet aerator permanently
or be sure that it is removed and cleansed of
organic debris weekly.
Finally, air is the source of spores such as
Aspergillus or of particles that carry respiratory
viruses, S. aureus or M. tuberculosis. Other than
isolation of patients expectorating potential
pathogens such as the patient with S. aureus
pneumonia, there is relatively little that can be
easily done about most airborne organisms
short of laminar air-flow reverse isolation. The
laminar air-flow room represents the ultimate
method for total reverse isolation. The essential
components include a room with a bank of
high-efficiency particle air (HEPA) filters along
one entire wall of the room through which air is
pumped by blowers at a uniform velocity forc-
ing it to move in a laminar pattern and exiting at
the opposite end of the room. The result is
essentially sterile air in the room, minimal air
turbulence, minimal opportunity for micro-
organism buildup, and a consistently clean
environment. To complete the isolation, sterile
water and sterile or low-microbial-content food
along with sterile supplies are utilized, and staff
members and visitors must don sterile garments
prior to entry and remain downstream from the
patient. Despite the proven efficacy of such an
approach, the cost [72], increased staff work
load, and increased psychological stress that
the patient suffers have not allowed this
technology to be used universally.
SUPPRESSION OF COLONIZING
ORGANISMS
Important areas to control in the granulocy-
topenic patient are the flora of the alimentary
canal and those of the skin. Daily bathing and
shampooing with an antiseptic solution such as
chlorhexidine or povidone-iodine will substan-
tially reduce skin infections. Since most other
infections originate from the alimentary tract
flora, suppression of the aerobic organisms
from mouth to anus will likewise substantially
reduce infections. Although oral nonabsorbable
antibiotic combinations, such as gentamicin,
vancomycin, and nystatin, have been proven
efficacious, there are side effects with their use
[72]. The most notable disadvantages are the
acquisition of aminoglycoside-resistant gram-
negative rods and poor patient compliance
due to the disagreeable taste. An alternative
approach is to use oral agents that selectively
156 II. PRINCIPLES OF MANAGEMENT
suppress the aerobic potential pathogens,
leaving intact the anaerobic flora that in turn
will assist in preventing colonization with
other newly acquired organisms (i.e., maintain
"colonization resistance") [73]. The most com-
monly used regimen today is trimethoprim-
sulfamethoxazole (TMP-SMZ) plus nystatin,
but, although proven to be efficacious [74], this
combination has no effect against some impor-
tant bacteria such as P. aeruginosa and may have
some potential for delaying the return of normal
numbers of granulocytes following chemother-
apy [75]. Finally, it is important to observe
patients carefully for the acquisition of TMP-
SMZ-resistant organisms, and the development
of subsequent fungal infections [67, 75].
Suppression of Potentially
Reactivating Organisms
Suppression of colonizing potentially pat~o­
genic organisms is important for the patient
who is granulocytopenic; similarly, the suppres-
sion of pathogens that remain dormant within
the host and that can be reactivated by the
cellular immunosuppression associated with
chemotherapy, radiation, malnutrition, and the
primary neoplastic disease is of equal impor-
tance. The need for isoniazid prophylaxis for
the patient with a positive tuberculin skin test,
or with previously untreated but inactive pul-
monary tuberculosis, is clear. Despite the risk
in the older-aged cancer population of isoniazid
hepatitis, this preventative measure should
not be overlooked. While TMP-SMZ is im-
portant as an infection prevention modality for
patients with granulocytopenia [74], it is also
critical for the patient with cancer and cellular
immune deficiency. These patients have a pre-
disposition to develop P. carinii (i.e., marrow
transplant recipient, acute lymphocytic leuke-
mia). TMP-SMZ prophylaxis can be a highly
effective and safe prophylaxis [67].
The patient undergoing marrow transplan-
tation, or induction chemotherapy for acute
leukemia who prior to therapy is seropositive
for antibody to herpes simplex virus has a 60%-
80% chance of developing a reactivation of this
viral infection once therapy is initiated [26, 27].
These viral reactivations, while usually mild in a
normal individual, are responsible in immuno-
suppressed patients for frequently prolonged
and severe infections with significant associated
morbidity, including pain, ulceration (site of
secondary bacterial and fungal infections), and
decrease in the patient's ability to maintain his
own oral nutrition. Acyclovir, a new, minimally
toxic but effective antiviral agent has been found
to be virologically and clinically effective for the
suppression of viral reactivation [26, 68].
Summary
The patient with cancer has become one of the
most frequently encountered immunocom-
promised hosts. The wide range of neoplastic
diseases now being treated with intensive com-
bination chemotherapy and radiation allows
for a heterogeneous patient population that is
at an increased risk of infection because of the
presence of a number of different predisposing
factors. Yet an understanding of the factors
that increase the risk of infection, and the patho-
gens, and principles involved in the diagnosis,
treatment, and prevention of such infections,
allows for the orderly and intelligent approach
to the problem of infections in patients with
cancer.
References
1. Schimpff SC: Infections in the compromised
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JE (eds) Principles and practice of infectious
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2. Remington JS: The compromised host. Hosp
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Quantitative relationships between circulating
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 9. PRINCIPLES OF INFECTION MANAGEMENT
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14. Aisner J, Murillo J, Schimpff SC, Steere AC:
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15. Winston DJ, Jordan MC, Rhodes J: Allescheria
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18. Murillo J, Schimpff SC, Brouillet MD: Axillary
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25. Schimpff SC: Surveillance cultures. J Infect Dis
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26. Saral R, Ambinder RF, Burns WH, et al.: Acy-
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27. Meyers JD, Flournoy N, Thomas ED: Infection
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28. Vaughan WP, Saral R, Anderson LR, Burke PJ:
The frequency and pattern of cytomegalovirus
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30. Wade JC, Wiernik PH, Schimpff SC, Hoofnagle
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413-422,1983.
31. Williams DM, Krisk JA, Remington JS: Pulmo-
nary infection in the compromised host. Am
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32. Abdallah PS, MarkJBD, Merigan TC: Diagnosis
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33. Springmeyer SC, Silvestri RC, Sale GE, et al.:
The role of trans bronchial biopsy for the diag-
nosis of diffuse pneumonias in immmunocom-
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34. McDonald GB, Sharma P, Sale G, et al.: Infec-
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after marrow transplantation. Gastroenterology
82:1127,1982.
35. Whitecar JP, Luna M, Bodey GP: Pseudomonas
bacteremia in patients with malignant disease.
Am J Med Sci 260 :216-223, 1970.
36. Umsawasdi T, Middleman EA, Luna M, Bodey
GP: Klebsiella bacteremia in cancer patients. Am
J Med Sci 265:473-482,1973.
37. Klastersky J. Cappel R, Daneau D: Clinical
significance in in vitro synergism between anti-
J biotics in gram-negative infections. Antimicrob
158 II. PRINCIPLES OF MANAGEMENT
Agents Chemother 2:470-475,1972.
38. Lau Wk, Young LS, Black RE, Winston DJ, Lin-
ne SR, Weinstein RJ, Hewitt WL: Comparative
efficacy and toxicity of amikacin/carbenicillin
versus gentamicinl carbenicillin In leukopenic
patients: a randomized prospective trial. Am J
Med 62:959-966, 1977.
39. Love LJ, Schimpff SC, Schiffer CA, Wiernik PH:
Improved prognosis for granulocytopenic
patients with gram-negative bacteremia. Am J
Med 68:643-648,1980.
40. Wade JC, Schimpff SC: Antibiotic therapy for
febrile granulocytopenic patients. In: Klastersky
J, Staquet MJ (eds) Combination antibiotic ther-
apy in the compromised host, vol 9. New York,
Raven, 1982, pp 125-146.
41. Smith CR, Lipsky JJ, Laskin OL, Hellmann DB,
Mellits ED, Longstreth J, Lietman PS: Double-
blind companson of the nephrotoxicity and
auditory toxicity of gentamicin and tobramycin.
N EnglJ Med 302:1106-1109,1980.
42. Stuart RK, Braine HG, Saral R, Lietman PS,
Fuller DJ: Carbenicillin-trimethoprim-sulfame-
thoxazole versus carbenicillin-gentamicin as
empiric therapy of infection in granulocytopenic
patients: a prospective randomized, double-
blind study. AmJ Med 68:876-885,1980.
43. Grose WE, Bodey GP, Rodriguez V: Sulfame-
thoxazole-trimethoprim for infections in cancer
patients. JAMA 237:352-354,1977.
44. Wade JC, Schimpff SC, Newman KA, Fortner
CL, Standiford HC, Wiernik PH: Piperacillin
or ticarcillin plus amikacin: a double-blind
prospective comparison of empiric antibiotic
therapy for febrile granulocytopenic cancer pa-
tients. Am J Med 71 :983-990, 1981.
45. Winston DJ, Ho WG, Young LS, Hewitt WL,
Gale RP: Piperacillin plus amikacin therapy
versus carbenicillin plus amikacin therapy in
febrile, granulocytopenic patients. Arch Intern
Med 1663-1667, 1982.
46. Wade JC, Schimpff SC, Newman KA, Fortner
CL, Moody MR, Young VM, Wiernik PH:
Potential of mezlocillin as empiric single-agent
therapy In febrile granulocytopenic cancer
patients. Antimicrob Agents Chemother 18:299-
306, 1980.
47. De J ongh CA, Wade J C, Schimpff SC, Newman
KA, Finley RS, Salvatore PC, Moody MR,
Standiford HC, Fortner CL, Wiernik PH:
Empiric antibiotic therapy for suspected infec-
tion in granulocytopenic cancer patients: a com-
parison between the combination of moxalactam
plus amikacin and ticarcillin plus amikacin. AmJ
Med 73:89-96,1982.
48. Pickard W, Durack D, Gallis H: A randomized
trial of moxalactam versus tobramycin plus ticar-
cillin (T + T) in 50 febrile neutropenic patients
[abstr 5]. In: 22nd interscience conference on .
antimicrobial agents and chemotherapy, Miami
Beach, Florida, 4-6 October 1982, p 66.
49. Joshi J, Ruxer R, Newman K, Finley R, Moody
MR, Drusano G, Tenney J, Schimpff SC: Dou-
ble b-lactam versus an amino glycoside +b-
lactam combination as empiric therapy for gra-
nulocytopenic cancer patients [abstr 383]. In:
24th interscience conference on antimicrobial
agents and chemotherapy, Washington DC, 8-
10 October 1984, p 158.
50. Sanders C, Sanders WEJr, Goering RV: In vitro
antagonism of beta-lactam antibiotics for cefox-
itin. Antimicrob Agents Chemother 21 :968-975,
1982.
51. Kuch NA, Testa RT, Forbes M: In-vitro and
in-vivo antibacterial effects of combinations of
beta-lactam antibiotics. Antimicrob Agents
Chemother 19:634-638,1981.
52. Moody MR, Young VM, Thadepalli H: Anti-
microbial synergism of piperacillin and gentami-
cin against Pseudomonas aeruginosa, Staphylo-
coccus aureus and Streptococcus faecalis. Che-
motherapy 26:21-27,1980.
53. Wharton RC, Sprecher SL, Moody MR,
Schimpff SC: In-vitro interaction of piperacillin
and ceftazidime on clinical isolates of Enterobac-
teria, Pseudomonas aeruginosa and Staphylococ-
cus aureus. In: Spitzy KH, Karrer K (eds) pro-
ceedings of the 13th international congress of
chemotherapy, Vienna, 28 August-2 September
1983, SE 2.11/1-4, 48/12.
54. Winston DJ, Barnes RC, Ho WG, Young LS,
Champlin RE, Gale RP: Moxalactam plus piper-
acillin versus moxalactam plus amikacin In
febrile granulocytopenic patients. Am J Med
77:442-450,1984.
55. De Jongh C, Joshi J, Newman K, et al.: Mox-
alactam plus piperacillin or amikacin: empiric
antibiotic therapy for febrile, neutropenic cancer
patients [abstr 943]. In: Proceedings of the 22nd
intcrscience conference on antimicrobial agents
and chemotherapy, American Society for Micro-
biology, Miami Beach, Florida, 1982.
56. Pizzo P, Thaler M, Hiemenz J, Cotton D,
Hathorn J, Commers J, Gress J, Marshall D,
Longo D, Browne M: Monotherapy vs. com-
bination antibiotics for the initial empiric man-
agement of febrile (F+) granulocytopenic (G+)
cancer patients [abstr 380]' In: 24th interscience
conference on antimicrobial agents and che-
motherapy, Washington DC, 8-10 October
1984, p 158.
57. Schiffer CA; Principles of granulocyte transfu-
sion therapy. Med Clin North Am 61:1119-
1131,1977.
58. Ziegler EJ, McCutchanJA, Fierer J, Glauser MP,
Sadoff JC, Douglas H, Braude AI: Treatment of
gram-negative bacteremia and shock with human
antiserum to a mutant Escherichia coli. N Engl J
 9. PRINCIPLES OF INFECTION MANAGEMENT
Med 307:1225-1230,1982.
59. Pizzo PA, Robichaud KJ, Gill FA, Witesbsky
FG: Empiric antibiotic and antifungal therapy
for cancer patients with prolonged fever and
granulocytopenia. AmJ Med 72:101, 1982.
60. Joshi JH, Schimpff SC, Tenney JH, Witerbsky
FG, Leving AS, Deisseroth AB, Glaubiger DL,
MacLowery JD, Magrath LT, Poplack DG,
Simon RM: Can antibacterial therapy be discon-
tinued in persistently febrile, granulocytopenic
cancer patients without demonstrable infection?
AmJ Med 76:450-457,1984.
61. Pizzo PA, Robichaud KJ, Gill FA, Newman
KA, Dejongh CA: Duration of empiric antibio-
tic therapy in granulocytopenic patients with
cancer. AmJ Med 67:194, 1979.
62. Kitahara M, Seth VK, Medoff G, Kobayashi GS:
Activity of amphotericin-B, 5-fluorocytosine
and rifampin against six clinical isolates of Asper-
gillus. Antimicrob Agents Chemother 9:915-
919,1976.
63. Aisner J, Schimpff SC, Bennett JE, Young VM,
Wiernik PH: Aspergillus infections in cancer
patients: association with fireproofing materials
in a new hospital. JAMA 235:411-412,1976.
64. Young RC, BennettJE, Vogel CL, Carbone, PP,
De Vita VT: Aspergillosis: the spectrum of the
disease in 98 patients. Medicine 49:147-173,
1970.
65. Diamond RD, Krzesicki R, Epstein B, Welling-
ton J: Damage to hyphal forms of fungi by hu-
man leukocytes in vitro: a possible host defense
mechanism in aspergillosis and mucromycosis.
Am J Pathol 91 :313-323, 1978.
66. Wade JC, Schimpff SC: Infections in patients
with suppressed cellular immunity. In: Klasters-
ky J, Staquet MJ (eds) Medical complications
in cancer patients. New York, Raven, 1981,
pp273-290.
67. Hughes WT, Kuhn S, Chaudhary S, Feldman S,
Verzosa M, Aur RJ, Pratt C, George SL: Suc-
159
cessful chemoprophylaxis for Pneumocystis
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1426,1977.
68. Wade JC, Newton B, Flournoy N, Meyers JD:
Oral acyclovir prophylaxis of herpes simplex
virus infection after marrow transplant. Ann
Intern Med 100:823-827, 1984.
69. Fahey JL, Scoggins R, UtzJP, Szwed CF: Infec-
tion, antibody response and gamma globulin
components in multiple myeloma and macro-
globulinemia. AmJ Med 35:698,1963.
70. Winston DJ, Schiffman G, Wang DC, Feig SA,
Lin CH, Marso EL, Ho WG, Young LS, Gale
RP: Pneumococcal infections after human bone
marrow transplantation. Ann Intern Med 91:
835-841,1979.
71. Schimpff SC: Infection prevention in patients
with cancer and granulocytopenia. In: Grieco
MH (ed) Infections complicating the abnormal
host. New York, Yorke Medical Books, 1980,
pp926-950. .
72. Schimpff SC, Greene WH, Young WM, Fortner
CL,Jepsen L, Cusack N, BlockJB, Wiernik PH:
Infection prevention in acute nonlymphocytic
leukemia: laminar air flow room reverse isolation
and oral, nonabsorbable antibiotic prophylaxis.
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73. Van der Waaij D, Verhoef J: New criteria for
antimicrobial therapy: maintenance of digestive
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cerpta, 1979.
74. Pizzo PA, Schimpff SC: Strategies for the pre-
vention of infection in the myelosuppressed or
immunosuppressed cancer patient. Cancer Treat
Rep 67:223-234,1983.
75. WadeJC, Dejongh CA, Newman KA, Crowley
J, Wiernik PH, Schimpff SC: Selective anti-
microbial modulation as prophylaxis against in-
fection during granulocytopenia: trimethoprim-
sulfamethoxazole vs. nalidixic acid. J Infect Dis
147:624-634, 1983.
III. DIAGNOSIS AND
MANAGEMENT OF
HEAD AND NECK
NEOPLASIA
 10. INITIAL DETECTION AND
EVALUATION: INTRAORAL
NEOPLASMS

Douglas E. Peterson
C. Daniel Overholser, Jr.
Stewart A. Bergman
Todd Beckerman

This chapter reviews the principles and techni- structures and palpate the neck in their patients,
ques used to detect and evaluate intraoral can- particularly those individuals at risk. By virtue
cer. These concepts have direct clinical impor- of their training, dentists are the individuals
tance; survival rates, which vary with site, can be most integrally involved with oral health and
improved with early detection (figure 10-1) [1- disease. Thus, the responsibility for early recog-
7J. In addition, many people see their dentist nition of oral pathologic changes is frequently
routinely, thereby providing the opportunity theirs.
for early detection. These clinicians should thus
carefully and regularly examine all intraoral Anatomic Considerations for
Intraoral Cancer
The complex anatomic structure of the oral cav-
ity has a direct influence on the course of oral
cancer in a patient (figure 10-2 and tables 10-1
ILl
to 10-3); 80% of all intraoral malignant tumors
~ occurring in patients in the United States arise
<r from the tongue or floor of the mouth [8J.
...J
Malignant tumors of this region spread local-
§;
:;: 40
ly by direct extension along and through the
<r
:>
rJ)
30 anatomic planes formed by the muscles and
ILl
o Lip
their associated fascia, and by lymphatics to re-
> 20 gional lymph nodes in the neck. Epidermoid
§ • Tongue
o Oropharynx (squamous cell) carcinomas, which account
• Other Mouth
~ t::. Floor of Mouth for approximately 90% of intraoral cancers,
metastasize late in their natural history; ade-
100~.J.1--'--'-!.....!:5--'-.J.....JL...J.....J10::-'-.J.-L..J.-:I5':--'---'-..J.....J~:--...J
nocarcinomas of salivary glands metastasize
YEARS AFTER DIAGNOSIS earlier.
All muscles in the floor of the mouth either
FIGURE 10-1. Relative survival rates for epidermoid attach to the hyoid bone or insert into the
carcinoma of the oral cavity for patients diagnosed tongue (figure 10-2). Several muscles, such as
1950-1973. With permission from Sonis ST, Fazio the genioglossus, geniohyoid, and mylohyoid
RC, Fang LC: Principles and practice of oral medi- muscles, attach to the arch of the mandible. The
cine. Philadelphia, WB Saunders, 1984, p. 487. presence of these muscles and their associated
Peterson et al., HEAD AND NECK MANAGEMENT OF THE CANCER PA TIENT.
© 1986. Martin.s NijhofJ Publishing. All rights reserved. 163
 A

tJiga\lril:
(anterior belly)

submental lymph nodes

digaslric
(anterior lar lymph node

digastric muscle
(posterior belly)
 10. INITIAL DETECTION AND EVALUATION: INTRAORAL NEOPLASMS 165

TABLE 10-1. Anatomic distribution of oral carcinoma TABLE 10-3. Estimated new cancer cases in 1984 by
primary site and sex
Number of
Anatomic site patients Percentage Total Male Female
Lower lip 5399 38 Buccal cavity and
Tongue 3117 22 oropharynx 27,500 18,700 8000
Floor of mouth 2479 17
Gingiva 923 6 Lip 4900 4200 700
Palate 786 5.5 Tongue 4900 3200 1700
Tonsil 673 5
Upperlip 553 4 Salivary gland
Buccal mucosa 245 2 Floor of mouth
Uvula 78 0.5 Other sites 9800 5800 4000

Total 14,253 100 Oropharynx 7900 5500 2400

From Cancer statistics, 1984. CA 34:14, 1984.
From Shafere' at. [15], p. 113; as modified from Krolls SO, Hoffman
S: Squamous cell carcinoma of the oral soft tissue: a statistical analy-
sis of 14, 253 cases by age, sex, and race of patients. J. Am. Dent.
Assoc. 92:571, 1976.
severe trismus are common presenting com-
plaints, arising from invasion of the palatoglos-
TABLE 10-2. Estimated 1984 oropharyngeal cancer sus, styloglossus, and hyoglossus muscles.
incidence rate per 100,000 by primary site and sex

Total Male Female Patient History

A thorough assessment of the patient begins
Buccal cavity and with a careful history, in which the history of
oropharynx 11.7 8.0 3.7 present illness as well as underlying medical,
Lip 2.1 1.8 0.3 dental, social, and family histories are developed.
Tongue 2.1 1.4 0.7 Pain, bleeding, obstruction, and/or presence or
sensation of a mass should be recorded. No
Salivary gland such symptoms may be present, however;
Floor of mouth intraoral cancer can be asymptomatic until it
Other sites 4.2 2.5 1.7
becomes secondarily infected or reaches an
Oropharnyx 3.3 2.3 1.0 advanced stage.
The history may be of importance in the
determination of associated risk factors that
fascia usually prevent extension of tumors into alert the clinician to the potential for malignant
the submental area until the later stages of disease. Risk factors associated with intraoral
disease. The mandibular arch slows extension cancer include chronic alcohol use, chronic
laterally, since tumor must first penetrate the trauma, tobacco use (cigarettes, pipes, cigars,
periosteum and then spread through bone be- smokeless tobacco), occupational exposure to
fore invading the buccal soft tissues. Although carcinogens, family history of cancer or immune
bony invasion can occur, invasion of the body deficiencies, leukoplakia/ erythroplakia, history
of the tongue and spread posteriorly into the of oral cancer or cancer at other sites, and
submandibular glands and pharynx is much (possibly) herpes simplex virus I infection and
more likely. Limitation of lingual mobility and syphilis. Identification of these factors in the
patient history should alert the clinician [9, 10].
Although many patients may be unaware of
intraoral cancer, some patients who are aware of
FIGURE 10-2. The complex anatomic structure of the
symptoms may deny that any pathologic condi-
oral cavity. (A) 'Frontal and (B) saggital views; (C)
inferior view of floor of the mouth muscles and their tion exists. The word "cancer" is encountered
attachments. With permission from Vidic B, Melloni regularly by most patients because of both
BJ: Applied anatomy of the oral cavity and related broad societal emphasis on the difficulties of
structures. Otolaryngol Clin North Am. 12:3-14, cancer management, as well as education of the
1979. public by medical and dental groups. Because
166 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
of fear, patients may be reluctant to seek pro-
fessional advice on an intraoral lesion and
thus delay evaluation and/or treatment. This
is unfortunate, as prognosis will often be less
favorable.
On the other hand, dentists and physicians
may encounter the "cancerophobic" patient,
who presents for evaluation with only the
slightest of symptoms. While the possibility of
cancer exists, many times the patient's fears are
unfounded, and observation and reassurance are
sufficient.
In summary, history may be of considerable
value when evaluating risk factors, treatment,
and overall prognosis.
Examination
Accurate assessment can be achieved by de-
tailed, systematic intraoral examination with
a methodical sequence. Proper positioning of
both the patient and the examiner, a good light
source for direct and indirect visual examina-
tion, and proper supplies are essential.
Lips and perioral structures should be ex-
amined for ulceration, bleeding, white lesions,
or localized swelling. Dentures should then be
removed if present. Utilizing bidigital palpa-
tion, a mirror, and good lighting, the examiner
can then retract the right buccal mucosa,
observing color, texture, and presence of thick-
ening, friability, keratotic areas, or ulcers. This
combined palpation-inspection technique can
then be used as the maxillary labial mucosa and
left buccal mucosa are examined (figure 10-3),
returning to the mandibular labial mucosa. The
FIGURE 10-3. Use of mirror and bidigital palpation
permits examination of buccal mucosa. Other
intraoral structures can be examined using direct or
indirect vision. (see Chapter 24)
FIGURE 10-4. Palpation of anterior cervical lymph
nodes is achieved through proper positioning of
patient.
alveolar mucosa and gingiva, as well as hard
and soft palates, can be visualized using the
mirror. The lateral borders of the tongue can
be examined by placing a 2" X 2" gauze on the
anterior third and reflecting it to either side.
Examination of the posterior one-third is
critical, since this is the most common site
for epidermoid carcinoma in the oral cavity
[7J; even though the patient may be slightly un-
comfortable and gag upon palpation, the area
must be thoroughly examined. Finally, the
floor of the mouth and the ventral tongue can
be visualized by having the patient raise the
tongue toward the palate, and drying the
mucosa with 2" X 2" gauze.
Extraoral tissues must be examined as well.
As with intraoral examination, following a
methodical sequence is critical to successful
examination. Palpation of the multiple lymph
node groups (e.g., digastric, submental, sub-
mandibular, anterior and posterior cervical, and
pre- and post auricular) is essential (figure 10-4).
Characteristics of clinically detected nodes
should also be noted, including pain, size, num-
ber of nodes, laterality, consistency, encapsula-
tion, and fixation; classic metastatic lymph node
involvement is characterized by painless, hard,
and/or fixed nodes. The size of lymph nodes is
also significant in staging and prognosis.
A single site within the oral cavity may drain
to several groups of lymph nodes. Lymph
drainage of the tongue frequently crosses the
midline, and bilateral lymph node involvement
may occur with tumors near the midline. Num-
ber and size of the involved lymph nodes and
determination of laterality are therefore of
much greater prognostic value than lymph node
 10. INITIAL DETECTION AND EVALUATION: INTRAORAL NEOPLASMS
location. Regardless of the site of primary
tumor, the presence of an enlarged lymph node
proved histologically positive is an ominous
finding in any patient with epidermoid carcino-
ma, since survival rates for these patients are
approximately 50% of survival rates for patients
whose tumors are confined to the primary site
[6]. Prognosis is particularly poor when nodal
involvement is multiple or contralateral, or
when tumor erodes through the node capsule
into the soft tissues of the neck. Palpation of
any other neck masses should be similarly noted
as to size, extent, location, and texture.
Neurologic integrity may be determined by
testing for paresthesia/anesthesia, which can
be delineated initially using the tactile ("pin-
prick") method. Decreased sensation (especially
of sudden onset without clear cause) following
the branches of the fifth cranial nerve may
suggest tumor infiltration in a patient with
either primary or metastatic disease in the head
and neck. In addition, referred ear pain occurs
frequently in patients with head and neck can-
cer, including that within the oral cavity. The
reader is referred to chapter 11 for more detailed
discussion of the extraoral examination.
Appearance of Intraoral
Precancerous and Cancerous Lesions
As noted earlier, intraoral cancer is often pain-
less until late in its progression; most lesions are
detected upon routine clinical examination.
Although primary epidermoid cancer is clas-
sically defined as having "raised," indurated
borders and central necrosis, many variations
from this appearance may be encountered [lI-
B]. Conversely, many noncancerous changes in
the oral cavity may be confused with cancer
[14] (table 10-4). Indeed, the only rule with
cancer is that "there are no rules."
Leukoplakia ("white patch") (figure 10-5)
should be used only as a clinical descriptor for a
white plaque that cannot be removed by gentle
rubbing and for which no etiology can be
identified [15]. If leukoplakia is noted, history
of risk (e.g., smoking, alcohol use, trauma,
or chronic irritation) can be of some value in
determining the significance of the lesion. If the
clinician feels the lesion may be reversible,
10- to 14-day recall may be appropriate. If the
lesion has not resolved at this point, biopsy and
histologic diagnosis are indicated since up to
167
TABLE 10-4. Intraoral lesions that may clinically
appear as cancer
Syphilitic glossitis
Granulomatous lesions
Gumma (syphilis), tuberculosis
Leukoplakia
Erythroplakia .
Erythroleukoplakia
Vincent's ulceration
Apthous ulceration
Indolent traumatic ulceration
Giant cell tumor
Papilloma, benign tumor, mixed tumor
Wart
Fibroma
Hyperplasia
Lymphangioma
Chronic tonsillitis
Supratonsillar abscess, palatal abscess
Candidiasis
Nicotine stomatitis
Lichen planus
Reticular
Erosive
Vesiculobullous
Pemphigus
Benign mucous membrane pemphigoid
Erythema multiforme
6% of oralleukoplakias undergo malignant trans-
formation [9].
Erythroplakia ("red patch") (figure 10-6) and
erythroleukoplakia ("mixed lesion") (figure
10-7) are frequently cancerous [16]; although
encountered less frequently than leukoplakia,
these lesions should be aggressively pursued.
Differential diagnosis should include vesiculo-
bullous disease (pemphigus, benign mucous
membrane pemphigoid), as well as erythema
multiforme and ulcerative lichen planus.
Frankly cancerous intraoral lesions present in
a variety of ways. Epidermoid carcinomas can
present as exophytic, ulcerative, or infiltrative/
invasive lesions; verrucous carcinoma, a well-
differentiated epidermoid carcinoma, normally
presents as an exophytic lesion, while other
epidermoid carcinomas present as superficial,
spreading, ulcerative, or infiltrating lesions.
Accessory salivary gland tumors present as
indurations in the mucosa and submucosa.
Lymphomas present as smooth surface lesions
covered by stretched, shiny mucosa that is
occasionally ulcerated. Melanomas generally
present as pigmented, indurated lesions; however,
168 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA

A A

B
B

FIGURE 10-5. (A) Leukoplakia of lateral border of

tongue. (8) Biopsy revealed well-differentiated
epidermoid carcinoma. (150X, H&E)

pigmentation may be absent (i.e., amelanotic

melanoma). Metastatic tumors have varied
appearances, but occur mostly in submucosal
or intramuscular sites.

Diagnostic Techniques
Several diagnostic techniques may be useful in
determining the nature of the observed lesion
(table 10-5). One must remember that, although
most oral cancers are primary, metastases to the
oral cavity from nonoral malignancies can occur
[17, 18]. Thus, particularly in a patient with a
history of cancer, the clinician must be aware of
risk of oral involvement. Further, diseases such
as acquired immune deficiency syndrome may
present with neoplastic manifestations, such as
oropharyngeal Kaposi's sarcoma [19].
Careful examination, including radiographs,
pulpal evaluation (percussion, electrical and
c
FIGURE 10-6 (A) Erythroplakic lesion (arrows) in
floor of mouth. (8) Positive cytology exhibiting
pleomorphic cells with large, hyperchromatic nuclei.
x 250, Papanicolaou. (C) Biopsy revealed infiltrat-
ing, moderately-differentiated epidermoid carcinoma.
x 150, hematoxylin-eosin.
thermal testing), culturing (microbial, viral, fun-
gal) andlor serology will often be sufficient to
confirm the presence of noncancerous change.
However, if these above tests are equivocal, or
suspicion of cancer remains, biopsy is indicated.
 10. INITIAL DETECTION AND EVALUATION: INTRAORAL NEOPLASMS 169

TABLE 10-5. Comparison of nonradiologic diagnostic

techniques

Primary Primary
advantage/s disadvantage/s

1. Biopsy
IncisionalMinimal surgical Requires definitive
intervention; follow-up treat-
usually per- ment; false nega-
mits definitive tives may occur
diagnosis
Excisional Removes clinical Primary closure
lesion; usual- may be difficult
Iypermits to achieve; dif-
A definitive ficult to find site
diagnosis of a small lesion
that is complete-
Iyexcised
Fine needle Conservative; Generally restricted
minimal tumor to salivary
cell dissemina- glands, lymph
tion; minimal nodes; may not
pain be representative
Punch Minimal surgical May not be repre-
intervention; sentative; should
usually per- be followed by
mits definitive definitive
diagnosis surgery
2. Cytology
B Smear Quic~, nonin- High false-negative
vasive and false-
positive rates
FIGURE 10-7. (A) Erythroleukoplakic lesion (arrows)
Needle Quick, nonin- High false-negative
on lateral border of tongue. (B) Biopsy revealed
vasive rates
moderately-differentiated eeidermoid carcinoma.
(IS0X, H&E) 3. Toluidine Quick, nonin- False positive to
blue vasive; useful trauma, ulcera-
for determin- tion, granuloma-
BIOPSY ingwhereto tous disease
In general, excisional biopsy (figure 10-8A-C) biopsy
is preferred for small lesions (less than 3 mm in
diameter), while incisional biopsy (figure 10-
8D) is reserved for larger lesions. mucosa in close proximity to bone, cartilage,
Some clinicians feel that the individual and teeth, as well as sites of necrosis should
performing the excisional biopsy should be be minimized. Improper technique may result
prepared to assume responsibility for sequelae in tumor cell dissemination [21].
and subsequent management should the need In general, biopsy technique is relatively sim-
arise [20]. Although some controversy exists ple. Following delivery of a few drops of local
regarding this point, many clinicians feel anesthetic solution at the periphery of the le-
that incisional biopsy should be used when a sion, a number-IS scalpel handle and blade are
lesion is suspected of being malignant, and ex- used to create an elliptical (excisional) or wedge-
cisional biopsy should be used only for small, shaped (incisional) incision. The specimen must
benign lesions. Care must be observed in select- include both normal and abnormal tissue, for
ing the extent of removal, including depth, to histologic comparison. The tissue is placed in
minimize postbiopsy complications while at 10% formalin and sent to the pathology service.
the same time providing maximal opportunity A careful description of the specimen, as well as
to detect neoplasia if present. Removal of brief clinical history, name, age, and sex of the
170 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
A B
FIGURE 10-8. (A) Leukoplakia on the buccal mu-
cosa. (8) Excisional biopsy resulted in complete
clinical removal of lesion. (C) Sutures were placed, and
the patient was dismissed. Final diagnosis was con-
sistent with chronic irritation secondary to cheek-
biting. No cancerous changes were detected. Photo-
graphs courtesy of Dr. Duane De Yore. (D) Incision-
al biopsy of ventral tongue lesion.
patient should be included in the report.
Biopsy of accessory salivary gland tumors is
the same as for other oral lesions. Since the
overlying mucosa may be intact, one must
obtain sufficient depth to include the tumor
under the mucosa. If the tumor is very small and
is totally removed, the area must be well demar-
cated in case larger excision is subsequently
required.
Punch biopsy (figure 10-9) is an alternative
biopsy technique that utilizes a 5-mm instru-
ment inserted to the depth of 2-3 mm [4].
However, care must be taken to obtain clean
margins, using a "twisting" technique. Suturing
is usually not required. Fine-needle biopsy
(figure 10-10) may also be utilized in certain
instances. Commonly used for base of tongue,
lymph node, and salivary gland tumors, this
technique is preferred when concern exists
about potential tumor cell dissemination that
might result with other biopsy techniques. A
22-gauge needle, a special holder for 10- or
20-ml syringe, and conventional fixation and
staining techniques are used [4]. A multiple-
hole needle biopsy technique may be used
for removal of multiple specimens [22], as in
 10. INITIAL DETECTION AND EVALUATION: INTRAORAL NEOPLASMS
FIGURE 10-9. Punch biopsy technique. Use of a
twisting motion to a depth of 2-3 mm will usually
result in clean wound margins.
FIGURE 10-10. Fine-needle biopsy technique is useful
for biopsy of lesions of base of tongue. Photograph
courtesy of Dr. E.G. Elias.
detection of occult primary tumor of the
oropharynx.
Careful interpretation of the results of biop-
sy is critical regardless of technique used. One
must remember that a negative pathology report
should be considered carefully. If the clinician
remains suspicious that cancer is present, he/she
·should request that additional "cuts" be read by
171
the pathologist, or perform a second biopsy.
Both diligence and persistence remain essential
to the accurate assessment of the patient
suspected of having intraoral cancer.
OTHER TECHNIQUES
There are several techniques that, in certain cir-
cumstances, may be useful in the diagnosis and
evaluation of oral cancer. These techniques are
not substitutes for biopsy and histopathologic
diagnosis, but may be used as adjuncts to clini-
cal examination, for screening and biopsy site
selection, and in cases where a patient refuses
biopsy on the basis of a clinical examination
alone.
Exfoliative Cytology. This technique utilizes
superficial mucosal cells that have been col-
lected, fixed on a microscopic slide, and stained
(figure 10-11). Since most (95%) of oral cancers
are of epithelial origin, this technique may be
useful in sampling a suspicious lesion or oral
sites in a high-risk patient in a noninvasive way.
Possible results of cytologic examinations are
listed in table 10-6 [4]. When a negative report is
received, continued clinical suspicion should
mandate further cytology, or, preferably,
biopsy.
Toluidine Blue. Toluidine blue (tolonium
chloride) is a metachromatic dye that is fixed by
FIGURE 10-11. Obtaining specimen for cytologic
examination of lesion (arrow). No malignant cells
were detected.
172 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA

TABLE 10~6. Report of smear

Positive Criteria for malignant cellular

change are observed.
Negative No malignant cells are observed in
the specimen. These cells may
appear atypical but do not de~
monstrate malignant criteria. In
the event of continued clinical
suspicion or persistence of a
lesion, a negative report should
not be taken as conclusive. This
is particularly true in hyper~
keratotic lesions.
Suspicious or Cells seen that do not fulfill the
inconclusive malignant criteria adequately A
to allow a positive report, yet
reveal enough deviation from
normal to indicate follow~up
studies should be performed.
Inadequate Either cellular morphology is not
preserved adequately for inter~
pretation, or the presented
material is too scanty to be
a representative specimen.
From Silverman [4], p. 40.

cellular DNA and RNA [23-27] (figure 10-12).

Because of chromatin abberations, malignant
cells, unlike normal cells, will retain the dye
following attempted decolorization with acetic B
acid. This property enables toluidine blue to be
used as an aid in distinguishing between malig-
nant and nonmalignant lesions. When the dye is
applied to the epithelium of a malignant lesion
and viewed clinically, the area will appear dark
blue.
A toluidine-blue mouth rinse can be used as a
screening procedure for the detection of asymp-
tomatic, clinically occult epidermoid carcinoma
of the mouth and oropharynx in high-risk pa-
tients. The sensitivity of the toluidine-blue rinse
in detecting asymptomatic lesions with subtle
clinical signs is as high as 91 % [27]. This is im-
pressive considering that lesions of this type
would most likely remain undetected until they c
become symptomatic. However, the clinician
must use precision in following proper proce- FIGURE 10~12. Toluidine-blue staining technique to
dure, and, as with any clinical test, be experi- identify dysplastic or malignant tissue. (A) Small le-
sion in floor of mouth (arrow). (8) Dye is applied
enced in evaluating the results.
to floor of mouth. (C) After decoloration with 1%
Direct, in vivo application of toluidine blue to acetic acid, dye is retained in malignant site but not in
persistent erythroplastic oral lesions has been leukoplakic areas. This lesion was determined to be
used successfully as an adjunct to clinical ob- epidermoid carcinoma based upon subsequent his-
servation in deciding which of the lesions tologic examination. Photographs courtesy of Dr. Sol
should be investigated further for the presence Silverman, Jr.
 10. INITIAL DETECTION AND EVALUATION: INTRAORAL NEOPLASMS
of epidermoid carcinoma. The sensitivity of the
dye for detecting noninvasive dysplastic lesions
is considerably less. False-positive findings
occur with traumatized tissue, ulceration, and
granulomatous disease, as well as normal fili-
form papillae; however, Silverman et al. report
that in their experience the uptake of dye at the
margins of benign ulcerations is usually well-
defined, as opposed to ragged, diffuse uptake
patterns with dysplastic or malignant lesions
[27].
Thus, toluidine blue can be useful in identify-
ing those areas in a suspicious lesion that are
likely to provide the most productive biopsy
material for histopathologic diagnosis. As with
any technique, however, a negative finding
in the setting of clinically suspicious disease
should dictate further diagnostic pursuits.
Evaluation of the Patient
Once the diagnosis of a cancerous lesion is
made, the patient must be further investigated
for local and regional extent of the disease, as
well as for systemic involvement. Such evalua-
tions are essential to plan the appropriate ther-
apeutic approach and determine prognosis.
The evaluation of the head and neck cancer
patient includes both clinical and radiologic in-
vestigations, which, when synthesized, can lead
to a final decision for therapy and prognosis.
CLINICAL EVALUATION
In addition to the clinical history and physical
examination discussed previously, other evalua-
tions necessary are listed below:
1. Initial therapy: Determination should be
made as to whether surgery or radiation therapy
is to be the initial therapeutic approach.
2. Surgical reconstruction: The extent of the
defect and the methods for reconstruction
should be evaluated if surgery is contemplated.
3. Endoscopy: Some surgeons strongly feel
that endoscopic examination of the larynx,
hypophyarynx, nasopharynx, esophagus, and
trachea must be performed routinely in patients
diagnosed to have head and neck cancer. This
philosophy has developed because of the strong
evidence of a synchronous secondary primary
in these patients [28], and should be considered
for each patient.
4. Nutritional status: The nutritional needs of
the cancer patients must be considered and met.
173
Nutrition in the patient with compromised oral
function is reviewed in chapter 26.
5. Laboratory evaluation: Complete periph-
eral blood count, with white cell differentia-
tion and actual platelet counts, should be obtained
to determine whether the patient is anemic,
leukopenic or thrombocytopenic. Recently,
Elias (unpublished data) has also suggested
that the initial lymphocyte and monocyte levels
in peripheral blood, prior to other initiation
of therapy, may have prognostic value. In his
observation, patients with early stages of epider-
moid carcinomas and those with no regional
lymph node metastasis have higher lymphocyte
and lower monocyte levels, compared with
those with stages III and IV who have regional
lymph node metastasis. They have also observed
higher incidence of recurrence rates in the first
year after therapy in patients who have low
initial lymphocyte levels.
Coagulation studies (at least PT and PTT)
must be obtained to ensure no bleeding tenden-
cies. Complete blood chemistries should also be
reviewed, including serum electrolytes, blood
urea nitrogen, serum creatinine, liver function
tests, serum calcium, and phosphorus. Such data
will help document the nutritional status of the
patient and evaluate possible hepatic or renal
damage due to the disease or other underlying
factors. If the liver function tests are abnormal,
a liver scan is in order to rule out liver metas-
tasis. Electrocardiagram in addition to clinical
cardiac evaluation is helpful in evaluating the
cardiac status.
6. Immunologic evaluation: Immunologic
techniques may be useful in the diagnosis of cer-
tain oral premalignant [29] or malignant lesions;
at present, they represent useful research tools.
For example, antibody to herpes simplex virus
(HSV) may be elevated in patients with un-
treated oral cancer; in one study, IgM antibody
to HSV I was higher in these patients than in
patients with either acute or recurrent herpetic
infections or age-matched controls [30]. In addi-
tion, successful treatment of the oral cancer at
least one year prior resulted in no continued
elevation of levels of IgM antibody to HSV-I.
These data suggest that cancer of the mouth is
associated with expression of HSV-I antigens
that stimulate one immunoglobin class (lgM)
compared with another (IgG); HSV I may play
a role in the pathogenesis of oral cancer [31].
Monitoring of antibody levels may play a
role in evaluating premalignant and malignant
174 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
FIGURE 10-13. CT scan demonstrating epidermoid
carcinoma of the hard palate with invasion of the
maxillary sinus. Photograph courtesy of Dr. E.G.
Elias.
disease, as well as possible outcome of therapy.
The role of tumor cell markers in monitoring
presence, extent, and delineation following
therapy is not widely used at present, however,
and the existence of a specific marker for neo-
plasia debatable [32].
RADIOGRAPHIC EVALUATION
Deep fixation of tumor may be suggested upon
palpation; bone and/or cartilage may be in-
volved. Further diagnostic techniques should be
considered to permit precise delineation of
tumor [33] (See chapter 12).
Routine radiographs (panoramic radiograph,
lateral jaw, sinus films) serve initially to localize
a suspected lesion. Chest films should then be
obtained to rule out lung metastasis. This is
helpful if the physical examination or the symp-
toms suggest involvement of base of the skull,
mandible, or paranasal sinuses. Tomography
may be more helpful in determining precise
levels of bone infolvement, although it has
generally been replaced by computerized tomo-
graphy (CT) scanning.
CT scanning often yields the best results in
determining the extent of the disease, since it
permits more definition of osseous structures
adjacent to the lesion as well as extensions into
nasal and paranasal sinuses, base of skull, and
surrounding structures (figure 10-13) [34, 35].
Further, it can be used to rule out chest metas-
tases. It is also being used to determine the field
of irradiation; some radiation therapy machines
are equipped with computers to translate the
CT scan findings directly into the planned treat-
ment fields.
Angiography is not used routinely to evaluate
head and neck masses (figure 10-14). It may be
utilized, however, to evaluate large tumors in
relation to vital structures and their relation to
major blood vessels. Also, it may help docu-
ment invasion at the base of the skull. Angio-
grams may also be used to guide catheter place-
ment for chemotherapy infusion. They are
rarely used in differential diagnosis of tumors
such angioma, angiosarcomas, and chemodecto-
mas. Similarly, sialograms are not presently
commonly used; they are occasionally utilized
to differentiate an inflammatory process from a
neoplasm in the salivary glands.
Nuclear magnetic resonance (NMR) imaging
is a relatively new technique that has several dis-
tinct advantages over other imaging techniques
(figure 10-15) [36]. It does not utilize ionizing
radiation and is not affected by overlying bone
and gas; further, multiple planes can be imaged
without extra reconstruction time. However,
several difficulties with this technique are also
apparent, not the least of which is its inability to
demonstrate calcium deposits.
 10. INITIAL DETECTION AND EVALUATION: INTRAORAL NEOPLASMS 175

FIGURE 10-14. Arteriogram of patient with angiofi-

broma of the nasopharynx. Note degree of vascular-
ization. Photograph courtesy of Dr. J. Mirvis.

Because of the costs involved in its use as well

as its experimental nature, NMR is presently
available only in a few centers. It will predict-
ably be a valuable diagnostic tool, but much re-
search is needed before its clinical applicability
is determined. Its usefulness for imaging of
tumors of the head and neck remains to be
developed.
Nuclear scanning by measuring uptake of
radio labeled technetium-99 and gallium-67 is FIGURE 10-15. NMR imaging demonstrating para-
useful in characterizing tumor-specific changes. thyroid adenoma (arrow). No intensification tech-
Also, scanning of liver and bone is indicated if niques were used. Such imaging may be useful in the
serum alkaline phosphatase is elevated. Nuclear future for detection of intraoral neoplasia. Photo-
scans are generally more sensitive than conven- graph courtesy of Dr. E. George Elias.
tional diagnostic radiographs, and may be posi-
tive when conventional films are negative. positive; lesions this size can usually be char-
However, the technetium-99 scans are less spe- acterized clinically with a reasonable degree of
cific; infection, trauma, and inflammation can accuracy. The reader is referred to chapter 12
produce positive scans in addition to malignant for more detailed discussion.
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Radiology 124:75-80, 1977.
36. Lipuma JP, E1 Yousef SJ, Haaga JR, Alfidi RJ,
Bryan PJ, Resnick MI: Introduction to renal
nuclear magnetic resonance imaging. In: Javad-
logic cancer. Baltimore, Williams and Wilkins,
1983, pp 265-271.
37. Smith NJ, Teates CD, E1-Mahdi AM, et al.: The
value of gallium-67 scanning in the evaluation of
head and neck malignancy. Laryngoscope 85:
778-786,1975.
 11. INITIAL DETECTION AND
EVALUATION: EXTRAORAL
NEOPLASMS
Allen D. Hillel
Charles W. Cummings
The incidence of cancer of the upper respiratory
system is about 5% of all cancers. Each year an
estimated 35,000 new head and neck cancers
occur. Males are more than twice as frequently
affected than females. One of the most critical
factors in the management of these malignancies
is their early detection, which can result in
significantly decreased morbidity (functional
and cosmetic) and mortality.
Head and neck cancer can be categorized
in two broad nonanatomic areas. The majority
of upper respiratory system malignancies is
squamous cell carcinoma, nearly always arising
from the respiratory epithelium. Less frequent-
ly, nonsquamous cell malignancies of many his-
tologic varieties occur in the salivary glands,
thyroid gland, sinuses, lymph nodes, and other
tissues in the head and neck.
Squamous cell carcinoma of the upper re-
spiratory system occurs most frequently in the
lip; it occurs in the tongue, floor of mouth, ton-
sil, and larynx in decreasing incidence. General-
ly, specific criteria are used for establishing the
extent of the disease in the upper respiratory
system. Staging according to these criteria [1]
is performed in each case usually by means of
endoscopic evaluation under general anesthesia
(see appendix). This thorough examination
allows for precise evaluation of tumor size and
tumor location, and also allows for discovery of
a separate synchronous primary that occurs in
10%.-20% of cases. The spread of squamous
cell carcinoma in the upper respiratory system is
usually predictably to cervical lymph nodes,
which are also included in the staging examina-
tion.
Peterson et aI., HEAD AND NECK MANAGEMENT OF THE CANCER PATIENT.
© 1986. Martinus NijhofJ Publishing. All rights reserved.
Although staging in nonsquamous cell car-
cinomas of the head and neck also relies on
evaluation of location and cervical spread,
histologic diagnosis additionally plays an
importa',lt role in establishing treatment and
prognoS1S.
While definite etiologic factors in the de-
velopment of head and neck cancers have not
been ascertained, a number of predisposing
factors have been associated with specific malig-
nancies. Perhaps the most strongly associated
carcinogen is cigarette smoking [2], which is
almost always associated with cases of
squamous cell carcinoma of the oral cavity,
oropharynx, and hypopharynx. Alcohol is
another chemical carcinogen that has strong
associations with these same cancers. Betel nut
chewing has also been related to squamous cell
carcinoma of the buccal mucosa.
The Epstein-Barr virus has been implicated
with nasopharyngeal carcinoma. There is also a
suspicion that woodworking has an association
with nasopharyngeal carcinoma. Luetic glossitis
can be one of many etiologies of oral tongue
cancer (see chapter 10), and exposure to nickel
compounds might be associated with sinus can-
cers. There has been a rather definite correla-
tion between low-dose radiation exposure and
the occurrence many years later of thyroid car-
cinomas. As with most malignancies in hu-
mans, however, the origin of the disease process
in head and neck cancer remains unclear.
Squamous cell carcinoma of the upper respira-
tory system does, in a few cases, develop with
no known underlying factors. In any case, an
accurate history of social habits and job-related
179
180 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
exposure remains an important factor in eval-
uating these patients.
Presentation
The length of the illness before diagnosis is
variable, depending upon the individual, the
location of the tumor, and the aggressiveness
of the tumor. Presenting symptoms include
pain, bleeding, dysphagia (difficulty in swallow-
ing), odynophagia (pain upon swallowing),
otalgia (ear pain), hoarseness, nasal obstruc-
tion, hemoptysis, and ill-fitting dentures. Many
cancers, both of the squamous and nonsqua-
mous types, present as asymptomatic masses in
the neck or parotid regions. Sinus tumors can
present with symptoms of persistent infection,
and cancers in the nasopharynx or other areas
of the base of skull can present with loss of
specific cranial nerve function. In most cases
of squamous cell carcinoma, a history of sig-
nificant weight loss is usually part of the pre-
sentation.
Since most of these tumors can be silent in
their early stages, a complete head and neck ex-
amination by the dentist and family physician is
essential to diagnose the smaller, more treatable
lesions.
Evaluation
When the diagnosis of a head and neck cancer
is suspected, a thorough history of the present
illness with attention to predisposing factors
is important. In addition, a complete medical
history is essential to allow the physician to
FIGURE 11-1. Examination cabinet with instruments
for head and neck examination.
consider the overall health of his patient when
devising a treatment plan.
A thorough examination with appropriate
instruments is the next step when evaluating a
patient with suspected head and neck can-
cer (figure 11~1). For example, the presence or
absence of trismus as well as tongue mobility
can indicate the extent of disease in the oral
cavity and oropharynx. The mobility of the
vocal cords is a significant prognostic sign
of laryngeal cancer. The position of and/or
symptoms associated with the teeth can be an
indicator of bone involvement. Otologic ex-
amination can yield indirect evidence of naso-
pharyngeal involvement. Cervical examination
with bimanual palpation, when necessary, is
important in the establishment of nodal disease
(see Appendix).
While endoscopic evaluation is critical in
most cases, other diagnostic procedures need to
be performed before the tumor is anatomically
affected by endoscopic manipulation and biop-
sy. Radiographic studies are currently playing a
greater role in tumor evaluation. Computerized
axial tomography, arteriography, plain x-rays,
tomography, contrast radiography, and radio-
isotope studies have in many cases been indispen-
sable in tumor evaluation. Magnetic resonance
imaging appears to be a very promising means
of noninvasive examination.
Endoscopy and biopsy are the mainstays of
tumor evaluation, especially with mucosal carci-
nomas. The surgical pathologist plays a key role
in establishing tumor diagnosis. Histologic
diagnoses from another institution should be
verified by one's own pathologist. Salivary
gland and thyroid masses do not offer easy
access for biopsy, and surgical removal of the
mass is often necessary to establish the diagno-
sis. In these cases, intraoperative frozen-section
diagnosis can help the surgeon decide whether a
more extensive resection is necessary in a par-
ticular case. Recently, fine-needle aspiration of a
mass has been found to provide a preoperative
diagnosis in some cases.
Although distant metastasis of head and neck
cancers is not common, a basic metastatic work-
up should be part of every patient's pretreat-
ment evaluation. Appropriate blood studies
should be obtained, and all patients should have
a chest x-ray examination. Bone scans or liver/
spleen scans may be useful in patients with ad-
vanced disease.
 11. INITIAL DETECTION AND EVALUATION: EXTRAORAL NEOPLASMS 181

Treatment
The treatment plan for specific head and neck
malignancies is discussed elsewhere in this
text. As discussed, the treatment of cancers
involves three basic modalities of treatment:
surgery, radiation therapy, and chemotherapy.
Surgical excision is a frequently employed treat-
ment. The challenge of surgery is not only
adequate excision but also reconstruction of
function and preservation of cosmesis. Radia-
tion therapy is an effective tool in the treatment
of head and neck cancers, especially squamous
cell carcinomas, and is frequently used either
primarily for smaller lesions or in planned com- FIGURE 11-2. Indirect nasopharyngeal examination
bined therapy with surgical excision. Chemo- with mirror.
therapy, although very effective in many in-
dividual cases of head and neck malignancies,
does not have as yet a clearly defined role in
nerve palsy. Cervical node involvement is
the management of head and neck cancers. Nu-
common due to the rich lymphatic supply to
merous protocols are under way to evaluate
the nasopharynx. Histologically, the cancers
chemotherapy's place in the management of
are usually poorly differentiated squamous cell
squamous cell carcinomas.
carcinomas or lymphoepitheliomas. Due to
Evaluation and treatment of the patient with
the anatomic limits of the nasopharynx, neo-
head and neck cancer is best done by a team
plasms can infiltrate into the adjacent areas,
approach. In addition to the head and neck
such as the base of skull, orbit, eustachian tubes,
surgeon, radiation therapist, and medical onco-
nasal cavity, and even the intracranial cavity.
logist, the treatment group should include a
Nasopharyngeal carcinomas have a predilec-
prosthodontist, speech therapist, dietitian, tion for occurrence in Chinese; those people
psychosocial worker, and a specialized nursing born in China have a greater than 100-fold inci-
team. Consideration must be given to the func-
dence of disease compared with Caucasians.
tional and cosmetic defects a patient will suffer North American-born Chinese have only
as a result of his cancer treatment. When devis- sevenfold greater incidence than Caucasians
ing a treatment plan, specific attention must be [3]. In Hong Kong, nasopharyngeal carcinoma
paid to each patient's physical as well as emo- represents 18% of all malignant neoplasms
tional ability to undergo the rigors of therapy. [4] as compared with 0.25% in a worldwide
Consideration needs to be given to the patient's (Caucasian) survey [5].
age (physical, not chronological age) and the pa- Routine clinical examination of the naso-
tient's mental status. In some cases, although a pharynx is most easily performed by indirect
cure is not probable, a vigorous treatment plan mirror examination. This is performed by de-
will be undertaken in order to extend the "good pressing the tongue with tongue blades and
quality of life" of the patient. In other cases,
using a small mirror placed behind the soft
vigorous treatment will be offered in the hopes
palate (figure 11-2). An excellent view of the
of preventing the unrelenting pain of an un-
nasopharynx can also be obtained by use of
controlled primary, hoping that the patient
fiberoptic telescopes placed intraorally or in-
might instead succumb to a relatively painless
tranasally. If necessary, under local anesthetic and
distant metastatic process.
intravenous sedation, catheters can be placed
into the nose and drawn out through the mouth
Nasopharynx for purposes of retraction of the soft palate.
Nasopharyngeal carcinoma presents most Biopsies can be taken transorally or transnasally
frequently with an asymptomatic neck mass, with specially designed forceps. In some cases, a
nasal obstruction, nasal bleeding, unilateral general anesthetic is necessary to provide an
serous otitis media, or, less commonly, cranial adequate examination.
182 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
Radiographic studies can also be useful in
determining the presence or extent of naso-
pharyngeal disease. A soft-tissue lateral x-ray can
offer a general outline of the nasopharyngeal
area, but usually is effective only to demonstrate
large tumors. Plain radiographs of the base of
skull as well as tomograms can be effective in
determining bony erosion. Computerized axial
tomography can provide an excellent view of
the nasopharyngeal and base of skull area, and
perhaps is the most useful radiographic study of
the nasopharynx [6J.
The inaccessibility of the nasopharynx as well
as its intimate involvement with many crucial
structures at the base of skull render surgical
treatment ineffective. Radiation therapy is often
very effective in controlling and curing naso-
pharyngeal carcinomas. Although the cervical
area bilaterally is usually included in radiation
fields, surgical treatment is sometimes employed
also for control of neck disease.
Oropharynx
The oropharynx includes the soft palate, pala-
tine arches, tonsillar fossa, tonsillar pillars, re-
tromolar trigone, base of tongue, vallecula, and
pharyngoepiglottic folds. Patients with carcino-
mas in the oropharynx most commonly present
with a sore throat, neck mass, oral bleeding, and
weight loss. The malignant gradient increases as
the origin of the cancer moves posteriorly in the
oral cavity and reaches the oropharynx [7J.
Thus, cancers of the base of tongue are usually
more extensive (60%-70% are Tr T 4 ) and are
more biologically aggressive than buccal mu-
cosa or alveolar ridge cancers. The most striking
feature of oropharyngeal cancers is the high
proclivity for neck metastasis. Soft palate has
an incidence of 40% neck metastases; tonsillar
pillars greater than 50%; the retromolar trigone
and base of tongue up to 70% [8]. There is a
significant incidence of bilateral and contralater-
al metastases due to the rich lymphatics of the
area. There is also a high incidence of a second
primary in the upper aero digestive system. The
cure rates, especially for the larger tumors, are
not high. Treatment tends to be combined
surgery followed by planned radiation therapy.
The oropharyngeal area is best evaluated by
direct and indirect examination in the clinic.
The use of a head mirror frees both hands of the
examiner, and with two tongue blades a thor-
ough intraoral examination can be achieved
FIGURE 11-3. Reflecting head mirror allows examiner
to use two tongue blades for intraoral examination.
(figure 11-3). In addition, a large laryngeal mir-
ror can be used to examine the base of tongue
area. Intraoral palpation and bimanual palpation
(one finger inside of the mouth pressing against
the hand under the chin) are very useful in
determining the extent of disease, especially
when it is submucosal. For highly suspected or
biopsy-proven disease, an examination under
general anesthesia should be performed to allow
for a more accurate estimate of the extent of
disease.
Radiographic studies can provide some
additional information in the evaluation of
oropharyngeal tumors. Occlusal views can be
helpful in determining involvement of the inner
table of the mandible. A panorex is an excellent
screening radiograph to determine bone in-
volvement. Mandibular tomograms are useful to
examine the mandible in greater detail. Com-
puterized axial tomography is helpful in deter-
mining the extent of disease in the base of
tongue area.
In the tonsil and tonsillar region, the cancers
present most commonly in men in the seventh
decade. Tonsils are relatively insensitive, and
there is a paucity of symptoms in early tumors.
A sore throat may be the only symptom, and
the first clinical indication of disease is often a
neck metastasis. Extension is common locally
and early; 50% will have neck metastases [9].
In the palate, pain frequently is a presenting
symptom. Trismus indicates deep infiltration.
Metastasis to the neck is not uncommon and, in
about 25% of cases, presents in the contralateral
neck [10J.
In the base of tongue, the cancers tend to be
asymptomatic in the early stages and therefore
 11. INITIAL DETECTION AND EVALUATION: EXTRAORAL NEOPLASMS 183

usually present as large tumors. The tongue has

a rich lymphatic supply, and neck metastases are
not uncommon and are not infrequently bilater-
al. The cure rate for large base of tongue cancers
is rather low.
A more detailed description of initial detec-
tion and evaluation of intraoral neoplasms is
given in chapter 10; appropriate staging is pre-
sented in the Appendix.

Hypopharynx
The hypopharynx, as an anatomic area, is de-
fined as extending from the superior margins FIGURE 11-4. Indirect laryngeal examination with
of the epiglottis to the inferior border of the mirror.
cricoid. The posterior lateral wall, the pyriform
sinus, and the postcricoid area are the three sub-
divisions. Early hypopharyngeal cancers are
relatively asymptomatic. Attention needs to be
paid to patients' complaints in order to fuake an
early diagnosis. Early symptoms are ear pain
(referred), persistent sore throat, or pain on in-
gestion of hot foods and liquids. Late symptoms
are dysphagia, voice changes, neck nodes, ody-
nophagia, difficulty handling saliva, and weight
loss. Posterior pharyngeal wall cancers ate often
large and fungating. In one study, 80% were
greater than 5 cm in diameter when first dis-
covered [11]. These cancers are frequently
associated with second primaries.
Examination of the hypopharynx can be per- FIGURE 11-5. Laryngeal examination with rigid
formed in the clinical setting by use of a head fiberoptic telescope.
mirror and laryngeal mirrors. A laryngElal mir-
ror is placed against the posterior pharyngeal
wall, elevating the soft palate as the examiner extent of disease.
holds the patient's tongue forward and instructs Postcricoid carcinomas tend to be very
the patient to breathe (figure 11-4). Phonation aggressive. Patients tend to present late, and
during this examination is helpful in position- there is a high incidence of a secondary primary
ing the larynx such that the pyriform sinuses in the pharynx or esophagus. There is also a sig-
open. Fiberoptic telescopes are also useful in nificant occurrence of metastases to mediastinal
examining the hypopharynx (figure 11-5). nodes [12].
Rigid telescopes can be passed through the Pyriform sinus carcinomas are the most fre-
mouth or flexible telescopes can be passed quent hypopharyngeal cancers [13]. They are
through the anesthetized nose and directed usually asymptomatic and are frequently large
downward beyond the epiglottis. A direct laryn- when discovered. They can be locally extensive
goscopy performed under general anesthesia is into the endolarynx, to the aryepiglottic folds,
essential in determining the extent of hypo- or to the postcricoid mucosa. There is a very
pharyngeal lesions. high incidence of neck metastases. The cure rate
Soft-tissue x-rays of the hypopharynx are for pyriform sinus cancer is low.
occasionally useful in demonstrating a tumor;
barium contrast radiographs are much more
useful in determining the presence and extent of Larynx
a hypo pharyngeal lesion. Computerized axial Anatomically, the larynx can be divided into
tomography is also useful in demonstrating the three areas: the supraglottis, the glottis, and the
184 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
subglottis. The supraglottis includes the vallecu-
la, the false cords, the aryepiglottic folds, as well
as the glottic surface of the epiglottis. The glot-
tic area refers to the vocal cords proper, and the
subglottic area to the area immediately below
the vocal cords.
Since minor alterations of the configuration
of the vocal cords significantly affect speech
quality, laryngeal cancers usually present rather
early. Hoarseness is the most common present-
ing symptom.
The vocal cords can be seen in most patients
by indirect mirror examination. While using a
head mirror, the examiner grasps the patient's
tongue and places a laryngeal mirror against the
posterior pharyngeal wall while elevating the
soft palate (figure 11-4). The examiner instructs
the patient to phonate, which elevates the
larynx, and brings the epiglottis forward and
the vocal cords into view. Rigid and fiberoptic
telescopes can also be useful in examining
the more difficult patients (figure 11-5). Direct
laryngoscopy under general anesthesia again
plays an essential role in determining the extent
of disease.
Radiographic evaluation by means of barium
contrast studies can be helpful, especially when
a laryngogram is performed. This is done by
essentially having the patient aspirate barium
and then cough it up over the mucosa of the
larynx. The barium coating provides an outline
radiograph of the upper trachea and larynx
which is effective in outlining any irregularities.
Computerized axial tomography is also a useful
modality for examining the glottic and subglot-
tic areas.
Since the glottis has a poor lymphatic sup-
ply and is enclosed in a cartilagenous vault,
laryngeal carcinomas rarely metastasize to the
neck. The sub glottis and supraglottis have a
more abundant lymphatic supply and metas-
tases are more common. Classifications of
laryngeal carcinoma are based primarily upon
location and cord mobility (see Appendix). Ex-
tension to more than one site tends to indicate a
poor prognosis, as does a fixed vocal cord or
one with impaired mobility [14]. Tumors that
extend from the supraglottis to the subglottis
are called trans glottic and tend to have poorer
prognoses. Small laryngeal carcinomas tend to
have a very high cure rate with radiation ther-
apy alone. Larger tumors warrant a combined
treatment approach with both surgery and
radiation therapy. Partial laryngeal surgery with
voice preservation is an option in some cases
while total laryngectomy is employed for more
extensive lesions. Communication rehabilita-
tion is by esophageal speech, electrolaryngeal
devices, or created tracheoesophageal fistulas.
Nasal Cavity and Paranasal Sinuses
Carcinoma of the nasal cavity and paranasal
sinuses comprises 3% of malignancies involving
the upper respiratory tract. Carcinoma of the
maxillary sinus occurs in 1 per 200,000 people
per year [15]. Sinus tumors present most
commonly with facial pain (47%), facial swell-
ing (37%), or nasal obstruction (26%) [16].
Neck nodes are present in about 10% of
patients. Since sinus malignancies frequently
present with symptoms similar to a chronic
inflammatory condition, patients are frequently
treated for sinus infections for a long period of
time. The average delay between the onset of
symptoms and final diagnosis is about six
months [15]. Carcinomas of the nasal cavity and
paranasal sinuses occur most commonly in the
maxillary sinus. Cancers can arise in the
ethmoid sinus, and from there can involve the
frontal or sphenoid sinuses. Squamous cell
carcinoma occurs as the histologic lesion in
50%-80% of cases [17]. Other tumors include
adenocarcinomas and lymphomas, as well as
tumors of odontogenic origin.
Malignancies of the nasal cavity occur most
commonly on the lateral walls of the nose or on
the turbinates. The majority of these tumors are
polypoid or ulcerated lesions. Again, the pre-
dominant cancer in the nose is squamous cell
carcinoma that, due to the anatomic confines,
invades bone in about 30% of cases. Malignant
melanon:a does occur and generally has a poor
prognosIs.
Examination of the nasal cavity can be
achieved by use of a head mirror and nasal spe-
culum (figure 11-6). Decongestants that cause
mucosal constriction allow for a better intra-
nasal view. Local anesthetic can be sprayed into
the nose, which allows for the introduction of
fiberoptic nasal telescopes. A full set of fiberop-
tic telescopes contains angled lenses that allow
the examiner to look upward and even retrog-
rade. A puncture can be made through the later-
al wall of the nose into the maxillary sinus, and
telescopes can be introduced to allow for intra-
sinus examinations. Examination under anes-
thetic allows for a better intranasal examination,
 11. INITIAL DETECTION AND EVALUATION: EXTRAORAL NEOPLASMS
FIGURE 11-6. Intranasal examination with illumina-
tion from reflecting head mirror.
and allows for the examiner to gain access to the
maxillary sinus via a submucosal approach
through the anterior wall of the maxillary sinus.
Sphenoid, ethmoid, and frontal sinuses can also
be examined under general anesthesia, although
the approaches are more difficult than for the
maxillary sinuses.
Radiographic examination is essential in these
cases as physical examination is limited. Plain
radiographs and tomograms provide much in-
formation, especially when bone erosion is
present. Computerized axial tomography cur-
rently is the most useful investigative tool and
can provide a remarkably accurate delineation
of a tumor.
Cancers of the nasal cavity or paranasal
sinuses can extend into the oral cavity, with
symptoms of localized or referred pain to the
upper premolar or molar teeth often present.
Symptoms may be due to pressure or due to in-
volvement of the posterior-superior alveolar
nerve. Loosening of teeth or malocclusion may
occur along with swelling of the palate, alveolar
ridge, or gingivobuccal sulcus. The orbital area
can be involved with extension through the
walls of the ethmoid or maxillary sinuses. Di-
plopia or proptosis is sometimes present. In-
volvement of the soft tissues along the anterior
antral wall with bulging of the cheek can occur
in large tumors. Facial asymmetry and involve-
ment of buccal skin can also occur in advanced
cases. Staging is presented in the Appendix.
Treatment is almost always surgical and in
some cases can include orbital exenteration.
Some cases require a combined approach by the
head and neck surgeon and the neurosurgeon.
18S
Radiation therapy is usually part of a planned
combined treatment program.
Ear and Temporal Bone
The ear and temporal bone area can be divided
into three areas: the pinna, the external auditory
canal, and the temporal bone.
The pinna is most often involved with basal
cell or squamous cell carcinomas. Basal cell
carcinomas, although malignant, almost never
metastasize. Treatment is most commonly a
local excision, usually with some form of inter-
operative frozen-section diagnosis to determine
that the margins of the resection are free of
tumor.
Squamous cell carcinoma of the pinna is a sig-
nificantly more aggressive cancer. Ultraviolet
light is felt to be an etiologic factor, and Cauca-
sians of fair complexion appear to be genetical-
ly more susceptible than other people [18].
Squamous cell carcinomas can be locally inva-
sive as well as metastatic. In the pinna, there can
be fixation to the underlying dermis or cartilage
and, in these cases, more radical surgical ex-
cision is required. Malignant melanoma of the
ear does occur and is usually managed surgical-
ly. In addition, consideration must be given to
nodal metastases in both the parotid nodes and
the cervical nodes.
Carcinomas are rare in the external auditory
canal. The most common is squamous cell carci-
noma, although melanomas and adenocystic
carcinomas can occur. The symptoms are very
similar to a chronic otitis media and externa.
However, examination shows fissuring, oozing,
and bleeding.
Examination of the ear can be performed
most easily by using an electric otoscope. An
examiner skilled in the use of a head mirror can
use an open speculum which allows for instru-
mentation during the examination. More de-
tailed examination can be achieved by using an
operating microscope.
Radiographic examination of the ear is essen-
tial since the physical examination is somewhat
limited. Plain radiographs and tomograms are
very useful, especially if bony erosion is pres-
ent. Computerized axial tomography is a useful
investigative tool and can be very accurate in de-
monstrating extent of the disease.
Cancers of the external auditory canal can ex-
tend into the mastoid and into the middle ear.
Swelling behind the ear and facial nerve paresis
186 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
or paralysis are symptoms of more advanced
disease. Radiologic evaluation is important in
the evaluation of these cancers. Since carcino-
mas of the external auditory canal and middle
ear are frequently invasive into bone, treatment
requires a modified or radical temporal bone re-
section [19]. Radiation therapy is also employed
as part of a planned combined treatment pro-
gram [20].
Skin Cancers
Basal cell carcinomas are the most common
head and neck cancer. Basal cell carcinomas
occur 20-30 times more frequently than
squamous cell carcinoma of the skin. Clinically,
both can have a variable presentation, appearing
as smooth nodular growths, chronic ulcers,
ulcerous nodular lesions, or scaly plaques. The
border of the lesions may be rolled or flat.
These lesions are sometimes difficult to distin-
guish from other benign conditions. Basal cell
carcinomas, on rare occasions, can take an
aggressive clinical course with metastases to
lymph nodes and even intracranial spread [21].
Ultraviolet light appears to be an etiologic
factor in the development of squamous cell
carcinoma. Caucasians of light skin color, espe-
cially the elder male, are more sensitive to the
effects of sunlight than are darker races and
hence have a higher incidence of this type of
skin cancer [18]. Malignant melanoma, occurs
less frequently in the skin, occasionally arising
from a Hutchinson freckle. The prognosis of a
melanoma depends upon the level of invasion
and the extent of nodal disease.
Diagnosis is by biopsy. Treatment is a surgi-
cal excision with clear margins in basal cell carci-
noma and a wide excision in squamous cell car-
cinoma. More extensive procedures for control
of neck nodes as well as radiation therapy might
be indicated for squamous cell carcinomas.
Split-thickness skin grafts are frequently used
for immediate reconstruction to allow close
follow-up for a period of approximately one
year after treatment. At that time, a more
cosmetically acceptable reconstruction, which
tends to prevent early discovery of recurrence,
can be undertaken. Melanomas are treated by a
wide surgical excision with a margin 2-3 times
the diameter of the primary lesion. Depending
on the level of cutaneous invasion, a nodal re-
section might be indicated.
Salivary Glands
Salivary gland tumors most commonly occur in
the parotid gland, submaxillary gland, sublin-
gual gland, or minor salivary glands in order of
decreasing frequency. The most usual presenta-
tion is an asymptomatic mass in the parotid or
submaxillary gland. Most aggressive malignan-
cies can be associated with pain or involvement
of the facial nerve. Salivary gland tumors can
vary widely histologically, with some of the
more malignant tumors being squamous cell
carcinoma, adenoid cystic carcinoma, muco-
epidermoid carcinoma, malignant mixed tumor,
undifferentiated tumor, adenocarcinoma, and
melanoma.
Examination of the salivary gland area is by
direct palpation, with attention to whether the
mass is in the overlying skin or under the skin.
It is difficult to distinguish whether the mass is
in the deep lobe of the parotid or, much more
rarely, in the masseter muscle. Bimanual palpa-
tion performed with one finger intraorally is
also very useful in many cases, and is essential to
evaluate large or deep lesions for parapharyn-
geal extension.
Radiographic studies can be helpful in eval-
uating salivary gland tumors. During a sialo-
gram, a dye is injected intraorally through the
duct opening; the ductal system of the gland
is then outlined. Computerized axial tomogra-
phy (CAT) can be very useful in demonstrating
a salivary gland lesion, and a sialogram in con-
junction with a CAT scan can also demonstrate
the ductal system and its relationship to the
tumor.
The majority of salivary gland tumors are be-
nign, but their presentation as a salivary gland
mass is identical to that of a malignant tumor.
This presents a diagnostic and therapeutic
dilemma in that there is no way to distinguish
between a benign and malignant salivary gland
mass other than by tissue diagnosis. Fine-needle
aspiration is of some use in preoperative evalua-
tion, but a nondiagnostic fine-needle aspirate is
no assurance that a malignancy is not present. In
addition, except in a pregnant or unhealthy
individual, benign tumors are also treated by
excision. Therefore, the definitive evaluation
of salivary gland masses is an excisional biopsy.
Incisional biopsies are associated with a much
higher frequency of recurrence and metastasis.
With a parotid mass, a superficial parot-
idectomy with preservation of the facial nerve
 11. INITIAL DETECTION AND EVALUATION: EXTRAORAL NEOPLASMS
is performed. If intraoperative frozen-section
diagnosis [22] indicates an aggressively malig-
nant lesion, a total parotidectomy and neck dis-
section must be considered. Masses in the sub-
mandibular or sublingual gland are excised in
total with the gland. Minor salivary gland
tumors are generally easily biopsied through the
oral cavity, and an appropriate excision can then
be performed. Radiation therapy, while not def-
initively proven as effective as for squamous
cell carcinoma of the upper respiratory system,
is felt to be of benefit and is often given post-
operatively as part of a combined planned treat-
ment program. The prognosis with salivary
gland malignancies is variable, depending on the
extent of the disease at presentation as well as
the histologic type [23]. Squamous cell carcino-
ma, malignant mixed carcinoma, mucoepi-
dermoid carcinoma, undifferentiated carcinoma,
adenocarcinoma, and melanoma can be aggres-
sive and associated with a short survival. Pa-
tients with adenoid cystic carcinomas, while
having an 80% five-year survival, have about a
15% 20-year survival.
More extensive discussion of salivary gland
neoplasia is presented in chapter 13.
Thyroid
Thyroid carcinoma most frequently presents as
an asymptomatic mass in the thyroid gland in a
euthyroid patient. Thyroid scanning is an essen-
tial part of the diagnostic evaluation, with most
malignancies appearing as nodules that do not
take up radioactive tracers ("cold nodules").
Ultrasound is effective in determining whether a
nodule is cystic (in which case there is low
likelihood of malignancy). Fine-needle aspira-
tion [24, 25] is a technique that is frequently em-
ployed diagnostically although, as in salivary
gland tumors, it can provide a false-negative
diagnosis. Often the only definitive diagnostic
procedure for a solitary nodule that does not
take up radioactive dye is a thyroid lobectomy
to allow for thorough histologic examination.
Papillary carcinoma is the most common and
least aggressive type of thyroid carcinoma [26],
although it can have multiple foci in a gland.
Papillary carcinoma represents approximately
50% of all malignant tumors of the thyroid.
Follicular carcinoma accounts for about 20% of
thyroid cancers. It is a somewhat more aggres-
sive cancer and has a higher incidence of distant
metastasis. Many of the tumors have both papil-
187
lary and follicular components. The usual treat-
ment for papillary or follicular carcinomas is a
subtotal or total thyroidectomy with removal of
any neck nodes that are present, followed with
radioactive iodine therapy to ablate any remain-
ing disease.
Medullary carcinoma accounts for about 10%
of malignant thyroid tumors. An elevated serum
thyrocalcitonin level is a strong indicator of the
presence or recurrence of this disease. This can-
cer has a tendency for early metastasis to cervi-
cal and mediastinal nodes as well as direct ex-
tension into the larynx and esophagus. These
tumors often present with vocal cord paralysis,
airway compromise, or dysphagia. The treat-
ment is total thyroidectomy as well as neck
dissection and mediastinal dissection when
necessary.
Poorly differentiated carcinomas of the thy-
roid, although rare, form a group of one of the
most aggressive cancers in the head and neck.
The tumors usually spread beyond the thyroid
to regional lymph nodes and into other adjacent
soft tissues in the neck. Treatment is a wide sur-
gical excision of the thyroid if possible as well as
neck dissection. This is followed by external
beam radiation therapy. In spite of such radical
treatment, there have been no cures reported.
Neck Mass
The head and neck oncologist is occasionally
confronted with a patient who presents with a
neck mass without an apparent primary. Open-
neck biopsy, while ascertaining the cell type,
does not determine the primary site, and is
possibly associated with a higher incidence of
metastases [27].
The etiology of an isolated neck mass is
varied. Benign lesions can be traumatic in etiol-
ogy (hematoma, aneurysms, foreign body), as
well as infectious (inflammatory node, tuber-
culosis, cat-scratch fever, toxoplasmosis, mono-
nucleosis etc.) or congenital (branchial cleft
cyst, thyroglossal duct cyst). The neck mass
might be result or a primary tumor, malignant
or benign. The mass can represent a metastatic
node from a head and neck primary, or a
metastatic node from a distant site. In addition,
the neck mass might be a lymphoma.
Neck masses generally have a somewhat
different differential diagnosis, depending on
whether they are midline or lateral. Midline
masses more commonly are thyroglossal duct
188 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
cysts or thyroid nodules. Lateral masses have a
wider variety of possibilities, including lesions
of infectious origin such as tuberculous nodes,
atypical mycobacterial nodes, cat-scratch fever,
toxoplasmosis, and mononucleosis; of con-
genital origin such as branchial cleft cysts; and
of neoplastic origin such as angiomata, carotid
body tumors, salivary gland tumors, lympho-
ma, and metastatic lymph nodes.
Evaluation of the neck mass requires a thor-
ough history, thorough head and neck exam-
ination, laboratory studies, skin tests, and
appropriate radiographic studies (chest x-ray,
barium swallow, thyroid scan, sinus x-rays, etc.)
If the source of the primary is not ascertained
by these methods, the patient should undergo
an endoscopic evaluation under general anesthe-
sia. If no primary is found, blind biopsies of the
nasopharynx, base of tongue, and tonsils should
be performed. A needle biopsy or open-neck
biopsy be performed only if there is no primary
discovered using the above technique.
Conclusion
In summary, malignancies of the head and neck
can be grouped into two non anatomic catego-
ries: squamous cell carcinoma of the upper
respiratory system and non squamous cell car-
cinoma. The squamous cell carcinomas require
precise staging of the extent of the primaries as
well as of the cervical nodal disease. The treat-
ment plan and prognosis are based upon tumor
location, the extent of the tumor, and the
extent of cervical disease (i.e., tumor staging)
as well as individual consideration of each
patient's general health, social situation, and
preferences. While radiation therapy is effective
in smaller lesions, larger lesions are usually
treated with a combined surgical and radiation
therapy approach.
The nonsquamous cell carcinomas of the head
and neck area occur in the salivary glands, thy-
roid glands, sinuses, lymph nodes, and other
soft tissues of the neck. Evaluation of these
malignancies involves an accurate delineation
of their location and involvement with adjacent
soft tissues, as well as a determination of histo-
logic type. Except for lymphoma, treatment
usually involves a surgical excision, usually
followed by radiation therapy. Prognosis is
variable depending upon site and tumor cell
type.
References
1. Staging of cancer of head and neck sites and of
melanoma. American Joint Committee on Can-
cer, 1980.
2. Williams RR, Horn JW: Association of cancer
sites with tobacco and alcohol consumption and
socioeconomic status of patients: Interview
study from the 3rd National Cancer Survey. J
Natl Cancer Inst 58:525-547,1977.
3. Dickson RL: Nasopharyngeal cancer: an evalua-
tion of 209 patients. Laryngoscope 91 :333-354,
1981.
4. Digby KM, Fook WL, Che YT: Nasopharyngeal
carcinoma. Br J Surg 28:517-537,1941.
5. Bailar JC III: Nasopharyngeal cancer in white
populations: a worldwide survey, UICC (Union
Int Cancer). Monogr Ses 1 :18, 1967.
6. Hoover LA, Hanofee WN: Differential diag-
nosis of nasophamgeal tumors by computed
tomography scanning. Arch Otolaryngol 109:
43-47, 1984.
7. Rubin P: Cancer of the head and neck:
oropharynx. JAMA 217:940-942,1971.
8. Conley J: Concepts in head and neck surgery.
Stuttgart, Georg Thieme, 1970.
9. Micheau C, Cachin Y, Caillon B: Cystic metas-
tases in the neck revealing occult carcinoma of
the tonsil. Cancer 33:228-233,1974.
10. Hillel AD, Fee WE Jr: Malignant tumor of the
palate. In: English GM (ed) Otolaryngology.
Philadelphia, Harper and Row, 1982, pp 1-9.
11. Cunningham MP, Catlin 0: Cancer of the
pharyngeal wall. Cancer 20:1859-1866,1967.
12. Som ML, Nussbaum M: Surgical therapy of
carcinoma of the hypopharynx and cervical
esophagus. Otolaryngol Clin North Am 2:631,
1969.
13. Bryce DP: Pharyngectomy in the treatment of
carcinoma of the hypopharynx. In: Conley J (ed)
Cancer of the head and neck. Washington DC,
Butterworths, 1967, pp 341-346.
14. Kirchner JA, Som MA: Clinical significance of a
fixed vocal cord. Laryngoscope 81 :1029-1044,
1971.
15. Batsakis JG (ed): Tumors of the head and neck:
clinical and pathological considerations, 2nd edn.
Baltimore, Williams and Wilkins, 1979.
16. Bush SE, Bagshaw MA: Carcinoma of the
paranasal sinuses. Cancer 50:154-158, 1982.
17. Frazell EL, Lewis JS: Cancer of the nasal cavity
and accessory sinuses: a report of the manage-
ment of 416 patients. Cancer 16:1293-1301,
1963.
18. Johnson WC, Helwig EB: Adenoid squamous
cell carcinoma. Cancer 19:1639-1650, 1966.
19. Conley, J, Schuller DE: Malignancies of the ear.
Laryngoscope 86:1147-1163,1976.
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20. Wang CC: Radiation therapy in the management
of carcinoma of the external auditory canal,
middle ear, or mastoid. Radiology 116:713-715,
1975.
21. Coker DD, Elias EG, Viravathana T, McCrea E,
Hafiz M: Chemotherapy for metastatic basal cell
carcinoma. Arch Dematol119:44-50, 1983.
22. Hillel AD, Fee WE Jr: Evaluation of frozen sec-
tion in parotid gland surgery. Arch Otolaryngol
109:230-232,1983.
23. Byun YS, Fayos JV, Kim YH: Management of
malignant salivary gland tumors. Laryngoscope
90:1052-1060,1980.
24. Frable WJ, Frable MA: Thin needle aspiration
189
biopsy in the diagnosis of head and neck tumors.
Laryngoscope 84:1069-1077,1974.
25. Lowhagen T, Granbert PO, Lundell G, et al.:
Aspiration biopsy cytology in nodules of the
thyroid gland suspected to be malignant. Surg
Clin North Am 59:3-18,1979.
26. Sisson GA, Feldman DE: The management of
thyroid carcinoma metastatic to the head and
mediastinum. Otolaryngol Clin North Am
13:119-126, 1980.
27. McGuirt WF, McCabe BF: Significance of node
biopsy before definitive treatment of cervical
metastatic carcinoma. Laryngoscope 88 :594-
597,1978.
 12. DIAGNOSTIC RADIOLOGY FOR
HEAD AND NECK NEOPLASMS
WITH EMPHASIS ON
COMPUTERIZED TOMOGRAPHY
Alfred L. Weber
James V. Manzione
The radiologic evaluation of head and neck
neoplasms constitutes an important part in their
diagnosis and treatment. The introduction of
computerized tomography (CT) and the further
development of this modality since 1972 have
contributed significantly to the staging of these
neoplasms. CT not only demonstrates soft-
tissue densities, but also bony structures, mus-
cles, fascial planes, opacified vascular structures,
and enlarged lymph nodes. CT, however, fails
to differentiate the various histologic types of
lesions in the majority of cases. Features such as
size of the lesion, marginal definition, lytic bone
destruction, sclerotic bony reaction, bony ex-
pansion, calcific densities, fat content, and oblit-
eration of fascial planes are utilized to delimit
the spectrum of diagnostic possibilities.
Conventional films including tomography are
also indicated as preliminary examinations in
the investigation of head and neck neoplasms.
They provide a survey of the abnormality in
question and form the basis for special studies
such as CT and angiography. They are often the
first examination to demonstrate a lesion that
may be suspected from the history and clinical
examination.
Mandible
TECHNIQUE
Lateral Oblique Projection. This is the most
common and most useful projection applied in
the evaluation of the mandible. It is made with a
Peterson et al., HEAD AND NECK MANAGEMENT OF THE CANCER PATIENT.
© 1986. Martinus NijhofJ Publishing. All rights reserved.
small 5 X 7-inch film cassette which is applied
to the lower jaw over the area of interest. The
x-ray tube is positioned on the opposite side of
the face with the beam directed cranially at an
angle of about 30° and the central beam directed
toward the area of interest. In the cranial
angulation, the beam passes below the ipsilateral
uninvolved side of the mandible and thereby
avoids bony superimposition. This view pro-
vides good visualization of the body, angle, and
ascending ramus of the mandible.
Posteroanterior (PA) Projection. The PA
projection of the mandible supplements the
lateral oblique projection. The head is in a neu-
tral position with the symphysis of the mandible
adjacent to the film cassette. The central beam
projects through the midportion of the mandi-
ble and forms a right angle with the film cas-
sette. This view is useful for evaluation of
lesions in the mandibular body or symphysis.
Panoramic Radiograph. The panoramic view
supplements the conventional mandibular series
and provides less image superimposition and
improved bony detail. It provides a curved
plane tomogram of the mandible and lower face.
The x-ray tube revolves around the front of the
patient during exposure while the drum con-
taining the film revolves around the back of the
patient's head. This view demonstrates the en-
tire mandible, including the condylar and coro-
noid processes, and is often utilized to survey
the mandible for bone destruction (figure 12-1).
191
192 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
FIGURE 12-1. Carcinoma of oral cavity invading left
mandible. Panorex view demonstrates lytic bone de-
struction in the body and ascending ramus of the left
mandible. Compare with normal right mandible.
Occlusal Projection. The occlusal projection
is valuable in cases of suspected pathologic bony
changes, predominantly in the lingual surface of
the mandible. The film is positioned within the
intraoral cavity. The x-ray beam is directed per-
pendicular to the plane of the film packet. The
anterior portion of the hard palate can also be
demonstrated with this projection by angulating
the beam caudally at about 65°-70°.
CT Evaluation of the Mandible [1]. The
axial CT section is the preferred method for
assessment of the mandible and the adjacent
soft-tissue structures [1]; 4-mm contiguous sec-
tions are obtained of the bone and soft-tissue
utilizing window techniques extending from the
inferior margin of the mandible to the tem-
poromandibular fossa. Because of the config-
uration of the mandible, only segments are
demonstrated on a single CT section. Axial
CT scan at the level of the temporomandibular
joints demonstrates the ovoid, obliquely ori-
ented condyle that is contained within the tem-
poromandibular fossa. Anterior to the condyle is
the articular eminence that is seen as a slightly
curvilinear structure. The condyle is separated
from the external auditory canal by the tym-
panic portion of the temporal bone. About 1 cm
below the condyle is the triangular-shaped man-
dibular neck. Sections through the mid portion
of the ascending ramus demonstrate a thin, flat
bony plate with a medial concavity. The man-
dibular foramen appears on the inner surface
of the mid ascending ramus as an obliquely
oriented foramen. The mandibular foramen is
overlapped by a thin bony lamella. Sections
slightly above the angle of the mandible dem-
onstrate the body and anteriorly the sym-
physis pubis (figure 12-2A and B).
RADIOLOGIC FINDINGS AND
PATHOLOGIC CONDITIONS
Ameloblastoma. The ameloblastoma is the
most common benign tumor of the jaw. It is a
locally aggressive tumor and tends to recur if
incompletely excised. The lesion may grow to a
large size and extend outside the mandible and
maxilla [2]. The soft-tissue component of the
tumor is best evaluated by CT. The CT image
shows low-density cystic areas intermingled
with muscle density tumor tissue [2, 3] (figure
12-3). Rim enhancement may be noted around
the cystic areas. Bone window setting provides
detailed analysis of the area of bone destruction
and/or bony expansion.
Malignant Tumors. Epidermoid carcinoma is
the most common malignant tumor of the man-
dible and, less frequently, maxilla. The lesion
usually arises from the surrounding anatomic
structures including tongue, floor of the mouth,
tonsillar area, gingiva and alveolar mucosa,
buccal mucosa, soft palate, hard palate, and
oropharynx. Oral carcinoma involves the jaw
by direct extension to the alveolar process and
lingual surface of the mandible. Radiographical-
ly (mandibular and panorex views), a concave
defect, either smooth but more often irregular,
is demonstrated at the alveolar crest. Extensive
lytic bone destruction may be noted in ad-
vanced lesions [4] (figure 12-1). A pathologic
fracture is a sequence of widespread permeative
bone destruction. CT is the preferred modality
to demonstrate bone destruction and outline
the soft-tissue component of the tumor (figure
 12. DIAGNOSTIC RADIOLOGY FOR HEAD AND NECK NEOPLASMS
A left mandible. Axial CT section of the mandible dem-
B superoinferior extent of the disease process.
FIGURE 12-2. Axial CT section of normal mandible
and oral cavity. (A) Normal axial CT section (bone
window setting) through body and symphysis of
mandible. (B) Normal axial CT section (soft-tissue
window) through body and symphysis of mandible
and demonstration of normal floor of mouth and
tongue.
12-4). Enlarged metastatic lymph nodes can
be searched for in the respective lymph node
drainage areas.
Oral Cavity
TECHNIQUE
The oral cavity, including oropharynx, is best
evaluated with 4- to 5-mm-thick scan sections
193
FIGURE 12-3. Ameloblastoma, anterior portion of
onstrates an expansile lesion. Note enhancing rim
of lesion anteriorly and laterally. Low density within
lesion indicates a cystic component.
made at contiguous intervals. The scans are
made with the Reid's baseline perpendicular to
the table top. Angles of 20° above or below the
Reid's baseline can be made to circumvent arti-
facts caused by amalgam and other restorations
in the teeth. Slightly tilted sections do not signif-
icantly alter the appearance of the air spaces and
soft-tissue structures. Bone windows should
be utilized for detailed assessment of the man-
dible, maxilla, and hard palate. Thinner sections
can be added for detailed analysis of small ana-
tomic areas, including the foramina and canals.
Supplemental coronal sections demonstrate the
RADIOLOGIC FINDINGS AND
PATHOLOGIC CONDITIONS
Tumors of the oral cavity and oropharynx are
most often squamous cell carcinomas. These
tumors tend to be less well-differentiated and
metastasize earlier than other head and neck
malignancies, particularly as one moves more
posteriorly and inferiorly. CT has been very
useful in delineating the extent of local and deep
infiltration of these malignant tumors [5] (figure
12-4). If these lesions are small and poorly
circumscribed, however, demonstration and
assessment of extent may be difficult to deter-
mine by CT.
Carcinomas of the posterior tongue are
194 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
A
B cinomas, or unclassified. The remaining 2% are
FIGURE 12-4. Carcinoma of floor of mouth with
invasion of mandible and extension into adjacent
tongue and oropharynx. Axial CT section with bone
window setting demonstrates lytic bone destruction
of body ofleft mandible near angle.
reflected by increased density and obliteration
of the muscular planes (figure 12-4). Ulceration
is characterized by irregular soft-tissue defects.
The CT can assess spread across the midline to
the contiguous structures (pre-epiglottic space,
oral cavity, and oro-, hypo-, and nasopharynx)
and lymph node metastases. In cases that
manifest with lymph node metastases, an
occult primary tumor in the oral cavity and
oropharynx may be detected by CT. The
suspected area can then be investigated with a
needle aspiration or incisional biopsy.
CT is very useful for following the response
of the tumor to therapy such as radiation or
chemotherapy. It is essential to do a baseline
study approximately 5-6 weeks after the com-
pletion of treatment. In some cases, the deep
fatty, soft-tissue planes may revert to normal,
but, in other cases, persistent radiation-induced
edema and fibrosis make the interpretation of
recurrent tumor difficult. A persistent bulky
mass, however, is unusual and should be con-
sidered evidence of persistent or recurrent
tumor.
Nasopharynx, Parapharyngeal
Space, and Infratemporal Fossa
TECHNIQUE
The nasopharynx is optimally investigated with
contiguous 4- to 5-mm axial and coronal CT
sections utilizing soft-tissue and bone window
settings. The scan area should include the base
of skull and extend inferiorly to the tip of the
soft palate. For determination of lymph node
metastases and orbital and intracranial invasion,
contrast material should be infused.
RADIOLOGIC FINDINGS IN MALIGNANT
TUMORS OF THE NASOPHARYNX
Most nasopharyngeal malignancies (80%) are
either keratinizing or nonkeratinizing squa-
mous cell carcinomas. Approximately 18% are
either adenocarcinomas, adenoid cystic car-
either lymphomas, sarcomas, or a miscellaneous
group of tumors.
The nasopharyngeal tumor manifests on
CT as an exophytic mass or infiltrating lesion
[6]. The hallmark of an infiltrating lesion is
thickening of the wall of the nasopharynx,
along with deep infiltration of the soft-tissue
structures and obliteration of the fascial planes
that surround the airway, deep musculature,
and vessels (figure 12-5A). Extension into these
deep spaces may occur without any sign of an
overlying mucosal abnormality. From the para-
pharyngeal space, the nasopharyngeal tumor
 12. DIAGNOSTIC RADIOLOGY FOR HEAD AND NECK NEOPLASMS
A Plain sialography with conventional tomogra-
B
FIGURE 12-5. Carcinoma of the nasopharynx. (A)
Axial CT section demonstrates a carcinoma of the
nasopharynx on the right with invasion of the para-
pharyngeal space and erosion of C-l. (B) Axial CT
section with bone window shows erosion of C-l on
the right.
can invade or displace the parotid gland. It can
also extend to the carotid sheath and base of
skull, with intracranial extension via the forami-
na, predominantly the foramen lacerum. Ero-
195
sion is also encountered in the clivus and floor
of the sphenoid sinus and sella. Posterior exten-
sion may involve the jugular fossa and cervical
spine (figure 12-SB). Tumor may also spread
into the orbits via the infratemporal fossa,
pterygopalatine fossa, and inferior orbital
fissure. Most often, the high jugular and lateral
retropharyngeal nodes are involved by carcino-
ma of the nasopharynx. CT is fairly accurate in
discovering occult or palpable metastases. The
various types of malignancies in the naso-
pharynx, however, cannot be differentiated by
CT. Malignant tumors can be simulated by in-
filtrating inflammatory processes, including
mucormycosis and malignant external otitis.
Salivary Glands
TECHNIQUE
phy or CT are radiologic modalities utilized in
the evaluation of salivary gland tumors [7]. Be-
cause of greater sensitivity, CT should be the
method of choice for assessment of benign and
malignant salivary gland tumors. Both the parot-
id and submandibular glands are well shown in
the straight axial projection. Coronal views are
added when parapharyngeal or base of skull ex-
tension is suspected. When a mass is palpated, a
thin smudge of barium paste is placed onto the
skin overlying the mass. The marker is useful
subsequently for anatomic-radiologic correla-
tion. A digital radiograph (scoutview or topo-
gram) is exposed to aid in the selection of arti-
fact-free projections as well as to provide a basis
for a final summary of the anatomic planes that
have been imaged.
RADIOLOGIC FINDINGS AND
PATHOLOGIC CONDITIONS
The CT density of the parotid glands is variable
from patient to patient and ranges from a slight-
ly higher density than fatty tissue to the density
of muscle. The density of the submandibular
glands normally is in the range of muscle.
Lymph nodes are found within and outside the
parotid gland, but no lymph nodes are demon-
strated within the submandibular gland. CT is an
efficient modality to define the intraglandular
location of benign and malignant tumors and to
demonstrate spread beyond the gland capsule.
Benign tumors appear as discrete, sharply mar-
ginated, high-density masses situated within a
196 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
FIGURE 12-6. Pleomorphic adenoma of left parotid
gland. Axial CT section demonstrates a homoge-
neous, sharply defined mass in the superficial portion
of the left parotid gland.
"FIGURE 12-7. Small cell carcinoma of the left parotid
gland. Axial CT section reveals an ill-defined infiltra-
tive lesion in the superficial portion of the parotid
with extension to the deep lobe. Note normal right
parotid.
normal, low~density parotid gland (figure 12-6).
Invasive malignant tumors are poorly defined
(figure 12-7) and marginated, and represent a
radiodense lesion which may extend beyond the
gland into the fascial plane. Malignant tumors
may transgress adjacent anatomic structures and
extend into the skull base, lateral pharyngeal
space, and vascular sheath. In some cases, low-
grade malignant lesions such as mucoepider-
moid carcinoma and adenoid cystic carcinoma
may simulate benign lesions in that they are
sharply marginated and contained within an
otherwise normal parotid gland. CT is useful
for separating lesions that arise in the deep
portion of the parotid gland from tumors that
arise in the parapharyngeal space or lateral
pharyngeal wall. Tumors within the subman-
dibular gland may be difficult to discern from
normal glandular tissue because of the higher
attenuation values of this gland. In these in-
stances, a CT sialogram-performed after
introduction of 10% water-soluble contrast
material-may be performed to demonstrate
the lesions. CT attenuation values of tumors are
variable, and it is not possible to determine the
histologic nature of salivary gland tumors.
Inflammatory disease in general produces a
relatively diffuse, irregular radiodense lesion in
an enlarged gland. These inflammatory masses,
without correlation of clinical findings, may
be difficult to differentiate from infiltrating
tumors. The sialogram usually provides radio-
logic signs of inflammation such as dilatation
of ducts and sialectasis. In some cases, primary
intraglandular masses cannot be distinguished
from adjacent extraglandular masses as is
encountered in lymph node diseases such as
lymphoma.
Paranasal Sinuses
TECHNIQUE
The routine examination of the sinuses consists
of four projections that include two frontal
projections (Waters and Caldwell views), a base
(submentovertex) view and a lateral view. These
preliminary examinations usually form the basis
for additional studies, including conventional
tomography and CT. Conventional tomogra-
phy, preferably polytomography , is carried out
in the anteroposterior and lateral projections at
5-mm intervals. Deep tissue invasion and orbital
or intracranial extension can only be indirectly or
ferred from bone destruction; the tumor proper
is not visualized in its extent. Axial and coronal
4- to 5-mm CT sections with soft-tissue and
bone window settings provide the ideal method
for mapping out malignant tumor extension and
for assessing the degree of bone destruction.
 12. DIAGNOSTIC RADIOLOGY FOR HEAD AND NECK NEOPLASMS 197

RADIOLOGIC FINDINGS AND

PATHOLOGIC CONDITIONS
Many different types of malignant tumors
involve the paranasal sinuses. The majority of
these tumors are represented by squamous cell
carcinomas. In a series of 200 cases, 81 % of
paranasal sinus carcinomas arose in the maxillary
antra [8]. They extended into the other sinuses
in advanced cases. The extent, rather than the
degree of differentiation, of squamous cell carci-
noma of the paranasal sinuses is the most im-
portant determinant in the prognosis. Because
of the advanced stage of these tumors, extension
into adjacent areas such as the nasal cavity,
orbit, oral cavity, pterygopalatine fossa, intracra-
nial cavity, nasopharynx, and cheek is common.
CT has been widely applied in recent years to
the evaluation of paranasal sinus malignancies A
[8]. Axial and coronal sections are obtained fol-
lowing infusion of contrast material to detect
tumor extension into the aforementioned areas.
In some cases, blocked secretion in the sinus
cavity may be distinguished from tumor on the
basis of differential enhancement and the re-
cording of different attenuation values. CT has
been most useful in demonstrating tumor exten-
sion outside the sinus and nasal cavities and into
the intracranial cavity, orbits, pterygoid and in-
fratemporal fossae, parapharyngeal space, and
skin (figure 12-8A and B). Most paranasal sinus
malignancies display insufficient density charac-
teristics to allow a specific histologic diagnosis,
even with contrast enhancement. Obliteration
of low-density fascial planes between muscles is
a reflection of tumor invasion, assuming that
hemorrhage or edema from inflammatory dis-
ease or surgery has already been excluded. CT is
able to detect tumor calcification, as is seen with
fibro-osseous lesions, chondrosarcomas, and B
osteosarcomas, and can demonstrate demineral-
ized or destroyed bony walls. Lymph node FIGURE 12-8. Squamous cell carcinoma of the right
metastases have been reported in 32% of cases paranasal sinuses. (A) Coronal CT section demon-
[8], predominantly involving the lateral ret- strates a large tumor involving the right antrum, nasal
ropharyngeal and the upper cervical group of cavity, and ethmoid sinus, with extension into the left
lymph nodes (jugulodigastric). ~n suspected ethmoid sinus and nasal cavity, anterior cranial fossa,
right orbit, and right cheek with extensive bone de-
lymph node metastases, a CT of the upper neck
struction. (B) Axial CT section demonstrates tumor in
should be obtained. Computed tomography has the right pterygopalatine fossa with extension into
not only been useful before treatment, but has the infratemporal fossa and parapharyngeal space in
also become essential in the detection of early addition to areas mentioned under A. Again, note
tumor recurrence. A baseline scan taken 4-6 extensive bone destruction and some low-density areas
weeks after surgery to define the postoperative within the tumor, probably secondary to necrosis.
cavity is followed by a contrast-enhanced scan
every 6 months over a period of 3 years
[9]. With the baseline scan for comparison,
198 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
polypoid thickening within the postoperative
cavity may indicate early recurrence, and a
biopsy of the abnormal area should be per-
formed.
Neck
TECHNIQUE
The patient is positioned supine with the chin
extended so that the horizontal ramus of the
mandible is parallel to the x-ray beam; 4- or 5-
mm contiguous axial sections are obtained from
the base of the skull to the thoracic inlet. All
patients are given contrast material intravenous-
ly that is infused over a period of about 15 min.
Scanning commences after approximately 150 cc
have been infused. The opacification of blood
vessels allows one. to separate vessels from
enlarged lymph nodes or other structures. In
order to accomplish increased contrast enhance-
ment of vessels or vascular lesions such as
carotid body tumors, a rapid bolus of contrast
material should be injected followed by fast
sequential scans of the area of interest. In
vascular lesions, preferentially a plain scan
should be obtained to ascertain the degree of
enhancement after the bolus injection of con-
trast material.
RADIOLOGIC FINDINGS AND
PATHOLOGIC CONDITIONS
Lymph Node Pathology. CT has become a
useful tool in the assessment of lymph node
metastases in the neck [10]; clinically occult
nodal metastases may be detected. The follow-
ing criteria have been established for nodal dis-
ease [10]: (a) A mass involving lymph nodes
with a central lucency , irrespective of size. This
low-density area may be surrounded by a
peripheral uniform-enhancing rim (figure 12-9).
(b) A mass in the lymph-node-bearing area,
having a diameter greater than 1.5 cm. (c) Oblit-
eration of fascial planes around a large node,
which usually indicates extension of primary
disease into adjacent tissue. The obliteration
of fascial planes in metastastic disease is more
focal, rather than diffuse, like an inflammatory
process. (d) Three or more contiguous iU-
defined nodes measuring 8-15 mm in diameter.
Inflammatory nodes, however, cannot be
distinguished on the basis of the CT density or
margin. The location of the nodal metastases
FIGURE 12-9. Metastatic disease of the right neck.
Axial CT section demonstrates a sharply defined low
density area with an enhancing rim in the right neck
beneath the sternocleidomastoid muscle and adjacent
to the vascular sheath.
may give a clue to the location of the primary
site of the malignant tumor.
Lymphomas [11]. These lesions are the most
common cause for unilateral neck masses in pa-
tients between the ages of 20 and 40 years. The
CT characteristics of lymphoma~ are quite vari-
able. The lesion on CT is usually homogeneous,
sharply defined, with a density similar to muscle
(figure 12-10). There is usually no enhancement
and low-density areas are occasionally encoun-
tered within the tumor. A streaky enhancement
pattern has been reported, but has no specific
connotation.
Chemodectomas [12]. These tumors reveal an
intense homogeneous enhancement pattern on
CT (figure 12-11). The most common site is the
carotid bifurcation. A plain CT scan followed
by a rapid bolus injection should be performed
to ascertain the characteristic enhancement pat-
tern of this very vascular lesion. CT analyzes
the size, location, and the superoinferior extent,
and the relationship of the tumor to the internal
and external carotid arteries.
Thyroid Gland Pathology. There are no CT
characteristics of a thyroid lesion that are reli-
able indicators of benignity or malignancy [11].
Malignancy is suggested when a thyroid tumor
is associated with nodal enlargement in the neck
or mediastinum, evidence of destruction of
bone or cartilage, recurrent laryngeal nerve
palsy, and invasion of the lumen of the trachea
 12. DIAGNOSTIC RADIOLOGY FOR HEAD AND NECK NEOPLASMS 199

Angiography [13]. Angiography is rarely

indicated in head and neck malignancies. The
indications consist of (a) assessment of cross
circulation in cases where the carotid artery
has to be surgically removed, (b) demonstration
of the vascular supply of a hypervascular lesion
(chemodectoma, hemangiopericytoma, rhab-
domyosarcoma), and (c) use for positioning of a
catheter for intravascular chemotherapy.
In a hypervascular lesion, tumor can be
embolized prior to surgical removal to decrease
blood loss during extirpation.

References
FIGURE 12-10. Hodgkin's lymphoma. Axial CT
section demonstrates homogeneous, sharply defined
enlarged nodes in the anterior and posterior triangle
of the right neck. Note normal left side.
FIGURE 12-11. Chemodectoma at right carotid
bifurcation. Axial contrast CT scan demonstrates an
enhancing lesion in the right neck at the carotid
bifurcation. Note normal left carotid artery and jugu-
lar vein adjacent to anterior portion of sternocleido-
mastoid muscle.
or larynx. CT density characteristics of various
thyroid lesions are nonspecific. Occasionally,
amorphous collections of calcification may be
identified within the lesion. The calcification is
not a specific finding and does not allow dif-
ferentiation of benign from malignant thyroid
tumors. Calcification is encountered in 25%-
35% of benign and malignant thyroid lesions.
l. Osborn AG, Hanafee WH, Mancuso AA: Nor-
mal and pathologic CT anatomy of the mandible.
AJR 139:555-559,1982.
2. Weiss JS, Bressler SB, Jacobs EF Jr, Shapiro J,
Weber AL, Albert DM: Maxillary ameloblasto-
ma with orbital invasion: a clinicopathologic
study. Ophthalmology, (in press).
3. Hutzanu Y: Computed tomography of man-
dibular ameloblastoma. J Comput Assist
Tomogr 8:220-223,1984.
4. Stafne EC: Value of roentgenograms in diagnosis
of tumors of the jaws. Oral Surg 6:82,1953.
5. Mruaki AS, Mancuso AA, Harsnberger HR,
Johnson LP, Meads GB: CT of the oropharynx,
tongue base and floor of the mouth: normal anat-
omy and range of variations and applications in
staging carcinoma. Radiology 148:725, 1983.
6. Silver AJ, et al.: Computed tomography of the
nasopharynx and related spaces. II. Pathology.
Radiology 147:733-738, 1983.
7. Rabinov K, Weber AL: Radiology of the salivary
glands. Boston, GK Hall, 1984.
8. Weber AL, Stanton AC: Malignant tumors of
the paranasal sinuses: radiologic, clinical and
histopathologic evaluation of 200 cases. Head
Neck Surg 6:761-776,1984.
9. Som P, Shugar J, Biller H: The early detection
of antral malignancy in the post maxillectomy
patient. Radiology 143:509-513, 1982.
10. Mancuso AA, Maceri D, Rice D, Hanafee W:
CT of cervical lymph node cancer. AJR 136:381-
385,198l.
1l. Reede DL, Whelan MA, Bergeron RT: CT of
infrahyoid neck. II. Pathology. Radiology
145 :397-402, 1982.
12. Ferris R, Kirschner L, Mero J, Fields R, Fulcher
T: Computed tomography of a carotid body
tumor. J Comput Assist Tomogr 3:834-835,
1979.
13. Lasjaunias P: Craniofacial and upper cervical
arteries: functional, chemical and angiographic
aspects. Baltimore, Williams and Wilkins, 1981.
 13. NEOPLASMS OF THE
SALIVARY GLANDS
Marvin P. Fried
The salivary glands are usually divided into
the major glands (which are the paired parotid,
submandibular, and sublingual glands) and
the minor salivary glands that are found in the
mucous membranes throughout the upper aero-
digestive tract. The consideration of neoplastic
processes of these structures is as varied as their
locations and has but a secondary relationship
to the production of saliva and the digestive
process. The tumor cell types are numerous,
with therapy and prognosis determined by not
only the tumor histology, but also location.
The classification of these tumors has been
only addressed over the past half-century and is
still undergoing evaluation. With the changing
pathologic perspective, diagnostic techniques
and therapeutic modalities evolve as well. This
chapter addresses these newer concepts as well
as time-honored and accepted principles.
Anatomy
THE PAROTID GLAND AND FACIAL NERVE
The parotid gland is a triangular structure that is
superficial to the posterior aspect of the mandi-
ble lying anterior and inferior to the ear. It is
surrounded by connective tissues derived from
the superficial layer of the deep cervical fascia
[1, 2]. The overlying parotid fascia extends to
the zygomatic arch and medially the fascia is
applied to the masseter muscle. The fascia also
extends into the gland, dividing it into lobes
and compartments and rendering it firm and
poorly distensible. The deep portion of the
gland lies in proximity to the lateral pharyn-
geal space, allowing for potential passage of
infections to the fascial spaces in the neck. The
parotid is separated from the anteriorly and in-
Peterson et aI., HEAD AND NECK MANAGEMENT OF THE CANCER PATIENT.
© 1986. Martinus Nijho/f Publishing. All rights reserved.
feriorly placed submandibular gland by the sty-
lomandibular ligament.
Although superficial and deep lobes of the
parotid gland have been described, there is no
true plane separating the gland into these divi-
sions. This distinction is purely one based on
the relationships of the glandular tissue to the
facial nerve that courses from posterior to ante-
rior through the substance of the parotid. That
portion of the gland overlying the facial nerve is
considered "superficial" (80%) and the remain-
ing tumor is "deep" (20% )-an important
surgical consideration rather than an anatomic
one [3].
The gland extends from the zygomatic arch
to below the mandible and from the anterior
aspect of the sternocleidomastoid to the mid-
portion of the masseter muscle, as well as ex-
tending deeply behind the ascending ramus of
the mandible, anterior to the external auditory
canal and mastoid process (figure 13-1).
Skin, subcutaneous tissue, and occasional
lymph nodes lie superficial to the parotid as
well. The posterior belly of the digastric muscle
as well as the stylohyoid, stylopharyngeus, and
styloglossus form the medial muscular bound-
ary of the parotid space. Anteriorly, the gland is
in proximity to the medial and lateral pterygoid
muscles as well as the masseter.
The parotid (or Stensen's) duct arises from
the anterior aspect of the parotid, coursing over
to the masseter muscle halfway between the
corner of the mouth and the zygomatic arch. It
then turns deeply .to penetrate the buccinator
muscle at the level of the maxillary second
molar. The intraoral orifice of the duct may be
difficult to see and is often hidden in a fold of
buccal mucosa. Accessory glandular tissue usually
accompanies the parotid duct, occasionally giv-
201
202 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
~Ir-:--=\- Facial Vein
Faciol Artery
FIGURE 13-1. The relationship of the major salivary
glands to the surrounding vasculature.
ing rise to masses overlying the masseter. The
transverse facial artery (a terminal branch of the
external carotid) and vein are in close proximity
to the parotid duct and often run parallel to it.
The region within and deep to the substance
of the gland just anterior to the ear is laden with
vessels and nerves. The external carotid artery
divides into the superficial temporal and inter-
nal maxillary arteries. The external jugular vein
is composed of tributaries arising from the
superficial temporal and internal maxillary veins
joining to form the posterior facial vein, with a
branch from the posterior auricular vein [2]
(figure 13-1).
The auriculotemporal nerve, a branch of the
mandibular division of the trigeminal (V), lies
deep to and usually posterior to the superficial
temporal vessels. It is the parasympathetic se-
cretomotor innervation of the parotid, com-
municating with the temporal branch of the
facial nerve and the otic ganglion. Postgustatory
sweating (Frey's syndrome) and redness in the
distribution of this nerve may occur after parot-
idectomy. This is due to the faulty regeneration
of secreting fibers contained in the auriculo-
temporal nerve to the sweat glands in the skin
overlying the gland. Eating then causes facial
sweating. The otic ganglion, which contributes
secretory fibers, receives branches from the
lesser petrosal nerve from the tympanic plexus,
derived from the glossopharyngeal (IX).
The parotid gland is rich in lymph nodes and
channels lying superficial, deep, and within the
gland. The superficial nodal afferent drainage to
the parotid area can arise from the eyelids, lac-
rimal glands, nose, frontotemporal region of the
scalp, the external auditory canal, and pinna.
Deeper lymphatics drain from the external and
middle ear, oral cavity, and nose [2].
The facial nerve leaves the temporal bone
through the stylomastoid foramen, almost im-
mediately entering the posterior aspect of the
parotid gland. The nerve at this point lies slight-
ly posterior and lateral to the styloid process
and anterior to the mastoid process. As the
nerve enters the gland, it divides into the tem-
porofacial and cervicofacial portions; however,
it first gives rise to branches to the posterior
auricular and stylohyoid muscles. The two
major nerve divisions then subdivide into five
branches (the pes anserinus: goose foot): the
temporal, zygomatic, buccal, mandibular, and
cervical innervating the facial muscles. These
are not totally independent nerves, since con-
necting fibers allow innervation of the same
muscle groups by various branches. Many
variations of the branching pattern have been
described [1, 2, 4], confirming the intertwining
network, but there is no presurgical method
of determining the patterns. Some consistent
landmarks are present, however, that assist in
the operative identification of the nerve. The
main trunk lies 1-2 cm deep to an inferior pro-
jection of the conchal cartilage, the "pointer."
The tympanomastoid suture line is the "valley"
of the nerve and leads directly to the stylo-
mastoid foramen with the nerve 5-10 mm deep
and anterior to the suture line [5]. The man-
dibular division lies superficial to the posterior
facial vein and crosses it. If identified, retro-
grade dissection can lead to the pes anserinus.
The greater auricular nerve is a branch of the
cervical plexus derived from C2 and C3 and
supplies sensation to the portion of the auricle
and skin of the face near the tragus. It is routine-
ly sacrificed during a parotidectomy and pa-
tients should be forewarned about the dimin-
ished sensation that will ensue. The nerve is
found posterior to the sternocleidomastoid
muscle, coursing over this muscle as it travels
superiorly to divide below the external auditory
canal. It also serves as a potential nerve graft
source if the facial nerve needs to be sacrificed.
THE SUBMANDIBULAR GLAND
The submandibular gland lies in the space of the
same name bounded by the anterior and pos-
 13. NEOPLASMS OF THE SALIVARY GLANDS
Sublingual Gland
SIlb/nandibular Gland
FIGURE 13-2. The relationship of the major salivary
glands to the deep musculature and nerves. Inset
shows the submandibular and sublingual ducts in the
anterior floor of the mouth.
terior bellies of the digastric muscle and the in-
ferior border of the body of the mandible. Pos-
teriorly the gland is separated from the parotid
by the stylomandibular ligament. The anterior
portion of the gland lies against the mylohyoid
muscle as well as extending medially to the
lateral sublingual space in proximity to the
genioglossus muscle [2]. It, like the parotid
gland, is covered by the superficial layer of the
deep cervical fascia, as well as skin and sub-
cutaneous tissue, and the platysma muscle. The
marginal mandibular nerve runs in the super-
ficial plane and is preserved in resection of the
submandibular gland. Identification of the pos-
terior facial vein, with upward retraction of this
vessel, also assists in avoiding injury to this
branch of the facial nerve. An aggregate of su-
perficiallymphatics and nodes lies in the super-
ficial layer, occasionally giving rise to hyper-
plastic adenopathy that can be confused with
submandibular enlargement; this adenopathy
may represent either neoplastic or inflammatory
disease.
The deep surface of the gland is composed of
the hyoglossus muscle as well as the mylohyoid,
stylohyoid, and styloglossus muscles. The
hypoglossal and lingual nerves (and with them,
the submandibular ganglion) and submandibu-
lar duct are found in this deep layer, the lingual
nerve above the duct and the hypoglossal below
it (figure 13-2). The arterial supply to the gland
203
is via the facial and lingual arteries. In surgical
removal of the submandibular gland, the facial
artery is ligated both superficial and deep to the
gland.
. The submandibular duct lies above the
mylohyoid as it courses anteriorly to the floor
of the mouth. It is crossed twice by the lingual
nerve. Before the duct terminates, it is in prox-
imity to the sublingual gland, and may receive
a duct from this structure.
Parasympathetic innervation to the subman-
dibular gland is via the chorda tympani nerve
(from the facial nerve) to the submandibular
ganglion, with postsynaptic fibers arising here
to terminate in the gland; sympathetic supply
comes to the gland by way of the lingual nerve.
Efferent lymphatic drainage from the gland is
to the deep jugular chain. The nodes surround-
ing the submandibular gland receive their drain-
age from the lips, facial skin, nose, and anterior
oral cavity.
THE SUBLINGUAL GLAND
The paired sublingual glands occupy a position
in the anterior floor of the mouth, above the
mylohyoid muscle and below the oral mucosa
just posterior to the mandibular symphysis, the
two glands almost meeting anteriorly. The
lingual and hypoglossal nerves as well as the
submandibular duct run in close proximity to
this gland.
The ductal structures (ducts of Rivinus) num-
ber more than a dozen from each gland and arise
from the upper surface to empty directly into
the oral cavity. The more anteriorly placed
ducts may join to form a larger structure (the
duct of Bartholin) that unites with the subman-
dibular duct [6] (figure 13-2).
The lymphatic drainage from the gland is to
the submental and submandibular nodes. The
parasympathetic supply to the sublingual gland
is similar to that supplying the submandibular.
The sympathetic nerves travel with the facial
artery [2].
THE MINOR SALIVARY GLANDS
Minor salivary glands are scattered throughout
the oral cavity and pharynx (figure 13-3), being
especially concentrated in the lateral floor of the
mouth, tongue, and superior pole of the tonsils
(Weber's glands). Each gland has but one or two
ducts opening directly to the mucosa. Although
considered here in terms of neoplasia, Weber's
glands may give rise to peritonsillar abscesses
when infected.
204 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
FIGURE 13-3. Secretions from the mmor salivary
glands of the palate.
Embryology
The three paired major salivary glands appear at
6-8 weeks in the fetus as primordial ectodermal
buds that arise from the oral epithelium and
arborize as solid ductal structures [7]. These
ductal elements proliferate into the surrounding
mesenchyme, which stimulates ductal differ-
entiation, forming acini and ultimately acquiring
alumen.
The parotid arises from the corner of the
mouth and the bud formed migrates posteriorly
to the ramus of the mandible, creating the parot-
id duct and subsequent glandular elements. The
submandibular gland tissue appears at six weeks
and the sublingual at eight weeks. The subman-
dibular buds migrate along the floor of the
mouth, coming to rest overlying the mylohy-
oid. The sublingual tissue remains under the
tongue with multiple separate ducts, arising
from a solid parenchyma.
Although the acinar maturation progresses
postpartum, the fetus can produce saliva; IgG
can be found in salivary samples in newborns up
to ten days of age, with IgA becoming detect-
able at that time, reaching adult levels much
later in childhood [7].
Physiology
Daily salivary secretion can vary from 1 to 4
liters with wide ranges in flow rates, depend-
ing on numerous factors. Saliva is necessary
for functions such as oral lubrication, speaking,
and swallowing, as well as the physical effect
of sweeping foreign substances into the
oropharynx. It assists in the maintenance of
dental health by reducing plaque as well as hav-
ing an antibacterial effect. Amylase contained
in saliva begins the digestive process by acting
on starch.
Salivary composition changes with flow as
well as with the gland from which it is derived.
The parotid is a serous gland, the acini being
uniform and secreting fluid devoid of mucin,
whereas the sublingual is preponderantly muci-
nous, secreting primarily mucoproteins . The
submandibular gland is mixed, containing both
mucous and serous elements.
Sodium and chloride concentrations increase
in proportion to the flow of saliva. Bicarbonate
initially increases, but rapidly stabilizes, where-
as potassium remains relatively consistent re-
gardless of flow rates [8]. Other constituents
include protein, urea, and uric acid. The major
protein in parotid secretion is amylase, being far
reduced in submandibular saliva and absent in
 13. NEOPLASMS OF THE SALIVARY GLANDS
secretions from the sublingual glands. Other
proteins include blood group substance, secre-
tory IgA, lysozyme, and enzymes such as lactic
acid dehydrogenase, acid and alkaline phospha-
tase, and lactoperoxidase [9]. The greater the
mucin content, the more viscous saliva be-
comes, the least viscosity seen in parotid secre-
tion a?d the most viscosity found in sublingual
secretIOn.
Parotid and submandibular secretions ac-
count for approximately 90% of total saliva
produced, the sublingual contributing 3% and
the minor salivary glands 7%
The neural control of salivary secretion arises
in the pontine superior and inferior salivatory
nuclei. Afferent innervation arises in the oral
cavity, pharynx, and olfactory regions. Efferents
are via parasympathetic and sympathetic chan-
nels. Parasympathetics to the parotid leave the
inferior saliva tory nucleus to travel in the glos-
sopharyngeal nerve via the tympanic nerve and
lesser superficial petrosal nerve, synapsing in
the otic ganglion. Postsynaptic fibers reach the
parotid through the auriculotemporal nerve.
Sympathetic supply arises in the thoracic roots,
ascends in the cervical plexus, and synapses in
the superior cervical ganglion. Postganglionic
fibers reach the parotid (as well as the other
salivary glands) by way of fibers traveling with
the arterial supply.
Parasympathetic innervation to the subman-
dibular and sublingual glands arises in the su-
perior salivatory nucleus, leaves the pons by
ACINUS INTERCALATED
DUCT
RER
myoepithelial cell Goigi apparatus
20S
way of the nervus intermedius of the facial
nerve, and courses in the chorda tympani to join
into the lingual nerve. Synapse occurs in the
submandibular ganglion, with postsynaptic
fibers then reaching the glands. Alteration in
neuronal impulses can affect acinar secretion
and ductal absorption as well as glandular blood
flow.
Since the parotid and submandibular glands
account for the overwhelming volume of sali-
vary secretion, conditions that affect these glands
can exert profound alterations in salivary flow.
Increased flow can occur as a consequence of
smoking cigarettes, rabies, oral inflammation,
heavy-metal poisoning, oral muscular activity,
or eating highly seasoned foods [9]. Many more
factors, however, cause diminished flow and
subsequent xerostomia [10]. Factors can in-
fluence the salivary center, such as emotional
changes (fear, depression, excitement), organic
disease (brain, tumors), or drugs. The outflow
tracts may be affected by encephalitis, mass
lesions, trauma, medication, or surgery in or
about the cranial nerves. Glandular function can
be diminished by obstruction, infection, irradia-
tion, aplasia, or surgical removal, as well as by
Sjogren's syndrome. Metabolic disturbances
causing dehydration, diabetes insipidus, cardiac
failure, uremia, or edema decrease salivary flow.
Moreover, numerous drugs affect salivary flow.
FIGURE 13-4. Diagrammatic representation of the
salivary gland unit. With permission from Regezi and
Batsakis [11).
STRIATED EXCRETORY
DUCT DUCT
206 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
These include such diverse categories as an-
algesics, anticonvulsants, antihistamines, anti-
hypertensives, antispasmodics, diuretics, decon-
gestants and expectorants, muscle relaxants, and
many psychotropic medicines [9].
Histology
The functioning salivary unit is composed of
acini (serous or mucous) that lead to an interca-
lated duct, then to a striated duct and into intra-
and interlobular excretory ducts. The acinar
cells surround a central lumen, and they in turn
have myoepithelial cells at the periphery (figure
13-4). The acinar cells are highly functional cells
containing Golgi apparati, rough endoplasmic
reticulum, and secretory granules. The interca-
lated duct is a conduit composed of cuboidal
cells. The striated ductal cells have membrane
invaginations and mitochondria, as do renal
tubular cells, with similar functions of fluid and
electrolytic transport [11]. The more distal ex-
cretory ducts eventually empty intot the oral
cavity and pharynx.
The myoepithelial cells surrounding the acini
contract and thereby assist in moving the saliva
into the ductal system. These cells contain fila-
ments resembling those of smooth muscles, as
well as cytokeratin found in epithelial cells.
Although myoepithelial cells have no secretory
function, they can store glycogen [12].
The basal cells of the salivary intercalated and
excretory ducts give rise to other cells in the
gland. The excretory duct reserve cells form the
ductal columnar and squamous cells while the
intercalated reserve cells may give rise to acinar
cells, intercalated ducts cells, myoepithelial cells,
or striated duct cells [11].
Oncocytes may be seen in salivary glands of
older individuals and appear to represent de-
generated cells. They are most frequently found
in the region of the intercalated ducts and acini
[11 ].
These cellular characteristics have implica-
tions for the histogenesis of salivary gland
tumors (infra vide).
Epidemiology of Salivary
Gland Tumors
According to statistics furnished by the Amer-
ican Cancer Society, 2000 estimated salivary
gland cancer deaths occurred in 1983.
Of this total, 1400 will have been men [13]. The
exact number ofg new cases of salivary gland
tumors is much more difficult to assess. The
predominant tumor types are benign, not lead-
ing to death but rather local recurrence and de-
struction. In total, these tumors represent less
than 3% of all neoplasms of the head and neck
[3]. The predominant site of involvement is the
parotid, followed by the submandibular, sub-
lingual, and the minor salivary glands. Benign
tumors make up nearly 80% of growths within
the parotid, but less than half of tumors in the
other salivary glands [3].
Although an association of salivary gland
cancer and breast carcinoma has been implied,
this has not been statistically confirmed either
with an increased association of breast cancer in
patients having had a previous salivary gland
malignancy or vice versa [14].
A strong association has been detected in pa-
tients receiving prior radiation exposure in the
head and neck region with subsequent develop-
ment of salivary gland neoplasia. An analysis of
individuals living in and around Hiroshima with
salivary gland tumors demonstrated a signifi-
cantly higher incidence of these tumors in
those patients exposed to the atomic bomb,
when compared with those not exposed. The
incidence increased with proximity to the
hypocenter [15, 16]. All cell types of tumor
were noted, but especially malignancy. In those
exposed to 300 cGy or more, the number of cases
of neoplasia was significantly (p<0.01) greater
than expected.
Patients exposed to radiation for therapy of
benign disorders of the head and neck also
appear to have a higher incidence of salivary
gland neoplasia. The radiation has been pre-
viously delivered during childhood for dis-
orders of the tonsils and adenoids, as well as oti-
tis, mastoiditis, and cervical adenitis [17-19].
The latent period between the radiation treat-
ment and diagnosis averages 15 years or more.
This appears to occur in all cell types, but more
often affects the parotid gland.
Spectrum of Neoplasia
As the understanding of the histopathology of
salivary gland neoplasia has evolved, so have the
systems of classifying these disorders. This has
occurred because of the new techniques used to
study histologic tissue, as well as the surgical
 13. NEOPLASMS OF THE SALIVARY GLANDS 207

TABLE 13-\. Classification of epithelial salivary gland approach now accepted. Wide resection and not
tumors enucleation is standard therapy. This allows for
lower recurrence rates due to adequate resec-
Type of lesion Variations tion and a clearer definition of the true biologic
Benign Mixed tumor (pleomorphic adenoma) behavior of various tumor types [20]. Batsakis
Papillary cystadenoma lymphoma- [3] has unified this philosophy into a workable
tosum classification (table 13-1).
(Warthin's tumor) Regezi and Batsakis [11] have also proposed
Oncocytoma-oncocytosis a histogenic scheme to explain the genesis of
Monomorphic rumors salivary gland neoplasms. They postulate that
Basal cell adenoma the majority of these tumors arise from progen-
Glycogen-rich adenoma itor cell lines that are reserve cells, namely, the
Clear cell adenoma intercalated and excretory duct cells. This
Myoepithelioma
bicellular theory of origin takes into account
Sebaceous tumors
Adenoma current light- and electron-microscopic data
Lymphadenoma (table 13-2).
Papillary ductal adenoma (papilloma) Another important aspect of categorizing
Benign lymphoepitheliallesion tumors is by staging their clinical extent. For
Unclassified most neoplasms of the head and neck, this is
Malignant Carcinoma ex pleomorphic adenoma done by a universally accepted TNM system.
(carcinoma arising in a mixed Unfortunately, no such system has been sub-
tumor) scribed to by the majority of head and neck
Malignant mixed tumor (biphasic surgeons. Most often the size, consistency, loca-
malignancy) tion, and nodal status are described without a
Mucoepidermoid carcinoma specific stage being assigned. The American
Low grade Joint Committee for Cancer and End-Results
Intermediate grade Reporting has proposed a TNM classification in
High grade 1978 that is now undergoing a retrospective
Adenoid cystic carcinoma
analysis to formulate a workable and meaning-
Acinous cell (acinic) carcinoma
Adenocarcinoma lui system [21; see appendix). This is used
Mucus-producing adenopapillary
and nonpapillary carcinoma TABLE 13-2. Histogenetic scheme for salivary glands
Salivary duct carcinoma (ductal neoplasms
carcinoma)
Other adenocarcinomas Normal
Oncocytic carcinoma (malignant Cell of origin structure Neoplasm
oncocytoma)
Clear cell carcinoma (nonmucinous Excretory Excretory Squam.ous cell
and glycogen-containing or duct re- duct carCInoma
nonglycogen-containing) serve cell Muco~pidermoid
Primary squamous cell carcinoma carCInoma
Hybrid basal cell adenoma/adenoid
cystic carcinoma Intercalated Acinic Acinic cell carcinoma
duct re- Mixed tumor
Undifferentiated carcinoma
Epithelial-myoepithelial carcinoma serve cell Monomorphic
of intercalated ducts adenoma
Miscellaneous (includes sebaceous, Myoepithelioma
Stensen's duct, melanoma, and car- Intercalated Adenoid cystic
cinoma ex lymphoepitheliallesion) duct carcinoma
Metastatic
Unclassified Myoepithe- Adenocarcinoma
lium
Oncocytic tumors
According to Batsakis [3]. Striated
duct
Modified from Regezi and Batsakis [11].
208 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
primarily for the major salivary glands. Nerve
involvement is ascertained, whether it be the fa-
cial, hypoglossal, lingual, or others. This is not
the only classification scheme that has been
proposed, but may be the one most universally
accepted.
Disorders Mimicking Neoplasia
The salivary glands can be affected by the same
conditions that afflict other organs, such as in-
flammatory, vascular, metabolic, and congenital
abnormalities. Many of the disorders are unique;
however, certain mimic neoplasia, causing
isolated tumorous lesions. Some are common,
such as bacterial sial adenitis, others rare, such as
necrotizing sialometaplasia. It is not the
purpose of this section to deal with all of these
diseases, but rather to highlight those that can
be confused with true tumors.
SIALADENITIS
An acute or chronic inflammatory process may
be due to one of many causes. Any of the sali-
vary glands may be involved, but the parotid and
submandibular are most common. The affected
gland is usually diffusely swollen and tender and
not often confused with a tumor.
Viral sialadenitis is typified by mumps.
However, other agents such as cytomegalovi-
rus, Coxsackie virus, and ECHO virus can be
responsible. This is accompanied by a low-
grade fever and an enlarged, tender gland. The
saliva from the swollen duct is clear or occa-
sionally contains flecks of white desquamating
epithelial cells. In contrast, acute bacterial
sial adenitis is very painful, the patient is febrile,
and grossly purulent saliva can be expressed
from the duct. The most frequent pathogens in
this condition are Staphylcoccus aureus and
Streptococcus pneumoniae. Many of these pa-
tients are elderly, dehydrated, and have poor
dentition.
Obstructive sialadenitis can mimic either viral
or bacterial disease, depending on the presence
of a secondary infection. The submandibular
gland is most often involved. Calculi can pro-
duce recurrent sialadenitis or can occur second-
ary to these infections with associated stricture
formation. Calcium and phosphate salts are
deposited in areas of stagnant flow, giving rise
to a calculus. Initially, the pain and swelling in
the obstructed gland is intermittent, occurring
during or after meals. When total obstruction
is present, the symptoms are slow to subside
and secondary infection rapidly ensues.
Granulomatous diseases such as tuberculosis
(and atypical mycobacteria), sarcoidosis, cat-
scratch disease, and actinomycosis can produce
salivary gland inflammation, as well as lymph-
adenitis in or near the salivary glands, simu-
lating a tumor mass. Often an acute inflamma-
tory process occurs, but occasionally a slightly
tender, enlarging growth with few systemic
symptoms is the only manifestation.
ACALCULOUS SIALADENOPATHY
A broad range of disorders can cause isolated
salivary gland enlargement. Most often the
swelling of the parotid gland is recurrent, affect-
ing both children and adults. By definition, no
ductal obstruction can be found. An inflamma-
tory process will often occur bilaterally leading
to a lymphocytic infiltration, various degrees of
glandular architectural disruption, and the
formation of myoepithelial islands [22]. The
precise etiology of this family of lymphoepithe-
lial lesions is obscure, whether due to chronic
and recurrent infection or an autoimmune pro-
cess [23]. The swelling can be isolated, giving
the clinical (and even sialographic) impression
of a tumor. There appears to be no consistent
predictable correlation among the variables of
duration, severity, sialography, and histo-
pathology in acalculous parotid sialadenopathy
when this has been investigated in a double-
blind fashion [22].
Some patients do develop associated local and
systemic symptoms. These include xerostomia,
keratoconjunctivitis, and a connective tissue
disorder, most frequently rheumatoid arthritis
(Sjogren's syndrome). Other collagen diseases
may occur such as lupus erythematosis, periar-
teritis nodosa, or scleroderma. Rarely, some
patients will progress to a true lymphoreticular
proliferation, such as pseudolymphoma, true
lymphoma, Hodgkin's disease, or sarcoma [23].
Other possible causes of parotid swelling
include metabolic derangements such as gastro-
intestinal disease (e.g., carcinoma of the eso-
phagus, dysentery, celiac disease), nutritional
deficiency (vitamin A, pellegra, beriberi), cir-
rhosis, and uremia. Endocrine factors such as
diabetes, hypothyroidism, menopause, preg-
nancy, and lactation can give rise to asympto-
matic salivary glandular enlargement [24].
Radiation therapy to other areas in the head
and neck can diminish salivary flow, leading
to stasis and sialadenopathy. Drugs, such as
 13. NEOPLASMS OF THE SALIVARY GLANDS
iodine, and heavy metals (mercury, copper, and
bismuth) can cause inflammatory swelling, and
allergic responses to a wide array of medications
have been reported [23].
CYSTIC LESIONS
Any minor salivary gland can become ob-
structed, causing cystic dilatation and a sub-
sequent retention cyst arising in the oral cavity
or pharynx. If the retention cyst occurs in the
sublingual gland, a ranula is formed. All of
these lesions are soft and covered by normal
epithelium.
The parotid, however, is the site of the vast
majority of salivary gland cysts, and cystic le-
sions account for up to 5% of parotid gland
masses, not all of which are benign [25, 26].
Most of these masses are unilateral and require
excision for definitive diagnosis.
A cystic lesion in a child is most frequently
benign and includes entities such as lymphan-
gioma, hemangioma, dermoid cysts, and bran-
chial cleft cysts. Dermoid cysts occur in isolation
whereas branchial cleft anomalies arise from the
first branchial cleft and may be associated with
ectoderm and its appendages as well as meso-
derm (Work's classification type II). Those
branchial cleft cysts without appendages and
simply having a squamous epithelial lining
arising near the auricle are classified as type 1.
Either type, however, lies in close proximity to
the facial nerve, which must be preserved at
time of excision [25].
In the adult, either benign or malignant con-
ditions may be cystic. Recurrent infections or
ductal dilatation after stricture formation may
lead to parenchymal destruction and the de-
velopment of a cyst. Retention cysts may occur.
Cysts may be found in association with pleo-
morphic adenoma, adenoid cystic carcinoma,
mucoepidermoid carcinoma, and cytodenoma
lymphomatosum (Warthin's tumor) [25, 26].
Therefore, wide excision with clear margins is
necessary.
OTHER LESIONS
Necrotizing sialometaplasia is an inflammatory
process involving the minor salivary glands,
causing ulceration; it can be mistaken for a
malignant tumor, such as squamous cell carci-
noma or mucoepidermoid carcinoma [27, 28].
Most often found in the oral cavity, this lesion
can also occur in any area of the head and neck
where mucus-secreting glands occur. The pain-
209
ful ulcer may be antedated by trauma, or
be associated with tobacco and alcohol abuse.
Histologically there is squamous metaplasia,
but no malignant cells can be found within the
marked inflammatory response. The process
heals spontaneously and requires no treatment
after the diagnosis is made. No cause for necro-
tizing sialometaplasia has been found, although
infarction of the glandular tissue has been
suspected. This could be due to local trauma
or vasculitis. The infarction leads to ischemic
necrosis, ulceration, metaplasia, and finally
fibrosis [27].
Lipoma, although a common tumor, is rarely
found in the areas of the salivary gland. It has
been reported in association with the parotid
gland [29], mimicking a true salivary gland neo-
plasm. Lipomas occur most often in men in
the fifth and sixth decades of life, and do not
produce neurologic or dermal symptoms. They
tend to be soft, painless, mobile, and slowly
enlarging. There is no absolute method to
diagnose a lipoma preoperatively, so that the
surgical approach should be that for any parotid
tumor.
Extramedullary hematopoiesis occurring in
the parotid has been found in a patient with
myelofibrosis who presented with a parotid
mass [30]. Agnogenic myeloid metaplasia usual-
ly appears with hepatosplenomegaly and a nor-
mochromatic, normocytic anemia. The involve-
ment of the salivary gland is quite rare.
Diagnosis
HISTORY
Regardless of the age of the patient, the most
common presenting symptom of salivary gland
tumors in any site is a painless, enlarging mass.
Because the majority of these tumors are be-
nign, the mass tends to grow slowly. The associ-
ated symptoms are related to the primary site of
the tumor and the surrounding tissue. In the
parotid region, inquiry into facial nerve func-
tion and trismus should be made. Benign parot-
id tumors may reach massive proportions with
preservation of facial nerve function, while
small malignancies overlying the main trunk can
cause varying degrees of facial weakness.
In a series reported by Conley and Baker [4],
over 50% of patients with malignant parotid
tumors presented with a painless mass, 32% had
pain associated with the mass, and nearly 20%
 STAGING DIAGRAM (conl.l

JOINT C£HTlR F'OfII O'TOLAftYNIOLOIY

....,
OAT[
HAlltaIfD MEDICAL SCHDOL
HOeP1TAL NO.
HEAD AND NECK STAGI NG 01 AGRAM 111fT" o..n
,"",lelAlil
000Cl0IJII[

"'liliA1ft' STAQ[

A B

FIGURE 13-5A and B. Diagrams used to depict the site of the primary cancer and the location of the nodal disease in the head and neck region.
 13. NEOPLASMS OF THE SALIVARY GLANDS
had evidence of facial nerve weakness. Pain and
nerve palsy were most often found in the pres-
ence of squamous cell and adenoid cystic carci-
nomas.
Because the submandibular gland is fre<J.uent-
ly involved with inflammatory conditions,
tumor may be mistaken for sialadenitis. The
absence of pain, swelling, pus from the duct,
a~d progressive enlargement should be warning
signs.
Minor salivary gland neoplasms often pre-
serve the overlying mucosa. Ulceration is un-
usual.
PHYSICAL EXAMINATION
A complete head and neck examination should
be performed on any patient suspected of
having a malignancy. Inspection should include
assessing the location of the tumor, its size,
and the characteristics of the skin or mucosa.
The duct from the gland must be examined and
the expressed saliva described (clear, purulent,
speckled). The presence of one lesion does
not preclude others, and synchronous lesions
should be sought. Palpation should be thorough
and often needs to be bimanual. The consistency
of the lesion should be described. Facial and
cervical adenopathy must be evaluated. Cranial
nerve examination is mandatory, especially of
the trigeminal, facial, lingual, glossopharyngeal,
and hypoglossal nerves.
Although benign tumors often occupy the
superficial portion of the parotid gland, only
half of parotid malignancies are confined to this
lateral portion; 10% are limited to the deep
lobe, 30% to both, and another 20% of malig-
nancies extend out of the boundaries of the
parotid [4].
When the examination is completed, results
should be recorded on a tumor diagram (figure
13-5A and B). This gives a permanent record of
the location of the primary and possible nodal
metastases. Malignant tumors may require mul-
tiple modalities of therapy, changing the size
and consistency of the tumor. In this situation,
the tumor diagram of the original lesion be-
comes mandatory in assessing the efficacy of
treatment.
Distant metastases are uncommon in these
tumors, but, when appropriate, chest tomogra-
phy, liver function studies, and bone scans may
be needed.
211
RADIOGRAPHY
The physician faced with a firm, progressively
enlarging salivary gland mass will often seek
assistance in making a diagnosis of inflamma-
tory versus neoplastic process, and benign from
malignant. Radiography has gone through
various phases of acceptance in its utility as a
diagnostic tool. This is because of the limited
value in differentiation of various histologic
tumor types. Moreover, when the physician has
decided that a process may be neoplastic, a
surgical procedure is almost always indicated.
The use of computerized tomographic scanning
with sialography and the possibilities of nuclear
magnetic resonance scanners in the future are
altering this concept (see chapter 12).
Plain films of the anterior floor of the mouth
and cheek may demonstrate calculi if they are
radiopaque, which is rare for parotid stones,
and may occur only in 50% of submandibular
calculi.
Contrast sialography of the submandibular
and parotid glands is a relatively simple proce-
dure that delineates the details of the glandular
ductal architecture [31, 32]. Obstructing calculi
are clearly demonstrated, as are ductal stric-
tures. Sialadenitis, whether congenital or the
result of recurrent inflammation or a benign
lymphoepithelial lesion, is characteristic in
appearance. Unfortunately, the degree of sial-
adenitis on sialography may not reflect the
degree of parenchymal alterations [22]. Tumors
displace the duct system and may be defined as
. arising from the deep or superficial portion of
the gland.
Nuclear scanning of the major salivary glands
has been possible because of the functional
activity of the striated duct cells. The transport
capabilities of these cells allow them to secrete
some radionuclides (such as 1251 and 99'fC) into
the ducts. Scanning for radioactivity may then
demonstrate gland function. The greatest use
of the nuclear scan has been proposed to be
the capability of delineating certain tumors.
Warthin's tumors and oncocytomas have been
thought to appear as hot nodules on pertechne-
tate scans. This is not always the case, so that
the usefulness of the scan in diagnosing a spe-
cific histologic type of lesion is limited.
Xerosialography [33] uses the combined tech-
niques of sialography and xeroradiography. It
affords better detail than routine sialography,
especially when the ducts overlie bone. Because
of the amount of radiation exposure, however,
212 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
the use of xeroradiography has diminished over
recent years.
Computed tomography (CT) has now be-
come the most useful of the radiographic proce-
dures. Sialography in combination with CT
scans gives the added benefit of demonstrating
the ducts as well as the lesion under question.
This assists in identifying tumors lying out of
the substance of the gland (especially in the deep
lobe of the parotid or those in the parapharyn-
geal space) [34]. The relationship to the facial
nerve can be evaluated [35]. The newer high-
resolution scanners can demonstrate tumor char-
acteristics that differentiate between benign and
malignant lesions. Benign tumors appear
as discrete, sharply marginated, high-density
masses within an otherwise normal gland. In-
vasive malignancies present as poorly defined,
dense lesions that traverse fat and fascial planes.
Inflammatory disease most commonly appears
as a relatively diffuse, irregular area of increased
density in an enlarged gland. Although a focal
inflammatory process may be difficult to dis-
tinguish from a malignancy, the overall sensi-
tivity of CT scanning is quite high [36]. With
continued technological improvements in CT
scanning and the availability of magnetic res-
onance imaging it seems certain that both sen-
sitivity and specificity of radiography should
improve, making preoperative evaluation more
accurate.
BIOPSY
The concept of seeding of salivary tumors dur-
ing incisional biopsy has been well established.
The difficulty of later resection and the possibil-
ity of facial as well as other nerve injuries are
overwhelming reasons to avoid this surgical
approach. Because of this, wide resection for
diagnosis, and often therapy, is accepted treat-
ment. In the parotid, lobectomy is the proce-
dure of choice; in the submandibular, total
gland removal; in the sublingual and minor
glands, wide excision.
The increased popularity of fine-needle
aspiration biopsy has come about because of the
simplicity of a technique that can afford valu-
able preoperative information: A 22-gauge nee-
dle is attached to a 20-cc syringe (figure 13-6)
and the mass is aspirated for cellular material. It
can then be prepared as for other cytologic
specimens [37].
Recent studies [37-39] have confirmed the
high overall accuracy in making the appropriate
diagnosis. False positives and false negatives
FIGURE 13-6. A fine-needle (22-gauge) aspiration de-
vice using a 20-cc syringe is shown that enables the
physician to perform aspiration with one hand while
stabilizing the mass with the other (Handle: Cameco
Syringe Pistol, Enebyberg, Sweden).
are rare, and seeding of tumor along the needle
tract has not been reported in any salivary gland
neoplasm. The technique does not jeopardize
surgical resection and offers rapid, inexpensive
information when the extent of resection is
planned. The surgeon can then integrate the
clinical impression with the cytologic diagnosis.
This becomes critical in parotid surgery where
wide resection may mean sacrificing the facial
nerve.
The head and neck surgeon will often seek
additional information intraoperatively by re-
questing a frozen section. The pathologist can
offer a high rate of agreement when frozen-
section diagnosis is compared with that made
on permanent sections. Difficulties arise with
malignant tumors, however, especially in recog-
nizing a mucoepidermoid tumor, and in distin-
guishing adenocarcinoma from adenoma, and
mucoepidermoid or adenoid cystic carcinoma
from benign mixed tumor [40, 41]. In this cir-
cumstance, as in many tumors of the head and
neck, the clinician and pathologist must work in
concert. A patient whose tumor shows rapid
growth and fixation and produces facial nerve
weakness should be strongly suspected of hav-
ing a malignancy regardless of frozen-section
diagnosis. If any doubt exists in the mind of
either physician, then a diagnosis should be
withheld until permanent sections are reviewed.
Tumors of the Parotid Gland
Of the parotid tumors, 80% are benign and
 A B c

FIGURE \3-7. (A) Large pleomorphic adenoma of the parotid gland in a 22-year-old man. (B) Tumor and parotid exposed. (C) Tumor dissected free of the facial
nerve (arrow) and retracted inferiorly. .

N
-'"
214 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
20% are malignant. This is in contrast to the
submandibular glands in which half of the
tumors are malignant, with an even higher rate
of malignancy in the sublingual gland [42, 43].
The age distribution follows a bell-shaped curve
with the highest incidence of benign tumors in
the fifth decade of life, and malignancy in the
sixth decade. In general, salivary gland tumors
occur more often in females than males; how-
ever, cystadenoma lymphomatosum predomi-
nates in males [43].
MIXED TUMOR
(PLEOMORPHIC ADENOMA)
The benign mixed tumor accounts for 55%-
65% of all parotid tumors and has a female-to-
male predilection of 60 :40 [44]. These tumors
present as a slow-growing, painless, well-
demarcated mass, often in the tail of the parotid.
Examination reveals a smooth, firm, mobile le-
sion in the presence of otherwise normal neuro-
logic findings (no facial weakness or numbness).
Because of the absence of discomfort, mixed
tumors (and other benign lesions as well) can
grow to a large size before the patient may seek
medical care. They are almost invariably soli-
tary, but multiple tumors have been reported
[44] (figure 13-7a-c).
The gross appearance suggests a marginated
capsule, which in actuality represents compres-
sion of adjacent tissue [45]. Enucleation of the
tumor alone leaves residual outgrowths of the
mass that later appear as recurrences. Separate
foci of a mixed tumor rarely occur. This is the
basis of the principle of wide excision in order
to prevent recurrent tumor.
Histologically, both epithelial and mesen-
chymal elements must be present for a diagnosis
of mixed tumor. The mesenchymal components
may be mucoid, fibroid, chondroid, vascular, or
myxochondroid [3].
The recurrence rate of mixed tumors varies
widely. With superficial parotidectomy as the
treatment of choice, however, the rate can be
lowered to almost zero [42]. The surgical proce-
dure for recurrent mixed tumors is far more dif-
ficult than for the initial resection. Recurrences
are usually nodular clusters that are as slow
growing as the initial tumor. If a parotidectomy
is performed, recurrences, if they do occur, are
more likely after resection for very large tumors
or those involving the deep lobe. If the tumor
arises in an elderly patient, observation may be
the best option. If a surgical procedure is to be
performed, wide resection with facial nerve
preservation should be attempted [46]. The use
of magnification is mandatory. Scarring makes
nerve identification quite difficult [47]. Occa-
sionally the facial nerve is deliberately sacrificed
with repair by nerve graft using either the great-
er auricular, which lies in the operative field, or
the sural nerve. The sural nerve has the advan-
tage of being of appropriate size, out of the field
of surgery for a neoplasm, and contains fascicles
that can be anastomized to the branches of the
facial nerve.
PAPILLARY CYSTADENOMA
LYMPHOMATOSUM (WARTHIN'S TUMOR)
Warthin's tumor represents the second most
common benign lesion of the parotid gland and
comprises approximately 6% of all parotid neo-
plasms [48]. It appears to originate from ductal
elements in association with lymphoid tissue
either within or surrounding the parotid gland.
This is supported by the presence of ductal in-
clusions in parotid lymph nodes, the occurrence
of some of these tumors external to the gland, as
well as its true multicentricity [14, 48]. Warth-
in's tumor may occur as multiple unilateral
tumors as well as bilaterally.
A papillary cystadenoma presents as a
rounded, smooth, mobile, firm mass in the tail
of the parotid. It is almost nonexistent in other
salivary glands. It is benign, with malignant
transformation being quite rare, as is facial
nerve involvement. Males are affected five
times more than females (figure 13-8).
The gross appearance of this tumor is smooth
and lobulated, containing a brown fluid in
cystic spaces with gray lymphoid areas. Histol-
ogically, an oncocytic epithelium and lymphoid
stroma are invariably present.
Because of the presence of possible multi-
ple tumors, wide excision (parotidectomy) is
mandatory. The contralateral gland should be
examined for disease once a diagnosis is con-
firmed. Recurrence probably represents a
second primary left behind rather than a return
of the original lesion.
ONCOCYTOMA
The salivary oncocyte is a cell derived from an
acinus or intralobular duct that has undergone
cytoplasmic change in response to unknown in-
fluences [3]. This cell is rarely present before the
patient is 50 years old. It is a component in the
Warthin's tumor as well as the oncocytoma.
 13. NEOPLASMS OF THE SALIVARY GLANDS
FIGURE 13-8. Massive parotid papillary cystadenoma
lymphomatosum (Warthin's tumor) in a 75-year-old
man that has eroded the overlying skin without evi-
dence of facial nerve weakness.
The true oncocyte contains large numbers of
hypertrophic and often distorted mitochondria
[14].
The tumor itself is rare and arises predomi-
nantly in the parotid. Its incidence varies from
0.5% to 1.2% of all parotid gland tumors.
Almost all of these lesions are benign, although
malignant oncocytomas have been reported
[49]. The lesion is well circumscribed and not
encapsulated. The histology is that of swollen,
eosinophilic granular cells. As in other benign
lesions, therapy is total surgical removal.
MONOMORPHIC ADENOMAS
Monomorphic adenomas can be viewed as a
subgroup of benign tumors consisting essential-
ly of a single cell type, whereas the mixed tumor
is composed of both myoepithelial cell and in-
tercalated duct cell derivatives. The monomor-
phic adenomas may be myoepitheliomas, epi-
myoepithelial tumors, or variants of the basal
cell adenoma. The frequency of monomorphic
adenomas is low, being less than 2% of all of
salivary gland tumors [45].
Since the first description by Kliensasser and
Klein [50], basal cell adenoma, with its solid,
trabecular-tubular, and canalicular variants, has
been increasingly recognized as a distinct entity.
215
It is the most common monomorphic adenoma.
Cases have been reported principally from the
parotid gland and minor salivary glands of the
upper lip, and in lesser numbers from the oral
cavity, lower lip, hard palate, and submandibu-
lar gland [51]. The basal cell tuIhor appears to be
totally epithelial in origin and may be inter-
preted as a counterpart of the pleomorphic ade-
noma in which the myoepithelial component is
minimally expressed.
Parotid basal cell adenomas appear in patients
older than those in whom mixed tumors de-
velop (seventh decade compared to the fifth in
pleomorphic adenoma). A possible relationship
with adenoid cystic salivary carcinoma has been
described, the basal cell adenoma being a benign
counterpart [51]. It is usually well encapsulated
and lies superficially in the parotid gland.
The other types of monomorphic tumors are
exceptionally uncommon and myoepithelomas
are clinically undistinguishable from mixed
tumors. The most important consideration in
regard to the membranous or hybrid basal cell
variants is the necessity of not confusing them
with adenoid cystic carcinomas, which may
have a similar histologic appearance. Recurrence
in the benign adenomas is rare, and the con-
sequences of aggressive surgery when a malig-
nancy is misdiagnosed should be avoided [3].
SEBACEOUS TUMORS
Ectopic sebaceous elements III the head and
216 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA

neck (e.g., Fordyce spots in the oral cavity) are

not uncommon and may also occur in the sali-
vary gland. The most common gland affected is
the parotid. This can be a normal variant in up
to 33% of the adult population [3]. The origin
of these tumors is unknown, although an
ectodermal derivation would account for the
parotid, but not the submandibular, sebaceous
cell lesions. The most common of these very
rare tumors is the sebaceous lymphadenoma, in
which sebaceous glands in a lymphoid matrix
are found. Carcinomas of sebaceous tissue also
occur, but a benign form of pure sebaceous tis-
sue neoplasia may not exist. Sebaceous elements
are also found in association with other neo-
plasms, such as mixed tumors, mucoepidermoid
carcinomas, and Warthin's tumors [3].

CARCINOMA EX
PLEOMORPHIC ADENOMA
According to Batsakis et al. [45], carcinoma ex
pleomorphic adenoma is an epithelial malignancy
arising from a mixed tumor; metastases contain
only the carcinoma. This is by far the most
common of malignant mixed tumors. The true
malignant mixed tumor can be either a benign
mixed tumor that inexplicably metastasizes
without change in histology, or a heterologous
carcinoma (or carcinosarcoma) that metastasizes
with both epithelial and stromal elements
(figure 13-9). The carcinoma ex pleomorphic
adenoma may appear in either of two clinical
forms. The one seen most frequently is a malig-
nancy arising in a patient with a known benign
mixed tumor for a considerable period of time,
and may be the development of a malignant
focus within an older tumor. The second, less
common occurrence, is the de novo presence of
a malignancy in a newly discovered mass (often
present for less than one year) and is more com-
mon in younger patients.
Most often the patient will describe a rapid
growth of a mass noted for years that may be
accompanied by facial pain and weakness-
both ominous signs. In a series reported from
Memorial Sloan-Kettering Hospital, malignan-
cies associated with mixed tumors occurred in
5% of all salivary neoplasms (146 of 743
patients). These arose in the parotid in 73% of
cases, the submandibular in 16%, and in minor
salivary glands in 11 %.
The recurrence rate is high, owing in part to
failure to note the malignant nature of the
FIGURE 13-9. Carcinoma ex pleomorphic adenoma of
the parotid gland arising de novo and diffusely en-
larging the right parotid gland in this 48-year-old
man. No facial nerve weakness or cervical adeno-
pathy was present.
tumor on initial histologic examination. Necro-
sis, hemorrhage, cystic change, softening, and
an irregular border should alert the physician
to the possibility of malignancy [45]. For
appropriate diagnosis, mesenchymal tissue
(myxoid, chondroid, or fibroid) should be
found in association with malignant epithelial
structures. In a tumor suspected of harboring
carcinoma ex pleomorphic adenoma, multiple
samples are required since the tumor may be
isolated to one area.
Recurrences in the parotid gland may occur
in half of the patients. Nodal metastases have
been found in 12% and distant sites (lung, bone,
brain) in 28% [52]. A poor prognosis is associ-
ated with inadequate initial therapy, tumors of
over 6 cm in size, or multiple nodes in the pri-
mary site. Fixation of the primary as well as nodal
disease are also ominous findings. Because of
these statistics, Spiro et al. suggest wide regional
resection in association with a neck dissection
to improve cure rates that, in their series, were
40%,24%, and 19% from five-, ten-, and 15-
year intervals [52].
 13. NEOPLASMS OF THE SALIVARY GLANDS
MUCOEPIDERMOID CARCINOMA
Mucoepidermoid carcinoma encompasses a
spectrum of tumors of varying biologic activity
from very slowly growing to aggressive. It com-
prises up to 10% of salivary gland tumors. It
is found primarily in the parotid (up to 90%),
much less frequently in the submandibular, and
rarely in the sublingual and minor salivary
glands [53].
Histologically, these tumors contain at least
two cell types: epidermoid and mucus secreting.
According to Batsakis et al. [53], these cell types
can be further differentiated into "maternal,"
intermediate, epidermoid, clear, columnar, and
mucus cells. These cells may produce cystic
structures within the tumor. The overall histol-
ogical pattern depends on the relative composi-
tion and number of the representative cell types.
The clinical behavior of these tumors appears to
be reflected in the histology and they can be
classified into low-grade, intermediate-grade,
and high-grade malignancies. Low-grade muco-
epidermoid carcinomas are histologically well
differentiated, composed of predominantly
columnar and mucus cells forming glandular
and cystic spaces. Intermediate-grade tumors
contain predominantly epidermoid and inter-
mediate cells and are more cellular and solid,
with greater local invasion. High-grade tumors
may be variable, but more anaplastic. Sub-
groups of these carcinomas may contain pri-
marily epidermoid cells, giving a pattern similar
to squamous cell carcinoma, both mucus and
epidermoid cells, and a third with all cell types,
but with anaplasia and frequent mitoses [3).
Mucoepidermoid carcinomas may occur in
any age group and equally in the sexes. They
may be superficial in the parotid or highly
infiltrative. Low-grade malignancies are true
carcinomas and, although apparently locally
benign, they may metastasize. High-grade
carcinomas metastasize to cervical nodes and
to distant sites such as lung and bone. They fre-
quently recur. The low-grade neoplasm is for-
tunately ten times more common than the high-
grade variant [4). The survival is also reflected
in the tumor types, with 90% expected for
low-grade and only 20%-30% for the more
aggressive tumors.
Therapy should consider the potential in-
vasiveness of these carcinomas. Low-grade
tumors require wide resection of either the su-
perficiallobe or total gland if found in the deep
217
lobe. More extreme surgery for higher-grade
mucoepidermoid tumors necessitates neck dis-
section, sacrificing the facial nerve (with im-
mediate grafting). In high-grade carcinomas,
temporal bone, mandible, skin, and auricle
may need to be sacrificed [42). Nerve grafting
should be performed whenever possible, and
the need for chemotherapy and radiation may
be present as well (infra vide).
ADENOID CYSTIC CARCINOMA
(CYLINDROMA)
Adenoid cystic carcinoma is an epithelial can-
cer, probably derived from the intercalated duct
cell [11). It arises in all of the salivary glands of
the head and neck, but is relatively more fre-
quent in the minor salivary glands than in the
major ones. It accounts for less than 5% of all
parotid neoplasms and 10%-15% of neoplasms
of the submandibular gland, and over 30% of
those in the minor glands [54, 55].
The presenting symptoms may vary. In the
parotid, almost all patients present with a pro-
gressively enlarging mass frequently (over 20%)
associated with pain and often (10%) with facial
nerve weakness or paralysis [4, 56). A character-
istic of adenoid cystic carcinoma is its tendency
for perineural invasion, which accounts for the
high incidence of pain and facial nerve involve-
ment. Invasion of nerves is an almost constant
microscopic finding [3).
Although its slow growth suggests a benign
tumor, this tumor has a high recurrence rate and
frequent local and systemic spread. The gross
tumor appears well demarcated, but no true
capsule exists and a regional infiltrative pattern
is usual. Histologically, four patterns have been
described: cribriform, cylindromatous, solid or
basaloid, and tubular [55). There is no correla-
tion found in mucoepidermoid carcinoma be-
tween histologic type and clinical behavior,
although tubular types may have a better prog-
nosis and solid less so. The cystic spaces are not
glandular spaces, but rather pseudocysts sur-
rounded by replicated basement membrane
[55).
Nodal metastases have been found in 15% of
patients, but distinct disease occurred in 43% of
patients reported by Spiro and associates from
Memorial Sloan-Kettering Hospital [57, 58].
The lungs are most frequently affected, suggest-
ing vascular rather than lymphatic dissemina-
tion. These metastases are often multiple.
218 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
Many patients may have a prolonged course
of frequent local recurrence and slowly growing
distant metastases. Some patients may succumb
to a more aggressive tumor. There are recur-
rences in the parotid in up to 40% of patients
[56], suggesting inadequate initial therapy. Mis-
diagnosis may occur on frozen section and a
final decision as to the extent of resection may
need to await permanent sections.
Treatment should be primarily surgical with
adeq uate margins, assisted by frozen sections
once the histologic nature of the adenoid cystic
carcinoma has been confirmed. Nerve resection,
leaving margins free of tumor, with grafting
should be performed. Neck dissection for
palpable nodal disease is advised.
Irradiation is a variable adjunct to therapy for
nonresectable recurrences, for positive surgical
margins, for local control in inaccessible tumors
(such as minor salivary glands), and for patients
not able to withstand large surgical procedures
[4,54,56].
Success of treatment must be measured over
many years in adenoid cystic carcinoma. At five
years, 75% of patients with parotid neoplasia
would be survivors. By 20 years, a 13% survival
rate can be expected, and even lower in minor
salivary gland primaries [3].
ACINIC CELL CARCINOMA
Acinic cell carcinoma is less common than
the other major types of salivary carcinomas
that have been described above (carcinoma ex
pleomorphic adenoma, mucoepidermoid and
adenoid cystic carcinoma). It accounts for up to
5% of all parotid gland tumors and 15% of
parotid malignancies [59]. It may occur in the
other major salivary glands, but less frequently
than in the minor glands of the oral cavity [53].
Because of its relative rarity, few reports of large
numbers of cases exist.
This tumor grows slowly, presenting most
often as painless mass rarely producing facial
weakness. Involvement of the facial nerve is
more common in recurrent lesions or advanced
disease. It is most frequent in patients 30-50
years of age and, in some reports, twice as com-
mon in females than in males [59, 60]. It is only
second to Warthin's tumor in its incidence
bilaterally [60].
The histogenesis of the acinic cell carcinoma
is not entirely certain. However, it probably
arises from the acinar cells or the cells of the
terminal tubule or intercalated ducts [53]. The
appearance is of normal salivary gland serous
cells, containing secretory granules as well as
ductlike structure that have clear cytoplasm.
Recurrence may occur in up to half of pa-
tients and tends to be local and multiple. Local
disease in residual parotid tissue is much more
common than regional lymph node metastases.
Perineural spread may occur without evidence
of invasion. Hematogenous spread may be
noted in preterminal and long-standing cases
with lung, liver, bone, and brain involved [59].
Despite the benign nature of these tumors,
they are carcinomas, necessitating resection of
the mass with normal surrounding tissue (su-
perficial or total parotidectomy) with preserva-
tion of the facial nerve whenever possible. A
neck dissection is rarely indicated. Although
overall recurrences may be up to 50%, wide
excision can lower this to 10%. Recurrences are
difficult to treat surgically because of fibrosis
and the multiplicity of tumor sites.
Survival rates are over 75% for 5 years,
63% for 10 years, and 44% for 15 years of
follow-up in the series reported by Perzin and
Li Volsi [61], which included 51 cases. Poor
prognosis was associated with positive surgical
margins, deep lobe involvement, larger tumors
(which also appeared to be rapidly growing),
numerous mitoses and atypical cells, infiltra-
tion, and lympadenopathy.
ADENOCARCINOMA
These tumors do not fit into any definite cate-
gory already described and represent various
histologic patterns: tubular or ductal, papillary,
and undifferentiated [55]. They can represent
up to 15% of parotid malignancies. There is no
sex predilection nor peak age of occurrence.
No neurologic deficits occur, but fixation to
surrounding structures may be present [3].
These tumors are histologically glandlike
with the only similar lesion being the muco-
epidermoid carcinoma. Adenocarcinomas lack
the squamous elements.
Most of these tumors are noninvasive, with
the more aggressive tumors behaving like low-
grade mucoepidermoid carcinomas; even in pa-
tients presenting signs of advanced disease, only
20% died of the neoplasm [42]. Recurrence is
a poor prognostic finding, signifying a higher
mortality. Lymphatic and distant (bone and
lung) spread also portends poor survival.
Infiltrating salivary duct carcinoma is a type
of adenocarcinoma with distinct characteristics,
 13. NEOPLASMS OF THE SALIVARY GLANDS
histologically resembling ductal carcinoma of
the breast. This tumor is found most often in
the parotid gland in patients in their seventh de-
cade and occurs as a rapidly enlarging, painless
mass. Facial nerve paralysis is frequent. Nodal
and distant spread is common, especially to
lung, bone, and brain. The metastatic rate is
75% and tumor-related mortality is 73% from
this very rare neoplasm [62]. Because of the his-
tologic similarity to breast and prostate carcino-
ma, primary tumors in these sites metastatic to
the parotid must be excluded prior to a defini-
tive diagnosis of infiltrating salivary carcinoma.
Undifferen'tiated carcinomas are of glandular
derivation, but do not fall into any specific sub-
set. Undifferentiated areas can be found in other
salivary gland tumors. Pure undifferentiated
carcinomas are highly malignant and account
for less than 3% of tumors of all major salivary
glands and less than 5% of parotid tumors (3].
Older patients (60-70 years) are usually
affected. The carcinomas also occur in associa-
tion with mixed tumors of long duration and in
general carry a poor prognosis, being compara-
ble to carcinoma ex pleomorphic adenoma.
SQUAMOUS CELL CARCINOMA
This uncommon cancer presents in the parotid
gland as a stoney hard mass fixed to the sur-
rounding structures and skin. It is highly malig-
nant, grows rapidly, causes pain and facial nerve
paralysis, and involves regional lymph nodes in
half of patients [4, 63]. The rarity of this tumor
should be kept in mind when keratinizing neo-
plastic epithelium is encountered histologically,
since metastatic epidermoid carcinoma as well
as mucoepidermoid carcinoma must be ex-
cluded from consideration.
Squamous cell carcinomas infiltrate locally
and regionally, rarely producing distant metas-
tases. The prognosis is related to the stage of the
tumor rather than to the histologic appearance
[3]. A 19% five-year survival rate has been
reported [42]. Tumors over 6 cm, facial nerve
paresis or paralysis, skin ulceration, local re-
currence, and metastases are considered to be
evidence of advanced disease.
Therapy necessitates radical surgery involv-
ing composite resection of the parotid, neck
dissection, and resection of adjacent structures
including muscle, mandible, and temporal
bone when necessary. Ancillary treatment with
radiation and chemotherapy is often required.
Because of the infiltrative nature of these
219
malignancies, deep lobe tumors may extend to
the infratemporal fossa. These occult parotid
cancers are often squamous cell carcinomas.
Symptoms of preauricular pain, trismus, and
numbness may be noted as well as a fullness
posterior and deep to the angle of the mandible.
These tumors can be overlooked for quite some
time, being confused with trigeminal neuralgia
or atypical facial pain [64]' A CT sialogram aids
in the diagnosis.
LYMPHOMA OF THE PAROTID
Malignant lymphomas are known to arise in
cervical nodes and, although the parotid con-
tains lymphoid tissue, malignant lymphoma of
this gland is not often found. Primary lympho-
mas of the salivary glands are quite rare, involv-
ing the parotid, occasionally the submandibular,
and may not be seen in the other glands [65].
Lymphoma involving parotid nodes is seen
more frequently than extranodal disease. Most
extranodal lymphomas are lymphocytic or his-
tiocytic [3].
Patients harboring lymphoma often have
symptoms consistent with an nonspecific
sialadenitis. Indeed, a definite association exists
between Sjogren's syndrome and the develop-
ment of malignant lymphoma. This may occur
in up to 5% of patients with Sjogren's syn-
drome, approximately 44 times that expected in
the normal population [66], and may be related
to the presumed autoimmune nature of the
underlying disorder.
A complete evaluation for staging of the
lymphoma is mandatory prior to the institution
of treatment, since localized disease responds to
radiation and a disseminated process requires
chemotherapy. Response to treatment depends
on the cell type and stage as with lymphomas
elsewhere.
Extramedullary plasmacytomas have also
been diagnosed in the parotid and submandibu-
lar glands [67].
OTHER PAROTID TUMORS
A variety of other epithelial tumors exist, as
noted in table 13-1. Clear cell tumors appear to
arise from intercalated ducts, are composed of
epithelial and clear myoepithelial cells, and
should be regarded as low-grade carcinomas
[45].
Oncocytes may develop into neoplasia, but
make up less than 1% of all salivary gland
tumors, with both benign and malignant
220 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
variants known to occur. It may be difficult to
separate the benign oncocytoma from malignant
forms. The parotid is the most frequent site.
The benign growth is encapsulated, lobulated,
slow growing, and occasionally bilateral. Re-
currences do not occur after adequate excision.
Oncocytic carcinoma is even less frequent,
spreads to lymph nodes,and produces multiple
local recurrences, with a prognosis similar to
that of acinic cell carcinoma [3].
In addition to the epithelial tumors, the parot-
id can give rise to embryonal rhabdomyosarco-
mas, fibrosarcomas, malignant neurilemmomas,
liposarcomas, and hemangiopericytomas.
METASTASES TO THE PAROTID GLAND
The lymph nodes in and about the parotid drain
the scalp, ear, eyelids, nose, lacrimal glands, and
facial skin as well as the paranasal sinuses and
naso- and oropharynx. Thus, the potential for
lymphatic spread to the area is great.
Malignant melanoma and squamous cell car-
cinoma are especially prone to metastasize to
the parotid, making up the 80% of the total [3].
Melanomas often arise in the temporal scalp,
the auricle, and the lobule of the ear, as well as
the face. Parotid nodes may be affected prior
to those in the neck. In contrast, squamous cell
primaries can be found in the oral cavity,
sinuses, pharynx, and external ear.
Lung, heart, kidney, and gastrointestinal tract
are sites outside of the head and neck that may
be primary locations. A survey by Yarring-
ton of over 250 conservative parotidectomies
yielded a 4% unsuspected metastatic rate of pri-
maries below the clavicles [68]. The most com-
mon primary was lung. He specifically excluded
patients in whom a parotidectomy was per-
formed as part of a large composite procedure
for a known malignancy outside the parotid
gland. Often the unsuspected primary had been
treated years before.
In primaries arising on the head and neck,
parotid gland disease carries a poor prognosis
with an overall 12.5% five-year survival. Ther-
apy must therefore include resection of the
primary, parotid gland and neck dissection
whenever feasible.
Tumors of the Submandibular Gland
Tumors of the submandibular gland are rel-
atively rare, comprising only 10% of all salivary
gland neoplasms [69]. When compared with the
parotid, however, up to 50% of submandibu-
lar gland tumors are malignant. Of the benign
tumors, 95% are pleomorphic adenomas [4].
Most disorders of the gland are inflammatory
with the characteristics of pain, erythma, inter-
mittent swelling, and purulent secretions from
Wharton's duct. A more chronic process may
be difficult to differentiate from neoplasia, and a
painless, slowly enlarging mass must always be
suspect. Pain in submandibular tumors is a late
finding that occurs when a tumor erodes the
floor of the mouth or fixes to mandibular
periosteum [70]. Neurologic deficits are rare,
owing to the lack of intimate proximity of
nerves to the submandibular gland, as compared
with the facial nerve and the parotid. Paralysis
of the marginal mandibular nerve may be noted
in malignant tumors, and tongue weakness due
to hypoglossal nerve invasion is rare. Only 11 %
of submandibular malignancies manifest nerve
involvement [69].
The duration of symptoms is variable, rang-
ing from months to many years. Benign tumors
may be present for more than five years before
the patient seeks medical care. Patients with
malignant lesions will often present within two
years of noting a mass [71]. Skin fixation is rare.
Cervical node metastases may be found in
approximately 15% of patients with malignant
tumors.
Diagnosis of these tumors is found largely in
the history and physical examination once an
inflammatory process has been excluded from
consideration. Radiographic studies may be
performed (supra vide), especially if a malignan-
cy is suspected. Excision· of the entire gland is
the diagnostic (and often therapeutic) approach.
Incisional biopsy is rarely warranted except in
the presence of an ulcerative tumor. If evidence
is noted of a possible malignancy (fixation, pain,
nerve weakness, cervical adenopathy), the pa-
tient should be informed of the possibility of
wide resection.
As noted above, benign tumors of the gland
are almost exclusively pleomorphic adenomas.
Oncocytomas and Warthin's tumors are rarely
found. Excision of the entire gland for benign
tumors is therapeutic.
Adenoid cystic carcinoma is the most com-
mon malignant submandibular gland tumor,
accounting for approximately one-third of malig-
nancies [70]. These tumors are slowly growing
and infiltrate along nerves as do their parotid
counterparts. There is a high rate of local recur-
 13. NEOPLASMS OF THE SALIVARY GLANDS
renee with extensions along lingual, hypoglossal,
and alveolar nerves, and to the mandible.
Cervical lymph node metastases are not un-
common. If submandibular adenoid cystic car-
cinoma is analyzed separately, an incidence of
34% metastatic disease has been noted as com-
pared with 10% for parotid tumors. This high
incidence of neck metastases may be due to
direct extension out of the confines of the sub-
mandibular gland to surrounding nodes or
direct extension to surrounding tissue, rather
than lymphatic embolic spread [72).
Because of the high rate of local recurrence
and nodal metastases, wide resection of the
contents of the submandibular triangle, in-
cluding local nerves and regional nodes, should
be performed. The mandible may need to be
sacrificed. A postoperative course of radiation
therapy may need to be added as well. When
viewed over a 15- to 20-year perspective, the
survival rate from adenoid carcinoma may be no
more than 10% [70].
Mucoepidermoid and malignant mixed tu-
mors are the next most frequent malignancies,
each accounting for slightly less than 20% of
these tumors. Squamous cell carcinoma, adeno-
carcinoma, acinic cell carcinoma, and other rare
tumors complete the list [70, 71). A local recur-
rence rate of 50% can be expected, nodal metas-
tases occur in over one-third of patients, and
distant disease is nearly 40%. The lung is the
most frequent site of spread. All of these para-
meters are higher for submandibular disease
when compared with the parotid gland.
It also appears that higher disease-free cure
rates are obtained for parotid malignancies
when compared with the submandibular gland
-five- and ten-year cure rates of submandibu-
lar malignancies are half of similar rates of the
parotid (32% and 24%, compared with 62%
and 54 %) [71). This may be due to a higher inci-
dence of low-histologic-grade carcinomas in the
parotid. The frequent local recurrences and
higher rate of aggressive tumors and metastases
suggest that wide resection in conjunction with
partial mandibulectomy and neck dissection
should be advocated for these carcinomas. Con-
ley and Baker have suggested the use of irradia-
tion in inadequate margins, recurrent cancers,
extension outside of the gland capsule, nerve
invasion, and an undifferentiated and adenoid
cystic carcinoma [4].
221
Tumors of the Sublingual Gland
Neoplasias of the sublingual glands are the
rarest of the growths of the major salivary
glands. Their importance lies in the frequency
of malignant tumors (80%). The most common
of these has been the adenoid cystic carcinoma,
followed by mucoepidermoid carcinoma.
The most common presentation is a mass
under the tongue and some limitation of func-
tion because of the location of the growth. Most
patients are 30-50 years of age.
Diagnosis as well as therapy consists of re-
moval of the entire gland and surrounding
structures, which can be performed without
great sacrifice of function. If nodal disease
is palpated, a neck dissection should be per-
formed. Survival statistics are not available for
these tumors, which in 1969 numbered 46
reported cases [63, 69).
Tumors of the Minor
Salivary Glands
The minor salivary glands are "minor" only in
their size. Although their acini do not form
major conglomerate organs like the larger
paired salivary glands, they are functionally and
neoplastically important. They are primarily
mucus-secreting glands located in the oral cav-
ity, nose and paranasal sinuses, pharynx, larynx,
and tracheobronchial tree. Tumors of the "ma-
jor" glands (including the submandibular and
sublingual) are five times as common as those of
the minor glands. Most of the minor gland
tumors are located in the oral cavity and most
often in the palate, followed in frequency by the
tongue and buccal mucosa [4,69]. The incidence
of malignancy varies according to series re-
ported, ranging from 31% to 91%, but averag-
ing approximately 60% of all minor salivary
gland neoplasms, a much higher rate than the
larger glandular counterparts. Of the benign
tumors, the vast majority (over 90%) are mixed
tumors with mucoepidermoid carcinoma being
the most frequent malignancy encountered.
Most minor salivary gland tumors remain
silent for prolonged periods of time, often
belying their potentially malignant nature. Pain
is rare and associated symptoms are infrequent.
In the larynx, hoarseness may be a presenting
complaint while obstructing tracheobronchial
tumors may produce slowly progressive dys-
pnea, often mimicking asthma. Fortunately, the
222 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
most common anatomic sites are accessible to
inspection, palpation, and biopsy. Involvement
of contiguous structures necessitates procedures
such as a CT scan, which also assists in formu-
lating an appropriate therapeutic approach [73].
Treatment of benign tumors, essentially
pleomorphic adenomas, is resection with sur-
rounding normal tissue to diminish the like-
lihood of local recurrence. Resection may be
difficult in some locations because of the
compromised remaining structures.
Tumors of the minor palatal salivary glands
occur about as frequently as squamous cell car-
cinomas in the same location, with some sali-
vary gland tumors found in the hard palate and
more squamous cell lesions in the soft palate
[74]. The predilection of the palate for. salivary
gland tumors is explained by the high concen-
tration of these glandular elements in this area.
The average age of patients with palatal tumors
is 50 years. In this location, as in other minor
salivary gland sites, the adenoid cystic carcino-
ma is the most frequent malignancy, followed
by mucoepidermoid carcinoma and adenocarci-
noma [74, 75]. Treatment of these tumors
requires wide resection, often with removal of
bone and traversing nerves. This is especially
true in patients with adenoid cystic carcinomas,
which tend to infiltrate along nerve sheaths. The
addition of radiation therapy for residual dis-
ease after surgical resection or for salvage has
been reported to increase control of the primary
[76]. Local recurrences in the palate are few,
with poor prognosis associated with a large
primary tumor, nerve, blood, bone, or connec-
tive tissue invasion and cervical node metastases
[75].
Other than the palate, minor salivary gland
tumors of the oral cavity can occur in the mu-
cosa of the lip, cheek, uvula, floor of the mouth,
tongue, peritonsillar region, and retromolar trig-
one. The mucosa is often intact and the tumor
apparently cystic [77]. The histologic distribu-
tion is similar to that of tumors of the palate,
with adenoid cystic carcinoma the most com-
mon malignancy, but mucoepidermoid carcino-
ma is most often seen in the retromolar and
maxillary tuberosity areas as well as the floor of
the mouth. Adenocarcinomas have a predilec-
tion for the tongue [73]. The base of the tongue
is also rich in minor salivary glands, giving rise
to both benign and malignant processes. Early
symptoms are rare and the tumors remain sub-
mucosal. Diagnosis necessitates deep biopsies
and combined surgical and radiation therapy
appears to yield the best results [78].
Other sites of involvement include the nasal
cavity, paranasal sinuses, pharynx, larynx, and
trachea. Sinonasal tumors may be silent for
some time, filling the anatomic cavity prior to
causing symptoms. The therapy of these tumors
is made more difficult because of the inaccessi-
bility of the surrounding tissue to adequate re-
section. In recent years, however, wider skull
base ablations have been performed compatible
with meaningful patient survival. Irradiation for
malignancies in this region is often mandatory.
Minor salivary gland tumors of the pharynx,
larynx, and trachea are uncommon (figure 13-
lOa and b). Benign lesions can be controlled by
local resection, and malignancies (especially
tracheal) often have a poor prognosis regardless
of treatment modality.
Salivary tissue has been known to exist out-
side of both the major and minor glands. This
tissue has been found in association with para-
nasal sinuses and middle ear as well as in the
neck. This heterotopic salivary tissue can subse-
quently give rise to tumors. Although this is a
rare event, the discovery of a neck mass contain-
ing salivary gland carcinoma may represent a
primary cervical process rather than a metastatic
deposit. Radical therapy should be withheld
until the primary as well as the neck mass have
been defined [79].
Salivary Gland Tumors in Children
Of all salivary gland tumors, approximately 3%
occur in children [80, 81]' Vascular tumors,
namely, hemangiomas and lymphangiomas,
account for the most common neoplasm, occur-
ring in more than half of children with salivary
masses. The hemangioma presents in early
childhood and, as in this case in most of the
vascular tumors, occurs primarily in the parotid
gland. The diagnosis is not difficult to make,
the mass being soft, compressible, with a blue
FIGURE 13-10. (A) Monomorphic adenoma (mem-
branous basal cell adenoma) arising from a minor
salivary gland of the right lateral pharyngeal wall in a
62-year-old man. (B) Radiographic demonstration of
the tumor mass, outlined by contrast material, ex-
tending from the inferior pole of the tonsil to the
pyriform sinus. From Triest et al. [51].
 13. NEOPLASMS OF THE SALIVARY GLANDS 223

B
224 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
tinge to the overlying skin, and often with a
cutaneous telangiectasia or hemangioma noted
as well. Growth reaches a maximum by six
months of age and often regresses thereafter.
Resection should be delayed to assess the inher-
ent biologic nature of the hemangioma. Parental
pressures often force surgical intervention.
Surgery is made more difficult because of the
lateral and superficial position of the facial nerve
as well as the multifocal nature of the heman-
gIOma.
Lymphangiomas are less common than he-
mangiomas and arise from prolific growth of
lymphatic channels that enlarge to form cystic
spaces in close relationship to normal glandular
tissue. These masses slowly enlarge, often dis-
turbing the position of the facial nerve [63].
Unfortunately, these growths show no involu-
tional pattern, and therapy is surgical removal.
Of the benign epithelial salivary gland tumors
in children (as in adults), the pleomorphic ade-
noma is the most common (see table 13-3). In a
analysis compiled by Schuller and McCabe,
85% of the benign epithelial neoplasms were
mixed tumors [81]. Clinically they behave as do
the same growths in adults and the treatment is
similar. Incomplete removal or enucleation is
associated with local recurrence. Pleomorphic
adenoma appears in children 7-12 years of age
as a slowly growing mobile mass, often being
over 2 cm in size on presentation [82]. Mixed
tumors may occur in any gland, but are most
frequent in the parotid. Other benign salivary
gland neoplasms include the lymphoepithelial
lesion, cystadenoma, Warthin's tumor, neuro-
fibroma, and xanthoma.
Over half of firm salivary gland tumors in
children are malignant. This excludes the vas-
cular growths from consideration. Most of
these malignancies are found in the parotid-
histologically, mucoepidermoid carcinoma ac-
counts for nearly 50%, followed by the acinic
cell carcinoma, undifferentiated carcinoma, and
adenocarcinoma [80, 81]. Adenoid cystic and
squamous cell carcinomas, rhabdomycosarco-
ma, malignant mixed tumor, lymphoma, and
lymphosarcoma have also been described (see
table 13-3).
Most malignant tumors occur in older chil-
dren and most often in the parotid. Symptoms
are the same as in the adult and in general the
biologic behavior is similar. The undifferenti-
ated carcinoma, however, appears to be a more
malignant lesion in children, carrying a poor
prognosis from rapid tumor dissemination [63,
82]. Treatment is surgical with preservation of
the facial nerve whenever possible. Ancillary
modes of treatment (radiation and chemother-
apy) may be required and can be of benefit (infra
vide). The therapeutic approach to all firm
tumors in children should be the same as in
the adult, with wide local excision the first
approach to both benign and low-grade malig-
nant disease. The use of additional treatment is
reserved for high-grade malignancies.
The Role of Radiation Therapy in
Salivary Gland Neoplasia
As has been addressed above, the primary mo-
dality of treatment for the vast majority of all
types of salivary gland tumors, regardless of
location, is surgery. Over the past few years,
radiation has been shown to be a beneficial ad-
junctive treatment modality. Indeed, in certain
circumstances, radiation may be the only desir-
able treatment option.
The decision to consider radiation therapy
must be based on the location of the neoplasm
as well as the histologic type. There is little
doubt that radiation therapy is not warranted
after total surgical excision of the tumor with
adequate surgical margins in low-grade tumors
[83].
Radiotherapy should be contemplated when
low-grade tumors are not adequately excised or
if there is a recurrence of a malignant neoplasm.
High-grade tumors have a distinct propensity to
local recurrence, infiltration, and metastatic
spread, even if measured over years rather than
months, and therefore radiation has a place
when treating these tumors.
If neural, perineural, lymphatic, periosteal, or
bone infiltration is found upon examination of
the pathologic specimen, radiation is beneficial,
especially in cases of adenoid cystic carcinoma
[83, 84]. Adenoid cystic carcinoma has a high
recurrence rate although slowly growing, and
dissemination of tumor is frequent. Five-year
recurrence rates have been diminished with the
combined use of radiation and surgery when
compared with surgery alone [84].
Patients with unresectable tumors that show
fixation or deep infiltration, and those patients
who are too old or infirm to tolerate a large
surgical procedure, are definite candidates for
radiotherapy.
Finally, the presence of cervical nodes may be
 13. NEOPLASMS OF THE SALIVARY GLANDS 225

TABLE 13-3. Epithelial salivary neoplasms in children

Neoplasm (benign) % Neoplasm (malignant) %

Pleomorphic adenoma 85.6 Mucoepidermoid carcinoma 48.9

Lymphoepitheliallesion 2.7 Acinic cell carcinoma 12.2
Cystadenoma 2.7 Undifferentiated carcinoma 9.4
Warthin's tumor 2.7 Adenocarcinoma 7.5
Plexiform neurofibroma 1.8 Undifferentiated sarcoma 6.0
Xanthoma 1.8 Malignant mixed tumor 6.0
Neurilemmoma 0.9 Adenoid cystic carcinoma 4.0
Adenoma 0.9 Squamous cell carcinoma 2.0
Lipoma 0.9 Mesenchymal sarcoma 1.3
Rhabdomyosarcoma 1.3
Malignant epithelial tumor 0.7
Ganglioneuroblastoma 0.7
110 cases 149 cases

From Schuller and McCabe [81].

treated with combined modalities. Radiation still survive and function.

alone has not been shown to be as effective as
surgery as the sole mode of treatment for cervi-
cal metastatic disease.
The results of combined treatment can in-
crease local control and afford improved cosmet-
ic results since residual microscopic disease can
be managed after surgical resection [85, 86].
Dosages in the range of 6000-7000 cGy must be
used, with even higher' amounts needed to con-
trol un resectable disease. If the tumor is resect-
able, total extirpation followed by radiation,
using the above guidelines, is more effective
than partial resection [87].
The presence of facial nerve paralysis is not
invariably an indication of incurability of a
parotid malignancy. Survival rates of 26% have
been reported by Conley and Hamaker [88] in
patients with parotid neoplasia and facial nerve
palsy. Byun and associates [87] have reported
76% local control and 58% five-year survival in
a similar group of patients treated aggressively
with combined radical surgery (with nerve
sacrifice) and high-dose radiation therapy. The
possibility of salvaging the facial nerve must be
an individual consideration and can only be jus-
tified in low-grade tumors if any degree of local
control can be anticipated. The preservation of
the facial nerve with known tumor infiltration
can best be viewed at this time as an inadequate
cancer operation. Immediate facial nerve graft-
ing is appropriate in most situations using either
the greater auricular or sural nerves. These
grafts can tolerate postoperative radiation and
Tumors of the minor salivary glands, espe-
cially of the palate, can be treated by radiation.
These tumors are often quite difficult to control
by surgical resection because of their location.
Primary control has been improved, but no
series is as yet large enough to determine the
benefit in overall survival [84, 891.
The precise role of radiation therapy in the
treatment of salivary gland malignancies has yet
to be completely defined and documented. As
the importance of postoperative function and
cosmetics increases, as well as the surgical capa-
bilities of reconstruction improve, radiation will
tend to playa bigger part in the management of
the malignancies.
The Role of Chemotherapy in
Salivary Gland Neoplasia
The use of chemotherapeutic agents in the man-
agement of stage-III and -IV squamous cell car-
cinoma of the head and neck has been well
established. Although the ultimate benefit for
prolonged survival has yet to be determined,
chemotherapy appears to be an acceptable addi-
tional treatment regime for these tumors. The
role of chemotherapy for salivary gland neo-
plasms is difficult to evaluate because of the
lower incidence of these tumors, their slower
growth, the infrequent use of these agents, and
the numerous drugs available [90]. Suen and
Johns have approached the problem by review-
226 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
ing the literature for evaluable cases and adding
others by a survey of some treatment centers
[91]. Even with the additional cases afforded by
a retrospective review, protocols that are of
consistent benefit have not as yet been achieved;
42% of all patients (total number, 85) represent-
ing various histologic types had a partial (32%)
or complete (10%) response. It was noted that
two general groups could be detected. One
group was the adenocarcinomalike malignancies
(adenoid cystic, adenocarcinoma, carcinoma ex
pleomorphic adenomas, and acinic cell) that re-
sponded best to adriamycin, cis-platinum, and
5-fluorouracil. The other group was composed
of squamouslike cancer (squamous cell and
mucoepidermoid carcinomas) that responded to
methotrexate and to cis-platinum. Suen and
Johns have postulated that the two groups may
be derived from histogenetically dissimilar stem
cells.
Adenoid cystic cancers have been the pre-
dominant tumors treated with chemotherapy.
This is probably because they are among the
more common malignant salivary gland tumors
and also because of their relentless behavior.
The high rate of local recurrence and distant
metastases, in spite of surgery or radiation ther-
apy, reflects the failure of standard treatment.
Of the agents currently available, cis-platinum
appears to be the most effective whether given
intravenously 80-100 mg/ cm2 of body surface
area [92], or intraarterially in comparable dos-
ages [93]. Tumor regression has been noted in
up to 70% of patients treated [92] as well as the
benefit of subjective pain relief [91,92].
A recent report from the Dana-Farber Cancer
Institute utilizing combination chemotherapy
has demonstrated that some patients with local-
ly recurrent disease can go on to a definitive sur-
gical procedure with potentially curative results
if a tumor response can be achieved [94]. It
should be noted that these are preliminary re-
sults that reflect an experience with but a few
patients and these results have not been ana-
lyzed from the perspective of many years. The
potential is present, however, for a cooperative
study to assess this mode of therapy for ad-
vanced salivary gland malignancies. As a pri-
mary modality, the lack of consistent response
makes it less than satisfactory.
Results of Management of Salivary
Gland Neoplasia
An overview of treatment results is addressed in
chapter 18; however, certain points should be
emphasized. The most common salivary gland
tumor site, and often the most difficult to man-
age, is the parotid gland. The first consideration
in the parotid as well as other salivary gland
locations is the histologic type of the tumor as
well as the clinical stage. The initial approach
will often require total excision by means of a
superficial parotidectomy as both diagnostic
and therapeutic modalities, especially for benign
tumors, low-grade mucoepidermoid and acini
cell carcinomas. Survival for these histologic
types can be expected to be 80%-90% or
greater. The higher-grade malignancies are as-
sociated with poorer survival rates that depend
on the histologic type as well as the mode of
therapy employed [95, 96].
Lymph node metastases occur most often in
high-grade mucoepidermoid and squamous cell
cancers [95]. The need for a neck dissection,
whether classic or modified, should then be
determined on the basis of palpable cervical
lymphadenopathy, the size of the primary
tumor, and the histology.
The significance of facial nerve weakness has
been addressed above, but it does portend
malignancy and a poor prognosis. The decision
to sacrifice the nerve and to graft must be made
at the time of surgery. The concept of preser-
vation of the nerve by doing less of a "cancer
operation" and relying on postoperative che-
motherapy or radiation to be curative has not
stood the test of time. It appears attractive in
principle, but must be viewed in the perspective
of often slow-growing malignancies. The sac-
rifice of nerves in other locations is not as devas-
tating to the patient and is often undertaken
more readily.
There may be local recurrence of malignant
salivary gland disease in up to one-third of
patients, and it is highest in the parotid where
initial surgery may be limited by attempts to
preserve the facial nerve. Even if initial surgical
therapy is aggressive (i.e., nerve sacrifice), there
can be frequent recurrences [95].
Survival after tumor recurrence in any loca-
tion is poorer than for nonrecurrent cancers.
Five-year disease-free survival after treatment
for recurrent tumors has been reported to be
37% for parotid, 60% for submandibular, 50%
 13. NEOPLASMS OF THE SALIVARY GLANDS
for minor salivary gland neoplasms, and 41 %
overall [97]. Wider resection must be under-
taken in these situations, often combined with
neck dissection and postoperative radiation.
This is particularly true of undifferentiated,
squamous cell, and high-grade mucoepidermoid
carcinomas in which local recurrences are often
the cause of death [42].
The addition of radiation therapy has been
shown to improve tumor control for local
microscopic disease, its effectiveness being
related C1irectly to the tumor volume that is'
present [97, 98]. Local recurrences have been
reported to be reduced to 14% in patients
receiving postoperative radiation when com-
pared with 54% in patients not receiving radia-
tion when there was known microscopic disease
at or close to the surgical margin [96].
Treatment of salivary gland neoplasia is in
flux, with newer forms of therapy undergoing
evaluation. No absolute dictum holds fast in all
situations, but the basic principles of appropri-
ate diagnosis and judicious management remain
the primary considerations.
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RM: The place of irradiation in the treatment of
malignant tumors of the salivary glands. Curr
Probl Cancer 1:13-30,1976.
84. Elkon D, Pope TL, Constable WC: Adenoid
cystic carcinoma of the salivary gland. Arch
OtolaryngoI106:410-413,1980.
85. Chung CT, Sugarman RH, Ryoo MC, King
GA, Yu WS, Dalal PS: The changing role of
external beam irradiation in the management of
malignant tumors of the major salivary glands.
Radiology 145:175-177, 1982.
86. Fletcher GH: Place of irradiation in the manage-
ment of head and neck cancers. Semin Oncol
4:375-385,1977.
87. Byun YS, Fayos JV, Kim YH: Management of
malignant salivary gland tumors. Laryngoscope
90:1052-1060,1980.
88. Conley J, Hamaker RC: Prognosis of malignant
tumors of the parotid gland with facial paralysis.
Arch Otolaryngol101 :39-41,1975.
89. Chung CK, Rahman SM, Constable WC: Malig-
nant salivary gland tumors of the palate. Arch
OtolaryngoI104:501-504,1978.
90. Rentschler R, Burgess MA, Byers R: Che-
motherapy of malignant major salivary gland
neoplasms. Cancer 40:619-624, 1977.
91. Suen JY, Johns ME: Chemotherapy for salivary
gland cancer. Laryngoscope 92:235-239,1982.
92. Schramm VL, Srodes C, Myers EN: Cisplatin
therapy for adenoid cystic carcinoma. Arch
Otolaryngol 107:739-741, 1981.
93. Sessions RB, Lehane DE, Smith RJH, Bryan N,
Suen JY: Intra-arterial cisplatin treatment of
adenomal cystic carcinoma. Arch Otolaryngol
108:221-224,1982.
94. Posner MR, Ervin TJ, Weicheselbaum RR,
Fabian RL, Miller D: Chemotherapy of ad-
vanced salivary gland neoplasms. Cancer
50:2261-2264,1982.
95. Johns ME: Parotid cancer: a rational basis for
treatment. Head Neck Surg 3:132-144,1980.
96. Fu KK, Leibel SA, Levine ML, Friedlander LM,
Boles R, Phillips TL: Carcinoma of the major
and minor salivary glands: analysis of treatment
results and sites and causes of failure. Cancer
40:2882-2890,1977.
97. Hanna DC, Dickason WL, Richardson GS,
Gaisford JC: Management of recurrent salivary
gland tumors. Am J Surg 132:453-458, 1976.
98. Skidnia H. Hornback ND, Hamaker R, Linge-
man R: Carcinoma of major salivary glands.
Cancer 45:693-697,1980.
 14. NONMUCOSAL NEOPLASMS OF
THE MAXILLOFACIAL REGION
Leonard B. Kaban
Robert Chuong
Tumors of the maxillofacial region make up a
small percentage of all neoplasms seen in
humans. Of this small group of patients, the
majority have intraoral mucosal tumors, i.e.,
squamous cell carcinoma or adenocarcinoma.
Nonmucosal tumors of the maxillofacial region
make up an even smaller percentage of human
neoplasms [1]. Understanding these tumors is
difficult because their low incidence is coupled
with a great variety of tumor types.
This chapter reviews soft-tissue and bone
neoplasms of the maxillofacial region not origi-
nating from the oral mucosa. Salivary gland
tumors are discussed in chapter 13. The biologic
behavior of these tumors, histologic diagnosis,
and clinical management of the patient are
emphasized.
For the sake of discussion, we classify tumors
as central or peripheral, even though this is
sometimes difficult, e.g., a mucoepidermoid car-
cinoma involving bone and overlying mucosa
may have originated in either soft tissue or
bone. Central jaw tumors may be derived from
odontogenic or nonodontogenic mesenchymal
or epithelial tissues and they may be benign or
malignant. Benign nonodontogenic mesenchy-
mal tumors comprise the overwhelming majori-
ty of jaw tumors in children [2, 3]. In the adult
population, odontogenic epithelial tumors such
as ameloblastoma are more common. Soft-tissue
tumors include vascular lesions, neurofibro-
matosis, and soft-tissue sarcomas. Primary
malignant tumors of the bone and soft tissue of
We would like to thank Dr. Joseph E. Murray and Dr. John
B. Mulliken for their assistance in the preparation of this
chapter and for allowing the inclusion of patients depicted
in figures 14-8 and 14-9.
Peterson et al., HEAD AND NECK MANAGEMENT OF THE CANCER PATIENT.
© 1986. Martinus NijhofJ Publishing. All rights reserved.
the head and neck are discussed in chapters 10
and 11.
Benign Nonodontogenic Tumors
Nonodontogenic tumors are classified accord-
ing to their presumed tissue of origin (table
14-1) and include (1) benign mesenchymal,
(2) malignant mesenchymal, (3) vascular, (4)
hematopoietic/reticuloendothelial, (5) neuro-
genic, and (6) malignant epithelial tumors. Some
lesions, however, have been placed into con-
ceptually convenient categories rather than
specific tissue of origin groups, e.g., aneurysmal
bone cyst into the category of vascular lesions,
and histiocytosis into the hematopoietic/
reticuloendothelial group.
BENIGN MESENCHYMAL TUMORS
Giant Cell Lesions
DIAGNOSIS. Giant cell lesions include (a) giant
cell reparative granuloma (GCRG), (b) brown
tumor of hyperparathyroidism, and (c) giant
cell tumor. Giant cells found in these tumors are
of little diagnostic importance and are present in
a variety of benign and malignant jaw tumors;
these include aneurysmal bone cyst, fibrous
dysplasia, cherubism, ossifying fibroma, and
osteogenic sarcoma.
The peak incidence of giant cell reparative
granuloma is between 10 and 20 years of age. It
occurs more commonly in females than males
(F:M ratio = 2:1) and in the mandible more
often than the maxilla. The premolar-molar re-
gion is the most common location. The tumor is
rarely located posterior to the six-year molar
and GCRG is the most common central jaw
tumor that occurs in the anterior body and
231
232 Ill. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA

TABLE 14-1. Classification of nonodontogenic jaw

tumors
I. Benign mesenchymal tumors
A. Giant cell lesions
1. Giant cell reparative granuloma
2. Giant cell tumor
3. Brown tumor
B. Fibro-osseous lesions
1. Fibrous dysplasia
2. Cherubism
3. Cementifying fibroma
4. Ossifying fibroma
5. Osteoblastoma
C. Myxoma
D. Lipoma
FIGURE 14-1. Brown tumor of hyperparathyroidism.
E. Benign mesenchymoma
A three-year-old boy with painless, slowly enlarging
II. Hematopoietic and reticuloendothelial tumors maxillary mass. Biopsy revealed a pattern consistent
A. Histiocytosis with giant cell reparative granuloma. Laboratory
B. Burkitt's lymphoma workup established a diagnosis of hyperpara-
C. Lymphoma thyroidism.
D. Multiple myeloma
E. Plasmacytoma
finding may be a mild facial asymmetry noticed
III. Neurogenic tumors by a family member. Radiographically, GCRG
A. Neurofibroma
B. Neurilemmoma appears as a un i- or multiloculated radiolucent
C. Neuroma lesion.
D. Ganglioneuroma Brown tumor of hyperparathyroidism (fig-
E. Neuroblastoma ure 14-1) has clinical and histologic features in-
F. Melanotic neuroectodermal tumor distinguishable from GCRG. It must be consid-
IV. Vascular tumors ered in the differential diagnosis of all giant cell
A. Vascular malformation lesions of the maxillofacial skeleton, particularly
(capillary, lymphatic, venous, arterial, when there is recurrent disease. This lesion is
mixed) the result of osteoclastic bone resorption in
B. Hemangioma response to an elevated parathyroid hormone
C. Aneurysmal bone cyst level. Hyperparathyroidism may be primary
V. Malignant mesenchymal tumors (parathyroid adenoma or hyperplasia) or sec-
A. Osteogenic sarcoma ondary (in association with chronic renal fail-
B. Chondrosarcoma ure). Serum calcium and alkaline phosphatase
C. Fibrosarcoma are elevated and serum phosphorous is low.
D. Ewings's sarcoma The diagnosis is confirmed by an elevated
E. Malignant mesenchymoma parathyroid hormone level. Panoramic or dental
F. Liposarcoma radiographs may demonstrate thinning or par-
G. Malignant giant cell tumor tial disappearance of the lamina dura around
VI. Malignant epithelial tumors teeth [4]. Resorption lacunae in the phalanges
A. Squamous cell carcinoma of the fingers is another radiographic sign of
B. Mucoepidermoid carcinoma this disease.
C. Adenoid cystic carcinoma "True giant cell tumors" of the jaw bones are
D. Adenocarcinoma rare and there is considerable controversy in the
literature as to their existence. Giant cell tumors
of the long bones characteristically occur in a
symphysis of the mandible. patient group older (greater than 20 years of
GCRG is usually asymptomatic and discov- age) than those of the jaws; they are more local-
ered as an incidental radiographic abnormality. ly aggressive, recur more frequently, and 15%-
Symptoms, when they occur, include local 30% become frankly malignant with a tendency
swelling without pain or paresthesia. The initial for lung metastases. We and others [3, 5-7] have
 14. NONMUCOSAL NEOPLASMS OF THE MAXILLOFACIAL REGION
A B
FIGURE 14-2. Giant cell tumor. (A) An eight-year-
old boy with rapidly expanding anterior mandibular
mass, interpreted as giant cell reparative granuloma
histologically. Diagnosis of giant cell tumor was
made on basis of clinical behavior and histology.
(B) Occlusal radiograph demonstrates destructive
changes of anterior mandible with displacement of
teeth.
reported the existence of aggressive, locally re-
current giant cell lesions of the jaws. These le-
sions are histologically indistinguishable from
GCRG, but present with rapid onset of swelling
and rapid growth, pain, paresthesia, cortical
perforation, and invasion of soft tissue. Radio-
graphs demonstrate a radiolucent lesion with re-
sorption of the roots of the teeth. These lesions
demonstrate multiple recurrences after curet-
tage and may even recur after wide en bloc
resection. They do not demonstrate histologic
change after recurrence, suggesting little or no
tendency to undergo malignant transformation.
There has been only one well-documented case
of a malignant giant cell tumor of the jaw [8].
The case reported by Hayward [9] was prob-
ably an osteosarcoma of the mandible [10].
Based on our experience [3], there is a giant cell
233
lesion of the jaws intermediate between the
GCRG, which is slow growing and clinically
innocuous, and the aggressive, sometimes
malignant giant cell tumor of the long bones. It
is reasonable to call this lesion giant cell tumor
of the jaw (figures 14-2 to 14-4).
Although histologic criteria have been de-
scribed to distinguish GCRG from giant cell
tumor [10, 11] differentiation by these criteria
alone is not always possible. The giant cell
tumor has a higher density of multinucleated
cells of larger size than those of the GCRG and
exhibits relatively little hemorrhage and hemo-
siderin and little or no reactive osteogenesis.
Primary or secondary hyperparathyroidism can
only be ruled out by chemical means. Distinc-
tion among these various lesions must be guided
by their clinical features.
TREATMENT. Treatment of giant cell lesions of
the jaws must be based primarily on the biologic
behavior of the tumor. Curettage is appropri-
ate primary treatment for GCRG. Resection
may be required for recurrent disease after
hyperparathyroidism has been ruled out. En
bloc resection is the preferred approach to giant
234 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
FIGURE 14-3. Giant cell reparative granuloma. (A) A
six-year-old boy with very slowly growing tumor of
mandible. Diagnosis was giant cell reparative granu-
loma. There were multiple recurrences after curettage
procedures. Cure was ultimately achieved by en bloc
resection. (B) Radiographic appearance five years
after resection and bone graft reconstruction. There
has been no recurrence.
FIGURE 14-4. Histology of giant cell lesions. Essen-
tially indistinguishable histology of various giant
cell lesions of different biologic behavior patterns.
(A) "Brown tumor" of hyperparathyroidism. This is
biopsy of mass depicted in figure 14-1. x 260,
hematoxylin~eosin. (B) Giant cell tumor of mandi-
ble, corresponding to lesion depicted in figure 14-2.
x 130, hematoxylin~eosin. (C) Slow-growing giant
cell lesion, corresponding to lesion described in
figure 14-3. x 130, hematoxylin~eosin.
14. NONMUCOSAL NEOPLASMS OF THE MAXILLOFACIAL REGION 235

c
 A

c
 D E

FIGURE 14-5. Myxoma. A four-year-old girl with tender swelling of right mandible, initially misdiagnosed as
osteomyelitis. Because of continued expansion during treatment with antibiotics, the patient was referred for
further evaluation. Biopsy established diagnosis of myxoma, leading to resection and immediate reconstruction
with rib graft. (A) Frontal photograph of child at initial evaluation. (B) Preoperative panoramic radiograph
demonstrates irregular radiolucency of midbody region of right mandible (arrows). (C) Spindle-shaped cells in a
myxoid background consistent with myxoma. x 350, hematoxylin-eosin. (D) Frontal appearance seven years
after resection and reconstruction. Mandibular growth has been normal. Contour deficiency of right mandible
is noted. (E) Lateral view of face seven years after treatment. (F) Panoramic radiograph seven years after treat-
ment. There has been no recurrence.

237
238 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
cell tumors of the jaws as defined in the pre-
vious paragraphs, even when the pathologist
labels the lesion as GCRG. Brown tumors of
hyperparathyroidism will often regress when
the primary illness is treated by parathyroidec-
tomy. Residual mass may be safely curetted
without fear of recurrence as long as the endo-
crine disease is under control.
Myxoma. Myxoma is considered by many au-
thors to be of odontogenic origin, because these
tumors rarely occur outside the jaw bones. For
example, in one series of 11,000 bone tumors,
there were only three myxomas not in the man-
dible or maxilla [12]. In our experience, myx-
omas most frequently occur in non-tooth-
bearing regions of the mandible and hence are
considered to be of nonodontogenic, mesen-
chymal origin [3].
The peak incidence of myxoma is in the
second to third decades of life, with a mean age
of 30 years at the time of diagnosis [13].
However, these tumors are frequently reported
in children under age 10 [3, 14]. The posterior
mandible is the most common location; the
anterior maxilla and mandible are only rarely
affected (figure 14-5).
DIAGNOSIS. Adults present with a slowly ex-
panding tumor, occasionally accompanied by
pain. In children, there is more rapid expansion,
frequently accompanied by pain; the tumor
may be mistaken for an acute infection such as
osteomyelitis. Paresthesia is uncommon, even
when tumor growth is rapid.
The angle of the mandible is most commonly
involved and tenderness is usually present.
Teeth may be loose if involved. Radiographi-
cally, the lesion presents as a multiloculated
radiolucency. Cortical perforation is common
and the lesion, with fine radiopaque bone mark-
ings, may be visible primarily in the soft tissue.
When the posterior maxilla is involved, the
antrum is often invaded.
Grossly, these tumors are rubbery in con-
sistency with a shiny, gelatinous cut surface sur-
rounded by a fibrous capsule that is incomplete.
Histologically, there are few mesenchymal cells
and fibroblasts in a clear myxomatous stroma.
This stroma surrounds very delicate reticulin
fibers and may resemble the stellate reticulum of
developing teeth. The histologic pattern of this
tumor may be quite innocuous, even in the
presence of rapid clinical growth and tissue
destruction. The treatment must therefore be
guided by the biologic behavior of the tumor as
well as the histology. Malignant transforma-
tions or metastases have not been reported.
TREATMENT. Treatment of myxoma must be
aggressive. This lesion has a 25% recurrence
rate [15] that is explained partly by its locally
aggressive, infiltrative behavior, resulting in
multiple fingerlike extensions into surrounding
bone. Inadequate removal by curettage no
doubt explains some of the tendency for recur-
rence described in the literature. The appropriate
treatment for myxoma is en bloc resection with
at least 5-mm margins. In the case of small
tumors, marginal resection may be successful.
After resection, reconstruction may be per-
formed at the same operation.
Fibro-osseous Lesions. Fibro-osseous lesions
include a group of related tumors in which nor-
mal bone is replaced by fibrous and mineralized
tissue, blood vessels, and giant cells in variable
proportions. The lesions generally included in
this group are (a) fibrous dysplasia, (b) cherub-
ism, (c) ossifying fibroma, and (d) osteoblas-
toma.
FIBROUS DYSPLASIA.
Diagnosis. Fibrous dysplasia of the jaw bones
is typically monostotic although it may be part
of a generalized disease with or without endo-
crine abnormalities (precocious puberty) and
cafe-au-lait spots (Albright's syndrome). This
tumor is characterized by painless swelling
appearing during the first or second decades of
life [16, 17]. Growth of the lesion is most active
during childhood; there may be periods of rapid
expansion that coincide with hormonal changes
such as in the pubertal growth spurt or pregnan-
cy. The lesions typically stop growing in adult-
hood and it is rare for patients to experience
major changes in size after age 25 [16, 18].
During periods of rapid growth, the patient
may experience pain, swelling, paresthesia, and
functional deficits such as impairment of vision
or ocular motility if the lesion involves the orbit,
or mandibular hypomobility if it involves the
temporomandibular joint, ramus, or zygomatic
arch.
In the jaws, the maxilla is involved more
commonly than the mandible. Extension from
the maxilla into the orbital floor may cause
proptosis. Infraorbital paresthesia is possible,
but occurs rarely. Tumors of the mandible often
occur at the angle and must be differentiated
 A

FIGURE 14-6. Fibrous dysplasia. A ten-year-old boy with slowly progressive, painless expansion of right maxil-
la, diagnosed as fibrous dysplasia. (A) Submental view of patient demonstrates anterior maxillary expansion
causing distortion of nose. (B) Preoperative Water's view demonstrates increased density of right maxilla. (C)
Axial CT scan demonstrating bony mass.

239
240 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA

from osteomyelitis, masseter hypertrophy, malignant transformation despite the rare oc-
myositis ossificans, and other primary jaw currence of spontaneous sarcomatous change.
tumors.
The radiographic appearance is variable and OSSIFYING FIBROMA
depends on patient age and history of the
Diagnosis. Ossifying fibroma is a variant of
tumor. In very young patients with rapidly
fibrous dysplasia, presenting as a painless swell-
expanding fibrous dysplasia, radiographs show
a multilocular radiolucent lesion with cortical ing. It involves the mandible more frequently
thinning. The teeth may be spread apart and than the maxilla. Growth of the tumor is
characteristically slow and the mass is usually
there is evidence of delayed dental eruption. In
present for a year or more before the patient
older patients with clinically quiescent lesions,
seeks treatment. The tumor is more commonly
radiographic appearance may be that of a mixed
a localized mass than a generalized local en-
radiolucent-radiopaque or simply a radiopaque
mass. Metabolic indicators of systemic bone largement as in monostotic fibrous dysplasia.
disease such as serum calcium, phosphorous, Pain is usually absent. Displacement of teeth
and alkaline phosphatase are normal (figure 14- may occur. Peak incidence is in the third and
fourth decades [2, 22].
6).
Radiographically, the ossifying fibroma
Histology of fibrous dysplasia demonstrates
presents as a well-defined radiolucent lesion
a mixture of fibrous tissue, bone, giant cells,
in its early stages. With time, it becomes more
blood vessels, and mast cells. Smith [18] has
calcified and appears as a mixed radiolucent-
attempted to correlate disease activity with his-
opaque lesion with less distinct borders.
tology, noting a positive correlation between
Histologically this tumor is a well-circum-
the cellularity of the connective tissue matrix
scribed fibro-osseous lesion with more distinct
and the rate of tumor growth. Kaban et al. [19]
margins than fibrous dysplasia. Spicules of bone
have noted a correlation between the numbers
lined by osteoblasts and osteoclasts are present
of mast cells and osteoclasts with disease activ-
within a fibrous stroma.
ity. These efforts are of potential benefit in
Treatment. Treatment consists of local exci-
treatment planning and predicting prognosis.
sion or enucleation. The lesion is usually well
Treatment. The usual indication for treatment
demarcated and easy to separate from adjacent
of fibrous dysplasia is to improve appearance.
bone; it may be encapsulated. A similar lesion,
When the lesion has been stable for more than
cementifying fibroma, may be difficult to distin-
a year in adults, the tumor can be contoured.
guish radiographically and histologically except
Contour excision or burring has been the usual
for its proximity to the teeth. Treatment is the
surgical treatment. More recently, Munro and
same for both lesions.
Chan [20] have advocated complete excision of
There have been reports of aggressive, locally
the bony mass and replacement with bone
destructive ossifying or cementifying fibromas
grafts. Most of their patients had frontal, orbital,
that have demonstrated local recurrence after
and zygomatic fibrous dysplasia. Others have
enucleation and curettage [3, 23]. Treatment
reported osteotomy of the maxilla and/or man-
in these cases must, of necessity, be en bloc re-
dible in combination with contour excision [21]
section with margins into normal tissue. This
in patients who have malocclusion secondary to
aggressive variant of ossifying-cementifying
abnormal growth as well as contour abnormali-
fibroma usually occurs in the maxilla in young
ties. The functional problems most frequently
children. Attempts to correlate histology with
encountered that require surgery are proptosis,
this aggressive behavior have not been suc-
impairment of vision, trismus, and paresthesia.
cessful.
In these cases, surgery is performed when the
functional problem becomes evident, under-
CHERUBISM
standing the potential for recurrence if the
fibrous dysplasia is not quiescent. Diagnosis. This is a familial, polystotic,
Malignant transformation of fibrous dyspla- fibro-osseous lesion, first described by Jones in
sia has been reported after radiation therapy. 1933 [24]. The bony architecture of the jaws is
Radiation has no place in the treatment of this replaced by fibrous tissue in which there are a
disease. Sudden rapid expansion of fibrous variable number of giant cells. It is an autosomal
dysplasia should be viewed with suspicion of dominant disease with 50%-70% penetrance in
 14. NONMUCOSAL NEOPLASMS OF THE MAXILLOFACIAL REGION
females and 100% penetrance in males. Expres-
sivity is variable, but the lesion is generally bi-
lateral and symmetric when it occurs. There
have been isolated cases with spontaneous
mutation reported.
Cherubism is usually evident by 3-4 years of
age, presenting with slowly progressive, pain-
less swelling of the jaws. The mandible is more
often affected than the maxilla, and mandibular
disease is usually more severe. Jaw swelling dis-
plays the greatest increase in size during the first
two .years after onset of the disease. Swelling
reaches its peak by age 10 and may start to
regress at the time of puberty. Involvement
is confined to the maxillofacial skeleton. The
deciduous teeth may be shed early, and the per-
manent dentition is characterized by missing
and delayed eruption of teeth. Firm, non tender
cervical adenopathy is also characteristic. Skin
pigmentation occurs in one-third of cases
and the possibility of some relationship to
Albright's syndrome has been raised, but not
clearly established.
The radiographic appearance is characteristic
and consists of bilaterally symmetric radiolu-
cent lesions of the jaws with marked cortical ex-
pansion and thinning. The posterior mandible is
the most commonly affected area. Unerupted
teeth appear to be floating in the largely radio-
lucent jaw bone. Even when the lesion is
extensive, the mandibular condyles are spared.
When the lesions regress, the affected bones
display greater radiodensity.
Cherubism is not associated with systemic
metabolic disease and serum calcium, phos-
phorous, alkaline phosphatase, and parathyroid
hormone levels are normal. Histologically,
cherubism may be indistinguishable from the
GCRG. A fibrous stroma is filled with giant
cells and small blood vessels.
Diagnosis is based on the characteristic clini-
cal presentation and positive family history.
Cherubism differs from GCRG in its symmetric
distribution and location at the angle of the
mandible rather than anterior to the first molar.
Treatment. Treatment of cherubism consists
of observation and close follow-up during the
growth phase. In late childhood or early teens,
after involution of the lesion occurs, any
residual contour abnormality can be surgically
corrected. Realizing that surgical contouring
prior to involution may result in rapid regrowth
of the tumor, early operative intervention may
be indicated if the deformity is severe. It is dif-
241
ficult to deal with early loss of deciduous teeth
and late eruption of the permanent teeth. Space
maintainers must be used to prevent space loss
and crowding of the permanent dentition.
Treatment must be individualized because
there are reported cases of rapid growth of jaw
tumors in early childhood with airway com-
promise [25]. In these rare cases, resection is
carried out as a life-saving maneuver. It is of
note that the histologic appearance of cheru-
bism is not helpful for predicting growth of the
lesion, its treatment, or ultimate prognosis.
OSTEOBLASTOMA AND OSTEOID OSTEOMA
Diagnosis. Osteoblastoma is rare in the jaws.
The most common sites are the vertebrae and
long bones, accounting for 80% of cases.
Osteoblastoma of the jaws occurs in children
and young adults with an age range of 5-22
years [26, 27]. Swelling, often with dull pain, is
the predominant symptom (figure 14-7). Since
the calvarium is the second most common site,
trismus may be the initial complaint if the tem-
poral bone is involved.
Osteoid osteoma is histologically indistin-
guishable from osteoblastoma. Both display
trabeculae of woven bone and osteoid against a
background of vascular fibrous tissue. The ma-
jor difference is based on growth potential [28].
The osteoid osteoma is smaller, rarely larger
than 1 em in diameter. In addition, this lesion
usually produces very severe pain, usually most
intense at night.
Radiographically, osteoblastoma presents as
a solitary radiolucency in contrast to osteoid
osteoma, which has a distinct sclerotic bound-
ary around an otherwise similar radiolucency.
Treatment. Proper treatment of both entities
is an en bloc excision with margins. Simple
curettage results in recurrence.
VASCULAR LESIONS
Vascular birthmarks of the maxillofacial region
are common, but usually involve skin, muscle,
and mucosa; primary bone lesions are rare.
Vascular lesions have been difficult to under-
stand, in part because of the confusing terminol-
ogy in the literature. In 1982, Mulliken and
Glowacki introduced a biologic classification
system that distinguishes between hemangiomas
and vascular malformations [29]. Boyd et al. re-
ported on vascular lesions of the maxillofacial
region using this classification, finding that true
242 III. DIAGNOSIS AND MANAGEMEl'\T OF HEAD AND NECK NEOPLASIA

c
o

fiGURE l4-7. Osteoblastoma. Tumor of base of skull and glenoid fossa presenting as slowly expanding swelling
and progressive trismus. (A) Frontal view of face preoperatively. (B) Preoperative axial CT scan demonstrates
radiopaque lesion of right TMJ, extending into infratemporal space. (C) Preoperative sagittal CT scan demon-
strates lesion at base of skull near temporomandibular joint. (D) Postoperative axial CT scan demonstrates
area of resection around foramen ovalc.
 14. NON MUCOSAL NEOPLASMS OF THE MAXILLOFACIAL REGION
hemangiomas of bone are extremely rare and
represent less than 1% of hemangiomas of the
maxillofacial region. In contrast, one-third of
vascular malformations exhibit some involve-
ment of the underlying bone [30]. The third
vascular lesion included in this discussion is the
aneurysmal bone cyst.
Hemangioma
DIAGNOSIS. Hemangiomas are true tumors of
vascular endothelium and are the most common
benign tumor of childhood. Hemangiomas are
usually not present at birth, exhibit rapid post-
natal growth until the child attains approx-
imately one year of age, and then the lesions
undergo slow involution, usually completed by
age 5-7 years. These tumors exhibit rapid en-
dothelial cell turnover and contain large num-
bers of mast cells per high-powered field during
the proliferative phase. Hemangiomas charac-
teristically affect the skin of the maxillofacial re-
gion. Fewer than 100 cases [31] of hemangioma
of the facial bones have been reported, the
majority occurring in the mandible. Many of
these "hemangiomas," however, were probably
vascular malformations. Sudden, rapid expan-
sion may have reflected hemodynamic altera-
tions induced by trauma, infection, or endo-
crine change, such as puberty or pregnancy.
The central jaw hemangioma is usually re-
ported as a slowly enlarging painless mass.
Spontaneous bleeding is rarely a problem in
these lesions, although extensive hemorrhage
may occur with dental extractions. Radio-
graphically, the hemangioma appears as a multi-
locular radiolucency or may have a "soap
bubble" configuration with indistinct borders.
There is nothing specific about this radiographic
appearance. Teeth may be displaced, but exter-
nal resorption usually does not occur [32].
TREATMENT. Occasionally, high-dose corti-
costeroids are used to control growth during the
rapid proliferative phase if there is danger to
vital structures such as the eyes and eyelids.
Otherwise, hemangiomas are observed and resi-
dual tumor is removed after involution occurs.
Central jaw hemangiomas rarely bleed spon-
taneously and usually do not require treatment.
If problems arise because of bleeding, usually
around the teeth, arteriography is necessary to
define the anatomy of the lesion. Selective
embolization of afferent vessels and en bloc
resection can be performed if necessary.
243
Vascular Malformation
DIAGNOSIS. These lesions are morphogenetic
abnormalities of vascular channels. They are de-
scribed by the vessels involved, e.g., lymphatic,
capillary, venous, mixed venous-lymphatic,
arterial, and arteriovenous fistulas; 35% of
malformations exhibit direct bony involvement
[30]. Malformations are present at birth, grow
commensurately with the host, and may enlarge
secondary to trauma, infection, and bleeding
within the lesion (figure 14-8). Histologically,
they exhibit normal endothelial cell cycle and
normal numbers of mast cells. Vascular chan-
nels are normal in appearance, but increased in
density and number. Radiographically, there are
a variety of changes, such as decreased density,
change in shape, and increase in size of the
affected bone. Hypertrophy and distortion of
bone are characteristic of lymphatic malforma-
tions. Arterial malformations are associated
with destructive changes of bone.
Clinical presentation depends on the type of
malformation. Patients with port-wine stain
(capillary malformation) rarely have bone in-
volvement unless the port stain is mixed with
venous or arterial malformation. There may be
some distortion of adjacent bone without any
intraosseous malformation. Port-wine stains
may be associated with Sturge-Weber syndrome
in which case there may be seizures, calcifica-
tion of the falx cerebri, and intraoral gingival
hemangiomas or pyogenic granulomas. Lym-
phatic malformations produce problems with
intermittent swelling, pain, erythema, fever, and
tenderness over the malformation, particularly
in association with other local infections such as
upper respiratory infection, otitis media, or den-
tal infection. Lymphatic malformations char-
acteristically produce distortion of underlying
bone with hypertrophy, increase in size, and
distortion of shape being the most common
changes. Venous malformations may involve
bone directly. Patients complain of intermittent
swelling, pain, and fever. The malformation
may be tender and phleboliths may be palpable
within the lesion. Differentiation among cel-
lulitis, thrombophlebitis, or phlebothrombosis
may be difficult. Underlying bone may be dis-
torted with abnormal size and shape as well as
displacement. There may also be direct bone
involvement with malformation in which case
there is danger of exsanguinating hemorrhage
with any local surgery such as extraction of
 B

c
FIGURE 14-8. Vascular malformation of mandible and surrounding soft tissues. (A) Rapid expansion of vascular
malformation secondary to infection. The patient was unable to close his mouth. (B) Panoramic radiograph
demonstrates distortion of the mandible and displacement of teeth. Note multiple phleboliths in surrounding
soft tissues. (C) Appearance after resolution of infection. (D) Arteriogram demonstrates diffuse nature of vascu-
lar malformation.
 14. NONMUCOSAL NEOPLASMS OF THE MAXILLOFACIAL REGION
teeth. High-flow lesions such as arterial or
arteriovenous fistulas present with an enlarging,
warm, red, tender swelling with a palpable thrill
and audible bruit. The teeth may be loose and
depressible in the socket. Radiographically,
there are destructive changes in the bone; teeth
within the malformation are spread apart.
TREATMENT. Treatment is directed toward
management of intercurrent infection and con-
trol of bleeding when it occurs. Coagulation
abnormalities must be investigated and treated if
bleeding occurs and if operation is contem-
plated. Specifically, patients with large vascular
malformations may be at risk for abnormal
coagulation because of chronic consumption
coagulopathy. Turbulent flow within the mal-
formation produces platelet adhesion and
aggregation and intravascular coagulation that
consumes clotting factors. Prothrombin and
partial thromboplastin time must be obtained as
well as platelet count, fibrinogen level, fibrin
split products, and consultation with hema-
tology.
Operative treatment is sometimes necessary
to stop bleeding, to remove infected teeth, or
to repair traumatic injury. Total resection of
vascular malformations is not possible in all
but the smallest lesions. Arteriography is help-
ful to document the anatomy of the afferent and
efferent vessels and extent of the malformation.
Embolization may be helpful preoperatively to
reduce the bleeding and to permit partial resec-
tion.
Aneurysmal Bone Cyst. The aneurysmal
bone cyst is a vascular lesion that most com-
monly affects the vertebrae and long bones.
Aneurysmal bone cysts of the jaws make up
only 27% of all such lesions [33].
DIAGNOSIS. Females are affected more com-
monly than males and the mandible is the usual
location. Patients present with painless swelling
and a history of prior trauma. Radiographically,
there is a multilocular radiolucent lesion or a
"soap bubble" appearance. Cortical expansion,
sometimes with perforation, and surrounding
periosteal bone formation, are characteristic.
When these lesions are aspirated or surgically
explored, blood characteristically "wells up"
and the lesion is sometimes misdiagnosed as a
hemangioma [34].
Aneurysmal bone cysts are not true,
epithelial-lined cysts. Rather, they are blood-
filled spaces lined by flat spindle cells, often
245
surrounded by giant cells as well as elastic or
muscle fibers. Some areas may be histologically
indistinguishable from GCRG.
TREATMENT. Treatment consists of thorough
curettage; recurrence is uncommon. Hemor-
rhage is significant as the lesion is being re-
moved, but ceases once it has been completely
curetted from surrounding bone.
HEMATOPOIETIC-
RETICULOENDOTHELIAL TUMORS
Hematopoietic tumors are discussed in chapters
19-21. For the purpose of this chapter we
will mention the occasional case where a patient
presents for evaluation of a jaw lesion that turns
out to be lymphoma, histiocytosis, multiple
myeloma, or Burkitt's lymphoma.
Lymphoma. Primary lymphoma of the jaws is
rare. The long bones are the most common site
of skeletal involvement [35]. To categorize a
central bone lesion as primary lymphoma,
secondary invol~ment from an extragnathic
focus must be exeluded.
Primary lymphoma of the maxilla typically
involves the antrum, with relative sparing of the
alveolar bone. Proptosis may be the first sign as
tumor invades the orbit from below. Swelling
and pain are common. If lymphomas of the
antrum are included as maxillary tumors, the
maxilla is the most common facial bone to be
involved by lymphoma. Older men (50s to 70s)
are most commonly affected. Regional adeno-
pathy may represent foci of the same disease
process.
Radiographs reveal zones of irregular radio-
lucency, usually with poorly defined bound-
aries. Periosteal new bone formation is usually
absent. Diagnosis is confirmed by biopsy. The
reader is referred to any number of texts for
discussion of management of lymphoma.
Histiocytosis. Histiocytosis is a disease of
unknown etiology in which collections of
cholesterol-laden histiocytes accumulate in hard
and soft tissues. Three distinct forms are recog-
nized: (a) eosinophilic granuloma, a localized
form; (b) Hand-Schuller-Christian disease, a
disseminated chronic form; and (c) Letterer-
Siwe disease, a malignant disease of acute onset
with poor prognosis. Onset of disease is usually
in early or late childhood but may first appear in
late adolescence or in the adult.
Eosinophilic granuloma presents as bony ex-
246 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
pansion, beginning in the bone marrow and
causing cortical deformation and thinning [36].
The most common sites of eosinophilic granu-
loma are in the craniofacial skeleton, particular-
ly the mandible and maxilla. The posterior body
and angle regions of the mandible are most
often affected. Dental symptoms may be the ini-
tial focus of attention, including tooth mobility,
gingival ulcerations, premature loss of teeth,
and delayed healing of extraction sites [37].
Radiographically, the teeth appear to be "float-
ing" in soft tissue with loss of surrounding
bone. These findings may mimic periodontal
disease.
Hand-Schi.iller-Christian disease results in
complaints referable to multiple organ sys-
tems [38]. Affected patients are usually in the
first or early part of the second decade of life,
are often of short stature, and of lower than
normal body weight. Diabetes insipidus, prop-
tosis, and dental malocclusion may be caused
by infiltration of the hypothalamus, the orbit,
or the jaws. Christian's triad consists of lytic
lesions of the skull, diabetes insipidus, and
exophthalmos; its presence is consistent with
but not mandatory for the diagnosis.
Other findings in Hand-Schi.iller-Christian
disease are hepatic and splenic enlargement,
eczematous skin lesions, and deafness, the latter
caused by tumor infiltration into the mastoid air
cells.
Letterer-Siwe disease is the most severe form
of histiocytosis, usually presenting in very
young children (less than two years old) and
often following a fulminant course with massive
involvement of the liver and spleen, generalized
lymphadenopathy, and pancytopenia. Bone
lesions are usually less marked in this acute
form of histiocytosis [39].
Central lytic lesions of the jaws may occur in
any of these three types of histiocytosis. In
addition, jaw involvement may be the first sign
of disease. Periodontal tissue infiltration by eosin-
ophils and histiocytes may produce gingival
swelling or ulceration and mobile or displaced
teeth. The presentation of histocytosis may be
variable and is often not considered in the dif-
ferential diagnosis of jaw lesions in children and
even less commonly in adolescents or young
adults.
Radiographically, all forms of histiocytosis
produce "punched out" radiolucencies with
no calcification in their boundaries and little
surrounding sclerotic reaction. If a lesion is
detected in the jaws, radiographic survey of
the skeleton, including the skull, must be per-
formed to help classify the disease. There is sig-
nificant alveolar bone resorption producing the
appearance of teeth "floating" in empty space.
Unifocal eosinophilic granuloma should be
treated by enucleation and/or low-dose radia-
tion (600-1000 rad). In general, treatment is
with combination chemotherapy, usually cor-
ticosteroids together with other drugs (alky-
lating agents, antifols, cytotoxic antibiotics).
Burkitt's Lymphoma. Burkitt's lymphoma
is an undifferentiated form of lymphoma that
frequently causes extranodal disease. First
reported in 1958 [40] and subsequently recog-
nized as a malignant lymphoma, this disease is a
systemic process that may be caused by a virus,
as deduced from epidemiologic data [41].
However, the etiology is not definitely estab-
lished.
This disease affects males predominantly.
Although usually affecting children, this disease
may occur at any age. Multiple organ systems,
most commonly extranodal, are involved, in-
cluding the abdominal or pelvic viscera, re-
troperitoneum, facial and long bones, central
nervous system, and salivary glands [42].
Jaw involvement occurs more commonly in
the African form of this disease and may pre-
cede the clinical appearance of disease in other
systems. The maxilla is involved twice as fre-
quently as the mandible although bimaxillary
involvement is not uncommon. Jaw disease pre-
sents with premature exfoliation of teeth and
associated swelling. Pain is mild and paresthesia
is uncommon. Since the posterior maxilla is
most commonly involved, proptosis may be the
first sign as tumor extends through the antrum
to the orbit.
Burkitt's lymphoma causes bony destruction
and therefore radiolucent defects in the jaws.
An early finding may be loss of the lamina dura
around the root apices.
Untreated, this disease has an extremely poor
prognosis with death occurring within six
months in most cases. Treatment with high-
dose alkylating agents and selective surgical de-
bulking will result in remission in over 90% of
the cases. Relapse, when it occurs, may respond
to further chemotherapy [43].
 14. NONMUCOSAL NEOPLASMS OF THE MAXILLOFACIAL REGION
NEUROGENIC TUMORS
The most common neurogenic tumors encoun-
tered in the jaws are the traumatic neuroma,
neurofibroma, neurilemmoma, and malignant
Schwannoma. Less common are the melanotic
neuroectodermal tumor of infancy and the
ganglioneuroma. The neurilemmoma and neuro-
fibroma are of Schwann cell origin. They are,
however, histologically separate tumors. The
traumatic neuroma is not a true neoplasm and
will not be discussed further.
Neurilemmoma. The neurilemmoma is also
called Schwannoma. It arises from the sheath of
Schwann, which encases peripheral rtefVes. The
Schwann cell is capable of producing coHagen
that is present in both the neurilemmoma and
neurofibroma. The neurilemmoma characteris-
tically produces pain, usually localized to the
site of involvement, occasionally accompanied
by paresthesia and swelling. The majority of re-
ported cases have involved the mandible. There
is no apparent age or sex predilection [44~46].
Radiographically, the central neurilemmoma
appears as a unilocular or multilocular radio-
lucency with well-defined borders, con8istent
with its discrete capsule. It is usually a solitary
lesion.
Histologically, neutites are not incorporated
into the tumor, which is composed of two dis-
tinct tissue types: Artttlni type A, consisting of
pallisading Schwann eells, and Antoni type B,
consisting of a network of reticulin fibers and
small cystic spaces. Verocay bodies are collec-
tions of Schwant} cells around a central, acellu-
lar, eosinophilic mass. All of these tissues are
derived. from Schwann cells.
Treatment is surgical. Complete enucleation
is curative. The neurilemmoma has no sig-
nificant malignant potential.
Neurofibroma. Neurofibroma, although also
derived from Schwann cells, has clinical and
histologic features distinct from the neurilem-
moma. The neurofibroma is nonencapsu-
lated. Approximately one-third of patients with
neurofibromatosis have bone changes consisting
of cystic lesions with expansion, subperiosteal
erosion, or bony hypoplasia without radiolu-
cent change [47, 48]. The latter has been re-
ported in association with facial neurofibromas.
Central neurofibromas of the jaws occur more
often as solitary lesions rather than as part of
generalized neurofibromatosis [46]. The bone
247
adjacent to or directly involved by neurofibro-
ma is extremely vascular.
Central neurofibromas usually induce dull
pain and paresthesia. Most have occurred in the
mandible [49], appearing radiographically as a
fusiform expansion of the mandibular canal.
Bone adjacent to overlying soft-tissue neurofib-
roma may appear as a multilocular radiolucency
with cortical thinning and irregular boundaries
(figure 14-9).
Histologically, the neurofibroma is com-
posed of Schwann cells and neurites in an
irregular pattern without the organoid tendency
of the neurilemmoma.
Sarcomatous degeneration in neurofibro-
matosis occurs in approximately 15% of cases
although no specific figure is available for
central jaw lesions. It is, however, known that
solitary lesions rarely undergo malignant trans-
fotmation.
'Treatment should be surgical excision. The
inferior alveolar nerve is sacrificed when treat-
ing mandibular lesions. Interposition nerve
grafting and bony reconstruction should be
considered. Bone adjacent to or directly in-
volved by neurofibroma is extremely vascular
and may bleed briskly when manipulated. Total
resection is not always possible.
Malignant Schwannoma. Malignant peripheral
nerve tumors are usually of Schwann cell origin,
closely resemble mesenchymal sarcomas, and are
called malignant Schwannoma or neurogenic
sarcoma [50, 51]' Malignant transformation
of neurofibroma accounts for most of the malig-
nant nerve tumors. Some investigators believe
that most primary malignant tumors are sarco-
mas arising from endoneurium or perineurium.
This lesion appears radiographically as an
enlargement of the mandibular canal or as a
unilocular radiolucency with hazy borders.
Sarcomatous transformation occurs most com-
monly in adolescents and young adults while
the de novo sarcomas occur more often in older
adults. Pain, swelling, and paresthesia are the
usual symptoms.
Histologic features of malignant Schwanno-
ma are variable, even within the same tumor,
and are nearly identical to the fibrosarcoma.
Fibrous tissue, osteoid, and cartilage may be
found. Nerve sheath elements must be present
to make the diagnosis.
Proper treatment is wide resection, usually
with adjunctive radiation. This tumor has a
248 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA

FIGURE 14-9. Neurofibromatosis with maxillary and mandibular involvement. (A) Frontal view·of extensive
neurofibroma of right face, including frontal, temporal, maxillary, and mandibular regions. (B) Axial CT scan
displays the diffuse nature of the neurofibroma with associated bony distortion. (C) Radiolucent lesions and
bony distortion of the right mandible and maxilla are demonstrated by this panoramic radiagraph.
 14. NONMUCOSAL NEOPLASMS OF TIlE MAXILLOFACIAL REGION 249

tendency to recur and each recurrence displays lial tumors.

more aggressive behavior. Pulmonary metas- Central malignant epithelial tumors occur
tases have been reported in 20% of cases [52]. most commonly in the mandible (2:1 relative to
maxilla). Eversole et al. [58] reported that 75%
Melanotic Neuroectodermal Tumor of of 32 cases of central squamous cell carcinoma
Infancy. The melanotic neuroectodermal
were associate~ with an odontogenic cyst, pre-
tumor of infancy was first reported in 1918 as
sumably resultmg from malignant transforma-
"congenital melanocarcinoma." Many other
tion of cyst epithelium under the influence of
names have been applied to this lesion as a result
chronic inflammation. Such carcinomas are
of multiple theories as to the true tissue of ori-
more radiosensitive and tend to metastasize
gin [53]. Presently there is general agreement
later than their oral mucosal counterpart.
that this tumor arises from neural crest, sup-
Central salivary gland tumors usually occur
ported by. the associated elevation of urinary
in the posterior jaw, arising from ectopic sali-
concentrations of vanilmandelic acid, a feature
vary gland tissue in the retromolar area of the
of other tumors derived from neural crest
mandible, from the lining of the antrum or
(neuroblastoma, pheochromocytoma gang-
from metaplastic odontogenic cyst lining. Cen-
lioneuroblastoma) [54]. .'
tral mucoepidermoid tumors appear to be more
Children in the first year of life are usually
aggressive than those of the minor and major
affected, most cases occurring in the first six
salivary. glands, i.e., there does not appear to be
rr:onths. It has been reported in extragnathic
the eqUivalent of the low-grade form clinically
sites (scapula, mediastinum, epididymis, cere-
[59].
bellum), but usually involves the anterior maxil-
la. in the c~nine region, presenting as swelling
with elevatIOn of the lip. Mandibular involve-
ment is rare. There are no constitutional symp- Odontogenic Tumors
toms. The lesion may be brown or black. A
When the cO~I?lex .cellular inductive process of
radiolucency with displacement of the tooth
odontogenesls IS disturbed, odontogenic cysts
germs is typical [53, 55].
and tumors may result. Odontogenic tumors
The tumor is nonencapsulated with infiltrat-
~re classified according to germ layer of origin,
ing projections of tumor cells in alveoli-like
I.e., ~ctodermal, mesodermal, and mixed origin.
arrangement in a vascular fibrous stroma. Cells
Gorhn et al. [60] have classified odontogenic
with abundant pale cytoplasm contain variable
tumors in a useful format (table 14-2). The fol-
amounts of brown granules of melanin.
C?ccasionally locally aggressive, this is a
be~l&n tumor best managed by conservative
eXCISIOn. Recurrence has been reported in 15%.
None has metastasized [56]. TABLE 14-2. Classification of odontogenic tumors
Ganglioneuroma. The ganglioneuroma is 1. Epithelial tumors
comp.osed of sympathetic ganglion cells with 1. Ameloblastoma
associated Schwann cells and may be well dif- a) Peripheral
ferentiated or poorly differentiated. Originat- b) U nicystic
ing most commonly in the adrenal medulla and c) Solid, multicystic
sympathetic ganglia, this tumor has been re- 2. Adenomatoid odontogenic tumor
ported to have metastasized to the mandible [3, 3. Calcifying epithelial odontogenic tumor
(Pindborg tumor)
46]. Thoma and Goldman [57] reported a pri-
4. Ameloblastic fibroma
ma!y centra~ turr:or of the mandible. The pos- 5. Odontoma
tenor mandible IS the most common location. 6. Squamous odontogenic tumor
Weare ~ot aware of any report of central maxil-
l~ry leSIOns. Proper t~eatment is surgical resec- II. Mesodermal tumors
1. Myxoma (of questionable odontogenic origin)
tion. Chemotherapy IS employed if disease is
2. Cementoma
disseminated. a) Periapical cemental dysplasia
b) Cementifying fibroma
Malignant N onodontogenic Tumors c) Cementoblastoma
3. Odontogenic Fibroma
Incl.uded in this general category are the central
mahgnant mesenchymal and malignant epithe- From Godin et al.[60].
250 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
lowing discussion will highlight the ameloblas-
toma, adenomatoid odontogenic tumor, and the
cementoma group. The myxoma and cementify-
ing fibroma have been previously discussed in
the benign mesenchymal nonodontogenic
category.
AMELOBLASTOMA
The ameloblastoma is a tumor conslstmg of
proliferating odontogenic epithelium supported
by a fibrous stroma [61]. First described by
Cusak in 1827 [62], it accounts for less than 1%
of odontogenic cysts and tumors. Although the
ameloblastoma is generally viewed as a single
clinical and pathologic entity, recently emphasis
has been placed on the several biologically
distinct forms of ameloblastoma [63-65].
The ameloblastoma arises from enamel organ
tissue (ectoderm). A rare peripheral form has
been described that does not have an invasive
tendency, usually presents as an epulis like le-
sion, occasionally ulcerates and does not recur
after conservative excision [65]. The central
form may be of two types: unicystic, which
resembles the dentigerous or primordial cyst
clinically and radiographically [63], and the
multicystic (solid) [64].
The unicystic form presents as an apparent
odontogenic cyst, i.e., on routine radiographs as
a well-demarcated lucency, usually located in
the mandible, usually in the third molar region,
and often associated with an impacted tooth.
Diagnosis is usually established after the pre-
sumed benign cyst has been enucleated. His-
tologically, foci of amelobastic epithelium is
found in the wall of a cyst. Ameloblastic ele-
ments may sometimes be difficult to identify.
Robinson and Martinez [63] enumerate the his-
tologic criteria used to identify ameloblastic
epithelium. It is unclear as to whether such
lesions arise from dentigerous or primordial
cysts or whether they arise de novo.
Unicystic ameloblastoma occurs in a younger
age group: of 14 patients reported in one series,
ten were below the age of 20 years [63]. This is
in contrast to the usual, 39-year mean age that is
cited for patients affected by ameloblastoma.
Proper treatment of the unicystic variant is
enucleation. If there is evidence of tumor exten-
sion through the fibrous capsule, marginal re-
section should be performed with at least I-em
margins. There should be a low threshold to
perform further resection once the diagnosis is
established, particularly if the lesion was frag-
men ted during its removal. The importance of
pathologic examination of multiple sections of
an apparent odontogenic cyst must be empha-
sized since ameloblastic elements may exist only
in a localized zone [63]. Although initial treat-
ment is the same for the benign cyst and the
unicystic ameloblastoma, follow-up is obvious-
ly influenced by the diagnosis, and instances
of histologically bland forms of the latter may
display more aggressive behavior [63]. This
nonpredictability is an example of disparity
between histology and clinical behavior.
The multicystic (solid) form is the classic type
that most clinicians consider when presented
with the diagnosis of "ameloblastoma." It
usually presents as a .swelling of the jaw without
pain or paresthesia. Rarely is there breakdown
of oral mucosa. Radiographs reveal cortical
expansion and thinning around a multilocular
radiolucency. Root resorption may occur.
The multicystic form grows slowly, invades
locally through the intertrabecular spaces of
cancellous bone but rarely through cortical
bone, and recurs at a high rate (as high as 55 to
90% in various series) [61, 64, 66]. The mandible
is involved in 80% of cases, about three-fourths
of which occur in the molar-ramus area. Metas-
tases have been documented, but examples are
exceedingly rare [67, 68].
Various histologic patterns have been de-
scribed (follicular, plexiform, granular cell,
acanthomatous), but there appears to be no
associated clinically significant difference in
biologic behavior patterns [69].
Treatment must be resection with 1-1.5 em
of uninvolved bone margins. Because this tumor
tends to infiltrate through the intertrabecular
spaces, tumor boundaries are difficult to deter-
mine grossly. Tumors involving the posterior
maxilla must be treated more aggressively than
lesions of the mandible or anterior maxilla be-
cause the thinner walls of the maxilla offer less
resistance to invasion and perforation and be-
cause of the proximity to the pterygomaxillary
fossa, infratemporal space, and orbit (figure
14-10) [64]. Curettage is inadequate treatment.
When a discontinuity defect of the mandible re-
sults from resection, immediate reconstruction
with autogenous bone grafts should be carried
out. Maxillary defects should be managed with
skin grafts as necessary and dental prostheses at
the time of resection.
Recurrence after conservative surgical exci-
sion occurs in 50%-60% [70, 71] as compared
 14. NONMUCOSAL NEOPLASMS OF THE MAXILLOFACIAL REGION
FIGURE 14-10. Ameloblastoma of left maxilla. (A)
Intraoral photograph displays the ulcerated lesion of
the left maxilla and associated root exposure. (B)
Panoramic radiograph demonstrates radiolucent
lesion with irregular borders. (e) Resection consisted
of posterior dentoalveolar segment. (D) Follicular
pattern of ameloblastoma with ameloblastic cells sur-
rounding tissue resembling stellate reticulum. X 130,
hematoxylin-eosin.
with 4.5% after wide resections [70]. Recur-
rence may occur as late as ten years postoper-
atively, so long-term follow-up is essential [72].
251
ADENOMATOID ODONTOGENIC TUMOR
This is a benign, slow-growing lesion that is
probably a hamartoma rather than a true neo-
plasm [73]. It consists of a well-encapsulated
collection of proliferating epithelium arranged
in ductlike tubular structures with interspersed
collections of an amorphous, eosinophilic mate-
rial. It occurs almost exclusively in the anterior
tooth-bearing areas of the jaws; 40% are asso-
ciated with an impacted tooth, usually a canine.
The maxilla is involved most often (60%). Pain-
less swelling is the most common presentation.
252 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
Females are affected more often than males (2:1)
and affected individuals are usually in the
second or third decades of life [74].
Radiographs show a well-circumscribed uni-
locular lucency, often surrounding an impacted
tooth. Within the lucency are small foci of
calcification.
Awareness of the biologic and histologic be-
havior of this lesion is crucial to prevent mis-
diagnosis as ameloblastoma. One important dis-
tinction is the well-defined capsule seen around
this lesion in contrast to the unencapsulated
ameloblastoma. Original suggestions that this
tumor represented a variant of the ameloblasto-
ma are invalid. The term "adenoameloblasto-
ma" is potentially misleading and should be
discarded.
Treatment is enucleation; recurrences have
not been reported.
CEMENTOMA
Periapical Cemental Dysplasia. Cemento-
mas include a variety of jaw lesions derived
from the periodontal membrane. The tertn
"cementoma" should usually more appropri-
ately be called periapical cemental dysplasia
(PCD), an often asymptomatic lesion involving
the anterior mandibular teeth, usually discov-
ered on routine radiographs. Following an ini-
tial radiolucent phase, it progressively calcifies.
Lesions are usually multiple and teeth are vital.
No treatment is necessary [22].
Cementifying Fibroma. The cementifying
fibroma may be indistinguishable from the
ossifying fibroma by histologic examination,
although cementum may be more ovoid and
densely calcified and the tumor may have a
more intimate relationship with the root apices.
In contrast to PCD, this entity tends to occur in
the mandibular premolar-molar area. All of
these lesions are histologically quite similar to
one another and to fibrous dysplasia. The im-
portant distinctions are the differences in clini-
cal behaviors. Whereas PCD is typically biolo-
gically quiescent, cementifying fibroma or any
of the other fibro-osseous lesions may display
rapid expansion that is often not explained by
the histology [23]. Treatment must then be de-
tertnined by clinical behavior. Enucleation or
conservative excision is curative.
ODONTOGENIC KERATOCYST
Although the purpose of this chapter is to dis-
cuss central jaw tumors rather than cysts, the
odontogenic keratocyst warrants some discus-
sion because of its frequently aggressive biolo-
gic behavior. It often displays rapid growth,
cortical perforation, induction of sensory dis-
turbances, and a high rate of recurrence [75, 76].
It may be appropriate to consider this lesion
a neoplasm. Its aggressive behavior is not
explained by the bland histologic appearance
of ortho- or parakeratinization and basal cell
polarization nor is the greater tendency for
recurrence of the parakeratinized variety ex-
plained [77]. This is another example in which
treatment must be guided by biologic behavior
rather than histologic appearance.
Conclusion
Tumors of the maxillofacial skeleton encompass
a broad spectrum of histologic and biologic pat-
terns. Benign, nonodontogenic mesenchymal
tumors predominate in children although odon-
togenic tumors are more common in the adult
population.
Treatment of these tumors must be deter-
mined on the basis of histology and biologic be-
havior, realizing that there are multiple exam-
ples illustrating a lack of correlation between
these two factors (giant cell lesions, cherubism,
odontogenic keratocyst). Resection rather than
curettage is usually the appropriate therapy
when there has been earlier treatment failure by
local tumor removal, rapid tumor expansion,
or when tumor extensively invades the jaw.
Although there should be concern about dis-
turbance of facial growth after major extirpative
treatment of tumors of the maxillofacial com-
plex in children, these considerations are second-
ary to tumor removal and are not necessarily
valid when early reconstruction with auto-
genous tissue is performed (figure 14-5) [3, 78].
Further study is necessary to establish more
precise correlation between variations in clinical
behavior and changes at the cellular level to
improve our abilities to plan treatment and to
discuss prognoses of these tumors.
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 15. SURGICAL MANAGEMENT OF
HEAD AND NECK NEOPLASIA
E. George Elias
Head and neck tumors can be classified into be-
nign and malignant varieties. While the surgical
management of benign lesions is usually by
local excision, the malignant lesions will be
managed by wider resection and may require
regional lymphadenectomy, depending on the
site of the primary, the extent of the disease
(i.e., stage) and the cell type. Therefore, prior
to definitive surgery, a biopsy is usually per-
formed to establish the diagnosis, and the pa-
tient has to be evaluated for the extent of the
disease.
The most common malignant primary tumor
in this area is the squamous cell (epidermoid)
carcinoma. Other malignant primaries include
adenocarcinoma, undifferentiated carcinoma,
lymphoma, melanoma, chondrosarcoma, and
soft-tissue and bone sarcomas. In addition,
metastases from other primary sites in the body
(mainly lung and gastrointestinal tract) can be
encountered in the head and neck region. The
management of such metastases depends mainly
on the systemic control of the disease. How-
ever, palliative head and neck surgery may play
some role in management of these patients. This
chapter discusses surgical management of head
and neck neoplasia. Some discussion of diagno-
sis and evaluation at the sites involved is pre-
sented; see chapters 10-14 for further detail.
Diagnosis and Staging
A suspicious skin or mucosal lesion must be
biopsied for histologic documentation. Such
biopsy should include normal tissue adjacent to
the lesion. This will help the pathologist to
determine whether the lesion is primary or
metastatic. The biopsied tissue must not be
crushed. The exact site of the lesion must be
stated, and the pathologist should be informed
Peterson etal., HEAD AND NECK MANAGEMENT OF THE CANCER PATIENT.
© 1986. Martinus NijhoJf Publishing. All rights reserved.
of the nature of the lesion, i.e., whether it is
exophytic, ulcerative, or invasive. A negative
pathology report should not stop the surgeon
from rebiopsying a suspicious lesion. It should
be kept in mind that the presence of one lesion
does not exclude the presence of another one, as
multicentric lesions are often encountered in the
area of the head and neck. Therefore, once the
diagnosis is established, the patient must under-
go complete physical examination and workup
for accurate clinical staging and to rule out other
primaries. The surgical approach will depend to
a great extent not only on the site and size of
the primary lesion, but also on the status of the
cervical lymph nodes, and whether or not the
patient has distant metastases from such lesion
(see the Appendix for staging).
The mucosa can be the site of two lesions that
can be precancerous or early cancer. Such le-
sions require special attention for their diagno-
sis and management that differ from the well-
established tumors that will be discussed under
each anatomic site:
1. Leukoplakia. Carcinoma may develop in
leukoplakia in about 6% of the cases [1] and
therefore it should be biopsied. The biopsy
should be obtained from the thickened or
suspicious area. Patients with speckled or
dysplastic leukoplakia have a 28% or 13%
chance of developing carcinoma, respectively.
However, those with leukoplakia simplex
have a 0% chance. Therefore, small lesions
can be excised, while extensive lesions can
be observed. Recently, 13-cis-retinoic acid
lozenges are being tried in the management of
such patients [2].
2. Erythroplakia. This red, velvety mucosal
lesion must be considered carcinoma until
proven otherwise [3]. This lesion is usually in
255
256 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
situ or early invasive squamous cell carcino-
ma. Therefore, it should not only be biopsied,
but should be completely excised with few
millimeters of margin and histologically ex-
amined for absence of tumor invasion and
free margins.
Management of Head and Neck
Tumors According to Site
The head and neck region, referred to as the up-
per aerodigestive system, can be divided into
definite anatomic sites: the nasal cavity, the
nasopharynx, the oral cavity, the oropharynx,
the larynx, the hypopharynx, and the paranasal
sinuses, mainly the maxillary sinuses (figure
15-1). These sites are of great importance for
reasons of exact staging of the disease, as well as
lymphatic drainage on which depend the sur-
gical and radiation therapeutic approaches and
the prognosis. Therefore, the pathology and
management will be presented according to
these anatomic sites.
NASAL FOSSA
The nasal fossa is anatomically outlined an-
teriorly by the nares, posteriorly by the
nasopharynx, medially by the septum, laterally
NASOPHARYNX
OROPHARYNX
HYPOPHARYNX
FIGURE 15-1. The major anatomic sites in the head
and neck region. The nasal fossa and the oral cavity
are separated anteriorly from the nasopharynx and
oropharynx posteriorly by an imaginary vertical line
that passes in front of the sphenoid superiorly to the
larynx inferiorly. This places the base of the tongue in
the oropharynx.
by the maxillary sinuses, and superiorly by the
frontal, ethmoid, and sphenoid sinuses. The
lymphatic drainage of the anterior part is to the
submaxillary lymph nodes, while the posterior
part drains into the retropharyngeal and the
upper internal jugular chain.
The most common tumors in the nasal cavity
are the benign polyps. These can be snared or
surgically excised. On the other hand, malig-
nant tumors are rare and are more common in
women than men. Such tumors can be accom-
panied by benign polyps. The most common
malignant tumor is squamous cell carcinoma.
Other tumors of nasal fossa may include adeno-
carcinoma (including cylindroma), lymphoma,
plasmacytoma, chondrosarcoma, neurogenic
tumors (including olfactory neuroblastoma),
melanoma, and metastatic tumors. Surgical ex-
tirpation of the disease followed by irradiation
is indicated in squamous cell carcinoma and
adenocarcinoma, including cylindroma. Mela-
noma and sarcomas should be treated surgically
with wide margins of resection. This is followed
by reconstruction or prosthetic rehabilitation.
NASOPHARYNX
The nasopharynx is outlined anteriorly by the
posterior nares and the septum, posteriorly by
the first and second cervical vertebrae, inferiorly
by the soft palate, superiorly by the basilar part
of the occipital bone and the sphenoid and
cavernous sinuses, and laterally by the openings
of the eustachian tubes. The posterior and later-
al walls are surrounded by the pharyngeal fascia
that attaches to the base of the skull and lies in
front of the foramen magnum, and medial to the
petrous portion of the temporal bone. Cranial
nerves II - VI are related to the cavernous sinus,
while cranial nerves IX-XII, the sympathetic
nerves, the internal carotid artery, and the inter-
nal jugular vein lie in the retroparotidean space.
The nasopharynx drains freely to the retro-
pharyngeal lymph nodes, causing compression
of the cranial or sympathetic nerves as the first
manifestation of the disease. It also drains to
the jugular and spinal accessory chain, and the
patient may present with enlarged lymph nodes
in these areas. It is estimated that more than
25% of patients with nasopharyngeal carcinoma
have invasion of the base of the skull [4]. N aso-
pharyngeal tumors are rare in this country and
are more common in men than women. The
most common tumors are the squamous cell
carcinoma, anaplastic carcinoma, and lym-
 15. SURGICAL MANAGEMENT OF HEAD AND NECK NEOPLASIA 257

phomas. The only role of surgery is to establish of the tongue (anterior two-thirds), floor of
the diagnosis, since these tumors are treated by mouth, buccal mucosa, hard palate, and lower
radiation therapy. The five-year disease-free jaw. Its cancers constitute 5% of all human can-
survival in squamous cell and anaplastic carci- cers. Smoking and alcohol are the main etiologic
noma is 29% [5]. However, there is strong evi- factors except for buccal cancer (associated with
dence now that these carcinomas may have bet- betal-nut and tobacco chewing), and lower lip
ter response if treated by irradiation and con- cancer (associated with sunlight, wind, and frost
comitant chemotherapy in the form of a low- exposure).
dose bleomycin or cisplatinum. Lower lip lesions are more common than
those of the upper lip. Lip cancer is most com-
MAXILLARY SINUS monly seen in older men. The lymphatics from
The maxillary sinus is anatomically outlined the lower lips drain to the submaxillary and up-
anteriorly by the cheek and floor of the orbit, per cervical lymph nodes. The ~pper l~p drains
superiorly by the floor of the orbit, posteriorly to the same lymph nodes as well as to the
by the pterygomaxillary fossa, and inferiorly by preauricular lymph nodes. Small lesions can be
the base, which is a thin bone that is divided treated surgically with wedge resection with
by the insertion of the inferior turbinate. The 1-cm margin and primary closure. This should
lymphatic drainage is to the submaxillary, include suturing of the muscle, the skin, and the
retropharyngeal, and jugular lymph nodes. The mucosa, while keeping the vermilion border in
tumors of the maxillary sinus are more common line for good cosmesis. Larger lesions will need
in men and include: squamous cell carcinoma of
the true antrum or secondary to invasion from
the upper gingiva, chondrosarcoma, osteosar-
coma, Ewing's sarcoma, Burkitt's lymphoma
and, rarely, adenocarcinoma or plasmacytoma.
Surgery and postoperative irradiation are indi-
cated in patients with squamous cell carcinoma,
adenocarcinoma, and in malignant gingival
tumors that belong to these two types. Osteo-
sarcomas and chondrosarcomas are managed
by wide local resection with less than 50%
five-year survival [6]. Maxillectomy is the treat-
ment of choice for carcinoma confined to the
antrum. As a rule, inferiorly located carcinoma
of the maxillary sinus has the best chance for
cure. If the lesion is located in the anterior wall
of the sinus, all structures under the skin of the
cheek must be removed. If the lesion has broken
through the wall of the sinus, the skin of the
cheek must be included in the resection. If carci-
noma has involved the roof of the antrum, the
orbital contents are resected with the maxilla. If
tumor invades the anterior ethmoidal sinus, the
nasal septum and the entire ethmoidal sinus
have to be removed. If tumors extend through
the posterior wall of the antrum, the pterygoid
plate is resected with the maxilla as well as
the ethmoid sinus. Ewing's sarcoma, Burkitt's
lymphoma, and plasmacytoma are managed by
FIGURE 15-2. Abbe-Estlander flap is used to recon-
irradiation and systemic chemotherapy. struct large lip defects. If more than one-third of the
lip is to be resected, half of the defect size is taken
ORAL CAVITY from the other lip and rotated on its vascular pedicle;
The oral cavity consists of the upper and lower 2-3 weeks later, the pedicle is severed and the vermil-
lips, upper and lower gingivae, mobile portion ion reconstructed in both lips.
258 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
sacrifice of a large part of the lip and will require
an Abbe-Estlander-type flap (figure 15-2)
from the other lip to reconstitute equality be-
tween the upper and lower lips. Tumors of the
commissure will require large resection with
face advancement flap to reconstitute the com-
missure (figure 15-3). There is no need to carry
out prophylactic neck dissection, as only 5%-
10% of lip cancer and 19% of commissure le-
sions develop regional lymph node metastases
[7]. If metastases develop, neck dissection is in
order. The overall five-year survival is 89%,
with a control rate of 92%.
Lower gingival lesions are more common
than those of the upper gingiva and metastasize
more often to the submaxillary and cervical
lymph nodes. While small lesions (less than 3
cm) can be treated by wide local excision (in-
cluding partial mandibulectomy) or by irradia-
tion, larger lesions (3 cm or more) are treated
with radical excision, radical neck dissection,
and postoperative irradiation. If the neck is clin-
ically negative, the neck can be radically irradi-
ated prophylactically. However, if suspicious
lymph nodes are felt in the submaxillary area or
in the neck, lymph node dissection should be
carried out followed by radiation therapy. The
five-year survival rate for patients treated with
surgery alone is 43% for cancers of the man-
dibular gingiva and 40% for cancers of the max-
illary gingiva [8].
FIGURE 15-3. Face advancement flap (lateral view) is
the best method to cover large commissure defects,
with excellent function and cosmesis. The incisions
extend from the upper and lower borders of the de-
fects across the face to meet near the ear lobe. The
facial vessels are ligated. The full thickness of the flap
is moved forward to cover the defect. The mucosa
inside can also be moved in the same fashion.
Mandibular resections are carried out for
tumors that invade the mandible, such as
epidermoid carcinomas of the gingiva or floor
of mouth, or for primary tumors of the bone
such as osteosarcoma of the mandible. This re-
sults in deformity and dysfunction if left unre-
constructed. The use of the Joe Hall Morris
biphasic appliance during surgery and for 12
weeks postoperatively results in bridging the
bone defect by fibrous tissue. This gives excel-
len t function and fair cosmesis. It also has the
advantage that it does not delay postoperative
irradiation. Recently, with the major advances
in reconstructive surgery, several techniques
have been developed for reconstruction not
only of the mandible, but also of the maxilla and
zygomatic arch. These will be discussed under
reconstructive surgery.
Floor-of-mouth lesions constitute 15% of
oral cancers, with men more frequently afflicted
than women. The tumors are usually squamous
cell carcinoma and can present as a superficial
induration, ulceration, or deeply invasive and
infiltrative lesions. These tumors may extend to
the mandible or actually invade the periosteum
and even the bone. Metastases to submandibular
and internal jugular lymph nodes are usually
encountered during the course of the disease.
Bilateral neck metastases are frequently seen.
Small lesions of up to 2 cm in diameter of the
superficial type can be well controlled by radia-
tion therapy. Deeply invasive lesions regardless
of size are managed with wide excision with a
minimum of 2-cm margins. The surgical defect
can be reconstructed by tongue flaps or naso-
labial skin flaps. Larger lesions may require
sacrifice of part of the tongue or the mandi-
ble, and more extensive reconstruction with a
deltopectoral skin flap or a pectoralis major
myocutaneous flap. Elective radical neck dissec-
tion is highly recommended in such cases [9]. If
cervical lymph nodes are palpable, therapeutic
lymphadenectomy is carried out followed by
irradiation. If the primary lesion is near the
midline, it is advisable to perform a suprahyoid
lymph node dissection on the contralateral side.
If positive lymph nodes are encountered on the
opposite side, a modified radical neck dissection
is in order. The overall control rate is about
66%, with 65%-85% survival for small lesions
and 50% for larger lesions treated by surgery
and radiation. Patients with large lesions that
are treated by irradiation only have poor surviv-
al of 27% [9]. Cylindromas should be treated
 15. SURGICAL MANAGEMENT OF HEAD AND NECK NEOPLASIA
with very wide excision of the primary site with
a minimum of 3-cm margin. This is followed by
radiation therapy.
Buccal mucosa lesions constitute less than
10% of oral cancers, and are more frequent in
men. These tumors are mainly epidermoid car-
cinomas and can present clinically as exophytic
or ulcerative lesions. The overall five-year sur-
vival is 40%. It is estimated that 50% of the
patients will develop lymph node metastases.
Local recurrence and metastases to the cervical
lymph nodes are poor prognostic signs. The
five-year survival of those with local recurrence
is 24%, and for those with cervical lymph node
metastases is 35%. Small lesions must be surgi-
cally excised with 2-cm margins and include
the underlying muscle. The skin of the cheek
may be preserved. Larger or more invasive
tumors require wider resections and the sac-
rifice of the skin of the cheek, radial neck dissec-
tion and cheek reconstruction with skin flaps,
and postoperative irradiation [10]. Verrucous
lesions of the buccal mucosa are considered
well-differentiated squamous cell carcinomas.
These rarely metastasize and are radiation re-
sistant. Surgical excision is the only effective
method of treatment.
Tumors of the hard palate constitute 0.5% of
oral cavity cancers. The lymphatics of the hard
palate drain behind the dental arch to the deep
cervical, submaxillary, and retropharyngeal
lymph nodes. Tumors of the hard palate include
epidermoid carcinoma (the most common),
salivary gland tumors, cylindroma, and bone
tumors. Wide resection is the treatment of
choice for all malignant tumors. This may in-
clude partial or sometimes total maxillectomy.
Radical neck dissection is not carried out unless
there is evidence of metastases in these lymph
nodes. Postoperative radiation therapy should
be administered to epidermoid carcinoma,
cylindroma, and high-grade malignant salivary
gland tumors. The overall five-year survival for
epidermoid carcinoma is 40% [11]. Rehabilita-
tion of the patient, especially after maxillectomy
with an upper denture with obturator, must be
planned prior to resection [12].
The mobile portion of the tongue is identified
as the anterior two-thirds of the tongue, and ex-
tends from the circumvallate papillae to the tip.
Squamous cell carcinoma is the most common
tumor of the tongue. The most common site is
the lateral border (80%). Less common are the
dorsum (over 10%) and the tip (6%). These
259
tumors have a potential for early metastases to
the submandibular and cervical lymph nodes.
Small lesions of 2 em or less can be treated by
partial glossectomy or radiation therapy and the
patient is observed for local recurrence and the
development of lymph node metastases. Larger
lesions require wide resection of the primary
with a minimum of 2-cm margin that may result
in total or subtotal glossectomy, and regional
lymphadenectomy, followed by irradiation
[13]. This is because of high incidence of metas-
tases to the regional lymph nodes. It is esti-
mated that 35% of patients with oral tongue
cancer have clinically positive lymph nodes on
admission; of these, 5% are bilateral. The inci-
dence of metastases to lymph nodes increases
with the size of primary [14].
It has been estimated that 30% of patients
with intraoral squamous cell carcinoma have
positive lymph nodes on admission and, of
these, 4% will have bilateral nodal metastases in
the neck [15].
OROPHARYNX
The oropharynx constitutes the soft palate, the
tonsils and tonsillar fossae, the base of the
tongue, and the peri epiglottic area.
The base of the tongue is the portion behind
the circumvallate papillae, and it forms the
anterior wall of the valleculae. It has very rich
lymphatics that penetrate the pharyngeal wall.
The most common tumors in this area are
epidermoid carcinoma and lymphoma. These
should be differentiated from thyroglossal cyst,
salivary and mucus gland tumors and cysts,
hypertrophic lymphoid tissue, lingual thyroid,
and metastatic lesions. Squamous cell carcinoma
has a poor prognosis; the surgical management
is mutilating and includes glossectomy, partial
or total laryngectomy 23% of the time, and
radical neck dissection followed by irradiation.
This is because 56% of these patients have posi-
tive neck nodes. The operative mortality is 4%,
with a local recurrence rate of 27% and a re-
gional recurrence· rate in the neck of 10%; the
overall five-year survival is 37% [16]. Such poor
results led some surgeons to manage such pa-
tients with irradiation only. Recently, radiation
therapy and low-dose bleomycin are being tried
in these lesions. It has been pointed out, how-
ever, that the only apparent reason for the poor
prognosis in carcinoma of the base of the tongue
is that most of the patients present with more
advanced stages compared with its counterpart
260 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
of the anterior two-thirds of the tongue [17].
Therefore, early detection will probably play
a major role in improving the survival of these
patients. On the other hand, lymphomas are
usually of the histiocytic type and should be
differentiated from poorly differentiated squam-
ous cell carcinoma and treated according to
their stage.
Soft palate tumors are usually epidermoid
carcinomas, mostly encountered in men be-
tween the ages of 50 and 70. These tumors do
not metastasize early; however, the incidence of
metastases to the cervical lymph nodes increases
if these tumors are large. The treatment of
choice is surgical resection or radiation for small
tumors (stage I), but wide resection and post-
operative irradiation are indicated for larger
lesions [11]. The patients are then observed and,
if and when cervical lymph nodes become in-
volved by metastases, radical neck dissection is
performed. The overall five-year survival is less
than 40%, but the stage of the disease carries
the most significant prognostic factor [18, 19].
These patients have a low incidence of distant
metastases, but they are known to be candidates
for other primary epidermoid carcinomas in
head and neck, lungs, and esophagus.
Tonsillar area (tonsil and fauces) tumors are
usually epidermoid carcinomas or lymphomas.
These should be differentiated from rare infec-
tious lesions such as tuberculosis or syphilis.
Small epidermoid carcinomas (T 1 lesions) can be
resected through an intraoral approach followed
by radical irradiation. Large epidermoid carci-
nomas require wide resection through man-
dibulotomy that includes resection of part of
the pharyngeal wall and radial neck dissection
followed by irradiation [20, 21]. The overall
five-year survival is about 40% and depends on
the stage of the disease at the time of the initial
diagnosis. These patients also have a tendency
to develop another primary carcinoma in the
head and neck area, lungs, and esophagus over
25% of the time.
Tumors of the periepiglottic area are usually
radiosensitive epidermoid carcinomas. There-
fore, small lesions are usually treated by irradia-
tion. However, larger lesions require partial or
total laryngectomy with radical neck dissection,
as the lymphatics in this area drain to the jugular
chain.
HYPOPHARYNX
The hypopharynx is the lower subdivision of
the oropharynx. It extends from the level of the
tip of the epiglottis superiorly to the level of the
lower border of the cricoid cartilage inferiorly.
It comprises the pyriform sinus, the postcricoid
region, and the posterior pharyngeal wall.
Epidermoid carcinoma is the most common
cancer, occurring mainly in the pyriform sinus
(75 %) and the posterior pharyngeal wall (20%),
and least commonly in the postcricoid region
(5 %). It is more common in males in the sixth
and seventh decades of life. Almost 70% of the
patients present with enlarged cervical lymph
nodes, i.e., advanced stages. Surgical manage-
ment depends on the extension of the disease
into the larynx, the thyroid or cricoid cartilages,
the upper esophagus, and the involvement of
the ipsilateral and contralateral neck nodes.
Such extent can be determined by endoscopy,
by radiologic technique, and by CT scanning.
The main approach is laryngopharyngectomy
with radical neck dissection. However, the
overall five-year survival is about 30%. This has
led some surgeons to recommend radiation
therapy as the primary treatment, leaving
surgery to treat recurrence or residual disease
[22,23].
LARYNX
The most common tumor of the larynx is pri-
mary epidermoid carcinoma, which carries a
better prognosis when compared stage by stage
with cancers of the oral cavity, oropharynx, and
hypopharynx. The laryngeal area can be divided
into three anatomic sites: supraglottic, glottic,
and subglottic.
The supraglottic area includes the epiglottis,
the false cords, and the medial aryepiglottic
folds. The diagnosis is usually made by indirect
laryngoscopy and confirmed by direct laryn-
goscopy and biopsy. Tomograms and CT scan
can help in determining the extent of the disease
(see chapter 12). Small lesions (Tl and some T 2 )
can be treated by conservative supraglottic re-
section sparing the glottis, i.e., partiallaryngec-
tomy. This operation saves the voice and has a
low recurrence rate of 1.2% [24]. If the margins
of the resection are not free of tumor, however,
total laryngectomy is in order. In addition, if
the tumor has invaded the thyroid cartilage, a
true vocal cord, the vallecula or base of tongue,
or more than one arytenoid, total laryngec-
tomy should be performed. In more advanced
lesions, radical neck dissection on the domin-
 15. SURGICAL MANAGEMENT OF HEAD AND NECK NEOPLASIA
ant side should be added to the laryngectomy.
The glottic region is 1.5-2.0 cm in its vertical
dimension and includes the vocal cords and
their anterior commissure. It is the most com-
mon site of cancer of the larynx. Patients
usually present with persistent hoarseness. The
diagnosis is usually made by indirect laryngo-
scopy looking for the nature of the lesion and its
extent in the form of cord fixation and the status
of the anterior commissure. Keratosis, atypia,
carcinoma in situ, and microinvasion can pre-
sent as white or red patches on the vocal cords
and are treated by local limited excision and in-
definite observation [25]. On the other hand,
stage-I carcinoma (with mobile cord) is treated
by radiation therapy. Fixation of the vocal cord
is to be treated by laryngectomy. It should be
kept in mind that life prevails over voice [26].
The subglottic region extends from 0.5 cm
below the vocal cords superiorly to the inferi-
or border of the cricoid cartilage. Tumors in
this area are usually epiderm<;>id carcinoma,
but are extremely rare and constitute 1% of all
laryngeal cancers. These are common in men
who usually present with hoarseness, trouble in
breathing, and/or hemoptesis. The diagnosis is
made by direct laryngoscopy and biopsy. The
treatment is total laryngectomy [27].
The larynx in general can be the site of other
malignant primary tumors such as cartilagenous
tumors, minor salivary gland tumors, soft-tissue
sarcoma, or melanoma. Such tumors are treated
by laryngectomy, except for melanoma, which
requires laryngectomy and radical neck dissec-
tion. Primary oat cell carcinoma of the larynx is
rare [28], and it seems that the primary manage-
ment is by radiation therapy. Laryngectomy
and radical neck dissection are preserved for
those who have local or regional recurrence
or persistent disease. Because early systemic
metastases are common, these patients must also
receive systemic chemotherapy similar to oat
cell carcinoma of the lung.
Metastatic carcinoma to the larynx does
occur. Renal cell carcinoma has been the most
frequent one, followed by melanoma, and
breast, lung, prostatic, and gastrointestinal can-
cers [29]. Although the primary management in
these cases must be directed to the treatment
of the systemic disease, local control of the
laryngeal lesion is essential to maintain the air-
ways and the voice, if possible.
Benign tumors of the larynx such as polyps,
inclusion cysts, fibromas, lipomas, chondromas,
261
my~)I?as, and myoblastoma are treated by local
excIsion.
The main complication after partiallaryngec-
tomy is aspiration; if the patient cannot control
aspiration, this necessitates total laryngectomy.
Total laryngectomy has a 25% complication
rate in the form of pharyngocutaneous fistula.
This incidence increase to 75% if partial or total
pharyngectomy is added to the laryngectomy
[30]. Preplanned reconstruction by myocu-
taneous flaps may decrease the incidence of this
complication. Furthermore, it is of utmost im-
portance that laryngectomy patients be rehabili-
tated by learning esophageal speech or by learn-
ing to use one of the external or implantable
speech devices.
SALIVARY GLANDS
Benign and malignant tumors are encountered
in both the major and minor salivary glands (see
chapter 13). These tumors are common in the
major salivary glands and constitute 4% of the
head and neck neoplasia, with the parotid gland
being the most prevailing.
The most common presenting symptoms of
benign tumors are slow-growing, painless swell-
ing in the area of the gland. Pain, fast-growing
tumors, and nerve paralysis are signs of malig-
nancy. Salivary gland tumors are classified into
three groups:
1. Benign tumors, such as hemangiomas,
lipomas, neurolemmomas, oxyphylic adenoma
(oncocytoma), and papillary cystadenoma lym-
phomatosum (Warthin's tumor). These tumors
are usually treated by excision of the gland or
superficial parotidectomy (if encountered in the
superficial lobe of the parotid gland).
2. Mixed tumors (pleomorphic adenoma) are
usually benign (less than 10% are malignant)
and are mostly found in the superficial lobe of
the parotid gland. Superficial parotidectomy
with preservation of the facial nerve is the ideal
surgical approach. Because of the anatomic rela-
tion of the parotid gland, the pharyngeal wall on
the affected side must be inspected and palpated
prior to surgery to rule out deep lobe involve-
ment of the parotid. If mixed tumors are en-
countered at other sites, excision of the affected
gland or the area is sufficient. Recurrent benign
mixed tumor of the parotid is rare and, if it
occurs, the surgical procedure should be tai-
lored to the individual case. If a patient is re-
262 Ill. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
ferred after freshly excised or biopsied tumor,
parotidectomy with excision of the skin that is
involved is recommended. If the patient is seen
after following old excision of such tumor, it is
preferred to wait and then reresect in fresh
planes. Radiation therapy is not to be used as
the primary treatment in benign mixed tumors
[31].
3. Malignant tumors are divided into two
groups: (a) the low-grade mucoepidermoid and
acinic cell carcinomas, which are treated by
wide local excision; and (b) the high-grade
malignant tumors, which are treated by radical
extirpation that may include regional lymph-
adenectomy followed by irradiation. These
tumors include high-grade mucoepidermoid,
adenocystic, squamous cell, and anaplastic car-
cinomas. Recurrent mixed tumors may signify
malignant potential and must also be treated
with wide, radical excision. Adenocarcinomas of
the salivary glands are mostly found in minor
salivary glands (68%), the parotid gland (28%),
and then the submandibular gland (4%)'. The
overall five-year survival is about 40% and de-
pends on the site of origin, the cell type and
grade, the size, and the stage [32]. The facial
nerve can be preserved in parotid malignancy
under three conditions: (a) the tumor must be
less than 3 cm; (b) it must be low-grade malig-
nancy; (c) the nerve does not penetrate the
tumor [33]. Otherwise, the nerve has to be sac-
rificed in radical parotidectomy. Finally, parot-
idectomy may be performed to remove peri-
parotid lymph nodes for potential or actual
metastases from melanoma or epidermoid carci-
noma of the skin of face or ear [34-36].
THYROID GLAND
A mass or a nodule in either lobe of the thyroid
gland signifies pathology. While benign colloi-
dal goiter is common in adult women, a thyroid
nodule has a higher incidence of being malig-
nant in men. Children and young adults that
present with thyroid nodule are considered
malignant until proven otherwise. Patients that
have irradiation to the face, neck, or mediasti-
num during infancy or childhood have a 7%
chance of cancer of the thyroid gland [37]. A
thyroid mass present for years without change
in size is probably benign and can be treated
by SYNTHROID (Flint Laboratories, Deerfield,
Illinois 60015). Sudden increase in the size of
a thyroid nodule may signify malignancy or
hemorrhage in the nodule. A solitary thyroid
nodule has a 20% chance of being malignant,
compared with only 5% in a multinodular
gland. However, there are definite indicators for
malignancy of the thyroid gland. These include
a hard thyroid mass, the presence of cervical
lymph node metastasis, fixation of the thyroid
mass to surrounding structures, or the presence
of vocal cord paralysis. Most of these are late
signs.
The availability of thyroid scanning and
ultrasound can help in evaluating thyroid
nodules. A cold nodule on the scan that is solid
by ultrasound and not cystic has 20%-30%
chance of being malignant [38]. This is because
benign adenoma and fibrosis can give the same
picture. On the other hand, cystic lesions have a
2% chance of harboring malignancy. This inci-
dence also increases if the ultrasound reveals
complex pattern such as a cyst with solid areas.
Hot nodules by scan are usually due to hyper-
functional benign adenomas and are rarely
malignant. Aspiration cytology and needle
biopsy of thyroid nodules have not been of
great help and are unreliable [39]. There are four
types of thyroid cancers:
1. Papillary adenocarcinoma, which is usually
mixed type (papillary-follicular) is the most
common type and constitutes 60%-80% of all
thyroid cancer [40, 41]. It usually metastasizes
to regional lymph nodes. The tumor is not en-
capsulated.
2. Follicular carcinoma is the second common
type with an incidence of 20%. This tumor is
always encapsulated and metastasizes via the
blood to other organs. These two types are the
well-differentiated carcinomas, with the papil-
lary type having a better ten-year survival than
the follicular. The prognosis depends on the
stage of the disease and the patient age. Patients
who are 40 or younger have better survival than
the older group [42]. The overall five- and ten-
year survivals are 95% and 85%, respectively.
The surgical approach to these two types is
similar and includes total removal of the affected
lobe of the thyroid and the isthmus, and sub-
total lobectomy on the opposite side to pre-
serve two of the parathyroid glands. The laryn-
geal nerves must be visualized and preserved.
The reason for performing subtotal thyroidec-
tomy is that over 20% of these tumors are
multicentric [40, 41]. Any palpable cervical
lymph nodes present should be removed or a
 15. SURGICAL MANAGEMENT OF HEAD AND NECK NEOPLASIA
modified radical neck may be performed. The
author personally performs total thyroidec-
tomy, preserving the parathyroid glands, and
removing the palpable cervical lymph nodes.
The patient is then left with no thyroid therapy
for 6-7 weeks and is then given a therapeutic
dose of 100 mCi of 131 1, followed by mainte-
nance SYNTHROID tablets daily. Locally invasive
tumors (i.e., the carcinoma has invaded the thy-
roid capsule and attached to the surrounding
structures) are rare and are treated surgically
by removing all gross tumor but preserving
the vital structure. The patient is then treated
by 131 1 and SYNTHROID. These patients have a
poorer prognosis, however, with a ten-year
survival of 60%. Extensive radical surgery has
not been proven to improve the survival [43,44].
3. Medullary carcinoma can be part of multi-
ple endocrine neoplasia syndrome (MEN-2).
This lesion has a tendency to be multicentric in
the thyroid gland and metastasizes early to re-
gional lymph nodes and by the blood to other
organs, mainly lung and liver. The family mem-
bers have to be investigated to rule out the famil-
ial type. Plasma calcitonin level is an excellent
marker in establishing the diagnosis and in the
follow-up of these patients and their families.
As a part of the MEN-2, adrenal medullary
hyperplasia or pheochromocytoma may be
present; these should be treated first to avoid
hypertensive crisis during thyroid surgery. The
surgical treatment of medullary carcinoma is
total thyroidectomy with bilateral modified
radical neck dissection and mediastinal dissec-
tion if the regional lymph nodes are involved. If
the cervical lymph nodes are not involved, it is
advisable to sample the cervical and the upper
mediastinal lymph nodes, even if these appear
normal to rule out micrometastases [45]. If the
patient has hyperparathyroidism as part of the
MEN-2 syndrome, parathyroidectomy is to be
performed in the same setting. The five- and
ten-year survival is 57% and 50%, respectively,
with patients under the age of 45 doing better
than the older ones. All patients must be main-
tained on thyroid therapy.
4. Anaplastic carcinoma is usually unresect-
able and biopsy is the only role of surgery.
Occasionally, however, total thyroidectomy
can be done. Aggressive surgery does not
change the fatal course of the disease. Radiation
therapy and chemotherapy by adriamycin are
being tried with limited success. Thyroid ther-
apy is indicated for replacement. The thyroid
263
gland can also be the site of lymphoma, as will
be discussed later.
PARATHYROID GLANDS
The parathyroid glands control calcium metab-
olism. Hyperactive gland( s) can give rise to
primary hypercalcemia, which can be due to
one of the following: (a) single adenoma (the
most common cause), (b) multiple adenomas,
(c) hyperplasia of the glands, or (d) carcinoma
of a parathyroid gland (rarely). These patients
infrequently present with a palpable mass in the
neck. In fact, most of these patients are asymp-
tomatic for a long time and their hypercalcemia
is often discovered on routine testing of their
serum chemistries. If hypercalcemic patients be-
come symptomatic, they may present with
nephrocalcinosis, weakness, peptic ulcers, pan-
creatitis, dyspepsia, or excessive diuresis.
Primary hypercalcemia is characterized by
elevated serum calcium and serum parathor-
mone levels. If serum calcium is elevated but the
parathormone level is decreased, however, this
is a secondary hypercalcemia. This is not due to
parathyroid pathology, but can be due to one of
the following conditions: (a) excessive use of
diuretics, (b) metastatic malignancies, (c) hyper-
vitaminosis D, (d) sarcoidosis, (e) milk-alkali
syndrome, or (f) chronic renal failure. Control
of the underlying cause in secondary hypercal-
cemia will cause reversal, except in patients with
chronic renal failure who are on dialysis; sub-
total parathyroidectomy is indicated in these
cases.
The surgeon who is planning to explore the
neck for a parathyroid disease must be familiar
with certain characteristics of these glands.
There are four parathyroid glands in 90% of the
patients; however, 5% may have three glands
only, while 3.5% have five glands. Each gland
weighs 35-40 mg. The parathyroid glands are
pale structures and are usually located two on
each side behind the thyroid gland. In 80% of
the cases, the inferior thyroid artery supplies the
lower two glands if not the four glands. Several
reports have described abnormal positions of
the parathyroid glands, but the fact is that one
or more may be displaced inferiorly into the up-
per mediastinum either anteriorly or posterior-
ly. Although a single adenoma in one gland can
cause primary hypercalcemia in 80%-90% of
the cases and only 10%-20% have multiple
gland disease, it is highly recommended that the
264 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
four glands be explored and biopsied at the time
of the initial surgery to minimize the need for
reexploration for persistent postoperative
hypercalcemia [46 J. Reoperative exploration for
parathyroid pathology is successful in 70%-
80% of the cases, but is extremely difficult and
carries significant morbidity in the form of per-
sistent hypercalcemia, hypoparathyroidism, and
laryngeal nerve injury. In such cases, preopera-
tive localization of the diseased glands by CT
scan, arteriography, and venous sampling is jus-
tified [47). On the other hand, if normal para-
thyroid glands were accidentally removed or
devascularized during surgery, they can be suc-
cessful auto transplanted to prevent hypocalce-
mia [48).
Extranodal Lymphoma and
Extraosseous Plasmacytoma
Primary lymphoma and plasmacytoma have
been reported in the nasal cavity, nasopharynx,
tonsils, base tongue, pharyngeal wall, larynx,
and parotid and submandibular glands. The
lymphomas are usually of the histiocytic type.
Lymphoma and plasmacytoma can present clin-
ically as firm, globular masses without muco-
sal ulceration or with minimal central ulceration.
Lymphomas may be misdiagnosed as poorly
differentiated carcinoma [49], and careful histo-
logic examination of the biopsy must be under-
taken to avoid unnecessary extensive surgery.
Local control of these tumors can be achieved
by radiation therapy in these radiosensitive
tumors, but the patients must be treated accord-
ing to the stage of the disease for these poten-
tially systemic diseases.
Primary lymphoma of the thyroid gland can
present as a fast-growing thyroid tumor. On
surgical exploration, it grossly resembles ana-
plastic carcinoma, which can be differentiated
by frozen section. Once the diagnosis is made,
all gross tumor should be excised by total thy-
roidectomy, preserving the laryngeal nerves and
the parathyroid glands. Postoperative radiation
therapy will control the disease locally, but the
patient should receive systemic chemotherapy.
Enlarged Cervical Lymph Node
Some patients present with enlarged cervical
lymph nodes, which can be due to one of the
following conditions: (a) nonspecific infections,
mainly streptococcal infections of the oral cav-
ity and/or oropharynx; (b) specific infections,
such as infectious mononucleosis,' tuberculosis
(TB), or fungal infections; (c) autoimmune dis-
orders as in rheumatoid nodules or in aquired
immune deficiency syndrome (AIDS); or (d)
malignant conditions such as lymphoma or
metastatic carcinoma from a known or un-
known primary.
An accurate history and physical examination
can be of great value in determining or suspect-
ing the cause of enlarged cervical nodes. The
physical examination should include complete
head and neck examination. If infection is
suspected, antibiotic therapy and continuous
observation of the patient on a biweekly basis
for 6-8 weeks will probably eliminate most of
the nonspecific infections. The patient must be
observed until such lymph nodes become com-
pletely unpalpable. Serum heterophile antibody,
two weeks after the onset, will determine
whether such enlarged lymph nodes are due to
infectious mononucleosis. On the other hand, if
these enlarged lymph nodes persist, further in-
vestigation is indicated.
Needle aspiration for cytopathologic exami-
nation may establish the diagnosis of metastatic
carcinoma, but is of much less help in diagnosing
other conditions [50]. A diligent reexamination
of the upper aero digestive system is in order to
detect a primary tumor in the area. If such pri-
mary is found, the patient is to be treated ac-
cordingly. However, if no primary tumor is
found, and the needle aspiration is negative or
not conclusive for a tumor type, excisional
biopsy of such an enlarged lymph node is in
order to establish the diagnosis. If possible, the
skin incision may be placed within the future
surgical incision if neck dissection is contem-
plated.
The excised lymph node must be freshly di-
vided and submitted for (a) aerobic and anaero-
bic culture and sensitivity, (b) acid fast smear
and TB cultures, (c) fungal cultures, and (d)
histopathologic examination. Appropriate anti-
biotics can then be instituted if the patient has
an infection. If fungal infection is suspected, se-
rum for antibody levels should be obtained prior
to applying fungal skin tests. Autoimmune
disease may be hard to diagnose, as the biopsy
may reveal hyperplastic lymph node. If malig-
nancy is detected in the biopsied lymph node,
however, the pathologist has to characterize its
nature and, if possible, the place of origin. The
biopsy may reveal (a) lymphoma (Hodgkin's or
 15. SURGICAL MANAGEMENT OF HEAD AND NECK NEOPLASIA
non-Hodgkin's) or (b) metastatic carcinoma
(epidermoid, adenocarcinoma, anaplastic) or
melanoma. Patients who are found to have
lymphoma must undergo complete staging, as
the type of therapy will depend on the cell type
and the stage of the disease.
Patients presenting with metastatic carcinoma
in their cervical lymph nodes have to undergo
direct laryngoscopy and pharyngoscopy besides
careful assessment of the oral cavity, the
nasopharynx, and the thyroid gland. These
patients can then be divided into four main
groups:
1. Those who have epidermoid carcinoma in
the cervical lymph nodes with unknown or
occult primary, which is now thought to origi-
nate more often from the hypopharynx rather
than the nasopharynx. However, it is highly re-
commended that multiple blind biopsies be
obtained from the nasopharynx, tonsils, base
of tongue, and pharyngeal wall. Because
epidermoid carcinomas can also originate from
the lungs or esophagus, a chest x-ray, broncho-
scopy, esophagogram, and esophagoscopy
should be performed in search of the primary. If
the primary in the lung and esophagus is ruled
out, it can be presumed that it originated in the
head and neck region. Such patients are man-
aged by radical neck dissection and postopera-
tive radiation therapy that must include both
sides of the neck, nasopharynx, oropharynx,
and hypopharynx [51].
2. Those who present with metastatic adeno-
carcinoma with unknown primary can be di-
vided again into two subgroups: (a) Upper neck,
where the tumor can be considered to arise from
salivary glands or thyroid. The patient can
benefit from radical neck dissection with or
without radiation therapy. (b) Lower neck (i.e.
supraclavicular area), where the tumor may
arise from sources below the clavicles such as
breast, lung, gastrointestinal tract, ovaries, or
adrenals. Such areas have to be investigated, and
these patients may be treated for widespread
metastases by chemotherapy with or without
radiation.
3. Anaplastic carcinoma must be differenti-
ated from histiocytic lymphoma. Primary
anaplastic carcinoma may arise from the
nasopharynx, oropharynx, hypopharynx, or
thyroid. On the other hand, these tumors may
represent distant metastasis from other organs
such as pancreas, adrenal, or urinary bladder.
265
Radical neck dissection and radiation therapy
may play some role in the management of those
patients with head and neck origin, but has no
role in the others.
4. Patients who present with metastatic
melanoma may benefit from radical neck dis-
section. Their prognosis is poor, however, since
(a) if the primary is in the skin or mucosa of the
head and neck region and cannot be detected, it
will continue to metastasize; and (b) if the pri-
mary that cannot be detected is outside the head
and neck region, such cervical lymph nodes
represent distant metastasis and radical neck
dissection will not influence the course of the
disease. However, occasionally there is a long
survival after radical neck dissection.
It can be hypothesized that an occult primary
lesion either can be so small that it cannot be
detected clinically or, in theory, it may be re-
jected after it has metastasized. The metastasis
may constitute resistant clones of cells that may
continue to metastasize until they overcome the
patient.
Finally, benign conditions such as inclusion
cysts and lipomas may present as masses in
the neck. These may originate from the skin
and subcutaneous tissue. Others are congenital,
e.g., thyroglossal duct cyst and branchial cleft
cysts. These and other benign tumors of muscle,
fibrous tissue, or nerve origins-e.g., myoma,
fibroma, or neuromas and thyroid nodules-
must not be confused with lymph node con-
ditions discussed above.
Surgical Management
RADICAL NECK DISSECTION
The purpose of this procedure is to remove the
regional lymph nodes. To accomplish this, all
neck contents lying between the superficial and
deep layers of the deep cervical fascia are excised
en bloc, preserving vital structures such as the
carotid artery and the vagus and phrenic nerves.
The surgical approach can be achieved through
a variety of skin incisions; however, optimal
cosmetic results can be obtained by the MacFee
incisions. The MacFee skin incisions are two
transverse incisions. The lower one is parallel to
and one finger breadth above the clavicle, ex-
tending from the midline anteriorly to the edge
of the trapezius muscle posteriorly. The upper
incision extends from the level of the hyoid
bone anteriorly to one finger breadth below the
angle of the mandible, then upward to the tip
266 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
of the mastoid bone posteriorly. The two inci-
sions are carried down through the skin, sub-
cutaneous tissues, and platysma muscle. Three
skin flaps are then developed. Care should be
taken not to injure the mandiblular branch of
the facial nerve under the upper flap.
The superficial layer of the deep cervical fas-
cia constituting the outer limits of the neck con-
tents is revealed. The resection starts from the
lower neck in an upward direction by severing
this fascia at the level of the clavicle. The sternal
and clavicular heads of the sternocleidomastoid
muscle are severed and reflected upward. Fur-
ther dissection identifies the carotid sheath,
which is opened. The carotid artery and the
vagus nerve are identified and preserved. The in-
ternal jugular vein is doubly ligated and suture
ligated and severed. The dissection is then car-
ried out posteriorly to the edge of the trapezius
muscle, identifying and preserving the phrenic
nerve as it crosses the scalenus anterior muscle,
and identifying and severing the omohyoid
muscle.
All the contents of the neck are reflected su-
periorly and the dissection continues at the
plain of the omohyoid muscle. If the procedure
is being performed electively (i.e., no involved
cervical lymph nodes), the accessory nerve can
be preserved posteriorly near the edge of the
trapezius muscle. Anteriorly, the strap muscles
(the sternohyoid and the sternothyroid muscles)
and the thyroid lobe are preserved unless the
procedure is being performed for midline le-
sions or with laryngectomy or esophagectomy;
in such cases, these are excised. If the larynx is
not to be removed, however, the superior and
recurrent laryngeal nerves must be preserved.
During the dissection, the cervical roots are
identified and also preserved.
Approximately 1.5 cm above the carotid
bifurcation, the hypoglossal nerve is identified
as it crosses transversely and is preserved. The
upper end of the onohyoid muscle is severed
from the hyoid bone. The digastric muscles may
be preserved if not involved by tumor. The
digastric triangle is then dissected, removing the
contents including the submandibular gland,
but preserving the lingual and hypoglossal
nerves if that side of the tongue is preserved.
The myohyoid and hypoglossus muscles, which
form the floor of the triangle, are also preserved.
The dissection is then continued posteriorly to
include the tail of the parotid gland and to dis-
sect and ligate the upper end of the internal
jugular vein, which lies under the posterior
belly of the digastric muscle as it enters the
base of the skull. The floor of the dissected
neck, outside the digastric triangle, now con-
sists of the splenius capitis, levator scapulae,
and the scalene muscles lying in a posterior-
superior to an anterior-inferior position. This
floor is crossed vertically by the carotid artery
and the vagus and the phrenic nerves, and the
accessory nerve if preserved. The hypoglossal
nerve lies transversely above the carotid
bifurcation. The wound is then irrigated and,
after complete hemostasis, a closed drain sys-
tem is inserted through the lower skin flap.
The wounds are closed airtight in two layers
by approximating the platysma muscle and the
skin.
In a composite resection, part of the oral
cavity may be resected in continuity with the
neck dissection. In such a case, the digastric
muscles, the myelohyoid, the hyoglossus, the
geniohyoid, and the genioglossus muscles may
be resected.
Bilateral radical neck dissection is sometimes
required, but it carries a high morbidity and
mortality if carried out synchronously [52].
Therefore, the bilateral radical neck dissection
can be performed in two separate settings, two
weeks apart. Another approach is to perform a
modified radical neck dissection, in which the
internal jugular vein is preserved after being
skeletonized, on one side. Other modifications
have been reported in which the internal jugular
vein, the sternocleidomastoid muscle, and the
accessory nerve are routinely preserved [53],
violating the principles of en bloc resection.
However, its efficacy cannot be determined for
the lack of controls.
RECONSTRUCTIVE SURGERY
All defects in the head and neck region have to
be covered for two reasons: to reconstitute
function and cosmesis. Small facial defects fol-
lowing excision of basal cell or epidermoid car-
cinomas of the skin can be covered by primary
closure. Moderate-sized defects require skin
grafting or local skin flaps. The same concept
applies to scalp and mucosal defects. If skin
grafts are used in the face, the full-thickness
type is preferred as it results in less contracture,
scarring, and deformity. Some areas do not
allow easy reconstruction and prostheses must
be used, e.g., externally for total ear or nose,
 15. SURGICAL MANAGEMENT OF HEAD AND NECK NEOPLASIA
and internally for the roof of the mouth.
Larger and more extensive defects can be
divided into three groups: (a) external skin
defects, (b) internal mucosal and underlying
muscle defects, and (c) compound external and
internal defects (e.g., in epidermoid carcinoma
of the buccal mucosa or the floor of the mouth
with invasion of the overlying skin). Such de-
fects require flap reconstruction for the external
or internal use. Occasionally a combination of
two flaps, or a modification of one flap, is used
for external and internal reconstruction. These
flaps must be planned preoperatively.
The most significant advances in head and
neck surgery have been the use of regional flaps
in the rehabilitation of large wounds. If postop-
erative irradiation is planned, however, it must
be initiated within 4-6 weeks from the date of
definitive surgery. All reconstructive surgery
therefore should be carried out within that
period; otherwise, it must be postponed until
after radiation therapy.
There are several types of flaps available for
FIGURE 15-4. Dorsal tongue flap is elevated to cover
a large defect in the lateral pharyngeal wall. The pedi-
cle can be divided 3-4 weeks later, after the flap has
healed in its new bed. Similarly, a lateral tongue flap
can be used to cover the floor of the mouth or cheek.
Its pedicle may not need to be severed.
267
reconstruction:
1. Tongue flaps (figure 15-4). These flaps are
utilized to cover internal mucosal defects such
as pharyngeal wall, floor of mouth, or cheek.
The pedicle may be based posteriorly or ante-
riorly, and can be obtained from the dorsum or
lateral aspect of the tongue. They can be severed
later after flap-take, or left intact if it does not
interfere with deglutition [54]. Local mucosal
flaps can also be utilized.
2. Skin flaps. These flaps consist of skin, the
subcutaneous tissues, and the fascia of the
underlying muscle. The length of each flap de-
pends on its blood supply through its base and
pedicle. If a longer flap is required to reach the
planned surgical defects or if the patient is arte-
riosclerotic or diabetic, it is advisable to delay the
flap. Delaying the flap means dividing its skin,
subcutaneous tissue, and fascial margins, but
keeping its base intact. It is then elevated tem-
porarily from its bed to ligate all its deep blood
supply. The flap is then relaid back in its origi-
nal donor site and sutured. This will increase
the blood flow through its base over the next
couple of weeks, and allows the flap to depend
on its blood supply via its base and pedicle.
Two and one-half weeks later, definitive sur-
gery is performed and the flap is reelevated
from its bed (keeping its base intact) and used
to cover the surgical defect. The donor site is
closed primarily (as in nasolabial flaps) or cov-
ered with split-thickness skin graft. These flaps
can be used to cover internal, external, or com-
pound defects. If they are used to cover com-
pound defects, the distal ends can be folded on
themselves, or covered by skin grafts at the
time of the delay. The part of the flap between
its base and the used distal part is usually intu-
bated on itself if it crosses other skin surfaces.
When the distal part of the flap heals in its new
bed in 2-3 weeks, the pedicle is divided; the
intubated part is then fileted and placed back
in its original bed after removing the split-
thickness skin graft, except for the missing part
that has been used to cover the surgical defect.
When these flaps are used for internal lining,
a controlled orocutaneous fistula is left at the
time of the definitive surgery, and this is closed
when the flap is divided. Examples of skin
flaps are the forehead flap, posterior cervical
flap, cervical flap (figure 15-5), Bakamjian delto-
pectoral flap (figure 15-6) [54], and nasolabial
flap [55].
3. Myocutaneous flaps. For these flaps, an
268 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
FIGURE 15-5. A cervical flap can be used to cover
skin defects on chin or face, or internally to recon-
stitute pharyngeal or esophageal wall. Note the wide
base that is essential for this flap.
island of desired size of skin and the underlying
subcutaneous tissue and fascia is outlined and
severed from all surrounding tissues. A full
thickness of the underlying muscle is then sev-
ered in a semi-island fashion preserving the site
of the blood supply. The full thickness of the
muscle carrying the blood supply to the island is
dissected off the rest of the muscle on both sides
forming a muscle pedicle that extends to the
origin of the vessels. The island of skin, sub-
cutaneous tissue, fascia, and the underlying
muscle pedicle are mobilized and placed under
the skin flaps of the neck to reach the surgical
defect for coverage. The skin island can be uti-
lized for internal or external coverage. These
flaps have several advantages: (a) a single stage
reconstruction; (b) they give soft tissue bulk to
the defect; (c) such flaps do not require delaying
or closure of controlled fistula at a later date; (d)
the muscle pedicle also furnishes carotid cover-
age. The donor site can usually be closed pri-
marily after undermining the skin edges. A skin
graft may occasionally be required to close the
donor site. The main flap used in the head and
neck area is the pectoralis major type (figure 15-
7) [56]. This flap can be used in combination
with the deltopectoral flap by mobilizing the
deltopectoral one first, then dissecting the mus-
cle pedicle.
----=:::---..
\
--- 1 I
FIGURE 15-6. Bakamjian deltopectoral flap. The
'--
blood supply is from branches 2, 3, 4, and 5 of the
internal mammary artery. If it extends to the anterior
aspect of the shoulder, it requires no delaying (except
in arteriosclerotic and diabetic patients). If it extends
to around the shoulder, or below on the upper arm,
delaying the flap is advisable. The distal end can be
folded on itself or covered by skin graft to cover
compound defects. This flap has been used in com-
bination with pectoralis major myocutaneous flap
(figure 15-7) for double coverage of compound de-
fects.
4. Osteomusculocutaneous flaps. These are
exactly the same as the myocutaneous flaps, ex-
cept that the dissection includes part of the
underlying bone, i.e., these flaps carry skin,
muscle, and bone. Such flaps are capable of re-
constructing large bone and soft-tissue defects.
In the case of the pectoralis major osseomyocu-
taneous type, part of the fifth rib is mobilized
on the same muscle pedicle and is used to recon-
struct the mandible [57, 58].
5. Free flaps. With the advances in micro-
vascular surgery, large defects of bone and soft
tissue (skin and muscle) can also be recon-
structed by free flaps obtained from distant sites
in the body. In this approach, a long artery and
 15. SURGICAL MANAGEMENT OF HEAD AND NECK NEOPLASIA
FIGURE 15-7. Pectoralis major myocutaneous flap.
The muscle pedicle carries the blood supply to the
skin island that can be used to cover internal or exter-
nal defects.
vein with their soft tissue and bone are removed
from normal healthy site. The free flap is then
placed in the area needed and the blood vessels
are anastomosed in the head and neck region.
The most used types are the latissimus dorsi [59]
and groin [60, 61] free flaps.
6. Another method that can be used to recon-
struct bone defects is the freeze-dried allogeneic
bone combined with autologous cancellous
bone and bone marrow, with a 95% success rate
[62, 63]. However, this is to be carried out at a
separate surgical setting and after the mucosa
has healed to prevent contamination of the
graft. Metal appliances placed between man-
dibular fragments at the time of the resection to
restore continuity usually result in wound de-
hiscence and flap necrosis, leading to fistula
formation; therefore, they should be avoided.
PREOPERATIVE PREPARATION
Once the diagnosis has been established, the
exact site and size of the primary as well as the
regional lymph node status must be precisely
described and preferably outlined on a dated
diagram (figures 15-8 to 15-10). A decision re-
garding resectability of large tumors is usually
based on x-ray or CT scan examination of the
269
base of the skull and/or cervical spine, in addi-
tion to the clinical findings. Panoramic views
may be helpful to determine whether man-
dibulectomy is needed if the tumor is near the
mandible. The patient must undergo a com-
plete workup that should include chest x-ray,
electrocardiogram, complete blood count with
differential and actual platelet counts, complete
urinalysis, serum electrolytes with fasting blood
sugar and blood urea nitrogen, and liver chemis-
tries including prothrombin time, serum bili-
rubin, SGOT, SGPT, LDH, total protein, and
albumin. In addition, serum calcium, creatinine,
and uric acid should be obtained. The patient's
nutritional status should be assessed and im-
proved if possible (see chapter 26). Anemia
should be corrected. If digitalization and/or
hydration are required, these must be carried
out. Some of these patients are folate deficient,
and this should be corrected. The use of multi-
vitamins is highly recommended. Liver and
bone scans should be pedormed if serum alka-
line phosphatase or liver enzymes are abnormal.
If the patient is considered for preoperative
adjuvant therapy such as preoperative irradia-
tion or chemotherapy, discussion of such an
approach with the patient and the concerned
members of the family is appropriate at this
time. Furthermore, the plan of resection and its
extent, whether the wound will be closed pri-
marily or the defect will be reconstructed by
skin or myocutaneous flaps or prosthesis, and
the application of temporary or permanent
tracheostomy should be presented to them.
The patient should be evaluated for prosthesis
prior to surgery, and the patient must be seen
by the radiotherapist prior to surgery (if post-
operative irradiation is contemplated). Large
skin flaps may be needed for reconstruction of
large defects resulting from definitive surgery.
Such skin flaps may require one or more delays,
i.e., such skin flaps are outlined and partially
severed, but left in place to ensure viability and
increase blood flow from the base. This must
be carried out 2V2-3 weeks prior to definitive
surgery. On the day prior to surgery, oral
cleansing (e.g., 1% neomycin solution every 4
h) should be initiated to reduce incidence of
wound infection and dehiscence. Systemic anti-
biotics such as a combination of gentamicin and
clindamycin are also used [64]. Intravenous
hydration is essential as it prevents the period of
anuria during surgery or in the immediate post-
operative period.
FIGURE 15-8. Diagrams of oral cavity and oro-
pharynx: upper anterior views and lower lateral
views. These are used to outline the exact location
and extent of the primary prior to surgery or radia-
tion therapy. The exact date of an examination and
patient identification are added.

FIGURE 15-9. Diagrams of the larynx: an upper view

to the left, and a lateral view to the right. These are
used to outline the exact location and extent of the
primary prior to any therapy. The exact date of the
examination and patient identification are added.

270
 15. SURGICAL MANAGEMENT OF HEAD AND NECK NEOPLASIA
FIGURE 15-10. Diagrams of the right and left sides of
the head and neck region outline the lymph nodes.
The involved lymph nodes should be exactly marked
prior to therapy. The exact date of the examination
and patient identification are added.
OPERATIVE APPROACH
For surgery of the oral cavity or oropharynx,
anesthesia should be administered via naso-
trachial intubation. Tracheostomy is to be per-
formed if surgery involves the posterior part of
the oral cavity, oropharynx, hypopharynx, or
larynx to prevent airway obstruction secondary
to laryngeal edema. Tracheostomies can be
performed at the beginning of the procedure or
at the end. If tracheostomy is contemplated,
however, it can be performed first under local
anesthesia; the patient is then intubated through
the tracheostomy. At the beginning of the pro-
cedure, a nasogastric tube should be inserted for
two reasons: First, it can be kept on suction
during surgery and for the first postoperative
day to prevent vomiting and aspiration. Second,
it can be used for feeding from the second or
third _postoperative day on, until the patient
is able to use the oral cavity. The head, neck,
and chest must be elevated to minimize blood
loss. The neck is hyperextended to facilitate the
dissection.
The operative approach has two objectives: to
271
eliminate the disease at the primary site and the
regional lymph nodes, and to reconstitute func-
tion and cosmesis. Surgery on the primary site
consists of wide resection with safe and tumor-
free margins. This has to be documented histo-
logically by obtaining multiple biopsies for
frozen sections from the surrounding tissues
prior to closure of the defect. Patients who have
had preoperative radiation therapy or che-
motherapy that resulted in reduction of the
tumor size should undergo the resection as
planned on the original extent of the disease. No
resection should be carried out within the area
that has been involved by tumor. Small surgical
defects can be closed primarily. Larger defects
may require mobilization of small flaps from
neighboring tissue, or the use of local flaps such
as tongue flaps. However, extensive defects can
be corrected by reconstruction using skin flaps
or myocutaneous flaps.
Radical neck dissection is carried out prophy-
lactically or therapeutically to remove regional
lymph nodes. The indications for radical cervi-
cal lymphadenectomy have been discussed under
each site. It includes removal of all Iymph-node-
bearing area between the two layers of the deep
cervical fascia. Certain muscles, such as the ster-
nocleidomastoid and omohyoid muscles, are
sacrificed, as these lie within the space. Other
muscles are removed, depending on the site of
272 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
the primary. These include the strap muscles
and part of the thyroid gland. The digastric
muscle may be resected for large tumors of the
oral cavity. In a standard radical neck dissec-
tion, the internal jugular vein is removed. The
only structures to be preserved are the muscles
that form the floor of the neck, the carotid
artery, the vagus and phrenic nerves, and the
lingual and hypoglossal nerves. The accessory
nerve can be preserved if the neck dissection is
carried out prophylactically or electively, i.e., if
there is no evidence of lymph node metastases.
However, it is highly recommended to resect
the accessory nerve if neck dissection is per-
formed therapeutically for lymph node metas-
tases.
Suprahyoid lymph node dissection is some-
times carried out for small lesions with metas-
tatic potential. Similarly, small midline lesions
with high propensity for metastases require bi-
lateral suprahyoid lymphadenectomy. If metas-
tases are encountered in the lymph nodes, total
neck dissection on the afflicted side is in order.
If bilateral neck dissections are required, it is
preferable to perform complete neck dissection
of the prominent side of the primary and mod-
ified radical, i.e., with preservation of the inter-
nal jugular vein on the opposite side. Another
approach would be to perform both radical
neck dissections on two separate settings about
two weeks apart. Patients with cervical metas-
tases from a controlled primary who refuse
radical neck dissection can be treated by limited
resection of the cervical metastases followed by
radical neck irradiation.
Palliative surgery is sometimes used in head
and neck tumors. This is aimed at reducing the
disease and eliminating or preventing complica-
tions arising from the disease, such as fungating
masses, fistula, or bleeding. Surgery can also be
used for rescue of patients with recurrence
either locally or regionally after failure of prim-
ary therapy by surgery or irradiation. The leva-
tor scapulae muscle can be used to cover an ex-
posed carotid artery in previously irradiated
skin.
In a composite approach (e.g., if radical neck
dissection is carried out in conjuction with re-
section of a primary in the oral cavity or
oropharynx), the neck dissection must be per-
formed first as it is less contaminated than is the
primary site. Our group prefers to carry out the
neck dissection from its inferior aspect, upward
toward the primary. The neck is then covered
and the dissection is continued en bloc or sepa-
rate at the primary. The wounds are then irri-
gated thoroughly with normal saline. The pa-
tient must by placed on systemic antibiotic
coverage.
Emergency surgery is required for airway ob-
struction (tracheostomy), or ruptured carotid
(ligation). Infection sites in the neck must be
drained instantly to prevent laryngeal edema
or loss of tissues that may result in carotid ex-
posure and secondary rupture.
POSTOPERATIVE CARE
Postoperative care is essential in preventing and
minimizing complications. Immediate post-
operative care is of utmost importance to ensure
an excellent airway. The head should be elevated
to reduce edema. Infection can be prevented
through the use of antibiotics and good suture
line care. The drains must be kept functional
and clear to avoid any accumulations under the
flaps. Hydration and feeding are to be main-
tained via intravenous or nasogastric tube. The
intake and output must be monitored to avoid
over- or underhydration. As noted earlier, the
nasogastric tube is used in the first postopera-
tive day for suctioning of gastric contents and
air to avoid vomiting and aspiration. After that,
it is used for feeding. The patient is ambulated
and the upper aerodigestive system frequently
but gently suctioned to prevent stasis, infection,
and aspiration.
Late postoperative care is continued toward
suture line care. If infection is noted, it must be
drained immediately, cultured, and proper anti-
biotics reinstituted to prevent osteomyelitis.
The patient is carefully evaluated for dietary
intake and weight gain, and function through
rehabilitation. Speech therapy should be started
for laryngectomy patients. With the healing of
the surgical trauma, the patient may be consid-
ered for postoperative adjuvant therapy in the
form of irradiation, chemotherapy, or both, de-
pending on the stage of the disease. It should be
emphasized that the therapy directed at disease
control is to be carried out as soon as possible
and not delayed for reconstructive reasons.
FOLLOW-UP
Whether or not the patient is to receive adjuvant
therapy, he must be observed for local and/or
regional recurrence or new lesions by frequent
 15. SURGICAL MANAGEMENT elF HEAD AND NECK NEOPLASIA
examination of the head and neck region. He
should be evaluated for systemic metastasis
by abdominal examination and periodical chest
x-ray and blood chemistries. It is generally
recommended that the patient be seen every
three months for three years, and then every
six months after that. Suspected recurrences or
metastases must be documented histologically if
at all possible, with dates and site of failure. This
is essential to measure the disease-free survival.
Early detection of local or regional recur-
rences or new primary may permit another sur-
gical extirpation of the disease. If the recurrent
disease is not resectable and no further radiation
therapy can be administered, chemotherapy can
be considered. Future therapy with response
duration and time and site of failure have to be
continuously recorded to obtain the overall sur-
vival. Such information is essential to evaluate
the response to the treatment administered.
Finally, all efforts should be made to enter the
patient on controlled studies to further improve
survival rates.
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18. Fee WR Jr, Schoeppcl SL, Rubenstein R:
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20. Maltz R, Shumrick DA, Aron BS, Weichert KA:
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27. Shaha AR, Shah JP: Carcinoma of the subglottic
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 16. RADIOTHERAPEUTIC
MANAGEMENT OF HEAD AND
NECK NEOPLASIA
Daphne Y. Tong
General Considerations in
Radiotherapy
Surgery and radiation therapy are the estab-
lished curative treatment modalities for carcino-
ma in the head and neck region. Assuming a
comparable cure rate, the advantages of irradia-
tion may include:
1. The absence of a major operation and its
mortality (1 %-2%).
2. The avoidance of tissue loss, without func-
tional or cosmetic defect.
3. The surgical salvage of irradiation failure is
on the whole more successful than vice
versa.
However, medically infirm or elderly patients
are often referred for irradiation. One must be
aware of the fact that the lengthy course of irra-
diation (6-8 weeks) and its side effects may be
more draining on the patients than an operation
which may require 1-2 weeks of hospital stay.
RADIATION DOSE/TIME/FRACTIONATION
Conventional external (photon and/or electron)
beam treatment for the head and neck region is
delivered once a day, five days per week, with a
daily tumor dose ranging from 180 to 225 cGy. A
smaller daily tumor dose may provide less acute
reaction or chronic side effect, but prolongs the
treatment course and requires a higher total
dose to achieve the same control rate. High-
er daily fractionation shortens the treatment
course, but may lead to more severe acute and
chronic complications. The regression rate of
the tumor during treatment represents only its
Peterson et aI., HEAD AND NECK MANAGEMENT OF THE CANCER PATIENT.
© 1986. Martinus NijhofJ Publishing. All rights reserved.
radio responsiveness, not necessarily its radio-
curability. The total dose should not be judged
by tumor response to treatment alone. Persis-
tence of tumor at completion of radiotherapy
often correlates with higher recurrence rate [1].
Total tumor dose required to eradicate the
malignancy has been derived empirically from
retrospective analysis. The dose is also modified
by the surrounding normal structures and the
exten t of the lesion.
Different fractionation schemes have been
tried in which treatments are given less than five
times per week and the daily dose is higher. No
advantage regarding tumor control or side
effects has been gained [2]. Randomized trials of
conventional (200 cGy) versus high fractional
dose (400 cGy) radiation therapy daily, five days
per week, in advanced head and neck cancer
reported by Weissberg and coworkers showed
equivalent results [3].
In advanced head and neck tumors, multiple
daily fractionations have been reported to be
well tolerated with good results without long-
drawn treatment courses for patients [4, 5].
Randomized trials of this scheme are under way
in this country.
Split-course schemes, with a rest period in-
serted during the radiation course, have been
tried in the past to allow healing of mucositis
during the treatment. They failed to show an
advantage over the conventional scheme [6].
IRRADIATION OF PRIMARY TUMORS
The radiation fields usually encompass the
tumor volume with an adequate margin of
normal-appearing tissues that may harbor sub-
clinical disease. After a dose of 4500-5000 cGy,
275
276 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
r._______rPostauricular nodes
Facial nodes
Submandibular nodes -t~:;;:;;;:'Sr.~ /
Submental nodes
Subdigastric node
Anterior cervical nodes
Delphian node
Supraclavicular nodes
FIGURE 16-\. Lymph nodes of the head and neck
regIOn.
which should be sufficient to sterilize minimal
amounts of squamous cell carcinoma in tissues
not disturbed by surgical intervention [7], the
field is reduced to deliver a higher dose to the
tumor volume. The final dose to this "booster
treatment" is in the range of 6000-7500 cGy,
depending on the tumor stage and volume of
tissue involved. A change of quality or energy
of external beam may be considered for the
booster treatment, depending on tumor regres-
sion. Interstitial implant or intracavitary irradia-
tion is often used to deliver a high dose to the
tumor volume with minimal dose to the sur-
rounding normal structures.
IRRADIATION OF REGIONAL NODES
The subdigastric node area is the major drainage
site for most of the primary tumors of the head
and neck region (figure 16-1). For lesions of the
soft palate, the posterior tonsillar pillar and the
nasopharynx, high jugular, and spinal accessory
lymph nodes are commonly involved. For
lesions of the oral cavity, the submandibular
nodes are als0 at high risk. When lymphatic
obstruction develops from lymph node biopsy
or tumor, diversion of lymph flow occurs and
the contralateral neck nodes are at risk of being
involved.
In treating cancers of the oropharynx, sup-
raglottis, larynx and hypopharynx, most of the
high-risk upper neck nodes are included in the
portal arrangement for the primary lesion. For
nasal cavity, nasopharynx, paranasal sinus, oral
cavity, and large glottic lesions, the radiation
portals must be extended to cover the nodes.
When the nodes are clinically non palpable and
the risk of subclinical disease is around 15%-
20% or greater, the nodes are usually irradiated
to a minimum dose of 4500-5000 cGy. The
criteria for elective lymph node irradiation de-
pend on primary site, size of lesion, histologic
grade, risk of subclinical disease, risk of bilateral
neck disease, relative morbidity of treating the
nodal area related to the risk of subclinical dis-
ease, patient reliability for follow-up examina-
tion, and possibility of surgical intervention
should disease appear in the neck.
The justification for elective irradiation of
the low jugular and supraclavicular nodes is
emphasized by Sagerman and coworkers [8],
who reviewed 72 patients given preoperative
irradiation of 5000 cGy over five weeks for
stage-III and IV supraglottic, glottic, and pyri-
form sinus cancers. Among those whose lower
neck and supraclavicular region were treated,
10% developed a local recurrence whereas,
among those without irradiation to the above-
mentioned areas, 32% died with local recur-
rence.
When clinically positive lymph nodes are pre-
sent, radiation can cure a substantial number of
patients. The dose required usually increases
 16. RADIOTHERAPEUTIC MANAGEMENT OF HEAD AND NECK NEOPLASIA
with the size of the nodes. Interstitial implant
can be used in selected cases to boost the dose to
the lymph nodes. For subclinical disease, 5000
cGy is sufficient. When nodes are 1-2 cm in size,
6000 cGy with additional 500-1 000 cGy through
reduced portal is recommended. Nodes of 3-5
cm in size require 1500-2000 cGy boost after
6000 cGy to a generous portal. Massive fixed
nodes may require a dose as high as 8000-9000
cGy with the shrinking-field technique.
Small lymph nodes of 1-2 cm can be effec-
tively eradicated with radiation. Bigger nodes
may require combined radiotherapy and sur-
gery for better control. The preoperative doses
range from 5000 to 6500 cGy, depending on
the size and fixation of the nodes. Too high a
preoperative radiation dose may jeopardize the
surgical procedure and wound healing.
The trachael stoma is often at risk for recur-
rence after laryngectomy or laryngopharyn-
gectomy for advanced tumors, especially when
there is subglottic tumor extension, and multi-
ple involved lymph nodes in the neck [9]. Once
there is recurrence, the salvage result is poor. It
is recommended to include the tracheal stoma in
the radiation field in high-risk patients to a
dose of 5000-6000 cGy in 51-6 weeks. Mucositis
of the stoma is often the limiting factor in de-
livering a high dose.
When multiple lymph nodes containing
malignancy involve the low jugular chain, upper
mediastinal nodes should be irradiated to 4500
cGy over five weeks even in the absence of
detectable mediastinal adenopathy.
COMBINED SURGERY AND
RADIATION THERAPY
Lesions with high cure rate are dealt with by
using the single-treatment modality to avoid
unnecessary morbidity. More advanced lesions
benefit from a combination treatment. Whether
radiation is given before or after surgery be-
comes almost an institutional choice. Analy-
sis· of available data suggests no difference in
loco regional control or survival when compar-
ing the two sequences [10]. Surgeons generally
prefer to operate on nonirradiated tissues, hence
reducing the mobidity of delayed wound heal-
ing, fistula formation, or flap necrosis. Pre-
operative irradiation is recommended when the
lymph node is fixed or as a trial to judge the
response of the primary tumor. If the tumor re-
sponse is less than satisfactory after 4500-5000
277
cGy over five weeks, surgical intervention
should be contemplated about four weeks later.
Postoperative radiation therapy is considered
when the risk of recurrence above the clavicle
exceeds 20%. It is indicated for the tumor bed
when positive or close surgical margins are
noted on the pathologic specimen. It is also
recommended when there is cartilage or bone
invasion, perineural spread, and high-grade
histology. Postoperative neck irradiation is in-
dicated when there are multiple positive node
invasions through the node capsule, and high-
grade histology predicting a high risk of recur-
rence in both the dissected neck and the con-
tralateral neck.
Postoperative radiation therapy carries an
advantage over preoperative radiation therapy
in less operative morbidity, more information
of tumor extent for radiation treatment plan-
ning, and safe use of a higher radiation dose. Its
disadvantages include the delay in starting the
radiation therapy with possible tumor growth
during the recuperating period, larger treatment
volume to encompass the surgical scars and dis-
section volume, and the higher dose required to
accomplish the same control rate due to hypoxia
of the postsurgical tissues. Marcus and cowork-
ers analyzed the time-dose factors related to
control above the clavicle for 71 patients with
squamous cell carcinoma of the head and neck
treated by surgery and postoperative radiation
therapy [11]. A dose of 6000 cGy over six weeks
provides a control rate of approximately 90%,
but for those patients requiring longer treat-
ment times (7-8 weeks) or higher-risk patients,
a dose of 6500 cGy over seven weeks is pre-
ferred. In their series, approximately 8% of the
patients treated by postoperative irradiation
developed serious late complications, mainly
pharyngeal stenosis in patients having laryn-
gopharyngectomy. The five-year survival was
47% in those who received at least 6000 cGy and
22% for those who received less than 6000 cGy
postoperatively.
In the final report on a randomized study by
the Radiation Therapy Oncology Group where
preoperative and postoperative irradiations
were compared, the postoperative arm showed
significantly better locoregional control and
survival benefit versus the preoperative in ad-
vanced head and neck cancers [12].
278 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
Oral Cavity
The oral cavity consists of the lip, the anterior
two-thirds of the tongue (oral tongue), the floor
of the mouth, the upper and lower gingivae,
the retromolar trigone, the hard palate, and the
buccal mucosa.
LIP
Leukoplakia is commonly seen on the lower lip
and may precede carcinoma for years. Squa-
mous cell carcinoma is the most common malig-
nant tumor of the lip. Early lesions may be treated
with equal success with either radiation or sur-
gery. Irradiation is usually preferred for lesions
over 1.5 cm in length, for lesions involving the
commissure, and for lesions for which complex
surgical reconstruction is required. Combined
surgical and radiotherapeutic approaches are in-
dicated for advanced lesions that invade the
bone, nerve, or lymph nodes.
Treatment and Results. Forms of treatment
consist of external radiation beam, interstitial
implants, or a combination of both. Interstitial
implants can be in the form of removable
sources such as iridium 192 or radium needles,
or permanent gold implant. Interstitial implant
is recommended for well-localized lesions,
while the external beam is recommended for
more extensive ones. Orthovoltage or electron
beam is the choice for external irradiation with
custom-made lead shields placed behind the lips
to reduce the exit radiation to the oral cavity.
Small lesions can be satisfactorily treated with
4000 cGy in ten fractionations. Larger lesions
require 5000-6000 cGy in 4-6 weeks for better
control and cosmetic result.
Lymph nodes at submental and submandibu-
lar regions primarily drain the lymphatics of the
lips. Sub digastric nodes can be involved some-
times. However, the incidence of nodal metasta-
sis is quite low (10%-15%). Elective neck
irradiation is not recommended unless the
TABLE 16-1. Results of irradiation for lip cancer (al! stages)
Control by
Authors radiotherapy
MacKay and Sellers [13] 84%
MacComb et al. [14] 97%
Pigneux et al. [15], (192Ir) 95.5%
tumors are of high-grade histology, extensively
infiltrating, involve the buccal mucosa, and are
recurrent.
Results of radiation are very good with at
least 80% tumor control rate and excellent
cosmetic effect. Table 16-1 presents the repre-
sentative radiation results in the literature.
FLOOR OF THE MOUTH
The majority of neoplasms are squamous cell
carcinomas. About 5% of malignant lesions are
adenoid cystic and mucoepidermoid carcino-
mas. With regard to squamous cell carcinoma,
approximately one-third of the patients will
have clinically positive nodes on admission;
4% will have bilateral nodes. The subsequent
appearance of neck nodes occurs in 20%-35%
of the untreated necks [16-18].
The first-echelon nodes are submandibular
and subdigastric nodes. Submental nodes are
seldom involved. Being a midline structure,
bilateral lymphatic drainage results in a high in-
cidence of bilateral cervical lymphadenopathy.
Fletcher reported that nine of 19 patients with
ipsilateral positive nodes developed contralater-
al cervical disease if prophylactic neck treatment
was not given [19].
Treatment and Results. Leukoplakia may be
observed, excised, or treated with cryotherapy.
For early carcinoma, surgery and radiation
produce similar control data. After excisional
biopsy, interstitial implant can be used alone
to deliver 5500-6500 cGy to the tumor bed,
depending on the amount of disease left
behind. Elective neck irradiation should be
administered when the tumor is cut through
during the biopsy. In edentulous patients, the
intraoral cone can be used as an alternative to
the interstitial implant to treat a small area with
superficial tumors [20]. The doses vary from
5000 to 6000 cGy in 3-5 weeks.
Small lesions 1-3 cm in size can be cured with
5-year
Additional Overall determ.
salvage local control survival
8% 92% 89%
1% 98% 94%
4.5% 100%
 16. RADIOTHERAPEUTIC MANAGEMENT OF HEAD AND NECK NEOPLASIA
TABLE 16-2. Local control rate with radiation for carcinoma of the floor of the mouth
Stages
Authors Stage T t
(No or N+)
Chu and Fletcher [21]
(M.D.A.H.)
External beam + implant 48/49 (98%)
Fu et al. [22]
(U.C.S.F)
External beam only 29/38 (76%)
radiation with the advantage of electively treat-
ing the neck nodes in high-risk cases. If intersti-
tial implant is used alone for small lesions, the
dose is 5000-7000 cGy in 5-7 days to the tumor
volume. When an external beam is used for big-
ger lesions, 5000 cGy is given together with an
interstitial implant of 2000-2500 cGy as a boost-
er. The intraoral cone could replace the inter-
stitial implant when the location of the tumor
is suitable for the appliance or the patients are
at high risk for anesthesia.
When the lesions are moderately advanced,
rim resection of the mandible and tumor often
produces cure with acceptable cosmetic and
functional results. Results of irradiation are im-
proved when interstitial implants are used alone
or as part of the treatment (table 16-2). How-
ever, both local control rate and complication
rate rise with increasing radiation dose. If only
the periosteum or gingiva is involved, radiation
therapy is not contraindicated. Local control is
still quite good, but the incidence of major com-
plications in patients with large, fixed lesions is
high. If surgery can be performed without
major morbidity, it is the treatment of choice.
When advanced lesions involve the mandible
or cause fixation of the tongue, combined sur-
gery and radiation therapy is often employed;
however, the cure rate is small. When post-
operative radiation is used, the dose should be
6000-7000 cGy in 7-8 weeks, depending on the
pathology report and surgical findings.
Management of the neck follows the general
principles stated at the beginning of this
chapter.
The results of control with radiation therapy
alone at the University of Florida are 88% Th
76% Tz, and 48% T 3. The ultimate control after
salvage is 88% Tb 94% T 2 , and 68% T3 [23].
The absolute five-year survival for all stages is
279
Tz TJ
(NoorN+) (No orN+)
68/77 (88%) 46/60 (77%)
21/39 (54%) 8/30 (27%)
43%, and determinate five-year survival is 60%
[24].
ORAL TONGUE (ANTERIOR TWO-THIRDS)
Approximately 95% of the oral tongue neo-
plasms are squamous cell carcinoma. Uncom-
mon lesions include minor salivary gland
tumors and verrucous carcinoma.
As the tumors grow, tongue musculature and
the floor of the mouth are often infiltrated. Sub-
mandibular and subdigastric nodes are the first-
echelon lymphatic drainage. However, anterior-
ly situated lesions may drain directly to the
midjugular nodes. Uncommon as it is, this
spread pattern should not be overlooked in de-
signing the treatment portals. With abundant
anastomosis of lymphatic channels, bilateral
lymphatic drainage is possible. Contralateral
lymph nodes are at risk of tumor involvement
when ipsilateral nodes are present or when the
lymphatics are obstructed or disturbed by
surgery. The incidence of occult disease in these
lymph nodes is 25%-54% [25-27]. About
34%-65% of cases present with clinically posi-
tive neck nodes [28]. Patients with ipsilateral
nodes have a 27% risk of developing contra-
lateral neck nodes [24].
Treatment and Results. For early lesions (TI
and T 2), the control rate is similar with opera-
tion or radiation therapy. Surgery is the treat-
ment of choice for small, well-circumscribed le-
sions on the tip or on the dorsum of the tongue
that can be closed primarily. Irradiation is
selected for some lesions to preserve the func-
tions of speech and deglutition. If excisional
biopsy of a small lesions leaves an inadequate
margin, interstitial implant to doses of 5500-
6600 cGy in 5-7 days ensures a higher control
rate.
280 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA

FIGURE 16-2. External beam portals for intraoral

tongue lesions. (A) Lateral portals to cover the pri-
mary tongue lesion and the upper neck. (B) Anterior
portal to include the midjugular nodes and the lower
neck with midline block to shield the larynx.
 16. RADIOTHERAPEUTIC MANAGEMENT OF HEAD AND NECK NEOPLASIA
TABLE 16~3. Local control rate of oral tongue cancer with radiotherapy
Control with irradiation
Authors
Chu and Fletcher [21] (49/52) 94.3% (83/100) 83% (39/66) 59% (50/52) 94.5% (88/100) 88% (45/66) 68%
Mendenhall et at. [23J (7/8) 88% (18127) 67% (7/22) 32% (8/8) 100%
Moderately advanced lesions (T2 and T 3 ) can
be cured with irradiation if the tumors are more
superficial with minimal infiltration. The suc-
cess rate increases with more emphasis in using
interstitial implant as the sole modality or part
of the irradiation course [29, 30]. The dose is
approximately 7000-7500 cGy with combination
external beam and interstitial irradiation.
Those T 2 and T 3 lesions with deep infiltration
will have a higher control rate with combined
surgical resection and postoperative radiation
therapy 4-6 weeks later to the oral cavity and
neck. The dose range to the tumor bed is 6500-
7000 cGy, depending on the clearance of the
surgical margin.
Combined treatment may cure some ad-
vanced T 4 lesions; however, results are dismal,
especially when massive neck diseases are
present.
Elective irradiation of the bilateral neck nodes
is part of the treatment plan and is favored when
the primary lesions are larger than 1 cm. In the
series reported by Meoz et aI., subsequent neck
metastases developed in 36% of cases without
elective neck treatment. This incidence was re-
duced to 16.6% after 5000 cGy through bilateral
portals to the upper neck [31]. While the sub-
digastric nodes are included in the lateral portals
together with the oral cavity (figure 16-2), the
upper midjugular nodes and the lower neck can
be irradiated with an anterior oppositional field.
The local control rate with radiation alone
and with salvage treatment is shown in table 16-
3. The absolute five-year survival rates accord-
ing to Mendenhall et al. are 45% stage I, 59%
stage II, and 30% stage III, and the determinate
five-year survival rates are 100% stage I, 71 %
stage II, and 35% stage III [23].
BUCCAL MUCOSA
Low-grade squamous cell carcinoma represents
the majority of malignant tumors in this region.
Centrally located lesions can extend to the
underlying muscles, while peripheral tumors
281
Ultimate control after salvage
(22127) 81 % (12122) 55%
spread into the buccogingival sulcus, onto the
gingiva, and eventually the bone. The lymphatic
drainage empties to the submandibular and sub-
digastric nodes first. The incidence of positive
nodes at presentation is 9%-31 % [25-27] and
the risk of occult disease is 16% [16].
Treatment and Results. If the lesion is small
enough that excision and primary closure can be
easily performed, surgery is expeditious and
curative. Lesions large enough to require exci-
sion and graft or when near the commissure are
preferably managed with radiation alone. When
the maxilla or mandible is involved, surgery is
preferred. Radiation portals are designed to
spare the surrounding normal structure by
employing the electron beam, intraoral cone,
or interstitial implant (figure 16-3).
Results from M.D. Anderson Hospital showed
a 72% (70 of 97) local control rate with irradia-
tion alone and 83% ultimate control rate with
surgical salvage [32]. Ash reported the results in
374 patients with carcinoma of the buccal mu-
cosa of all stages [16]. Radiation therapy was
used in 97% of the cases. Initial tumor control
was 53% with early lesions and 25% with ad-
vanced lesions. The corresponding figures were
69% and 34% after salvage. The absolute five-
year survival was 35%.
HARD PALATE AND GINGIVA
The majority of tumors in these regions are
squamous cell carcinoma, except in the hard
palate where minor salivary gland tumors are
more frequent. Epidermoid carcinoma of the
maxilla or mandible arises from odontogenic
epithelium or from epithelium trapped during
embryonic development. Other uncommon
tumors include verrucous lesions, ameloblasto-
ma, or even melanoma. The first-echelon lymph
nodes are the submandibular and subdigastric
nodes for this region.
Upper Gingiva and Hard Palate. Primary
282 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
FIGURE 16-3. Interstitial implant with 192Ir seeds for
buccal mucosal lesion. (A) Lateral view. (B) Antero-
posterior view.
tumors at this region tend to invade the adjacent
structures as they grow. About 13%-24% of
the cases present with positive lymph nodes [33,
34], while 22% harbor occult disease in the neck
[16].
TREATMENT AND RESULTS. Small, discrete, su-
perficial lesions can be excised or irradiated.
Mold technique allows high mucosal dose to the
involved area with minimal irradiation of the
adjacent normal structures (figure 16-4). The
patient can be treated 5-6 h per day over 5-6
treatments to deliver a mucosal dose in the
order of 7000 cGy, depth dose at 3 mm 5000 cGy.
If the lesion is extensive yet superficially in-
volves the hard palate, radiation therapy may be
used for the p-rimary lesion and the neck nodes
to avoid surgical defect of the hard palate. When
bone invasion is suspected or obvious, surgical
resection is preferred with additional postopera-
tive irradiation as needed. A prosthesis can be
made after partial maxillectomy. Chung and
coworkers noticed an improvement of results
with supervoltage irradiation versus orthovol-
tage in treating squamous cell carcinoma of the
hard palate. All seven patients treated with su-
pervoltage radiation achieved local control.
Two out of three additional patients had local
control after supervoltage salvage. The total
control rate was 90% (9 of 10). Their absolute
five-year survival was 35% and determinate sur-
vival 56%. The five-year s!lrvival in the litera-
ture ranges from 21 % to 36% [33].
Lower Gingiva. Squamous carcinoma of the
gingiva can be either exophytic and ulcerated or
infiltrating. The proximity of bone facilitates
frequent osseous involvement. Slow-growing
tumors may produce atrophy of adjacent bone,
creating a saucerized defect while aggressive le-
sions actually invade the bone. Cervical lymph
node metastases appear quite frequently (18%-
52%) [25, 34-36]. Occult disease occurs in
17%-19% [16,35].
TREATMENT AND RESULTS. Small, superficial le-
sions can be cured with irradiation. If practical,
intraoral cone or mold is preferred to concen-
trate the dose to the involved areas. Because of
the frequent complications that follow cancer-
ocidal doses of radiation to large volumes of the
 16. RADIOTHERAPEUTIC MANAGEMENT OF HEAD AND NECK NEOPLASIA
A
B lymphatic spread of about 40% [40,41]. The in-
FIGURE 16-4. Acrylic mold containing mes capsules
arranged according to the rules of Patterson-Parker
to irradiate a flat lesion on the left upper gingiva. The
bite block with impressions of the lower teeth allows
the patient to hold the mold in the mouth tightly.
(A) Dorsal view. (8) Ventral view.
mandible, lesions of the lower gingiva are usual-
ly handled by surgical resection. Bone invasion
significantly worsens the prognosis. Among the
48 cases of all stages irradiated at M.D. Ander-
son Hospital, 54% achieved local control; after
surgical salvage, 62.5% achieved control. The
five-year determinate survival of the irradiated
group was 53% [32].
Oropharynx
The oropharynx includes the tonsillar region
(tonsillar fossa, tonsillar pillars, retromolar tri-
gone), the soft palate, the base of the tongue,
and that portion of the pharyngeal wall between
the nasopharynx and the pharyngoepiglottic
fold.
283
Squamous cell carcinoma accounts for 95%
of the malignant lesions. Lymphoepithelioma
and malignant lymphoma mainly involve the
tonsil and the base of the tongue. Minor salivary
gla~d tumors and plasmacytoma are rare in this
regIOn.
The treatment and results involving the
pharyngeal wall are discussed in the section on
the hypopharnyx because the natural history,
treatment, and prognosis are similar.
TONSILLAR REGION
Lesions in this region tend to involve the adja-
cent structures, making it difficult to identify
whether they arise from the fossa or pillar first.
Extension to glossotonsillar sulcus and the base
of the tongue occurs often (40%) [37, 38],
markedly reducing the local control rate.
The pattern of spread is to the subdigastric
node first and then to the jugular chain. How-
ever, lesions from the posterior tonsillar pillar
are more likely to spread to the spinal accessory
nodes and the high jugular chain node. Lesions
of the tonsillar fossa have a higher propensity
for lymphatic spread. The incidence of positive
nodes is 53%-76% [37, 39]. Tumors from the
anterior tonsillar pillar and retromolar trigone
are better differentiated with an incidence of
cidence of contralateral neck disease increases
when there is invasion of the soft palate within
1-2 em of the midline, lingual involvement, or
clinically positive nodes in the ipsilateral neck.
Treatment and Results. Early lesions T J and
T 2 are highly curable by irradiation alone,
reserving surgery for failure. If the tumors are
relatively confined to the tonsillar region, with-
out the above-mentioned risk factors for con-
tralateral neck involvement, various techniques
have been used to spare the contralateral oral
pharynx and salivary glands. Mixed high-energy
photons (8-20 MV) and high-energy electrons
(17-20 MV) are often used at M.D. Anderson
Hospital, while unilateral photon portals or
ipsilateral oblique wedged pair portals are
adopted in other institutions. When the lesions
are encroaching upon the midline, parallel
opposed photon portals are commonly used,
with a 2:1 or a 3:2 weighting favoring the
involved side. Equally weighted parallel lateral
opposing portals are recommended whenever
the tumor extends across the midline or when
contralateral neck nodes are positive. Elective
284 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
ipsilateral neck irradiation is indicated. High-
risk patients should have the contralateral neck
treated employing the same guideline and tech-
nique as for the primary lesions. The required
dose to control the tumor escalates with the size
and extension of the lesions. In the analysis of
129 tonsillar squamous cell carcinomas treated
with radiation therapy reported by Shukovsky
and Fletcher, doses of 6500 cGy for Th 7000
cGy for T z, and 7000-7500 cGy for T3 and T4
are required to control about 90% of the tumors
[42]. The doses required for anterior tonsillar
pillar and retromolar trigone are even higher:
7000 cGy for T h 7200 cGy for T 2> and 7500
cGy over seven weeks for T3 [40].
For moderately advanced Tz and T3 lesions,
irradiation is still the treatment of choice with
surgery reserved for salvage, since planned
preoperative irradiation and operation did not
significantly improve local control rate [43, 44].
However, surgery should be offered when the
lesions fail to regress after 5000 cGy. Advanced
T 3 and T 4 lesions are handled with combined
surgery and postoperative irradiation, especially
when the mandible is involved.
The local control rate relative to primary
tumor size is shown in table 16-4. The presence
of lingual involvement reduced the cure rate and
survival considerably. In Wang's series, the
three-year disease-free survival was 55% with-
out, and 25% with, tongue involvement [38].
Likewise, the presence of lymph nodes also re-
duces the local control rate. In Tong's series, the
local control rate dropped from 69% to 41 %
with clinically positive neck disease [37].
SOFTPALATE
Almost all soft palate squamous cell carcinomas
occur on the oral side of the palate. The
TABLE 16-4. Local control rate of carcinoma
of the tonsillar region with radiation therapy
Stages
Authors T\ Tz T3 T4 Total
Wickstrum [45] 94% 88% 48% 22% 66%
including salvage
Tong et al. [37] 88% 67% 49% 6% 54%
including salvage
Wang [38] 82% 60% 15% - 44%
presalvage
nasopharyngeal side of the palate is hardly ever
involved with malignancy. Lymphatic spread is
first to subdigastric lymph nodes and then to
the jugular chain. Lindberg and coworkers
reported an approximately 20% incidence of
occult neck disease [41]. Approximately 50% of
the cases present with positive cervical nodes,
16% being bilateral nodes [24]. The incidence of
positive lymph nodes increases with the pri-
mary tumor size: 8% for T 1 , 36% for T2> and
about 66% for T3 and T4 [24].
Treatment and Results. Small lesions con-
fined to the uvula can be easily excised without
functional impairment. For most early and ad-
vanced lesions, radiation therapy offers good
results of control and minimal functional mor-
bidity. Equally weighted parallel opposed lateral
external beam portals are generally used to en-
compass the entire soft palate and the first-
echelon lymph nodes for possible occult disease
in the neck. For small lesions, the boosting dose
may be delivered through intraoral cone or
single-plane seed implant. Radon or gold seeds
are used for permanent implant. The after-load-
ing iridium-192 removable implant technique
was reported by Goffinet and coworkers [46].
Seydel and Scholl reported a 68% control rate
among the 31 patients treated with doses of
6000-7000 cGy [47]. In addition, Gelinas and
coworkers reported the M.D. Anderson Hospital
study, in which 68 (92%) of 74 of the cases were
controlled with irradiation alone. The control
rate for TI and Tz was 100%, for T3 82%, and
for T4 50%. Four of the six patients with T3 and
T 4 lesions had subsequent surgery for failure,
and one of them was cured [48].
BASE OF THE TONGUE
Lesions at the base of tongue often remain
asymptomatic and are diagnosed after the
metastases show up. Carcinoma of the base of
the tongue tends to infiltrate deeply into the
substance of the tongue and may invade the
glossopharyngeal sulcus and the lateral wall of
the pharynx. Vallecular lesions can eventually
penetrate into the preepiglottic space.
Like the other anatomic sites in the
oropharynx, the subdigastric lymph nodes are
first involved with tumor spread, and then the
jugular chain. However, the posterior cervical
nodes are also at risk. About 75% of patients
will present with lymphadenopathy; 30% will
have bilateral nodes [24].
 16. RADIOTHERAPEUTIC MANAGEMENT OF HEAD AND NECK NEOPLASIA
Treatment and Results. Irradiation and
surgery achieve similar cure rates for early base-
of-tongue tumors. In some centers, glossectomy
is still recommended as the treatment of choice.
Surgery often causes greater disability, involv-
ing either supraglottic laryngectomy or total
laryngectomy. Patients either are unsuitable for
the procedure or unwilling to accept the con-
sequences. Irradiation is certainly an alternative.
External beam irradiation of lesions of the
base of the tongue is arranged with parallel
opposed lateral portals to encompass the prim-
ary lesion and bilateral neck nodes. Spanos and
coworkers analyzed the time-dose-volume re-
lationship related to the local control of these
lesions and concluded that a dose of 6000-6500
cGy in 6~ weeks is required for 90% control in
tumors of 2 cm or less in size, while 7500 cGy in
7! weeks is required for 80% control in lesions
that are larger than 2 cm but not massive [49].
At conventional fractionation, the portals are
reduced after 5000 cGy to boost the tumor-
bearing areas to higher doses. This boost treat-
ment could be delivered with an interstitial
iridium-192 removable implant or external
beam by way of reduced lateral portals or
submental portals tilted cephalad to avoid the
previously irradiated spinal cord. The latter
technique is mainly for lesions located centrally
and posteriorly on the base of the tongue.
In irradiating the neck nodes electively, the
author recommends coverage of the upper jugu-
lar, submandibular, and posterior neck nodes
bilaterally with the primary portals. The lower
neck nodes can be treated with anterior field,
shielding as much normal structure as possible,
depending on the nodal status. If the posterior
neck nodes are involved or at high risk, they can
be boosted with electron beams of appropriate
energy once the spinal cord tolerance to irradia-
tion is about to be reached (4400-4500 cGy over
4-5 weeks).
The treatment results reported by Spanos and
coworkers showed that the control rate at the
primary site was 91 % for Th 71 % for T 2 , 78%
for T 3, and 52% for T 4 [49]. The overall control
rate was 74%. The absolute two-year disease-
free survival was 51 %. Blumberg and cowork-
ers reported their experience with radiation
alone, which resulted in local control of 100%
for Th 55% for Tb 38% for T 3 , and 20% for T4
lesions [50]. The overall control with radiation
was 48%. Among patients who were treated
with external beam plus surgery or interstitial
285
implant, eight of nine achieved local control.
They felt that external irradiation alone was not
adequate for more advanced lesions.
Hypopharynx
The sites to be discussed in this anatomic region
are pharyngeal walls, pyriform sinus, and post-
cricoid pharynx.
More than 95% of malignant tumors are
squamous cell carcinoma or its variants. Early
spread to adjacent soft tissues and cartilage is
common. The muscle planes of the neck and
perineural lymphatics provide the pathway of
tumor extension. Spread from hypopharyngeal
lesions may extend superiorly almost to the base
of the skull.
Lymphatic channels are profuse in the pyri-
form sinus. The subdigastric node is the most
commonly involved, followed by the jugular
chain. Posterior neck nodes are occasionally
invaded. About 75% of patients have positive
nodes at presentation and at least 10% are bi-
lateral [51]. The lymphatic spread patterns from
pharyngeal wall lesions are similar, but the
spinal accessory chain is often involved. About
55% of the patients present with positive nodes,
17% bilaterally [51].
TREATMENT AND RESULTS
Postcricoid lesions are usually handled with
radical surgery and reconstruction.
Pyriform Sinus. Small lesions confined to the
pyriform sinus (T 1) are locally controlled in
85%-90% of cases by partial laryngopharyn-
gectomy or irradiation [52]. Irradiation poses
an advantage of covering the lymphatics and
preserving the normal pharyngeal function. For
larger lesions (T 2 and T 3) involving the pyri-
form sinus apex, or when fixation is present
secondary to tumor infiltration, total laryngo-
pharyngectomy is indicated. When the tumor
is exophytic, located in the upper part of the
pyriform sinus, irradiation may be tried first. If
the tumor regression at 4500-5000 cGy is less
than satisfactory, surgery is carried out later.
For more advanced, infiltrative lesions, radical
surgery with neck dissection followed by post-
operative irradiation is preferred.
Parallel opposed lateral portals are used to
treat the primary lesion and regional nodes on
both sides of the neck. The superior border
should be 2-3 cm above the mastoid tip to en-
286 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
compass the parapharyngeal nodes. The inferior
border should be 2 cm below the superior bor-
der of the cricoid to ensure adequate coverage of
the pyriform apex. Elective posterior neck node
irradiation is recommended, while therapeutic
irradiation of them requires electron beam
boost after 4500 cGy to the spinal cord or sur-
gical intervention. Wedges or compensators are
often used to ensure dose homogeneity while
differential dose weighting may be selected
according to the tumor extension. The usual
dose is 6500 cGy over 6-7 weeks for T\ lesions,
and 7000-7500 cGy over seven weeks for larger
lesions, if treated definitively. Preoperative or
postoperative radiation doses follow the general
guidelines stated previously.
Local control rates with radiation alone at the
University of Florida are 79% for Tb 60% for
T 2, 50% for T 3 , and 1 out of 7 for T4 lesions.
After surgical salvage, the control rate for T2
lesions increased to 90% [52].
Jesse and Lindberg compared the results of 67
patients with carcinoma of the pyriform sinus
where necks were treated by a surgical proce-
dure relative to 49 similar patients whose necks
were treated by combining radiation therapy
with a surgical procedure [53]. Regional failure
was 30% in the group having only a surgical
procedure and 14% in the group receiving both
radiation and surgical therapy. Their preopera-
tion radiation dose was 5000 cGy and post-
operative radiation dose was 6000 cGy to both
sides of the neck.
Marks and coworkers analyzed the data
of pyriform sinus carcinoma at Washington
University [54]. The majority of the patients
received only 3000 cGy in three weeks pre-
operatively, followed by partial or total laryn-
gopharyngectomy; 63% of the patients were
treated with unilateral portals. Their regional
failure rate was 28%, double the rate reported
by Jesse and Lindberg's group. Not only did
failure occur at the primary site and ipsilateral
neck, but also in the contralateral neck. This
further emphasizes the importance of adequate
radiation doses and portal arrangement even
when surgical resection is part of the treatment
modality.
Pharyngeal Wall. Small, exophytic lesions of
the lateral pharyngeal wall respond to radiation
well, but larger, infiltrative lesions require
surgery. Results of either irradiation or com-
bined surgery and irradiation of the posterior
pharyngeal wall are poor owing to the infiltra-
tive nature of the disease with the skip areas
and the profuse lymphatic channels there. The
opposed lateral portals should cover the entire
posterior pharyngeal wall initially, from the
base of the skull down to the esophageal inlet.
All lymph nodes are treated electively if clinical-
ly negative. When neck nodes are present, exter-
nal beam may be supplemented with interstitial
implant by either gold or radon seeds. In such
cases, it would be cautious to reduce the spinal
cord dose from external photon beam to 3000-
4000 cGy and complete the lymph node treat-
ment with either neck dissection or electron
beam.
Marks and coworkers reported a high inci-
dence of complications even with a preoperative
dose of 2500-3000 cGy [55]. It is advisable to
perform surgery first when combined treatment
is contemplated.
Meoz-Mendez and coworkers reviewed the
radiotherapy results of 164 patients with lesions
of both posterior and lateral pharyngeal walls
[56]. The local control was 91 % for T I, 73 % for
Tb 61 % for T 3 , and 37% for T 4 • After surgical
salvage, the corresponding figures were 100%,
78%,71%, and 41%, respectively. At the time
of death, the local failure was 38%, neck failure
6%, and distant failure alone 10%.
Larynx
Anatomically the larynx is divided into the sup-
raglottic larynx, and the glottic and subglottic
regions. The supraglottic larynx consists of the
epiglottis, aryepiglottic folds, the false vocal
cords, the ventricles, and the arytenoids. The
glottis includes the true vocal cords and the
anterior commissure. The subglottic area begins
about 5 mm below the undersurface of the vocal
cords to the level of the first tracheal ring. Near-
ly all laryngeal neoplasms are squamous cell
carcinoma or its variants.
SUPRAGLOTTIC LARYNX
The supraglottic structures are richly supplied
with capillary lymphatic plexus which passes
through the preepiglottic space and the thyro-
hyoid membrane to the subdigastric nodes.
Some lymphatic trunks drain directly to the
middle or lower jugular chain.
The incidence of clinically positive nodes is
55% at the time of diagnosis; 16% are bilateral
[51]. Subclinical disease occurs in 16%-26% of
 16. RADIOTHERAPEUTIC MANAGEMENT OF HEAD AND NECK NEOPLASIA
cases. The subsequent appearance of posItIve
nodes in the untreated neck is about 33% [7].
Treatment and Results. Treatment of early
lesions could be accomplished with either sup-
raglottic laryngectomy or full-dose irradiation.
Patients with poor pulmonary function or who
are medically unfit for the surgical procedure
are better managed with irradiation. Medium-
sized lesions of the suprahyoid epiglottis or
aryepiglottic folds are preferably treated by
irradiation while those of the infrahyoid epi-
glottis or false cord are better treated by supra-
glottic laryngectomy since they are often under-
staged. Selected exophytic large lesions in the
upper part of the supraglottic larynx can be con-
trolled with a high rate of success. Most ad-
vanced lesions, especially with cartilage invasion
or trans glottic lesions fixing the vocal cords, are
managed with a combination of totallaryngec-
tomy and irradiation. When there is advanced
neck disease (N2 and N3)' combined treatment
is frequently necessary.
Parallel opposed lateral portals cover the
primary lesion, its extension, and potential
lymph nodes. The usual doses are 6000-6500
cGy for TI and 7000 cGy for T2 and early T3
lesions [57]. Doses for the clinically positive
lymph nodes follow the general guidelines.
Wang reviewed 184 cases of supraglottic car-
cinoma treated by megavoltage radiotherapy. A
determinate three-year disease-free rate was
38%; 68% of the group had T3 and T4lesions
and 51 % had nodal metastases. For Th Tz, T 3,
and T 4 lesions, the determinate three-year dis-
ease control rates were 89%, 66%, 21 %, and
23%, respectively. The control rates for patients
without and with nodes were 63% and 17%,
respectively [58].
Fletcher and Hamberger analyzed the causes
of failure in irradiation of squamous cell carci-
noma of the supraglottic larynx [59]. Their local
control rate for TI and T2 lesions was 87.5%
with primary irradiation. Only a few T 3 and T 4
cases were managed with irradiation alone.
Fu and coworkers reported their results of
173 cases of supraglottic laryngeal carcinomas.
Their treatment policy was either surgery or
radiotherapy for stage-land II disease, and
combined surgery and radiotherapy for stage-
III and IV disease. The ultimate control rate of
the primary lesions was 73% for the entire
group and 90% forTh 80% forTz, 79% forT 3,
and 56% for T4 lesions. Control of cervical
287
lymph node metastases was achieved in 71 % of
Nh 38% of Nz, and 75% of N3 nodes [60].
GLOTTIS
Apart from the usual squamous cell carcinomas
in this region, carcinoma in situ is rather com-
mon on the vocal cords. Verrucous carcinoma
occurs in about 1%-2% of patients with carci-
noma.
Invasion of the vocalis muscle causes fixation
of the vocal cord. Advanced lesions may pene-
trate the thyroid cartilage to involve the thyroid
gland and neck soft tissues.
Lymphatic spread from the glottic region is
very rare unless the tumor extends to the sub-
glottic or supraglottic region. For T2 and small
T 3 lesions, the incidence of neck nodes is less
than 5%. It increases to 20%-30% for large T3
and T4 lesions [24]. Anterior commissure and
anterior subglottic invasion is associated with
involvement of the midline pretracheal node
(Delphian node).
Treatment and Results. Carcinoma in situ
can be cured by complete stripping of the mu-
cosa of the cord followed by frequent and care-
ful observation for possible regrowth. How-
ever, repeated stripping results in thickened
vocal cords and poor voice quality. Besides, the
histologic interpretation between carcinoma
in situ and microinvasion can be difficult. Most
centers thus advocate irradiation of carcinoma
in situ earlier. The dose is usually 6000 cGy in
six weeks.
Verrucous lesions were often reported to be a
contraindication for irradiation because of their
lack of response and the possibility of develop-
ing into anaplastic aggressive lesions. A few re-
ports showed that irradiation can control verru-
cous lesions [61]. The surgical approach is still
the commonly accepted practice, but the author
would not hesitate to treat such lesions with
irradiation when the yatient is medically un-
suitable for or refuses the operation. The dose is
the same as for a well-differentiated squamous
cell carcinoma of the similar stage.
Early TI and T2 lesions can be controlled
with hemilaryngectomy or definitive irradia-
tion, but the latter is preferred for better voice
quality after treatment. Advanced vocal cord
lesions T 3 and T 4 are treated with total laryn-
gectomy with postoperative radiation therapy if
needed.
The portals used for early vocal cord lesions
288 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
are about 5 x 5 cm from the thyroid notch to
the inferior border of the cricoid cartilage. Neck
nodes are not at risk. When lesions are bigger,
involving surrounding structures, the subdigas-
tric and midjugular nodes should be included in
the lateral opposed portals. Wedges or compen-
sators are often used according to the neck con-
tour and tumor extent. The optimal dose-time
relationship for carcinoma of the vocal cords
has been examined by various centers and the
results showed a "flattening" of the dose-
response curve in the data analyses [62, 63].
Horiot and coworkers advocate 6000 cGy in six
weeks for superficial small vocal cord lesions,
6500 cGy in six weeks for small exophytic can-
cers, and 7000 cGy in 6! weeks for bulky and
more advanced cancers [63]. Million and co-
workers use similar dose ranges [24].
The local regional control with radiation
alone for mobile cord is 77%-91 %. The salvage
rate is 83%-89% with surgery after radiation
failure. The five-year survival is in the range of
80%-90% [62-65]. When the mobility of the
cord is impaired, the radiation control rate is
64%-75%, with a salvage rate of 65%-75%,
and the mean five-year survival 64% [63-65]. In
Wang's series, radiation alone controlled only
27% of the cases with fixed vocal cords. The
salvage rate was 44% and the mean five-year
survival was the same [64].
Harwood and De Boer noted a highly sig-
nificant difference in local control rates with
radiotherapy among the T2 glottic cancers when
comparing cases with normal vocal cord mobil-
ity (76.7% locally controlled) versus impaired
vocal cord mobility (51.1 % locally controlled)
(p = 0.015) [66]. However, Van den Bogaert and
coworkers felt that impaired mobility per se was
not a bad prognostic factor, but was associated
with poorer prognosis only when it was com-
bined with tumor extension [67]. For such le-
sions, surgery was used after irradiating to 4000
or 5000 cGy without obvious improvement in
cord mobility or tumor regression.
SUBGLOTTIC LARYNX
Lesions in this region are uncommon. They
tend to involve the undersurface of the vocal
cords and the cricoid cartilage. Lymphatic chan-
nels are scarce and drain to the Delphian node
or lower jugular chain.
Treatment and Results. Superficial lesions in
that region can be treated with irradiation de-
finitively. More advanced lesions require com-
bined surgery and postoperative irradiation,
which should include the tracheal stoma to a
cancerocidal dose to prevent stomal recurrence.
Pretracheal and lower jugular nodes are elec-
tively irradiated in advanced lesions. There are
no good data on dose-time relationship in the
result of irradiation of this particular region.
N asopharnyx .
The nasopharynx is lined with ciliated columnar
epithelium that contains mucus and seromucus
glands. The most frequent neoplasm is epider-
moid carcinoma (85%) among which are squa-
mous cell carcinoma, lymphoepithelioma, and
transitional cell carcinoma. Lymphoma com-
prises 10% of the malignant tumors. The rest
are adenocarcinoma, juvenile angiofibroma, and
other rare types of tumors.
Tumors in the nasopharynx tend to invade
the base of the skull frequently (25%). Subse-
quent to erosion through the foramen ovale or
foramen lacerum, the tumor may eventually
reach the cavernous sinus area involving cranial
nerves II-VI on the affected side, with nerve VI
being most vulnerable. Other sites like the post-
erior ethmoids, the maxillary antrum, the nasal
cavity, pterygoid fossae, and orbit are often
invaded by direct tumor expansion.
The nasopharynx is richly supplied with sub-
mucosal lymphatic capillary plexus. Tumor cells
spread along the jugular and spinal accessory
chains as well as the retropharyngeal nodes.
Subdigastric and upper jugular nodes are most
commonly involved. At the time of presenta-
tion, about 70%-90% of patients have neck
nodes, about 50% bilateral [32, 34]. Enlarged
nodes in the upper jugular chain may produce
pressure paralysis of cranial nerves IX-XII and
the sympathetic chain.
TREATMENT AND RESULTS
The anatomic location of nasopharyngeal
tumors renders surgery infeasible. Irradiation is
the treatment of choice in most cases except for
small sarcoma or adenocarcinoma. Juvenile
angiofibromas are preferably excised, although
they respond to irradiation favorably.
The lateral opposed portals are commonly
used to encompass the nasopharynx, posterior
ethmoid sinuses, posterior nasal cavity, post-
erior orbit, posterior maxillary sinus, base of the
skull including the.foramen ovale, lacerium, spi-
 16. RADIOTHERAPEUTIC MANAGEMENT OF HEAD AND NECK NEOPLASIA
nosium, magnum, pterygoid fossae, posterior
and lateral oropharyngeal wall, and retropharyn-
geal nodes. When there is cranial nerve II-VI
involvement, the superior border is raised to
above the cavernous sinus to include the pitui-
tary, the base of the brain, and the adjacent
intracranial contents. The anterior field is
added whenever the tumor invades the orbit,
ethmoids, anterior nasal cavity, or maxillary
sinus. The dose contributed by each field de-
pends on the tumor extent. The lateral fields are
often rotated positively by about 5° to keep the
divergent exit beam from hitting the contra-
lateral eye lens. Intracavitary irradiation with
the mold technique [68] or with pediatric endo-
tracheal tubes [69] is employed originally for the
treatment of recurrence, but can be employed as
a boosting irradiation in the initial treatment.
Neck nodes are electively irradiated. The
upper neck nodes above the thyroid notch are
included in the lateral fields with the primary
lesion, while the lower neck nodes and supra-
clavicular fossae can be treated with anterior
and posterior portals with laryngeal block.
The radiation dose for squamous cell carcino-
ma ranges from 6500 to 7000 cGy, while that for
lymphoepithelioma is about 6000-6500 cGy
[32]. The doses for lymphoma are the same as
for other sites in the body: 3000-4000 cGy for
lymphocytic lymphoma, and 5000-6000 cGy for
histiocytic lymphoma.
The five-year survival rate ranges from 32%
to 62% as indicated in table 16-5. The presence
of cranial nerve involvement or bone destruc-
tion worsens the prognosis substantially. Moss
and coworkers reviewed the results reported in
the literature and noted that the five-year sur-
vival was reduced from 41 % without to 24%
with those grave signs [73]. The five-year sur-
TABLE 16-5. Five-year survival for nasopharyngeal carcinoma by primary tumor staging
Authors
Tl
Wang (1940-1971) [70) 56%
(251 patients)
Hoppe et aI. (1956-1973) [71) 76%
(82 patients)
Tl - 3
Huang (1958-1973) [72) 43%
(1605 patients)
289
vival for lymphoma is better than that for
lymphoepithelioma, which in turn is better
than that for squamous cell carcinoma (57% vs
43% vs 30%). Likewise, the five-year survival
decreases with the status of the cervical lym-
phadenopathy. It is approximately 55% with-
out neck nodes, 40% with ipsilateral nodes, and
23% with bilateral or fixed adenopathy.
Nasal Vestibule, Nasal Cavity, and
Paranasal Sinuses
NASAL VESTIBULE
This space is the entrance to the nasal cavity,
lined by skin with hair follicles and sebaceous
glands. Tumors in this location are the same as
skin cancers and the treatment principles for
skin cancers apply here. Lymphatic spread may
be bilateral to submandibular nodes. The facial,
submental, and preauricular nodes can some-
times be involved.
Treatment and Results. Surgery and irradia-
tion are equally successful for early lesions, but
irradiation offers better cosmetic results. Ad-
vanced lesions with cartilage or bone destruction
are preferably managed surgically if operable.
A radiotherapist may choose the intracavitary
mold for superficial lesions, the interstitial
implant for moderately sized lesions, or the
external beam for more extensive tumors [74].
The external beam arrangement can be a single
anterior portal or two opposed lateral portals
with a wax bolus around the nose and wedges to
assure homogeneous dose distribution. The
doses to the cartilage and adjacent bones are less
with megavoltage beams from cobalt 60 or a 4-
MeV linear accelerator than with orthovoltage.
Stages Total
T2 T3 T.
41% 18% 25% 40%
68% 55% 1/10 62%
T•.
23% 32%
290 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
Elective irradiation of cervical lymph nodes is
indicated when the primary disease is extensive
and highly undifferentiated.
Wang analyzed 36 patients with squamous
cell carcinoma of the nasal vestibule. Of the
three patients eligible for three-year disease-free
evaluation, 23 (74 %) were alive and well after
irradiation alone. For Th T 2 , and T 3 lesions, the
three-year disease-free rates were 84%, 71%,
and 50%, respectively [75].
Haynes and Tapley obtained local control in
19 of 22 patients with squamous cell carcinoma
of the nasal vestibule. One of the three recur-
rences was subsequently salvaged by surgery
[74].
NASAL CAVITY
Among the malignant tumors in this region,
squamous cell carcinoma is the most common.
Others include minor salivary gland tumors,
lymphoma, esthesioneuroblastoma, soft-tissue
and bone sarcomas, inverting papilloma, and
midline lethal granuloma.
The lymphatics of the olfactory region of the
nasal cavity spread to lymph nodes alongside
the jugular vein at the base of the skull in the
lateral pharyngeal space. The lymphatics of the
respiratory part of the nasal cavity terminate
either in a lateral pharyngeal node or the sub-
digastric node. The incidence of lymphatic
metastases is about 10%-15%.
Treatment and Results. Most lesions can be
dealt with by surgery or irradiation. When cos-
TABLE 16-6. Survival of paranasal sinus tumors according to treatment modality
Authors Survival
Holste (1967) 621219 (28%)
5-year absolute
Boone (1968) 52/121 (43%)
5-year absolute
Badib (1969) 48/344 (14%)
5-year determinate
Hamberger (1970) 148/591 (25%)
5-year absolute
Lewis (1972) 1911677 (28%)
5-year determinate
Cheng (1977) 3-year 17/50 (34%)
absolute disease free
Modified from Lee and Ogura [80].
metic loss is implied with resection, radiation
therapy is used as an alternative. External beam
irradiation is used with combined anterior and
lateral portals. Midline lethal granuloma is
treated with radiation therapy with generous
portals, encompassing the paranasal sinuses to
about 5000 cGy in five weeks.
Bosch and coworkers reported their experi-
ence with 40 consecutive cases of cancer of the
nasal cavity. Radiation therapy was used in 85%
of the cases and a five-year survival of 50% was
obtained in these patients [76].
Ellingwood and Million reported their ex-
perience with 15 patients. The local control rate
was 14 of 15, with the absolute recurrence-free
survival 95% at two years and 54% at five years
[77].
PARANASAL SINUSES
The paranasal sinuses consist of the maxillary
sinuses, ethmoid sinuses, and sphenoid sinuses,
all lined with the same mucosa contiguous with
one another and the nasal cavity. The type of
neoplasms in the paranasal sinuses is the same
as that in the nasal cavity. The incidence of
lymphatic spread is low, occurring when the
tumor's growth extends outside the sinuses. In
the case of maxillary sinus tomors, subman-
dibular and jugulodigastric nodes may be in-
volved when the tumors invade the oral cavity
and buccal mucosa. Parapharyngeal nodes may
be involved when the maxillary sinus tumors
invade the nasal cavity or nasopharynx. Pezner
and coworkers found cervical adenopathy in 13
Cases
Surgery ± Radiation treated by
irradiation alone radiation
34% 15% 19%
30% 34% 44%
29% 10% 38%
45% 19% 49%
33% 20% 21%
48% 22% 52%
 16. RADIOTHERAPEUTIC MANAGEMENT OF HEAD AND NECK NEOPLASIA
FIGURE 16-5. Isodose curve with anterior and lateral
wedged portals to treat maxillary carcinoma.
(21%) of 63 on admission, whereas nine (lS%)
of the remainder developed adenopathy later
[7S].
Treatment and Results.
MAXILLARY SINUS. Surgical resection is the
treatment of choice for localized lesions. Com-
bined surgery and radiation therapy is recom-
mended for more advanced lesions. The radia-
tion portals include a combination of anterior
and lateral beams to include the maxillary
antrum, the adjacent nasal cavity, ethmoid
sinus, the nasopharynx, and the pterygopalatine
fossa (figure 16-5). Adequate coverage for the
orbital floor is essential for lesions in the supra-
structure of the maxillary sinuses. The dose is
usually 6500-7500 cGy to lower the recurrence
rate. Pre- or postirradiation yields similar re-
sults [79].
291
When there is involvement of the oral cavity
or nasopharynx by the tumor, elective neck
irradiation may be considered.
Lee and Ogura reported their experience with
96 patients with maxillary sinus tumors [SO].
Primary tumor control was achieved in 69% of
the patients receiving combined treatment, in
14% of patients with radiation alone, and in
49% of all patients. The five-year absolute
disease-free survival was 3S% with surgery and
irradiation, 26% with surgery alone, and 0%
with radiation alone.
ETHMOID SINUS. Tumors in the ethomid sinus
tend to be extensive. Irradiation is quite effec-
tive. If the lesions are resectable, surgery is car-
ried out followed by postoperative irradiation.
Anterior and one or two lateral portals with dif-
ferential weighting are often used to irradiate
the ethmoid lesions.
Results of radiation therapy alone in treating
'lesions of the ethmoid sinus are limited. Elling-
wood and coworkers combined the results of
292 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
ethmoid with sphenoid sinus. Their five-year
control rate was five (56%) of nine. The five-
year absolute survival was 13 (50%) of 26 [77].
Cheng and Wang reported an absolute three-
year cure rate of zero of five with irradiation
alone, and two (33 %) of six with surgery and
postoperative irradiation [81].
SPHENOID SINUS. The treatment of malignancy
in this region is the same as that for the
nasopharynx. Tumors are rare in the sphenoid
sinus. The results of treatment in this region are
o.ften incorporated with the results for paranasal
SInuses as a group.
The results of treating paranasal sinus tumors
reported in the literature are summarized in
table 16-6.
Salivary Glands
MAJOR SALIV ARY GLANDS
The major salivary glands consist of the parotid,
submandibular, and sublingual glands. Tumors
of the major salivary glands account for about
4% of all head and neck neoplasms. Approx-
imately 25% of parotid tumors and 50% of
submandibular tumors are malignant.
Acinic cell tumors are slow-growing, low-
grade malignancies. They can recur 20-30 years
after incomplete resection. Mucoepidermoid
carcinomas can be low grade or high grade.
Adenocarcinoma, poorly differentiated carci-
noma, anaplastic carcinoma, and squamous cell
carcinoma behave aggressively. Adenoid cystic
carcinoma is characterized by its perineural in-
volvement. Lymphatic spread also occurs.
The lymphatic drainage of all three major
salivary glands empties into the jugulodigastric
and upper deep cervical nodes with an occasion-
al trunk draining directly to the middle deep
cervical nodes.
Treatment and Results. Low-grade malig-
nant neoplasms and small, high-grade lesions
may be treated by surgical resection alone. Post-
operative radiation therapy is added for low-
grade lesions with positive surgical margins or
recurrence, for most high-grade lesions, for
selected benign mixed tumors when residual
disease is present after an operation or recur-
rence, and for multiple regional node metastases.
Radiation therapy is used for inoperable tumors
with occasional success.
The radiation portals should include at least
(;\
/
FIGURE 16-6. Isodose curves from a pair of wedged
oblique photon portals to irradiate the parotid gland
with minimal radiation to the surrounding normal
structures.
the tumor bed and the ipsilateral upper neck for
parotid gland tumors, the entire ipsilateral neck
for submandibular gland lesions if the neck is
clinically uninvolved. The tumor dose is 6000-
6500 cGy postoperatively for suspected micro-
scopic disease, and 6500-7500 cGy for known
residual disease. Inoperable lesions require a
higher dose; an interstitial implant can be used
as a boost. The parotid gland can be treated with
a pair of wedged photon portals (figure 16-6)
or a single lateral portal with a combination
of electron and photon beams to spare the
contralateral oral cavity and parotid gland.
When perineural invasion is present, the portal
should be extended to cover the nerve path-
ways to the base of the skull.
The local recurrence rate of benign mixed
tumors after conservative excision or enuclea-
tion is approximately 20%. It can be substan-
tially reduced with the addition of postoperative
irradiation [82]. After superficial parotidec-
tomy, the recurrence rate is less than 5%.
Malignant tumors tend to recur locally after
an operation in about 30% of the cases for high-
grade lesions. Guillamondegui and coworkers
reported a 14% recurrence rate after postopera-
 16. RADIOTHERAPEUTIC MANAGEMENT OF HEAD AND NECK NEOPLASIA 293

TABLE 16-7. Local control of salivary gland tumors versus treatment modalities

Surgery Surgery and irradiation

Authors patient number (%) patient number (%)

Alaniz and Fletcher (1965) [84] 19/28 (68%)

Fu et al. (1977)[85] 26/36 (72%) 19123 (83%)
King and Fletcher (1971) [86] 43/46 (93.5%)
Rossman (1975) [87] 7120 (35%) 5/6 (83%)
Spiro et al. (1975) [88] 1631268 (61 %)
Shidnia et al. (1980) [89] 22/38 (58%) 21/30(70%)

tive irradiation for high-risk patients [83].
The results reported in the literature are sum-
marized in table 16-7. Byers and coworkers re-
ported 22 cases of submandibular gland tumors;
the local control was 64% and the survival was
50% [90].
The possible role of fast neutrons in the irra-
diation of salivary gland tumors was first de-
scribed in 1975 when Catterall reported control
rates as high as 90%. Most of the tumors in her
report were advanced [91]. Further studies of
this modality in major salivary gland cancers are
currently being carried out in North America.
MINOR SALIVARY GLANDS
Tumors of the minor salivary glands are uncom-
mon and tend to occur most often in the hard
palate, paranasal sinuses, and nasal cavity where
the minor salivary glands populate more dense-
ly than the other sites. Benign mixed tumors are
the commonest among the benign lesions of the
minor salivary glands. About two-thirds of the
malignant tumors are adenoid cystic. Perineural
spread is a frequent feature. Lymphatic spread
occurs in about 20% of adenoid cystic carcino-
mas. The incidence of lymph node involvement
increases in high-grade tumors (malignant
mixed tumors, adenocarcinomas, and high-
grade mucoepidermoid carcinomas) to 30%-
50%. At least 25% of the patients develop
distant metastasis.
Treatment and Results. The same treatment
philosophy for major salivary gland tumors ap-
plies here. For most lesions, 6500-7000 rad in
seven weeks to the primary lesion is indicated.
For microscopic disease, 5500-6000 rad is
usually adequate. The regional lymphatics are
electively irradiated depending on the histologic
grade and site of origin of the tumor.
Wang reported a three-year disease-free sur-
vival rate of 63% (20 of 32) when radiotherapy
was used to treat minor salivary gland malig-
nancies of the oral cavity and oropharynx. Five
of these 20 patients failed subsequently. Of
all failures, 88% occurred regionally. Distant
metastases alone occurred in 12% [92].
More detailed discussion of salivary gland
neoplasms and their management is presented in
chapter 13.
Chemodectoma or Paraganglioma
These tumors arise from specialized neuroen-
docrine receptors-paraganglia. They are his-
tologically benign, but the clinical progress is
malignant. Metastasis is rare, occurring in prob-
ably less than 5% of cases. As the tumors grow
slowly, they may erode bone by pressure and
wrap around or attach to important structures.
Carotid body tumors are usually located at the
bifurcation of the common carotid artery. As
the tumors expand, they may encircle the exter-
nal and internal carotid vessels, extending to-
ward the cervical spine, the base of the skull,
and the lateral pharyngeal space.
Temporal bone tumors are most commonly
found in the region of the jugular fossa and are
located in the adventitia of the superior bulb of
the internal jugular vein. They can also be found
along the course of the branches of the hypo-
glossal and vegus nerves. Names such as glomus
jugulare, glomus tympanicum, or glomus intra-
vagale are according to the sites of the tumors.
TREATMENT AND RESULTS
If a lesion can be removed without risk of
mortality or morbidity to normal structures,
surgical excision is satisfactory. Otherwise, irra-
diation is an alternative choice of treatment with
a high success rate and minimal side effects.
The slow rate of shrinkage led to the erroneous
belief that these tumors were radioresistant. In
fact, success should be gauged by the lack of
294 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
TABLE 16-8. Local control rate of chemodectomas with irradiation
Authors Tumor dose (cGy)
Smith (1970)[93J 3500
Hatfield et al. (1972) [94J > 4000
Tidwell and Montague (1975) [95J 4250-5000
Cole (1977) [96 J 4000-5000
Dickens et al. (1982) [97J 3760-5640
tumor regrowth and permanent improvement
in symptoms and signs rather than by angio-
gram findings alone.
Doses of 4000-5000 cGy in 4-5 weeks to the
tumor volume are commonly used to control
the disease. This dose range is below the toler-
ance of the surrounding normal tissues, includ-
ing the brain stem.
The results of irradiation reported in the
literature are summarized in table 16-8. Local
control I?eans regression and absence of disease
progressIOn.
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 17. CHEMOTHERAPEUTIC
MANAGEMENT OF HEAD AND
NECK NEOPLASIA
Muhyi Al-Sarraf
Head and neck cancer is a term that encom-
passes heterogeneous types of malignant tumors
occurring in heterogeneous groups of patients.
Histologically, squamous cell carcinoma is the
m()st common type. Because of this heter-
ogeneity, the natural history, disease-free sur-
vival, overall survival, and the local and regional
failure may vary from one report to another.
Surgery and/or radiation therapy are the most
proven effective methods of treatment for pa-
tients with early-stage disease. Surgery, when
applicable, may offer the most control of these
early cancers, but is associated with high de-
grees of morbidity and deformity, both func-
tionally and cosmetically. Radiotherapy for TI
and T2 lesions may provide an excellent cure
rate with good preservation of function; the
salvage rate with surgery for irradiation failure
is higher than it is for radiation after surgical
failure.
In patients with more advanced disease
(stages III and IV), surgery and/or radiotherapy
will control fewer head and neck cancers with-
out recurrence. The introduction of chemother-
apy has seen recent and significant development
in the treatment of these patients during the last
decade. Alone, chemotherapy has provided pal-
liation for some of these patients with recurrent
and metastatic disease. When combined with
surgery and/or radiotherapy, an improved sur-
vival may be obtained in patients with locally
advanced cancers.
Chemotherapy for Recurrent and
Systemic Squamous Cell Cancers of
the Head and Neck
A large number of single cytotoxic agents have
Peterson et aI., HEAD AND NECK MANAGEMENT OF THE CANCER PATIENT.
© 1986. Martinus Nijho/f Publishing. AU rights reserved.
been tested in patients with metastatic· head
and neck cancers and have shown antitumor
activity. These include, but are not limited
to, methotrexate (MTX), bleomycin (BLM),
cis-diamminedichloroplatinum II (cis-platinum,
or CDDP), 5-fluorouracil (5-FU), cyclophos-
phamide (CY), adriamycin (ADR), and vin-
blastine (VLB). Many combinations of agents
with or without CDDP have been tried in these
patients for the purpose of improving results of
chemotherapy Or decreasing drug toxicity.
Before addressing the results of these clinical
trials, it is very important to emphasize the im-
portance of factors that may affect the response
rate to chemotherapy (table 17-1) or the factors
that may affect the overall survival of patients
with recurrent and metastatic head and neck
cancers (table 17-2).
Response to systemic chemotherapy was
found to vary according to the primary site of
origin, previous therapy (whether surgery and/
or radiotherapy), performance status, and the
metastatic sites measured for such response-
local, regional, or systemic [1-7]. Previous ex-
posure to chemotherapy may influence the re-
sults of response to subsequent chemotherapy
[6, 7]. Other factors need to be reemphasized
when comparing results of different investiga-
tors.
1. Definition of response. Were only complete
and partial tumor responses reported or were
those patients with less than partial response
(minor response) included in such reports?
Were malignant lesions evaluable and mea-
surable (e.g., lung nodule) or only evaluable
(bone)?
2. Adequate therapy. The number of courses
299
300 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
given and the incidence of acceptable drug
toxicity before stopping such agents are also
important factors that may influence the re-
sponse rate.
3. Number and selection of patients. A small
number of patients treated, selection and ex-
clusion of certain patients, reports from a
single institution, and measuring response
rates only for evaluable patients but not all
entered patients on the study tend to give a
higher response rate and better results.
Many factors affect the results of the response
rate to chemotherapy; other factors may affect
the quality and the overall survival of these pa-
tients. Causes of death in patients with recur-
rent and metastatic head and neck cancer may
be related directly or indirectly to the disease,
therapy, or their complications, or even to un-
related disorders. Since the effectiveness of
chemotherapy is not only measured by the re-
sponse rate but the duration of survival for these
patients, it is very important to review the actual
cause of death of these patients.
SINGLE-AGENT CHEMOTHERAPY
The three most investigated single agents in pal-
TABLE 17-1. Factors that may affect the response rate
to systemic chemotherapy in recurrent and metastatic
disease
1. Performance status
2. Previous therapy
a. Surgery
b. Radiotherapy
c. Chemotherapy
1. adjuvant
2. palliative
3. Metastatic sites
a. Local
b. Regional
c. Systemic
4. Other
a. Primary site
b. Tumor differentiation
c. Type of response (CR, PR, MR)
d. Measurable disease vs evaluable disease
e. Adequate chemotherapy course; number of
doses; incidence of toxicity
f. Selection of patients
g. Number of patients treated; small series vs
large series
h. Single institution vs cooperative group
i. Evaluable patients vs entered
TABLE 17-2. Factors that may affect survival in recur-
rent and metastatic disease
1. Performance status
2. Response to systemic chemotherapy
3. Metastatic sites
4. Intercurrent disease
5. Complications of cancer or therapy
a. Aspiration pneumonia
b. Tumor bleeding
c. Other
6. Other
liative therapy of head and neck cancer patients
are MTX, BLM, and CDDP.
Methotrexate. MTX (table 17-3) is the most
studied agent in patients with recurrent disease.
The overall response rate ranged from 8% to
63 % in evaluable patients. In a collected large
series representing reports of single arm or
randomized trial in which MTX was utilized,
the overall response rate (complete response,
CR; and partial response PR) was 31 % (305/
988); the reported CR ranged from 0 to 15%.
Various dose schedules (low, intermediate,
high, and very high dose) were used with or
without leucovorin rescue. Woods et al. [23].
reported on 72 patients randomized to receive
weekly intravenous (i. v.) MTX at doses of 50
mg/m2, 500 mg/m2, or 5 g/m2. Toxicity was
most severe with the high-dose schedule. No
significant difference in duration of survival
among the three therapy groups was found. The
frequency and duration of such therapy varied
among reports. In spite of the wide range of re-
sponse rates and considering the factors that
may influence such a response, it is our opinion
that no real differences exist in the response
rates to different regimens. More important,
most of these reports do agree on the short
duration of response (median, three months)
and the overall survival of these patients treated
with MTX (median, six months). Also, most
studies reported that the survival of patients
who responded to chemotherapy was signi-
ficantly longer when compared with the sur-
vival of the nonresponders. The efficacy of
single-agent MTX in patients with metastatic
squamous cell cancer of the head and neck can
be assessed only by good randomized and well-
stratified clinical trials.
At Wayne State University, we gave MTX at
a dose level of 40 mg/m 2 i.v. weekly without
 17. CHEMOTHERAPEUTIC MANAGEMENT OF HEAD AND NECK NEOPLASIA 301

TABLE 17-3. Response rate to methotrexate in recurrent and metastatic disease

No.eval. %
Author Year patients No.CR No.PR Response
Drelichman et al. [4]
and Al-Sarraf [8] 1980 24 2 6 33
Amer et al. [6]. 1979 42 12 29
Bell et aI. [9] 1979 29 10 66
Capizzi et aI. [10] 1970 21 13 63
De Conti and
Schoenfeld ]5] 1980 161 8 32 25
Frei et al. [11] 1980 60 30 50
Hong et al. [12] 1983 17 4 24
Kaplan et aI. [13] 1981 61 16 26
Kirkwood et al. [14] 1981 49 21 43
Lehane et al [15] 1980 105 35 33
Lane et al. [16] 1968 27 4 10 52
Leone et al. [17] 1968 24 7 5 50
Mitchell et aI. [18] 1968 19 3 3 32
Papac et al. [19] 1967 15 8 53
Priestman [20] 1973 40 3 8
Vogler et al.[21] 1979 154 10 32 27
Williams et al. [22] 1982 68 24 16
Woods et aI. [23] 1981 72 2 21 32
Total 988 305 31

TABLE 17-4. Response rate to bleomycin in recurrent and metastatic disease

No.eval.
Author Year patients No.CR No.PR % Response
Bonadonna et al. [24] 1972 48 17 38
Durkin et aI. [25] 1976 81 4 6
EORTC[26] 1970 54 7 17
Haas et al. [27] 1976 64 12 19
Halnan et aI. [28] 1972 54 3 21 45
Yagoda et aI. [29] 1972 46 6 13
Total 347 6 67 21

rescue in patients with adequate renal function.
Our overall response rate (CR + PR) was 30%
for all patients entered and evaluated with eval-
uable and measurable lesions. The main drug
toxicity that we encountered with MTX was
myelosuppression; leukopenia (WBC < 4000/
mm3 ) occurred up to 75% of the time. Many of
these patients needed dose decrease according to
t?e severity and length of the myelosuppres-
SIon.
Bleomycin. BLM is another well-studied sin-
gle agent in patients with squamous cell cancer of
the head and neck (table 17-4) and other sites.
BLM was mainly given intramuscularly (i.m.)
or by i.v. infusion (bolus) on a weekly or twice-
weekly frequency. BLM was given by infusion
for 72-120 h when given with other agents. The
overall response rate to this agent was 21 % (73/
347). The complete response rate was 2% (6/
347). Besides mucositis, skin toxicity, fever and
chills, and myelosuppression, the most serious
toxicity was pulmonary. Because of the threat
of this side effect, many head and neck cancer
patients with poor or borderline pulmonary
functions were usually excluded from BLM
therapy. No statistically significant differences
were found with regard to response rate or de-
grees of toxicities due to BLM whether it was
given by i.m. or i.v. route [27]. At the present
302 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA

TABLE 17-5. Response rate to CDDP in recurrent and metastatic disease

No. eval. No. No. %

Author Year Dose schedule patients CR PR Response

Hayat et al. [30J 1978 100 mg/m2 q 3 wk 14 2 14

Hill et al. [31J 1975 0.5-2.5 mg/kg 31 7 23
q 5-10 d
Hong et al. [12J 1983 50 mg/m2 d 1&8 21 5 29
Jacobs et al. [32]"" 1978 80mg/m2/d 18 6 39
infusion 'I 3 wk
Panettiere et al. [33J 1980 50 mg/m2 d 1 65 5 11 25
&8q4wk
Randolph and Wittes [34J 1978 40 mg/m2 q wk 13 1 3 31
Sako et al. [35J 1978 120 mg/m2/d 15 2 3 33
q3wk
20 mg/m2/d x 5 15 1 3 27
Stephens et al. [36 J 1978 50 mg/m2 dl-8 48 3 10 27
q4wk
Wittes et al. [37J 1977 3 mg/kgq3 wk 26 2 6 30
Wittes et al. [38]"" 1979 120 mg/m2 q 3 wk 22 1 8 41
Total 288 17 64 28

* Includes previously untreated patients.

TABLE 17-6. Response to other major single agents in recurrent and metastatic disease
No: eval. ;Rang~ no. patients % Range % Overall
Agent patients In senes response response
Methotrexate 988 15-161 8-63 31
(table F-3)
Bleomr;;cln 347 46-81 6-45 21
(tab e 17-4)
Cis-p'latinum 288 13-65 14-41 28
}table 17-5)
5- luorouracil [3~ 118 15
PorfiromyclIi 40J
Vinblastine [4
ft
Cyclophosp'hami e [39J 77
75
35
36
15
29
Adriamycin [4 ~ 34 24
5- UD
CCNUf I]
rO, £
H pdroxlurea 1J
IJ
18
40
34
39
8
6
BCNU 41 12 25

time, BLM is used in combination with other
agents (especially vinca alkaloids and/or CDDP)
in patients with recurrent head and neck cancer
or as induction combined therapy before sur-
gery and/or radiotherapy for locally advanced
disease. Also, because of the radiation-sen-
sitizer property of BLM, it has been used with
radiation simultaneously to increase the local
and regional control rates and to improve the
results of using radiation alone in these patients.
Cis-platinum. CDDP is the most recently in-
troduced and effective agent in patients with
squamous cell cancers of the head and neck and
other sites. It has antitumor activity, even in pa-
tients previously treated with other chemother-
apeutic agents. As a single agent, many dose
schedules have been used as shown in table 17-
5. Some of the reasons behind the variations in
the doses have been to minimize the nausea and
vomiting, the renal side effects, or to establish
an outpatient schedule. The best accepted dose
is 100-120 mg/m2 i.v. with hydration and man-
nitol diuresis given every three weeks to pa-
tients with adequate renal function (creatinine
clearance> 60 ml!min).
In spite of the various dose schedules, the
overall response rate of the single-agent CDDP
 17. CHEMOTHERAPEUTIC MANAGEMENT OF HEAD AND NECK NEOPLASIA 303

in patients with head and neck cancer was 28%
(81/288). The range of response rate was 14%-
41 %; the response rate was higher if previously
untreated patients were included in these trials
[32, 38]. Because of the clinical response rate to
CDDP, combinations with BLM, and most
recently with 5-FU, are being used in patients
with recurrent cancer (see the section on Cis-
platinum combination) or as initial induction
therapy in patients with locally advanced head
and neck cancers.
Other Single Agents. Those presently on the
market have been tested in patients with recur-
rent head and neck cancers (table 17-6). Most of
these reports were from single institutions with
small number of patients included and as part of
the large phase-II trial of the agents. Antitumor
activity was reported with 5-FU, CY, por-
firomycin (analogue of mitomycin C), vinca
alkaloids, ADR, and nitrosoureas. Because of
the reports of antitumor activity of these agents
and of possible different action and side effects
from the commonly tested agents (MTX, BLM,
CDDP), these agents have been used as part of
combination chemotherapy in head and neck
cancers.
Investigational Agents. These continue to be
introduced for clinical testing; many have been
investigated in patients with head and neck
cancer (table 17-7). Most of these trials were
conducted in patients with recurrent cancer
who had been previously treated with many che-

TABLE 17-7. Response rate to investigational agents in recurrent and metastatic disease

No. eval.
Author Year Agents patients CR+PR %

Boccardo et al. [42] 1982 Thioproline 16 0 0

Campbell and 1980 Ftorafur 14 1 7
AI-Sarra£[43]
Chapman et al. [44] 1981 Mitoguazone
(Methyl GAG) 16 3
Creagan et al. [45] 1981 PAL A 19 0 0
[46] 1979 Maytansin 31 1 3
Forastiere et al. [47] 1983 AZQ 18 0 0
Kish and AI-Sarraf [48] 1983 AZQ 19 0 0
Kish and AI-Sarraf [49] 1983 Aclacinomycin 18 1 6
Papac and Fischer [50] 1971 Cytosine
arabinoside 20 4 20
Perry et al. [51] 1983 Mitoguazone
(Methyl GAG) 22 9 41
Ratanatharathorn 1982 m-AMSA 23 2 9
et al. [52]
Rozencweig et al. 1976 Triethylene
[40,41] Melamine (TEM) 16 2 13
1977 Hexamethyl-
melamine 81 9 11
Cycloleucine 11 1 9
5-FUDR 40 3 8
MeCCNU 43 5 12
Streptonigrin 22 2 9
Porfiromycin 75 11 15
Azotomycin 36 2 6
TMCA 14 1 7
VM-26 16 0 0
VP-16 40 0 0
Dibromodulcital 12 3 25
Bakers antifol 7 1 14
Shah et al. [53] 1982 ICRF-159 21 2 10
304 Ill. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA

motherapeutic agents. They constitute a small
number of patients from single institutions with
poor performance status. The overall response
rate reported is less than 10%; it is usually a
partial response and is of short duration. These
responses have occurred primarily in patients
who have not received previous chemotherapy
for recurrent disease due to certain disorders
that prevented the use of such active agents
(MTX, BLM, CDDP).
Since the response to known active single
agents or combination chemotherapy (other
than CDDP) in patients previously treated with
chemotherapy is very poor [6J, some of the
possible antitumor activity of the new agents in
head and neck cancer may be overlooked when
being used in phase-II trials when the majority
of the patients have previously received sys-
temic chemotherapy.
COMBINATION CHEMOTHERAPY
The tremendous success with combination che-
motherapy for patients with testicular cancer,
leukemia, and Hodgkin's disease led many in-
vestigators to test a combination of active agents
in the treatment of patients with recurrent head
and neck malignancies. Most of these trials rep-
resent a small number of patients from single
institutions. The overall response rate varied
from one report to another, but does not seem
any different when compared with single-agent
therapy. Unfortunately, neither the complete
response nor the overall survival were better
with the use of combination chemotherapy
versus single agents in head and neck cancer
patients. The incidence and degrees of drug
toxicities varied, depending on the type and
dose of each agent being used in the combina-
tion. To achieve better and more uniform com-
parisons of these trials, the following divisions
can be used.
Cyclophosphamide Combination. Since CY
as a single agent has shown activity in patients
with head and neck cancer, many CY combina-
tions have been reported in the last five years
(table 17-8). The overall response rate was 44%
(138/313), with a range of 11 %-69%. The num-
ber of patients in this series ranged from nine to
40. The common CY combination used was
with BLM, MTX, and 5-FU agents (five re-
ports). The overall response rates in these trials
were 11 %, 36%, 55%, 59%, and 69% [55, 56,
58, 59, 64]. Adding vincristine (Oncovin) to
this combination of CY, BLM, MTX, and
5-FU did not improve the response rate [59].
Mitomycin-C Combination. With the re-
ported activity of mitomycin C (mito-C) ana-
logue (porfiromycin) against head and neck
cancer [6, 66, 67J, mito-C combinations were
reported (table 17-9). These consisted of five
reports with a small number of patients in each
trial and with different other agents given, parti-

TABLE 17-8. Response rate to cyclophosphamide combinations in recurrent and metastatic disease

No. eval.
Author Year Agents patients CR+PR %

Amer [54] 1980 CyOB 14 8 57

Bianco et al. [55] 1978 CyBMF 9 1 11
Cortes et al. [56] 1980 CyBMF 40 22 55
Didolkar et al. [57] 1981 CyOBM 20 9 45
Fazio et al. [58] 1976 CyBMF 35 24 69
Holoye et al. [59] 1978 CyOBMF 22 11 50
Lester et al. [60] 1979 CyBMF 22 13 59
CyOBMA(L) 34 6 18
Livingston et al. [61] 1976 CyOBMMeA 28 12 43
Perry et al. [62] 1980 CyOBM 7 3 43
Presant et al. [63] 1979 CyABu 31 11 35
Stathopoulos et al. [64] 1976 CyBMF 25 9 36
Wittes et al. [65] 1977 CyBMA 26 9 35
Total 313 138 44
A, adriamycin; B, bleomycin; Bu, BeND; Cy, cyclophosphamide; F, 5-fluorouracil; L, leucovorin; M, methotrexate; Me, methylo-CCNU;
and 0, oncovin (vincristine).
 17. CHEMOTHERAPEUTIC MANAGEMENT OF HEAD AND NECK NEOPLASIA 305

TABLE 17-9. Response rate to mitomycin combinations in recurrent and metastatic disease
No. eva!.
Author Year Agents patients CR+PR %
Amer et a!. [6] 1979 MiOB 12 3 25
Porf,B 10 2 20
Miyamoto [66] 1978 MiB 33 22 67
Wheeler et a!. [67] MiOB 7 4 54
MiOBM 19 15 79
81 46 57
Total
B, bleomycin; M, methotrexate; Mi, miwmycin; 0, Oncovin (vincristine); and Porf, porfiromycin.

cularly BLM and vincristine (Oncovin). The
overall response rate with mito-C combination
was 58% (46/81) with a range of 20%-70%.
Nitrosourea Combination. The activity of
the single-agent nitrosoureas, BCNU, CCNU,
Or methyl-CCNU were reported in patients
with recurrent head and neck cancer [40, 44].
Combinations of these nitrosoureas were used
in these patients with an overall response rate of
36% (811223) (table 17-10). The response rate
varied from 26% (24/91) in a large trial at
cooperative-group level [15] to 50% (19/38) in a
small, single-institution investigation [68].
Cis-platinum Combination. Since the intro-
duction of CDDP in the mid-1970s and reports
of its activities in patients with squamous cell
carcinomas, including those arising in the head
and neck areas, many CDDP combinations
have appeared in the literature (table 17-11).
The most common CDDP combinations were
with BLM-with Or without vinca alkaloid
agents (vincristine Or vinblastine). The overall
response rate to CDDP combination in patients
with recurrent head and neck cancers was 43%
(246/577). The range for the overall response
rate was 13%-100%. All the studies were from
single institutions except one [22], which was
from a cooperative-group level and had 66
evaluable patients. Of interest are the response
rates reported to CDDP, CY, and ADR from
the same institutions: 64% (16/26) and 7% (11
14) [72, 73]. Differences in performance status,
dose schedule, and other factors may have
accounted for the differences in response rates.
At Wayne State University [1, 4, 8], the com-
bination of CDDP, Oncovin, and BLM (COB)
in selected patients with adequate renal and
pulmonary functions produced a response rate
of 50% (11122) and 40% (11127) in two con-
secutive trials. Using the same combination
with vinblastine (VLB) instead of vincristine,
Williams et al. [22] reported a 20% (13/66)
response rate while Perry et al. [82] reported a
response rate of 45% in 42 patients treated. The
combination of CDDP and 96-h 5-FU in-
fusion produced an overall response rate of
70% (21130) in patients with recurrent head
and neck cancers [2, 3]. The complete response
rate was 27% (8/30). These were patients with
good performance status; some patients had no
previous radiotherapy. This high response
rate with good complete remission to CDDP

TABLE 17-10. Response rate to nitrosourea combination in recurrent and metastatic disease
No. eva!.
Author Year Agent patients CR+PR %
Huang et al. [68] 1980 CCNU,MVB 38 19 50
Lehane et a!. [15] 1980 MeCCNu,MB 91 24 26
Livingston et a!. [61] 1986 MeCCNU,
MOBCyA 28 12 43
Presant et a!. [63] 1979 BCNU,CyA 31 11 35
Richman et a!. [69] 1976 CCNU,OBAN 35 15 44
Total 223 81 36
A, adriamycin; B, bleomycin; Cy, Cytoxan; M, methotrexate; N, nitrogen mustard; 0, Oncovin; and V, vinblastine.
306 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA

TABLE 17-11. Response rate to cis-platinum combination in recurrent and metastatic disease

No. evaL
Author Year Agents patients CR PR %

Amer et aL [I] 1980 COB 22 11 50

Amrein et aL [7] 1983 COB 33 1 9 30
Drelichman et aL [4] 1980 COB 27 3 8 4C
and AI-Sarraf [8]
Brown et aL [70] 1980 CVB 22 2 8 45
Caradonna et aL [71] 1979 CBM 19 3 11 74
Creagan et a!. [72] 1981 CACy 25 3 13 64
[73] 1981 CACy 14 1 7
Elias et a!. [74] 1979 CB 11 6 55
Ervin et a!. [75] 1981 CBM 11 3 8 100
Jacobs [76] 1981 CM 12 3 25
J akse et aL [77] 1981 CA 21 2 4 29
King et aL [78] 1979 COBM 29 3 4 24
Kish et a!. [2,3] 1982 CF 30 8 13 70
Kaplan et a!. [79] 1979 CBM 46 8 21 63
Kuten et aL [80] 1983 CBM 12 3 2 42
Murphy et aL [81] 1980 CBM 24 2 9 46
Perry et aL [82] 1982 CVB 42 6 13 45
Vogi and Kaplan [83] 1979 CBM 31 7 12 61
Vogi et aL r841 1982 CBMMi 34 5 15 59
Von Hoff et aL [85] 1981 CMB 22 6 3 27
Wittes et aL [86] 1975 CB 24 13
Williams et aL [22] 1982 CVB 66 13 20
Total 577 246 43
A, adriamycin; B, bleomycin; C, cis-platinum; Cy, cyclosphosphamide; F, 5-tluorouracil; M, methotrexate; Mi, mitomycin; 0, Oncovin
(vincristine); and V, vinblastine.

TABLE 17-12. Response rate to nonplatinum combinations in recurrent and metastatic disease

No. evaL
Author Year Agents patients CR+PR %

Amer et aL [6] 1979 AF 10 2 2C

Costanzi et aL [87] 1976 MBH 17 10 59
Eisenberger et aL [88] 1980 BH 20 9 45
Jacobs [89] 1982 MF 30 5 16
Pitman et a!. [90] 1980 MF 16 15 94
Raafat and Oster [91] 1980 MOBFHc 15 2 13
Price et al [92] 1978 MOBFAHc 85 57 67
Ringborg et a!. [93] 1983 MF 16 9 56
Thatcher et a!. [94] 1981 MBFA, VitA 25 10 40
Woods et aL [95] 1979 MOB 33 8 24
Yagoda et aL [96] 1975 MB 15 8 55
Total 282 135 48

A, adriamycin; B, bleomycin; F, S-fluorouracil; H, hydroxyurea; He, hydrocortisone; M, methotrexate; and 0, Oncovin.

 17. CHEMOTHERAPEUTIC MANAGEMENT OF HEAD AND NECK NEOPLASIA 307

TABLE 17-13. Response rate in randomized studies in recurrent and metastatic disease

No. evaI.
Author Year Agents patients CR+PR %
Drelichman et al. [4] 1980 M 24 8 33
AI-Sarraf [8] COB 27 11 40
De Conti and 1981 M 81 21 26
Schoenfeld [5] M(L) 80 19 24
M(L),CyCA 76 14 18
Holoye et al. [59] 1978 CyBMFO 22 11 50
CyBMF 22 13 59
Hong et al. [12] 1983 M 17 4
C 21 6
Kaplan et aI. [13] 1981 M 61 16 26
CBM 61 28 46
Kish et al. [97] 1983 CF, infusion 11 8 72
CF, bolus 7 1 14
Lehane et al. [15] 1980 M 105 35 33
MBMe 91 29 26
Williams et al. [22] 1982 M 68 11 16
CVB 66 13 20
B, bleomycin; C, cis-platinum; Ca, cytaradine, Cy, cyclophosphamide; F, 5-fluorouracil; L, leucovorin, M, methotrexate; Me, methyl-CCNU;
0, Oncovin (vincristine), and V, vinblastine.

and 5-FU needs to be confirmed. Also, we have
found that a CDDP combination is the most
effective chemotherapy in patients with naso-
pharyngeal carcinomas (regardless of the histo-
logic type) after radiotherapy relapse.
Other Combinations. Many other drug
combinations have been designed and tried in
patients with metastatic head and neck can-
cers (table 17-12). Most of these combinations
contain MTX and BLM with or without other
agents. The overall response was 48% (135/282)
with a range of 13%-94%. This high response
may reflect the good performance status of
these patients and some may have had no prior
therapy. Pitman et al. [90] reported a high re-
sponse rate in patients with advanced head and
neck cancers treated with combinations of MTX
and 5-FU. Recently, Jacobs [89], using the same
dose schedule in a larger number of patients, did
not confirm such a high response rate.
RANDOMIZED TRIALS
Considering the number of trials and reports
with single agents or combination chemother-
apy for patients with recurrent disease, only
eight randomized trials have been performed
and reported to date (table 17-13). Most ofthese
trials were based on randomization between a
single agent (MTX) and a combination of agents
using CDDP, MTX combinations, or both. [4,
8,12,13,15,22,97]. Only two trials compared
one combination with another [59, 97].
We reported on the randomized study be-
tween single MTX and COB with stratification
based on previous radiotherapy and a patient's
performance status (PS) [4, 8]. No differences
were found in response rate, duration of re-
sponse, or survival between the two groups. Re-
sponders to either therapy survived statistically
longer than nonresponders, as did patients with
good PS when compared with poor PS.
De Conti and Schoenfeld [5] compared MTX
with high-dose MTX with leucovorin rescue
with a combination of high-dose MTX with res-
cue, CY, and cytarabine and reported response
rates of 26% (21181), 24% (19/80), and 18%
(14/17), respectively. At the present time, no
combination has been reported to be better than
single-agent MTX for response rate and/or
overall survival of the patients treated.
In our experience, the PS was found to be the
important factor in determining the response
rate and subsequent survival of patients with
recurrent head and neck cancers treated with
chemotherapy [6]. The -response rate for pa-
tients with good PS (;;070%) was 32% (24174),
fair PS (50%-60%) was 19% (7/36), and poor
PS «50%) was 13% (5/38). The mean survival
in weeks for these groups were 28,16, and nine,
308 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
respectively (p=O.OI).
It is very important to have randomized,
stratified trials to test the efficacy of chemother-
apy in those patients with recurrent disease.
Stratification has to be done on the basis of PS,
previous radiotherapy, previous chemotherapy
(induction or palliative), and the sites of the
measurable lesions.
CHEMOIMMUNOTHERAPY FOR
RECURRENT AND METASTATIC
SQUAMOUS CELL CARCINOMA OF
THE HEAD AND NECK
Many attempts to improve the results of ther-
apy in patients with advanced and recurrent
squamous cell carcinoma of the head and neck
by using the combination of chemoimmu-
no therapy have been reported [98-110]. A
number of studies have shown that patients
with head and neck cancer had impaired
delayed-hypersensitivity reactions, a decrease in
the absolute lymphocyte count, and impaired
lymphocytic responses to mitogenic stimulation
[111-113] (see chapter 7). This immunodepres-
sion increases with advancing stages of the can-
cer and with prior surgical resection and/ or
radiation therapy. In addition to tumor burden
itself, alcohol, heavy smoking, malnutrition,
and weight loss (all important associated factors
in head and neck cancer) have been implicated
in the production of immunodeficiency [103,
114-116).
Many nonspecific agents that are known to
produce active stimulation of the immune
system have been used in combination with
chemotherapeutic agents, including: bacillus
Calmette-Guerin (BCG), MER, levamisole,
and Corynebacterium parvum. In 1973,
Donaldson [98] reported that BCG and iso-
niazid continued to show promise as adjuvant
to MTX in nonrandomized patients with
squamous cell cancer of the head and neck. Of
32 patients treated, 20 experienced greater than
50% (CR + PRJ regression of their malignant
disease. Many of these patients had no previous
therapy and some had previous surgical resec-
tion only.
Richman et at. [69] in 1976 reported on a
randomized study of patients with squamous
cell cancer of the head and neck; 14 received the
combination of BLM, ADR, CCNU, On covin,
and nitrogen mustard (BACON) and 20 pa-
tients received the same regimen plus BCG by
scarification. The response rate to BACON
alone was 50% (7/14, all PRJ while 8/20 (40%)
responded to BACON + BCG (3 had CR). No
statistical difference was found in the duration of
response between the two groups. Significantly
longer survival was reported in favor of patients
treated with BACON plus BCG (p=0.014) as
compared with survival of patients treated with
BACON alone. Five toxic deaths due to therapy
occurred in the first eight weeks; four of these
occurred in the patients treated with BACON
without BCG. Although this study was ran-
domized, it was not stratified to important prog-
nostic factors; there was unequal distribution of
patients on each arm (14 vs 20) and overall a
small number of patients was included in either
group. There were subsequent reports [99] from
the same institution on the results of BCG
adjuvant immunotherapy in 100 patients with
squamous cell cancer of the head and neck. Five
separate studies were carried out, including
single-agent (MTX) or combination (BACON)
chemotherapy alone and with INH and/or
BCG. No statistically significant differences
were found in regard to patient response, remis-
sion duration, or overall survival regardless of
whether BCG was used or not.
Well-controlled trials reported by Woods et
al. [100], Papac et al. [103], and Buechler et al.
[105] failed to support the possible advantage of
using BCG with chemotherapy for response,
duration of response, or survival versus che-
motherapy alone in patients with advanced or
recurrent head and neck cancers.
Zbar et al. [108] reported that intralesional
injection of BCG or BCG cell walls caused re-
gression of established tumors and prevented
the development of cervical lymph node metas-
tases in inbred guinea pigs after injection of
tumor cells into buccal pads.
Randomized trials with MER or C. parvum
and/or chemotherapy in patients with advanced
or recurrent squamous cell cancer of the head
and neck failed to demonstrate the advantage
of immunochemotherapy over chemotherapy
alone for response rate, response duration,
survival, or severity of toxic effects.
In spite of the early good report with non·
randomized trials with the use of BCG, INH
and MTX in patients with advanced head ane
neck cancers, larger randomized studies failec
to show such advantage over chemotherap)
alone.
 17. CHEMOTHERAPEUTIC MANAGEMENT OF HEAD AND NECK NEOPLASIA
INTRAARTERIAL CHEMOTHERAPY FOR
HEAD AND NECK CANCER
Intraarterial chemotherapy would seem to be
ideal for the treatment of patients with head and
neck cancers because of the accessibility of arte-
rial blood vessels and the frequently localized
nature of the malignant disease. Intraarterial in-
fusion of chemotherapy has been used alone in
patients with recurrent head and neck cancers or
with radiotherapy in the treatment of unresect-
able head and neck malignant tumors [117-
133]. Several approaches and different single or
combined cytotoxic agents have been used for
infusion chemotherapy to head and neck cancer.
The most commonly used drugs are MTX, 5-
FU, BLM and, more recently, CDDP. When
these agents are used with radiation therapy in
patients with advanced and unresectable lesions,
the chemotherapy is used for two purposes: (a)
cytotoxic and (b) possible radio sensitizer and/
or potentiator effect.
The possible advantages of the intraarterial
chemotherapy infusion are to deliver a higher
concentration of the antineoplastic agent to the
tumor region and to decrease the systemic
toxicity. To assure such decrease in systemic
side effect of methotrexate when used intra-
arterially, oral or i.m. antidote leucovorin has
been used.
Most of the complications are local, and due
to the cytotoxic agent used and/or related to the
use of the indwelling catheter. Those due to
chemotherapy include mucositis, dermatitis,
and pain. Patients usually require prolonged
hospitalization with constant nursing care and
patient cooperation to keep the catheter in
place. Some of the local complications include
clotting, breaking or kinking of the catheter,
possibility of air embolism, hemorrhages, and
infection at the site of the catheter. One of the
more serious problems with intraarterial che-
motherapy infusion to the head and neck cancer
is that of neurologic complications.
To overcome some of these sequelae, the
transfemoral artery has been used for intermit-
tent infusion of cytotoxic agents like CDDP,
and a percutaneously refillable, totally implant-
able pump has been used for continuous infu-
sion of chemotherapy at a uniform rate [131].
Most of the studies reporting the use of in-
traarterial chemotherapy in patients with head
and neck cancer are single-arm trials with selec-
tion of the patients treated. The overall response
309
rate reported was slightly higher than when the
same agent was used systemically. Matras et al.
[134] reported a~ response rate of 65% in 31
patients with inoperable cancers treated with
intraarterial infusion BLM and MTX with
radiotherapy versus 20% in 30 patients treated
with i.v. BLM and Cytoxan plus radiotherapy.
However, four of 31 and 11 of 30 intraarterial
and i. v. groups, respectively, did not receive
radiation therapy because of huge tumor size
and poor general condition. Because of the lack
of well-randomzied and stratified studies to
show the real advantage of intraarterial therapy,
and because of the complications and/or cost
associated with the procedure, the efficacy of
intraarterial chemotherapy for patients with re-
current or unresectable head and neck cancer
needs to be proven.
Chemotherapy for Previously
Untreated Squamous Cell Cancers
of the Head and Neck
In patients with locally advanced head and neck
cancers (stages III and IV), the combination of
surgery and radiotherapy (preoperative or post-
operative) has been used to improve the in-
cidence of local control and eventually the
survival of these patients. In patients with un-
resectable disease, radiotherapy has been the
accepted primary modality for possible reduc-
tion of tumor volume and to increase the
chances of subsequent surgical resection. Un-
fortunately, the overall survival of this group of
patients continues to be poor; further clinical
trials are needed to improve the length and the
incidence of cure. In an attempt to achieve
better results, chemotherapy has been added as
part of the multimodality therapy for patients
with locally advanced head and neck cancers.
Before discussing the results of combining
chemotherapy with surgery and/or radiother-
apy, it is very important to stress the factors that
may influence the end results of such trials.
If chemotherapy is used as initial induction
therapy before surgery and/or radiotherapy,
many factors may affect the response rate (table
17-14). The most important factor is the actual
stage of the head and neck cancers in T and N
terminology. Stage-III cancer is composed of at
least four groups-T1N1Mo, T 2 N 1M o, T3NoMo,
and T 3N 1M o-while stage-IV disease is com-
posed of more than 12 groups and subgroups.
310 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
TABLE 17-14. Factors affecting response rate to
induction chemotherapy in previously untreated
patients
1. Stage
2. Performance status
3. Tumor differentiation
4. Site of primary cancer
5. Type of chemotherapy
6. Number of courses
7. Single institution vs cooperative group
8. Other
TABLE 17-15. Factors that may affect survival of
patients receiving induction chemotherapy
1. Stage
2. Performance status
3. Tumor differentiation
4. Response to chemotherapy
5. Type of response to chemotherapy
6. Other
The overall response rate (especially the com-
plete response rate) to induction chemotherapy
may differ according to the T and N stages of
the cancer. As noted previously, another impor-
tant factor that may influence the reported
response rate to chemotherapy is that single-
institution results usually have a higher re-
sponse rate than the same chemotherapy used
in a cooperative group. Many factors may
influence the results of the single-institution
studies, including the selection of patients, PS,
and the number of patients treated.
In patients treated with multimodality ther-
apy, many factors may influence the disease-
free survival and the overall survival results
reported (table 17-15). The PS and the actual
T and N stages of the disease are the most im-
portant factors. Other possible factors that may
influence the survival of these patients are: the
high incidence of second primaries, particularly
in the head and neck area, esophagus, and/or
lung; the incidence of intercurrent disease; poor
follow-up of these patients; and refusal of ther-
apy, especially surgery.
In combination with surgery and/or radio-
therapy, chemotherapy has been used as initial
induction therapy, combined with radiotherapy
as sensitizer or potentiator or given following
surgery and radiotherapy.
COMBINATION OF CHEMOTHERAPY
AND RADIATION
Combined Chemotherapy Agents and Radio-
therapy. The combination of vincristine,
BLM, and MTX with irradiation was used by
Clifford et al. [135] and O'Connor et al [136].
The initial protocol [135] goal was to give six
courses of chemotherapy but, because of the
associated severe mucositis and dysphagia, the
number of chemotherapy courses was reduced
to four. The area maximally affected was related
to the treatment fields and mucositis presented
as a problem for some patients after the admi-
nistration of two courses of chemotherapy and
about 3000 cGy. In some patients, the treatment
was delayed for days because of this reaction.
Other side effects included alopecia, derma-
titis (confined to the irradiated fields), and
peripheral neuropathy. Disease-free survival of
the combined groups was 66% at 12 months
and 52% at 24 months. This was statistically
significant when compared with historical con-
trol patients treated with radiotherapy alone
who had disease-free survival of 35% and 26%
at 12 and 24 months, respectively. Overall sur-
vival for the combined group was 76% and 61 %
at 12 and 24 months and for the irradiated his-
torical group 63% and 39% (p=0.05). A recent
report on these patients [136] with longer
follow-up continued to show the advantage of
combined chemotherapy and radiation over the
historical control of only radiotherapy has been
done.
Bezwoda et al. [137] found in a randomized
trial that the overall response rate to radiother-
apy or radiotherapy plus combined chemother-
apy was not significantly different. However, a
significant difference in survival was found in
favor of the combination group. The degree of
stomatitis suffered by the combined group was
greater than in those treated with radiother-
apy alone. The hematologic toxicities were also
higher, with one death in the combined group.
Malaker et al. [138] used split-course radiation
and kinetically based combination chemother-
apy for treatment of stage-III and stage-IV head
and neck cancers. Of 29 patients, 23 had com-
plete remission of their primary tumor, but in
the regional nodes, the larger the tumor mass,
the less was the incidence of complete remis-
sion. Overall toxicity was higher, especially
weight loss and mucositis.
The combination of vincristine, BLM, and
 17. CHEMOTHERAPEUTIC MANAGEMENT OF HEAD AND NECK NEOPLASIA
MTX produced a complete response rate of the
primary tumor of 6%; this increased to 46%
after irradiation and was reported by Marcial et
al. [139]. The level of toxicity they reported was
acceptable. Smith et al. utilized BLM, ADR,
and 5-FU with radiotherapy and reported 66%
(20/30) complete response rate and 34% partial
response in patients with advanced head and
neck cancer who completed the treatment
schedule [140].
Hydroxyurea and Radiotherapy. Hydroxy-
urea, at concentrations having no effect on cells
in other stages of the cell cycle, was first shown
in Chinese hamster cell cultures to inhibit DNA
synthesis, selectively killing those cells that
were synthesizing DNA [141,142].
Hydroxyurea, combined with radiation ther-
apy in patients with locally advanced head and
neck cancer, has been tried by many investiga-
tors [143-148]. This drug was chosen because it
blocks cells at the G 1-S border in addition to its
cytotoxic effects; consequently, blocked cells
became sensitized to irradiation and were fur-
ther sensitized when the drug was present after
exposure [149, 150].
Richards and Chambers [144] found that the
survival of patients who received hydroxyurea
and radiotherapy with or without surgical re-
section was better when compared with those
patients who had radiation therapy alone. In
comparing survival between the two groups at
each site of primary tumor, the same results
were obtained. This study was neither ran-
domized nor stratified for important prognostic
factors.
Stefani et al. [145] reported on a randomized
double-blind trial of hydroxyurea compared
with placebo in conjunction with radiotherapy
for patients with head and neck cancer. Com-
parison of the two groups for primary tumor
regression, regional node response, and survival
failed to show statistically significant differ-
ences. Increased reactions (mucositis, epidermi-
tis, edema, and bone marrow suppression) were
observed with the hydroxyurea group as com-
pared with the placebo group. Distant metas-
tases subsequently developed in 22.8% (13/57)
of the hydroxyurea group and in 7.5% (4/53) of
the placebo group.
Methotrexate and Radiotherapy. MTX,
given orally or i.v. prior to radiotherapy in
patients with locally advanced head and neck
311
cancer has been studied by many authors [151-
1561-
Friedman et al. [153] reviewed their experi-
ence with oral or i.v. MTX followed by
radiotherapy and came to the conclusion that
the addition of MTX had only a minor impact
on the cure rate of these patients when com-
pared with radiotherapy alone.
Lustig et al. [154] reported on a group of 75
patients randomized to i.v. MTX plus radiation
or radiation alone and found no significant sta-
tistical difference between the two groups in the
three-year survival rates. In another group of 48
patients treated with oral MTX prior to radia-
tion therapy, a statistically significant improved
survival was reported. The number of patients
developing oral toxicity from MTX was signi-
ficantly greater (p=0.001) in the oral MTX
group (43/48, 90%) than in the i.v. MTX group
(10/36, 28%). There was no relationship be-
tween the severity of oral toxicity and survival.
Fazekos et al. [151, 152] reported on the exper-
ience of the Radiation Therapy Oncology
Group (RTOG) with a combination of MTX
followed by radiation (312 patients) or defini-
tive radiotherapy alone (326 patients). No sig-
nificant differences were found in the results
between the two groups. The number of annual
deaths among the two randomized arms was
essentially equal during the five-year follow-up.
Median metastasis-free survival was 12-13
months in both categories. Mucositis and delay
of radiotherapy occurred more commonly with
the combined therapy group. The ability to
control cancer among the largest of the two
groups was largely a function of tumor size (T
and N) with superior clearance among T3-T4
primaries of the oropharynx (66% of 354) con-
trasted to 48% of 146 oral cavity tumors. The
extent of the nodal involvement had significant
impact on survival.
Other reports on i.v. MTX with radiation
therapy in the treatment of patients with head
and neck cancer have described variable results
[157-159]. Although MTX has been widely
used for many years in patients with head and
neck cancer, there is still conflict over the opti-
mum dose and the frequency of administration.
In most of the above studies, MTX was given
before radiation-presumably to minimize the
development of mucositis. It is possible that the
time and dose of MTX may be crucial if im-
proved results are to be obtained.
312 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
5-Fluorouracil and Radiotherapy. 5-FU
administered systemically [6] or by intraarterial
infusion [160, 161] was found to have antitumor
activity in patients with head and neck cancer.
When 5-FU was combined with radiotherapy,
the results demonstrated a concentration-
dependent enhancement of the effect of radia-
tion on both tissue culture and animal tumor
systems [162-164]. Lawton et al. [165] were
encouraged by the results obtained with intra-
arterial infusion of 5-FU and concomitant
radiotherapy. Gollin and Johnson [166] re-
ported on the utilization of preradiation in-
traarterial 5-FU infusion in 54 patients with
advanced head and neck cancer compared with
the same number of patients treated with irra-
diation only. This was not a true randomized
study and, in some patients, preplanned neck
dissections following radiotherapy were per-
formed; in other cases, surgery was performed
following the failure of radiotherapy to control
their disease. Three patients had no gross
evidence of residual disease following 5-FU
infusion, but biopsies in each case were positive;
27 patients demonstrated a regression of 50%
or more (partial response) to the chemotherapy.
In spite of good regression with the 5-FU
intraarterial infusion, no difference in cure rates
or survival was noted between the combined
therapy groups and the radiation-only group.
There was a significant prolongation of sur-
vival for those patients who responded to intra-
arterial 5- FU infusion in comparison to those
who did not respond to chemotherapy.
A randomized study was reported by Lo et
al. [167] on the combination of systemic 5-FU
and radiation therapy versus radiotherapy alone
in patients with advanced epidermoid cancer of
the head and neck. Both local control and sur-
vival were better in the combined treatment
group than in the group with radiotherapy
alone. However, the difference was statistically
significant only in the oral cavity cancer pa-
tients. Both acute and late complications were
also increased in the group of patients who re-
ceived combined therapy.
Bleomycin and Radiotherapy. Many investi-
gators have suggested that the combination of
BLM and radiotherapy would produce an im-
proved therapeutic effect since BLM causes a
scission of DNA and inhibits DNA synthesis as
well as DNA repair [168, 169].
Jorgensen [170] showed that the biologic
effect of BLM resembles that of x-ray irradia-
tion, indicating that the combination of ble-
omycin and radiotherapy may have a synergistic
effect.
Hansen et al. [171] reported on the use of
sequential BLM and irradiation on patients
with T3 cancers of the head and neck. Of 65 pa-
tients, 26 responded to BLM therapy for two
weeks and 73% of them were tumor free after
radiotherapy. Of those patients with minor re-
sponse to BLM, 50% were tumor free after irra-
diation. The overall tumor-free incidence after
sequential irradiation was 55%, compared with
45% tumor-free patients treated with simul-
taneous BLM and irradiation.
Shanta and Krishnamurthi [172] reported the
results of a randomized study in patients with
stage-III and stage-IV oral cancers utilizing
concurrent radiotherapy and intraarterial or i.v.
BLM versus radiotherapy and i.v. or i.m. dis-
tilled water. Patients with the combined therapy
had better response and survival as compared
with control. The most serious morbidity re-
ported was severe mucositis. Protraction of the
radiation and reduction of the individual drug
dose lowered the intensity of the reaction, but
never eliminated it.
Recently, Shah et al. [173] reported on the
effects of BLM and radiotherapy in patients
with head and neck cancers; 25 patients were
treated with this combination and were com-
pared with another 36 patients with head and
neck cancer treated with radiotherapy alone
during the same period. All patients were fol-
lowed for two years. The incidence of response
rate and survival was not statistically significant
between the two groups; however, the inci-
dence of mucositis with BLM plus radiotherapy
(83 %) was significantly more than that of
radiotherapy alone (50%).
Other investigators [174-182] reported differ-
ent results with the combination of bleomycin
and radiotherapy either simultaneously or se-
quentially. All reported on the higher incidence
of mucositis that resulted in prolonged treat-
ment time and/or disruption of the treatment,
especially in the bleomycin concurrent with
irradiation therapy group. No significant differ-
ence in the complete response rate with respect
to BLM dose and rate and no correlation be-
tween the degree of mucositis and response
were found [182].
The concept of combination chemotherapy
and radiation in the treatment of locally ad-
 17. CHEMOTHERAPEUTIC MANAGEMENT OF HEAD AND NECK NEOPLASIA
vanced squamous cell carcinoma of the head and
neck, particularly unresectable lesions, is attrac-
tive and may be useful when compared with
radiotherapy alone. The main problems,
however, are: (a) selection of the best agent(s),
(b) times and doses of the chemotherapy in rela-
tionship to radiation, (c) cumulative or additive
side effects (e.g., mucositis) that may interfere
with the delivery of each modality of therapy
and acceptance by patients, and (d) the need for
randomized and prospective studies with stra-
tification to prove the effectiveness of the com-
bined modality approach and to select the best
combination.
Although the most common single agents
selected for combination with irradiation in
treatment of patients with head and neck car-
cinoma were hydroxyurea, MTX, or BLM,
the efficacy of these agents combined with
radiotherapy is not yet established. Most of
these agents cause mucositis of the oral cavity,
which seems the most important factor in inter-
ruption of therapy; these agents may not be
practical in this type of combined therapy. It is
expected that the search for better and safer
agents to combine with radiotherapy will con-
tinue in the near future. These agents should
have the following characteristics when com-
bined with radiation:
1. Synergistic effects: when the combined effect
is greater than the simple addition of actions
of the individual therapy.
2. Potentiation: when the nontoxic doses of an
agent combined with radiation results in an
enhancement of radiation-induced tumor
damage.
3. Additive effect: enhancement of antitumor
effect, whereas the toxic effects are not en-
hanced.
CDDP and Radiotherapy. eDDP is one of
the chemotherapeutic agents that possesses
most of these characteristics (intra supra) and
seems one of the ideal agents to be tested in
clinical trials combined with radiotherapy for
patients with head and neck carcinoma. eDDP is
an active agent in squamous cell cancers of the
head and neck; it will not produce stomatitis
and should not interfere in delivery of radio-
therapy to the head and neck cancers. eDDP
possesses properties of radiosensitization that
have been observed both in vitro and in vivo
313
[183-190]. It has been suggested that the cyto-
toxic activity of eDDP is independent of cell
age; radiation enhancement is both dose and cell
cycle phase dependent [191]. The combination
of simultaneous eDDP therapy and radiation
for patients with advanced head and neck can-
cers is presently under way at Wayne State Uni-
versity, Detroit, Michigan, and the Radiation
Therapy Oncology Group (RTOG) [192].
ADJUVANT CHEMOIMMUNOTHERAPY
OF HEAD AND NECK CANCER
In patients who had good local control of their
head and neck cancer through more effective
radical surgery and radiation therapy, systemic
recurrences have caused an increased percentage
of therapy failures. Because of this, adjuvant
systemic therapy has been attempted to improve
these results.
The use of immunotherapy with or without
chemotherapy as adjuvant to standard therapy
of surgery and radiotherapy has been reported
by many investigators [193-195]. Taylor et al.
[193] reported on the use of MTX i.v. before
surgery and radiation and further chemotherapy
following surgery and radiotherapy for one
year. This group was compared with those pa-
tients who received the same amount and dura-
tion of chemotherapy combined with BeG that
was given intradermally on alternate sides of
the neck. Those patients randomized to immuno-
therapy whose tumor was available for vaccine
preparation were also given neuraminidase-
treated cells mixed with BeG every two weeks
for six treatments and then monthly for one
year. The recurrence rate for the chemothera-
py group was 50% and for the chemoimmuno-
therapy group was 35%. This difference was
not statistically significant. The overall num-
ber of patients (50) included in this study was
small; all sites, stages, and histologic differen-
tiations were included. Lack of a control arm
without systemic therapy precluded drawing any
meaningful conclusions from this randomized
study.
Szpirglas et al. [194] randomized patients
with tongue and floor of mouth cancers in re-
mission after initial treatment as follows: (a) no
treatment; (b) chemotherapy with MTX for two
years and BLM for a total dose of 450 mg; (c)
immunotherapy with subcutaneous or i.m. in-
jection of C. parvum every week for two years.
There was a delay in the onset of recurrences
in the groups receiving chemotherapy or im-
314 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA

munotherapy. However, no statistical differ-
ences were found between the three groups in
the disease-free survival. No statistical differ-
ences in survival were reponed after recurrence
of the disease, and patients who received che-
motherapy had the least favorable course after
recurrence of their disease.
In a randomized study, Wanebo et al. [195]
utilized levamisole versus placebo as an ad-
juvant to postsurgical resection; preliminary
analysis revealed no differences of statistical
significance in disease-free survival between the
two groups.
Since the application of immunotherapy in
other solid tumors has been disappointing and
the use of chemoimmunotherapy in good
randomized trials in patients with recurrent
head and neck cancers has had no advantage
over chemotherapy alone, the advantage of us-
ing adjuvant immunotherapy in patients with
head and neck cancers is in very serious doubt.
INITIAL CHEMOTHERAPY IN PATIENTS
WITH HEAD AND NECK CANCER
Because of the increased local toxicities with the
combination of chemotherapy and radiation at
the same time, attempts were made at using the
same agent(s) as initial therapy followed by
surgery and/or radiotherapy. In general, there
has been little evidence of improved survival of
patients with locally advanced head and neck
cancers as compared with historical control
[196-200].
With the introduction of CDDP as an effec-
tive agent in patients with recurrent cancers of
the head and neck, many trials were initiated
with CDDP combinations. Early results have
shown that previously untreated squamous cell
carcinomas of the head and neck are much more
responsive to this type of chemotherapy than is
recurrent malignant disease [1, 197].
In most of the studies, the combination of
CDDP and BLM was used [197, 201-203] or
was used in combination with other agents [75,
204-212] (table 17-16). CDDP combinations
have proven very effective in producing objec-
tive tumor response in patients with locally
advanced and previously untreated cancers.
Cytotoxic Agents and Response Rate.
CDDP alone in doses of 120 mg/m2 i.v. every
three weeks for no more than three courses
was given to 22 patients with previously un-
treated head and neck cancers [205]. Most of
these patients had stage-IV disease (19/22). Six
patients had no clinical node involvement. The
overall reponse rate was 40% with one (4%)
complete response and eight (36 %) partial re-
sponses.
The combination of CDDP and BLM given

TABLE 17-16. Response to induction chemotherapy with cis-platinum and bleomycin in previously untreated
cancer

No. eval. No.

Author Year Patients courses Agents CR PR %
Al-Sarraf et al. [204] 1979,81 77 2 COB 22 39 80
[211]
Amrein et al. [7] 1983 37 2 COB 2 23 67
Brown et al. [206] 1980 23 3 CVB 5 12 74
Elias et al. [74] 1979 22 1 CMB 4 12 73
Ervin et al. [219] 1981 29 2 CMB 7 22 100
Glick et al. [203] 1980 29 2 CB 14 48
Hong et al. [201] and Hong 1979,82 41 2 CB 7 22 73
and Shapshay [212]
Kloss et al. [202] 1981 16 3 CB 1 12 81
Kuten et al. [80] 1983 10 3 CMB 2 5 70
Randolph et al. (197] 1978 21 2 CB 4 11 71
Schuller et al. [214] 1983 58 1-3 CMOB 15 20 66
Spaulding et al. [215] 1982 50 2 COB 11 33 88
Tannock et al. [216] 1982 33 2 CMB 3 17 60
Vogletal. [217] 1982 22 2 CMB±MC 2 15 77
Wittes et al. [205] 1979 21 1 CMVB 10 48
C, cis-platinum; 0, Oncovin; B, bleomycin; Y, Velban; M, methotrexate; and Me, mitomycin C.
 17. CHEMOTHERAPEUTIC MANAGEMENT OF HEAD AND NECK NEOPLASIA
in 2-3 courses produced a response rate of
48%-81% (average 72/105, 69%) [197, 201-
203]. Complete response rates ranged from 0 to
21%.
The addition of MTX [150] and/or vinca
alkaloid agents (vincristine or vinblastine) [7,
80,205-207,209,211,216,219] given for 1-3
courses every three weeks did not improve the
overall response rate 78% (2811382) with a
range of 48%-100%. The complete response
rate ranged from 0 to 28%. Some of the patients
with clinically complete response had no viable
tumor after surgical resection or biopsy [207,
209,211].
Many patients with carcinoma of the head
and neck cannot take advantage of the high re-
sponse rates achieved with the above combina-
tions containing BLM because of their previous
smoking history and age. Pulmonary functions
cannot be marginal and still withstand therapy
with BLM. The pulmonary toxicity seen with
BLM is cumulative and irreversible. On this
basis, we felt the need for another drug to be
combined with CDDP for patients with locally
advanced head and neck cancers. We have re-
ported a 31 % response rate to single-agent 5-
FU given as i.v. push in advanced previously
treated head and neck cancer patients [6].
Because of the increased myelosuppression
associated with 5-FU bolus, we have favored
continuous 5-FU infusion [220].
In an attempt to avoid the pulmonary toxicity
of BLM and to maintain a high tumor response
rate, we chose two courses of the combination
of CDDP and 96h-infusion of 5-FU for pa-
tients with previously untreated head and neck
cancer [220, 221]. A total of 26 patients were
treated with this combination; all had epider-
moid carcinoma and all were clinically stage-IV
and inoperable; 50% (13 patients) had multiple
primaries of the head and neck or esophagus
TABLE 17-17. Response rate in three separate studies
Response COBx2
Complete 22 (29%)
Partial 39(51%)
Minimal 11 (14%)
None 5 (6%)
Complete!partial 61!77
(80%)
315
and many had poor pulmonary functions that
excluded them from higher-priority protocols
containing BLM; 24 patients had no previous
therapy and two had had previous radiotherapy
and had developed a second primary two and
seven years later, respectively.
The response rate we observed was 19.2% (5/
26) complete and 69.3% (18/26) partial, for a
total of 88.5%. Although all patients were
initially inoperable, six underwent resection
following chemotherapy and another six under-
went resection after chemotherapy and irradia-
tion. Toxicities were acceptable and all were
reversible without any fatalities. No impairment
was produced that precluded other therapies.
We started using three courses (every 21 days)
of CDDP and 12o-h 5-FU infusion in patients
with locally advanced head and neck cancers
[220,222-225]. The complete response rate was
54% (33/61) and in 39% (24/61) partial re-
sponse was achieved, with an overall response
rate of 93 %. Toxicities again were acceptable
and reversible [225].
Although the overall response rate to three
courses of CDDP and 120-h 5-FU infusion or
CDDP, oncovin, BLM (COB) combination
was no greater, the increase in complete re-
sponse rate with the three courses of CDDP
and 5-FU was statistically significant (p=0.04)
(table 17-17).
The overall types and severity of drug-
produced toxicities were not different between
the three studies (table 17-18). Fever, alopecia,
and pulmonary toxicity were more related to
the CDDP, Oncovin, BLM combination. High-
er incidence of leukopenia in the last group of
patients treated may be related to the three
courses of chemotherapy and/or simultaneous
radiotherapy to the second primary cancer of
the esophagus in five patients.
Since the start of trials with 5-FU infusion
CACP+96h CACP+120h
5-FUx2 5FUx3
5 (19%) 33(54%) p= 0.04
18 (69%) 24 (39%)
3 (5%)
3 (12%) 1 (2%)
23126 57!61
(88%) (93%)
316 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
TABLE 17-18. Drug toxicity in three separate studies
COB
Type [77]
Leukopenia 21 (27%)
Thrombocytopenia 3 (4%)
Nausea/vomiting 55 (71 %)
Diarrhea
Stomatitis 5(7%)
Renal 8(10%)
Skin 10(13%)
Fever 23 (30%)
Alopecia 40(52%)
Pulmonary 4(5%)
Phlebitis
and CDDP and the report of superior response
rate to the three courses, we searched the litera-
ture for a possible synergism between these two
agents. To our surprise, we found evidence dat-
ing back to 1971 of such synergism between
CDDP and 5-FU given daily for five days [226-
231 J. Schabel et al. [231] in 1979 reported no
additive toxicity to vital normal cells from the
combination of 5-FU and CDDP in mice.
Marked therapeutic synergism was observed be-
tween these two agents in mice bearing L1210
leukemia treated with CDDP alone, 5-FU
alone, or CDDP plus 5-FU [231]. These investi-
gators reported that 60% of the animals treated
with the drug combination were cured and the
median lifespan of the drug-treated mice dying
of leukemia exceeded the median lifespan of
those treated with either agent alone.
In summary, the CDDP combination pro-
duced high tumor response rate (80%-90%) in
patients with previously untreated advanced
epidermoid cancer of the head and neck. The
complete response rate was up to 54 % and the
drug toxicities were acceptable and reversible.
Number oj Chemotherapy Courses and the
Timing of Chemotherapy. Now that we have
more effective combinations and safer agents,
many questions need to be answered by further
clinical trials. One of these questions is the
number of courses of chemotherapy to be given.
In other words, what can be considered an
adequate trial of chemotherapy in multidisci-
plinary therapy?
In most of the reported series so far, up to
three courses of chemotherapy have been ad-
CACP+96h CACP+120h
5-FU[26] 5-FU [61]
7 (27%) 25(41%)
1 (9%) 7(11%)
19 (70%) 35 (57%)
8(13%)
2(8%) 7(11%)
7 (27%) 26 (43%)
2(3%)
1 (4%) 5(8%)
2(8%) 6(10%)
ministered; few workers have used only one
course of treatment. In all these series, the over-
all tumor response rate and the incidence of
complete clinical response had increased with
each course administered.
The present head and neck NCI contract
utilized one course of CDDP and BLM before
definitive surgery [232]. The response rates of
the first 113 patients receiving a single course of
induction chemotherapy were eight (7%) com-
plete responses and 47 (42%) partial responses
at the primary site (49% overall). Response of
neck nodes was separately assessed in 76 pa-
tients having clinically positive regional lym-
phadenopathy; 11 CRs (14%) 31 PRs (41%) of
the neck nodes were observed (55% overall).
Schuller et al. [214, 233] reported on the
response rate to induction chemotherapy with a
four-drug regimen in 58 patients with epider-
moid carcinoma arising in the oral cavity,
oropharynx, or hypopharynx. The overall che-
motherapy response rate was 66%, with 28% of
the responders having a complete response after
three courses of chemotherapy. The incidence
of response and the complete remission in-
creased with each course of therapy.
At Wayne State University, in three separate
and sequential studies, the overall response rate
and the complete tumor response clinically in-
creased with each course of induction che-
motherapy (table 17-19).
In our last study with three courses of CDDP
and 120-h 5-FU infusion, the complete response
was 54% and the overall response rate was 93%
in 61 patients treated. Even with this increased
benefit, we did not jeopardize these patients
with increased toxicity or the severity of these
 17. CHEMOTHERAPEUTIC MANAGEMENT OF HEAD AND NECK NEOPLASIA
TABLE 17-19. Incidence of response with each course of chemotherapy in the three separate studies
COB
Courses CR PR
One 3 42
(4%) (53%)
Two 22 39
(29%) (51%)
Three
Overall 61177
(80%)
side effects, as seen in table 17-18. This increase
in complete clinical response also increased the
incidence of histologically negative resections
(9) or biopsies (8); all those patients with nega-
tive resections after chemotherapy (12) are alive
and free of disease. Of patients treated with
three courses of CDDP and 120-h 5-FU infu-
sion, 13 of the 33 complete responders had sub-
sequent surgical resection. Nine of the 13 had
no histologic evidence of tumor either in the
primary site or in the radical neck specimeri.
Eight additional patients had biopsies made
prior to institution of radiotherapy that showed
no histologic evidence of residual tumor post-
chemotherapy. Patients with recurrent disease
beyond surgery or radiotherapy or dissemi-
nated epidermoid cancer of the head and neck
were treated with 6-8 courses of these combina-
tions with good results and acceptable toxicity
[234].
We feel that up to six courses of the combina-
tion of CDDP and 5-FU would be adequate
therapy with acceptable side effects; with in-
creasing benefit, this combination should pos-
sibly be utilized as induction chemotherapy or
as part of the multimodality therapy in patients
with previously untreated head and neck can-
cers.
Another very important point that needs to
be answered is the timing of chemotherapy in
relation to other modalities of therapy, especial-
ly surgery, in patients with resectable, locally
advanced head and neck cancers. Combination
chemotherapy was given first as induction to
test and objectively measure antitumor re-
sponse, to evaluate drug side effects, and to test
the feasibility of combining chemotherapy with
other accepted standard therapies (surgery and
317
CACP+96 h CACP+120 h
5-FU 5-FU
CR PR CR PR
1 16 2 25
(4%) (62%) (6%) (71%)
5 18 13 19
(19%) (69%) (37%) (54%)
22 11
(63%) (31%)
23/26 33/35
(88%) (94%)
radiotherapy). Now that the effectiveness of
induction chemotherapy and its safety have
been established, the question still needs to be
answered as to the timing of such effective anti-
tumor·modality-before surgery, after surgery,
or after surgery and postoperative radiotherapy.
We have just tested a pilot feasibility study for
the combination of radical surgery, following
by three courses of CDDP and 5-FU followed
by radiotherapy [235]. This study was carried
out in patients with resectable stage-III and
stage-IV epidermoid cancer of the head and
neck. Drug toxicity was acceptable and rever-
sible with no added complications during or
by completion of radiotherapy. Some of the
reasons that led us to select this route of timing
of chemotherapy in relationship to other mod-
alities of therapy were:
1. The type and extent of surgery for the same
site and stage of head and neck cancer may
not be the same for previously untreated
patients and those patients responding (up to
90%) to induction chemotherapy, especially
the complete responders as compared with
those with no therapy before surgery.
2. About one-third of the patients may refuse
surgical resection after response to induction
chemotherapy, especially the clinically com-
plete responders. Some patients refuse radio-
therapy and even further chemotherapy.
3. With the excellent overall response (80%-
90%) and a complete response of up to 54%
produced by induction chemotherapy on
advanced and bulky disease, we do hope to
have as good an effect with these agents after
surgery at the microscopic level of the dis-
ease.
318 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
4. Tolerance of chemotherapy with CDDP
alone or after one course of CDDP and BLM
followed by surgery and postoperative
radiotherapy in the recent NCI head and
neck cancer study was very poor. Therefore,
we elected to administer these effective com-
binations of chemotherapy before radiother-
apy.
In patients with unresectable head and neck
cancers, the timing of chemotherapy is less con-
troversial. Most studies use the CDDP com-
bination administered before total radiotherapy,
and usually before surgery, for persistent dis-
ease or at the time of local recurrence for pos-
sible salvage.
More recent studies at Wayne State Universi-
ty and the Radiation Therapy Oncology Group
as well as at other institutions are testing the
feasibility of combining CDDP and radiother-
apy simultaneously. The doses and frequency of
CDDP administration have varied between one
study and another. These and other innovative
ideas need further extensive trials to prove their
efficacy.
Responses to Chemotherapy as Predictors
for Response to Radiotherapy. During our
three consecutive trials since 1977 with initial
chemotherapy followed by surgery and/or
radiotherapy for patients with locally advanced
head and neck cancers, we observed that re-
sponse to chemotherapy predicted further re-
sponse to subsequent radiation therapy [236].
Patients with less than complete clinical re-
sponse to induction chemotherapy (partial or
no response) and who had measurable disease
clinically and received subsequent preoperative
radiation of 5000 cGy or total radiotherapy of
6600 cGy were evaluated. In 60 such patients, the
majority had stage-IV cancers; these patients
were treated initially with either COB [211] or
CDDP and 96-h 5-FU infusion for two courses
[220, 221] or CDDP and 120-h 5-FU infusion
for three courses [222,223, 225].
In 42 patients in whom partial tumor response
was achieved, only one (2.4%) did not respond
to further radiotherapy. The majority of these
patients were converted to complete remission
clinically by the radiotherapy and some even
had histologically negative specimens after
surgical resection.
In 18 patients who were considered as having
no response to initial chemotherapy, only one
(5.6%) responded to further radiotherapy and
lived more than three years. All other patients in
this group died within a 12-month period in
spite of the fact that many had salvage surgery
for persistent cancers.
No differences were found between the two
groups with regard to sex, age, stage of the can-
cer, site, tumor morphology, or type of che-
motherapy given. Other reports have confirmed
this finding [80, 139,216].
Factors that Influence Response to
Induction Chemotherapy
SEX. There was no statistically significant dif-
ference in the overall response rate or the inci-
dence of complete response based on the sex of
the patients. The response rate in females was
97% (28/29) and in males it was 84% (113/135).
The complete response rate was 42% and 36%,
respectively. Our patient population was drawn
from two hospitals, Harper-Grace of Detroit
and Veterans' Administration (VA) Hospital of
Allen Park, Michigan. All patients from the VA
Hospital were male and no differences were
found in response rates to induction chemother-
apy according to the hospital or between the
sexes of Harper-Grace Hospital patients only.
RACE. The overall response rate to initial che-
motherapy was not different in white patients
(88%) as compared with response rate in black
patients (84%) with locally advanced head and
neck cancer.
The clinically complete response rate in black
patients (41 %) was higher than complete re-
sponse to chemotherapy in white patients
(33%); however, this difference was not statisti-
cally significant.
SITE. Table 17-20 shows the response rates to
initial combination chemotherapy according to
the site of the primary cancer. The overall
tumor response ranged from 33% in patients
with unknown head and neck primaries and N3
neck disease to 90% in patients with cancer of
the tonsil. No statistical differences were found
in the overall response rate or the complete
response rate to systemic chemotherapy and the
site of the primary cancer.
MORPHOLOGY. The overall response rate to
initial chemotherapy in patients with well-
differentiated cancers of the head and neck was
79% (11114); in patients with moderately differ-
entiated lesions it was 85% (82/96) and in poor-
ly differentiated it was 88%. These differences
 17. CHEMOTHERAPEUTIC MANAGEMENT OF HEAD AND NECK NEOPLASIA 319

TABLE 17-20. Site and response to induction chemotherapy

Oral Pyriform
Response Tongue cavity SInus Tonsil Larynx Pharynx Unknown

CR 19 (42%) 10(30%) 5 (23%) 11 (52%) 9 (39%) 6(35%) 0-

PR 21 (47%) 19 (58%) 13 (59%) 8 (38%) 10 (44%) 9 (53%) 1 (33%)
MR 3 (7%) 2 (6%) 2(9%) 2 (10%) 3 (13%) 0- 2 (6%)
NC 2 (4%) 2 (6%) 2(9%) 0- 1 (4%) 2 (12%) O-
CR + PR/total 40/45 29/33 18122 19121 19123 15/17 113
(89%) (88%) (88%) (90%) (83%) (88%) (33%)

were not significant. The complete clinical
response rate to induction chemotherapy ranged
from 29% in patients with well-differentiated
tumors to 46% in patients with poorly differ-
entiated cancers. Again, no statistical differ-
ences were found between the complete re-
sponse rate and the tumor morphology.
STAGE. No differences were found between
the overall response rate and the stage of the
head and neck cancer. The majority of the pa-
tients included in our studies of induction che-
motherapy had stage-IV disease. During the last
trial of CDDP and 120-h 5-FU infusion for
three courses, we analyzed the patients in more
detail to evaluate the stage of the cancer and the
response rate to chemotherapy (table 17-21)
[225]. Again, no differences were found in the
overall response rate and the stage-III or stage-
IV tumors of the head and neck. At the same
time, no differences were found in the overall
response rate and the size of the primary lesion
(T) or of the regional node involvement (N). If
we compared the clinically complete tumor re-
sponse, the incidence dropped in the higher the
T or the N disease, it seems clear, as shown in
table 17-22, that it is the factor of the N disease
that influences the complete responses to che-
motherapy. In patients with T4NoMo disease,
TABLE 17-21. Stage and response to induction
chemotherapy of CDDP and 120-h 5-FU Infusion
Response Stage III Stage IV
CR 7 (78%) 26 (50%)
0-
PR 24 (46%)
MR 1 (1 %) 2 (4%)
NC 1 (11 %) O-
CR + PR/total 719 50/52
(78%) (96%)
TABLE 17-22. Stage-IV (T.N o_3 only) and complete
response to induction chemotherapy with cis-
platinum and 120-h 5-FU Infusion
Response T.N o T.N J T.N z T.N 3
CR 8 3
PR 9
NR
CR/total 819 112 112 3/12
(89%) (50%) (50%) (25%)
the complete response rate was 89% as com-
pared with those patients with T4N3Mo disease,
who had complete responses of only 25%.
Factors that Influence Survi'oal of Patients
on Multimodafity Therapy. It is very impor-
tant for any multi modality therapy or adjuvant
therapy to prove its effectiveness. This includes
not only the response rates to such therapy, but,
more importantly, whether this response rate
can be translated to improvement in disease-free
survival, quality of survival, and overall survival
of these patients.
RESPONSE TO INITIAL CHEMOTHERAPY AND SUR-
VIVAL. Patients on multimodality therapy had
initial chemotherapy of two or three courses
three weeks apart. Two weeks after the end of
the last chemotherapy, these patients usually
underwent surgery and/or radiotherapy. The
usual delay of starting the standard and defini-
tive therapy of surgery and/or radiation is 5-8
weeks.
In our first trial with two courses of COB in
77 patients with locally advanced head and neck
cancer, all patients had minimal follow-up of
two years. We found that responders to che-
motherapy (CR or PRJ had statistically better
survival than nonresponders to initial che-
320 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
motherapy; in spite of that, these patients had
the standard therapy subsequent to the comple-
tion of chemotherapy [210, 211]. Patients with a
complete response to induction chemotherapy
had a median survival of 80 weeks; patients with
partial tumor response had a median survival of
79 weeks; those patients who did not respond
to chemotherapy had a median survival of 35
weeks (p=0.004). The influence of response to
initial chemotherapy prior to definitive radio-
therapy or surgery also had been reported by
Ervin et al. [75].
There are at least two possible explanations
for the favorable influence of response to che-
motherapy and the survival of patients on mul-
timodality treatment. First, this positive in-
fluence could be real, since these patients have
their recommended standard therapy of surgery
and/or radiation after completion of chemo-
therapy. This will have to be proven by good
randomized studies. Second, the possibility
exists that responders to chemotherapy are being
selected as the better survivors of these patients
in spite of this high response to initial che-
motherapy. As we have seen, the response to
chemotherapy has predicted the further re-
sponse to radiation therapy. We believe that the
first possibility is the most probable explanation
for the positive effect of response to induction
chemotherapy and the improved survival of
these patients.
STAGE AND SURVIVAL. As mentioned above,
and as expected, the stage of the head and neck
cancer statistically influenced the survival of
patients or the multimodality therapy they
received that included initial chemotherapy,
regardless of the other factors (including re-
sponse to the chemotherapy) [210]. Patients
with stage-III disease had a median survival of
91 weeks compared with a median survival of 67
weeks for those patients with stage-IV cancer
(p=0.04). We are certain that the different types
of the stage-IV disease influenced the survival of
these patients; patients with stage TINa have
better possible survival than patients with stage
T4N3 disease.
MORPHOLOGY AND SURVIVAL. Although there
were no differences between the overall re-
sponse or the complete response rate to induc-
tion chemotherapy and the tumor morphology,
we found and reported [210, 211] statistical
differences in survival according to the tumor
differentiation. In our first trial with COB, the
median survival of 54 patients with moderately
differentiated epidermoid head and neck can-
cers was 85 weeks as compared with 45-week
median survival of those patients with poor
differentiated tumors. This finding may need
further documentation by other institutions and
by us, since we are evaluating those patients
treated with two or three courses of 5-FU and
CDDP. Statistical differences in survival and the
morphology of cancer are seen in spite of the
response to chemotherapy, the stage, the site, or
the subsequent treatment with surgery and/or
radiation.
In summary, the feasibility and the antitumor
effectiveness of CDDP combinations prior to
definitive surgery and/or radiotherapy have
been established. The definitive role of such
combinations in improving survival and the
quality of such survival needs to be proven with
good randomized and stratified national studies.
The timing of chemotherapy in relationship to
surgery and/or radiotherapy in an effort to
achieve the best results from the multimodality
approach has to be studied and evaluated.
The need for better and safer cytotoxic agents
and the need for evaluation of what is con-
sidered as adequate therapy with these agents
must continue to add to the improved results of
multimodality therapy. The possibility of de-
laying radiotherapy, or limiting the extent of
ablative surgery for cosmetic or other reasons,
(see chapter 15) needs to be evaluated in the fu-
ture.
Chemotherapy for Salivary
Gland Cancer
Tumors of the salivary gland are rare and are
usually treated with surgery and radiation
therapy. Disease-free survival and site of first
recurrence may vary according to the histologic
types (adenocarcinoma, mucoepidermoid carci-
noma, adenoid cystic carcinoma, etc.), tumor
differentiation, and completeness of initial re-
section [237].
When salivary gland cancers recur locally or
regionally beyond further surgical resection
and/or radiotherapy or systemically, chemo-
therapy has been used in these patients.
Because of the rarity of this type of cancer,
most of the reported series of chemotherapy for
palliative treatment are small and usually in-
volve various types of salivary gland cancers
and/or many types of combinations of che-
motherapeutic drugs that are administered.
 17. CHEMOTHERAPEUTIC MANAGEMENT OF HEAD AND NECK NEOPLASIA
Many single agents were found to have anti-
tumor activity and have been used singly or in
combination in treatment of patients with sali-
vary gland cancers [238-247]. The most com-
mon cytotoxic agents used are MTX, 5-FU,
ADR, CY, CDDP, and mito-C.
A recent review by Suen and Johns of 85
cases of cancers of the salivary gland treated
with chemotherapy indicated the overall re-
sponse rate was 42% [239). Higher response
rates in local-regional disease as compared to
distant metastasis was reported.
In patients with adenoid cystic cancer of the
salivary gland, responses have been reported to
ADR, CDDP, 5-FU, or to combination che-
motherapy [242-247].
For further discussion of salivary gland neo-
plasia, see chapter 13.
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1977.
239. Suen JY, Johns ME: Chemotherapy for sali-
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 18. ASSESSMENT OF SUCCESS OF
TREATMENT OF HEAD AND NECK
NEOPLASIA
R. Kim Davis
Stanley M. Shapshay
The assessment of success of therapy in head
and neck cancer has historically been a difficult
problem. Cancers arising in the head and neck
represent about 5% of cancers in men and 2%
of all cancers in women occurring in the United
States. The estimated number of cases of head
and neck carcinoma in 1981 in the United States
was approximately 37,000 while the number of
deaths was approximately 10,000. These num-
bers represent a small proportion of the total
number of cancer cases and mortality; because
of this, few institutions have an opportunity to
treat a large number of cases of head and neck
cancer. This problem is further compounded
because there are numerous sites of origin of
head and neck neoplasia in the upper aerodiges-
tive tract. When treatment of head and neck
cancer is classified by specific sites of origin,
even cancer centers with large numbers of pa-
tients find difficulty in accumulating very many
patients. For this reason, there are very few
prospective randomized studies of head and
neck cancer.
Difficulty in assessment of treatment also
arises because of the nature of the most com-
mon malignancy, squamous cell carcinoma.
This problem concerns cancer multicentricity
and differences in tumor behavior depending
upon the primary site of origin, and will be
addressed later in this chapter, as will melanoma
and salivary gland neoplasia of the head and
neck.
The TNM system of cancer staging from the
American Joint Committee on Cancer still re-
mains the common language in "classification"
and in end-result reporting, despite several
Peterson et al., HEAD AND NECK MANAGEMENT OF THE CANCER PATIENT.
© 1986. Martinus Nijho/f Publishing. All rights reserved.
drawbacks and inconsistencies [1] (see the
Appendix). Treatment success must be defined
for stages of cancer as determined by this
system.
In the last several decades, it has generally
been accepted that early squamous cell carcino-
ma of the head and neck (stages I and II) is cur-
able in high percentage (70%-90%) by either
surgery or radiation therapy. The choice of
which form of therapy to use has been a func-
tion of the age of the patient, the location of the
tumor, the functional outcome anticipated, the
morbidity of either procedure, the cost effec-
tiveness, and the clinician's bias. Before 1970,
squamous cell carcinomas in more advanced
stages (III or IV) were generally treated by
either irradiation or by surgical excision. Neck
disease was usually treated by radical neck dis-
section unless the nodes were unresectable.
During the last two decades, the flexible inter-
play of irradiation therapy and surgery has
evolved. Stage-III and IV cancer has usually
been treated by a combination of radiation ther-
apy and surgery, either preoperative irradiation
or postoperative irradiation. Most recently,
postoperative radiation therapy has been the
general treatment of choice.
The rationale of combining irradiation with
surgery for larger primary cancers or in multiple
metastatic neck disease has been based on the
fact that disease-free margins are often difficult
to obtain. Even radical surgical procedures can
fail at the margins, leaving diffuse microscopic
disease that is not resectable. Conversely, the
failure to eradicate all malignant cells despite
high dosages of radiation therapy has been felt
331
332 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
to be due to the large number of hypoxic cells in
a fungating tumor. The concept that surgery can
remove all but microscopic disease has been
coupled with the concept that irradiation suc-
cessfully will eliminate remaining tumor.
This chapter analyzes the success of treatment
of squamous cell carcinoma, with special atten-
tion given to stage-III and IV disease. The
analysis concentrates on the few prospective,
randomized studies that have been done; in
addition, it includes most of the major reported
clinical experiences of the last 2-3 years, espe-
cially addressing the role of "standard treat-
ment" (surgery and irradiation). This chapter
also focuses on the current role of chemo-
therapy in head and neck cancer; the National
Cancer Institute-sponsored study using cis-
platinum and bleomycin is the only large ran-
domized prospective study and is discussed in
some detail.
Multicentricity of Squamous
Cell Carcinoma
The concept of "field cancerization" was
presented originally by Slaughter in 1946 [2].
Tobacco smoking primarily and alcohol con-
sumption secondarily are considered important
etiologic factors inducing widespread dysplasia
and carcinogenesis. A recent prospective study
by McGuirt et al. found 14 (17%) of 81 head
and neck cancer patients to have synchronous
head and neck primary lesions [3]. In a study by
Gluckman and Crissman of 5337 cases of upper
aerodigestive tract carcinoma, a total of 736 pa-
tients (14%) developed second primary cancers
[4]. This study originated from the Neoplastic
Disease Registry based at the University of
Cincinnati and represented all head and neck
cancer cases in the greater Cincinnati area. The
cases seen only at the University of Cincinnati
Medical Center showed a 20.9% incidence of
second primary carcinomas [5]. Of the fully
evaluable patients, 351 of 548 patients had
metachronous second primary carcinomas
while 197 had synchronous carcinomas. The
five-year survival of single head and neck cancer
patients was 35% while the five-year survival of
multiple primary cancer patients was 22.3%.
The synchronous carcinoma patients had a five-
year survival of 27.7% and the metachronous
carcinoma patients had a 17% five-year sur-
vival. The lower survival with metachronous
carcinomas was felt to be due to the fact that
earlier treatment (i.e., especially with irradia-
tion) probably limited the ability to treat the
metachronous cancers. When laryngeal cancers
were analyzed, 2135 patients had 247 primary
lesions identified; 211 of these lesions could be
analyzed and, distressingly, 88 of these 211 had
second primaries that were found in the lung or
esophagus.
In the study by Shapshay et aI., 28 (19%) of
150 consecutive patients developed multiple
primary lesions [6]; 14% of these were synchro-
nous. They called special attention to the fact
that 11 (7%) of the 150 were esophageal cancers.
Almost all reports of therapy surveyed for this
chapter excluded patients from analysis who
were dying of second primary lesions, which
occurred at a 6%-8% frequency in these series.
Site-by-site Analysis of Primary
Squamous Cell Carcinoma
ORAL CAVITY
Analysis of treatment success in the oral cavity
has traditionally studied either the anterior
tongue or the floor of mouth. In a report by
Platz et al. in which 802 patients with carcinoma
of the oral cavity were retrospectively analyzed,
the overall success rate of treated patients at
three years was somewhat distressing [7]. Treat-
ment in this series consisted of surgery in 56.1 %
of cases, irradiation in 13%, and combined
surgery and irradiation in 19.6%; 11 % received
no therapy. Survival at three years with no
evidence of disease (NED) was 68% for stage-I
cancer (161 patients), 52% for stage II (241
patients), 39% for stage III (231 patients), and
17% for stage IV (169 patients). Interestingly,
an attempt was made to analyze T 1 patients
whose tumors infiltrated adjacent structures
versus those with no infiltration. In the group
with infiltrating Tl cancers without lymph node
metastasis, the three-year NED rate was 66%
compared with 48% in the group with infiltra-
tion.
Three reports dealing with anterior tongue
cancer are summarized in table 18-1 [8-10].
Particular attention should be directed to the
poor Tl NED rates when surgery and irradia-
tion are used as single modalities of treatment of
even early cancer.
The report by Marks et al. on results of treat-
ment of floor-of-mouth cancer presents some
interesting conclusions [11]. Treated were 826
 18. ASSESSMENT OF SUCCESS OF TREATMENT OF HEAD AND NECK NEOPLASIA
TABLE 18-1. Therapy for anterior tongue carcinoma (three-year NED status)
Surgery
Stage I 13126 (50%)
Stage II 6/18 (33%)
Stages III and IV 4/13 (31 %)
patients with floor-of-mouth cancer were
treated. Small surface lesions were treated by
local excision; small lesions invading the floor
of mouth without lymph node involvement
were treated by radiation therapy alone, while
larger lesions and palpable lymph nodes were
treated by preoperative irradiation and surgery.
In stage-I cancer, surgery gained control of the
floor-of-mouth lesions in only three of seven
patients initially, but in all seven with secondary
therapies; however, three of these four failures
were treated by segmental mandibulectomy.
Radiation therapy in stage-I cancer controlled
seven of 11 patients (two-year NED), while
nine of 11 were secondarily controlled. When
surgery and radiation were used in stage-I can-
cer, nine of ten were controlled. For stage-II
cancer, radiation controlled eight of nine pa-
tients. No stage-II patients were treated by
surgery alone. Surgery and irradiation were
used to control 15 of 17 stage-II patients. With
stage-III/IV cancer, radiation alone gained con-
trol of seven of 13 patients, whereas radiation
and surgery used together controlled 27 of 36
patients. In this series, 41 % of patients de-
veloped radiation complications. The authors
concluded that small-field external beam irra-
diation should be added to local surgical exci-
sion for even small surface lesions. They recom-
mended that radiation therapy only should not
be used for primary tumor treatment, but that
patients should have elective irradiation of all
primary sites. They also recommended elective
neck irradiation for No necks.
In an M.D. Anderson Hospital study of 104
patients with anterior floor-of-mouth cancer,
TABLE 18-2. Oral cavity therapeutic results
Surgery
Stage I 16/33 (48%)
Stage II 6/18 (33%)
Stages III and IV 4/13(31%)
333
Radiation Both
3/8 (37.5%) 14/18 (78%)
4/14 (29%) 20/30 (67%)
5/34 (15%) 7/13 (23%)
Guillamondegui et al. found the following rates
of success [12]: Stage-I and II cancer treated by
surgery alone had an 89% three-year NED rate.
The patients with stage-llII disease treated with
radiation alone had a 64% three-year NED. In
stage-IIIIIV disease, patients treated by surgery
only had a 56% three-year NED. Those treated
by irradiation alone had a 27% NED rate and
those treated with combined surgery and irra-
diation had a 50% NED rate.
These studies, summarized in table 18-2, call
into question the usually expressed belief that
stage-I and stage-II disease in this area can be
cured in the 70%-90% range using either
surgery or irradiation. Success rates were,' in
fact, much lower than this. All authors sug-
gestedthat the main site of surgical failure when
treating stage-I and II disease without neck dis-
section has been in the neck, and that the site of
failure using radiation therapy has been at the
primary. This leads to an apparent conclusion
that combined treatment should be used in
stage-IIII disease. Many clinicians would con-
sider this to be excessive therapy, especially for
stage-I disease. Some light on this problem may
be shed, however, by Yamamoto et al. [13], who
investigated the mode of invasion of oral cavity
cancer to determine the clinical course and sen-
sitivity to bleomycin therapy. Mode of invasion
is shown in table 18-3. Primary and secondary
metastases were found in nine (75%) of 12
T1NoMo cancers that had grade-IV (diffuse) in-
vasion versus only four (14%) of 28 in all other
grades. The best approach to TI cancer may well
be to locally excise the initial cancer (i.e., wide
local excision) and then base subsequent irradia-
Radiation Both
10/19(57%) 23128 (82%)
12123 (52%) 35/47 (74%)
12/47 (25%) 27/36 (52%)
334 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
TABLE 18-3. Mode of invasion (Jacobsson's criteria)
I. Well-defined borderline
II. Cords, less-marked borderline
III. Groups of cells, no distinct borderline
IV. Diffuse invasion
Cordlike invasion
tion therapy or no therapy on the mode of in-
vasion in the T J cancer.
Squamous cell carcinoma of the cheek mu-
cosa was addressed in a study of 121 patients by
Bloom and Spiro (14] in which 80 patients were
treated exclusively by surgery whereas other pa-
tients had combinations of preoperative irradia-
tion and surgery. Radical neck dissection was
performed in 49%,39 of whom had metastases
proven after histologic examination of speci-
mens. Survivals expressed by stage were 77%
for stage I, 65% for stage II, 27% for stage III,
and 18% for stage IV. The incidence of nodal
metastases was 11 % for stage I, 41 % for stage
II, and 56% for stage III. The authors recom-
mend surgery with postoperative irradiation for
all but the smallest T J lesions. It appears that the
necks should be treated prophylactically by
neck dissection or irradiation therapy in stage-II
to stage-IV -level cancers.
CARCINOMA OF THE TONSILLAR REGION
Radiation therapy has played a major role in
treatment of tonsillar carcinoma as well as
oropharyngeal carcinoma. Historically, TJ and
T 2 lesions of either site have been treated by
curative irradiation. Patients with stage-III and
stage-IV disease in these sites have been treated
either by curative full-course irradiation, with
surgery reserved for salvage, or by combined
treatment. Wang reported 75%, 50%, and 15%
three-year survival rates for patients with T],
T z, and T3 tumors, respectively, using such an
approach [15]. Horwitz and Boles reported an
absolute five-year survival rate of 46.6% with
radiation and surgical salvage [16], while Fayos
and Lampe successfully treated 39.8% of their
tonsillar tumors with irradiation therapy [17].
Tong et a!. reported on 104 patients treated
with radiotherapy with surgery reserved for
salvage [18, see chapter 16]. Their three-year
NED rates were 100% for patients with TJ
lesions, 74% for those with T2 lesions, 47%
for those with T 3 lesions, and 0 for those with
T4lesions. All patients who were stage T3 or T4
who were primary site failures failed to survive.
Neck disease was reported to be present in
25% of those with Tl lesions, 42% of those
with T2 lesions, 56% of those with T3 lesions,
and 94% of those with T4 lesions. Only three
of 27 patients who failed in the neck were
salvaged by surgery. This study reported that
tongue involvement decreased survival signif-
icantly. The three-year NED rate of patients
without tongue involvement was 55% versus
25% with those with tongue involvement.
The failure to control stage-III and stage-IV
disease with irradiation alone coupled to the
lack of ability to surgically salvage most of these
patients has led many clinicians to use a com-
bination of surgery and irradiation in stage-III
and stage-IV disease in this site. In a prospective
study reported by Shrewsbury et a!., 96 patients
were evaluated with cancer of the tonsillar re-
gion [19]. Radiation remained the primary form
of treatment for TJ tumors. T2 and T3 tumor
treatment was individualized depending on the
nature of the tumor. Patients with superficial or
exophytic tumors were treated with full-course
irradiation therapy, while patients with deeply
infiltrating primary cancers or palpable neck
disease were treated by combined therapy. All
infiltrating T3 and T4 tumors were treated by
combined therapy if the patients were operable.
Results of this series with three-year follow-up
are shown in table 18-4. The total survival for
T4 cancers was only 8%. In the stage-III group,
there were 11 patients who were T3NoMo and
treated by irradiation alone; only three of these
11 survived. The authors concluded that, even
in the group of patients previously treated by
irradiation alone (i.e., the T3NoMo patients),
these patients should, in fact, have combined
therapy. Similar results were reported by
Rabuzzi et al. in 58 patients treated with com-
bined therapy utilizing preoperative irradiation
TABLE 18-4. Tonsillar carcinoma therapeutic results
(three-year rates)
Radiation &
Radiation Surgery
Stage I 7/9 (78%) 5/5 (100%)
Stage II SilO (50%) 9/11 (81%)
Stage III 4127 (15%) 16121 (76%)
Stage IV OliO (0%) 113 (33%)
 18. ASSESSMENT OF SUCCESS OF TREATMENT OF HEAD AND NECK NEOPLASIA
[20]. All patients were analyzed at three years
after therapy. In stage-II disease, eight (100%)
of eight patients were alive with NED; in stage
III, 11 (78 %) of 14 alive with NED; and in stage
IV, eight (50%) of 16 alive with NED.
The other major oropharyngeal site of cancer
is in the base of the tongue, where most patients
have traditionally been treated by irradiation for
cure. Parsons et al. recently studied 89 patients
using primary irradiation with surgery reserved
for salvage [21]. Local control at two years was
gained in six (75%) of eight stage-I patients, ten
(67%) of 15 stage-II patients, 14 (64%) of 22
stage-III patients, and three (13%) of 24 stage-
IV patients. In this series, all patients with T2
and T 3 disease were treated by external irradia-
tion with either implants or external boost to
the primary site. Of the 36 patients who de-
veloped local failure in this series, 25 of 36 were
originally inoperable. Of the other 11, two pa-
tients could be salvaged. Of 39 patients with N2
and N3 neck disease, 19 were not controlled in
the neck by radiation therapy.
HYPOPHARYNX-PYRIFORM SINUS
Cancer of the pyriform sinus and of the hypo-
pharynx in general has been recognized to be a
very malignant tumor with a dismal prognosis.
Several recently reported studies support this.
Bataini et al. reported on 434 patients treated
with full-course irradiation with surgery reserved
for possible salvage [22]. In this group of pa-
tients, the three-year NED rate was nine
(24%) of 37 for Tl lesions, 21 (40%) of 53 for T2
lesions, and 84 (24%) of 344 for T 3 lesions. The
total three-year NED rate was 26%. The inci-
dence of locoregional failure was 229 (53%) of
434. Of these, 119 failed at the primary site, 40
failed in the neck only, and 70 had combined
failure in the primary site and neck. Ten patients
in whom salvage surgery was attempted failed
to survive. For T 1 and T 2 disease, local control
was gained in 65% (three-year NED) of pa-
tients who received greater than 6500 cGy, and
in only 36% of patients who received less than
6500 cGy.
In a series reported by Shah et aI., 340 pa-
tients were treated for pyriform sinus cancer of
whom 78% were treated by surgery only [23].
The overall five-year cure rate was 25%. In this
series, only 24 % of their patients had T 3 disease
and only 11 % had fixed nodes.
The inability to gain local control or achieve
335
significant survival with either irradiation or
surgery as a single modality has long been
recognized. When surgery was followed by
postoperative irradiation, the incidence of
locoregional failure reported by Fletcher was
only 4% [24]. Nonetheless, survival with the
combined therapy group has remained in the
30%-40% range. In a study by Persky and
Daly, 66 of 180 patients who received combined
therapy with preoperative irradiation and sur-
gery survived for five years whereas only one of
18 patients who received irradiation therapy
alone survived for five years [25].
Driscoll et al. reported a five-year NED rate
of 22 (31 %) of 70 patients [26]. In their series,
five (19%) of 26 patients treated with irradiation
alone had a five-year survival. Of those treated
by surgery alone, seven (39%) of 18 survived
for five years, while 16 (52 %) of 31 patients
treated with combined therapy had a five-year
NED rate. In this study, recurrences developed
loco regIonally in 77% of the irradiation therapy
only group, in 61 % of the surgery only group,
and 52% of the combined therapy group. A
study by EI Badawi et al. showed similar results
[27]. The two-year NED rate for surgery only
patients was 40% in the T 3 and T 4 tumors (81 of
203). For the radiation therapy only group, the
two-year NED rate was 23 (48%) of 48 with Tl
and T2 tumors. Patients treated with surgery
and postoperative irradiation had a 50% two-
year NED rate (23 of 46) whereas patients
treated with preoperative irradiation and sur-
gery had a 47% NED rate (eight of 17). When
failures above the clavicle were analyzed,
patients treated by irradiation alone had a 21 %
local regional failure rate (ten of 48) versus
those treated by surgery and postoperative
irradiation who had the before mentioned 11 %
local failure rate (14 of 125). Patients treated by
surgery only had a 39% local regional failure
rate (80 of 203) whereas those treated with pre-
operative irradiation and surgery had a 29%
(five of 17) local regional failure rate. The over-
all five-year survival was 25% in the surgery
only group and 40% in the surgery and post-
operative irradiation group.
The largest prospective randomized study
of head and neck cancer has been undertaken
by the Radiation Therapy Oncology Group
(RTOG) [28]. Their preliminary data in patients
with hypopharyngeal disease show 35 patients
randomized to a preoperative irradiation and
surgery group versus 38 patients randomized to
336 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
surgery and postoperative irradiation therapy.
These patients have been followed for an aver-
age of 20 months. Survival is 38% in the pre-
operative group versus 42% in the postopera-
tive group. Local regional control was obtained
in 51 % of the preoperative group versus 59%
in the postoperative group. Neither of these dif-
ferences is statistically significant.
In summary, while local regional control was
significantly improved in the onr study by
Fletcher using combined therapy with postop-
erative irradiation [24], no series has shown a
statistically significant improvement in survival
with any of the modalities of therapy. The
generally expressed opinion in the medical liter-
ature that combined therapy leads to better sur-
vival remains to be documented. It currently
appears that the best justification for combined
therapy in this group (probably best done with
surgery and postoperative irradiation) is that
fewer patients will develop local regional fail-
ure, resulting in improvement in their quality of
life.
LARYNX
Glottic Cancer. Analysis of success of therapy
in laryngeal cancer is a somewhat more pleasing
task, as patients generally have done better in
response to therapy. This analysis will be done
by comparing early cancer of the larynx (T \ and
T 2 ) in one group versus more advanced cancers
(T3 and T 4 ) in a second group. In addition,
laryngeal cancer will be divided into endo-
laryngeal cancer versus supraglottic and sub-
glottic cancer.
The mainstay of treating stage-I laryngeal
cancer has been irradiation therapy. Wang has
shown that full-course irradiation for early
laryngeal cancer is highly successful [29]. In
patients with normal true vocal cord mobility,
Wang showed that 240 (94%) of 255 patients
with lesions of the anterior two-thirds of the
vocal cord without anterior commissure in-
volvement were NED at three years. When pa-
tients presented with lesions of both anterior
cords and/or anterior commissure, 46 (82%) of
56 patients achieved a three-year NED rate.
When the lesion covered the entire vocal cord or
involved only the posterior one-third of the
vocal cord, 70 (75%) of 93 patients achieved a
three-year NED status. This shows a total re-
sponse rate of 88% in patients with normal cord
mobility. Patients with stage-II laryngeal cancer
who had impaired cord mobility showed only a
63% three-year NED rate. The poorer prog-
nosis of T \ and T 2 laryngeal cancer patients who
have impaired true vocal cord mobility has also
been shown by Chacko et al. [30] and Kaplan et
al. [31]. In the Kaplan series, these patients who
were treated by irradiation alone had a 50%
five-year NED rate versus an 87% rate when
treated by partial laryngectomy .
Early vocal cord cancer has been successfully
treated by surgery instead of irradiation ther-
apy. Lillie and De Santo reported 93 of 98
selected T\NoMo patients to be NED for five
years who were treated by transoral surgical
excision [32]. Of the five patients in their series
who developed recurrences, four were salvaged
by repeat transoral procedures while one patient
eventually required laryngectomy and subse-
quently died. Their experience in treating these
lesions showed that 20%-25% of the cancers
referred with a pathologic diagnosis of micro-
invasive disease on subsequent cordectomy
were found to have no cancer. This study raises
the question as to whether patients with early
T \ lesions who have excisional biopsy are not,
in fact, treated by the biopsy alone in significant
percentage. Subsequent irradiation therapy
would then represent overtreatment for these
patients.
Blakeslee et al. studied 84 patients who were
treated initially by transoral CO 2 laser limited
cordectomy [33]. These patients had laser ex-
cision of the surface epithelium down to the
underlying thyroarytenoid muscle done as the
initial staging (i.e., excisional biopsy) proce-
dure. In their series, patients with obvious thy-
roarytenoid muscle involvement were subse-
quently treated by irradiation or open partial
laryngectomy as were patients with positive
biopsies of the residual vocal cord after the
limited cordectomy. In their group, 35 patients
were sufficiently treated by the initial excisional
biopsy only. Of 35 patients, 31 (89%) achieved
a three-year NED status. Two of four patients
who failed were salvaged by irradiation for a
total NED rate of 94%. In addition, 15 of 15
patients with verrucous or spindle cell carcino-
ma treated by limited cordectomy were NED at
three years for a total three-year NED rate of 46
(92%) of 50 patients. The group of patients who
had laser excision and were found to have mar-
gins positive for carcinoma went on to receive
further definitive irradiation. Their three-year
 18. ASSESSMENT OF SUCCESS OF TREATMENT OF HEAD AND NECK NEOPLASIA
NED rate was 29 (85%) of 34. The five patients
in this group who failed irradiation underwent
total laryngectomy. Two patients were salvaged
and remained NED for a total NED rate of
91 %. In the total series, the overall three-year
NED rate was 94%.
The study by Lillie and De Santo, and that
by Blakeslee et aI., show that patients who are
carefully selected can be treated by limited
cordectomy through a transoral approach and
in significant percentage be saved the morbidity
of subsequent irradiation therapy. Radiation
therapy for all Tl lesions may, in fact, repre-
sent overtreatment and should be used more
selectively. This fact is further underscored by
Chacko et al. [30], who found an 11 % second
primary carcinoma rate in laryngeal cancer. To
save irradiation in these patients (particularly
younger patients) may enhance subsequent
treatment of their secondary lesions.
Treatment of stage-III and stage-IV laryngeal
cancer has been far less successful. These pa-
tients have been treated by full-course irradia-
tion, leaving surgery for salvage, either singly or
in combination with irradiation. Wang found
that only 13 (23%) of 56 patients with T3 endo-
laryngeal cancer achieved a three-year NED
rate with irradiation therapy alone [29]. Har-
wood and De Boer reported on 68 patients with
T 3 laryngeal cancer treated by irradiation with
surgery reserved for salvage and'showed a five-
year NED rate of 45% [34]. In the series of T3
laryngeal cancers reported by Kaplan et al., only
18% treated by irradiation alone achieved a
five-year NED status versus 80% who were
treated with preoperative irradiation and sur-
gery [31].
T4 laryngeal cancer has been poorly con-
trolled by any of the combinations of surgery
and irradiation or by either modality alone.
Supraglottic Cancer. Therapy for supraglot-
tic carcinoma as presented by Kirchner and
Owen [35] is summarized in table 18-5. The in-
cidence of decreased survival in stage-I disease
treated by surgery only was felt to be due to the
lack of regional therapy (neck dissection).
In a large European series, Skolyszewski and
Reinfuss showed a three-year NED rate of 67%
for patients with T 2 supraglottic carcinomas
treated by irradiation therapy [36]. In the pro-
spective randomized study of the Radiation
Therapy Oncology Group discussed earlier, 118
337
TABLE 18-5. Supraglottic cancer therapeutic results
Surgery Radiation Both
Stage I 9/21 (43%) 7111 (64%)
Stage II 6/8 (75%) 2/3 (67%)
Stage III 4/11 (36%) 3/7(43%)
Stage IV 2/5 (40%) 1/19 (6%)
patients with supraglottic carcinoma were ran-
domized to either the preoperative irradiation
and surgery group or the postoperative irradia-
tion and surgery group [28]. The overall surviv-
al at two years was only 54 (46%) of 118. Sur-
vival in the preoperative group was 29% versus
47% in the postoperative group. Local regional
control was obtained in 70% of the preoperative
group versus 79% in the postoperative group.
This difference in control was statistically sig-
nificant and was, in fact, the only statistically
significant difference in their whole series at
this point in time between preoperative versus
postoperative irradiation. It would appear that
combined therapy (surgery and radiation)
provides better cancer control, even in early
supraglottic cancer.
NASOPHARYNGEAL CARCINOMA
While nasopharyngeal carcinoma is relatively
rare among caucasians, it occurs with alarming
frequency among Chinese; indeed, the best re-
cent reports in the literature come from Taiwan.
Hsu and Tu analyzed the therapy in 966 pa-
tients from Taiwan with nasopharyngeal carci-
noma [37]. All patients were treated by full-
course irradiation therapy with some patients
receiving adjuvant chemotherapy after irradia-
tion. The overall NED rates were 49% at one
year, 43% at two years, 33% at five years, and
22% at ten years. By stage, 11 (1 %) of 966 pa-
tients had stage-I, 82 (8%) of 966 patients had
stage-II, 205 (21%) of 966 had stage-III, and
668 (69%) of 966 had stage-IV cancer. In stage-
IV disease patients, 66 patients (6.8%) of the
total group presented with distant metastatic
disease and all died within four years. In the
total group, 200 subsequently developed distant
metastatic disease for a total metastatic rate of
28%; 120 patients developed bone metastases,
69 hepatic metastases, 57 lung metastases, and
20 skin or lymph node metastases below the
clavicle.
338 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
The 108 patients who suffered a local recur-
rence without metastases were all reirradiated;
21 % are alive two years after the second treat-
ment and five are alive at five years; 65 patients
had a recurrence in the neck only, and 44% are
alive at two years after subsequent neck dissec-
tion and 31 % are alive at five years.
Hsu et aI., in a separate article, analyzed the
consequence of neck biopsies before definitive
diagnosis or treatment in nasopharyngeal carci-
noma [38]. Patients without biopsies were age-
matched to those with biopsies before diagno-
sis. The biopsy group consisted of 122 patients
versus 158 in their age-matched control group.
Analysis of survival in these groups showed
60% survival in the neck biopsy group versus
79% in the nonbiopsied group at two years,
41 % versus 59% at five years, and 31 % versus
40% at ten years. All of these differences are
statistically significant and showed the decrease
in survival when the neck is violated prior to
treating the primary lesion. McGuirt and Mc-
Cabe showed similar results in a study of squa-
mous cancer in the neck [39].
In a series of nasopharyngeal carcinoma
patients reported in the USA, Baker and Wolfe
studied 99 patients [40], 66 of whom had clini-
cally apparent cervical lymph nodes on pre-
sentation. Neck dissection was indicated in only
seven of 99 patients after definitive irradiation
(patients with residual neck disease after irradia-
tion in the presence of primary site control).
They found five-year survival rates of 67% in
patients with stage-I disease, 21 % in those with
stage-II disease, 22% in those with stage III
disease, and 19% in those stage-IV disease. All
patients were treated by irradiation with neck
dissections done only as noted above. Interest-
ingly, patients irradiated over longer treatment
periods (but not with greater amounts of irra-
diation) tended to survive longer, although this
was not statistically significant. In their series,
tumor control for 1950-1974 was only 53%
versus 71 % from 1974 to 1978, reflecting what
was described as better radiation techniques and
a tendency to use larger amounts of irradiation.
In spite of the improved local control, however,
survival was not increased. Nasopharyngeal car-
cinoma remains a radiotherapy treatment dis-
ease, with surgery reserved for the occasional
case of residual neck disease.
The study from the Radiation Therapy
Oncology Group has been discussed previously
in this chapter [28]; however, their analysis
combined both oral cavity and oropharyngeal
lesions. The two-year survival rate was 43%.
Survival was 39% in the preoperative irradia-
tion group, 35 % in the postoperative irradia-
tion group, and 33% in a group treated only by
irradiation with surgical salvage. In this
latter group, 14 patients who failed irradiation
underwent attempted surgical salvages of which
only two were successful. In oral cavity and
oropharyngeal neoplasia, local regional control
was gained in only. 56% of the preoperative
group, 53% of the postoperative group, and
39% of the irradiation only group. Only one
article has addressed a prospective randomized
study of combined therapy versus surgery
alone: Strong et al. evaluated 97 patients ran-
domized to preoperative irradiation with 2000
rad over one week followed immediately by
surgery, versus surgery alone [41]. Sites studied
were the oropharynx and hypopharynx in
stage-II and stage-III patients. For their total
group, the three-year NED rate was 39% in the
surgery only group versus 40% in the preopera-
tive irradiation and surgery group.
Chemotherapy in Head and Neck
Squamous Cell Cancer
The only large prospective randomized study of
adjuvant chemotherapy in head and neck cancer
was sponsored by the National Cancer Institute
as a multi-institutional trial [42]. It consisted of
three treatment arms: (a) surgery followed by
postoperative irradiation therapy, (b) inductioE
chemotherapy with one course of cis-platinum
and bleomycin followed by surgery and irra-
diation therapy, and (c) induction chemother-
apy with bleomycin and cis-platinum followed
by surgery, irradiation therapy, and mainte-
nance chemotherapy for six months with cis-
platinum. When the study was closed, there had
been 154, 141, and 150 patients randomized to
each of the three treatment arms who were
evaluable. Patients enrolled in this study had
operable stage-II pyriform sinus disease 0,
stage-III or stage-IV carcinoma of the
orpharynx, oral cavity, or larynx. For the pa-
tients who received chemotherapy, the induc-
tion regimen consisted of cis-platinum 100 mg/
m 2 by i.v. push on day 1, bleomycin 15 mg/m2
i.v. push on day 3, and then bleomycin 15 mg/
m 2 by continuous infusion on days 3-7. The
maintenance chemotherapy regimen consisted
 18. ASSESSMENT OF SUCCESS OF TREATMENT OF HEAD AND NECK NEOPLASIA
of cis-platinum 80 mg/m2 given by continuous
infusion over a 24-h period once monthly for
six months.
Of the 282 evaluable patients for whom clin-
ical response information was available there
were 22 complete responses (7.8%) to induction
chemotherapy, 114 partial responses (14.4 % ),
127 patients whose disease remained stable
(45 %), and 19 who had disease progression
(7%). Of 204 patients with nodal response
information, 29 (14.2%) achieved a complete
response (CR), 74 (36.3%) a partial response
(PR), 79 (38.7%) had stable disease, and 22
(10.8%) had disease progression. The overall
complete and partial response rate was approx-
imately 50%.
There was no difference found among the
three treatment groups in regard to survival.
Patients with a performance status of greater
than 90 on the Karnofsky scale did significantly
better than those patients with a performance
status of less than 80. Stage-II and stage-III
patients combined survived longer than did
stage-IV patients. Interestingly, patients with
laryngeal primaries did better than those with
oral cavity lesions. For the total groups, survival
at 36 months was 42% for patients with stan-
dard therapy and 47% for patients treated with
chemotherapy. In the group of patients receiv-
ing induction and maintenance chemotherapy,
only 13 patients completed the program of
chemotherapy.
A number of nonrandomized trials of induc-
tion chemotherapy in head and neck patients
have shown impressive response rates when
complete responses and partial responses (de-
fined as greater than a 50% reduction in the
product of two tumor diameters) are consid-
ered.
Elias et al. treated 22 patients with cis-
platinum 100 mg/m2 on day 1 followed by a
five-day infusion of bleomycin [43]. On day 10,
methotrexate 50 mg/m2 was given followed by a
36-h infusion of methotrexate 1500 mg/m2 with
leucovorin rescue. The overall response rate was
68% with an 18% CR rate. Six patients had
severe nephrotoxicity and two died.
Al-Sarraf et al. added vincristine to high-dose
cis-platinum and bleomycin and reported a 28%
CR rate with a combined CR and PR rate of
79% in 77 patients [44] (see chapter 17).
Schuller et al. used cis-platinum, methotre-
xate, bleomycin, and vincristine as a preopera-
tive adjuvant in 58 previously untreated patients
339
with an overall response rate of 66% [45].
Spaulding et al. used cis-platinum, vincristine,
and bleomycin in 29 previously untreated
patients and achieved an overall response rate of
95% [46].
Davis et al. found a CR rate with bleomycin,
cis-platinum, and vinblastine of 22% and aPR
rate of 44 % in previously untreated patients
[47]. They found no survival advantage in the
treatment group when compared with an histor-
ical control group. Of six patients who achieved
a chemotherapy-induced CR and underwent
surgery, five had residual disease found on his-
tologic review of their operative specimens.
Hong et al. noted a similar finding where six
of eight clinical CRs also had residual disease
histologically [48]. This certainly supports the
thought that chemotherapy alone cannot be
considered curative even in the presence of
complete clinical disease regression.
Three of five patients in the Davis study who
attained a CR to induction chemotherapy had
laryngeal or pyriform sinus disease. Two of
these patients underwent total laryngectomy
with neck dissections. The survivor of these
patients had no tumor present in the surgical
specimen. The other two patients who were sur-
vivors both were treated with definitive irra-
diation therapy after refusing laryngectomy. In
this same study, only one of eight patients in
the partial response and no response groups to
chemotherapy of laryngeal disease survived, this
patient having been treated by surgery and
postoperative irradiation therapy. This raises a
significant question as to whether patients who
are complete responders to chemotherapy and
are biopsy negative in the primary site can be
saved the morbidity of surgery and treated by
full-course irradiation alone. This is currently
being evaluated in an induction chemotherapy
study for advanced operable head and neck can-
cer at Stanford University. In this study, pa-
tients will receive methotrexate and bleomycin
as an initial arm of chemotherapy followed by
two cycles of cis-platinum and 5-fluorouracil
(5-FU). Patients who become biopsy-proven
complete responders will not undergo ablative
surgery, and will have only irradiation.
When the effect of chemotherapy in other
malignancies is carefully evaluated, it is noted
that only when CR rates approach 60%-70%
has any change in survival been seen. Currently
this level of complete responders has been
seen in a study by Weaver et aI., where patients
340 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
were given induction chemotherapy with cis-
platinum 100 mg/m2 and a 96-h infusion of 5-
FU 100 mg/m2 per day in two courses, or with
cis-platinum 100/m2 followed by a 120-h infu-
sion of 5-FU in three courses [49]. In this study,
26 patients who received the two-course regi-
men had a tumor response rate of 88.5%. Five of
26 patients had CRs to chemotherapy while 18 of
26 had PRs. Importantly, of the 18 patients who
received a three-course regimen of 5-FU and cis-
platinum, 61 % (11) achieved a CR, 6% became
partial responders, and 6% became minimal re-
sponders. This regimen is currently being evalu-
ated in several medical centers to determine
whether, in fact, this degree of CR can be
achieved. Predictable response at this high a CR
rate will probably reflect an increase in survival.
Even if current chemotherapy will not in-
crease the survival of patients, it may serve as
a useful prognosticator to determine which
patients can be saved the added morbidity of
surgery, as mentioned earlier. Complications in
surgery following chemotherapy have not been
increased over those in patients without prior
treatment. In addition, reduction of the primary
tumor in response to induction chemotherapy
may allow marginally curable patients to receive
more curative local therapy.
Squamous Cell Cancer Summary
Assessment of the current status of therapy for
head and neck squamous cell carcinoma leads to
several interesting conclusions. The only area
where current therapy is highly effective is in
the treatment of stage-I laryngeal cancer. A high
percentage of this is curable by either surgery or
irradiation therapy. As the morbidity of open
partial laryngectomy procedures has been wide-
ly recognized, radiation therapy has become
the standard of treatment of T1NoMo laryngeal
cancer. The question in this area is whether, in
fact, irradiating all stage-I laryngeal cancer is
indeed not overtreatment for a good number
of patients where excisional biopsy may have
removed the cancer. Patients with stage-II
en do laryngeal cancer and impaired vocal cord
mobility have a poorer prognosis than do stage-
II patients with normal cord mobility. A high
percentage of patients with normal mobility can
be cured with radiation therapy while those
patients with impaired mobility are probably
better treated by open partial laryngectomy.
The prognosis of patients with T1 and T2 oral
cavity cancer is poorer than generally recog-
nized. A diffuse pattern of cancer invasion por-
tends an unfavourable prognosis. These patients
may need combined treatment, which markedly
improved their survival in several series.
Treatment of stage-IV disease in all sites was
found to be as dismal as expected. A significant
question in reviewing this data is whether com-
bined therapy is really justified in these patients
because of its attendant morbidity.
The prospective randomized evaluations of
combined therapy with either preoperative or
postoperative irradiation yield few solid and
statistically significant differences among these
modalities. It is notable that,. in supraglottic
stage-II to stage-IV lesions, postoperative
irradiation does show a statistically significant
improval in local control and in fact may confer
a survival advantage. In pyriform sinus or
hypopharyngeal stage-II through stage-IV dis-
ease, it also appears that postoperative irradia-
tion may confer control and survival advan-
tages. The prospective data here are in fact very
limited and subsequent studies should be con-
ducted.
The current role of chemotherapy in stage-III
and IV head and neck cancer patients to date
shows no survival advantages. As regimens are
developed that consistently show higher CR
rates, survivals will hopefully increase.
Most regimens of induction chemotherapy
have not interfered with the ability to deliver
standard therapy, i.e., surgery and irradiation.
On the other hand, the only prospective ran-
domized study of adjuvant chemotherapy found
very poor compliance with completing a full-
course of maintenance chemotherapy. Protocols
need to be developed that will allow completion
of maintenance therapy.
Salivary Gland Malignancies
The salivary gland malignancies of the head and
neck are very uncommon neoplasms found
mostly in the parotid gland, but also in the sub-
lingual, submandibular, and minor salivarf
glands (see chapter 13). Therapy of these lesions
is extremely difficult because of their variable
histopathology, their equally variable clinical
course, and the intricate relationship of impor-
tant head and neck stru~ttlres to these neo-
plasms. For this reason, assessment of therapy
becomes even more difficult. Rankow and
Mignogna reviewed the literature and found
 18. ASSESSMENT OF SUCCESS OF TREATMENT OF HEAD AND NECK NEOPLASIA
only 46 reports of primary sublingual tumors
[50]: 37 of 80 reported cases involved malignan-
cy, with adenoid cystic carcinoma and muco-
epidermoid carcinoma being the most common
diagnoses. No statement of five-year survivals
can even be attempted with these extremely rare
lesions.
Primary submandibular gland neoplasms are
likewise rare. In 1972, Conley et al. reported
their experience with 115 patients who had sub-
mandibular gland neoplasia [51]; 53% of these
neoplasms were benign, all of which were be-
nign mixed tumors. In the malignancy group,
adenoid cystic and mucoepidermoid carcinoma
were equally common (31 % each). Of the ade-
noid cystic carcinoma patients, the five-year
survival was 47% and the ten-year survival was
11 %. Most of these patients had been treated by
combined therapy with total surgical excision
and irradiation. A more specific comment on
the type of therapy is not very meaningful, as
these patients were treated over a long period of
time and had different types of operations and
approaches to irradiation therapy.
In 1961, Chaudhry et al. reviewed the English
literature and found 1320 cases of intraoral
salivary gland tumors [52]. In this group, 60%
were benign and 40% malignant. Five-year sur-
vivals in this heterogeneous group were: for pa-
tients with adenoid cystic carcinoma, 38%, with
a 20-year survival of only 6%; mucoepidermoid
carcinoma, 67%; malignant mixed tumors,
66%; and for all adenocarcinomas, 57%. Con-
ley found that 30% of the minor salivary gland
malignancies that he had treated had tumor in
the margin, and a distant metastatic rate of 27%
[53]. The failure to obtain clear margins in
minor salivary gland tumors relates to the small
size of the minor glands and the relatively rapid
invasion of surrounding structures when malig-
nancy is present.
Most salivary gland malignancies (80%-
85%) occur in the parotid gland, allowing a
better analysis of success of therapy in this area.
It still should be recognized, however, that
cancers of the parotid gland represent only 1% of
all neoplasms, and are said to account for only
650 deaths per year. The percentage of malig-
nancies of all parotid neoplasms is reported to
be 20%-30%. The biologic aggressiveness of
parotid tumors correlates in general with their
histology. This has allowed the classification of
parotid malignancies into two groups: high
grade and low grade. Low-grade cancers include
341
low-grade mucoepidermoid carcinoma and aci-
nous cell carcinomas. High-grade carcinomas
include adenoid cystic carcinoma, high-grade
mucoepidermoid carcinoma, malignant mixed
tumor, squamous cell carcinoma, and adeno-
carcinoma. By far, the greatest frequency of
parotid malignancies are adenoid cystic and
mucoepidermoid carcinomas. The following
analysis of parotid malignancies will therefore
focus on these two types of malignancy. It
should be recalled from earlier discussion that
the other salivary gland malignancies are gener-
ally either adenoid cystic or mucoepidermoid
carcinomas; it may therefore be possible to ex-
trapolate the best treatment regimens in parotid
mali~nancy to these other salivary gland malig-
nanCles.
Surgery is recognized as the major mode of
therapy for parotid malignancies. Table 18-6,
however, demonstrates the unacceptable recur-
rence rates when surgery is used alone [54-59].
In the series reported by Hodgkinson and
Woods, 64% of their patients had sacrifice of
the facial nerve, suggesting that even aggressive
surgical procedures fail to gain good local con-
trol [56]. The series using combined treatment
clearly demonstrate the advantage of this
approach. In this light, seven indications for
postoperative irradiation in parotid malignancy
are useful: (1) high-grade cancers, (2) recurrent
cancers, (3) deep lobe cancers, (4) gross or mi-
croscopic residual disease, (5) tumor adjacent to
the facial nerve, (6) regional node metastases,
and (7) invasion of muscle, bone, skin, nerves,
or any extra-parotid extension [60].
While loca1 control has been improved by the
addition of irradiation to surgery, the incidence
of distant metastatic disease in salivary malig-
nancy is significantly greater than that seen with
squamous cell carcinoma of the head and neck.
Reported incidences of distant metastatic dis-
TABLE 18-6. Recurrence rates after therapy for
parotid malignancy
Surgery Surgery +
alone irradiation
Spiro et a1. [54] 27%
Woods et a1. [55] 36%
Hodgkinson and Woods [56] 38%
Rossman [57] 65% 17%
Elkon et a1. [58] 6%
Tapley [59] 9%
30%
342 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
ease range from 15%-40%. In view of these
findings, many institutions have added adjuvant
chemotherapy for salivary gland malignancy.
The total number of cases treated with che-
motherapy for parotid malignancy is indeed
small, and the best current review of is that of
Suen and Johns [61], who reviewed current
literature and also did an institutional review of
all cases of chemotherapy administered for
salivary gland malignancy and found an overall
response rate (complete and partial) of 42%. In
adenoid cystic carcinomas, CR occurred only
when cis-platinum was used as a single agent.
Several reports in the recent literature have also
found a remarkable response of adenoid cystic
carcinoma to cis-platinum. Sessions et al. reported
that this effect was enhanced by intraarterial cis-
platinum therapy [62]. It certainly seems that in
light of the high distant metastatic rate of this
tumor and the overall poor prognosis that the
addition of cis-platinum to current standard
therapy should be further investigated.
Chemotherapy for other parotid malignan-
cies has resulted in rare CR as well. Methotrex-
ate used as a single agent and methotrexate in
combination with 5-FU and adriamycin have
been found to induce infrequent complete re-
sponses in cases of mucoepidermoid carcinoma.
Likewise, infrequent complete responses to 5-
FU and hydroxyurea or adriamycin, cytoxan,
and cis-platinum have been seen in patients with
adenocarcinoma and in carcinoma arising from
a mixed tumor. As a general statement, there
seem to be two groups by which response to
chemotherapy can be judged. One group is the
adenocarcinomalike cancers-adenoid cystic
carcinoma, adenocarcinoma, and carcinoma-
arising in a mixed tumor. These tumors respond
best to adriamycin, cis-platinum, and 5-FU.
The other group is squamouslike cancers (either
squamous cell carcinoma or mucoepidermoid
carcinoma) that respond to methotrexate or to
cis-platinum. There are no current studies
showing tumor responsivenss to cis-platinum
and 5-FU; these agents may well be more active
in these malignancies, as discussed earlier in this
chapter [49].
Current therapy in salivary gland disease still
depends upon surgery as the main mode, with
postoperative irradiation playing an important
role in improving local control and possibly
survival. Several chemotherapeutic agents seem
to be active against salivary gland disease, and
the addition of these agents to standard treat-
ment may lead to improved survival secondary
to a decrease in the distant metastatic rate of
these lesions.
Hong et al. have shown that patients who
present with unresectable salivary gland disease
and are treated with induction chemotherapy
and irradiation may occasionally "become re-
sectable" and experience significant increases in
expected survival when surgery is later per-
formed [63]. In addition, Wang has shown that
patients with parotid area lymph node metas-
tases may be palliated effectively by radical irra-
diation [64]. Both series suggest that adjuvant
therapies (chemotherapy or irradiation) may
allow successful treatment in selected patients
previously felt to be unresectable, or resectable
only by radical therapies with facial nerve sac-
rifice.
Head and Neck Melanoma
Melanomas of the head and neck account for
approximately 20% of all melanomas. The
rationale for treatment of cutaneous melanoma
has been based on two histologic systems of
evaluation. Clark et al. described five levels of
tumor involvement: tumor involvement con-
fined to the epidermis (level I), tumor cells
invading papillary dermis (level II), tumor ex-
tending to the interface between papillary and
reticular dermis (level III), infiltration into re-
ticular dermis (level IV), and infiltration through
reticular dermis into the subcutaneous tissues
(level V) [65].
Breslow introduced the concept of measuring
the thickness of tumor involvement: measure-
ments from the top of the granular layer of the
epidermis to the deepest melanoma cells in the
dermis [66]. Lesions less than 0.76 mm in thick-
ness were generally found to have a very favor-
able prognosis in that they were less unlikely to
recur locally or to metastasize.
It has been generally accepted that level I and
II in Clark's system correspond to less than 0.6
mm in thickness. Lesions greater than 1.5 mm in
thickness in the Breslow system are comparable
to Clark's levels IV and V. Clark's level III then
falls roughly between 0.6 and 1.5 mm in thick-
ness.
The best treatment for melanoma has been
surgery. Most studies report that lesions less
than 0.75 mm in thickness can be adequately
controlled by wide local excision with no treat-
ment of regional lymphatics. For deeper lesions
 18. ASSESSMENT OF SUCCESS OF TREATMENT OF HEAD AND NECK NEOPLASIA
(i.e., level IV or V), elective nodal dissection has
generally been preformed.
The rationale for treatment of regional nodes
on an elective basis has been that melanoma has
been found to spread to the proximal lympha-
tics before further distal spread. In the head and
neck region, the proximity of regionallympha-
tics to primary disease sites allows for incon-
tinuity dissection in most cases.
Most currently reported results of surgery in
melanoma use the rationale mentioned above.
Olson et al. found that patients who underwent
wide local excision of lesions that were less than
0.75 mm thick have a five-year disease-free sur-
vival rate of 66% [67). In their series, no patient
whose lesion was less than 1 mm thick had local
recurrence or died as a result of melanoma. In
the same series, patients who underwent elective
neck dissection and who had negative findings
or only 1-2 positive nodes had a five-year sur-
vival rate of 53%. If more than three involved
nodes were found, the five-year survival rate
was 15%. Patterns of recurrence in their pa-
tients showed that relapse after nodal dissection
invariably presented with systemic disease; all
of these patients did poorly.
Storm et al. prospectively evaluated 69 pa-
tients with head and neck melanoma from 1971
to 1977 [68). With a follow-up period from one
to 75 months, patients without evidence of
nodal disease at initial presentation had a 13 %
recurrence rate versus a recurrence rate of 58%
in patients presenting with regional disease.
Patients with superficially invasive melanoma
had a 10% recurrence rate versus a recurrence
rate of 17%-33% in patients whose melanomas
were deeper than 0.75 mm. Patients with either
microscopic or clinically apparent regional
lymph node disease had a 50% recurrence rate
during the follow-up period. Interestingly, pa-
tients without lymph node metastases appeared
to have a good prognosis regardless of the depth
of invasion of the primary tumor. Patients with
regional lymph node metastases, however,
appeared to have a poor prognosis regardless of
the level of tumor invasion. The authors con-
cluded that the presence of nodal metastasis,
rather than the micro stage of the primary
tumor, appeared to be the dominate factor in
predicting outcome.
Many authors have commented that elective
neck dissection with or without parotidectomy
in head and neck melanoma may improve sur-
vival of patients who later undergo metachro-
343
nous nodal dissection for late development of
adenopathy. This impression has not been con-
firmed as yet by prospective studies or con-
clusive statistical analyses. In a series reported
by Roses et aI., 97% of patients with positive
lymph nodes eventually developed systemic dis-
ease [69]. It can be stated that elective neck dis-
section in patients with melanomas greater than
0.75 mm will certainly help stage the patient's
disease better. Patients without adenopathy
found on elective dissection have a very good
prognosis versus the poor prognosis of patients
in whom nodes are found on pathologic review.
Treatment of malignant melanoma of the ex-
ternal ear poses a special problem for head and
neck surgeons. Taking wide margins around
melanoma on the external ear would in many
cases result in total auriculectomies. In addition,
the question of whether parotidectomy is to be
included in initial treatment also arises since the
primary lymphatics of the external ear drain
into the parotid area. In a review of 102 cases of
malignant melanoma of the external ear, Byers
et al. addressed some of these questions [70).
Their series showed no correlation between
survival and the clinical appearance of the mel-
anoma. There was no significant difference in
survival based on the anatomic location of the
melanoma on the ear nor did any area of the ear
have a statistically significant propensity for
metastasis, deeper invasion, or a pathologically
thicker lesion. No patient with melanoma of the
external ear presented with or developed lower
jugular adenopathy. In their series, 42% of pa-
tients had clinically positive nodes: 15 patients
with preauricular nodes, four patients with
parotid nodes, and 14 patients with jugulodigas-
tric nodes. There was no significant correlation
between the region of nodal metastasis and sur-
vival. However, the correlation between posi-
tive or negative nodes and survival was highly
significant. Of the 42 patients with positive
nodes, 80% survived one year, 60% two years,
12% five years, and 10% ten years. Of the 60
patients with negative nodes, 98% survived one
year, 95% two years, 70% five years and 60%
ten years. Further, when the degree of thickness
of auricular melanomas was examined, the
authors found that, of 18 patients with lesions
of less than 1 mm, 90% survived one year, 65%
survived five years, and 65% survived ten years.
In patients with lesions greater than 3 mm thick,
70% survived one year, 55% two years, and
25% ten years. When the lesion was less than 3
344 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
mm thick, the incidence of nodal disease was
21 %; however, if the lesion was thicker than 3
mm, the incidence of metastatic regional disease
was 61%.
Treatment of the primary lesion consisted of:
(a) no treatment with follow-up only in patients
already excisionally biopsied, (b) wedge exci-
sion, (c) partial auricle amputation, and (d) total
auricle amputation. Total amputation was
restricted to patients whose disease was locally
disseminated at the time they were initially seen
or for patients with recurrence after partial
amputation. In those patients treated at the M.D.
Anderson Hospital, the local recurrence rate
was 8% [70]. In the series reported by Storm et
aI., six of seven cases of auricular malignant
melanoma were treated by only wide "V" exci-
sion versus total auriculectomy, and no patient
had local disease recurrence [68]. In light of
these two studies, it appears that partial ear re-
section may be appropriate in the initial treat-
ment of melanoma of the auricle. It certainly
achieves a better functional result for the patient
without apparent loss of the ability to eradicate
the tumor locally.
In the M.D. Anderson series, 33 patients had
prophylactic neck dissections and superficial
parotidectomies. Only four of 33 patients had
positive neck nodes found pathologically. In the
group of patients who underwent therapeutic
neck dissection and parotidectomy, the inci-
dence of false-positive staging was 17% while
the incidence of false-negative clinical staging in
the neck was 23%. Only four patients were
thought to have positive parotid nodes preoper-
atively versus 13 who actually did have positive
nodes on pathologic examination. The M.D.
Anderson group found no difference between
the ultimate control regionally of patients who
had classic radical neck dissection or functional
neck dissections with preservation of the ster-
nocleidomastoid muscle, the internal jugular
vein, and the spinal accessory nerve.
Regarding radiation therapy, it has been
traditionally thought that melanoma is radio-
resistant and few articles evaluating the effect of
such therapy in melanoma have been presented.
More recent thought has been that melanoma is,
in fact, not radioresistant, but requires treatment
at significantly higher dose per fraction amounts
than does squamous cell carcinoma of the head
and neck. These results are borne out by several
articles in the recent literature.
Harwood and Lawson found that, in patients
with lentigo malignum melanoma, radiation
therapy was highly successful in controlling
local disease [71]. Of 13 patients with lentigo
malignum, 11 were controlled locally without
recurrence from six months to five years follow-
ing irradiation therapy. Of 18 patients with len-
tigo malignum melanoma who were primarily
irradiated, 17 have been controlled in the same
follow-up period. Their results in nonlentigo
melanoma also demonstrate some radiosensitiv-
ity of melanoma. Of 15 patients irradiated after
inadequate excisional biopsy, 14 had local con-
trol, although six died of metastatic disease.
Only two of 16 patients irradiated for recurrent
melanoma were controlled. Their analysis of
local control rates versus irradiation fraction
size revealed that 17 (71 %) of 24 patients
achieved local control with a dose per fraction
greater than 400 cGy versus only three of 12 pa-
tients gaining local control with doses less than
400 cGy per fraction.
Johanson et ai. also found that nodular mela-
noma was radiosensitive to a high dose per
treatment regimen [72]. Of 22 patients treated
for microscopic residual disease following sur-
gical excision, 18 were found to be free of dis-
ease through a follow-up period of up to five
years. Seven of nine patients treated for gross
residual disease after surgery have had no re-
currence or progression of tumor in the irradi-
ated area. Five of these nine patients achieved a
complete remission and three of nine are alive,
free of disease, at ten, 13, and 42 months.
A total of patients with recurrent melanoma
were irradiated. Nine achieved complete remis-
sion and three were free of disease up to 56
months following irradiation. While irradiation
may have some role in treatment of melanoma
when given in high-dose fractions, the ultimate
benefit to patient survival remains to be deter-
mined. Evaluation of surgery and radiation
therapy data for malignant melanoma leads
quickly to the conclusion that, in melanoma
deeper than 0.75 mm, and particularly in mela-
noma that recurs or that presents with regional
disease, most patients will ultimately die of their
disease. This occurs through loco regional fail-
ure or, more commonly, through metastatic
spread. There is great need for systemic treat-
ment for melanoma; however, there are no good
systemic treatments at present that are available
as adjuvant therapy.
There have been, however, several interesting
studies performed that evaluated immunother-
 18. ASSESSMENT OF SUCCESS OF TREATMENT OF HEAD AND NECK NEOPLASIA
apy and melanoma. Adjuvant Corynebacterium
parvum immunotherapy was evaluated in a
study from the Southeastern Cancer Study
Group reported by Balch et al. [73]. In the total
group, there was no significant difference in the
three-year survival between patients treated
by surgery or those treated by surgery with
adjuvant immunotherapy. When patients were
subgrouped by tumor thickness, however, an
apparent benefit of immunotherapy was ob-
served in 49 patients who had melanomas
that were greater than 3 mm thick. Only five of
23 such patients who did not receive im-
munotherapy have relapsed to date, and their
three-year survival is only 33%. In the 175 pa-
tients with melanomas that were less than 3 mm
thick, both treatment arms had identical three-
year disease-free survival rates of 83%.
In a study of the natural history of resectable
metastatic melanoma, the M.D. Anderson Hos-
pital found that patients receiving bacillus
Calmette-Guerin (BCG) in this group had a
medium survival superior to that of a surgery
only group [74]. This increase in survival was
seen predominantly in patients who had
metastatic foci of melanoma resected more than
once, and who received BCG. Patients with
recurrent soft-tissue metastases appeared to
benefit most from BCG in prolonging disease-
free intevals. Only one of ten treated by surgery
alone had a disease-free interval longer than one
year versus nine of 16 patients who received
BCG.
These studies suggest that immunotherapy
may be of benefit in patients with more ad-
vanced head and neck melanomas but, because
of variable biologic behavior, further studies
should be carried out with larger numbers of
patients.
In summary, surgery remains the mainstay in
the treatment of cutaneous melanoma and is
highly effective in early melanoma (i.e., Clark's
levels I or II, or melanomas that in the Bres-
low classification are graded to be less than 0.75
mm thick). The benefit of elective regional treat-
ment (neck dissection and/or parotidectomy) in
head and neck melanoma is in staging patients,
and may confer some survival advantage. This
needs better prospective evaluation. Patients at
high risk for parotid spread may well best be
staged by superficial parotidectomy as reported
series demonstrate the difficulty of clinical
staging in this region. When neck dissection is
done as part of regional treatment, current evi-
345
dence suggests that modified radical dissections
accomplish the ends of regional treatment as
well as radical neck dissection.
Head and neck cutaneous melanoma is
radiosensitive to high dose per fraction treat-
ments, and this may offer some degree of pallia-
tion in advanced lesions or as primary treatment
in early lesions in patients in whom surgery is
not advised. Immunotherapy may also play a
role in advanced head and neck melanoma and
needs to be further evaluated. The hope for
the future is that regimens of systemic chemo-
therapy will be found that will be effective in
melanoma to prevent and treat systemic metas-
tasis.
Mucosal Melanoma
Approximately 5%-10% of melanomas of the
head and neck arise in the mucosa of the upper
aero digestive tract. The most frequently in-
volved site is the nose, with progressively fewer
lesions encountered as one descends through
the upper aerodigestive tract. In contrast to
cutaneous melanomas, mucosal melanomas
have not been subjected to any intensive clinical
pathologic investigations because of their rarity.
It is known that these lesions are nearly always
more lethal than their cutaneous counterparts.
After an extensive review, Batsakis et al. con-
cluded that the prognosis of primary mucosal
melanoma is not influenced by the head and
neck site of origin, the age or sex of the patient,
or the cytomorphologic features of the melano-
ma cells [75]. Because of the absence of histolo-
gic landmarks analogous to the papillary and
reticular dermis, Clark's classification system
cannot be applied to mucosal melanomas. In the
rare instances when the Breslow system has
been used to assess these melanomas, invasion
deeper than 0.5 mm has been associated with
decreased survival.
The major factor in failure of treatment is lo-
cal recurrence followed by distant dissemination.
The best five-year survival rate has ,been re-
ported by Snow et aI., with 26 well-documented
patients having a five-year survival rate of 38%
[76]. These patients were treated by wide en
bloc excision of the lesions. Large surgical series
by Shah et al. [77] and by Conley and Pack [78]
showed five-year survival rates of 22% and
26%; only 10% and 15%, respectively, of their
patients were free of disease. Batsakis et al. con-
cluded their review by stating that no patient is
346 III. DIAGNOSIS AND MANAGEMENT OF HEAD AND NECK NEOPLASIA
ever free of the lethal effects of mucosal melano-
ma [75].
Harwood and Cummings reviewed the litera-
ture and reported their experience with irradia-
tion therapy of these lesions [79]. With dosage
rates of greater than 400 cGy per treatment frac-
tion, they found complete remission in six of
seven patients versus similar remission in only
five of 18 patients treated with fraction sizes of
less than 400 cGy. They found a complete remis-
sion rate of 72% in 24 patients treated with
high-rad fractions. Seven of 18 patients who
achieved complete remission subsequently re-
lapsed. Only one of seven patients who failed to
respond to irradiation was salvaged by subse-
quent surgery. Because of the extensive surgery
necessary to encompass these lesions, the au-
thors recommend initial irradiation treatment as
the best form of palliation in this disease.
Because of the rarity of this lesion, there are
no studies are sufficient size utilizing irradiation
and surgery to make any statistical statement.
The bulk of evidence would suggest that initial
wide en bloc excision of these lesions offers the
best chance of long-term palliation. Radiation
regimens using high dose per fraction treat-
ments may represent acceptable palliation. Com-
bined therapy cannot currently be analyzed.
Adjuvant chemo- or immunotherapy cannot
be assessed.
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IV. HEAD AND NECK
COMPLICATIONS OF
CANCER THERAPY
 19. ORAL COMPLICATIONS
ASSOCIATED WITH HEMATOLOGIC
NEOPLASMS AND THEIR
TREATMENT

Douglas E. Peterson

Hematologic neoplasms and their treatment

often result in profound oral complications.
Chiefly infectious in nature, these complica-
tions range from mildly uncomfortable to debili-
tating to a degree that chemotherapy can no
longer be continued. This chapter reviews the
assessment, management and, ideally, preven-
tion of such complications, with distinction
made between those disorders related to natural
hematologic disease and those related to its
treatment.

FIGURE 19-1. Leukemic gingival infiltrate in a 42-

Disease-associated Complications
Hematologic neoplasms, by reason of the
organs involved, can be considered "naturally
metastatic." Dissemination of disease is often
widespread before clinical symptoms are
observed.
Direct and indirect effects on the oral struc-
tures can result. For example, metastases to the
intraoral structures (e.g., gingiva) (figure 19-1)
can occur; such lesions are typically observed
in acute monocytic leukemia [1]. Other sites
(including periapical) can also be involved [2]
(figure 19-2). These lesions then cause local
changes due to either invasion or compression
of contiguous normal structures.
Indirect changes can occur due to the altera-
tion in normal bone marrow function (infra
vide). Marked leukopenia, thrombocytopenia,
and erythrocytopenia can result as the marrow
is compromised. The patient is then at risk for
infection, bleeding diastheses, and anemia.
The oral manifestations described above can
cause the patient to seek medical/dental atten-
Peterson et al., HEAD AND NECK MANAGEMENT OF THE CANCER PATIENT.
© 1986. Martinus NijhofJ Publishing. All rights reseroed.
year-old patient presenting with ANLL. This infil-
trate partially resolved during subsequent induction.
tion. Oral symptoms in acute leukemia may be
among the earliest clinical occurrences; 17% of
patients with subsequently diagnosed acute
lymphoblastic leukemia, 17% with acute
myelogenous leukemia, and 12% with acute
myelomonocytic leukemia initially sought
dental consultation for their oral symptoms [3J.
The predominant early oral symptom in these
patients was oral bleeding and head and neck
lymphadenopathy.
Treatment-related Complications
DIRECT STOMATOTOXIC EFFECTS
These complications are a result of cytotoxic
drugs directly affecting oral tissues.
Mucositis. The cytotoxic effects of chemother-
apy upon replicating oral mucosal cells can re-
351
352 IV. HEAD AND NECK COMPLICATIONS OF CANCER THERAPY

B
A

FIGURE 19-2. (a) Periapical roentgenograph of man-

dibular right second molar in a 33-year-old patient
suit in severe oral mucositis [4-7]. Initially, the with relapsed acute myelogenous leukemia. Note the
patient feels a mucosal "burning" sensation widening of periodontal ligament space associated
within one week of administration of the drugs; with both roots and the slight external resorption of
the mucosa may appear erythematous. The the mesial root (arrows). These findings were not pre-
lesion subsequently ulcerates, either remaining sent on admission. Patient described intense pain in
this region; lower lip paresthesia was present. (b)
focal or becoming widespread and multiple;
Photomicrograph of tissue periapical to mesial root
confluency rapidly follows (figure 19-3). Histo- of mandibular right second molar seen in a. The bone
logic changes are associated with these clinical showed a dense concentration of abnormal cells con-
findings, and most commonly include epithelial sistent with leukemic or lymphomatous infiltrate. X
hyperplasia and collagen degeneration, as well 100. Photo courtesy Dr. T. Beckerman, Department
as glandular degeneration, epithelial atrophy, of Oral Pathology, Baltimore College of Dental
and dysplasia [8]. Surgeons, Dental School, University of Maryland at
Drugs that typically cause oral mucositis in- Baltimore, Baltimore, MD. From Peterson et al. [2],
clude methotrexate, adriamycin, 5-fluorouracil, with permission.
and bleomycin. Although it is difficult to pre-
dict which patients receiving these drugs will
develop mucositis, many studies suggest that
poor oral hygiene is a contributing factor
[9-15]. Also, in our experience, it appears that
patients who experience mucositis during one
course of chemotherapy will often experience
mucositis of similar extent and location during
subsequent courses of the same regimen. The le-
sions usually last for 10-14 days after cessation
of chemotherapy. The sites most commonly
involved include the tongue and buccal/labial
mucosa, although the oropharyngeal mucosal
surface may be generally ulcerated. Besides
causing considerable patient discomfort, the
ulcerated surface represents a portal of entry for
systemic dissemination of oral microbial flora.
The prevention or treatment of chemother- FIGURE 19-3. Mucositis on lateral border of tongue
apy-induced mucositis has not been studied following administration of 5-fluorouracil for breast
thoroughly. Thus, most management is empiri- carcinoma. This ulceration site is prone to secondary
cally and palliatively based (see chapter 24). infection.
 19. ORAL COMPLICATIONS ASSOCIATED WITH HEMATOLOGIC NEOPLASMS
Adequate management of mucositis can be a
difficult experience for both the therapist and
the patient. The ulcerated mucosa is very sus-
ceptible to further injury from normal func-
tions, including speech and mastication. The
patient should be reassured that healing will
occur after withdrawal of the cytotoxic agents.
Nutritional needs of the patient must also be
addressed (see chapter 26). Secondary infec-
tions likely to be present should resolve as the
hematologic profile returns to normal.
Xerostomia. Xerostomia may occur in certain
patients receiving cytotoxic drugs. Although its
occurrence would seem to appear relatively
innocuous, the disorder can lead to further
complications. For example, quantitatively and
qualitatively normal saliva helps to minimize
shifts in the oropharyngeal microbial flora [16,
17]. Xerostomia can contribute to impaired
masticatory and speech functions due to de-
creased lubrication of the mucosa; further, oral
mucositis, angular cheilitis, and salivary gland
infection may be exacerbated. Changes in levels
of salivary constituents (e.g., albumin) have
been correlated with presence of stomatitis in
cancer therapy patients [18].
In some cases, xerostomia may be palliated
with frequent oral rinses with sterile water or
saline; salivary stimulants, such as sugarless
gum, may also be used. Diets high in water con-
tent, e.g., JELLO (General Foods, White Plains,
NY 10625), should be encouraged. Commer-
cially available artificial saliva substitutes, e.g.,
XERO-LUBE (Scherer Laboratories, Dallas, TX
75234), may be used. Patients will often de-
scribe considerable relief from the effects of
xerostomia through prompt, topical, palliative
efforts to restore some level of moisture to the
oral cavity. Dried or cracked lips that occur
secondary to xerostomia should be gently
cleaned every 2-4 h with gauze and coated with
K-Y JELLY (Johnson and Johnson, New Bruns-
wick, NJ 08903). However, if the lesion is
secondarily infected, K-Y JELLY should be
avoided.
On occasion, chemotherapy patients may
complain of drooling and apparent sialorrhea.
These patients often have difficulty in managing
salivary secretions due to painful mucositis and
attendant dysphagia. Obviously, therapeutic
efforts to eliminate the predisposing ulcerations
should be promptly instituted; in addition, an
antisialogogue such as atropine sulfate can be
353
considered if no cardiac or other contraindica-
tions exist.
Neurotoxicity. Chemotherapy (chiefly plant
alkaloids) can cause severe, deep-seated, throb-
bing mandibular or maxillary pain in some pa-
tients. The diagnosis of this lesion is often made
by exclusion of more obvious causes, such as
carious involvement of the dental pulp resulting
in pulpitis and subsequent necrosis [2]. The pain
can be very uncomfortable to the patient,
mimicking pain of odontogenic origin; narcotic
pain control may be required. The neurotoxic-
ity is transient in nature, and subsides shortly
after cessation of the drug.
INDIRECT STOMATOTOXIC EFFECTS
OF CHEMOTHERAPY
These oral complications are secondary to al-
terations in other organs, such as bone marrow.
Mucosal Infection. Approximately 47% of all
acute infections arising in patients with acute
non lymphocytic leukemia (ANLL) are of
nosocomial origin [19]. Developing in a patient
who is debilitated due to both disease and che-
motherapy, these infections are life-theatening;
for example, infection is the leading cause of
morbidity and mortality in patients with ANLL
[19, 20].
Surveillance cultures of ANLL patients, in-
cluding those of their oral mucosa, reveal that
multiple pathogens can be acquired while the
FIGURE 19-4. An example of a microbial (Pseudomo-
nas aeruginosa) infection (arrow) of the palatal ging-
iva. The patient, who had acute myelogenous leuke-
mia, was admitted with fever (38.4°C) for treatment
of the systemic infection. Combined broad-spectrum
antibiotic coverage was used, and the lesion resolved
after marrow recovery.
354 IV. HEAD AND NECK COMPLICATIONS OF CANCER THERAPY
FIGURE 19-5. Candidiasis of the palatal mucosa. This
ANLL patient developed the lesion following induc-
tion with cytosine arabinoside and daunorubicin.
Patient was febrile (38.3°C); systemic amphotericin B
was used for treatment.
patient is hospitalized. Common pathogens in-
clude Pseudomonas aeruginosa, Staphylococcus
aureus, and Escherischia coli [19, 20]. In addi-
tion, a shift to primarily gram-negative bacilli
colonizing the oropharynx occurs generally in
hospitalized patients [21]; the oral flora changes
from chiefly aerobic and anaerobic gram-
positive cocci and bacilli to a flora in which
gram-negative organisms predominate. Broad-
spectrum antibiotic therapy can result in even
further shifts to more resistant bacteria or to
fungi such as Candida spp. and Torulopsis glab-
rata [22, 23]. Most infections in the compro-
mised host are caused by organisms that have
been colonizing at or near the site of infection
[19, 24-29].
Thus, the oral mucosa of the cancer patient
can readily become acutely infected by a variety
of organisms (figure 19-4), particularly when a
break in mucosal integrity occurs because of the
direct stomatotoxic effects previously described.
For example, in hospitalized patients with acute
or chronic leukemia in the blastic phase, the oral
infection rate is 32.9% [30]. Of these oral infec-
tions, approximately 52% are fungal, and 15%
are caused by herpes simplex virus (HSV). In a
related study, solid tumor patients who experi-
ence less intense myelosuppression and stoma-
totoxicity have an oral infection rate of 10%,
yet develop oral fungal infections at a frequency
of 69% and HSV infections at 11 % [31]. It is
frequently difficult clinically, however, to deter-
mine whether the ulcerated mucosa is second-
arily infected. Further, the inflammatory pro-
cess associated with these lesions is frequently
suppressed. The most consistent signs and
symptoms of oral infection in the myelosup-
pressed patient are pain, fever, and the presence
of some form of lesion.
As suggested by the data above, candida in-
fection is the most common oral fungal infec-
tion in myelosuppressed patients [32] (figure
19-5). The most frequent sites of oral candi-
diasis are the tongue, mucosa (palatal, buccal,
gingival) and the lip commissures. The clinical
appearance of oral candidiasis is varied, but is
typically described as raised, white, "curdy-
looking" lesions. The lesions are often painful
and, when abraded, are ulcerated. Fungal dis-
semination can occur through the ulcerated
mucosa. Smears prepared with either gram stain
or potassium hydroxide show evidence of
epithelial cells with associated ovoid or hyphae
forms. Topical nystatin rinses (100,000-400,000
U q.i.d.), clotrimazole troches (10 mg five times
daily), or systemic amphotericin B may be
necessary for healing.
Viral infection following chemotherapy
[33-35] or bone marrow transplantation (BMT)
[36-39] can result in considerable oral disease.
Viral infections are predominately caused by
HSV, varicella zoster virus, and cytomegalovirus
[40]. Perhaps the most frequent viral infec-
tion, oropharyngeal HSV infection can cause
considerable patient discomfort, interfere with
normal oral function, and can have fatal out-
come.
Intraoral HSV lesions are frequently multi-
ple, punctate lesions, the vesicle of which quick-
ly ruptures. Confluent ulceration then becomes
FIGURE 19-6. Acute herpes simplex virus infec-
tion in an ANLL patient undergoing amsacrine-
aziridinylbenzoquinone therapy. Use of systemic
acyclovir resulted in gradual resolution of the lesion.
 19. ORAL COMPLICATIONS ASSOCIATED WITH HEMATOLOGIC NEOPLASMS
evident (figure 19-6). Extraoral HSV lesions
usually present at the commissures and vermil-
lion borders of the lips, and/or on the phil-
thrum, and follow a similar pattern of vesicular
and ulcerative stages. Both intra- and extraoral
lesions are quite painful.
HSV -induced mucositis can be easily con-
fused with oropharyngeal mucositis secondary
to the direct stomatotoxic effects of either in-
duction drugs or conditioning chemoirradiation
regimens used prior to BMT. Early recognition
of HSV infection is important for a number of
reasons. HSV infection can often be managed in
light of recent therapeutic success with acyclo-
vir [41-43]; patients identified to be at risk for
HSV mucositis may benefit from acyclovir
prophylaxis [44]. However, acyclovir-resistant
HSV has been reported in some patients [45,
46].
Although the epidemiology of oral HSV in-
fections in patients receiving chemotherapy is
not well studied, more data exist for patients
undergoing allogeneic BMT (see chapter 21).
We recently retrospectively reviewed 627
allogeneic BMT patients (426 acute leukemia, 97
chronic leukemia, 90 aplastic anemia, 14 other)
transplanted between 1978 and 1982 at the Fred
Hutchinson Cancer Research Center; 236
(37%) patients developed infections [47]. The
sites of involvement included throat (49%), lip
only (16%), mouth only (15%), and mouth and
lips (16%). Univariant chi-square tests were
used to explore the relationship of various risk
factors to oropharyngeal infection: 560 patients
had pretransplant HSV antibody titers avail-
able; 204 of 330 patients with positive titers
(~1 :8) had subsequent infection compared with
two of 230 with negative titers (p«0.00005).
Additional associated factors among patients
with pre-BMT titers ~1:8 included diagnosis
(leukemia/aplastic anemia) (p=0.03), disease
status (relapse/remission) (p=0.02), radiation
conditioning regimen (p=0.02), and donor-
HSV titers. Incidence of infection among pa-
tients with pre-BMT titers ~ 1:8 did not appear
related to acute graft-vs-host disease, dose of
marrow infused, year of transplant, or patient/
donor sex.
HSV infection in these patients in over-
whelming due to reactivation of latent virus,
with the likelihood of viral latency increasing
with increasing age. Underlying illness and use
of total body irradiation for conditioning
appear to be significant risk factors that are
355
probably linked epidemiologically. Identifica-
tion of risk factors is important in determining
who will benefit most from the prophylactic use
of acyclovir.
Non-HSV infections also occur. For exam-
ple, varicella zoster infection, although not
commonly seen intraorally, may develop in
patients who are immunocompromised. These
lesions typically follow the distribution of the
trigeminal nerve. Acyclovir appears to be of
benefit in some of these patients [48].
Factors other than marrow suppression can
exacerbate oral infections. For example, remov-
able prostheses can increase risk of infection in
two ways. First, ill-fitting appliances can abrade
the mucosa, which is already impaired by toxic
effects of the chemotherapy, resulting in further
ulceration. Second, appliances soaked in den-
ture cups containing water or some denture
disinfectants can readily become colonized with
a variety .of pathogens, including Pseudomonas
aeruginosa, Escherischia coli, Enterobacter spp.,
Staphylococcus au reus, Klebsiella spp., T. glab-
rata and C. albicans [49]. Careful attention to
denture adaptation and soaking solutions is
therefore mandatory; with proper care, the
beneficial effects of enhanced appearance,
nutrition, and self-image can be preserved
for the chemotherapy patient by permitting
restricted denture use during treatment.
Periodontal Infection. Periodontal disease
(gingivitis and periodontitis) is an extremely
common infection, present in most adults in this
country [50]. In general, this disease, including
gingivitis and periodontitis, reflects the in-
flammatory response to bacteria that colonize
the surface of the tooth contiguous to the ging-
iva, metabolize local nutrients, and elaborate
toxins that eventually penetrate the epithelium
of the gingival sulcus. This ulceration of the
epithelium lining the space between the tooth
and gingiva results in a gingival pocket. In the
early stages of periodontitis, the connective
tissue attachment is lost near the crown of
the tooth and the pocket epithelium begins to
migrate apically along the root surface. At
this stage a periodontal pocket is recognized.
In periodontitis, unlike gingivitis, the inflamma-
tion affects the supporting bone. Alteration in
bone homeostasis occurs with a net loss of bony
support that, when advanced, is characterized
by mobility and eventual loss of the teeth.
Thus, gingivitis and periodontitis can be
356 IV. HEAD AND NECK COMPLICATIONS OF CANCER THERAPY

recently studied 12 patients (six ANLL, one

6 b. (28) small cell carcinoma, one Hodgkin's disease,

..'"' one non-Hodgkin's lymphoma, one testicular,

and two breast carcinoma) who developed acute
0
0 5 periodontal infections [57]. The indication for
0 periodontal culturing was tenderness to palpa-
~
tion in the setting of fever (""38.3°C). Subging-
.
U 4
Q.

c:
.~
ival probes and extensive aerobic/anaerobic
techniques were used to culture the acutely
U 3 infected site as well as a contralateral control
~
.: site. Standardized indices were used to assess
.
'0 2
..,"
periodontal status at the cultured sites.
All acute periodontal infections developed

"'.~'"
:;: during profound, persistent myelosuppression
·ii «1000 granulocytes/ill). All patients had mild-
w

(0)
0-99 100-499 500-999
Granulocyte Count (per,...1)
FIGURE 19-7. Incidence of periodontal (circles) and
nonperiodontal (triangles) infection in patients with
ANLL. Numbers in parentheses indicate absolute
number of infections. From Overholser et al [55],
copyright 1982, American Medical Association, with
permission.
characterized as an inflammatory response to
metabolites of a mixed infection established on
the tooth surface. The principal clinical sign is
bleeding through ulcerated epithelium, the total
surface area of which can become several square
centimeters as the periodontal pockets deepen.
However, it is usually chronic and asymptoma-
tic; thus, the patient is often unaware of its
presence. Late in its progression, pain, mobility,
and abscess formation may occur, leading the
noncancer patient to seek emergency dental
care.
Chronic periodontal disease present at admis-
sion that subsequently becomes acutely infected
is a frequent occurrence in patients receiving
profound, prolonged myelosuppressive che-
motherapy. We have previously reported that
acute periodontal exacerbations of preexistent
disease can account for approximately 25% of
all documented acutely infected sites in ANLL
patients during remission induction (figure 19-
7). As with other acute infections in the myelo-
suppressed patient [51, 52], acute periodontal
infections often present with minimal signs of
inflammation [53-56] (figure 19-8). It appears
that the causative organisms are varied; we have
'"
(2)
severe periodontal disease at time of acute ex-
acerbation. Suspected pathogens were detected
~ 1000 in high levels (>2% total viable count; TVC) in
eight patients; Staphylococcus epidermidis (two
patients), C. albicans (five patients) and P. aeru-
ginosa (one patient) predominated. Concom-
itant bacteremia developed in two of these pa-
tients. Candida albicans was recovered in un-
usually high concentrations (0.3%-20% TVC)
from both nonacutely infected control sites as
well as acutely infected sites. Comparatively,
the subgingival microflora of the remaining four
acutely infected patients was characterized by
predominately indigenous microflora. How-
ever, most organisms were in abnormal pro-
portions compared with control patients
without cancer.
These findings suggest that organisms com-
monly associated with acute infections in
FIGURE 19-8. Acute periodontal infection (arrow) in
a patient with ANLL. Patient had low-grade fever
(37.9°C), with this site as the clinically documented
source. Granulocyte count was 10011l1. This lesion
represents an acute exacerbation of preexistent mar-
ginal gingivitis.
 19. ORAL COMPLICATIONS ASSOCIATED WITH HEMATOLOGIC NEOPLASMS 357

myelosuppressed cancer patients as well as

combinations of indigenous oral flora may be
associated with acute periodontal infection.
Study of the influence of both degree of
periodontal disease as well as systemic antibio-
tics is currently ongoing.
In related studies, we have also observed that
the degree of periodontal disease present prior
to admission does not appear to correlate with
the frequency of acute periodontal infection;
in our experience, patients with minimal perio-
dontal disease can become acutely infected as
frequently as those with severe periodontal
disease. A
Carefully supervised mechanical oral hygiene
measures (scaling, polishing prior to induction,
followed by gentle brushing and flossing during
chemotherapy) appear to minimize acute perio-
dontal infection without increasing the risk for
systemic complications (bleeding, esophageal/-
pulmonary infections) [58]. However, these
trends must be confirmed by further investiga-
tion.
Management of acute periodontal infection
includes culturing and both local and systemic
therapy. Cultures should be taken of the in-
fected site by gently placing a probe into the
pocket and withdrawing a specimen under ni-
trogen gas flow (85% nitrogen; 10% hydrogen;
5% carbon dioxide) [59]; standard oral surveil-
lance cultures do not directly assess this site [60,
61]' Care in specimen collection and processing
under anaerobic conditions must be taken so as
not to eliminate potential pathogens from the
culture. While culture results are pending,
broad-spectrum antibiotic therapy should be
considered. Local therapy consists of (a) irriga- B
tion with effervescent agents, e.g., GLYOXIDE
(Marion Laboratories, Kansas City, MO
64137), which are toxic to anaerobic bacteria FIGURE 19-9. (a) Fistulous tract (arrow) detected
normally colonizing the periodontal pocket, as on preinduction oral examination in a patient with
well as (b) supervised gentle mechanical plaque ANLL. (b) Periapical radiograph of involved area
shown in a, showing bony dissolution (arrows). This
removal (dental brushing and flossing).
lesion may become acutely infected during periods of
As the patient's hematologic status returns to granulocytopenia.
normal, comprehensive periodontal care is re-
quired [62]. This approach will minimize risk
for future oral infections during subsequent munication of the dental pulp with the systemic
courses of chemotherapy. circulation, pathogens can readily disseminate.
Any patient who is scheduled to receive
Pulpal and Periapical Infection. Infected myelosuppressive chemotherapy should be
pulpal tissue (most commonly secondary to ca- evaluated orally, with careful attention to deep
rious involvement) can be a difficult acute infec- carious lesions and/or periapical pathology.
tion to manage in the myelosuppressed patient Pulpal pathology can be evaluated with a thor-
[63-65] (figure 19-9); because of direct com- ough history, radiographs, and thermal testing
358 IV. HEAD AND NECK COMPLICATIONS OF CANCER THERAPY

TABLE 19-1. Guidelines for endodontic care in patients about to receive myelosuppressive chemotherapy

Symptoms Radiographs Diagnosis Management

Lingering pain to No periapical Probable irreversi- Initial biomechanical preparation of

hot, cold pathology (PAP) ble pulpitis canal; temporary double closure
None PAP Probable necrotic No endodontic treatment unless patient
pulp has 7 days from completion of
endodontics to myelosuppression
«lOOOhll)
Spontaneous throb- PAP Probable necrotic Endodontics or extraction, depending
bing, lingering pulp with acute on overall state of patient and schedul-
pain infection ing of chemotherapy

(in which hot and/or cold stimuli result in
lingering pain, suggestive of irreversible pulpi-
tis). We use guidelines regarding management of
pulpal pathology in the individual facing immi-
nent chemotherapy that are based on presenting
pulpal symptoms [66] (table 19-1).
On occasion, teeth that are periodontally or
pulpally involved should be extracted. How-
ever, the timing of the extraction should be
carefully considered. In our center, the fol-
lowing guidelines are used [67]: (a) ideally, a
ten-day interval between date of extraction
and onset of myelosuppression «1000
granulocyteS/t..II); (b) platelet counts of at least
40,000/1-11, with platelet transfusions as indi-
cated; (c) no intraalveolar hemostatic agents;
and (d) primary closure.
Patients requiring chemotherapy occasionally
present with pulpally infected teeth that cannot
be restored and should be extracted; however,
there may not be the ten-day interval as de-
scribed above. Judicious management may call
for pulpal therapy (root canal) to eliminate the
acute infection prior to myelosuppression;
extraction can then be performed when the
patient's hematologic status returns to normal.
The reader is referred to chapter 9 for fur-
ther discussion of infection in the myelosup-
pressed host.
neoplastic involvement [68], since, as described
previously, most adults in this country have
some degree of periodontal disease. Chronic
trauma associated with normal functions of the
oral cavity can also induce minor hemorrhage,
which prompts the patient to seek professional
care.
Spontaneous palatal hemorrhage is often
observed when the platelet level becomes <50-
60,000/1-11 (figure 19-10); spontaneous gingival
oozing usually occurs below this level as well.
Patients who do not practice thorough oral
hygiene during their therapy are more prone to
gingival hemorrhage, since plaque can readily
form and exacerbate periodontal ulceration
existent prior to myelosuppression.
If sublingual hemorrhage occurs, airway
embarassment becomes possible. Since the
tongue may be displaced superiorly and poste-
riorly, frequent examinations are required. The
need for possible emergency intubation as well
as platelet support should be considered.
Although disconcerting to the patient, oral
hemorrhage associated with thrombocytopenia

Mucosal Hemorrhage and Anemia. Throm-

bocytopenia frequently occurs in patients with
hematologic neoplasms; this occurrence can be
secondary to either the underlying disease or its
treatment. Spontaneous gingival bleeding, spon-
taneous submucosal bleeding, and postoperative
hemorrhage (infra supra) are all of concern.
Spontaneous bleeding from the gingiva can be
one of the earliest clinical indications of im- FIGURE 19-10. Palatal ecchymoses in a patient with
paired bone marrow function resulting from platelet count of 28,000/1-11.
 19. ORAL COMPLICATIONS ASSOCIATED WITH HEMATOLOGIC NEOPLASMS
is rarely a debilitating complication except as
noted above. Gauze soaked in topical thrombin
can be used as needed, and is usually successful
in reducing oozing. However, continued oozing
can be very uncomfortable to the patient, who
will predictably experience difficulty in eating,
speaking, and sleeping. Platelet transfusions are
usually not required except in patients whose
platelet counts are profoundly suppressed, re-
sulting in hemodynamically significant bleeding
episodes. The benefit of platelet support needs
to be measured against the risk of development
of alloimmunization. Avoidance of trauma
(dietary, factitial, dental) should be stressed.
Anemia can be manifested in the oral cavity as
well. Typical changes include pallor of the oral
mucosa as well as atrophic glossitis, the latter
of which can usually be managed palliatively
until the underlying erythrocyte abnormality is
corrected.
Summary
Oral complications secondary to hematologic
neoplasms and their treatment frequently con-
tribute to the morbidity and mortality of the
patient. The oral cavity is prone to the direct
and indirect stomatotoxic effects of cancer che-
motherapy. Oral care should be both preventive
as well as therapeutic as indicated, to minimize
the risk for oral discomfort as well as systemic
complications.
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 20. HEAD AND NECK NEUROLOGIC
COMPLICATIONS OF MALIGNANCY
N. Simon Tchekmedyian
Richard S. Kaplan
Neurologic complications of malignancy in the
head and neck region may result from direct
tumor invasion of neural structures or adjacent
tissues or from the effects of systemic cancer.
Complications may also be related to the
various treatment modalities used in the man-
agement of both systemic cancer and cancer
involving the nervous system. This discussion
is divided into two sections: (a) complications
affecting mainly the brain, resulting from
malignant invasion, thrombocytopenia and co-
agulopathy, hypercalcemia, and toxicity of
therapy; and (b) complications affecting mainly
the meninges and cranial nerves, resulting from
malignant invasion and its management. Cere-
brovascular complications in patients with
cancer have been recently reviewed in detail
[1] and are not directly addressed here.
Brain
MALIGNANT INVASION
Any malignant tumor has the potential to
compress, invade, or metastasize to the dura
mater or the structures it covers and contains.
Primary or metastatic tumors located outside
the dura but in the head and neck area may
produce neurologic complications by local ex-
pansive or invasive growth, leading to damage
of nerves and intracranial structures. More
often, however, neurologic complications are
due to blood-borne metastases to meninges,
nerves, or brain from distant tumors.
Brain metastases constitute the most impor-
tant neurologic complication of malignancy be-
cause they are associated with radical changes in
life expectancy, quality of life, and therapeutic
needs of the affected patients. They may be
Peterson et aI., HEAD AND NECK MANAGEMENT OF THE CANCER PATIENT.
© 1986. Martinus NijhofJ Publishing. All rights reserved.
single or, more often, multiple; they may occur
alone or coexist with discrete or diffuse involve-
ment of other intracranial structures. Brain metas-
tases always originate hematogenously and are
commonly associated with obvious evidence
of disseminated cancer. In some instances,
however, brain metastases may be manifesta-
tions of an occult malignancy, an otherwise
localized tumor, or a previously treated and
controlled cancer.
Leukemia also may produce neurologic man-
ifestations by invading the brain. Myeloid leu-
kemic blasts may grow into solid tumor masses
called granulocytic sarcomas or chloromas that
lead to complications common to space-
occupying lesions. In other instances, high
numbers of circulating leukemic blast cells may
produce "leukostasis" in the brain, leading to
changes in mental status, intracranial hemor-
rhage, and death. We will focus on these three
distinct types of brain invasion by malignancy,
namely: brain metastases, chloromas, and
leukostasis.
Brain Metastases. Brain metastases occur
more frequently than primary brain tumors [2].
In two large autopsy studies of cancer patients,
the incidence of brain metastases varied between
9% and 15% [2,3]. Most are due to lung cancer
in males and to breast cancer in females. In fact,
these two primary tumors accounted for 76% of
all brain metastases in one radiotherapy series
[4]. About 25% of lung and 15% of breast can-
cer patients will develop brain metastases at
some point during their illnesses. Malignant
melanoma, carcinoma of unknown primary site,
testicular cancer, renal cell carcinoma and, less
frequently, other tumors account for the re-
maining cases (figure 20-1) [4].
363
364 IV. HEAD AND NECK COMPLICATIONS OF CANCER THERAPY

The reason these tumors metastasize to the

Location of o BRAI N METASTASIS Nu m ber of brain so frequently is unclear. It is postulated
Primary Tumor ,....::D::..,..M_E_TS-',_N_O_T_B_RA_'_N_---, Cases that tumors located in pulmonary parenchyma
TOTAL 9 10,916 have direct access to the pulmonary circulation
SK'NIMELANOMA)I='='c====;==='-= 234
and thus to the left heart and arterial tree, while
LUNG 1,440 tumor cells released from other sites enter the
UNKNOWN I===-::=====~ 136 systemic venous circulation and thus need to
121 traverse the pulmonary capillary bed before
TESTIS I=~'======:::;:~
BR E AS T "=c='===== 1,067 reaching the arterial system. However, it is of
KIDNEY 8 URETER 10 277 interest that within a specific tumor, cell sub-
SOFT TISSUE a. BONE t-'CL---:c--::===='=' 116 populations may differ markedly in their ability
208 to metastasize to a specific organ. Experiments
ESOPHAGUS 1-'-_ __ 184 in animal tumor models have demonstrated this
438 heterogeneity of metastatic behavior; moreover,
711 cell lines have been identified that possess
UPPER RESPIRATORY 353 specific cell surface properties and a high poten-
338 tial for successful implantation, survival, and
BLADDER 8 URETHRA 355 growth in the brain [11].
298 Other tumors are less prone to produce brain
OVARY a FALLOPIAN 364 metastases. Pancreatic, gastric, esophageal, pros-
413 tatic, colorectal, head and neck, uterine, and
ORAL CAVITY a PHARYNX 1'::-_ _ _--' 602 ovarian cancers uncommonly metastasize to the
LYMPH NODES .'j 969 brain and, when they do so, it is usually well
o 20 40 60 80 100
after detection of the primary tumor and in the
% CASES setting of widely disseminated or advancing
disease [2].
Inbetween these two extremes, there are
FIGURE 20-1. Metastases to brain and other sites
found at autopsy in one large series of cancer pa-
tumors with an intermediate or unpredictable
tients. In only 3% of all cases with brain metastases tendency to metastasize to the brain. These
were systemic metastases absent. Adapted from Pick- include breast cancer, cancer of "unknown
ren et aL [2], with permission. primary," squamous cell lung cancer, renal cell
cancer, choriocarcinoma, and testicular cancer.
Recent increases in the reported incidence of
Certain tumors are particularly prone to brain metastases [12-14] may be related to three
produce brain metastases. Oat cell carcinoma, phenomena: a higher incidence of lung and
adenocarcinoma and large cell carcinoma of breast cancer, an improvement in overall sur-
the lung, and malignant melanoma are notorious vival and extracerebral disease control achieved
for their tendency to metastasize to the brain [2, by modern therapy, and the advent of compu-
5-7]. With these tumors, brain metastases are terized tomography. It should be noted that,
often multiple and may occur prior to, simul- because of the poor penetration of most che-
taneous with, or after the identification of a motherapy agents into brain tissue, cell growth
primary growth. Patients with oat cell lung can- may proceed undisturbed in the brain "sanctu-
cer who respond to chemotherapy and survive ary" even when effective drugs are being used.
more than two years have a greater than 60% This seems to be a recapitulation of the experi-
likelihood of developing brain metastases. This ence in childhood acute lymphocytic leukemia
high incidence has led to the institution of in which central nervous system involvement
"prophylactic" cranial irradiation at the time of became prevalent only after effective treatment
chemotherapy-induced complete remission in for extracranial disease was developed [15].
these patients [8]. As many as 70%-90% of In an autopsy series of 2375 patients dying of
patients dying of malignant melanoma have cancer, intracranial metastases were found in
brain metastases [9, 10]. When brain metastases 24% and brain metastases in 15% [3, 16]. The
are the presenting evidence of malignancy, lung location of intracranial metastases in this series
cancer is by far the most common underlying is detailed in table 20-1; 18 % of all patients with
process. intracranial metastases had apparently isolated,
 20. HEAD AND NECK NEUROLOGIC COMPLICATIONS OF MALIGNANCY 365

TABLE 20-1. Intracranial metastases in 2375 patients with cancer

% All patients % All patients % All patients

with intracranial with brain with single
% All autopsies metastases metastases only brain metastases
(n = 2375) (n = 572) (n = 225) (n = 105)

Intracranial metastases 24 100

Intradural metastases
(brain and leptomeninges) 20 82
Brain metastases 15 63
Brain metastases only 9 39 100
Single 4 18 47 100
Cerebrum 15 39 81
Cerebellum 3 7 16
Brain stem 0.5 1 3
Multiple 5 21 53
Leptomeningeal metastases 8 32
Leptomeningeal
metastases only 3 12
Dural metastases 9 35
Dural metastases only 4 18
Adapted from Posner et a1. [16]. with permission.

single brain metastases. Although relatively
small in autopsy series, the subset deserves some
attention. Approximately one-third of clinical
brain metastases are single and surgical treat-
ment appears to offer better palliation than
radiation therapy [14]. Location of these metas-
tases is an important variable determining
potential resectability. Isolated metastases are
often found at the junction of white and gray
matter. Most authors feel that the distribution
of solitary metastases depends mostly on rela-
tive size and blood flow of different brain re-
gions. Thus, in the series mentioned, isolated
metastases occurred most commonly in the
cerebrum (81 %). Frontal, parietal, temporal,
and occipital lobes were affected in decreasing
order of frequency. The cerebellum accounted
for 16% of solitary metastases, and the brain
stem for 3% (table 20-1).
CLINICAL FINDINGS. Clinical manifestations
are due to increased intracranial pressure, local
tissue damage, and shift of intracranial struc-
tures; these vary with the location, size, and
number of the lesions and with the amount of
peritumoral brain edema. Common presenting
symptoms are headaches, focal weakness, men-
tal disturbances, and seizures. Ataxia, visual
deficits, aphasia, somnolence, memory loss, per-
sistent nausea or vomiting, and a host of other
complaints alone or in combination may occur.
Symptoms often evolve subacutely as would be
expected with a slowly growing tumor. Not un-
commonly, however, an acute neurologic event
(seizure, stroke, cerebral herniation) occurs pre-
sumably as a consequence of local cerebral
tissue irritation, sudden hemorrhage into a
metastasis or rapidly developing brain edema.
Although usually symptomatic, brain metas-
tases may also be asymptomatic or produce
vague and nonimpressive complaints. We have
been surprised by the striking extent of metas-
tases detected by computed tomography scan-
ning in some of these cases. Physical findings
more commonly consist of focal motor and/or
sensory defects, impaired cognitive functions,
papilledema, and ataxia. Certain findings have
localizing value; these include focal motor
deficit and focal seizures (corresponding motor
cortex), visual defects (optic tract), localized
unilateral headache (side of lesion), and dys-
metria (cerebellum). Ataxia may result from
lesions of the cerebellum, brain stem, or frontal
lobe or from hydrocephalus; unilateral ataxia
may result from a parietal lesion. Occas-
ionally, although the patient complains of gait
disturbance, ataxia is not demonstrable on ex-
amination.
Posterior fossa tumors characteristically raise
intracranial pressure abruptly and produce not
only ataxia but severe headache, vomiting, and
often papilledema. Brain stem lesions produce
366 IV. HEAD AND NECK COMPLICATIONS OF CANCER THERAPY

FIGURE 20-2. CT scan of the head in a patient with

breast cancer. (Left) Unenhanced study reveals large
lucent (dark) area of brain edema in the left hemi-
sphere, surrounding a more dense medially located
oval structure. Note right shift of midline. (Right)
Enhanced study shows marked contrast enhance-
ment and better definition of the lesion.
FIGURE 20-3. Head CT (enhanced) in a patient with
malignant melanoma and brain metastases presenting
with right hemiplegia. There is a large left paren-
chymal hemorrhage. Note blood density with a level
due to blood in the ventricular system.
 20. HEAD AND NECK NEUROLOGIC COMPLICATIONS OF MALIGNANCY
FIGURE 20-4. Unenhanced head CT in a patient with
malignant melanoma who developed hemiparesis
while thrombocytopenic. A right parenchymal bleed
is indicated by the presence of blood density; this
would be obscured in an enhanced study.
complex findings including vertigo, nystagmus,
ataxia, gaze palsies, and dysphagia. Sometimes,
unusual locations may lead to characteristic
manifestations. These include the pituitary (di-
abetes insipidus, with polyuria and hypernatre-
mia) and the fourth ventricle (hydrocephalus).
DIAGNOSIS. Computed tomography (CT) scan-
ning has made the diagnosis of brain metastases
reasonably simple and accurate. A metastatic
implant is often distinguishable on CT scan be-
cause of its density, disproportionate surround-
ing edema, contrast enhancement, or because
of distortion of adjacent visible intracranial
structures (figure 20-2). A metastatic nodule
may be hyper-, hypo-, or isodense in relation
to the normal brain tissue. Higher or lower
densities will make a metastasis visible. Blood
density renders hemorrhage due to the tumor
readily visible in un enhanced CT scans (figures
20-3 and 20-4). Intratumoral hemorrhage is a
frequent occurrence with melanoma, choriocar-
cinoma, and renal cell cancer. Calcifications are
very dense and occur in osteosarcoma. Even
when the tumor density is similar to that of the
367
brain, the less dense surrounding (peri tumoral)
edema which is almost always present will make
the tumor borders noticeable. The tumor will
appear to be a fairly well demarcated area of
higher density within a larger area of decreased
density (figure 20-2). Additionally, metastases
often become visible with the administration of
contrast material that will only enter areas with
altered blood-brain barrier, such as tumors
(figures 20-2 and 20-5). Contrast enhance-
ment occurs in most metastatic tumors and
provides a better definition of the exact size,
location, and number of metastases; it also in-
creases the sensitivity in the diagnosis of small
lesions with little peritumoral edema; the latter
can be missed in the unenhanced CT scan
(figure 20-5). Occasionally, strongly suspected
metastases are not identified on CT; a repeat CT
following the administration of a double dose of
contrast or a delay between contrast injection
and scanning may yield positive results [17].
Hydrocephalus, midline shifts, and changes in
size and shape of the ventricles often help in the
indirect assessment of metastases.
CT scan has a high degree of sensitivity in the
detection of brain tumors and without a doubt
is the diagnostic procedure of choice when
available. Alternative or complementary proce-
dures include radionuclide scan, angiography,
368 IV. HEAD AND NECK COMPLICATIONS OF CANCER THERAPY

FIGURE 20-5. Head CT in a patient with small cell

lung cancer. (Left) Unenhanced study does not reveal
brain metastases. (Right) Enhanced study clearly
shows multiple metastases.

FIGURE 20-6. Enhanced head CT in a patient with

breast cancer. (Left) Notice left lateral hemispheric
area of ring enhancement (arrowhead) with associ-
ated surrounding edema. Brain abscess may present
similar characteristics. (Right) At a higher level,
associated edema is noted.
 20. HEAD AND NECK NEUROLOGIC COMPLICATIONS OF MALIGNANCY
FIGURE 20-7. Un enhanced head CT in a patient with
breast cancer. The dense midline lesion is characteris-
tic of meningioma.
and electroencephalography (EEG). Spinal
tap is discouraged in the absence of meningeal
signs because it can precipitate herniation of
edematous brain.
In spite of being the best current diagnostic
modality, CT scan is less than totally accurate.
In a series where autopsies were performed on
patients dying within two weeks after a head
CT scan had been performed, it was shown that
about one-third of lesions more than 1 cm in
size had been missed [18]. Smaller lesions will
probably go unidentified in most cases. In fact,
about one-third of patients with malignant
melanoma diagnosed by CT as having single
brain metastasis were found to have multiple
metastases at autopsies performed within a
week of obtaining the CT scans [7]. CT scan
may not discriminate with certainty among
metastases and primary brain tumors, mening-
iomas, infarcts, abscesses, or other benign brain
lesions that are a diagnostic consideration. In
some of these cases, tissue diagnosis may be
necessary. Abscesses in particular may present
clinical and CT characteristics indistinguishable
from those expected from metastases (figure 20-
6). Brain abscess is a distinct possibility in pa-
369
tients who have undergone a surgical procedure
in the oral cavity. Benign meningiomas are not
rare as second neoplasms in women with a his-
tory of breast cancer (figure 20-7) [19]. Nuclear
magnetic resonance (NMR) scanning has the
potential to identify very small metastases and
to determine whether a given lesion is tumor,
abscess, or infarct.
CT scan is of great value in the planning and
execution of surgery. It is also invaluable in the
postsurgical follow-up period and in the assess-
ment of tumor response and complications
related to surgery, chemotherapy, and radio-
therapy. The orbital region is well defined and
tumor extension into underlying brain from an
extrinsic origin can be evaluated (figures 20-8
and 20-9). Complications of the procedure are
minimal and include radiation exposure of
about 10-40 cGy per procedure (1 cGy = 1 rad),
anaphylactic reactions to contrast material (one
in 10,000 patients or less), renal failure due to
contrast material especially in dehydrated pa-
tients, and promotion of seizures due to injec-
tion of contrast material in patients with brain
metastases [20, 21]. Intravenous (i.v.) valium (5
mg) prior to the injection of contrast has been
shown to decrease the incidence of contrast-
induced seizures in patients with brain metas-
tases [22].
370 IV. HEAD AND NECK COMPLICATIONS OF CANCER THERAPY
TREATMENT. The treatment of brain metastases
is, for the most part, palliative; its goal is to
provide the patient with the longest possible
useful survival. Occasionally a single (rarely
more than one) resectable metastasis in a patient
who has either no obvious primary tumor or an
otherwise well-controlled extracranial tumor
will lend itself to excision with the intent of
long-term control. Unfortunately, this cir-
cumstance is unusual, and even in this category
long-term survival is rare, usually because of
systemic tumor progression rather than central
nervous system (CNS) complications or relapse.
Brain metastases, if left untreated, will usually
result in death within a few weeks_ The modali-
ties of treatment commonly utilized are corti-
costeroids to control brain edema, phenytoin
and/or phenoba·rbital to control seizures, and
excisional surgery and/or radiation therapy for
tumor control. Chemotherapy has been of
limited value, but there is growing evidence that
established metastases, in which the blood-
brain barrier is disrupted, may respond to ap-
propriate systemic chemotherapy [23-25].
Corticosteroids are indicated in all patients
with symptomatic brain metastases to effect re-
lief of peritumoral edema. Steroids are particu-
larly useful in the reversal of general symptoms
such as headaches, lethargy, and confusion.
Dramatic results regarding these symptoms are
obtained in over 70% of patients and may occur
within hours [26]. The patient becomes able to
FIGURE 20-8. CT scan through the orbits in a patient
with lymphoma. (Left) There is a left retroorbital
mass (arrowhead). (Right) Mass no longer seen after
radiation therapy.
function and communicate and time is obtained
for further evaluation, discussion of the prob-
lem with the patient and family, and planning of
treatment. Focal neurologic defects are not re-
versible with steroids if due to tumor invasion.
Dexamethasone is used in pharmacologic doses,
commonly 16 mg/day in four divided doses
orally (p.o.) or i.v. The dose may be increased
up to 100 mg/day if needed. Steroids probably
do not offer tumor control; therefore, deteriora-
tion and death will occur in a period of several
weeks if other modalities of therapy to control
the disease are not instituted. Once other
modalities have been used, it may be possible to
gradually decrease the dose of dexamethasone
to prevent undesirable side effects (mainly
Cushing's syndrome with proximal myopathy,
salt and water retention, gastritis, catabolic
state, and immunosuppression). Dose reduction
should be undertaken gradually because steroid-
withdrawal symptoms (headaches, lethargy,
and general deterioration) may mimic recurrent
intracranial disease. Unless complete surgical
extirpation has been carried out, dexametha-
sone will usually be needed for the remainder
of the patient's life.
Phenytoin sodium is the drug of choice in the
event of seizures; it may decrease the bioavaila-
bility of dexamethasone and dose adjustments
 20. HEAD AND NECK NEUROLOGIC COMPLICATIONS OF MALIGNANCY
FIGURE 20-9. Head CT in a patient with diffuse
histiocytic lymphoma of the forehead. (Left) Bone
window study reveals bone destruction and extension
of tumor under the bone (arrows). (Right) Enhanced
CT reveals large lesion and defines its extension in
depth and the compression of brain parenchyma.
may be needed. Blood levels of phenytoin
should be monitored during therapy. In the
absence of seizures, the prophylactic use of
phenytoin is controversial. Some clinicians will
use it for cortical lesions or melanoma metas-
tases because of their higher tendency to pro-
duce seizures [14]. We prefer to use the drug
only for treatment, after seizures develop.
Surgery is limited to patients who present
with a single resectable metastasis and are
unlikely to die of uncontrollable extracranial
disease within the ensuing three months. This
subset constitutes less than one-fifth of all
patients with intracranial metastases and in and
of itself represents a group with a better prog-
nosis. This should be taken into account when
evaluating results of surgery versus radiation
therapy in these patients. Additionally, patients
suspected of having single brain metastasis but
without a proven primary tumor or with an un-
clear diagnosis are also surgical candidates since
histologic classification may be useful or man-
datory to the workup or therapeutic plan. De-
compressive surgery will be imperative when
life-threatening hemorrhage from a tumor
occurs unless the patient is felt to be terminal
from the viewpoint of systemic disease. Multi-
371
pie brain metastases are usually considered a
contraindication for surgery.
Corticosteroids and the availability of CT
scanning for diagnosis, operative planning, and
follow-up have made surgery for cranial metas-
tases a more feasible and less morbid procedure.
Primary brain tumors present indistinct margins
because they diffusely infiltrate the surrounding
brain tissue. In contradistinction, most isolated
brain metastases have dramatic surrounding
brain tissue edema and distinct tumor margins
facilitating surgical excision. As a consequence,
surgery in selected patients is uncomplicated
and rapid recovery occurs after the operation.
In one surgical series [27], overall surgical mor-
tality was 8.5%; mortality of patients having
elective surgery was 4%; 50% patients were
dead at six months and 75% were dead by the
end of one year. There were no five-year sur-
vivors in this series, but occasionally there have
been single cases reported. In this series and in
most centers, surgery is followed by whole
brain irradiation to control local (surgical bed)
disease and micrometastases [28]. Other recent
surgical series in selected patients show some
promising results [29-32]. However, there are
no prospective randomized controlled trials to
establish whether surgery or radiation offer bet-
ter results in the treatment of patients eligible
for surgery.
Radiation therapy is effective in the short-
term control of brain metastases; it is mainly
useful in improving quality of life during the
372 IV. HEAD AND NECK COMPLICATIONS OF CANCER THERAPY
period of survival since it produces stabilization
of the disease with improvement in neurologic
function in about 60% of patients for a period
averaging six months [33]. Typical therapy con-
sists of 3000 cGy administered in daily fractions
over a period of two weeks. This schedule has
been shown to be biologically equivalent to and
equally effective as 4000 cGy over four weeks.
In the setting of advancing extracranial disease,
there is little impact of radiation therapy upon
survival. In most series, median survival is about
4-6 months and over two-thirds of the patients
die of advancing systemic metastases. The
relatively small subset of patients having a
better performance status and less extensive
extracranial disease will have maximum benefit,
sometimes achieving one or two years of useful
survival. Patients with brain metastases from
choriocarcinoma treated with brain irradia-
tion and systemic chemotherapy have a better
outcome, with more than 40% long-term sur-
vival [34]. Excellent long-term survival and
potential cures have been obtained in selected
patients with nonseminomatous germ cell tes-
ticular tumors and brain metastases treated with
aggressive chemotherapy and radiation therapy
[35].
Systemic chemotherapy has not been consid-
ered to be effective in brain metastases in part
due to failure to penetrate brain tissue. Recent
experimental data challenge this concept [23-
25]. Disruption of the blood-brain barrier by
clinically evident tumors may render them sus-
ceptible to effective systemically administered
agents and further studies are needed to test this
possibility. Trials with drugs that cross the
blood-brain barrier and studies with intraarte-
rial (carotid artery) infusion chemotherapy are
ongoing at several centers. Intrathecal che-
motherapy is not effective in the treatment of
brain metastases.
In summary, brain metastases are generally,
but not invariably, associated with a poor prog-
nosis, with the vast majority of patients dying
within one year usually from systemic cancer in
spite of current treatment. During the period of
survival, patients may have significant palliation
from corticosteroids and radiation therapy.
Surgery is a reasonable choice when there is a
diagnostic doubt or when removal of a single
metastasis is anticipated to result in a relatively
prolonged useful survival.
Granulocytic Sarcoma (Chloroma). Granu-
locytic sarcomas are tumors composed of malig-
nant myeloid cells. These tumors are often
green (due to the presence of myeloperoxidase)
and are therefore also called chloromas. They
occur in acute myelogenous leukemia and in the
blastic or accelerated phase of chronic granu-
locytic leukemia and other myeloproliferative
disorders [36-38].
Chloromas can develop at any site, but most
commonly arise from the subperiosteal regions
of bony structures. The skull and, in particular,
the orbits, paranasal sinuses, and mastoids are
often involved. In these locations, granulocytic
sarcomas may grow adjacent to the dura mater
and compress the brain or cranial nerves, thus
producing neurologic impairment in the form of
focal deficits, increased intracranial pressure,
and nerve palsies. Chloromas may occasionally
be intracerebral [38-45]. Concomitant menin-
geal involvement should always be suspected.
Other common areas of involvement by chlor-
omas are lymph nodes, skin, gastrointestinal
tract, sternum, ribs, and proximal portions of
long bones.
Chloromas may be single or multiple and
usually develop at the time when overt acute
leukemia is present. Occasionally the tumor(s)
develop months before acute leukemia is di-
agnosed [46] and in these instances the diagnosis
of granulocytic sarcoma may be difficult or im-
possible on cytologic or histologic grounds.
Special stains such as chloracetate esterase and
antilysozyme immunoperoxidase as well as
ultrastructural studies may be needed in these
instances to exclude differential diagnostic pos-
sibilities such as lymphoma [36, 46]. The tumors
may also be harbingers of the accelerated phase
of otherwise stable myeloproliferative processes
[36]. Chloromas are very sensitive to radiation
therapy and respond well to 1000-2000 cGy.
They have also responded to systemic che-
motherapy, which is eventually needed in
virtually all cases since these tumors are local
manifestations of a generalized process. Radia-
tion therapy is of particular benefit for chlor-
omas of the brain.
Leukostasis. In patients with acute leukemia
or with the accelerated phase of chronic granu-
locytic leukemia, circulating immature cells
(blasts) in excess of 100,000/mm3 (100 X 109/
liter) in peripheral blood may produce stasis
(Ieukostasis) in small arterioles and veins. At
this level, blast cell thrombi are formed and
 20. HEAD AND NECK NEUROLOGIC COMPLICATIONS OF MALIGNANCY
local intravascular cell proliferation then leads
to leukemic nodule formation, blood vessel
wall rupture, and hemorrhage. This syndrome
does not imply true leukemic brain tissue inva-
sion, and cerebrospinal fluid examination does
not reveal leukemic cells unless concomitant
meningeal leukemia develops. Leukostasis may
occur at any organ site, is prominent in the
lungs, and has its most dramatic manifestations
in the brain where it often leads, unless prompt-
ly and aggressively treated, to early massive
intracerebral hemorrhage and death [47-51].
Leukostasis does not usually occur in the stable
phase of chronic myelogenous leukemia even
when circulating cells far exceed 100 X 109 Iliter.
This may be due to the smaller cell size, greater
deformability, or lesser capacity for prolifera-
tion in situ of the chronic leukemia cells. Clini-
cal manifestations of the syndrome have been
reported in childhood chronic myelogenous
leukemia and may be a result of the extreme
leukocytosis and relatively high percentage of
immature cells present in that disease [52).
About 10% of patients with acute leukemia will
present with initial leukemic blast cell counts of
over 100 X 109 /liter. In these patients, early
death during the first seven days of treatment is
frequent and is commonly due to intracerebral
hemorrhage secondary to leukostasis. The
clinical picture is characterized by tachypnea,
visual blurring, stupor, engorgement of retinal
veins, papilledema, and sudden deterioration
with coma and death. Sudden headache is a
particularly ominous symptom; it can be the
presenting manifestation and is often asso-
ciated with massive intracranial hemorrhage.
Hypoxemia, dehydration, hyperuricemia, and
renal impairment are common. Once intra-
cranial hemorrhage develops, the outcome is
virtually always fatal. If early death from
complications of leukostasis is prevented, these
patients will obtain complete remissions as
often as patients without hyperleukocytosis,
although overall they have a slightly worse
long-term prognosis [49, 53].
Leukostasis is a medical emergency and
should be aggressively treated to prevent early
death from intracerebral hemorrhage. The man-
agement should start with an assessment and
stabilization of respiratory and metabolic status
with emphasis on oxygenation and hydration.
Other specific measures used at the University
of Maryland Cancer Center include allopuri-
nol, cranial irradiation, and prompt institution
373
of effective chemotherapy; hydroxyurea and
occasionally leukopheresis are useful in selected
patients. Allopurinol should be started prompt-
ly and in high dosage to prevent severe hyper-
uricemia and renal failure from acute tumor
lysis syndrome at the time of systemic che-
motherapy. Immediate cranial radiation therapy
(400 cGy to the whole brain in one session) has
been given to these patients at our and other
institutions with the purpose of preventing in-
travascular leukemic cell proliferation with sub-
sequent hemorrhage [53-55). Definite evidence
that this measure is effective is lacking. At our
institution, those patients presenting with signs
of intracranial hemorrhage did not seem to
benefit from this or any measure. Conversely,
among those receiving radiation therapy prior
to the development of such signs, none died of
intracerebral hemorrhage [56). Hydroxyurea (3
g/m 2 p.o.) is often given to rapidly lower the
blood counts so that new foci of intracerebral
leukostasis are prevented. Leukopheresis may
occasionally be of help if sudden lysis of cells is
considered to pose excessive risks related to
hyperuricemia and renal impairment at pre-
sentation. Hydroxyurea and leukopheresis are
temporizing measures to be utilized only when
immediate systemic chemotherapy is not
feasible. It should be noted that, because of a
concomitant low hematocrit, whole blood
viscosity is usually not significantly elevated in
leukemic patients with hyperleukocytosis [57,
58). Packed red cell transfusions may elevate
whole blood viscosity and worsen stasis in the
microcirculation. Caution is recommended,
therefore, in the early transfusion of red blood
cells to these patients [57). Chemotherapy with
the agents selected for the particular type of
leukemia should be started as soon as possible,
usually after the above immediate measures
have clinically stabilized the patient.
THROMBOCYTOPENIA AND
COAGULOPATHY
The major neurologic complication of throm-
bocytopenia is intracranial bleeding. Coagula-
tion abnormalities may be pathogenically re-
lated to or may coexist with thrombocytopenia
and thus precipitate bleeding. Before platelet
concentrates were available for transfusion, fatal
intracranial, pulmonary, and gastrointestinal
bleeding were common causes of death in pa-
tients with thrombocytopenia secondary to acute
leukemia and its treatment [59). Experience
374 IV. HEAD AND NECK COMPLICATIONS OF CANCER THERAPY
..
..
r----.----r----.--~r--i.~
.,
10 20 30 40 >60
Bleed ing Time (min)
FIGURE 20-10. Inverse relations of bleeding time to
circulating platelet count in patients with thrombo-
cytopenia on the basis of impaired production. The
regression line is shown by the solid line, and 95 %
confidence limits are indicated by the shaded area.
Exce.rpted from Harker and Slichter [61], with per-
mlSSlon.
acquired in the prevention and treatment of
hemorrhage in leukemia patients during the last
two decades has set the basis for a rational man-
agement of thrombocytopenic cancer patients.
Normal platelet counts range from 150,000 to
450,000 per cubic millimeter (150-450 X 109 /
liter). Thrombocytopenia is defined as a platelet
count lower than 100 X 109/liter. Microscopic
examination of a stained blood smear is needed
to assess the number and appearance of platelets
and to exclude spuriously low platelet counts as
measured by automated equipment.
Relation of Platelet Counts to Bleeding
Time and to Type and Risk of Bleeding.
The degree of thrombocytopenia is a key
variable affecting the overall risk of bleeding and
correlates with the bleeding time. The normal
bleeding time varies with the technique em-
ployed and is 1-9 min by the method described by
Ivy et al. [60]. Other authors found normal
values of 4.5 ± 1.5 min using a carefully stan-
dardized technique [61]. When thrombocy-
topenia is due to decreased platelet production,
the bleeding time remains normal until the
platelet counts decrease below 100 X 109 /liter.
With counts below 10 X 109/liter, the bleeding
time is in excess of 30 min. Inbetween these two
extremes, there is a consistently linear correla-
tion between the platelet counts and the bleed-
ing times (figure 20-10) [61]. Similarly, there is a
direct quantitative relation between the platelet
counts and the risk and severity of hemorrhage
in patients with acute leukemia [62]. Thus,
platelet counts between 100 and 50 X 109/liter
are associated with slightly prolonged bleeding
times, minor skin or mucosal bleeding, and an
absence of severe hemorrhage. Counts between
50 and 20 X 109 /liter produce minor to moder-
ate dermal and mucosal bleeding, but do not
usually lead, in and of themselves, to severe
spontaneous life-threatening hemorrhage. Typ-
ically, petechiae, microscopic hematuria, posi-
tive stool guaiac, gingival bleeding, and epistaxis
occur in this setting. The bleeding time is
markedly prolonged, however, and traumatic
bleeding may be severe. With counts below 20
X 109 /liter, spontaneous bleeding may occur in
vital organs, including the central nervous sys-
tem, with a potential for serious morbidity and
mortality; counts below 10 X 109/liter particu-
larly have been associated with intracranial
bleeding and death in leukemia patients and
with an abrupt increase of severe hemorrhage in
solid tumor patients [62, 63].
Causes of Decreased Platelet Production. In
patients with malignancies, decreased platelet
production may result from bone marrow inva-
sion by leukemia, lymphoma, or solid tumor. In
addition, chemotherapy and/or extensive radia-
tion therapy will produce amegakaryocytic
thrombocytopenia for variable periods of time
due to bone marrow toxicity.
Causes of Decreased Platelet Survival and
Associated Coagulopathy. Fever and sepsis
decrease platelet survival and are often respon-
sible for a sudden drop in platelet counts. Causes
implicated are platelet adherence to bacteria
with subsequent phagocytosis by the monocyte-
macrophage system, endotoxemia, and changes
in the vascular endothelium [64]. In addition,
viral and bacterial infections may decrease
platelet production.
Disseminated intravascular coagulation
(DIC) also decreases platelet survival, produces
additional coagulation disorders, and often
leads to bleeding. DIC in cancer patients may be
due to sepsis, spontaneous or chemotherapy-
induced release of procoagulants from malig-
nant cells, disruption of the microvasculature by
tumor, liver disease with inadequate clearance
of activated coagulation factors, transfusion
reactions, and other factors [65]. Thrombocy-
topenia of mild degree (counts above 50 X 109/
 20. HEAD AND NECK NEUROLOGIC COMPLICATIONS OF MALIGNANCY
liter) is often produced by sepsis alone; sepsis is
often complicated by DIC and, when both
occur together, more severe thrombocytopenia
(counts below 50 X 10 9/liter) may develop [66].
DIC may complicate any solid tumor, but is
more commonly found with mucin-producing
adenocarcinomas such as prostatic, pancreatic,
gastric, and ovarian carcinomas. Most patients
with acute pro granulocytic leukemia present
with DIC that results from the release of
procoagulant activity contained in cytoplasmic
granules of leukemic cells.
Clinical manifestations of DIC range from
subtle delayed or prolonged bleeding at veni-
puncture sites to impressive diffuse bleeding in
skin, mucosal, and visceral sites. Bleedin,g is
mainly due to increased fibrinolysis. Thrombo-
sis is more common than bleeding in patients
with low-grade DIC due to solid tumors.
Laboratory findings include relatively low or
falling fibrinogen levels, increased levels of
fibrin degradation products, falling platelet
counts, schistocytes in the peripheral blood
smear, prolonged prothrombin and thrombo-
plastin times, and decreased levels of plasmin-
ogen and coagulation factors V and VIII.
Treatment of the underlying process, such as
cancer or infection, is the only definitive ther-
apy for DIe. Temporizing control of bleeding
and/or thrombosis may be obtained with trans-
fusions of blood products and anticoagulation
with heparin. Decreased platelet survival may
also result from splenomegaly, hemorrhage, and
immune destruction of platelets associated with
lymphoid malignancies, solid tumors, or drugs
such as sulfonamides or heparin.
Factors Affecting the Risk of Bleeding in
Thrombocytopenic Patients. Thrombocy-
topenia is a central factor affecting the risk of
hemorrhage, but platelet function defects,
coagulation abnormalities, performance of
invasive procedures or surgery, and underlying
structural lesions such as brain metastases are
important additional factors.
"Young" platelets are hemostatically more
effective than "old" platelets. Thus, the bleeding
time of patients with autoimmune thrombocy-
topenic purpura or with early regenerating bone
marrow function after chemotherapy is often
normal or near normal, even when platelet
counts are very low [61]. Conversely, bleeding
times longer than expected from the actual
platelet counts occur with intrinsically abnor-
375
mal platelets as in the myeloproliferative dis-
orders [67] or from extrinsic factors. The latter
include uremia, liver failure, and drugs such
as aspirin, indomethacin, other prostaglandin
inhibitors, dextran, mithramycin, and high
doses of penicillin, carbenicillin, or moxalactam.
Acetaminophen, codeine, and morphine are safe
in thrombocytopenic patients.
Associated coagulation abnormalities should
be corrected. Vitamin- K deficiency resulting
from nutritional deficits or poor absorption
leads to impaired production of factors II,
VII, IX, and X and is. corrected by vitamin-K
administration. Coagulation factor defects due
to liver damage secondary to tumor invasion,
viral infection, or chemotherapy do not resolve
with vitamin-K therapy and should be treated
with fresh frozen plasma or coagulation factor
concentrates. Vascular damage due to invasive
procedures, surgery, tumor invasion, or infec-
tion may produce severe bleeding when plate-
lets counts are below 50 X 109/liter.
Intracranial Bleeding. Intracranial bleeding
related to severe thrombocytopenia is often
subdural or subarachnoid. Recognition of sub-
dural location is important because surgery may
be required. Bleeding may be uni- or multifocal
and varies from small petechial extravasations to
massive fatal hemorrhage. Intracerebral hemor-
rhages also occur, but are commonly associated
with other abnormalities such as leukostasis or
brain metastases.
Certain factors increase the risk of intracra-
nial bleeding. Platelet counts below 10 X 109 /
liter are associated with spontaneous fatal
intracranial hemorrhage in patients with leu-
kemia. Sudden increase in intracranial pressure
from coughing, vomiting or retching, or the
Valsalva maneuver may produce bleeding.
Leukostasis and disseminated intravascular
coagulation increase both the risk and the sever-
ity of bleeding. Intracranial metastases from
solid tumors, especially from choriocarcinoma,
melanoma, and renal cell carcinoma often pro-
duce intracranial bleeding. It is reasonable,
therefore, to consider this group of patients at
high risk for an earlier and more aggressive
prophylactic platelet transfusion plan. At our
institution, 30 patients with CNS metastases of
solid tumors and thrombocytopenia were re-
viewed. These patients spent a mean of 26 days
with platelet counts between 20 and 50 X 109/
liter, but only three days with counts below 10
376 IV. HEAD AND NECK COMPLICATIONS OF CANCER THERAPY
x 109/liter [68]. None had CNS bleeding. In
this series, however, prophylactic platelet trans-
fusions were utilized and there were only three
cases of melanoma and one of hypernephroma,
and relatively better results may therefore have
been obtained. Nevertheless, it seems that with
adequate prophylactic platelet transfusions,
cytotoxic chemotherapy can be administered
with reasonable margins of safety to patients
with cerebral metastases. Retinal hemorrhages
are common in patients with thrombocy-
topenia, and may produce severe visual loss or
blindness. They occur more frequently in the
presence of anemia and their prevention calls for
red blood cell as well as platelet transfusions
[69].
When intracranial bleeding occurs, sudden
onset of headache, visual impairment, changes
in the level of consciousness, focal neurologic
deficits, seizures, respiratory impairment, coma,
and death may occur in rapid succession. Treat-
ment consists of intensive platelet transfusion
and, when indicated, neurosurgery; however,
results are poor. The management of throm-
bocytopenia is therefore directed toward pre-
vention of bleeding by means of prophylactic
platelet transfusions.
Platelet Transfusions. Prophylactic platelet
transfusions can prevent bleeding [70-72]. The
standard transfusion product consists of fresh
platelets obtained at the blood bank as a by-
product of whole blood donation by random
donors and its viability and function can be
maintained for seven days. Platelets may also be
obtained from HLA-matched donors or from
patients themselves prior to chemotherapy;
these products may be of importance to
alloimmunized patients who will reject transfu-
sions from random donors [73].
One unit of platelets contains the platelets
obtained from one unit of blood resuspended in
50 ml of plasma (0.55-1.1 X 1011 platelets).
Ideally, one would expect a transfusion incre-
ment of about 10 X 109/liter per transfusion
unit per square meter of body surface at 24 h
after transfusion. Ideal circumstances are un-
common, however, and smaller increments are
the rule. Usually 4-8 units of platelets are
pooled for a transfusion to an adult patient. In
the otherwise stable average-sized individual
with virtually no platelet production (e.g., a
stable, noninfected leukemic patient after induc-
tion chemotherapy), 6 units of platelets given
three times a week often suffice. In the absence
of platelet production, many physicians ad-
minister prophylactic transfusions to keep the
platelet counts above 20 X 109/liter. Prophylac-
tic platelet transfusions may be safely withheld
in stable patients with counts below 20 X 109/
liter when platelet production resumes after
chemotherapy. When platelet counts fall rapid-
ly, transfusions should be initiated at higher
platelet levels because the risk of bleeding is
increased [62]. The same applies when there is
fever, sepsis, DIC, brain metastases, leuko-
stasis, and coagulation abnormalities. When
procedures such as tooth extractions, lumbar
puncture, or surgery are imperative, platelet
counts should be kept above 50 X 109/1iter.
Posttransfusion counts should be checked prior
to the procedure. Platelets are transfused con-
tinuously during emergency surgery.
HYPERCALCEMIA
Cancer is the most common cause of symp-
tomatic hypercalcemia and occurs in as many as
20% of all cancer patients. Neurologic man-
ifestations are asthenia, apathy, lethargy, confu-
sion, mental deterioration, stupor, and coma.
Other common clinical features are constipa-
tion, nausea, vomiting, polyuria, polydipsia, de-
hydration, hypovolemia, and renal failure. The
above findings are more severe and frequent in
cancer-related hypercalcemia than in the hyper-
calcemia of hyperparathyroidism, sarcoidosis,
Paget's disease, or other benign conditions. The
clinical picture may be dramatic, representing
a medical emergency. Symptoms related to
hypercalcemia may be the first manifestation of
cancer, but in general an obvious malignancy is
present.
Breast cancer, almost always metastatic to
bone, accounts for half of all cases. Squamous
cell lung cancer and large cell undifferentiated
carcinoma of the lung are common causes, but
hypercalcemia is rarely associated with adeno-
carcinoma and oat cell carcinoma of the lung
[74]. Esophageal [75], head and neck [76], cer-
vical, any other squamous cell tumor, renal,
prostate and, less frequently, ovarian and other
carcinomas are additional causes. Multiple
myeloma is a common cause and lymphoid
malignancies are less common causes; although
rare, retrovirus-associated T-cell lymphoma
nearly always presents with hypercalcemia [77,
78]. Increased calcium mobilization from bone
seems to be the final common pathway or
 20. HEAD AND NECK NEUROLOGIC COMPLICATIONS OF MALIGNANCY
malignant hypercalcemia in all cases. Three
groups of patients are identified: those with
hematologic malignancies, those with solid
tumors with bone metastases, and those with
solid tumors without bone metastases.
Among patients with hematologic malignan-
cies, those with multiple myeloma have been ex-
tensively studied. Myeloma cells seem to induce
hypercalcemia by the local production and
secretion of an osteoclast-activating factor that
stimulates osteoclastic bone resorption [79].
Lymphoma cells may also release osteoclast-
activating or related factors [80]. In patients
with solid tumors and bone metastases, local
bone destruction by the metastatic process is
probably the cause of hypercalcemia. The third
group is the smallest (about 15% of hypercalce-
mic cancer patients) and consists of patients
with solid tumors without bone metastasis. Lung
cancer and hypernephroma are the most com-
mon in this subset and removal of tumor results
in reversal of hypercalcemia. These patients
have the so-called humoral hypercalcemia of
cancer, the mediators of which are not well
defined. Several humoral factors have been
implicated including prostaglandins, ectopical-
ly produced parathyroid hormone, colony-
stimulating activity, and transforming growth
factors, but none to date seem to explain the
hypercalcemia in the majority of cases [81].
Normal calcium levels for most laboratories
are 8.5-10.5 mg/dl and should be adjusted for
the albumin levels [82]. Severe hypercalcemia
(calcium greater than 15 mg/dl, or a markedly
symptomatic patient) and mild hypercalcemia
(calcium less than 13 mg/dl, patient ambulatory)
represent the extremes of a clinical spectrum,
but symptoms do not always correlate well with
calcium levels. Associated conditions that may
produce or exacerbate the hypercalcemia of can-
cer include dehydration, immobilization, bone
fractures, thiazide diuretics, overuse of vitamin
D, and hormonal treatment of breast cancer.
Severe hypercalcemia is a medical emergency and
should be managed promptly and aggressively.
When possible, treatment of the underlying
malignancy is the best approach, but long-term
palliative therapy is often required. Dehydra-
tion is the rule, and is partly due to a defect
in the concentrating ability of the kidneys
produced by hypercalcemia [83]. The acute
management of severe hypercalcemia should start
with i.v. normal saline. Several liters of saline
are often needed during the initial 24-h period.
377
The amount and speed of infusion should be
individualized. Large and frequent doses of
furosemide (80-100 mg every 1-2 h i.v.) have
been used to rapidly decrease calcium levels by
increasing urinary calcium excretion [84]. It
should be noted, however, that furosemide
should be given after adequate hydration and
that fluid and electrolyte replacement equal to
urinary losses should be permanently main-
tained. Peritoneal and hemodialysis have been
effective in patients with concomitant renal
failure who do not respond to or cannot be
treated with aggressive hydration [85, 86].
Although the acute situation may call for
aggressive hydration and diuresis, appropriate
hydration and judicious drug therapy will often
suffice. Several drugs are available: calcitonin,
mithramycin, corticosteroids, oral phosphate,
and indomethacin. Diphosphonates offer
promise but remain investigational. Drug
selection is based on tumor type (e.g.,
myeloma responds well to corticosteroids),
desired time to onset of action (e.g., calci-
tonin acts faster than mithramycin), and associ-
ated risk factors for toxicity (e.g., mithramycin
may induce bleeding). Salmon calcitonin de-
creases bone resorption and has some value
as an adjunct in the acute treatment of hyper-
calcemia [87]. The effect starts in hours, but
is not persistent after a few doses. The drug is
usually given intramuscularly (i.m.) or sub-
cutaneously (s.c.) (4-8 international units
[IU]/kg every 6-12 h), but can also be given by
24-h continuous i.v. infusion. Side effects are
minimal, but skin testing (1 IU intradermally) is
recommended. Mithramycin, an antitumor anti-
biotic, inhibits bone resorption [88] and is effec-
tive in lowering calcium levels [89] when given
in lower and less frequent doses than are needed
for optimal antitumor action. The hypocalcemic
effect starts within 24-48 h of administration
and persists for several, usually 3-7, days. The
usual dose in hypercalcemia is 25 Ilg/kg by
rapid i.v. infusion. Nausea is minimized by
more prolonged, 4- to 6-h infusions. A repeat
dose can be given in 48 h. If a response is
obtained, further doses should be given only
when calcium levels again increase. One to three
doses weekly are often needed for chronic con-
trol. Major complications associated with the
use of mithramycin for tumor treatment include
hemorrhage, nephrotoxicity, and hepatotoxicity
[90]. These side effects are dose and schedule
dependent and are unusual with infrequent
378 IV. HEAD AND NECK COMPLICATIONS OF CANCER THERAPY
small doses as used in hypercalcemia [89], but
may become significant with chronic use.
Oral phosphate is useful in the chronic treat-
ment of hypercalcemia. Its mechanism of action
includes calcium binding in the gastrointestinal
tract, deposition of calcium in soft tissues and
bone, and inhibition of bone resorption. The
effect starts after several days of therapy and the
usual dose is 2 g of phosphate p.o. per day in
four divided doses. The main side effects are
gastrointestinal intolerance, diarrhea and, with
chronic use, extraskeletal calcifications, renal
failure, and hyperphosphatemia. Glucocorti-
coids are effective in hypercalcemia of multiple
myeloma and other hematologic malignancies
[91, 92]. They block the effects of osteoclast-
activating factor on os teo clasts in vitro [93] and
decrease bone resorption in vivo [91, 92).
Although they are occasionally useful in the
hypercalcemia of breast cancer [94, 95], their
effect in the hypercalcemia of solid tumors is
poor and unpredictable [94, 96]. The effect takes
several days to occur and the usual dose is 40-
100 mg of prednisone or its equivalent daily in
divided doses. Prostaglandin synthesis inhibi-
tors, such as indomethacin and aspirin have
been occasionally effective, notably in hyper-
nephromas with hypercalcemia [97]; however,
their current role seems to be very limited.
NEUROTOXICITY OF NEOPLASTIC DRUGS
The therapeutic arsenal of the chemotherapist
now consists of more than 60 drugs. Most of
these are cytotoxic agents and have serious
dose-limiting side effects in various organ sys-
tems. Most do not have a very high "therapeutic
ratio"; that is, toxic effects of at least a mild de-
gree have to be accepted for therapeutic benefit
to be obtained. It is not surprising therefore that
relatively severe toxicity of some type is fre-
quently seen in patients undergoing aggressive
antineoplastic treatment.
Nonetheless, only a few agents are regularly
toxic to the nervous system. Methotrexate,
vincristine, 5-fluorouracil, cytarabine (cytosine
arabinoside, ara-C), L-asparaginase, and cis-
platinum are the main offenders, though other
drugs can occasionally cause CNS toxicity.
Neurotoxicity is the main side effect of both
intrathecal (i.t.) chemotherapy and cranial irra-
diation. Brain, meninges, and nerves may be
variously damaged with different degrees of
severity and at variable intervals after therapy.
Toxicities seen with some frequency are dis-
cussed; the subject has been recently reviewed
in detail [98).
Acute Meningeal and Brain Toxicities. A
syndrome of meningeal irritation commonly
follows intrathecal methotrexate given pro-
phylactically or therapeutically for meningeal
leukemia or carcinoma. Typically, stiff neck,
headache, nausea and vomiting, fever, lethargy,
and cerebrospinal fluid pleocytosis begin 2-4 h
after the lumbar i.t. injection and last for 12-72
h [99-106]. The frequency of this arachnoiditis
varies, but may occur in as many as 61 % of the
patients in some series [99, 102, 106). It is felt
that this complication occurs more frequently in
patients being treated for CNS relapse (rather
than prophylaxis) due to a cumulative effect
related to the frequency of dosing [106]. Long-
term sequelae do not seem to be related to acute
arachnoiditis [105]; moreover, cerebrospinal
fluid pleocytosis (polymorphonuclear leuko-
cytes, lymphocytes and monocytes) may be
seen following i.t. methotrexate therapy with-
out clinical symptomatology [106). Rarely, a
very dramatic arachnoiditis may be associated
with massive polymorphonuclear cerebrospinal
fluid pleocytosis and high fever, mimicking
bacterial meningitis [104]. The concomitant use
of cranial irradiation seems to decrease the fre-
quency of this reaction, perhaps by suppression
of the inflammatory response [106).
A severe and acute cerebral dysfunction
or "encephalopathy" consisting of diminished
level of consciousness and altered cerebral func-
tion has also been seen with i.t. administration
of methotrexate (and other antineoplastic
agents) by either the lumbar space or by a ven-
tricular catheter (Ommaya reservoir-see the
section Malignant invasion and its manage-
ment) [99, 100, 107, 108). This syndrome is
apparently similar in mechanism to the transient
or permanent paraplegia that has been seen after
i.t. administration of various antineoplastics.
The encephalopathy may improve as early as 48
h or as late as 2-5 months afterward, but may
not resolve in some patients. The myelopathy is
apparently largely demyelinative [109-112] and
not clearly related to the particular chemother-
apy drug, diluent, or other pharmaceutical
factors. Bleyer et al. [100] found 13-fold higher
mean cerebrospinal fluid (CSF) methotrexate
concentrations and/or longer half-lives in five
patients with acute meningeal or myeloencepha-
lopathic syndromes compared with 20 identical-
 20. HEAD AND NECK NEUROLOGIC COMPLICATIONS OF MALIGNANCY
ly treated patients without neurotoxicity; they
suggested that the toxicity was due to prolonged
exposure of neural tissue to excessive drug
concentrations. These patients did not have
evidence of subarachnoid block, but such a
mechanism might explain the encephalopathic
toxicity seen in brain tumor patients [113].
Bleyer and Dedrick [114] subsequently pub-
lished a report on a larger· series of CSF
methotrexate concentrations in 76 children and
adults without neurotoxicity and established a
pattern of normal pharmacokinetic behavior of
the drug.
Several mechanisms could elevate CSF drug
levels and predispose the patient to toxicity.
In particular, abnormalities of the CSF flow
dynamics may be considerably more prevalent
than commonly recognized. Methotrexate is
removed from the CSF primarily by CSF bulk
flow [100, 114]. Neoplastic infiltration of the
meninges and arachnoid granulations (or its re-
sidual effects) may reduce the resorption of CSF
and therefore of methotrexate to the systemic
circulation [100, 115, 116] or may force retro-
grade flow of CSF with higher methotrexate
concentration in the ventricles [116]. These
phenomena could partially explain the reported
increased frequency of complications with
therapeutic, as opposed to prophylactic, use of
methotrexate [100, 116]. With intraventricular
instillation, ventricular outflow obstruction
[107, 113, 117, 118] or placement of the ven-
tricular cannula so that its fenestrations are part-
ly in brain parenchyma predispose the patient to
subacute toxic effects. Moreover, abnormalities
of CSF flow have been demonstrated in patients
with meningeal malignancies (ventricular outlet
obstruction or disturbances of flow over the
convexities or in the spinal canal) [115]. Neuro-
logic exam and routine radiologic procedures
were not sufficient to detect these phenomena
[115], which, however, could be demonstrated
by radionuclide scintigraphy.
A "strokelike" syndrome consisting of apha-
sia or hemiparesis with or without seizures was
seen in eight of a series of 31 patients receiving
extremely high doses of methotrexate i.v. for
osteogenic sarcoma. The symptoms abated in a
few days in all patients and always occurred
during the first, second, or third dose of ther-
apy, not recurring with subsequent doses. CT
scans and other studies were normal, only EEG
abnormalities being detected [119]. They post-
ulated that the syndrome was due to necrosis of
379
subclinical pulmonary micrometastases that
might have emboli zed to the brain.
Occasionally, seizures may occur after i.t.
therapy. This has been reported in two young
patients given i.t. ara-C after prior systemic
chemotherapy, i.t. methotrexate, and cranial
irradiation [120].
Mental changes, confusion, delirium, and
coma have been reported in patients receiving
i.v. vincristine, but usually in circumstances
such that other causes or additional chemother-
apy may have been responsible [121]. In many
cases of apparent encephalopathy, and in some
cases of seizures, the toxicity may have been re-
lated to hyponatremia resulting from the syn-
drome of inappropriate secretion of antidiuretic
hormone (SIADH) [122, 123]. It would appear
that patients who develop seizures while on
therapy should be assumed to have another
cause, usually related to the malignancy, until
proven otherwise.
Although hyponatremia and SIADH are rare
with vincristine therapy, the relationship is well
documented in both adults and children. With
both vincristine and vinblastine, hyponatremia
may be moderate or severe and develops within
the first ten days after vinca therapy and re-
solves in 1-2 weeks [122-128]. Many of these
cases have been reported after the first or second
dose of vinca, suggesting that a cumulative effect
is not important, but many of them received in-
dividual doses in the very high dose range [125,
126]. Other symptoms and signs of vincristine
neurotoxicity may be mild at the onset of the
inappropriate ADH syndrome. Elevated vaso-
pressin levels have been measured [125, 128] and
the syndrome is felt to be due to a direct effect
of the drug on the hypothalamus, neurophyseal
tract, or posterior pituitary [127], the latter
areas being "outside" the blood-brain barrier
and thus accessible to the drug. Other che-
motherapeutic agents, particularly cyclophos-
phamide, may also be associated with SIADH
[129, 130].
Severe encephalopathy, peripheral neuro-
pathy, paralytic ileus, and other neurotoxicities
have been noted in patients receiving two- to
threefold overdosage of vincristine; patients
receiving 4-10 times the planned doses have
had lethal neurotoxicity including SIADH,
seizures, and irreversible coma [131]. Similarly,
accidental administration of vincristine by the
i.t. route has led to a lethal syndrome of ascend-
ing neurotoxicity including paresthesias, sen-
380 IV. HEAD AND NECK COMPLICATIONS OF CANCER THERAPY
sory loss, paraparesis, cranial nerve findings,
and coma [132-134].
Encephalopathy is the major neurotoxic reac-
tion of the class of enzymatic antitumor agents
collectively known as L-asparaginases. Cerebral
dysfunction occurs in 21%-60% of patients
[135]. Lethargy, drowsiness, somnolence, con-
fusion, personality changes, and depression are
frequent and rarely there is progression to
hallucinations or to stupor and coma [136].
Seizures are rarely reported and focal abnor-
malities not at all. Mild abnormalities may be
seen as early as the first day of therapy and most
patients improve within a few days to a week of
drug discontinuation [135, 137]. Adults are
somewhat more susceptible than children. Most
dosage schedules have demonstrated CNS
toxicity, but the frequency and severity do
appear to be greater with higher doses [135].
Nonetheless, most patients are able to continue
therapy so that the occurrence of mild or mod-
erate drowsiness does not necessarily preclude
completion of planned treatment. EEG in
symptomatic patients consistently shows diffuse
slowing [135, 136, 138] that tends to parallel the
clinical picture and returns to normal after L-
asparaginase is stopped.
In addition to the acute toxicity, a delayed
form of severe cerebral dysfunction has been re-
ported in 10% of treated patients. This begins
insidiously about a week after L-asparaginase
administration and lasts several weeks [139].
The mechanisms of both the acute type and this
delayed form of organic brain syndrome remain
theoretical rather than proven. L-asparaginase,
being a large protein molecule, does not cross
the blood-brain barrier in significant amounts
and therefore must not have any direct metabo-
lic effect on the brain. However, brain protein
synthesis might be diminished by depletion of
systemic L-asparagine and L-glutamine levels.
CSF asparagine may be markedly depleted even
though asparaginase reaches the CSF in negligi-
ble amounts [140]. Alternatively, the elevated
levels of L-aspartic acid, glutamic acid, or
ammonia that occur after treatment with aspar-
aginase might be toxic to the brain, leading to
the clinical and EEG findings. Moreover, aspar-
aginase regularly induces hepatotoxicity with
poor handling of the induc~d ammonia load and
this metabolic defect may be additive or occa-
sionally itself responsible for CNS symptoms.
Since the acute CNS toxicity may begin so
early in the course of therapy and reverses so
promptly, it is more likely due to toxic metabo-
lic products (L-aspartate, L-glutamate, ammo-
nia). The delayed, slowly resolving, and sub-
acute organic brain syndrome would be more
likely to relate to deficiency of brain protein
synthesis due to L-asparagine depletion [139].
In fact, infusions of L-asparagine in three pa-
tients with the latter presentation produced im-
provement [139]. In addition, both hemorrhagic
and thrombotic cerebrovascular accidents are
known to occur secondary to asparaginase-
induced clotting abnormalities [141, 142].
The primary neurologic toxicity of 5-
fluorouracil (5-FU) is an acute cerebellar syn-
drome which may consist of dysmetria, ataxia
of the trunk or extremities, unsteadiness of gait,
slurred speech, coarse nystagmus, and com-
plaints of dizziness [143-146]. Occasionally,
oculomotor disturbances are seen as well. This
syndrome has been seen in patients receiving
any schedule of 5-FU, but clearly occurs more
frequently with more intensive therapy [135].
The frequency varies between essentially none
with weekly doses of 7.5-15.0 mg/kg to as high
as 3%-7% in patients receiving loading courses,
monthly five-day courses, or high-dose weekly
therapy of 15-20 mg/kg/week [135]. So far,
there is not much evidence of cerebellar toxicity
with 120-h continuous infusion of 5-FU or with
chronic ambulatory infusion for as long as 30
days. The ataxia syndrome is probably not re-
lated to cumulative dose, but rather to the peak
plasma level of the drug [135,143]' It is virtually
always reversible within 1-6 weeks after 5-FU
is stopped or the dosage reduced.
5-FU readily crosses the blood-brain barrier
and achieves significant concentrations in the
CNS. Although 5-FU itself appears to be non-
toxic to the nervous system, the cerebellar
lesions that occur are nearly identical to those
produced experimentally by fluorocitrate [144,
147]. It has been proposed that fluorocitrate or
fluoroacetate is produced by the catabolism of
5-FU and is responsible for the cerebellar syn-
drome [147]. Numerous "modulators" of the
biochemical effects of 5-FU have been proposed
and tested in animals and/or in man. Several of
these, including thymidine and allopurinol,
have demonstrated a potential for increasing the
neurologic toxicity and shifting the spectrum
toward a toxic encephalopathy (seizures, hemi-
paresis, aphasia). The primary clinical impor-
tance of cerebellar toxicity is that it could be
confused with intracranial or meningeal metas-
 20. HEAD AND NECK NEUROLOGIC COMPLICATIONS OF MALIGNANCY
tases or remote effects of cancer. However, its
prompt reversibility and the results of CT scan
and lumbar puncture should answer this ques-
tion easily in most patients.
Procarbazine is a weak monoamine oxidase
inhibitor that rapidly crosses the blood-brain
barrier and may itself produce encephalopathy
or potentiate the sedative effects of pheno-
thiazines, barbiturates, and narcotics. Liver
microsomes of mice treated with procarbazine
have diminished cytochrome-P450 activity and
a decreased ability to metabolize these drugs
[148]. When the drug is given p.o. in full doses
as a single agent, CNS depression ranging from
mild drowsiness to profound stupor develops in
8%-31 % of patients, sometimes accompanied
by confusion, agitation, hallucinations, or
psychosis [135]. Milder toxic effects may resolve
even while procarbazine dosage is continued.
EEGs in stuporous patients have shown diffuse,
nonspecific slow wave activity. While some part
of this syndrome may be related to drug inter-
actions in a group of patients quite likely
to be receiving sedatives and other drugs, peri-
pheral neuropathy and reversible orthostatic
hypotension have been reported in 10%-20%
of patients who have received the drug for
several weeks. These patients may also have
dramatic myalgias in proximal muscle groups
[135]. These symptoms suggest some direct
neurotoxicity for this agent. Patients treated
concomitantly with sympathomimetic agents,
tricyclic antidepressants, or tyramine-contain-
ing foods may develop hypertension; occasion-
ally, a "disulfiramlike" syndrome is seen after
alcohol ingestion.
Other antineoplastic drugs are rarely re-
sponsible for acute encephalopathy. The intra-
carotid injection of BCNU, platinum, nitrogen
mustard, and other agents has been associated
with blindness, seizures and, rarely, with hemi-
paresis or alterations of consciousness. Cyclo-
phosphamide was reported to cause dizziness
and blurring of vision, but these complaints
are extremely unusual despite vast experience
with the drug. On the other hand, cyclophos-
phamide frequently causes a symptomatic
hyponatremia and an SIADH-like syndrome by
virtue of a transient decrease in free-water clear-
ance and urine volume with a fall in serum
sodium concentration 4-12 h after infusion and
lasting for up to 20 h [149, 150]. This is related
temporally to urinary excretion of the active
metabolites of the drug. The inability of ethanol
381
to ablate the water retention suggests that
cyclophosphamide has a direct effect on the
kidney [150].
Recent experience with high doses of ara-C (3
g/m2 every 12 h for 6-16 doses) as therapy for
refractory adult acute leukemia has been asso-
ciated with dose-limiting neurotoxicity. Ataxia,
incoordination, nystagmus, and somnolence
usually begin after 3-5 doses of the drug, may
progress to stupor and coma, and have not been
completely reversible in every case [151]. At
least one case of encephalopathy recurred even
when conventional doses of ara-C were substi-
tuted for the previously used high doses. 5-
Azacytidine is a related pyrimidine nucleotide
analogue, also used in leukemia therapy, that
regularly causes neuromuscular toxicity [152].
In more severely affected patients, however, this
may progress to confusion, irritability, pro-
found weakness, and somnolence [153].
Subacute and Chronic Encephalopathies.
Several delayed encephalopathic syndromes
occur in relation to intrathecal or intraventricu-
lar administration of methotrexate and may be
subacute or chronic, transient or irreversible.
These syndromes are potentiated by additional
systemic methotrexate and increase in frequen-
cy as i.t. and i.v. methotrexate and cranial irra-
diation are variously combined. In addition,
other chemotherapeutic agents such as ara-C
and thiotepa have occasionally been implicated
in similar syndromes.
The early 1970s saw a series of reports of de-
layed cerebral dysfunction with unique neuro-
pathologic findings related to prolonged ther-
apy with i.t. methotrexate for prophylaxis of
meningeal leukemia or for treatment of primary
brain tumors [113, 117, 154-158]' Clinically,
patients presented months to several years after
therapy with confusion, somnolence or irrita-
bility, ataxia, dementia, tremor, or seizures.
Sometimes there was progression to spasticity,
quadriparesis, visual disturbances, slurred
speech or other focal findings, coma, and death.
In other patients, partial recovery or stabiliza-
tion occurred.
The most important pathologic characteris-
tics of this disseminated necrotizing leukoen-
cephalopathy have been demyelination, multi-
focal white matter necrosis of coagulative type,
astrocytic reaction without inflammatory cellu-
lar reaction, and striking axonal damage. The
382 IV. HEAD AND NECK COMPLICATIONS OF CANCER THERAPY
deep white matter in the periventricular regions
and the centrum semi-ovale are preferentially
affected while the gray matter and basal ganglia
are spared. In some cases, little or no vascular
change is found, emphasizing the distinction
of this syndrome from simple delayed radiation
damage, in which thickened vessel walls with
fibrinoid necrosis are quite characteristic. In-
tracerebral calcifications have been observed in
some cases and are detectable radiographically
with some frequency, even in some asymptoma-
tic patients [157, 159-162].
As progress has been made in the therapy of
childhood leukemia and CNS prophylactic
therapy has been universally adopted, the
delayed necrotizing leukoencephalopathy syn-
drome has been seen more frequently. For ex-
ample, McIntosh et al. prospectively studied 23
children treated with cranial irradiation plus i. t.
and i.v. methotrexate and found that 12 of the
patients had developed, between the tenth and
18th months, neurologic symptoms apparently
unrelated to leukemia or infection. Five had
seizures followed by varying degrees of hyper-
kinesis, ataxia, and subnormal perceptual motor
skills. Psychometric testing showed significant
abnormalities in eight patients. Ten of 25 pa-
tients had intracranial calcifications [162].
In the CT scan era, earlier, subtler, or sub-
clinical abnormalities are being identified. For
example, in one series where CT scans were
performed on 32 children in continuous com-
plete remission 19-67 months after initiation of
CNS prophylaxis with 2400 cGy of cranial irra-
diation plus i.t. chemotherapy utilizing either
ara-C or methotrexate, 53% had one or more
abnormal findings. Symmetric areas of hypo-
density (particularly adjacent to the frontal
horns and in the centrum semi-ovale) were
found in four of the 14 methotrexate-treated pa-
tients, and intracerebral calcifications were seen
in one. Neither of these abnormalities were
identified in any patients receiving ara-C, but
the ara-C group had an incidence of approx-
imately 25% of ventricular dilatation and
another 25% incidence of dilatation of the sub-
arachnoid space, identical to the methotrexate
group. A control group of 11 patients had CTs
that were normal with the exception of one pa-
tient with minimal ventricular dilatation. This
and other series have implied that, whereas
some degree of cerebral atrophy is common in
many patients receiving i.t. chemotherapy of
any kind along with radiation therapy, the dis-
tinctive delayed necrotlzmg leukoencephalo-
pathy syndrome and the demyelinating changes
seen on CT scan occur primarily with the spe-
cific combination of i. t. methotrexate plus
radiation.
The largest single institution experience with
CNS prophylaxis is from St. Jude's Hospital
where 248 patients were given standard prophy-
laxis with 2400 cGy of cranial irradiation plus
five doses of i.t. methotrexate; 5% (12 patients)
developed clinically diagnosed leukoencephalo-
pathy [163]. Possibly the CT scanner or
prospective psychometric testing would have
revealed a significantly higher rate of clinical
abnormality. However, included in the St.
Jude's series was a very high risk subgroup of
children who had by random assignment
received maintenance with higher doses of i.v.
methotrexate in addition to their i. t. metho-
trexate and irradiation. Of 20 such children,
two developed CNS leukemia and required
additional chemotherapy after their original
prophylaxis and these two plus nine other
patients not relapsing in the nervous system
developed crippling leukoencephalopathy, an
incidence of 55% in these 20 patients.
It therefore appears that the syndrome is re-
lated to each of the modalities of CNS prophy-
laxis in childhood leukemia, but there are few
reports of leukoencephalopathy occurring when
low-dose cranial irradiation, or i. t. methotre-
xate, or i.v. methotrexate, is used alone [98,164,
165]. When two modalities of treatment are
combined, however, the frequency of toxicity
increases (figure 20-11). The compilation of
cases reported by Bleyer and Griffin suggests
that the risks of combining i.t. methotrexate and
high-dose i.v. methotrexate are minimal unless
radiation therapy has also been given [164]. On
the other hand, a combination of cranial irradia-
tion therapy plus i.t. methotrexate (the most
frequently used prophylaxis regimen) yields
about 5% incidence of clinical leukoencepha-
lopathy [163] and roughly a 30% incidence of
CT abnormality [161]. In one series, 33% of
patients treated with a very high dose of cranial
irradiation plus triple i.t. therapy (methotrexate,
ara-C, and hydrocortisone) developed patholo-
gically documented leukoencephalopathy [154].
The less common two-modality combination of
cranial irradiation plus high-dose i.v. metho-
trexate seems to yield about 15% symptomatic
cases of leukoencephalopathy [159, 164].
Finally, when all three modalities are used in
 20. HEAD AND NECK NEUROLOGIC COMPLICATIONS OF MALIGNANCY
FIGURE 20-11. Approximate risk of clinical leuko-
encephalopathy as a function of three treatment mod-
a~ities. From Bleyer and Griffin [164], with permis-
sIOn.
the same patient, the incidence may increase to
as high as 45%-55% as in the St. Jude's sub-
group previously mentioned [163]. The risk of
leukoencephalopathy increases directly with
irradiation dose in patients receiving systemic
methotrexate and also with the cumulative
methotrexate dose [157]. In all likelihood, a
direct relationship also exists with the cumula-
tive dose of methodtrexate administered i.t.
after cranial irradiation.
In fact, the sequence of administration of
irradiation or methotrexate seems to be of
major importance as a determinant of risk in
that there are no documented reports of de-
layed leukoencephalopathy in patients whose
methotrexate therapy was terminated prior to
irradiation and not resumed [164]. The com-
bination of radiation plus i.t. methotrexate is
particularly toxic when the radiation is given
prior to the methotrexate or simultaneously
with it [157]. (In contrast, a different, acute, and
life-threatening encephalopathy sometimes de-
velops at the time of irradiation in patients who
have active meningeal leukemia and are treated
with a sequence of i.t. methotrexate followed by
cranial irradiation [166]).
Although i.t. ara-C is associated with ven-
tricular dilatation and presumed cortical atro-
phy as often as is i.t. methotrexate, the low-
density lesions and calcifications more charac-
teristic of leukoencephalopathy have been seen
primarily in i.t. methotrexate patients. On the
383
other hand, i.v. ara-C apparently increases the
risk of intracranial calcification in patients re-
ceiving combined modality therapy [162] and
there is evidence that high-dose systemic ara-C
is neurotoxic [151] and therefore may potentiate
delayed neurotoxicity as well.
Methotrexate leukoencephalopathy usually
begins insidiously in the first year after cranial
irradiation, but may begin within a few weeks
or become evident one or two years later [157,
161, 164, 167]. The signs and symptoms most
frequently seen are confusion, drooling, somno-
lence or irritability, ataxia, tremors, dementia,
spasticity, quadriparesis, slurred speech, and
other focal findings [113, 117, 154-156]' Seizures
are frequent and an EEG nearly always demon-
strates diffuse, often asymmetric slow waves.
However, EEG abnormalities are extremely fre-
quent after CNS prophylaxis in both symp-
tomatic and asymptomatic children [168]. The
radionuclide brain scan may be unrevealing, but
the CT scan usually suggests the diagnosis.
Low-density, nonenhancing areas are seen first
adjacent to the frontal horns, then adjacent to
the occipital horns, and then along the entire
length of the ventricles [169]. Ventricular and
subarachnoid dilatation may be seen with or
without calcifications in the central white
matter [161, 162]. CT abnormalities have been
seen to improve in parallel with partial improve-
ment in the clinical leukoencephalopathic syn-
drome. CSF protein levels, enzymes (LDH
and SGOT), and glucose are typically abnor-
mal, but are nonspecific. Active demyelination
is indicated by elevated levels of myelin basic
protein (MBP) and the MBP may be considered
persuasive evidence in favor of the diagnosis
[170].
Methotrexate leukoencephalopathy is often
fatal, but most patients survive for a time with
chronic neurologic deficit. Some authors have
reported cases of complete recovery, but more
typically there is only partial improvement
clinically or by CT scan. Patients who are still
receiving methotrexate by any route should
have the drug discontinued; clinical improve-
ment is often noted in these circumstances, but
the rol~ of systemic folinic acid replacement is
uncertam.
Mineralizing microangiopathy with dys-
trophic calcification is a pathologically distinct
entity found at autopsy in 17% of 163 child-
hood leukemia patients [171]. It may be that
some reports of CT -detected intracranial cal-
384 IV. HEAD AND NECK COMPLICATIONS OF CANCER THERAPY
cifications may primarily represent this phe-
nomenon or the late effect of radiation itself.
Pathologically, the lesion always involves the
basal ganglia, specifically the putamen with or
without involvement of cortical sulci. The pro-
cess consists primarily of calcified mucopoly-
saccharide deposits within and around small
arteries, arterioles, capillaries, and venules.
These lesions had been responsible for clinical
symptomatology in only 14% of the patients
studied (headaches, focal seizures, incoordina-
tion, gait abnormalities) and were apparently
not responsible for any of the deaths [171].
Similar vascular changes are characteristic of the
late effects of radiation alone, and the time
course of mineralizing microangiopathy (all
cases presented more than ten months after
radiation therapy) and other clinical features
suggests that cranial irradiation in doses greater
than 1500 cGy was responsible for the syn-
drome. However, systemic or i.t. chemotherapy
may have contributed and multiple CNS re-
lapses greatly increased the apparent frequency
of the syndrome. Interestingly, calcification has
not been prominent in primary brain tumor pa-
tients treated with much higher doses of cranial
irradiation therapy plus a nitrosourea, but with-
out i.t. therapy. This may, however, reflect a
shorter mean survival for the brain tumor
patients.
A subacute progressive multifocal encepha-
lopathy has been reported in three patients
who had received high-dose chemotherapy with
BCNU (1500-2850 mg/m2 dose) followed by
autologous bone marrow transplantation for
different malignancies [172]. None of the
patients had received cranial irradiation. Con-
fusion, seizures, diplopia, and nystagmus de-
veloped within five weeks of therapy and were
followed by progressive neurologic impairment,
coma, and death in 2-4 weeks. Autopsy re-
vealed discrete foci of axonal damage and larger
areas of white and gray matter necrosis. The
presence of fibrinoid necrosis and fibrin throm-
bi was considered suggestive of BCNU-induced
damage of the cerebrospinal vasculature.
Cerebral Atrophy. Crosley et al. emphasized
the frequency of cerebral atrophy (65%) seen in
autopsies of 91 children with acute leukemia
[173]. In half of these, the atrophy was moder-
ate or severe. Statistical evaluation suggested a
relationship between degree of atrophy and the
use of i.t. methotrexate with or without cranial
irradiation or ara-C. Radiation alone did not
seem to be a significant predisposing factor.
This frequency corresponds rather closely to
the 53 % of patients treated with cranial irradia-
tion therapy and either i.t. methotrexate or i.t.
ara-C who had evidence of cerebral atrophy in a
CT series [161].
Pontine Abnormalities. There have been
sporadic reports of central pontine myelinolysis
in both childhood and adult leukemia, pre-
sumably as a consequence of either radiation
therapy itself or the combination of radiation
therapy and i.t. chemotherapy [98, 173].
Somnolence Syndrome. This is very com-
mon delayed reaction after antileukemic CNS
irradiation in children. It consists of a rapid
onset of lethargy, irritability, low-grade fever,
nausea, vomiting, and diarrhea beginning 3-8
weeks after completion of CNS prophylaxis,
accompanied by slowing of background fre-
quency on EEG [168,174-177]. This syndrome
usually abates spontaneously in 1-4 weeks. It is
often observed in patients who have received
both radiation and i.t. therapy (e.g., in 45% of
one large series), but it has certainly been seen
also in patients who have received only radia-
tion [175, 177]. A temporary disturbance in
myelin synthesis has been postulated as the like-
ly mechanism. It has been suggested that the
children who have experienced clinical somno-
lence syndrome are at risk for developing late
CNS dysfunction when followed over several
years without evidence of leukemic relapse
[168], and a rise in CSF betarmicroglobulin has
been noted in connection with the clinical syn-
drome [178].
Mechanisms of Neurotoxicity. The interac-
tions of cranial irradiation and chemotherapy
responsible for the various types of delayed
neurotoxicity are not well understood. Bleyer
and Griffin have outlined the theoretical possi-
bilities [164]. Drug and radiation are likely to
interact in such a manner that one renders the
other more toxic in one of three ways: overlap-
ping mechanisms of cytotoxicity, radiation sen-
sitization by the drug(s), or alteration of drug
kinetics by radiation. Perhaps the most likely
alteration in drug kinetics is increased per-
meability of the blood-brain barrier, since this
is a known effect of radiation. Endothelial cell
damage could allow diffusion of normally ex-
cluded drugs into the brain. Many authors have
 20. HEAD AND NECK NEUROLOGIC COMPLICATIONS OF MALIGNANCY
proposed this as the primary mechanism of
methotrexate leukoencephalopathy [113, 154,
157, 158, 168, 171, 179]. Such a phenomenon
could be on the basis of direct radiation damage
to the barrier in the form of small vessel injury.
Attempts to actually demonstrate an increase
of endothelial permeability to methotrexate in
animals has led to conflicting results [180-182].
Nonetheless, the immature CNS might be partic-
ularly vulnerable to such a permeability effect,
accounting in part for the observed frequency of
leukoencephalopathy in children. It has also
been suggested that methotrexate is toxic to the
nervous system by virtue of cytotoxic effects
on glial and endothelial cells, which, unlike
neurons, actively divide and are thus potentially
susceptible to the drug [183].
Unfortunately, there is no clear evidence that
such potential therapeutic interventions as ster-
oids, folinic acid, or other treatments can alter
the course of leukoencephalopathy. At present,
our most effective strategies are concerned with
prevention. It is presumably important to avoid
excessively high levels of CSF methotrexate,
and i.t. methotrexate dosage will be discussed in
the section Malignant invasion and its manage-
ment [184]. Most importantly, the interaction of
methotrexate and radiation can apparently be
almost entirely averted if all the methotrexate is
administered prior to cranial irradiation therapy
[157, 164]. However, such a technique has not
undergone large-scale trials to establish its
adequacy as CNS leukemia prophylaxis.
Finally, lower doses of cranial irradiation
may prove efficacious in prophylaxis, thus pre-
sumably reducing leukoencephalopathy and
other manifestations of radiation-chemother-
apy interaction. Several cooperative groups have
recently shown that 1800 cGy of cranial irradia-
tion instead of the previous standard 2400 cGy
can adequately prevent CNS relapse. However,
it is not clear that there has been any decrease in
late toxic effects with this dosage reduction.
Cranial Neuropathies. The neurologic toxic-
ity of the periwinkle alkaloids vincristine and
vinblastine is often dose limiting and has been
extensively reviewed [98,135, 185]. These drugs
and the newer vinca alkaloids arrest cell division
in metaphase by inhibiting microtubule forma-
tion in the mitotic spindle. Given at low con-
centrations, they have been shown to bind
directly to tubulin and prevent its polymeriza-
tion from soluble dimers to microtubules. Mic-
385
rotubules have been shown to be involved not
only in mitosis but also in axoplasmic transport
and in a variety of secretory functions, and
much of the neurotoxicity of the vincas may be
explained by disruption of these processes.
The earliest and most consistent sign of vin-
cristine neurotoxicity is loss of the Achilles-
tendon reflex and is virtually universal but
asymptomatic in many patients. The other deep
tendon reflexes in the lower extremities may be
lost in most patients with continued dosage
[135], but many patients still remain without
symptoms. Progressive parethesias in the hands
and feet, weakness, most prominently in dorsi-
flexion of the foot, and paralytic ileus are other
signs of progression of vinca neurotoxicity.
However, the cranial nerves may also be
affected by vincristine or vinblastine. Recurrent
laryngeal nerve involvement leads to vocal cord
paresis or paralysis, often bilaterally. Oculomo-
tor nerve dysfunction may be manifested as bi-
lateral ptosis without other abnormalities, or as
diplopia without ophthalmoplegias [186]. Rare
cases of optic neuropathy or atrophy have also
been reported, though poorly documented, and
recently three cases of transient cortical blind-
ness have been reported. One patient with op-
tic atrophy remained permanently blind. Bi-
lateral facial nerve palsies have also been de-
scribed. One or another of these findings may
occur in 10% of patients [186] and occasionally
they may represent the first evidence of vinca
toxicity. All the cranial nerve findings tend to
be bilateral and all are usually reversible on dis-
continuation or interruption of vinca therapy.
Severe jaw pain sometimes occurs suddenly
within a few hours of a first dose of vincristine
or vinblastine. The pathophysiology of this par-
ticular symptom is uncertain, but it probably
represents trigeminal nerve toxicity. The pain
often resolves spontaneously within a matter of
days, however, and usually does not recur with
subsequent doses [187].
Cisplatin (DDP) is the other cytotoxic agent
associated with a high incidence of cranial
neuropathy. There is no documented preferen-
tial accumulation of cisplatin in nervous tissue,
but, as might be expected of a heavy metal, neu-
ral toxicity has been seen with some frequency.
Ototoxicity of cisplatin is well known and has
been reviewed [98, 188]. Tinnitus occurs in
about 9% of patients treated with doses of up to
about 60 mg/m2, symptomatic hearing loss in
about 6%, and audiogram abnormalities (high-
386 IV. HEAD AND NECK COMPLICATIONS OF CANCER THERAPY
frequency pure-tone hearing loss) in at least
24%. Systematic follow-up with audiography
will reveal abnormalities in most patients. The
tinnitus is usually reversible, but audiographic
abnormalities may not be, and there is some
controversy as to the reversibility of symptoma-
tic hearing loss. Clinical deafness is infrequent
and is related to both dosage per course and
cumulative total dosage.
In animal models, deafness is due to loss of
hair cells in the organ of Corti, but this process
occurs at a location different from the site in-
jured by aminoglycosides. Ototoxicity has been
dose limiting for some patients and may become
so more frequently now that methods to reduce
nephrotoxicity are better understood. More-
over, the use of furosemide, itself potentially
ototoxic, to augment diuresis of DDP is theo-
retically hazardous. At present, the only way
known to ameliorate DDP ototoxicity is to
limit the single and/or cumulative dosages.
Baseline pre-DDP audio grams are recom-
mended, but there is no documented need for
serial studies unless the patient becomes symp-
tomatic, that is, unless the perception of speech
is affected [188]. Vestibular toxicity from DDP
IS rare.
Ophthalmologic toxicity from DDP was first
reported by Ostrow et al. [189]. A number of
patients with retrobulbar neuritis or papil-
ledema with or without peripheral neuropathy
have been seen. Some had resolution and com-
plete recovery and were able to receive further
DDP without difficulty. Other patients re-
mained permanently blind. One report de-
scribed a young man who developed both
seizures and transient cortical blindness after
a five-day course of DDP [190]. The blindness
resolved within 72 h with dexamethasone and
mannitol therapy. In this case, sequential CSF
samples analyzed for platinum concentration
yielded high platinum concentrations equal to
blood levels for the first to the 18th postinfusion
days. Moreover, a small unexplained rise in CSF
platinum level on the eighth day was associated
with a recurrence of seizures. This suggests that
some patients may achieve higher than expected
levels of the drug in the CNS and develop a cen-
tral type of heavy-metal toxicity. Elevated levels
could conceivably be related to subclinical
intra-CNS tumor that opens the blood-brain
barrier to the drug and is then eradicated by the
DDP that reaches it. This CNS toxicity does
not seem to increase with high cumulative DDP
doses as ototoxicity and peripheral neuropathy
do. Intracarotid infusions of platinum have been
associated with marked neurotoxicity including
focal or generalized encephalopathy and retinal
blindness [191]'
Meninges and Cranial Nerves
MALIGNANT INVASION AND
ITS MANAGEMENT
Neoplastic infiltration of the leptomeninges is a
serious and increasingly common complication
of cancer. Meningeal leukemia and lymphoma
and meningeal carcinomatosis denote a diffuse
or multifocal seeding of the meninges by the
malignant process, often with involvement of
cranial nerves, with or without concomitant
cerebral invasion.
The potential for meningeal involvement is
extremely high in certain hematologic malig-
nancies. Thus, more than 50% of children [15]
and about 50% of adults [192] with acute lym-
phoblastic leukemia (ALL) will eventually de-
velop meningeal relapse in spite of continuous
bone marrow remission, unless "presymptomat-
ic" or "prophylactic" CNS therapy is given as
part of the initial definitive treatment of the
disease. With the use of i.t. methotrexate and
cranial (2400 cGy) irradiation, the incidence of
CNS relapse in childhood acute lymphoblastic
leukemia has been sharply reduced to less than
5% [193]. Prophylaxis is also recommended in
adult acute lymphoblastic leukemia, but its pre-
cise role remains to be defined. CNS relapses
develop late in acute lymphoblastic leukemia
and may occur even after ten years of remission
[194]. Once overt in the meninges, the disease is
difficult to eradicate and recurrences are com-
mon but not inevitable. Some other lymphoid
malignancies [195] behave similarly (table 20-2),
but the risk is lower in acute nonlymphocytic
leukemia, which tends to involve the men-
inges less frequently but earlier (within a few
months of diagnosis) than acute lymphoblastic
leukemia.
Most solid tumors have a lower tendency to
invade the meninges and, when they do, the
clinical picture is often dominated by advanced
systemic carcinomatosis. However, certain
tumors have a relatively high potential for
meningeal invasion, notably small cell lung can-
cer, malignant melanoma, and breast cancer
(table 20-2). Due to the improved survival
achieved with more effective systemic therapy,
 20. HEAD AND NECK NEUROLOGIC COMPLICATIONS OF MALIGNANCY
TABLE 20-2. Relative frequency of meningeal involvement in various malignancies a
High
Childhood ALLb
Adult ALLb
Burkitt's lymphomab
T-cell lymphoblastic lymphomab
Immunoblastic lymphomab
CML blast crisis
.. ALL, acute lymphocytic leukemia; CML, chronic myelogenous leukemia; PDLL, poorly differentiated lymphocytic lymphoma; and
NSCLC, non-small-cell lung cancer.
b Prophylactic eNS treatment indicated.
C High incidence of brain metastases as well.
d Virtually all tumors have on occasion been reported to involve the meninges.
CNS failure may become more frequent with
some tumors [196-198].
Pathogenesis. Based on autopsy studies [199,
200], several mechanisms have been implicated
in the pathogenesis of meningeal leukemia.
Cells may gain access to the leptomeningeal sur-
faces and the CSF directly from adjacent bone
marrow by way of the adventitiae of veins and
the perineurium of nerves bridging the sub-
arachnoid space. Hematogenous spread with
migration of malignant cells through the walls
of subarachnoid veins is also seen. Microhemor-
rhages in patients with thrombocytopenia and
vessel wall invasion may provide additional sites
of entry. Once in the subarachnoid space, cells
may circulate via CSF and seed other sites. The
rate of cell proliferation in the CSF seems to be
slower than in the bone marrow [201, 202].
CNS leukemia remains basically a disease of the
arachnoid space and membranes until very ad-
vanced stages. With time, diffuse infiltration and
nodules or plaques of leukemic cells cover differ-
ent areas of the leptomeninges. Nerve sheaths
and nerve tissues become infiltrated, particular-
ly at the base of the skull. The pial surface of the
brain becomes involved diffusely including the
pial perivascular (Virchow-Robin) spaces, pro-
ducing disruption of the pial barrier and vascu-
lar compromise. As a result of these changes,
the dynamics of CSF flow are altered and
hydrocephalus, increased cranial pressure, and
papilledema result. Cranial nerve palsies and
diffuse cortical cerebral dysfunction are also
common and focal deficits or seizure activity
may occur.
Meningeal carcinomatosis may result from
similar mechanisms, but more frequently there
is direct tumor erosion into the subarachnoid
387
Intermediate Low
Small cell lung cancerb, c Colon cancer
Melanomac NSCLC
Acute nonlymphocytic leukemia Ovarian cancer
Diffuse histiocytic lymphoma Testicular tumors
Diffuse-PD LL Other d
Breast cancer
space from malignant deposits in the calvarium
or paraspinal areas or less often from in-
tracerebral metastases. Invasion by adjacent
tumor may be massive or may follow neural or
vascular pathways. Infiltration of nerve roots
such as seen in leukemia occurs and may be
massive in the cauda equina; malignant nodules
may erode into the underlying brain parenchy-
ma. Lymphomas may invade the meninges by
way of any of the mechanisms described for
both leukemia and carcinoma.
Clinical Findings. Clinical manifestations
may develop slowly or abruptly and result from
increased intracranial pressure, nerve root
involvement, or cortical brain damage. The
neurologic findings are characteristically multi-
focal with signs of abnormalities in several non-
contiguous levels of the CNS, but may not
localize at all. Common findings are headaches,
Irritability, lethargy, confusion, papilledema,
and visual loss that may be unilateral or bilater-
al, transient or permanent. Cranial nerve palsies,
especially of the seventh and sixth cranial
nerves, pain in a spinal root distribution, and
the cauda equina syndrome are common. Verti-
go, ataxia, seizures, and virtually any neurologic
impairment may occur. Meningeal signs are
notably uncommon. The hypothalamic syn-
drome, with hyperphagia and weight gain, may
be the presenting manifestation of CNS relapse
in childhood acute lymphoblastic leukemia
[203].
Diagnosis. The key diagnostic test is lumbar
puncture and cerebrospinal fluid examination.
In solid tumor patients, it is wise to obtain a CT
head scan first to detect concomitant brain
metastases that pose a risk of cerebral hernia-
388 IV. HEAD AND NECK COMPLICATIONS OF CANCER THERAPY
tion. In patients with circulating lymphoblasts,
an injection of i.t. methotrexate after CSF is
obtained is recommended [193]. In thrombocy-
topenic patients, subarachnoid hematoma with
paraplegia, although rare, can follow the lumbar
puncture [204], and platelet transfusions to keep
platelet counts above 50 x 109 /liter are desir-
able. Careful observation for signs or symptoms
of cord compression should follow.
Usually the opening pressure is elevated; the
glucose level may be decreased, and the protein
level and cell counts may be elevated. The only
definite diagnostic finding is the presence of
malignant cells. Malignant cells in CSF cytology
are the hallmark of leptomeningeal invasion
and do not usually occur with intracerebral or
subdural metastases unless the leptomeninges
are involved [205]. When definitely malignant
cells are found on cytology, the diagnosis of
leptomeningeal neoplasia is reasonably certain.
False-negative cytology is uncommon in leuke-
mia, but may occur in a large proportion of
patients with carcinomatous meningitis. Thus, a
single CSF cytology in a patient who eventually
develops carcinomatous meningitis has a 50%
chance of being positive [206-208]. Three serial
examinations will increase the overall sensitivity
to about 85%. It follows that, if the diagnosis
is highly suspected, repeat CSF sampling may
be helpful, although an overinvasive approach
should be tempered by the final therapeutic be-
FIGURE 20-12. Cytospin sample in patient with acute
lymphocytic leukemia with meningeal relapse. Sheets
of monomorphic immature cells are diagnostic.
nefit expected. False-positive cytology is rare
except in patients with lymphoid malignancies
where reactive cells are difficult to distinguish
from malignant cells.
CSF examination for malignant cells in
patients with leukemia or lymphoma is best
performed by the cytocentrifuge technique
(cytospin) while standard conventional cytolo-
gic examination is preferred in patients with
solid tumors. Both methods may be used to
maximize the diagnostic information. The
cytocentrifugation method is simple, fast, and
sensitive [209-211]. If a cytocentrifuge is not
available, the sedimentation technique may be
used [212]. Cytocentrifugation increases appar-
ent cell size and nuclear cytoplasmic ratio and
makes nucleoli more prominent. These changes
make cells look immature and therefore inter-
pretation may be difficult and require an expert
cytologist. Sheets of immature blast forms
are common in acute lymphoblastic leukemia,
but carcinomatous meningitis may be far less
~ellular.
CSF cell counts are variable. With high cell
counts (i.e., greater than 20 cells/I.II), if a mono-
morphic cell population with malignant features
is identified on cytospin smear, the diagnosis is
certain (figure 20-12). When the number of cells
 20. HEAD AND NECK NEUROLOGIC COMPLICATIONS OF MALIGNANCY 389

FIGURE 20-13. Cerebrospinal fluid cytology in

patient presenting with malignant melanoma and
meningeal carcinomatosis. Note clumps of malignant
melanoma cells.

FIGURE 20-14. Cytospin sample in patient with

recurrent lymphoma and multifocal central nervous
system findings including cranial nerve palsies. Note
cell in mitosis slightly right from center.
390 IV. HEAD AND NECK COMPLICATIONS OF CANCER THERAPY
is low (less than 10/1_tl), the diagnosis is more
difficult because only a limited number of cells
will be on the slide. In these cases, it is impor-
tant to focus on cell morphology. Clumps of
malignant cells are characteristic of carcinoma-
tosis (figure 20-13). In general, myeloid leuke-
mia and solid tumor cells are relatively easy to
identify. Lymphoid leukemia and lymphoma
cells may be very difficult to differentiate from
normal lymphoid or reactive CSF elements
[210]. Cells in mitosis are highly suggestive of
malignancy (figure 20-14). The presence of sig-
nificant numbers of granulocytes is not a feature
of meningeal leukemia or carcinoma and should
prompt a search for infection.
The cellular composition of lumbar and
ventricular CSF may be different since the
CSF develops a higher protein concentration
and higher cell count as it traverses normal
pathways from its site of production in the
ventricular choroid through the spinal subarach-
noid space. Therefore, samples obtained by
lumbar puncture and via Ommaya reservoir
may differ [213]. This should be remembered
especially when assessing response: remission
should be confirmed by lumbar CSF examina-
tion when initial lumbar CSF showed malignant
cells.
In selected cases with diagnostic difficulties,
certain tests such as immunofluorescence for
terminal transferase in lymphoblastic leukemia
[214] or beta-2-microglobulin determination in
leukemia and lymphoma [215] may be helpful.
CT scan is useful if intracerebral metastases are
suspected and may reveal hydrocephalus or
rarely thickening of the meninges suggestive of
neoplastic invasion at the base of the skull.
The main differential diagnosis is infection.
Bacterial, tuberculous, fungal, and viral mening-
itis may produce clinical manifestations similar
to malignant invasion and infection and neo-
plastic meningitis may coexist. Appropriate
stains and cultures of the CSF are essential,
particularly at presentation. Less often leuko-
encephalopathy, vincristine neuropathy, sub-
dural hematoma, or L'hermitte's sign may pose
diagnostic difficulties. The latter is a feeling of
electrical shock radiating down the spine and
over the extremities after neck flexion and
occurs as a transient (weeks or months) and be-
nign complication of spinal cord irradiation.
Management. Carcinomatous meningitis can
often be controlled for short periods of time
with i.t. chemotherapy, but most patients die of
advancing systemic refractory cancer within a
few weeks or months. The same is true for
leukemic and lymphomatous meningitis in
patients with refractory recurrent leukemia
or lymphoma. When leukemia or lymphoma
are confined to the meninges or involve the
meninges at a time when the systemic disease is
responsive to therapy, very significant palliation
and occasional long-term survival may be
achieved with appropriate treatment. This may
also apply to the occasional chemotherapy-
sensitive solid tumor patient who presents with
recurrent or initial disease localized to the
memnges.
In most cases, however, the management is
palliative in nature. Symptomatic and suppor-
tive treatments are of great importance. The
goals of therapy should be individualized and
depend heavily on the patient's preferences.
Discussions about prognosis and therapeutic
options with the patient and family are essential.
The treatment options are i.t. chemotherapy,
radiotherapy, and systemic chemotherapy and
can be used separately or in combination. Cra-
niospinal irradiation is not recommended as ini-
tial therapy because of its toxicity, and systemic
chemotherapy has thus far been largely ineffec-
tive. The standard current approach consists of
i.t. chemotherapy and local radiation therapy to
areas of focal symptomatic involvement.
Intrathecal Chemotherapy. Experience has
accumulated with the use of methotrexate and
cytarabine (ara-C); Thiotepa is an additional
agent in use. These drugs are often used singly,
but also have been tried in combination. A dose
is diluted in artificial spinal fluid (i.e., Elliott's B
solution) or preservative-free saline and injected
via lumbar puncture. A volume of CSF at least
as great as that being delivered (usually about 3
cc) is withdrawn and the solution is injected
very slowly, with frequent withdrawal of CSF
at short intervals to assure continued adequate
placement of the needle and to facilitate mixing.
This procedure, called "barbotage" is rather
cumbersome; further, lumbar injections induce
local arachnoiditis that may make repeated
access progressively more difficult. Fluoro-
scopic control after contrast injection may help
optimize drug delivery.
If only a few injections are needed (such as
for CNS prophylaxis), the lumbar approach is
reasonable. Inadequate drug delivery, however,
 20. HEAD AND NECK NEUROLOGIC COMPLICATIONS OF MALIGNANCY 391

disturbances in the CSF flow patterns. Radio-

nuclide imaging studies with lllindium-DTPA
delivered through an Ommaya reservoir in pa-
tients with neoplastic meningitis have shown a
70% incidence of abnormalities in one or more
of three patterns: ventricular outlet obstruc-
tions, spinal canal flow abnormalities, and flow
delays over the cortical convexities [115]. The
resulting drug distribution abnormalities may
lead to increased neurotoxicity and decreased
efficacy. Patients with ventricular outlet ob-
struction had in fact a significantly shorter sur-
vival. It is therefore desirable to study CSF flow
patterns prior to therapy at least in those pa-
tients with a chance for long-term palliation
[115].
The management of meningeal leukemia and
lymphoma may be viewed as a basic model for
the treatment of all neoplastic meningitides.
Methotrexate is often used initially. A fixed
dose of 12-15 mg twice weekly is appropriate
for all adults, adolescents, and children over
three years of age while children under three
years of age and adults over 60 may require low-
er doses [184]. Dosage adjustment based on
body surface area is not recommended because
FIGURE 20-15. Ommaya reservoir (see text). it results in overdosage of adults and under-
dosage of children. A "concentration x time"
may occur in about 15% of cases with this schedule of 1 mg every 12 h for three days
method. Moreover, cytotoxic drug concentra- was designed to be less neurotoxic and was
tions may not be achieved over the cerebral demonstrated to be so, but is not yet in wide-
hemispheres with this approach. For more spread use [217].
chronic use, such as in active meningeal leuke- CSF is obtained prior to drug injection each
mia, lymphoma, or carcinoma, it is useful to time. Biweekly injections are continued until
obtain a more reliable and practical delivery the CSF is free of malignant cells and the CSF
method. The Ommaya reservoir, originally de- protein is close to normal, which usually occurs
signed to treat fungal meningitis, provides easy after two or three weeks of treatment. After
access to the ventricular system for sampling such a remission is achieved, one weekly injec-
and drug delivery purposes [216]. It consists of tion is given for four weeks and single monthly
a reservoir connected to a catheter (figure 20- maintenance injections are given indefinitely
15). Under local anesthesia, the catheter is unless toxicity or relapse develop. This regimen
placed into the ventricular system via a burr is usually well tolerated and offers excellent pal-
hole and the reservoir is installed under the liation. Ara-C (50 mg) and thiotepa (10 mg)
scalp. The system is cosmetically acceptable and have been used instead of, or in combination
minimizes the discomforts of i.t. therapy. CSF with, methotrexate, following a similar overall
is obtained and drug is injected transcutane- plan of treatment [218, 219]. Meningeal carcino-
ously using a 25- or 23-gauge needle. After the matosis is more resistant to i.t. therapy and,
drug is injected into the reservoir, the latter is although short-term palliation may be obtained,
"pumped" so that the drug is transferred to the the results of treatment are inferior to those
ventricular system. achieved in meningeal leukemia/lymphoma. It
The entire leptomeningeal surface should be should be noted, however, that, even in solid
reached with adequate drug concentrations to tumor patients, systemic extrameningeal disease
improve efficacy. This may prove difficult be- is the most common cause of death after
cause active meningeal disease produces marked meningeal carcinomatosis is diagnosed.
392 IV. HEAD AND NECK COMPLICATIONS OF CANCER THERAPY
Radiation Therapy. Radiotherapy has its
main role in the palliation of focal neurologic
deficits, usually secondary to malignant inva-
sion of nerve roots. Cranial nerves, notably the
sixth and seventh, and the cauda equina are
often affected, although virtually any nerve root
may be involved. Cranial nerve palsies and
pain in radicular distribution should prompt
immediate therapy to prevent more severe,
irreversible neurologic damage. Irradiation
ports are tailored to cover specific local areas
of symptomatic involvement. Craniospinal
irradiation produces severe bone marrow sup-
pression that usually precludes further systemic
chemotherapy so we do not recommend it
unless other therapy has failed.
Those systemic chemotherapeutic drugs that
are able to penetrate the blood-brain barrier,
such as the nitrosoureas, have not been shown to
be effective in meningeal malignancies. High-
dose i.v. methotrexate with leukovorin rescue is
effective in the treatment of meningeallympho-
rna [220, 221] and high-dose systemic cytosine
arabinoside has been effective in five patients
with overt meningeal leukemia [222], suggesting
that systemic therapy may have a role in the
future.
Complications of Therapy. Local complica-
tions related to lumbar puncture and drug injec-
tion include arachnoiditis, subdural hematoma,
cord damage, and paraplegia. These were dis-
cussed in the section Neurotoxicity of neoplastic
agents. Complications related to the insertion
and use of the Ommaya reservoir are multiple
and include misplacement of the catheter
tip with direct or drug-related parenchymal
brain damage, catheter-tip migration, infection,
catheter occlusion, mechanical malfunction, and
seizures. Major complications leading to sub-
stantial morbidity and! or surgical revision
occurred in about 25% of patients in the earlier
series; these numbers may improve due to the
growing experience with the catheter in a num-
ber of institutions.
The acute (hours to days) tolerance to CNS
irradiation in the abscence of concomitant che-
motherapy is relatively good. Transient nausea,
drowsiness, headaches, fatigue, and anorexia are
common. The concomitant use of cranial irra-
diation and i. t. methotrexate in patients with ac-
tive meningeal leukemia has been associated
with the acute development of a severe encepha-
lopathy which can be fatal [166].
Subacute (days to weeks) radiation toxicity is
more common and consists of the "somnolence
syndrome" characterized by somnolence, irrita-
bility, anorexia, and nausea; it may also include
fever, dysphasia, ataxia, papilledema, and
exacerbation of previous focal findings. The
syndrome is reversible and was discussed in
the section Neurotoxicity of neoplastic agents.
Delayed (months to years) radiation toxicity
consists of cerebral necrosis that occurs
generally between one and five years of therapy
in areas of the brain exposed to 6000 cGy or
more. This toxicity is rare in patients with neo-
plastic meningitis in part due to their limited
survival. More disturbing are the reports (see
the section Neurotoxicity of neoplastic agents) of
intellectual dysfunction and late CNS structural
abnormalities after CNS prophylaxis with cra-
nial irradiation and i.t. methotrexate in acute
lymphoblastic leukemia patients who are other-
wise presumably cured. New approaches to
CNS prophylaxis (i.e., high-dose methotrexate
with leukovorin rescue, without cranial irradia-
tion) to minimize these sequelae are being
explored [15, 223].
Results of Therapy and Prognosis. The
majority of patients with neoplastic meningitis
ultimately die of complications related to
advancing refractory systemic cancer. Thus, it is
the status and response to therapy of the system-
ic malignancy that determine the final out-
come. In fact, CNS relapse in adult leukemia
may have little impact on overall survival [224].
Meningeal leukemia at presentation or as only
site of relapse in childhood acute lymphoblastic
leukemia is most responsive to treatment and
long-term palliation and occasionally long-term
disease-free survival may be reasonable goals. In
adults with meningeal leukemia, lymphoma, or
carcinoma the prognosis is poor, but acceptable
short-term palliation of CNS symptomatology
is obtained in most patients. In one representa-
tive series, symptomatic improvement was
achieved in almost all patients with meningeal
leukemia and normalization of CSF was
obtained in 90% of cases [225]. Intraventricular
therapy via subcutaneous reservoir was more
effective than therapy via lumbar puncture.
Most patients died of systemic refractory leuke-
mia and, in about half, no meningeal leukemia
was found at autospy. Symptomatic improve-
ment was obtained in over 50% of solid tumor
and lymphoma patients. Breast cancer seemed
 20. HEAD AND NECK NEUROLOGIC COMPLICATIONS OF MALIGNANCY
more responsive than lung cancer and melano-
ma, probably reflecting the different sensitivity
of the malignancies to the agents used [225).
Focal signs were more common in solid tumor
patients and rarely resolved with therapy. In
spite of aggressive i.t. chemotherapy, autopsy
studies consistently revealed extensive mening-
eal carcinomatosis in solid tumor patients [225).
In most series, survival varies from one to six
months, regardless of treatment [226, 227].
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 21. HEAD AND NECK
COMPLICATIONS OF BONE
MARROW TRANSPLANTATION

Mark M. Schubert
Keith M. Sullivan
Edmond L. Truelove

In the late 1950s, the technique of human mar-
row transplantation was first applied, and these
initial attempts were viewed with enthusiasm as
a means to treat blood dyscrasias or marrow
failure. However, these early attempts often met
with failure; in a study of 203 of the early mar-
row grafts, only 22 (11 %) were unequivocally
successful allogeneic transplants [1]. The prob-
lems preventing success included graft failure,
graft-versus-host disease (GVHD), bleeding
and infectious complications resulting from
marrow and immunologic ablation, and recur-
rence of disease [2]. During the 1960s, advances
in histocompatability typing, pretransplant
conditioning, immunosuppressive therapy, and
improved supportive care and infection control
laid the groundwork for a resurgence of human
marrow grafting. Today, marrow transplanta-
tion is considered an effective treatment for
severe aplastic anemia, acute leukemias, and im-
munodeficiency disorders [3-5] (see chapter 8).
Head and neck complications are frequently
encountered during marrow transplantation.
The type, timing, and severity of these com-
plications vary from patient to patient. Such
factors as (a) the patient's underlying disease and
prior therapy, (b) the type of pretransplant con-
ditioning regimen and posttransplant GVHD
prophylaxis, and (c) local and systemic infec-
tions and complications encountered following
transplant all play an important role. The ulti-
mate success of marrow transplantation de-
pends in large measure upon the ability of the
transplant team to render intensive specialized
patient care. A number of specialists including
Peterson et al., HEAD AND NECK MANAGEMENT OF THE CANCER PATIENT.
© 1986. Martinus Nijhoff Publishing. All rights Teseroed.
physicians, dentists, nurses, nutntlOnists, and
pharmacists are necessary to provide this critical
supportive care.
When considering management strategies for
head and neck complications, it is convenient
to divide marrow transplantation into four
phases from pretransplant to full recovery (table
21-1). Phase I covers the "pretransplant" period
and includes the pretransplant workup. Phase II
begins with chemoradiotherapy preparation,
is followed by marrow infusion (day 0), and
extends up to the time when sustained donor
hematopoietic engraftment has occurred. Pa-
tients are usually discharged from the hospital
with granulocyte counts greater than 1000/mm3
around days 30-35. Phase III includes the
period of outpatient follow-up over the next 2-
TABLE 21-1. Phases of marrow transplantation
Phase I Period of evaluation prior to chemo-
radiotherapy conditioning for marrow
transplantation
Phase II Period including chemoradiotherapy
conditioning (7-10 days prior to
transplant), marrow infusion (day 0),
and demonstration of sustained hema-
topoietic engraftment (approximately
day 35 after transplant)
Phase III Period including continued marrow
graft recovery during outpatient
follow-up (days 36-100 after trans-
plant)
Phase IV Period of full immunologic recovery
(;;;. day 101)
401
402 IV. HEAD AND NECK COMPLICATIONS OF CANCER THERAPY

TABLE 21-2. Relative frequency of head and neck complications

Phase"
II III IV
Chemoradiotherapy toxicity
Mucositis +++ ++
Esophagitis/pharyngitis +++ ++
Parotitis ++
Xerostomia +++ ++ +
Neurotoxicity ++ ++ +
Hemorrhage +++ +
Cataracts +++
Infections
Bacterial ++ +++ ++ +
Fungal:
Candida ++ +++ ++ +
Other (Aspergillus) + ++ ++ +
Viral
HSV + +++ ++
CMV + ++ +++ +
VZV +V2 + ++ +++
GVHD
Acute
Skin ++ +
Esophagus ++ ++
Eye + ++ +
Chronic
Skin ++ +++
Oral mucositis ++ ++
Xerostomia ++ ++
Esophagus ++ +++
Eye + ++ +++
Other drug toxicities
Aminoglycoside otoxicity + ++ ++ +
Methotrexate mucositis ++ ++
Neurotoxicity
Acyclovir + + + +
Methotrexate (LT.) + ++ ++
Cyclosporin ++ ++ ++
Other complications
Dysgeusia +++ ++
Esophageal reflux ++ ++ +
Dental caries (xerostomia) + +++
Abnormal jaw or dentition +
growth/development
aRelative frequency: -, not noted; +V2, rare; +, occasional; ++, frequent; and +++, very frequent.

3 months, during which full marrow function Phase I

becomes well established. Phase IV covers the
subsequent period of full immunologic recov-
ery. The major sites of head and neck complica-
tions include: (a) oral cavity; (b) ears, nose,
throat, and esophagus; (c) central nervous sys-
tem; (d) eyes; and (e) skin and scalp (table 21-2).
GENERAL EVALUATION
AND MANAGEMENT
The patient's overall clinical condition at the
time of presentation for marrow transplant has a
major impact on the head and neck complica-
 21. HEAD AND NECK COMPLICATIONS OF BONE MARROW TRANSPLANTATION
tioris occurring during this phase. The effects of
chronic conditions (e.g., sinusitus), health care
neglect (e.g., dental disease and associated
breakdown), manifestations of the complica-
tions of specific disease processes (e.g., hemor-
rhage, infection, and leukemic infiltrates), and
the effects of previous therapies combine to de-
termine the nature of presenting complications.
Preliminary evaluation and workup of patients
should attempt to identify problems that can be
eliminated or stabilized prior to the commence-
ment of high-dose chemotherapy conditioning.
Oral Cavity. Many transplant candidates have
neglected or avoided dental care for long
periods prior to transplant. Oral assessment
should include both clinical and radiographic
examinations to determine potential sources of
infection, irritation, and trauma [6]. The type
and amount of dental care that can be given will
depend on the urgency of the patient's trans-
plant, and the ability to provide adequate sup-
portive care. If possible, dental scaling and
prophylaxis should be performed. Moderate
and deep carious lesions should be stabilized. It
is important to keep in mind that it may be
as long as 4-8 months after transplant before
subsequent restorative care can be attempted.
Furthermore, patients receiving total body irra-
diation (TBI) can suffer varying degrees of
xerostomia that can accelerate the rate of decay,
resulting in rampant dental caries [7]. Sources of
oral irritation and trauma (sharp or fractured
teeth, poorly fitting dentures, etc.) should be
eliminated. This includes removal of orthodon-
tic bands and appliances, which can extensively
damage the oral mucosal surfaces, severely com-
promise oral hygiene efforts, and predispose
the patient to local infections, bacteremia,
and bleeding. Root tips, loose primary teeth,
and nonsalvageable teeth should be removed
if at all possible. Primary closure should be
obtained, if possible, and approximately 4-7
days or longer should be allowed for healing of
surgical sites prior to the onset of chemother-
apy. Neutropenic patients with white blood cell
counts of less than 2000/mm3 should be given
prophylactic antibiotics, and platelet transfu-
sions should be given if platelet counts are less
than 40,000/mm3 [8].
Recommendations for endodontic therapy in
these patients have not been clearly delineated.
Any active endodontic infection should be
403
eliminated. Asymptomatic pulpal pathosis
may not require immediate treatment, whereas
acute pulpal infections without involvement of
periapical structures can usually be sufficiently
relieved with initial endodontic therapy prior to
myelosuppression [8, 9].
Good oral hygiene can significantly limit the
severity of subsequent oral problems, and
instructions in proper brushing with a soft,
nylon-bristled toothbrush (Bass sulcular scrub),
flossing, and oral rinsing regimens should be
provided [10].
Ear, Nose, and Throat. Health histories should
be reviewed for evidence of sinus, nasal, or
otic infections. Follow-up exams should then
be directed at determining the status of these
disorders. Conditions that could flare during
myelosuppression should be stabilized. Patients
with a history of chronic sinusitis appear prone
to sinus complications in the immediate post-
transplant period.
Neurologic Toxicity. High-dose systemic and
intrathecal (I.T.) chemotherapy and cerebral
radiation may produce both immediate and late
neurologic toxicity with intellectual and cogni-
tive impairment [11, 12]. The combination of
cranial irradiation and I.T. methotrexate (MTX),
when administered for either treatment or
prevention or central nervous system leukemia
in children or young adults, may lead to the
development of leukoencephalopathy, a severe
form of neurotoxicity characterized by multi-
focal coagulative necrosis of the white matter of
the brain [13-15] (see chapter 20).
Phase II
This phase is marked initially by profound
pancytopenia and immune deficiency. Over the
first 3-4 weeks after transplant, there is gradual
repopulation of the marrow, and subsequent re-
turn of circulating granulocytes, red cells, and
platelets. The complications appearing during
this period are predominantly related to the
toxic effects of the preparative conditioning
regimens, the consequences of myelosuppres-
sion, and the emergence of acute GVHD. High-
dose cyclophosphamide and supralethal TBI
are associated with significant side effects.
Although the severity of some complications is
lessened with fractionated TBI when compared
404 IV. HEAD AND NECK COMPLICATIONS OF CANCER THERAPY

TABLE 21-3. Head and neck infections occurring after transplantation

Site/organism Infectious episodes

Winston Atkinson
Oral cavity et al. [18]a et al. [84]e
Candidiasis 18 20
Herpes simplex 5 6
Klebsiella pneumoniae 2
Pseudomonas aeruginosa 1
Serratia marcescens 1
Echo-II virus 1
Dental abscess 1 2
Not specified 1 1
Total 30 29

Winston Atkinson
N asopharynxlsinus et al. [18]a Johnson [37]b et al. [84]e
Candida albicans 2
Candida sp. + Staphylococcus sp. coag( + ) 2
Aspergillus sp. 1
Herpes simplex 3
Cytomegalovirus 1
Streptococcus pneumoniae 2 1
Staphylococcus sp. coag( + ) 1
Hemophillus influenza 2
Escherichia coli, Proteus mirabilis
N isseria menigititis 1
No organisms isolated 4 8
Not specified 3 27
Total 7 25 27

Winston McDonald Atkinson

Esophagus/pharynx et al. [18]a et al. [40]c et al. [84]e
Candidasp. 3 4 1
Herpes simplex virus 6
Cytomegalovirus 7
Viral + fungal (sp. not specified) 1
Cytomegalovirus + herpes simplex 3
Staphylococcus aureus
Bacterial (not specified) 11
Total 4 21 12

Winston Atkinson
Ear et al. [18]a et al. [84]e
Pseudomonas aeruginosa 1
Staphylococcus aureus, Proteus mirabilis 1
No isolate 2
Not specified 16
Total 4 16

Winston Jack Atkinson

Eye et al. [18]a et al. [52]d et al. [84]e
Pseudomonas aeruginosa 1
Staphylococcus aureus, Serratia marcescens 1
Herpes zoster 4
Herpes simplex 5 3
 21. HEAD AND NECK COMPLICATIONS OF BONE MARROW TRANSPLANTATION
TABLE 21-3 (Continued)
Purulent conjunctivitis
Total
CNS
Encephalitis
Aspergillus sp.
Herpes simplex
Meningitis
Klebsiella pneumonia
Not specified
Abscess
Staphylococcus aureus
Total
Study periods: (a) Win!ton et aI., through day 210; (b) Johnson, through day 100; (c) McDonald et aI., not specified; (d) Jack et aI., day 10 to
four years; and (e) Atkinson et al., greater than 160 days
with single-dose TBI schedules, the overall
benefits of fractionation are yet to be fully
defined [16, 17].
Infection is by far the most serious life-
threatening head and neck complication en-
countered during phase II (table 21-3). In
general, the presence of infection prior to
~ondi~ioning, the duration of neutropenia, the
mtenSIty of posttransplant immunosuppression,
and the absence of infection prophylaxis regi-
mens have been associated with an increased
incidence of infection [17-19].
ORAL CAVITY COMPLICATIONS
The most frequent sites of head and neck com-
plications during this phase are the oral cavity
and oropharynx, with one study showing that
~ignificant ~omplications in this region develop
mover 95 Yo of the adult transplant patients
receiving TBI [17]. The causes of oral com-
plications are varied, and most represent a com-
bination of several insults including chemo-
radiotheraJ?Y toxicities, infections, and physical
and chemical trauma (often associated with
"normal" oral function). The age of patients has
been observed to relate to the degree of break-
down. Children will usually have less mucositis
and xerostomia and heal more rapidly than
adults, which is in contrast to what has been re-
ported for patients receiving chemotherapy
only [20]. ~J?parently~ the. resistance to damage
an~ the abtlIty of eplthehal surfaces to repair
rapidly are enhanced in children. Oral com-
plications are manifested as mucositis, ulcera-
405
12
2 9 15
Winston Atkinson
eta!' [IS]a et aI. [S4]e
2
3 3
after transplant.
tion, hemorrhage, infection, and xerostomia.
Chemoradwtherapy Toxicities. Between four
and seven days after the initiation of preparative
chemotherapy, mucosal changes become clini-
cally evident. When chemotherapy is followed
by TBI, the breakdown of oral tissues is even
more marked. The initial mucosal changes after
~hemotherapy appear as atrophy, with the result-
mg generalized erythema being most evident
on the nonkeratinized surfaces of the buccal
and labial mucosa, floor of the mouth, lateral
and ventral tongue, and soft palate; eventually
the para- and orthokeratinized mucosal surfaces
o~ the dorsal tongue, hard p~ate, and gingivae
Will also demonstrate atrophiC changes. When
radiation is also utilized, the oral tissues will
transiently appear whiter because of radiation-
ind~ced ker~tinization [21]. In 3-5 days, this
whitened epithelium is desquamated, and the
resulting mucositis is significantly more intense
than that seen in patients who receive che-
motherapy only (figure 21-1). Furthermore
ra~iation will induce significant abnormalities i~
s:~hvary gland function. This is initially noted as
bilateral parotitis. Patients will have a thick
ropy mucus-saliva, which can progress to a ne~
total loss of salivary function. This radiation
damage varies from transient (several weeks in
children) to permanent (in some adults).
Xerostomia resulting from TBI has a signi-
ficant effect on oral tissues. Eating and talking
become difficult, and the oral tissues become
dehydrated and crack. Xerostomia also in-
406 IV. HEAD AND NECK COMPLICATIONS OF CANCER THERAPY
FIGURE 21-1. Phase II. Severe mucositis occurring 15
days after transplant with ulcerative mucositis and
thick mucous saliva. Patient was conditioned with
chemoradiotherapy.
fluences microbial colonization and infection
and, when it persists long enough, it can result
in severe xerostomia decay. Oxygen support
will further exaggerate drying of oral tissues.
Another insult to oral tissues can be the che-
mical irritation from frequent vomiting that is
induced by chemoradiotherapy. Gastric con-
tents can burn the compromised oral tissues,
especially when the normal epithelial barrier has
been attenuated or lost and the salivary mucins
that normally coat the tissues are lacking. The
contribution of nutritional deficiencies to the
breakdown of oral tissue, however, has been
minimized by the standard use of hyperali-
mentation [3].
Mucosal ulcerations are seen with chemo-
radiotherapy conditioning, though it is likely
that the effects of trauma andlor infection on
the compromised mucosal epithelium play a
major role in their full expression. Ulcerative
changes are most pronounced between days 7
and 14 after transplant, and are usually noted on
the buccal and labial mucosa and ventral tongue
[22]. If the ulcers are deep, bleeding can be a
problem because of vascular erosion and throm-
bocytopenia; shallower ulcers and erosive le-
sions tend to be covered by a firmly adherent
whitish-gray fibrinous exudate or plaque. It is
important to be aware of the contribution of in-
fections, especially viral, to the ulcerative break-
down seen in this phase, and cultures should be
taken (figure 21-2). Because mucositis is ex-
pected from the preparative conditioning regi-
men, other causes of breakdown are sometimes
not investigated, and timely and specific ther-
apy is delayed.
Oral Hemorrhage. Oral hemorrhagic prob-
lems during this period can be very dramatic
and can complicate the immediate posttrans-
plant period. Minor bleeding from gingival sulci
can occur when oral hygiene has been inade-
quate, while major hemorrhage is usually seen
with ulcerations. Oral herpes simplex infections
may contribute substantially to ulceration and
subsequent bleeding.
Infection. The profound neutropenia occur-
ring in the immediate posttransplant period puts
the transplant patient at high risk for oral in-
fection. Breakdown of the mucosal epithelial
barrier and the loss of other host defenses fur-
ther increase the risk of infection. In general, up
to half of the patients experience bacteremia
or other serious bacterial infections due to
predominantly gram-positive organisms that
commonly reside in the oral cavity [23, 24].
Fungal infections may also develop, especial-
ly when neutropenia is prolonged [23]. Candida
species are the most frequently isolated organ-
ism. Aspergillus species are the next most com-
mon fungal isolate, although it may also repre-
sent a contaminant [23, 24] (figure 21-3). The
potential of oral colonization and systemic
spread of fungal organisms has been recognized,
and implications for early recognition and man-
agement of oral candidiasis are obvious [25].
Viral infections are responsible for significant
morbidity following marrow transplantation
[23, 26, 27]. Approximately 40% of patients
excrete herpes simplex virus (HSV)-in almost
all instances these patients are seropositive for
HSV antibody before transplant, with these
posttransplant infections representing reactiva-
tion of latent virus [23]. Varicella zoster virus
(VZV), cytomegalovirus (CMV), adenovirus
 21. HEAD AND NECK COMPLICATIONS OF BONE MARROW TRANSPLANTATION 407

FIGURE 21-2. Phase II. Ulcerative mucositis with

severe hemorrhage in a patient eight days after trans-
plant. Cultures were positive for herpes simplex
virus. Healing of these lesions took over 35 days.

FIGURE 21-3. Phase II. Invasive Aspergillus infection

involving the left tuberosity and maxillary sinus in a
patient 39 days after transplant.
408 IV. HEAD AND NECK COMPLICATIONS OF CANCER THERAPY
FIGURE 21-4. Phase II. Significant facial swelling in
a patient seven days after transplant. Patient had
culture-proven herpes simplex lesions in lower left
buccal vestibule.
(AV), and Coxsackie virus have also been re-
covered from oral cultures, and all can cause sig-
nificant ulcerative mucositis. With mucosal
integrity severely compromised by the chemo-
radiotherapy conditioning regimens, viral ulcera-
tions can cause extensive, almost desquama-
tivelike breakdown that can be accompanied by
marked facial swelling [7] (figure 21-4). This
appearance may vary considerably from "clas-
sic" descriptions. Pain from viral lesions is often
excruciating and usually requires systemic nar-
cotic analgesia. Oral viral infections may sub-
sequently spread to involve the esophagus,
trachea, lungs, and eyes. With erosion of mu-
cosal vasculature, major oral hemorrhage can
result. Later in phase II, HSV lesions appear
more as discrete ulcerations rather than broad
areas of erosions.
Between 25% and 58% of documented sep-
ticemias originate from oral cavity infections
[18, 28, 29]. In addition, "normal" oral organ-
isms, especially those found in the gingival
sulcus, may contribute to febrile episodes. How-
ever, the frequency of severe periodontal in-
fections has been surprisingly low and they are
usually associated with significant preexisting
periodontal disease (bone loss and pocket depth
greater than 4 mm) or partially erupted third
molars (pericoronitis) (figure 21-5). The routine
use of broad-spectrum antibiotics capable of
suppressing the common oral flora may be a
major reason for the lack of significant clinical
periodontal infections.
Graft-versus-Host Disease. Acute GVHD is
noted to appear between five and 47 days (me-
dian 19) after allogeneic marrow transplant [30].
(see chapter 8). Skin, liver, and gut are the most
apparent sites of organ involvement. Because
the oral manifestations of acute GVHD are not
well documented, it may be difficult to distin-
guish acute GVHD from the toxic effects of
chemoradiotherapy during phase II [31].
FIGURE 21-5. Phase II. Periodontal lesion in a patient
15 days after transplant. Cultures were positive for
Pseudomonas sp. and HSV.
 21. HEAD AND NECK COMPLICATIONS OF BONE MARROW TRANSPLANTATION
Taste Complications. Following preparative
chemoradiotherapy, patients will usually com-
plain of dysgeusia or ageusia. This will be most
notable immediately after transplant, but can
last for over 60 days. Red meat has been
observed to be the most common food associ-
ated with dysgeusia, while hypergeusia is often
reported with sweets. Children, as a rule, report
a much more rapid recovery of taste than adults.
Taste aberrations can significantly interfere with
attempts to maintain adequate caloric intake
levels.
The tempo and timing of the resolution of
oral complications are affected by a variety of
factors. The use of MTX for GVHD prophyla-
xis has been noted to intensify mucositis and
delay healing; on the other hand, cyclosporin
A (CyA), a fungal metabolite with potent
immunosuppressive properties, is associated
with less oral involvement. This is related to
the fact that Cy A has less direct mucosal and
hematopoietic toxicity [32, 33]. The recovery
of the oral tissues has been noted to generally
parallel the rate of platelet and neutrophil re-
covery [34].
Management of Oral Complications
ORAL HYGIENE. General oral care regimens are
aimed at maintaining the highest possible level
of oral hygiene, preventing mucosal breakdown
and infection, and maintaining patient comfort.
Patients are instructed in efficient oral hygiene
that is appropriate for the patient's skill level
and condition [8, 10]. Basically, this includes
toothbrushing with a very soft nylon bristle
toothbrush, flossing, and frequent rinsing with
0.9% saline solution. Toothpastes are often irri-
tating and should be discontinued until mucosal
surfaces have healed (see chapter 24).
There is some controversy as to when routine
oral care should be stopped because of granu-
locytopenia and thrombocytopenia. Recent
studies have shown that it is possible to brush and
floss while neutropenic without increased inci-
dence of bleeding or bacteremia. In fact, careful
oral hygiene can decrease local infections and
lower the incidence of fevers of unknown origin
[8, 28, 29], which has been consistent with our
observations. Saline rinses are used to help re-
duce mucosal irritation, moisturize tissue, and
remove debris from the mouth. Patients are en-
couraged to use copious amounts frequently-
8-10 mouthfuls vigorously swis~ed about every
409
2 h. If patients are vomiting, the saline solution
can be made alkaline with sodium bicarbonate
(1 tsp per 32 oz. 0.9% saline solution). As oral
discomfort increases, patients should rinse more
frequently. Patients with severe mucositis have
been noted to rinse almost constantly while
awake and to substitute this for other pain
control therapy.
Hydrogen peroxide has been recommended
in a variety of combinations for routine oral
rinsing for hygiene and debridement [35, 36].
Though it is helpful in removing oral debris and
blood clots, however, it is irritating and may
even slow healing of ulcerations. Compliance is
also compromised by attendant discomfort.
Consequently, hydrogen peroxide is only rec-
ommended in transplant patients for specific
purposes (e.g., blood clot removal or periodon-
tal infections); instead, 10% carbamide perox-
ide, which is also effective, is recommended be-
cause it is better tolerated [8]. It is best to avoid
the use of mouthwashes and other alcohol- and/
or phenol-containing preparations, which are
drying and irritating.
The initial salivary gland inflammation that
results from TBI damage can be managed with
frequent ice-pack application and usually re-
solves within 2-3 days. Frequent rinsing with
saline solution and suctioning can help with the
removal of the viscous saliva that results from
radiation injury to the serous salivary gland aci-
ni. Saline rinses and artifical salivas can provide
symptomatic relief for xerostomia. Stimulation
of salivary flow with 1% pilocarpine, citric acid
(sugarless lemon drops), or sugarless mints is
also occasionally helpful.
ORAL ANALGESIA. Management of chemo-
radiotherapy-induced mucositis is predomi-
nantly limited to symptomatic measures (see
table 21-4). If normal saline is not effective,
topical anesthetics such as lidocaine, dyclonine,
benzocaine, cocaine, and topical diphenhydra-
mine are utilized. These agents can be applied
directly to lesions or rinsed as often as needed.
Patients, especially children, are cautioned to
avoid eating and otherwise traumatizing tissue
while their mouths are numb. Prolonged gar-
gling with anesthetics is not recommended be-
cause of the risk of aspiration and pulmonary
infection; atomizers and sprays may provide a
safer means of delivering topical anesthetics to
the oropharynx. Prolonged use of cocaine is
also not routinely recommended because of the
risk of ischemic necrosis due to vasoconstric-
410 IV. HEAD AND NECK COMPLICATIONS OF CANCER THERAPY

TABLE 21-4. Management of oral complications

Problem Treatment

Goal Method

Mucositis Palliation 0.9% saline rinses. Topical anesthetics (lidocaine, dyclonine, benzo-
caine, cocaine, etc.). Other topical agents (diphenhydramine, benzy-
damine). Coating agents (KAOPECTATE, AMPHOGEL). Analgesic drugs
(narcotics).
Infections
Bacterial Prevention Oral hygiene (brushing and flossing when indicated).
Treatment Topical antibiotics (tetracycline, vancomycin, neomycin, bacitracin,
povidine iodine, carbamide peroxide). Systemic antibiotics.
Fungal Treatment Topical agents (nystatin, clotrimazole, amphotericin B). Systemic agents
(amphotericin B, ketoconazole).
Viral (HSV, VZV) Treatment Topical (acyclovir ointment). Systemic (acyclovir LV. or P.O.).
Hemorrhage Prevention Oral hygiene (brushing, flossing, etc., to prevent periodontal bleeding).
Removal of sources of trauma (orthodontic bands, sharp teeth, etc.).
Treatment Direct pressure packs. Topical hemostatic agents (thrombin, microfibril-
lar collagen), pressure appliances (vacuum-formed vinyl mouth-
guards).
Salivary gland
Parotitis Palliation Ice packs, ice chips.
Xerostomia Palliation 0.9% saline rinses. Artificial salivas (carboxymethylcellulose solutions,
mucin solutions). Lubricants (antacid solutions, polyethylene oxide).
Salivary gland stimulants (sublingual 1% pilocarpine, sugarless lemon
drops, or mints).
Chronic GVHD
Mucositis Diagnosis Labial mucosa biopsy.
Palliation 0.9% saline. Topical steroids (betamethasone, triamcinalone, dex-
amethasone).
Treatment Systemic immunosuppressives (cyclosporine, prednisone plus cyc-
lophosphamide, azothioprine, procarbazine).
Other
Xerostomia- Prevention Intense oral hygiene (brushing and flossing) and topical fluorides.
induced decay
Management Restorative dental care.
Tongue polyps Management Surgical excision.

tion, although it may be used to control oral
bleeding (infra vide). When topical agents are
not effective in controlling pain, narcotics are
administered. The use of antacid solutions as
rinses has been recommended to help coat tis-
sues and reduce irritation, and can be of benefit
when there is frequent vomiting andlor xero-
stomia.
Benzydamine hydrochloride is an anti-in-
flammatory drug used extensively in Europe
and recently introduced in Canada to help re-
duce painful mucositis. Benzydamine provides
short-term topical anesthesia and extended pain
relief apparently through its anti-inflammatory
properties.
ORAL INFECTION MANAGEMENT. Oral infec-
tions are aggressively treated with both local
and systemic therapy. Cultures for possible
bacterial (including anaerobes), fungal, and viral
agents must be obtained. Often during this
phase, the causative organism cannot be recov-
ered, and empirical antibiotic therapy is util-
ized [23]. Topical antibiotics that can be used
for bacterial infections include tetracyclines,
vancomycin, neomycin, bacitracin, polymyxin
B, and povidine iodine. Use of carbamide per-
oxide is often effective for localized periodontal
infections. Antifungal agents including nystatin,
clotrimazole, and amphotericin B rinses can be
used topically, while oral ketoconazole and
 21. HEAD AND NECK COMPLICATIONS OF BONE MARROW TRANSPLANTATION
intravenous (LV.) amphotericin B are used
systemically. The drug of choice for HSV
infections is systemic acyclovir.
. ORAL HEMORRHAGE THERAPY. Oral hemor-
rhage is rarely a life-threatening complication,
but it may be a profoundly disturbing and
frightening event. Moist-gauze pressure packs
should be used first. More aggressive manage-
ment with topical hemostatic agents should be
utilized when pressure is ineffective or larger
areas are involved. Recent limited clinical trials
using vasoconstrictive agents (cocaine solution
5%) followed immediately by topical hemo-
static agents (thrombin or microfibrillar col-
lagen) have shown encouraging results (M.M.
Schubert, unpublished data). Custom vinyl
mouthguards are useful for applying pressure
and holding hemostatic agents against the site of
palatal or gingival bleeding. If bleeding is more
extensive, platelet infusions may be the only
effective means to control hemorrhage. The tim-
ing and frequency of clot debridement must be
carefully considered. This is best carried out
when platelet counts are adequate, and large
clots should be debulked while leaving the base
intact.
EAR, NOSE, AND THROAT
COMPLICATIONS
Sinus and Nasal Complications. Nasal and
sinus complications occur less frequently than
oral complications, with infection and bleed-
ing the major problems encountered. Acute
sinusitis is noted in less than 10% of marrow
transplant patients [18, 37]. Symptoms are atyp-
ical in that pain is usually less prominent and
pus and drainage are not always found. The
most consistent positive findings are usually
fever and abnormal sinus radiographs, but cul-
ture data may not always be conclusive. In 200
consecutive marrow transplant patients, 25
cases of sinus disease were detected [37]. Two
cases had convincing culture data identifying
the sinus as the source of infection; fifteen had
suggestive sinus cultures, and eight had no
growth. The prompt use of broad-spectrum
antibiotics for fevers of unknown origin and the
lack of sinus symptoms probably explain why
sinus aspirates are often sterile.
Over the last decade, the spectrum of bacte-
rial organisms causing infections in immuno-
compromised patients has shifted from gram-
negative species to gram-positive organisms
[23].
411
The organisms recovered from sinus irriga-
tions in transplant recipients are sometimes un-
usual for this site and include Staphylococcus
sp., Streptococcus sp., Proteus sp., Neisseria sp.,
Haemophilus sp., Escherichia coli, Pseudomonas
sp., Candida sp., Aspergillus sp., and cytome-
galovirus and herpes simplex [18, 37]. Viral
infections tend to cause a reactive sinusitis that
results from blocking of the ostium.
The emergence of invasive fungal infections
following marrow transplantation has caused
significant concern [24). Candida infections are
the most common fungal sinus isolate. Some
investigators have suggested that the diagnosis
of invasive aspergillosis should be suspected
in neutropenic patients in whom even a single
colony of Aspergillus is isolated from respiratory
secretions, despite the fact that this is an ubiq-
uitous fungus that can be frequently isolated
from the sinopulmonary tract [23, 38, 39]. The
difficulty in diagnosing fungal infections is well
documented. In febrile, neutropenic patients,
amphotericin-B therapy is often started when
fever persists in spite of broad-spectrum anti-
biotics [23]. Surgical intervention is often neces-
sary to control the spread of invasive fungal
disease. Although mycotic aneurysms are very
rare, they can represent a serious sequelae to
invasive fungal infections. Antihistamines are
administered along with specific antibiotic or
antifungal treatment.
Nasal hemorrhage is a common problem dur-
ing the early period after transplant. The major-
ity of these bleeding episodes occur on the
anterior nasal septal area, although posterior
drainage often causes them to be mistaken for
pharyngeal hemorrhage. The accumulation of
clots, mucus, and debris can further lead to
airway problems. Pressure packs with topical
hemostatic agents (thrombin, cocaine, silver
nitrate, etc.) are usually effective. However,
platelet transfusions may be necessary to con-
trol severe nasal hemorrhage. Increased humid-
ity can help prevent nasal dryness that increases
the risk of bleeding.
Otic Complications. Otic complications are
uncommon. Hearing loss may be caused by
medications such as aminoglycosides. Although
OtItIS media is rare, myofascial pain from the
muscles of mastication and eustachian tube
dysfunction have been noted to mimic otitis
symptoms. Otitis is managed traditionally with
antibiotics, and surgical interventions are re-
412 IV. HEAD AND NECK COMPLICATIONS OF CANCER THERAPY
commended only when invasive infections are
demonstrated.
Throat and Esophagus Complications.
Pharyngeal and esophageal complications
parallel those seen in the oral cavity [40].
Esophageal complications present as dysphagia,
odynophagia, chest pain, or bleeding. Chemo-
radiotherapy-induced mucositis and reflux
are responsible for about one-third of the causes
of pain and dysphagia after transplant. A recent
study has demonstrated that the esophageal
acid clearing is a two-step process that involves
esophageal (peristaltic) emptying followed by
acid neutralization by saliva [41]. Aperistalsis
and severe xerostomia are both noted follow-
ing marrow transplant and thus probably are
important for the production of acid-reflux
problems [42]. Infectious complications are
most frequently caused by viral and fungal
organisms. Herpes-group viruses (CMV and
HSV) cause about one-third of the esophagitis
complaints, while Candida is demonstrated in
9% of patients with esophagitis. These infec-
tions probably represent a spread of infection
from the oral cavity. About 22% of the esopha-
gitis noted in this phase is due to acute GVHD
[40]. Esophagoscopy is performed when symp-
toms suggest candidiasis since it is not possible
to clinically distinguish Candida, herpes, or
acute GVHD [39].
Anti-infective therapy is indicated if specific
organisms are ·identified. Most instances-of non-
infectious esophagitis respond to oral antacids
and antireflux measures. Antacids can be used as
needed; however, cimetidine is probably more
effective in patients with aperistalsis [42].
NEUROLOGIC COMPLICATIONS
Neurologic complications in the immediate
posttransplant period can be related to chemo-
radiotherapy, metabolic abnormalities, or central
nervous system (CNS) infections. Disturbances
caused by mechlorethamine are characterized
by a toxic encephalopathy with disorientation,
confusion, headaches, tremors, lethargy, para-
plegia, seizures, and vertigo, ana as a result it is
avoided as a preparative regimen [43]. These
acute symptoms have generally been noted to
clear within 2-3 months; however, some have
persisted and instances of delayed onset of CNS
abnormalities have also been noted. Toxicity in-
creases with patient age and with the additional
use of procarbazine or cyclophosphamide. In-
trathecal MTX has been shown to produce sub-
acute encephalopathy with somnolence, confu-
sion, irritability, tremor, ataxia, and convulsions
[44]. CyA has also been shown to produce CNS
side effects that include tremors, flat affect,
malaise, and depression [45, 46]. Recently,
acyclovir has been shown to cause neurologic
symptoms that have included lethargy, agita-
tion, tremor, disorientation, and transient
hemiparesthesias [47]. However, neurotoxicity
resulting from use of these drugs may possibly
represent a combined effect of chemotherapy
and radiation administered both for pretrans-
plant treatment of CNS leukemia and con-
ditioning for transplant [48]. The age of the
patient may be critical, with younger patients
being more susceptible than adults [49]. We re-
cently reviewed 217 patients with acute lym-
phoblastic leukemia (ALL) who underwent
transplantation in Seattle between 1970 and
1982 (J. Sanders, unpublished observation).
Median age was 15 years (range 2-49), and 62
had either active CNS leukemia at transplant
or a history of such involvement. Prior CNS
prophylaxis had been given to most patients:
LT. MTX (174 patients) and/or CNS irradia-
tion (150 patients). Since 1976, LT. MTX has
been given to all Seattle marrow graft recipients
with leukemia to prevent CNS relapse (two 12-
mg doses before transplant and six doses every
two weeks between days 32 and 102 after trans-
plant). Kaplan-Meier probability estimates of
CNS relapse among 72 patients not given post-
transplant LT. MTX was 38% compared with
8% relapse rate among 145 patients given such
CNS prophylaxis (p < 0.01). Seven patients
who received MTX, however, developed dis-
abling leukoencephalopathy 1-5 months after
transplant. It appears, however, that 1000 cGy
TBI may be administered safely to patients who
have previously received 2400 cGy cranial
prophylaxis [50, 51].
Neurologic infections are not common, but
have been reported. Bacterial brain abscesses and
meningitis may follow episodes of septicemia.
Fungal infections are usually associated with
multifocal invasive fungal infections [39]. CNS
candidial infections result from candidemia,
whereas Aspergillus may spread from contigu-
ous areas (i.e., sinus and nasal passage).
Drug-induced neurologic complications often
display a variable course. In the instances of acy-
clovir toxicity, abnormalities may resolve when
acyclovir is stopped, while symptoms caused
 21. HEAD AND NECK COMPLICATIONS OF BONE MARROW TRANSPLANTATION
by CyA may resolve with adjustment of dosages
[45, 47]. There is no effective therapy for leuko-
encephalopathy, and damage is usually perma-
nent (see chapter 20). When infectious causes
of neurologic complications are identified,
prompt and aggressive therapy is indicated.
OCULAR COMPLICATIONS
Eye complications in early phase II include
ocular dryness, infections, GVHD, and other
miscellaneous problems [52, 53]. Keratocon-
junctivitis sicca is the most common com-
plaint, with an incidence approaching 45% in
transplant patients [52]. Photophobia and pain
may be the presenting symptoms. Dryness is
diagnosed by Schirmer testing and slit-lamp
examination with fluorescein or rose bengal
stains. Viral and bacterial infections may also
involve the eye. Both VZV ophthalmicus and
HSV keratitis are seen. Subconjunctival hemor-
rhage followed by purulent conjunctivitis has
also been reported [53].
Eye complaints resulting from acute GVHD
have been observed in approximately 10% of
the patients diagnosed with acute GVHD and
include photophobia, pain, and blurred vision
as well as decreased lacrimation. Trophic ulcera-
tion and perforation of the cornea, hemorrhage,
keratoconjunctivitis, uveitis, and pseudomem-
brane formation have been reported in patients
with severe acute GVHD [52, 53]. Other optic
complications have included cicatricial lagop-
thalmos, proptosis, cranial nerve palsies, pre-
and intraretinal hemorrhage, and ectropion of
the lids.
Ocular dryness symptoms usually respond to
artificial tears and lubricants; occasionally, ste-
roids and moisture chambers may be effective.
Replacement therapy prevents corneal ulcera-
tion and scarring. Ulcerations generally respond
to bandage lens treatment. Infections of the eye
respond to conventional antibacterial and anti-
viral medication.
SCALP AND CUTANEOUS COMPLICATIONS
Scalp alopecia is noted following conditioning
with chemotherapy. Skin infections, though
not common, are predominantly of bacterial
origin (Staphylococcus aureus). Perioral HSV
and trigeminal VZV infections may also be
observed.
413
Phase III
Immunologic reconstitution following marrow
ablation depends upon proliferation of the
transplanted marrow donor cells. Profound im-
mune deficiencies are exhibited in the first 4-6
months after transplant [54-57]. Patients free of
GVHD subsequently recover immune function,
while those with GVHD will be immuno-
deficient for as long as their GVHD is active
[56, 58]. These patients show poor antibody
response to T-dependent and T-independent
antigens, impaired skin test reactivity to recall
and neoantigens, and impaired neutrophil che-
motaxis [58, 59]. In contrast, other assays show
normal in vitro immune function in the early
posttransplant period: mitogen and mixed lym-
phocyte culture response [56], absolute lym-
phocyte and surface markers [60, 61], and natu-
ral killer cell activity and antibody-dependent
cellular cytotoxicity [62].
In vitro B-cell function has been studied us-
ing direct and indirect hemolysis in gel assays
and polyclonal activation [63-65]. Patients with
chronic GVHD have deficient T-cell activity,
T-cell suppression of immunoglobin synthesis,
and failure of B-cells to secrete immunoglobin in
the presence of normal donor helper cells.
Patients are at high risk for infectious com-
plications in the early posttransplant period [18,
39, 66]. Bacterial, fungal, and viral infections
may develop even after resolution of granulocy-
topenia. Between one and three months after
transplant, 40%-50% of the patients con-
ditioned with TBI are noted to develop intersti-
tial pneumonia; in contrast, 15% of the patients
conditioned with only cyclophosphamide de-
velop interstitial pneumonia [39, 67]. No causa-
tive organism is identified in one-third of the
cases of interstitial pneumonia, i.e., idiopathic
interstitial pneumonia. The mortality rate from
these pneumonias is nearly 50%, and it is sus-
pected that TBI may be related to their develop-
ment. About one-half of interstitial pneumonias
are caused by CMV infection, with mortality
approaching 90%. Efforts to treat CMV-caused
pneumonia with a variety of antiviral agents
have been ineffective; however, preliminary
evidence has shown that CMV hyperimmune
globulin may prevent infection after allo-
geneic marrow grafting [68]. The risk of Pneumo-
cystis carinii pneumonia has been significant-
ly reduced with the prophylactic use of
trimethoprim-sulfamethoxazole.
414 IV. HEAD AND NECK COMPLICATIONS OF CANCER THERAPY
ORAL COMPLICATIONS
Early Phase III. Most patients demonstrate
mucosal healing and recovery during this phase.
Factors that retard oral recovery include irra-
diation, MTX prophylaxis, viral infections,
and acute GVHD. Although acute irradiation
effects on mucosa have decreased by this time,
the radiation-induced xerostomia persists, and
causes dehydration of tissues and renders them
more susceptible to trauma and infection.
Xerostomia also disturbs the oral microflora
[70]. Full mucosal recovery may be delayed un-
til MTX is discontinued on day 102; mucosal
surfaces during this phase will continue to look
erythematous and atrophic. Acute GVHD may
also contribute to continued mucositis. Patients
with mucositis report food sensitivity that can
interfere with proper nutrition and oral hy-
giene. Minor gingival oozing may be observed if
oral hygiene is not adequate and if platelets are
less than 20,000/mm3. Gingival health can
usually be improved by the removal of plaque,
debris, and other sources of irritation.
Oral viral and fungal infections are common
in phase III (figure 21-6). These infections are
closely related to the development and severity
of GVHD [69]. Fungal infections are most fre-
quently seen in patients with persistent granu-
locytopenia. Candida species are most com-
monly isolated, but locally invasive aspergillosis
may also be observed. HSV infections are the
most common viral problem, but VZV infec-
tions become increasingly frequent later in this
phase. Coxsackie infections (hand, foot, and
mouth disease), though rare, have also been seen
[23]. Patients previously treated with acyclovir
may develop HSV infection after the drug is dis-
continued. Recurrence is associated with delay
in the restoration of specific immune responses
[23]. Oral mucocutaneous viral infections tend
to be less extensive than they were in the earlier
phase due to improved local tissue resistance.
The clinical manifestations of HSV infections
in phase III have a more typical presentation,
with discrete ulcerative lesions involving the lips
and perioral tissues. HSV, however, can be re-
covered from oropharyngeal surveillance cul-
tures without evident lesions. VZV infections
can result in varicella-form lesions, dissemi-
nated herpes zoster, and uncomplicated zoster.
Postherpetic neuralgia occurs in 20% of pa-
tients regardless of type of therapy r271
A tendency for granulomatous growths to
appear on the tongue has been noted occasional-
ly during this phase (see figure 21-7). These
soft-tissue masses are painless, although they do
bleed when traumatized. They have been noted
on both the dorsal and lateral sides of the
tongue. The etiology of these polyps is not
known, but trauma is likely to be involved.
Management is predominantly surgical; when
recurrent trauma has been prevented, they have
been observed to resolve slowly over time.
FIGURE 21-6. Phase III. Oral and labial HSV infec-
tion in a patient 87 days after transplant. Ulcerative
lesions are evident on the tongue, labial mucosa, and
lips.
 21. HEAD AND NECK COMPLICATIONS OF BONE MARROW TRANSPLANTATION
FIGURE 21-7. Phase III. Granulomatous tongue
polyps in patient 91 days after transplant. These
growths were removed and histology revealed non-
specific granulation tissue; special stains for organ-
isms were negative.
Late Phase III. During this phase, the oral
manifestations of chronic GVHD are first
observed. Chronic GVHD develops in 25%-
40% of long-term survivors, and over 80% of
those with extensive chronic GVHD manifest
characteristic oral lesions [71, 72]. The time of
onset is usually 70-120 days after transplant.
Patients with extensive chronic GVHD oral
involvement complain of stomatitis and xero-
415
stomia. However, at 100 days after transplant,
this is a nonspecific complaint. Increasing oral
symptoms after day 100 are more likely to be
caused by GVHD. The most common clinical
sign of chronic GVHD is a generalized mucosal
thinning and an apparent decrease in "keratin-
ization" of the mucosal surfaces, with the tis-
sues appearing more erythematous and delicate
than usual. Mucosal surfaces often lose normal
architectural features, especially the stippling of
the attached gingiva and the filiform and fungi-
FIGURE 21-8. Phase IV. Lichenoid striae and plaques
on the buccal mucosa of a patient with chronic
GVHD 140 days after transplant.
416 IV. HEAD AND NECK COMPLICATIONS OF CANCER THERAPY
form papillae on the tongue. The most impres-
sive lesions, however, are the lichen planus like
and lupus like lesions (figure 21-8). White re-
ticular plaques and/or papular lesions can be
noted on most mucosal surfaces; erosive or
ulcerative lesions, usually covered by pseudo-
membranous fibrin clots, may also be found.
In patients with extensive sclerodermatous
skin involvement, there can be telangiectasia
with loss of elasticity of perioral tissues. Lymph-
ocytic inflammation and epithelial cell necrosis
have been noted on biopsies of the mucosal
and salivary duct epithelium [73].
A Sjogren's-like reaction with chronic
GVHD has been reported [74], and the asso-
ciated salivary physiology and sialochemis-
try have been studied. The decreased major
and minor salivary gland flow rates can range
from slightly depressed to a total lack of sali-
vary secretion, even after intense stimulation.
However, decreased flow rates from GVHD
cannot be clinically differentiated at this time
from those caused by radiation damage [75].
Sialochemistry provides a better means of de-
tecting GVHD, with elevated sodium levels and
lysozyme levels and decreased phosphate and
IgA levels being evident [76-78]. The finding of
decreased salivary IgA in patients with chronic
GVHD is consistent with the general immu-
nodeficiency noted in these patients [33].
Management of Oral Complications. Many
of the management strategies are similar to
those used in phase II. Patients with VZV infec-
tions are treated with acyclovir or vidarabine.
Late HSV infections are usually not re-treated
(to allow development of specific immune re-
sponses).
Xerostomia is treated symptomatically. It is
important that excellent oral hygiene be main-
tained in order to reduce the risk of decay.
Daily fluoride therapy is recommended for all
patients with severe or persistent oral sicca.
Routine dental procedures are not recom-
mended and only treatment that is absolutely
necessary should be attempted during this
phase.
Local therapy for oral chronic GVHD varies
in effectiveness. Topical steroids (dexametha-
sone, triamcinalone, and betamethasone) have
been snccessful in controlling mucositis and
may reduce lichenoid changes, but have no
effect on GVHD-induced xerostomia. The
control of the mucositis and xerostomia caused
by GVHD not only promotes general patient
comfort but also improved nutrition.
Labial mucosa and minor salivary gland biop-
sies are routinely done at the end of this phase
to help assess the overall presence and severity
of chronic GVHD [79]. The procedure is simple
and is carried out by (a) infiltration with local
anesthetic in the area of the mental foramen; (b)
removal of an elliptical wedge (6 x 3 x 3 mm),
which is placed in 10% formalin; and (c) closure
with 4-0 chromic gut suture. Patients usually
complain for 12-48 h of minor discomfort that
is managed successfully with acetaminophen
with or without codeine. This procedure has
caused no significant complications (infection,
bleeding, pain), although transient labial anes-
thesia and some bruising have been observed.
EAR, NOSE, AND THROAT
COMPLICATIONS
The major complications involving these sites
are infections, which tend to occur more fre-
quently in patients with delayed engraftment or
GVHD. Sinus pain is more frequent than it had
been earlier, and suppuration becomes more
common as gram.ilocyte counts increase. Bacte-
rial infections predominate, but Aspergillus in-
fection remains a major concern, as it is associ-
ated with a high incidence of mortality in this
population [24]. Antibiotics and antihistamines
are the primary treatment strategy, with surgical
drainage employed as needed.
Some complaints of ear and facial pain are
mistakenly attributed to sinus or ear problems,
when in fact they are due to myofascial pain
arising from the muscles of mastication. Con-
sidering the general discomfort and psycho-
logical stress of marrow transplantation, the
patient's increased clenching and bruxism and
resulting myofascial pain are understandable.
The masseter, temporalis, and lateral pterygoid
muscles should be palpated for trigger points
or muscle tenderness. Moist heat packs to the
muscles, relaxation techniques, and antianxiety
medications usually relieve symptoms. Occlusal
splint therapy can be utilized where initial
physical therapy and relaxation are not effective.
Pharyngeal and esophageal complaints are
less frequent during this phase. The onset of the
esophageal symptoms of dysphagia, odynapha-
gia, and retrosternal pain later in this phase can
be caused by infections (Candida, HSV, CMV,
and/or bacteria) or GVHD involvement.
Esophageal involvement occurs in 20%-32% of
 21. HEAD AND NECK COMPLICATIONS OF BONE MARROW TRANSPLANTATION
patients with extensive chronic GVHD [72, 80,
81]. Esophageal cultures, endoscopy, and biop-
sies are required to guide specific treatment.
NEUROLOGIC COMPLICATIONS
Neurologic complications noted during this
phase can be caused by delayed toxicity to high-
dose chemordiotherapy preparation, GVHD
prophylaxis with LT. MTX or CyA, or other
drugs such as acyclovir or phenothiazines, as
well as by recurrent leukemia and infections [33,
43, 49, 51]. The delayed toxicities to mech-
lorethamine are most often noted in patients
who had previously manifested acute toxicities
to this drug. Abnormalities include personality
changes, confusion, seizure, diplopia, dementia,
and communicating hydrocephalus. Tardive
dyskinesias are associated with phenothiazines,
and lethargy, agitation, tremor, disorientation,
and transient hemiparesthesia have been noted
with acyclovir. Viral meningitis and encephali-
tis, and metastatic abscesses from bacterial and
viral organisms have also been reported [23, 39,
70).
OCULAR COMPLICATIONS
Ophthalmic complications during this phase are
related to infection and acute (earlier) and chro-
nic (later) GVHD. Infections are predominantly
due to HSV and VZV. Photophobia and
lacrimation may be symptoms of GVHD, and
clinical manifestations include hemorrhagic or
purulent conjunctivitis, conjunctival ulceration,
and ultimately scarring of the conjunctiva [53].
Corneal involvement is noted as filamentary
keratitis and sloughing of the corneal epithe-
lium. Management of ocular complications is
similar to that mentioned in phase II.
SCALP AND CUTANEOUS COMPLICATIONS
By the end of this phase, scalp hair is about Va to
1/4 inch long, and eyelashes and moustaches are
near normal in length. Acneiform dermal le-
sions may be seen in patients receiving cortico-
steroids. Viral lesions of HSV and VZV can also
involve the face. Cutaneous manifestations of
chronic GVHD frequently involve the face and
may present as photosensitivity, generalized
mottled erythematous or violaceous rashes, re-
ticulated hyperpigmentation, leukoderma, and
partial alopecia [72, 82). Dyspigmentation, der-
mal induration, or nodularity are seen in the
localized forms [71, 81]. Left untreated, these
lesions progress from induration to sclerosis
417
with fascial fixation [83]. Vitiligo and premature
graying of hair and eyelashes have also been
observed [72).
Phase IV
This last phase is highlighted by the continued
recovery of marrow function. By one year after
transplant, immune function is found to be
normal although, in some patients, recovery
may take up to two years [70].
The most significant complications in this
period relate to infections, chronic GVHD, the
late effects of radiation, and recurrent leukemia.
Nearly half of the long-term survivors of
allogeneic marrow transplantation develop VZV
infections, and 90% of these occur within one
year of transplantation [27,84]. Other late infec-
tions in long-term survivors without chronic
GVHD are uncommon. In patients with chro-
nic GVHD, however, immune recovery may be
severely impaired [85]. Defects include impaired
granulocyte chemotaxis, decreased immunoglo-
bin secretion (especially IgA), impaired splenic
function, and impaired helper T-cell function
[58, 78, 85, 86). Pneumococcus sp. (29%) and
Staphylococcus sp. (26%) are the predominant
bacterial isolates in these patients, while VZV
(59%) and HSV (31%) are the most common
viral isolates [18,27,59,66,87]. Fatal infections
are frequently caused by pneumococcal
pneumonia and bacteremia. The head and neck
region is, however, the most frequent site of in-
fection, and accounts for 42% of the late infec-
tions in this phase (oral, 12 %; sinus, 11 %; ear,
7%; eye, 6%; throat, 5%; and CNS, 1%) not
including VZV infections involving this region
[84).
ORAL COMPLICATIONS
The most common complication in this phase
is xerostomia. Besides decreased taste discrim-
ination and increased difficulties in eating and
talking, the most significant consequence of
xerostomia is rampant dental decay. We have
noted that susceptibility to salivary gland radia-
tion damage generally increases with age and
may be more frequent with 1000 cGy single dose
than fractionated TBI (K.T. Izutsu and M.M.
Schubert, unpublished data). Jaw and dental
developmental abnormalities have been noted in
children receiving irradiation, and delayed
growth and development have been reported
[88-90]. Instances of retrognathic jaw rela-
418 IV. HEAD AND NECK COMPLICATIONS OF CANCER THERAPY
FIGURE 21-9. Phase IV. Severe ulcerative mucositis
of left buccal mucosa with associated lichenoid
changes in a patient with active chronic GVHD at
five years after transplant (mirror view).
tionships and arrested tooth development and
eruption have been observed.
Infectious complications of the oral cavity are
less common in this period than in the previous
phase. Oral candidiasis is the most frequent oral
infection, followed by bacterial pharyngitis/
tonsilitis, and oral and perioral HSV infections
[83]. The clinical presentation of gingivitis
and dental/periodontal abscesses is also more
"classic" than in earlier phases. The oral cavity
is the site of 12% of all the infections that occur
in this phase [84].
Most oral complications are related to
chronic GVHD. The major manifestations are
atrophy; ulceration; hyperkeratotic plaques,
patches, and striae; and xerostomia in patients
reminiscent of such naturally occurring auto-
immune diseases as lichen planus, lupus erythe-
matosus, scleroderma, benign mucus membrane
pemphigoid, and Sjogren's syndrome [71]
(figures 21-8 and 21-9). Xerostomia caused by
irradiation will usually improve between three
and 12 months after transplant, although some
patients may take up to 24 months to fully re-
cover. Resolution of xerostomia caused by
chronic GVHD, however, depends on adequate
management of the chronic GVHD. Increasing
xerostomia and/or mucositis around day 100
after transplant can herald the onset of chronic
GVHD. Oral biopsies reveal chronic lym-
phocytic inflammation of mucosal surfaces,
with epithelial cell necrosis and similar changes
apparent in minor salivary gland ducts [73]. We
routinely use labial mucosa and minor salivary
gland biopsies to screen for and to gauge the
extent of chronic GVHD at about day 90 and at
subsequent follow-up exams [79, 89].
Management of Oral Complications. Pa-
tients with normal hematologic function, no
GVHD, and normal salivary function are gener-
ally regarded as normal dental patients, though
some caution is advised for one year after
transplant because of persistent immune de-
ficiency. Elective dental treatment is generally
deferred during that period. Patients with
xerostomia should be monitored carefully for
compliance with oral hygiene measures (figure
21-10). They should receive daily topical
fluoride treatments with either rinses or gels
(applied with custom vinyl trays).
Patients with active chronic GVHD should
be followed carefully. The compromised mu-
cosal surfaces are prone to trauma, irritation,
and infection (especially periodontal disease).
Chronic candidiasis may be observed with
corticosteroid treatment. Mucositis associated
with chronic GVHD usually requires systemic
combined immunosuppressive therapy [72], and
topical steroid treatment is usually ineffective.
Clinical assessment for oral candidiasis can
be hampered by the lichenoid hyperkeratotic
changes noted with oral chronic GVHD; conse-
quently, gram stains or KOH preparations are
 21. HEAD AND NECK COMPLICATIONS OF BONE M ARROW TRANSPLANTATION
FIGURE 21-10. Phase IV. Rampant decay in a young
patient with chronic GVHD 1064 days after trans-
plant. She had significant xerostomia, had reported
a high-carbohydrate diet, and had not received any
dental care since discharge after transplant.
necessary to evaluate oral lesions [71]. Antifun-
gal therapy with topical nystatin or clotrimazole
is usually effective, although ketoconazole
may be indicated in more resistant cases.
EAR, NOSE, AND THROAT
COMPLICATIONS
As with the oral cavity, ENT complications are
related predominantly to chronic GVHD or to
associated infections. Sinusitis is the most fre-
quent infection, with 49 episodes noted in
198 patients with extensive chronic GVHD
[91]. In contrast, otitis media was noted in only
12 of the patients. Upper respiratory infections,
especially sinusitis, have become recognized
as a frequent complication of chronic GVHD.
These infections are usually caused by gram-
positive bacteria. An important contributing
factor may be the oral and bronchial-pulmonary
sicca and decreased secretory IgA concentra-
tions in patients with chronic GVHD [56, 58,
419
74, 78]. The high incidence of candidiasis prob-
ably relates to the frequent use of antibiotics
and immunosuppressive agents [23, 84].
Esophageal complications in this phase are
usually caused by chronic GVHD with a me-
dian onset of 220 days after transplant [80]
(figure 21-11). Lesions are characterized by a
desquamative esophagitis with web and stric-
ture formations, aperistalsis, and acid reflux.
The esophageal symptoms that accompany
these changes-dysphagia, painful swallowing,
and severe retrosternal pain-can be so severe
as to require constant narcotics and impair oral
alimentation.
The primary management of esophageal
symptoms includes antacids and antireflux mea-
sures. Cimetidine is used when pain is related to
acid reflux. In addition to the reported aperistal-
sis, the lack of salivary secretions in chronic
GVHD may also be a factor in the inability of
patients to adequately clear acid in the distal
esophagus [80]. Esophageal webs can usually be
broken by endoscopy or bouginage. Perforation
can occur with instrumentation, however, and
caution should be used. When esophageal stric-
tures cannot be adequately managed, it may be
necessary to utilize parenteral nutrition. The
control and stabilization of esophageal GVHD
depend on successful systemic immunosuppres-
sive therapy.
NEUROLOGIC COMPLICATIONS
Neurologic complications seen in this phase
usually represent continued problems from
phase III (figure 21-12). VZV infections can
cause palsies and neuralgias [27, 84]. Pneumo-
coccal meningitis and HSV encephalitis have
been noted [84, 91].
OCULAR COMPLICATIONS
Between 60% and 83% of patients with chronic
GVHD develop ocular involvement with symp-
toms of burning, itching, blurring, photopho-
bia, and dryness [53, 72, 82, 92]. Keratocon-
junctivitis sicca and cicatricial lagophthalmos,
corneal ulceration, iritis, and ectropion and
punctate keratitis are noted [52, 92]. Most of the
complications are related to the keratoconjunc-
tivitis, but iritis and choroiditis may also be
noted. Infectious complications of the eye are
usually associated with chronic GVHD. Puru-
lent conjunctivitis and herpes keratitis have
been reported [84] (figure 21-13).
Cataracts are a recognized late complication
420 IV. HEAD AND NECK COMPLICATIONS OF CANCER THERAPY
of bone marrow transplantation [88]. By six
years after transplant, approximately 80% of
patients given 1000-cGy, single-dose TBI de-
velop cataracts [48]. Fractionated TBI appears
to reduce the incidence to approximately 19%
[93]. In addition, cataracts develop earlier and
more frequently in patients with chronic
GVHD receiving corticosteroids [93]. In pa-
tients with aplastic anemia not receiving TBI,
cataracts develop only in those patients given
steroid therapy for GVHD.
Management of the ocular complications of
chronic GVHD is similar to therapy used in
other forms of keratoconjunctivitis sicca. It
includes lubricating drops and antibiotics,
bandage soft contact lenses, punctal occlusion,
tarsorrhaphy, and conjunctival flaps. Cataract
surgery, even in the presence of dry eyes, is
routinely performed without difficulty. Ocular
complications must be monitored closely to
prevent catastrophic consequences.
SCALP AND CUTANEOUS COMPLICATIONS
The most significant scalp or skin changes in
long-term survivors of marrow transplantation
are the scarring caused by VZV infections, and
chronic skin involvement (figures 21-13 and
21-14).
FIGURE 21-11. Phase IV. Barium esophagrams in a
patient with chronic GVHD. (A) Day 770. Anterior
view of the upper esophagus and hypopharynx. A
thick, eccentric web is evident at the level of the
esophageal inlet (arrow). (B) Day 1255. Anterior
view shows further narrowing of esophageal lumen
by the thick web (arrow). (C) Day 1255. Lateral view
shows stenotic esophageal lumen (arrow) at the level
of the cricopharyngens muscle. From McDonald et
al. [80], with permission.
OTHER PHASE-IV CONSIDERATIONS
Hormonal Considerations. Subclinical thy-
roid dysfunction has been reported in marrow
transplant patients conditioned with TBl. Ten
of 23 patients were found to have an elevated
thyroid-stimulating hormone level at a median
time of onset of 13 months after transplant [94].
The majority of children prepared for mar-
row transplantation with TBI have shown
decreased growth rates on longitudinal and
growth-velocity curves. Skeletal age has
matched chronologic age, but about one-third
of the children transplanted between the ages
of two and 15 have subnormal growth hormone
levels [88, 89, 95]. Hormone supplementation
may be necessary for growth and development
of secondary sex characteristics. Adrenal corti-
cal function has also been found to be sub nor-
 21. HEAD AND NECK COMPLICATIONS OF BONE MARROW TRANSPLANTATION
FIGURE 21-12. Phase IV. (A) Computed tomo-
graphic (CT) scan 182 days after transplant shows
nonobstructive hydrocephalus in a 22-year-old
woman with aplastic anemia prepared for transplant
with cyclophosphamide (150 mg/kg) and mechlor-
ethamine (0.5 mg/kg). (B) Repeat CT scan 385 days
after transplant is normal except for presence of a
ventricular shunt.
mal in 30% of patients studied.
Head and Neck Malignancies. Animal
studies have shown that there is a substantially
increased risk of developing malignancy after
the use of radiation for marrow transplantation
[96]. Reports of secondary malignancies follow-
ing marrow transplantation have been primarily
anecdotal, but at least 18 have been observed
[89]. These have included seven instances of re-
currence of leukemia in donor cell lines, five
solid tumors, and six lymphopoietic malignan-
421
FIGURE 21-13. Phase IV. Post-herpes-zoster infec-
tion scarring involving the face and scalp along the
distribution of the first division of the trigeminal
nerve in a patient 731 days after transplant. Note
cataract formation in eye.
cies. Head and neck malignancies have included
the development of glioblastomas in two pa-
tients who had received previous brain irradia-
tion, which was felt to be a possible factor in the
pathogenesis [97].
Over 95% of the leukemic recurrences after
transplant are in cells of host origin. Sites of
relapse appear similar to those seen in patients
treated with chemotherapy alone [98]. Isolated
eNS relapse has been significantly reduced
since the introduction of LT. MTX prophylaxis
between posttransplant days 32 and 102. In one
unusual instance of relapse, a five-year-old pa-
tient presented to his dentist approximately one
year after transplant with an apparent periodon-
tal infection associated with an exfoliating pri-
mary tooth. Biopsy revealed leukemic infiltra-
tion. He also was subsequently found to have
localized relapse in his maxillary sinuses.
Efforts to reduce recurrences have included
the addition of other chemotherapeutic agents
to the usual cyclophosphamide and TBI regi-
men, but initial results have not been encourag-
ing [99]. TBI schedules utilizing fractionated
radiation are also being studied [100]. Recently,
attention has been directed toward determining
whether GVHD could be used to help eliminate
leukemia cells in so-called adoptive im-
munotherapy [101]. The disappearance of
leukemia during episodes of acute GVHD has
been reported [102], and retrospective analyses
422 IV. HEAD AND NECK COMPLICATIONS OF CANCER THERAPY
have shown a 2.5-fold lower relapse rate among
allogeneic recipients experiencing grade-lIto IV
acute GVHD compared with syngeneic and
allogeneic recipients without GVHD [103].
Chronic GVHD is also associated with a possi-
ble antileukemic effect [104]. Clinical trials are
under way to determine whether GVHD can be
manipulated to augment this apparent anti-
leukemic effect.
Summary
Head and neck complications are frequently en-
countered after bone marrow transplantation,
and the early recognition and management of
these problems can significantly reduce morbid-
ity and mortality in marrow transplant patients.
The complications noted in the early phases
after transplant are primarily related to the direct
toxicities of the chemoradiotherapy preparative
regimens and the infectious and bleeding com-
plications resulting from marrow ablation. The
oral cavity is the most frequently involved site;
mucositis, oral infections, hemorrhage, and
xerostomia are prominent in the first several
months after transplant. Esophagitis, sinusitis,
and ocular and neurologic changes are also seen.
Graft-versus-host disease is a complex im-
mune disorder that can affect the head and neck
region. Acute GVHD occurs early after trans-
plant and has been noted to affect the mucosal
surfaces of the esophagus and conjunctiva.
Chronic GVHD occurs later in the posttrans-
plant course and causes much more extensive
FIGURE 21-14. Phase IV. Significant cutaneous in-
volvement in a patient with chronic GVHD one year
after transplant. He demonstrated an erythematous
rash, hyperpigmentation, and leukoderma.
damage. Oral mUCOSItIs, esophagitis and
esophageal web formation, and oral and ocular
sicca can cause significant morbidity. Chronic
GVHD and its therapy also significantly in-
crease the risk of infectious head and neck com-
plications. Other late complications may in-
clude development of relapse or malignancies,
CNS abnormalities, or cataracts.
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423
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424 IV. HEAD AND NECK COMPLICATIONS OF CANCER THERAPY
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 21. HEAD AND NECK COMPLICATIONS OF BONE MARROW TRANSPLANTATION
noy N, Sullivan KM, Sosa R, Deeg HJ, Ochs
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toI8:1183-1189,1980.
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T-cell subpopulations having unique regulatory
and cognitive function. Blood 59:696-701,
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61. Atkinson K, Hansen JA, Storb R, Goehle S,
Goldstein G, Thomas ED: T-cell subpopu-
lations identified by monoclonal antibodies
after human marrow transplantation. I. Hel-
per-inducer and cytotoxic-suppressor subsets.
Blood 59:1292-1298, 1982.
62. Livant S, Seigneuret M, Storb R, Prentice RL:
Analysis of cytotoxic effector cell function in
patients with leukemia or aplastic anemia before
or after marrow transplantation. J Immunol
124:481-490,1980.
63. Ringden 0, Witherspoon R, Storb R, Ekelund
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indirect hemolysis-in-gel assays. J Immunol
123:2729-2734, 1979.
64. Lum L, Seigneuret M, Storb RF, Witherspoon
RP, Thomas ED: In vitro regulation of im-
munoglobin synthesis after marrow trans-
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patients with and without chronic graft-versus-
host disease. Blood 58:431-439,1981.
65. Witherspoon RP, Lum LG, Storb R, Thomas
ED: In vitro regulation of immunoglobin
synthesis after human marrow transplantation.
II. Deficient T and non-T -lymphocyte function
within 3-4 months of allogeneic, syngeneic, or
autologous marrow grafting for hematologic
malignancy. Blood 59:844-850,1982.
66. Winston IJ, Schiffman G, Wang DC, Feig SA,
Lin CH, Marso EL, Ho WG, Young LS, Gale
RP: Pneumococcal infections after human mar-
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425
841, 1979.
67. Neiman PE, Reeves W, Ray G, Flournoy N,
Lerner KG, Sale GE, Thomas ED: A prospec-
tive analysis of interstitial pneumonia and
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136:754-767, 1977.
68. Meyers JD, Leszczynski J, Zaia JA, Flournoy
N, Newton B, Snydman D, Wright GG, Levin
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cytomegalovirus infection after marrow trans-
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Ann Intern Med 98:442-446,1983.
69. Elfenbein GJ, Saral R: Infectious disease during
Immune recovery after bone marrow trans-
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71. Schubert MM, Sullivan KM, Izutz1,l KT, et al.:
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72. Sullivan KM, Shulman HM, Storb R, Weiden
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73. Sale GE, Shulman HM, Schubert MM, Sullivan
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The predictive value of elevated labial saliva
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 22. ORAL COMPLICATIONS OF
RADIATION THERAPY

Peter B. Lockhart

Approximately 24,000 patients are diagnosed carotid artery are less significant with current
each year with malignant tumors of the head technologic and treatment planning methods.
and neck [1]. Many of these patients will be
treated with radiotherapy, surgery, or chemo-
therapy, either singly or in combination. Certain Acute Reactions to Radiotherapy
predictable sequelae of radiotherapy exist that
may be considered consequences of treatment MUCOSITIS AND ULCERAnON
rather than complications; these may be un- Mucositis, or inflammation of the mucous
avoidable consequences of curative radiother- membranes, is a universal and often painful con-
apy to the head and neck. There are, however, sequence of high-dose radiotherapy to the head
additional problems that occur as a result of and neck. Mucosal erythema is usually evident
radiotherapy that are preventable in both inci- within one week of the initiation of therapy;
dence and severity, and are therefore avoidable symptoms arise soon thereafter (figure 22-1).
complications. As radiation therapy progresses, the mucosa
Cell kinetic factors, radiosensitivity of nor- becomes thinned from direct killing and slough-
mal tissues, radiotherapeutic doses necessary for ing of rapidly replicating mucosal cells (figure
tumor control, and the complex anatomy of the 22-2). Mucosal breakdown and ulceration may
maxillofacial region often predispose patients to occur, depending on the timing and total dosage
serious treatment morbidity. The potential for of radiotherapy. After approximately two
pain, infection, and long-tenn functional dis-
ability with decreased quality of life dictate con-
scientious management before, during, and after
radiotherapy. This chapter discusses common
problems that can arise, as well as current
methods utilized both to improve patient toler-
ance to treatment and to decrease the risk of
preventable and potentially dose-limiting mor-
bidity.
Although nonoral complications such as de-
struction of nervous and vascular tissues do
occur, they are less common than oral changes.
The use of linear accelerators rather than
orthovoltage, and other changes in radiothera-
peutic technique, have resulted in a major de-
crease in the incidence and severity of head
and neck complications. Damage to dennis, to
hearing acuity, and to major vessels such as the FIGURE 22-1. Increased vascularity and generalized
inflammation of the .soft palate in 41-year-old man
The author wishes to thank Dr. T.]. Fitzgerald for his in- following 1500 cGy of radiotherapy for nasopharyn-
valuable help in the preparation of this manuscript. geal carcinoma.
Peterson et aI., HEAD AND NECK MANAGEMENT OF THE CANCER PATIENT.
© 1986. Martinus NijhoJf Publishing. All rights reserved. 429
430 IV. HEAD AND NECK COMPLICATIONS OF CANCER THERAPY
weeks and above 2000 cGy, the tissues become
more edematous. By the end of treatment, there
may be diffuse erythema, ulceration, spon-
taneous bleeding, and pseudomembrane forma-
tion secondary to loss of plasma from damaged
capillaries (figure 22-3).
The daily dosage of radiation will determine
the degree of erythema or mucositis, since de-
struction of the basal cell layer usually exceeds
the proliferation of new cells. This occurs at
doses between 180 and 220 cGy/day when given
five days per week [2]. Mucosal ulcerations can
occur either spontaneously or secondary to
minor trauma from teeth, oral appliances, or
abrasive foods. Ulcerations frequently occur on
the buccal and labial mucosa adjacent to teeth,
but may occur on any irradiated mucosal sur-
face (figure 22-2).
The ulcerations may be altered in severity by
such factors as recent or concomitant che-
motherapy, and (possibly) the skin sensitivity
of the patient [3] (figures 22-4 and 22-5). Ad-
ditionally, since most adults in the general
population have some degree of periodontal dis-
ease, the vast majority of dentulous patients re-
ceiving radiotherapy have gingival ulceration
adjacent to their teeth. Such ulceration com-
promises the epithelial barrier to the pathogenic
bacteria and fungal organisms that form a dense
mat between the teeth and the ulceration; radia-
tion to these oral sites can result in exacerbation
FIGURE 22-2. Oral cavity in a 65-year-old man
following 3600 cGy for tonsillar squamous cell carci-
noma. Note sloughing of both palatal and buccal
mucosal tissues (arrows); this condition gives the
clinical appearance of leukoplakia.
of periodontal ulceration.
Scatter radiation from metallic dental restora-
tions can cause "hot spots" on adjacent mucosa
[4] and may be difficult to prevent. Ulcerations
secondary to trauma, however, can often be
prevented by appropriate preradiotherapy ex-
amination and treatment, and close management
of problems that arise during therapy.
Pain secondary to ulceration is variable and
multifactorial in origin. Depending on the loca-
tion, size, and depth of the mucosal alteration,
pain can range from mild and of little conse-
quence to the patient, to severe pain that requires
systemic narcotics.
INFECTION
Acute oral infections during radiotherapy
most often occur with mucosal as opposed to
calcified tissues of the mouth. Preexisting
periodontal disease often progresses during
radiotherapy because of xerostomia, altered
nutrition, and decreased oral hygiene secondary
to pain and gagging. Preradiotherapy gingival
pocket elimination, thorough oral prophylaxis
(cleaning), and scrupulous oral hygiene home
care will greatly reduce or eliminate the inci-
 22. ORAL COMPLICATIONS OF RADIATION THERAPY 431

FIGURE 22~3. Soft palate of a 63-year-old man

following 4500 cGy for epidermoid carcinoma of
the nasopharynx. Note diffuse ulceration, a pale
pseudomembrane and punctate areas of denuded and
hemorrhagic-appearing mucosa. (arrows).

FIGURE 22-4. Palatal mucosa of a 48-year-old

woman with carcinoma of the base of the tongue.
Radiotherapy was interrupted at 3000 cGy due to
severe mucositis and candidiasis. Note sloughing of
mucosa (arrows).
432 IV. HEAD AND NECK COMPLICATIONS OF CANCER THERAPY

MANAGEMENT CONSIDERATIONS
Oral mucositis can have profoundly negative
effects on nutrition, sleep, and overall quality of
life, and can force an unscheduled interruption
in the radiotherapy treatment plan (figure 22-6).
Since preventive measures are not available,
management consists of palliation of mucosal
pain. Frequent rinses with salt and baking soda
(one teaspoon of each added to a quart of water)
can be employed as often as needed to decrease
the painful mucositis and eliminate the thick
secretions that accumulate in the mouth (table
22-1). Commercial mouthwashes are of ques-
tionable value and may be detrimental. The
alcohol base of these solutions may sting or
have a drying effect, and may cause an alteration
of the normal oral flora (see table 24-3).
Periodic rinses with topical anesthetics such
as viscous XYLOCAINE, DYCLONE, or BENADRYL
and KAOPECTATE (50/50) will often give tempor-
ary relief of pain. Such rinses should be used
when there are widespread rather than localized
painful areas. These rinses can be used every 2-
3 hours, but patients should be aware of possi-
ble systemic toxicity from increased absorption

FIGURE 22-5. Same patient as in figure 22-4.

Yellowish/white plaques (arrows) associated with Muscle dysfunction
candidiasis were noted on the buccal, labial, and -laryngeal
palatal mucosa following 3000 cGy. R -pharyngeal ......... Trismus
A -palatal Dysphagia Weight loss
./

\
-tongue
dence and severity of periodontal infections
during treatment. ~¢> Anorexia

Fungal organisms such as Candida spp. are 0 Altered taste

most often responsible for oral infection involv- Altered " , Poor healing
ing the mucosa. The buccal and labial mucosa,
palate, and dorsal tongue are most commonly Infection Nutrition,

I
involved, but any mucosal surface can be E Depression
affected. The etiology of this problem is multi- Nausea
factorial, but is largely determined by radio-
Altered sche,
therapy-induced alterations in saliva and the radiotheraJ
mucosa. P Xerostomia
Acute infection secondary to dental pulp y
necrosis can occur, but should be infrequent
Altered dentition
if the patient has had preradiotherapy dental
treatment. A thorough dental evaluation prior
to radiotherapy is therefore mandatory to mini- Mucositis/ulceration
mize infectious complications of odontogenic
origin, since subacute infections that have been
asymptomatic for years may become acute fol- FIGURE 22-6. Sequelae of radiotherapy to the
lowing radiation therapy. oropharynx.
TABLE 22-1. Management of oral sequelae of head and neck radiotherapy

Problem Time of onset Clinical signs and symp- Treatment

toms

Xerostomia >1000 cGy Dry mucosa, thickened Sugarless lemon candy.

saliva, sore throat Artificial sali va.
Frequent rinses with baking soda and
salt.
Papain rinse and spit to clear thick
secretions.
Mucositis >1000 cGy Erythematous, painful If mild-warm saline or dilute H 2 0 2
mucosa; pain with nnses.
hot, spicy foods Viscous XYLOCAINE or KAOPECTATE/
BENADRYL (50/50) rinses, expecto-
rate. Benzocaine in orabase for iso-
lated areas. Systemic pain medi-
cations (TYLENOL, PERCOCET).
Nonsteroidal antiinflammatory
analgesics.
Ulceration >4000 cGy Mucosal breakdown, Frequent irrigations, BENZOCAINE in
either spontaneous or ORABASE pm if localized; if exten-
with minor trauma sive, see Mucositis above. Watch
for secondary infection.
Infection
Bacterial Variable, ~ay be Pain, swelling, exudate, Antibiotics if systemic signs, scaling
preexlstmg erythema, most com- and irrigation if gingival in origin.
monly affecting gin- If pulpal origin, open tooth for en-
giva around teeth dodontics; if extraction necessary,
high-dose, prolonged antibiotic
coverage.
Fungal During radiotherapy Usually Candida spp. Mycostatin lozenges 100,000-
Small plaques or thick 300,000 U dissolved in mouth 4-5
white patches on oro- times/day. If ineffective, add
pharyngeal mucosa, MYCQSTATIN or MYCELEX lozenge
may be associated 3-4 times per day. Consider MYCO-
with sore throat NIZOLE, one 250-mg tab g.d.

Necrosis
Soft tissue May be spontaneous or Mucosal breakdown Avoid hot, cold, spicy foods.
(Mucosa) following minor Painful, slow healing BENZOCAINE in ORABASE for
trauma, usually seen palliative relief.
following intraoral
source of radiation
or implant

Bone
Noninfected Usually seen following Area of mucosal break- Careful removal of sharp spicules if
radiotherapy down with exposed irritating; necrotic bone will even-
alveolar bone, usually t~ally slough. Frequent H 2 0 2
asymptomatic nnses.
Infected Usually seen following Usually painful exposure High-dose, long-term antibiotic
radiotherapy of alveolar bone of coverage; if unsuccessful may
variable size with cli- require resection
nical evidence of
secondary infection
Taste alteration >1000cGy Metallic or altered taste Nutritional counseling, zinc helpful
that may progress to in some cases. Daily jaw exercise,
total taste loss dietary counseling, oral hygiene
Trismus Following high-dose Limited jaw opening, emphasis
radiotherapy to the pain with futher
temperomandibular attempt to open; may
joint be limited or perma-
nent
434 IV. HEAD AND NECK COMPLICATIONS OF CANCER THERAPY

of the drug through ulcerated mucosa. In addi- fluctuant, through the tooth (endodontically),
tion, care should be taken when these anesthet- or by extraction with appropriate antibiotic
ics are used before meals, as the gag reflex may coverage.
be impaired and aspiration can occur. Fungal organisms are responsible for most
If the areas of mucositis are localized, BENZO- oropharyngeal soft-tissue infections that arise
CAINE in ORABASE, or similar anesthetic oint- during radiotherapy (figure 22-5). Candidal in-
ment, can be applied with a "Q-tip" or finger, fection begins as a secondary infection of com-
as often as necessary, to dried mucosa. The ORA- promised mucosa and often spreads to adjoining
BASE holds the anesthetic in contact with the mucous membranes. Management of fungal in-
mucosa for a longer period of time. Systemic fection consists of oral rinses and swallowing, if
toxicity is less likely because BENZOCAINE oint- tolerated, of 100,000-400,000 U of NYSTATIN 3-
ment is less toxic than most anesthetic rinses, 5 times per day. NYSTATIN vaginal suppositories,
and a smaller area of mucosa is exposed to the 100,000 U q.i.d., can be added to this regimen,
drug (see table 24-4). If topical anesthetics are and may be preferable in order to prolong con-
inadequate to control pain, then use of systemic tact of the drug with mucosa. Other antifungal
analgesics or narcotics should be considered. drugs in both troche and systemic tablet form
Anti-inflammatory analgesics can be taken are felt to be more effective in some resistant
every 4-6 h, especially before meals and sleep. infections, and may be better tolerated by the
. As discussed above, gingival inflammation patient. Clotrimazole and ketoconazole are also
and infection is a universal finding in adults who used for treatment of these infections (see
have less than ideal oral hygiene, and who have table 24-4). In addition, topical amphotericin B
not had a thorough oral prophylaxis in recent
months. Such preexisting infection is usually
asymptomatic, but may become acute with
radiotherapeutic destruction of compromised
gingival tissues. Additional factors in the ex-
acerbation of gingival disease are the qualitative
and quantitative changes occurring with the
pathogenic microflora found on the teeth and
adjacent to the gingival mucosa. Scrupulous oral
hygiene measures, for which topical anesthetics
may be required, will reduce the bacterial
population and therefore the degree of gingival
inflammation and potential for bleeding. Gentle
debridement of the teeth with wet gauze
sponges; if brushing is too painful, will help re-
move debris and organisms until such time that
the patient can undergo a more thorough pro-
fessional cleaning.
Severe localized pain may also result from
acute gingival infection. This complication is
usually characterized by swelling and purulence
that requires antibiotic as well as surgical in-
tervention. Management consists of early and
appropriate systemic antibiotic coverage. Peni-
cillin, or erythromycin in the presence of peni-
cillin sensitivity, is the drug of choice for most
gram-positive oral infections. However, infec-
tions arising from deep periodontal pockets or
necrotic dental pulp chambers may result from FIGURE 22-7. Dorsum of tongue in a 69-year-old
anaerobic gram-negative or penicillin-resistent man. He experienced persistent tongue discoloration,
staphylococcal organisms requiring a broader bad taste, and elongated filiform papilla eight months
spectrum of coverage. Surgical drainage may following 7000 cGy of radiation therapy for squa-
be necessary, either through the mucosa if mous cell carcinoma of the hypopharynx.
 22. ORAL COMPLICATrONS OF RADIATION THERAPY
has been used in cases of resistant fungal organ-
isms (i.e., aspergillosis).
Dorsal tongue discoloration, along with
elongation of the filiform papillae ("black hairy
tongue"), is often observed during or following
radiotherapy (figure 22-7). Bacterial as well as
fungal organisms are implicated in the origin of
this problem, but causative organisms have not
yet been identified. This low-grade infection
does not appear to pose any threat to the pa-
tient. However, black hairy tongue can be a
painful phenomenon, may result in taste altera-
tion, and may be psycologically upsetting to the
patient. A biopsy of the tongue for histology, as
well as for bacterial and fungal cultures, may
identify the organism(s) involved and guide
therapy. Patients should be encouraged to brush
the tongue, as well as their teeth, in order to
reduce microbial load.
Postradiotherapeutic Problems and
Their Management
Complications following radiotherapy are pri-
marily related to injury to salivary glands and to
vascular and mucosal tissues. The majority of
these problems occur in the maxillofacial region
and include xerostomia, infection, radionecro-
sis, taste alteration, and trismus.
XEROSTOMIA
The problem of radiation-induced dry mouth Xerostomia
(xerostomia) has been well documented in the
+
past [5-8]. A prospective study of 150 head and
neck cancer patients reveals prolonged xerosto-
mia to be the major problem described by
patients following radiotherapy (P.B. Lockhart,
personal observation). Some degree of xerosto-
mia is universal when the major salivary glands
are involved. Dryness may begin as early as one +Periodontal inflammation
week into therapy, or at around 1000 cGy, and
may last from several weeks to throughout the
lifetime of the patient [9]. Edema and inflamma-
+ Alveolar bone loss
tory infiltration of the glands begin early in the
course of radiotherapy. Fatty degeneration,
necrosis, and acinar and small blood vessel
fibrosis subsequently occur. The parotid and
submandibular salivary glands normally secrete
serous saliva, although the submandibular
gland also contains mucous alveoli, the serous
component of the major salivary glands is
affected first and to a greater degree than is
the mucous component. The saliva becomes
435
thicker and more difficult for the patient to
manage. The pH of the saliva may decrease
from a normal of 6.8 to as low as 4.0; with time
the color of the saliva may change to white or
brownish. Along with decrease in saliva pro-
duction [10], there is a marked increase in
salivary Na+, CI-, Mg++ and protein content.
These changes can result in alterations in the
oral microbial flora such that cariogenic organ-
isms gain predominance [5].
There is at least partial return of saliva in most
patients, depending on radiation dosage and the
volume of involved salivary gland tissue. This
recovery may take from six months to over a
year following radiotherapy. Patients may be
constantly bothered with the need for irrigation
with water. Xerostomia results in significant
problems with chewing and swallowing food, as
well as difficulty with speech. Long-term effects
of xerostomia, however, are potentially more
deleterious. Dental infection from radiation-
induced caries is a common sequela in the
months or years following radiotherapy.
The pharyngitis/esophagitis that often ac-
Radiotherapy
5alivary gland fibrosis Epithelial cell death
.. ..
. .
t Salivary pH Mucositis and ulceration
'.
Carbohydrate intake t Oral hygiene
/
"
Plaque and calculus
.
/'
+Enamel demineralization
Pulpal necrosis
Periodontal abscess Periapical abscess
Extraction
Potential. osteonecrosis
FIGURE 22-8. Dental sequelae of radiotherapy.
436 IV. HEAD AND NECK COMPLICATIONS OF CANCER THERAPY

companies head and neck radiotherapy may

result in a change to a soft, high-carbohydrate
diet. Patients often select soft drinks and sticky
foods that lack a cleansing effect and predispose
the patient to an acidic environment (figures
22-6 and 22-8). Other secondary effects of radio-
therapy also contribute to the acceleration of
caries; these include drying and blockage of
nasal mucous membranes that result in mouth
breathing, and decreased oral hygiene com-
pliance because of mucosal sensitivity.
Management of xerostomia is an unresolved
problem. Several artifical salivas are available
that may- be helpful in reducing the discomfort
A
and secondary complications of xerostomia [11]
(see table 24-4). This material is usually formu-
lated with carboxymethylcellulose and has con-
stituents and viscosity similar to that of natural
saliva. This allows for replenishment of the
calcium and phosphates leached from teeth by
a lowered salivary pH. Patients often object,
however, to the taste or inconvenience of using
this agent, and return to the use of water in-
stead. Pilocarpine hydrochloride is reported to
stimulate saliva production in some patients
[12]. Sugarless gum or lemon drops may also
stimulate salivary flow. Papaine, a proteolytic
enzyme, can be used to dissolve fixed secretions
accumulating in the oropharynx.
Patients who use full dentures may experi- B
ence problems with denture retention because
of the loss of a film of saliva between the den- FIGURE 22-9. (A) Mandibular anterior teeth in a 41-
ture and the mucosa. Commercial adhesives year-old man 11 months following 6000 cGy for
may be helpful, but patients should be moni- squamous cell carcinoma of the nasopharynx. Note
tored carefully for mucosal trauma secondary to circumferential areas of decalcification (arrows). Pa-
poorly fitting dentures on compromised and tient was not compliant with the use of fluoride. (B)
dry mucosa. More advanced carious lesions (arrows) involving the
maxillary posterior teeth in a 43-year-old man 18
months following 6000 cGy for squamous cell carci-
INFECTION noma of the hypopharynx.
Periodontal disease is a common and chronic
problem for patients following radiotherapy.
As noted previously, pretherapy gingival infec- Numerous reports document the direct result
tion will progress at a variable rate following of radiation-induced xerostomia on the denti-
radiotherapy; alternatively, gingival disease may tion. Postirradiation caries usually occurs with-
arise in a previously healthy mouth. Xerosto- in the first year (figure 22-9). As noted pre-
mia, poor hygiene, and an increased sucrose viously, changes in the oral flora and the dental
intake will predispose the patient to chronic pulp as a result of radiotherapy are not generally
infection that may become acute at any time. felt to be the primary etiologic factors in radia-
The management of this problem does not tion caries [12, 13]; however, Brown et al. [5].
differ from that in the uncompromised patient detected a pronounced shift toward a highly
except for the ultimate management of teeth acidogenic and cariogenic oral microflora with
with moderate to severe alveolar bone loss, radiation-induced xerostomia. The major cause
and the desirability of appropriate prophy- of rampant dental caries is generally felt to
lactic antibiotics if selected therapy is required. be secondary to a xerostomia-related decrease
 22. ORAL COMPLICATIONS OF RADIATION THERAPY
FIGURE 22-10. (A) Mandibular anterior dentition in a
61-year-old man 20 months following 6440 cGy for
squamous cell carcinoma of the tongue. Note loss of
two mandibular incisor teeth as a result of advanced
caries (large arrows). Remaining teeth have both cer-
vical as well as incisal caries (small arrows). (B)
Radiograph of patient in A. Note missing crowns of
incisors lost due to severe caries. Appearance of bone
at apex of these teeth suggests chronic apical abscess
formation.
in dental plaque pH, decreased salivary flow
around the teeth, and a dietary increase of re-
fined carbohydrates.
Xerostomia-induced caries typically occur in
the cervical areas of the teeth, and may rapidly
progress to the pulp chamber; pulpal infection
and necrosis may ensue [10]. With time, the
clinical crown becomes amputated by cervical
decay (figure 22-10). Bacterial organisms dissem-
inate from the infected pulp chamber through
the root apex into the periapical alveolar bone.
With the compromised host defenses, a chronic
marrow infection develops that may subse-
quently become acute.
Infection from a pulpal abscess also repre-
sents a threat to the patient in terms of adequacy
of healing following endodontic or surgical
manipulation. Root canal (endodontic) therapy
avoids the significant alveolar trauma and bacte-
rial seeding that occurs during an extraction,
but itself carries significant risk. Healing of
437
periapical bone loss and infection depends upon
an adequate blood supply, lymphatic drainage,
and presence of viable osteoblasts. There is a
consensus among clinicians who manage these
patients that extractions should be avoided,
whenever possible, from the immediate pre-
radiotherapy period until several months to a
year after radiotherapy. There is not, however, a
clear consensus concerning the desirability of
root canal therapy as an alternative to extrac-
tions immediately prior to, during, or after
radiotherapy. Successful endodontic therapy
may require healing of the alveolar bone at the
apex of the tooth, and the eradication of organ-
isms and inflammation from the periapical
region. Vascular injury, especially in the man-
dible, will compromise the healing potential,
and may result in treatment failure in the future.
The long-term prognosis for the tooth, as well as
patient compliance with hygiene and dental
follow-up, are additional factors to consider in
the choice of treatment for odontogenic infec-
tion.
Endodontic treatment should be carried out
meticulously. Instrumentation. should be ac-
complished to the anatomic apex, using care
not to perforate the periapical region. Irrigating
solutions, root canal cements, and intracanal
medications should be utilized such that peri-
apical inflammation is minimized. Teeth should
438 IV. HEAD AND NECK COMPLICATIONS OF CANCER THERAPY
generally not be left open for drainage between
appointments. Antibiotic coverage throughout
therapy and for several days after obliteration
of the canal should aid in the resolution of
periapical disease. Although patients may be
asymptomatic following root canal therapy,
there may be a prolonged or failed healing of
the periodontal structures. Adequacy of heal-
ing is difficult to ascertain radiographically,
and chronic infection may persist and result in
osteomyelitis.
As noted, there is a significant risk of bone
necrosis from the extraction of teeth from
irradiated bone. In some cases, however, risk
from an extraction is outweighed by the risk of
any other form of treatment. Surgical technique
to reduce risk of complications includes careful
alveoloplasty, copious irrigation of the surgical
site, primary closure without tension on the
sutures, and appropriate antibiotic coverage for
gram-positive organisms including penicillin-
resistant Staphylococcus spp. If multiple extrac-
tions are indicated, consideration should be
given to limiting the number of extractions
performed at one time since there is decreased
healing potential from damage to lymphatic
drainage, vascularity, and osteoblastic activity.
RADIONECROSIS
Osteoradionecrosis. Osteoradionecrosis re-
sults from radiation damage to bone. High-dose
radiotherapy causes avascularity, fatty degen-
eration, enlarged lacunae, microfractures, and
reduction in number of osteocytes, osteoblasts,
and osteoclasts. The incidence of osteonecrosis
of the jaws is reported to be 2%-24% following
definitive radiation therapy for oral cancer
[14-16]. Morrish et a!., in a review of 100 pa-
tients treated with head and neck irradiation,
found that osteonecrosis developed in approx-
imately 24% of dentulous patients and in 13.6%
of the edentulous patients [17]; however, 85%
of the dentulous patients and 50% of edentu-
lous patients who received more than 7500 cGy
developed osteonecrosis. None of the patients
who received less than 6500 cGy developed
osteonecrosis.
Although necrosis most often occurs between
three and 12 months following radiotherapy,
the time period of greatest susceptibility for
necrosis is between six and eight months [18,
19]. However, patients are at risk for years
afterward; in the Morrish study, 15 of 22 cases
occurred more than two years after radiation
[17]. In spite of these statistics, however, the in-
cidence of osteonecrosis has decreased in recent
years due to improvements in surgical and
radiotherapeutic techniques and technology
[6,20].
Osteonecrosis, whether spontaneous or from
trauma from appliances or extractions, is more
likely to occur in patients who have had surgical
procedures in addition to radiotherapy. Radical
neck dissection, along with surgical manage-
ment of the primary tumor site, interfere with
the blood supply to the maxillofacial area, espe-
cially the mandible. Carl et a!. [20] reported that
osteoradionecrosis in these patients is more dif-
ficult to manage and less likely to heal when
conservative measures are used. Trauma and
mucosal/odontogenic infection greatly increase
the risk of mandibular osteonecrosis [21, 22].
The exact role of dental disease in the etiology
of bone necrosis is uncertain (see chapter 24),
but open mucosal wounds frequently precede
necrosis [23] (figure 22-11). Acute or chronic
infection in the presence of a radiation-induced
vascular compromise may result in mucosal
breakdown, exposure of compromised bone,
and a resultant osteonecrosis. For example, as
previously discussed, periodontal disease is
characterized by ulceration that results in close
approximation of alveolar bone to a variety of
pathogenic microflora. Patients with natural
teeth have more than twice the risk of develop-
ing necrosis than do patients who are edentu-
lous [16, 17]; further, analysis of the association
between preradiotherapy dental disease and
subsequent occurrence of osteoradionecrosis
suggests .that the incidence of necrosis is sig-
nificantly greater in patients with dental disease
[24].
Osteoradionecrosis may be septic or aseptic.
Septic necrosis is usually symptomatic and dis-
plays signs suggestive of infection. Aseptic ne-
crosis is usually asymptomatic, appears more be-
nign, and should be treated more conservatively.
Necrosis of either type is a serious problem for
the patient since the vascularity, cellularity, and
therefore the healing potential of the bone and
mucosa are altered. Since osteonecrosis may be
asymptomatic, all patients, especially those with
dental protheses, should be monitored carefully
for its occurrence. Early recognition of bony
necrosis, combined with conservative manage-
ment, may reduce the need for surgical in-
tervention.
 22. ORAL COMPLICATIONS OF RADIATION THERAPY 439

FIGURE 22-11. (A) This 59-year-old woman received 6100 cGy for squamous cell carcinoma of the floor of the
mouth. Note soft-tissue breakdown over the left mandibular body (large arrows), and tooth that has "fallen"
into this area of necrosis (small arrows). (B) Same patient as in A. Note surgical cuts that approximate the
root surface and periapical region of the lower molar (small arrows). Surgical involvement of dental root
surface and periodontal membrane created a nonhealing wound adjacent to the remaining incisor and molar
teeth. This resulted in prolonged osteonecrosis and further loss of teeth and bone. Note radiographic evidence
of periapical infection (large arrow).
440 IV. HEAD AND NECK COMPLICATIONS OF CANCER THERAPY

B
A

c
FIGURE 22-12. (A) This 70-year-old man received 6000 cGy for squamous cell carcinoma of the right mandibu-
lar alveolar ridge. Periapical infection from the mandibular right first molar existed, but was not noted prior to
radiotherapy. Six months after radiotherapy, the patient developed ulceration (arrows) on the right ventral
surface of his tongue. (B) Same patient as in A. Further thorough examination of the inferior medial surface of
the right mandibular body disclosed an area of necrotic alveolus (small arrows). The bony defect was only
visible indirectly by firm retraction ot the tongue and the use of a dental mirror (large arrows). Sharp bone
spicules were removed to decrease tongue irritation. (C) Same patient as in A and B, 18 months later. Patient had
returned several times over the preceding 18 months, complaining of a sore tongue. Each time, spicules of rough
bone were removed. Both the tongue ulcer and bony defect resolved following extraction of the molar (large
arrow). Note leukoplakic appearance of tongue lesion (small arrows).
 22. ORAL COMPLICATIONS OF RADIATION THERAPY
Management of osteoradionecrosis depends
upon location, size and symptoms of the le-
sion, as well as host and radiotherapy factors.
The dosage of radiation to bone is a major con-
sideration. Necrosis in bone that has received
higher doses of radiotherapy is usually more
painful and is less likely to heal spontaneously.
Osteonecrosis of surface alveolar bone that has
received lower doses of radiotherapy should be
observed. In general, even minor invasive pro-
cedures should be avoided since the involved
necrotic bone will slough; healing predictably
will occur over the underlying viable bone.
Loose fragments of bone that are irritating to
adjacent mucosa can be gently removed or
smoothed with a bone file. The patient should
be followed closely and encouraged to maintain
excellent oral hygiene to minimize accumula-
tion of pathogenic oral bacteria. Areas of ex-
posed bone should be kept clean with frequent
rinses of hydrogen peroxide and water.
Osteonecrosis may also occur as a result of
periapical infection (figure 22-12). Bone may
continue to necrose until the surface mucosa be-
comes involved. A culture should be obtained
for possible identification of anaerobic as well as
aerobic gram (+) organisms; Staphylococcus
aureus or S. epidermi.dis are commonly recovered.
Teeth responsible for osteonecrosis should
be extracted as atraumatically as possible with
appropriate antibiotic coverage (see the section
on Infection).
Outpatient management of osteonecrosis
includes oral penicillin (500 mg q.i.d.) or
erythromycin (500 mg q.i.d.) in the case of peni-
cillin allergy. Systemic antibiotics may be neces-
sary. Decreased vascularity after radiotherapy
dictates that the dose of antibiotics be high and
treatment prolonged, often for several weeks.
Hyperbaric oxygen therapy has been used in
the management of resistant cases of osteone-
crosis. Although this treatment has a sound
theoretical foundation, it has not proved to be
of major benefit in routine management due to
expense, stringent physical status requirements,
and the limited number of treatment centers.
The mechanism by which hyperbaric oxygen
promotes healing is unclear, but it has been
shown to be effective in certain instances in-
cluding reduction of pain [25-27]. The inade-
quate long-tertn result from hyperbaric oxygen
may be improved with judicious use of concom-
itant surgery [28].
441
In summary, healing of osteoradionecrosis
can take from several weeks to over a year, and
should be managed conservatively until intrac-
table pain or infection signals the need for
surgical intervention.
Soft-tissue Necrosis. Soft-tissue necrosis oc-
curs most often in patients who have received
radiotherapy from an intraoral as well as ex-
traoral source; it can occur from several months
to a year following treatment. Management is
directed at pain control and prevention of fur-
ther trauma to the mucosa. Frequent rinses
with salt and baking soda will help with local
debridement and palliation of pain. A 1% neo-
mycin solution has been suggested for exten-
sive and/or painful lesions [7]. Since soft-tissue
necrosis often occurs near the site of the pri-
mary tumor, and can require months for heal-
ing, the area should be monitored carefully to
rule out recurrence of malignancy (figure 22-
13).
TASTE ALTERATION
Taste loss (hypogeusia) or abnormality of taste
(dysgeusia) can develop following as little as 240
cGy [29]. By 3000 cGy, taste loss is almost com-
plete and may be pertnanent above 6000 cGy.
Hypogeusia, as well as dysphagia, xerostomia,
and mucositis, can have a profound effect on
the patient's nutritional intake (figure 22-6).
Perception of bitter and acidic foods is most
susceptible to change, while salt and sweet taste
is less affected. Sensory impairtnent is thought
to be secondary to injury to the microvillae, the
surface of the taste buds [30, 31], or to their in-
nervating nerve fibers [32]. Recovery begins 20-
60 days after treatment, and maximum recovery
usually occurs within 2-5 months. The degree
of taste recovery is radiation dose-dependent.
Zinc sulfate is reported to be helpful in increas-
ing taste acuity [33, 34], but may be of more
benefit in the acceleration of taste improvement
in the postradiation period than in the preserva-
tion of taste during radiotherapy [35].
TRISMUS
Trismus, or limited jaw opening, may result
from tumor involvement of the pterygoid mus-
cles or the temperomandibular joint (TMJ) it-
self. Trismus also occurs when a high dose of
radiation involves the TMJ, and may be an acute
sequela of radiotherapy. It usually occurs,
 A

FIGURE 22-13. (A) Intraoral appearance of a 78-year-old man who received 6000 cGy for squamous cell carcino-
ma of the posterior floor of the mouth. Both mandibular canines were irritating the ventral tongue mucosa
(arrows). Due to concern of chronic irritation to irradiated tongue mucosa, and the possibility that this area
might represent a new or recurrent malignancy, both canines were extracted. (B) Same patient as in A. Although
these teeth were not in the direct beam of radiotherapy, and appropriate precautions were taken during and
following their removal, both sockets failed to heal. The exposed bone (small arrows) persisted for several
months. Note also that the ventral tonguelfloor of the mouth area has not healed (large arrows), leaving open
the question of malignancy versus soft-tissue necrosis secondary to radiation and dental irritation.

442
 22. ORAL COMPLICATIONS OF RADIATION THERAPY
however, within six months of radiotherapy and
often becomes a lifelong problem. Fibrosis
occurs in the muscles of mastication and liga-
ments around the joint. Limited jaw opening
interferes with oral hygiene, speech, nutri-
tional intake, examination of the oropharynx,
and dental treatment, and can be particularly
discomforting to the patient. Early intervention
with jaw exercises may minimize trismus and
maintain mobility of the joint; patient compli-
ance is critical for success. The patient should
be instructed to place as many tongue blades as
possible between the anterior teeth and leave
them in place for several minutes, 2-3 times/
day. Additional tongue blades can be added as
the jaw relaxes. Dreizen et al. [31] recommend
mandibular opening exercises 20 times/day
and suggest that this may greatly minimize
muscle fibrosis and resultant masticatory
problems. Prosthetic appliances designed to
"stretch" the masticatory musculature may
also be useful in such cases.
Treatment Planning and Preventive
Considerations prior to, during and
after Radiotherapy
It was once common practice to extract all teeth
in patients about to receive radiation to the head
and neck. However, it is no longer believed
necessary to remove healthy teeth in highly
motivated patients due to improvements in
radiotherapeutic techniques, the understanding
that the more serious oral problems are largely
preventable, and the fact that psychological and
functional considerations in the preservation of
healthy teeth far outweigh the risk of main-
taining them. Preservation of teeth is especially
important in the pediatric patient, since radio-
therapy may result in incomplete development
and/or eruption of the permanent dentition.
Primary teeth may therefore be important for
an extended period of time.
Dental evaluation should include discussion
with the patient's radiotherapist concerning the
intended radiation dosage and field of radiation,
and the time available for dental treatment prior
to the onset of radiotherapy (figure 22-14).
These factors frequently have a major impact on
dental treatment planning and overall manage-
ment.
443
PRERADIOTHERAPY EV ALUATION
AND TREATMENT PLANNING
A major goal in the overall management of this
patient population is the prevention of post-
radiotherapy maxillofacial complications. Most
of the problems discussed above can be pre-
vented or limited in severity by careful prether-
apy examination and treatment. For example,
Keys and McCasland reported that hospitalized
patients entered into a dental care program prior
to cancer therapy had more teeth preserved,
fewer teeth extracted or restored after therapy,
and a lower caries incidence when compared
with a similar group not receiving pretreatment
dental care [36]. Patients who received regular
dental care had decreased incidence and severity
of oral infection and pain, and lost less weight
during radiotherapy. In addition, the incidence
of osteonecrosis was lower than that reported in
other studies in which pretreatment dental care
was lacking. The overall cost of this program
appeared reasonable as judged by the decrease
in the average number of clinic visits per patient.
A full-mouth series of dental radiographs
and a thorough clinical exam will identify teeth
in need of treatment before radiotherapy (figure
22-14). Since these patients will often receive
high doses of radiotherapy, the minimal dose
from dental films is of little consequence when
compared with the potential benefit. Carious
teeth without pulpal inflammation or necrosis
should be restored. An oral prophylaxis should
be given to eliminate local causes of gingival in-
flammation such as plaque and calculus; home
care instructions can be given at this time.
Periodontal pockets should be probed and
recorded, with review of the healing response
that occurs following the prophylaxis. Pockets
deeper than 4-5 mm may be difficult for
the patient to maintain, and may indicate the
need for selected extractions. Teeth should be
considered for extraction if they have mobility,
spontaneous pain, percussion sensitivity, or
clinical or radiographic evidence of pulpal dis-
ease; molar furcation involvement, especially
in the mandibular arch, may also dictate ex-
traction. However, gingival recession itself,
in the absence of mobility or significant bone
loss, is not an indication for extraction.
As noted previously, it is not clear whether
endodontic treatment prior to or following
radiotherapy has a more predictable outcome
than extraction. One study found poor success
from endodontic treatment in radiotherapy pa-
444 IV. HEAD AND NECK COMPLICATIONS OF CANCER THERAPY
tients [37]; another investigator suggested that
endodontics is the treatment of choice for dental
pulpal disease in these patients [38]. Endodon-
tics, however, is a less definitive treatment than
extraction, and should be carried out with fore-
thought in patients who will receive over 5000
cGy to the involved jaw. Mandibular teeth are
particularly susceptible to infection since their
vitality depends on the inferior alveolar arteries;
the collateral circulation found in the maxilla
is not present in the mandible. In general,
questionable teeth that might require extrac-
tion at some point in the future should be
managed definitively as early as possible prior
to radiotherapy. This is especially important
with mandibular teeth.
There is no consensus regarding the time
necessary between extractions and the onset of
radiotherapy. Controversy also exists concern-
ing the relative risk of osteonecrosis following
pre- versus postradiotherapy extractions [17,
18,20,39]. Some clinicians feel that extractions
can be accomplished safely up until the first day
of radiation. Daly and Drane, however, found
that 30% of 304 patients who had an average
extraction healing time of 11 days before radia-
tion therapy experienced osteonecrosis; 25% of
these patients had at least two weeks of healing
[42]. Therefore, it is suggested that there be a
minimum of ten days to two weeks between ex-
tractions and the initiation of radiotherapy since
new bone will not form before this time [15,
25, 40-42]. Multiple or difficult extractions,
however, may require several weeks for heal-
ing. In general, extractions should be done as
atraumatically as possible. Alveolar bone should
be smoothed off and tissue should be closed pri-
marily. Appropriate antibiotics should be used
to reduce the risk of postsurgical infection.
Teeth outside the irradiated area can often be
extracted following radiotherapy, if necessary,
with little risk (figure 22-13B).
XEROSTOMIA AND MUCOSITIS
In cases when the tumor to be irradiated is of
lateral origin (e.g., T2 tonsil or parotid lesion)
and does not involve midline structures, shield-
ing of the uninvolved parotid gland can preserve
a significant amount of salivary function. Be-
cause of the devastating psychological and phys-
iologic consequences of obliteration of salivary
function, shielding should be considered when
there is no risk of contralateral tumor invasion
or lymphatic involvement.
At the present time, there is no preventive
modality for mucositis that occurs in the direct
beam of a moderate to high dose of radiother-
apy. However, thorough pretherapy dental
prophylaxis, elimination of rough or sharp teeth
and appliances, and scrupulous oral hygiene
during therapy should reduce the incidence and
severity of ulceration.
CARIES PREVENTION
Following the examination, prop~ylaxis, .and
surgical/restorative treatment, Impressions
should be taken for construction of fluoride
trays. The increased risk for rampant dental
caries following radiotherapy is well docu-
mented, and the preventive benefit of daily top-
ical fluoride cannot be overstated. Daly [7]
found that 69% of patients who received radia-
tion to the head and neck, and who did not
use a daily topical application of fluoride gel,
developed radiation caries. In contrast, 25% of
patients who had good compliance with daily
fluoride use developed caries. In addition to
prevention of dental caries, fluoride may help
eliminate postirradiation dental root surface
hypersensitivity to cold, hot, acidic, and sweet
foods.
Patients should be instructed to use a soft-
bristle brush and dental floss. The complete re-
moval of dental plaque each evening, followed
by the use of 0.4% stannous fluoride gel in trays
for 5 min, will virtually eliminate the possibility
of xerostomia-related caries. One of several
brushing techniques can be used, but emphasis
should be placed on cleaning the area of tooth
adjacent to and under the free marginal gingiva
(see chapter 24).
Compliance with the use of fluoride may be a
problem; patients often stop using the trays
either because of inconvenience or a problem
with gagging. Stannous fluoride gel toothpastes
(0.4%) are now available for use in caries
prevention. The advantage of this method of·
fluoride application is that it eliminates the extra
step of the fluoride trays and allows for fluoride
application during routine brushing. Several
studies [36, 43-45]. have shown that various
programs of hygiene and fluoride application
are highly effective in preventing caries in pa-
tients with xerostomia. However, a comparison
of the benefit of one fluoride delivery system
over another, and the problem of maintaining
compliance in the daily use of fluoride, remain
to be studied.
 22. ORAL COMPLICATIONS OF RADIATION THERAPY
.
Discuss case with radiotherapist
Clinical examination
.
Dentulous patient
.+
Full series radiographs
Treatment planning
/Surgical
+-
Treatment" ' "
Endodontic
.
Oral prophylaxis and
hygiene instruction
.
Restorative and
prosthetic treatment
Fluoride trays
FIGURE 22-14. Preradiotherapy treatment planning.
(*) Surgical, endodontic, and prosthetic treatment
determined by the time available before initiation of
radiotherapy.
Patients should be followed closely for com-
pliance following initiation of this thorough
dental care program, especially during radio-
therapy. Changes may be necessary in diet
and home care as patients become xerostomic
and encounter painful mucositis. If not pre-
vented by pain, patients should be encouraged
to continue brushing with a soft-bristle brush
(further softened by hot tap water) as well as
gentle flossing. A topical anesthetic may be-
come necessary for pain prior to any home care.
If brushing must be discontinued, frequent
mouth rinses will help eliminate bacterial and
food debris. Patients should be switched to a
neutral sodium fluoride if unable to tolerate an
acidulated phosphate fluoride. If absolutely
necessary due to pain, fluoride trays or rinses
can be temporarily discontinued during radio-
therapy.
DENTAL MANAGEMENT OF THE
EDENTULOUS PATIENT
Since many of the long-term problems follow-
ing radiotherapy relate to dental and periodon-
tal infection, the preradiotherapy evaluation of
the edentulous patient is less involved than that
445
of the dentulous patient (figure 22-14). A
panorex radiograph should be taken to identify
residual root tips, impacted teeth, or infection
that may not be clinically evident. In addition, a
thorough clinical exam will identify sharp or
.
Edentulous patient
prominent areas of alveolar bone. These bony
protuberances may occur over extraction sites,
.
the lingual surface of the anterior aspect of
~ Panarex radiograph
the mandible (lingual tori), or in the posterior
.
mandible over the mylohyoid ridge. Such
Surgical treatment* conditions should be considered for surgical ex-
posure and recontouring, if time exists prior to
radiotherapy. This surgery may prevent the
Prosthetic evaluation
and treatment* overlying, friable mucosa from breaking down,
resulting in ulcer formation over poorly vas-
I
cularized bone. The management of impacted
teeth depends on the depth of impaction, the
risk of late eruption or breakdown of mucosa
overlying the tooth, and the time available for
healing prior to radiotherapy. Deeply impacted
teeth with overlying bone can usually be left in
Radiotherapy place without risk of late problems. Compara-
tively, soft-tissue impactions may later develop
a communication with the septic oral environ-
ment and become infected; however, extrac-
tions of such teeth are usually not indicated if
less than 2-3 weeks remain for healing prior to
the initiation of radiotherapy.
Denture use during and after radiotherapy is
another controversial issue (see chapters 23,
24). Although necrosis of mucosal tissues can
occur spontaneously, mucosal trauma is more
often caused by teeth or oral appliances. A ques-
tionnaire concerning advice given to patients
revealed disparate views between radiothera-
pists and prosthodontists [19]; recommended
insertion times for dentures following radio-
therapy range from one to three years [7, 46,
47]. In general, risk of bone necrosis under den-
tures is felt to be significant in patients who
have had teeth removed just before or after radio-
therapy; patients who have had extractions and/
or alveolectomy within one month prior to
radiotherapy or following radiotherapy (or who
have irregular ridges within the radiation field)
should wait 6-12 months prior to construction
of new dentures [48, 49]. On the other hand,
patients who had dentures before therapy may
receive dentures soon after radiotherapy, pro-
vided the ridges are smooth and there have been
no extractions within one month prior to
radiotherapy. Some patients should never wear
dentures, depending on patient cooperation, the
status of the mucosal and bony sudaces, and the
446 IV. HEAD AND NECK COMPLICATIONS OF CANCER THERAPY
dose of radiotherapy.
Close monitoring of the oral mucosa under
dentures will usually reveal areas of denture
irritation. The elimination of "high spots" on
the denture base, and abstinence from denture
use until complete healing has occurred, should
prevent progression of the ulcer to bony expo-
sure. Denture use during radiotherapy, how-
ever, should be generally avoided whenever pos-
sible since denture irritation to irradiated mucosa
will aggravate mucosal pain and interfere with
healing (figure 22-15); if the patient experiences
no pain with denture use, however, and is close-
ly monitored for mucosal breakdown, dentures
can be worn during the day. In this latter case,
dentures may need one or more relines following
radiotherapy due to changes in the oral mucosa.
Care should be used with irritating and heated
materials in the construction of a prosthesis, or
during any other dental treatment, to prevent
soft-tissue necrosis; patients should be
cautioned to avoid hot foods (figure 22-16).
Nutritional complications as sequelae of
radiotherapy to the jaws are universal and often
complicate the overall health of the patient
(figure 22-6). Taste loss and xerostomia, along
with alterations in tongue, palatal, pharyngeal,
esophageal, and jaw function, may limit the
patient's ability to masticate. Prohibition of
FIGURE 22-15. Anterior mandibular ridge in a 43-
year-old woman two years following 5600 cGy for
squamous cell carcinoma of the tongue. The patient
insisted on wearing her dentures 24 h a day. Note
that the alveolar mucosa overlying the mandibular
ridge has broken down, exposing a large area of
necrotic bone (arrows).
denture use may further interfere with the
maintenance of adequate nutritional intake. It
appears that the risk of osteonecrosis related to
denture use is small in the radiation patient with
healed mucosa [18, 48]; further, the need for
adequate nutritional intake and the cosmetic im-
portance of dentures to the patient outweigh the
possibility of osteonecrosis.
POSTRADIOTHERAPY DENTAL
MANAGEMENT
Dental management following radiotherapy
consists of close monitoring of oral hygiene and
the use of fluoride. Compliance is the major
consideration in the postradiotherapy dental
management of these patients. Failure to under-
stand the significance of chronic oral infection
may lead to indifference on the part of a patient
who must cope with the psychological and
physiologic effects of cancer therapy. Thorough
instruction with periodic recall is necessary to
ensure that patients themselves take responsi-
bility for the maintenance of a healthy mouth.
 22. ORAL COMPLICATIONS OF RADIATION THERAPY
FIGURE 22-16. This 49-year-old man complained of a
sore throat 11 months following 5940 cGy for
squamous cell carcinoma of the hypopharynx. A
careful history revealed that he had burned his soft
palate and uvula (arrows) with hot food. These le-
sions were painful and took over five weeks to heal,
during which the patient lost 20 pounds. The history
of hot-food intake precluded the necessity of a biop-
sy to rule out a new malignancy. (Note also the
"hairy" appearence of the tongue.)
A hygiene recall schedule should be designed
that reflects individual needs, with considera-
tion for potential for oral infection and com-
pliance with home care. Periodic recall should
identify carious lesions and periodontal disease
that, with early intervention, will not progress
to alveolar bone infection.
Since pathogenic organisms responsible for
caries and periodontal disease thrive on refined
carbohydrates, these substances should general-
ly be avoided. Sugar-containing soft drinks and
candy should not be used to alleviate the symp-
toms of xerostomia. Since many foods contain
high quantities of nonnutritional cariogenic car-
bohydrates, it is difficult to maintain a diet free
of such additives. Therefore, patients must be
made aware of the direct relationship between
sucrose and refined carbohydrates and the
growth of pathogenic bacteria.
. An additional concern in the rostradiother-
apeutic period is the possibility 0 recurrence of
447
malignancy or the onset of a new primary
tumor. It has been suggested that radiotherapy
itself may result in late onset of a new malignan-
cy within the radiation field [20]. These patients
are therefore at increased risk for tumor recur-
rence that may initially be evident on mucosa
visible on routine examination. A careful
evaluation of nonhealing areas of mucosal
ulceration should therefore be performed.
Summary
Comprehensive management of patients receiv-
ing radiotherapy to the head and neck dictates
that they have a thorough dental evaluation as
part of their overall treatment planning. Early
and appropriate patient education and dental
treatment, along with careful management
during and after radiotherapy, will significant-
ly decrease the incidence and severity of com-
plications, improve quality of life, and increase
tolerance to therapy.
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3. Weichselbaum RR, Epstein J, Little JB: In vitro
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V. SUPPORTIVE CARE
 23. PROSTHETIC MANAGEMENT

John Beumer, III

Louis G. De Paola
Robert J. Leupold

I. MANAGEMENT OF THE tained, to extensive resections resulting in dis-

PATIENT AFTER SURGERY/
IRRADIATION
The treatment of patients with cancer does not
cease with elimination of the disease. Rehabili-
tation is an essential phase of cancer treatment
and should be considered from the time of di-
agnosis. Surgical resection often creates large
defects accompanied by dysfunction and dis-
figurement. Radiation therapy produces sig-
nificant morbidities and unique tissue manage-
ment problems. Speech, swallowing, control of
saliva, and mastication can be adversely affected.
If these cosmetic and functional impairments
are not corrected or minimized, the patient may
be unable to resume a normal working and
social life.
Classification
Cancer patients who require maxillofacial re-
habilitation may be arbitrarily classified accord-
ing to their postreatment surgical defects and
morbidities.
Maxillary Defects. These patients have defects
of the maxilla and adjacent soft tissues. Maxil-
lary defects range from small perforations of the
hard or soft palate to extensive resections of the
maxilla, soft palate, and paranasal sinuses,
often including adjacent structures such as the
orbit and cheek.
Mandibular Defects. These patients have re-
sections confined to the mandible and adjacent
soft tissues. Mandibular defects range from
limited resections of the mandible and adjacent
soft tissue, with mandibular continuity main-
Peterson etal., HEAD AND NECK MANAGEMENT OF THE CANCER PATIENT.
© 1986. Martinus Nijhojf Publishing. All rights reserved.
articulation of the mandible along with resec-
tion of portions of the tongue and floor of
mouth in continuity with the lymphatics of the
neck.
Facial Defects. These patients have defects
ranging from orbital exenteration to excision of
all or a portion of the nose, ear, or cheek. Also
included in this category are patients with
combination oral and facial defects.
Radiation Therapy. These patients have been
treated with a cancercidal dose of ionizing
radiation. This mode of therapy produces
changes in the volume and consistency of saliva
along with changes in the hard and soft tissues,
which must be considered in both surgical and
prosthodontic rehabilitation.
Maxillary Defects
Most tumors requiring maxillary resection arise
either from the paranasal sinus or palatal epithe-
lium or from the minor salivary glands present
in the palatal submucosa. Resection of many of
these tumors requires either a partial or a total
maxillectomy. A radical maxillectomy entails
resection of the entire maxilla to the midline,
usually with exposure gained by reflection of a
lip and check flap. A partial maxillectomy is less
encompassing and may be performed transoral-
ly. The amount of soft palate included in these
resections is variable and depends on the need to
obtain tumor-free margins.
DISABILITIES
Defects of the hard or soft palate lead to a vari-
ety of functional disabilities. Speech becomes
unintelligible because of hypernasality; mastica-
tion is difficult, particularly in the edentulous
453
454 V. SUPPORTIVE CARE
patient, because of loss of dental structures and/
or the palatal areas; swallowing is awkward
since food and liquids may escape into the nasal
cavity and out the nose; the nasal mucous mem-
branes become desiccated upon abnormal expo-
sure to the oral environment; nasal and sinus
secretions collect in the defect area and may be
difficult to control; and facial disfigurement can
result from lack of midface bony support or
facial nerve weakness. In some cases, tumor
invasion requires exenteration of the orbital
contents.
Rehabilitation after resection of the hard or
soft palate is best accomplished prosthodon-
tically. Customarily, a temporary prosthesis
known as an immediate surgical obturator is
placed at the time of surgery. During the healing
period, this prosthesis is relined periodically
with temporary denture reliners to compensate
for tissue changes secondary to organization
and contracture of the wound. When the defect
becomes well healed and dimensionally stable
(usually 3-4 months after surgery), the defini-
tive prothesis is fabricated.
Compromised retention, stability, and sup-
port are the main problems in fabricating a use-
ful obturator prosthesis. The remaining teeth,
therefore, become extremely valuable in provid-
ing support and retention for these restorations.
The purpose of these prostheses is to restore the
physical separation between the oral and nasal
cavities, thereby restoring speech and swallow-
ing to normal as well as providing support for
the lip and cheek.
TREATMENT
It is essential that the prosthodontist examine
and consult with the patient before surgery (see
chapter 15). The sequence of treatment should
be explained to the patient, and diagnostic casts
and appropriate roentgenograms should be
obtained. With this information, the prosth-
odontist is ready to consult with the surgeon
about the design and fabrication of the surgical
obturator. Modifications in the surgical plan
that may improve the prosthetic prognosis, but
will not adversely affect tumor removal, should
be discussed at this time. The surgeon can im-
prove the prosthetic prognosis by considering
the following modifications:
1. A split-thickness skin graft should be used to
line the cheek flap surface of the defect. The
skin graft provides a keratinized surface to
FIGURE 23-1. Skin graft lining the lateral wall of
radical maxillectomy defect.
support the prosthesis and forms a scar band
at the junction of the skin graft and oral
mucosa that can be engaged prosthetically to
improve retention, stability, and support
(figure 23-1).
2. If the surgeon can preserve some of the
palatal mucosa normally included in the pa-
latal resection, and reflect this tissue during
the bony resection of the palate, it can later
be used to cover the medial cut margin of the
palatal bone. If this palatal margin of the de-
fect is covered with keratinized mucosa, the
prosthesis may engage this surface more com-
pletely, thus improving its lateral stability.
3. An attempt should be made to save as much
of the maxilla as possible, consistent with
tumor control. The more palatal shelf area
that remains, the more support will be pro-
vided for an obturator prosthesis.
4. The transalveolar bony resection should be
made as far as feasible from the tooth adjacent
to the proposed defect. This practice results
in higher levels of bone around this tooth,
making it more suitable as a partial denture
abutment.
5. If the soft palate does not retain the ability to
effect palatopharyngeal closure, it should be
resected. If a posterior, nonfunctioning band
of soft palate remains after surgery, it often
prevents proper placement of the palato-
pharyngeal obturator (figure 23-2).
SURGICAL OBTURATION
Immediate coverage of a palatal defect with a
surgical obturator will greatly simplify the pa-
 23. PROSTHETIC MANAGEMENT
FIGURE 23-2. Nonfunctional posterior band of soft
palate prevents optimal placement of pharyngeal
obturator. From Beumer et al. (1979).
tienr's postoperative course. The obturator pro-
vides a matrix upon which the surgical packing
can be placed, minimizes contamination of the
wound in the immediate postoperative period,
and enables the patient to speak and swallow
effectively immediately after surgery. The sur-
gical obturator is useful in both dentulous and
edentulous patients.
Fabrication of this prosthesis is simple. An
irreversible hydrocolloid impression is obtained
of the maxillary arch and the anterior portion of
the soft palate, and the cast is retrieved. The
obturator's size is determined by the surgical
boundaries of the resection, as indicated by the
surgeon. In the dentulous patient, teeth in the
path of the surgical resection are removed from
the cast (figure 23-3). Care should be taken to
extend the surgical obturator posteriorly past
the proposed posterior soft palatal resection line
to seal off the defect effectively. The prosthe-
sis is processed in autopolymerizing methyl
methacrylate. It can be altered at surgery by
trimming the resin or by adding a temporary
denture reliner. The prosthesis is wired to re-
maining teeth, alveolar ridge, or other available
structures (zygomatic arch, anterior nasal spine,
etc.) (figure 23-3c).
455
After the surgical packing is removed (8-10
days after surgery), the prosthesis is relined
with a temporary denture reliner. As healing
progresses, the obturator is periodically relined
and extended further into the defect; 3-4
months after surgery, and after initial wound
contracture is complete, the definitive pros-
thesis is begun. Edentulous patients with max-
illary defects often require a longer period of
healing because the defect must be engaged
more aggressively so as to maximize stability,
support, and retention.
DEFINITIVE OBTURATOR PROSTHESIS
Defects of the hard palate are restored most
effectively with a prosthesis. Surgical recon-
struction is usually neither possible nor desir-
able after resection in this region. If teeth are
present, they greatly improve denture retention
and stability. Speech, swallowing, mastication,
and facial contour can be restored with prop-
er extensions and obturation. The obturator
should extend maximally along the lateral wall
of the defect (figure 23-4). This high lateral ex-
tension improves retention and lateral stability
and provides support for the lip and cheek. The
movement of the coronoid process into the dis-
tolateral area of the defect must be accounted
for during border molding and final impression
procedures. The extension superiorly along the
medial margin of the defect should not exceed
456 V. SUPPORTIVE CARE

A B

FIGURE 23~3. (A) Margins of proposed surgical resection outlined appropriately for fabrication of immediate
surgical obturator. Teeth included in resection are removed and alveolar ridge area reduced modestly laterally
and distolaterally. Vestibular depth on side of resection determines superior extension. (B) Interproximal exten-
sions of completed immediate surgical obturator are perforated to facilitate retention at surgery. (C) Immediate
surgical obturator in position and retained to remaining teeth and palate with wire ligation. Note that Weber-
Fergusson surgical approach was used. Tension on cheek flap is adjusted before prosthesis was retained and
defect packed with gauze.
 23. PROSTHETIC MANAGEMENT 457

LATERAL WALL
OF DEFECT

JUNCTION OF
SKIN GRAFT
AND MUCOSA

FIGURE 23-4. Definitive obturator prosthesis. (A)

Diagrammatic frontal section of a radical maxil-
lectomy with obturator prosthesis in position. (B)
Typical obturator of methyl methacrylate resin.
From Beumer et ai. (1979).

FIGURE 23-5. Facial contours (A) without obturator

prosthesis, and (B) with obturator prosthesis. Note
improved contours of left cheek area. Patient is also
wearing an orbital prosthesis.
458 V. SUPPORTIVE CARE

the level of the repositioned palatal mucosa; if it

does, it provides little benefit and may result in
unnecessary and painful ulceration of the res-
piratory mucosa lining the nasal septum. In
selected edentulous patients, extension onto the
nasal surface of the soft palate posteriorly or
into the nasal aperture anteriorly may improve
retention.
When the prosthesis is completed, speech
and swallowing are within normal limits and
appearance is greatly improved (figure 23-5).
The patient should be recalled periodically for
adjustments and examination for recurrent dis-
ease. Most prostheses require relining within
the first year because of slow but continuous
tissue changes on the periphery of the surgical
defect.

DEFINITIVE SOFT-PALATE PROSTHESIS

Defects of the soft palate require different and
more complex prosthetic treatment. Palato-
pharyngeal closure normally occurs when the
soft palate elevates and contacts the contract-
ing lateral and posterior pharyngeal walls of
the nasopharynx. When a portion of the soft
palate is excised or when the soft palate is perfo-
rated, scarred, or neurologically impaired, com-
plete palatopharyngeal closure may not occur.
Speech becomes hypernasal and normal swal-
lowing is not possible. With a pharyngeal
obturator, the patient may be able to reestablish
palatofharyngeal closure if the peripheral por-
tion 0 the muscular palatopharyngeal mechan-
ism still exhibits normal movements (figure
23-6). The obturator must not interfere with
respiration, impinge upon soft tissues during
postural movements, or hamper the tongue
during swallowing and speech.
The soft-palate obturator remains in a fixed
position in the nasopharynx and does not
attempt to duplicate normal movements of the
soft palate. The inferior surface of the obturator
remains level with the hard-palate contour,
which in most patients is at approximately the FIGURE 23-6. Definitive soft-palate prosthesis. (A)
level of the anterior tubercle of the atlas. The Lateral soft-palate defect after resection of squamous
inferior margin of the posterior surface of the cell carcinoma of anterior tonsillar pillar and soft
palate. Residual palatopharyngeal mechanism on the
obturator contacts Passavant's pad, if present, right side continues to function. (B) Pharyngeal
and extends approximately 10 mm superiorly obturator attached to denture. (C) Obturator in
into the nasopharynx. During respiration and position. During palatopharygeal closure, the resid-
the production of nasal speech sounds, the space ual soft palate elevates and contacts the medial
around the obturator reflects the potential for margin of the obturator.
muscular contraction. During swallowing and
the production of oral speech sounds, this
sphincteric muscular network moves into con-
 23. PROSTHETIC MANAGEMENT 459

tact with the stationary acrylic resin obturator,

establishing palatopharyngeal closure. A cor-
rectly designed and fabricated obturator will
usually result in the return of normal speech and
swallowing for patients with acquired soft-
palate defects. However, there are instances
when speech therapy can help correct dis-
tortions associated with articulation that are
not adequately corrected by the obturator
prosthesis.

Mandibular Defects
The management of malignant tumors associ- FIGURE 23-7. Tongue sutured to buccal mucosa.
ated with the tongue, the mandible, and adja-
cent structures represents a difficult challenge
for the surgeon, the radiation oncologist, and large portions of the tongue prevents appropri-
the prosthodontist, in regards to control of the ate "valving" (closure) and/or interaction with
primary disease and to rehabilitation after treat- other oral structures. This loss, combined with
ment. The most common intraoral sites for the loss of motor and sensory innervation plus
squamous cell carcinoma are the lateral margin impaired mobility, leads to misarticulation of
of the tongue and the floor of the mouth. Both many speech sounds. Other articulators such as
locations predispose the mandible to the inva- the lower lip may also be affected. Deglutition is
sion of tumor, often necessitating its resection less impaired, and most patients learn to swal-
along with large portions of the tongue, the low effectively. The degree to which mastication
floor of the mouth, and the regional lymphatics. is affected depends on the amount of mandible
removed as well as the status of tongue func-
DISABILITIES tion. If much of the mandible is segmented and
Disabilities resulting from such resections in- removed, the remaining functional mandibular
clude impaired speech articulation, difficulty in segment(s) will be retruded and deviated
swallowing, deviation of the mandible during toward the surgical site at the vertical dimen-
functional movements, and poor control of sion of rest. When the mouth is opened this
salivary secretions. There is also severe cosmetic deviation increases, leading to an angular path
disfigurement. These patients present a far more of opening and closing. In addition, loss of the
difficult rehabilitation problem than do patients proprioceptive sense of occlusion leads to un-
with maxillary surgical defects. It is usually not
possible to restore function in patients after
mandibular resection, and permanent cosmetic
disfigurement is inevitable. Consequently these
patients experience many frustrations, and
few return to presurgical levels of social func-
tion. Rehabilitation frequently requires the co-
ordinated efforts of several disciplines, includ-
ing social service, psychiatry, prosthodontics,
surgery, speech therapy, and dietetics.
Advanced tumors of the anterior two-thirds -_ROTATION
POINT
of the tongue and floor of mouth often require
extensive resection of bone and soft tissue. The
degree of speech impairment after such resec-
tions depends on the extent to which tongue
function is affected. In most of these lesions,
large amounts of the tongue are resected and
what remains is often used for primary closure FIGURE 23-8. Diagrammatic representation of frontal
of the surgical wound (figure 23-7). The loss of plane rotation. From Beumer et al. (1979).
460 V. SUPPORTIVE CARE
coordinated, less precise movement of the
mandible. Loss of attachment of the muscles
of mastication on the surgical side also makes
the mandible rotate upon forceful closure.
Viewed from the frontal plane, teeth in the
mandible on the surgical side move away from
their opposing maxillary teeth after initial
contact has been made on the nonsurgical side
and as the force of closure is increased (figure
23-8). These factors, combined with impaired
tongue function, may prevent effective masti-
cation in some patients. The severity and per-
manence of mandibular deviation vary, depend-
ing on a number of complex .factors. Some
patients soon attain an acceptable interocclusal
relationship without adjunctive therapy, while
others are never able to do so.
Control of saliva is adversely affected by most
resections of the tongue and mandible. These
resections often obliterate portions of the lin-
gual and buccal sulci, so there no longer exists a
means of collecting and channeling secretions
posteriorly. Also, the motor and sensory in-
nervation of the lower lip on the resected side is
often lost, impairing oral competency and pre-
venting the patient from detecting secretions
escaping from the mouth. Impaired tongue con-
trol and mobility and drooping of the corner of
the mouth on the defect side also contribute to
poor saliva control.
When removal of tumors in the anterior floor
of mouth requires that the mandible be resected
anteriorly, the disabilities are very severe unless
mandibular continuity is restored at the time of
initial tumor resection. If it is not restored, the
two remaining posterior fragments are pulled
medially by the residual mylohyoid muscles and
superiorly by the muscles of mastication. This
displacement of the mandibular remnants
severely disfigures the face, prevents intercuspa-
tion of teeth in dentulous patients, and pre-
cludes use of partial or complete dentures. In
addition, with its anterior mandibular attach-
ment lost, the tongue retrudes posteriorly and
may occlude the oral airway. Many of these dif-
ficulties are partially alleviated if the missing
portion of the mandible is reflaced with an allo-
plastic implant at the time 0 resection, thereby
maintaining mandibular continuity. The intrin-
sic and extrinsic muscles of the tongue may be
sutured to the implant, ensuring a more anterior
tongue position and less risk of airway obstruc-
tion. Such implants result in little distortion of
the tissue bed and allow for easy visualization
and recognition of recurrent disease.
The nature and degree of the disabilities
secondary to impaired tongue function after re-
section of lesions in the anterior floor of the
mouth are proportional to the amount of tissue
resected and to the nature of surgical closure
(figure 23-9). In most cases, motor control is
usually unimpaired and the functional deficits
depend on the degree of tongue mobility. The
resection of primary tumor and the required
oral closure, however, often lead to excessive
drooling. Sensory and motor innervation of the
lower lip may be bilaterally impaired, affecting
oral competency and precluding saliva control
in some patients.
In tumors confined within the mandible or
to the alveolar ridge, resection of the primary
tumor results in only minimal loss of soft tissue,
and the resulting disabilities are less severe. A
simple marginal resection that retains bony con-
tinuity results in little morbidity other than
alteration of sulci and denture-bearing surfaces.
In discontinuity defects, some deviation of the
mandible results from scar contracture and
muscle imbalances. Tongue function, however,
is rarely affected. In these lesions, the tongue
may be used for closure of the surgical wound,
but little of the tongue is resected and the
hypoglossal nerve on the resected side remains
intact. With normal bulk and unimpaired motor
control, the slight loss of tongue mobility
secondary to surgical closure does not seriously
affect saliva control, speech, or swallowing. If
FIGURE 23-9. Tongue sutured to labial mucosa to
close the wound after anterior mandibular resection.
From Beumer et aI. (1979).
 23. PROSTHETIC MANAGEMENT
FIGURE 23-10. Tongue release and vestibuloplasty.
These procedures improve tongue mobility and per-
mit construction of dentures. A split-thickness skin
graft was placed at surgery to line the new vestibule
and raw surface of the tongue. From Beumer et al.
(1979).
control of saliva is affected, it is primarily due to
impaired innervation of the lower lip on the re-
sected side, resulting from the radical neck dis-
section. Mandibular deviation is less profound
than that seen in resections resulting in more
extensive soft-tissue loss.
SECONDARY SURGICAL PROCEDURES
Vestibuloplasty, Tongue Release, and Skin
Grafts. Vestibuloplasty and tongue release are
of particular value when mandibular continuity
has been maintained or restored. The creation of
vestibules enables the patient to pool saliva
more efficiently and allows for extension of
denture flanges (figure 23-10). Creation of an
attached keratinized mucosa on the ridge sur-
face with either a skin graft or a palatal graft
improves stability, support, and retention of
a partial or complete denture. The patient's
appearance may also be improved, because a
prosthodontic restoration can now be molded
to provide contour and support for the lower
lip and cheek portions of the resected area. Im-
provement of speech is less noticeable, except
in patients with anterior soft-tissue defects. In
these patients, the motor and sensory innerva-
tions of the tongue are usually intact and the
tongue dysfunctions result from its immobility.
Tongue release and vestibuloplasty may aid
selected patients with unrestored mandibular
discontinuity defects.
461
MANDIBULAR GUIDANCE RESTORATIONS
If mandibular continuity is not restored, there
are a number of methods that will reduce the
degreee of mandibular deviation. These include
intermaxillary fixation, mandibular-based guid-
ance restorations, and palatally based guidance
restorations. The methods of choice depend on
many factors and should be combined with a
well-organized mandibular exercise regime [1-
3].
An old approach that has received some at-
tention recently is to place the patient im-
mediately into intermaxillary fixation, using
arch bars and elastics, and to maintain fixation
for 5-7 weeks after surgery. Although no con-
trolled studies have been performed to evaluate
this approach, some clinicians feel that it is
beneficial [4]. It appears most useful in patients
with resections confined to the mandible with
little associated soft-tissue loss. In these pa-
tients, scar contracture is minimal and, since
ample soft tissue is available for surgical closure,
mandibular deviation is actually due to muscle
imbalances and impaired proprioception. Using
intermaxillary fixation in these patients main-
tains the proprioceptive sense of occlusion and
enables most patients to assume appropriate in-
tercuspal positions after fixation is removed.
If intermaxillary fixation is not employed, the
patient should be placed on an exercise program
as early as possible after surgery. Upon max-
imum opening, the mandible is displaced by
hand as forcefully as possible toward the non-
surgical side. These movements tend to lessen
scar contracture, reduce trismus, and improve
maxillo/mandibular relationships. Exercises
should be carefully demonstrated to the
patient and notes made periodically to record
the degree of progress.
The earlier mandibular guidance therapy is
initiated, the more successful the result. If the
patient has undergone an extensive bony and
soft-tissue resection, a classic radical neck dis-
section, and radiation therapy, and if a consider-
able period of time has elapsed since the surgical
procedure, guidance procedures are more dif-
ficult and a faulty occlusal relationship may re-
sult. Unfortunately, those patients suffering the
most severe deviations of the mandible because
of extensive soft-tissue loss, tight wound clo-
sure, radiation therapy, and/or a classic radical
neck dissection are most susceptible to those
complications (fistula formation, flap necrosis,
and other postsurgical morbidities) that delay
462 V. SUPPORTIVE CARE

c
 23. PROSTHETIC MANAGEMENT
the beginning of mandibular guidance therapy.
If the mandible can be manipulated into an
acceptable maxillo/mandibular relationship, a
cast mandibular resection prosthesis [5] is
appropriate. This prosthesis consists of a re-
movable partial denture framework with a metal
flange extending 7-10 mm laterally and supe-
riorly on the buccal aspect of the bicuspids and
molars on the unresected side. This flange en-
gages the maxillary teeth during mandibular
closure, thereby directing the mandible into an
appropriate intercuspal position. The partial
denture framework must be stable and retentive
to counteract the lateral forces generated on the
flange during closure. The guidance flange is
constructed of cast chrome-cobalt metal, and
modifications are made with acrylic resin.
A second design confines the guidance ramp
and index to a maxillary prosthesis. This form
of guidance prosthesis is indicated for patients
whose severe deviation prevents manipulation
of the mandible into any form of acceptable
occlusal contact. Maxillary guidance ramps are
more adjustable than mandibular guidance
ramps. They are usually constructed of acrylic
resin with either cast or wrought-wire retainers,
since they usually serve only temporarily until
an acceptable occlusion can be established
(figure 23-11).
The success of mandibular guidance therapy
depends upon the nature of the surgical defect,
early initiation of guidance therapy, coopera-
tion of the patient, and other factors. Patients
with extensive posterior base-of-tongue lesions
requiring significant soft-tissue resection and
radiation therapy are often unable to achieve
useful intercuspal relationships. Mandibular
guidance therapy is most successful when the
resection involves bony structures only, with
minimal sacrifice of tongue, floor of mouth, and
adjacent soft tissues. The prognosis for man-
dibular guidance therapy is also improved when
FIGURE 23-11. Maxillary guidance prosthesis. (A)
Severity of mandibular deviation did not permit
establishment of appropriate maxillo/mandibular re-
lationships with guidance ramp. (B) When ramp was
formulated and delivered, mandibular teeth occluded
lingual to the desired position. (C) As scar contracture
loosened, ramp was adjusted so that patient achieved
an adequate interocclusal relationship. From Beumer
et al. (1979).
463
patients have not had a radical neck dissection
or have not been irradiated.
DEFINITIVE PROSTHESES
The prosthetic prognosis of removable pros-
theses for patients with resections of the tongue
and mandible is variable. In some patients, only
appearance can be improved while, in others,
mastication is a reasonable objective. In patients
with mandibular defects, placement of the de-
finitive prosthesis is not as urgent and the pros-
thetic prognosis not as favorable as in patients
with maxillary defects.
Partial Dentures. The usual principles of
partial denture design and fabrication should be
followed. Major connectors should be rigid,
occlusal rests must direct occlusal forces along
the long axes of teeth, guiding planes should be
employed to increase stability and bracing, re-
tention mu~t be within the limits of physiologic
tolerance of the periodontal ligament, and max-
imum support should be gained from the adja-
cent soft tissues. Retainers, minor connectors,
and proximal plates should be designed so that
they do not subject the remaining teeth to
excessive lateral forces during function. The
design should also consider the need for clean-
sibility, in view of the problems head and neck
cancer patients have in maintaining oral hygiene
and controlling plaque.
In patients with lateral discontinuity defects,
it may not be possible to design a framework
with retainers that disengage during function
because of the altered patterns of force upon the
prosthesis. Viewed from the frontal plane, the
arc of closure of the mandible is angular rather
than vertical, with unilateral forces of occlusion
confined to the nonresected side. Rotation of
the mandible in the frontal plane causes the re-
sected side to drop down out of occlusion as the
force of contracture on the unresected side is in-
creased. The location of the fulcrum line of a
partial denture is not easily determined because
of the difficulty in predicting movement pat-
terns of the prosthesis during function. A sug-
gested partial denture design for a typical
lateral mandibulectomy defect is shown in
figure 23-12. The forces of occlusion are un-
ilateral, so the axis of rotation (fulcrum line) of
the partial denture deviates from the norm. By
placing the occlusal rest on the mesial of the
bicuspid, it is possible to place a retainer on the
bicuspid that disengages during expression of an
464 V. SUPPORTIVE CARE
OCClUSAL VIEW
A
Fulcrum
l i n c - ....'
Anterior
BUCCAL VIEW
Occlusal rests
- - - - - - - ; ; ; . - - - A"is of rotation
FIGURE 23-12. Suggested design for partial denture.
(A) Occlusal view. (B) Buccal view. "I" bar retainer
on left side disengages with occlusal pressure. Similar
retainer on right side is placed at height of contour to
avoid applying torque to this abutment. From Beum-
er et al. (1979).
occlusal load. However, a retainer cannot be
positioned in a retentive area on the opposite
cuspid, which disengages during occlusal func-
tion. Consequently, this retainer either must be
placed on the height of contour or must be flexi-
ble enough that an occlusal load will not expose
the cuspid to undue pathologic stress. All partial
denture frameworks should be physiologically
adjusted with rouge and chloroform or a similar
medium.
After the partial denture casting has been
...
Occlusal load
Postenor
fabricated, verified, and adjusted, an altered cast
impression is obtained of the edentulous areas.
Particular attention should be paid to the lingual
extension on the unresected side, especially the
polished surfaces. This extension, when suitably
developed, provides additional retention and
stability. Maximum extension of the denture
base is always attempted. Coverage of the buc-
cal shelf on the unresected side is essential to
maximize support. Centric relation records are
made and occlusal schemes developed that are
consistent with the unilateral mandibular move-
ment patterns of mandibulectomy patients. The
partial denture prostheses are delivered, ad-
justed, and periodically monitored in the usual
way.
 23. PROSTHETIC MANAGEMENT
A
FIGURE 23-13. Prosthetic restoration of a nasal
defect. (A) Postrhinectomy defect secondary to a
recurrent squamous carcinoma of skin. (B) Nasal
prosthesis in position.
Complete Dentures. Edentulous patients with
lateral discontinuity defects of the mandible
have little hope of ever being able to masticate
as efficiently as before surgery, but complete
dentures may improve their saliva control, ap-
pearance and, in some cases, their ability to
articulate certain speech sounds. A number of
factors affect the patient's ability to function
with complete dentures:
1. With only one-half or two-thirds of the
mandible remaining, stability, support, and
retention of the mandibular denture are com-
promised.
2. Since most patients will have received radia-
tion therapy either before or after surgery,
the oral mucosa is atrophic and fragile, pre-
disposing it to soft-tissue irritation. Chronic
alcohol abuse and/or poor nutrition may
further compromise the health of oral mu-
cous membranes. The diminished output and
465
B
thick, mucinous nature of the saliva that re-
mains after radiation impair retention; the
saliva is inadequate to lubricate the denture-
mucosal intersurface.
3. The angular pathway of mandibular closure
induces lateral forces upon the dentures that
tend to dislodge them.
4. The deviation of the mandible creates abnor-
mal maxillo/mandibular relationships that
may prevent ideal placement of the denture
teeth over their supporting structures.
5. The impairment of motor and/or sensory
control of the tongue, lip, and cheek limits
the ability of the patient to control dentures
during function. The integrated neuromuscu-
lar balance between tongue, lips, and cheeks
that serves to stabilize complete mandibular
dentures in normal patients is disrupted in pa-
tients with mandibular discontinuity defects.
6. Unilateral forces of occlusion tend to tip and
dislodge both maxillary and mandibular
dentures during function.
The prosthetic prognosis depends on many
complex factors, including amount of mandibu-
466 V. SUPPORTIVE CARE
lar deviation, character of mandibular move-
ments, postsurgical lip posture and control,
tongue control and mobility, and previous
radiation therapy. The status of the remaining
tongue is probably the most important prog-
nostic factor. If motor and/or sensory control
has been significantly impaired, the prosthetic
prognosis becomes extremely guarded. The
mobility of the tongue is less important. If the
patient can move his tongue in several direc-
tions, he will probably be able to stablilize the
mandibular denture during function. Obvious-
ly, patients who have lost significant amounts of
tongue in combination with resection of one of
the hypoglossal nerves, accompanied by con-
siderable local paresthesia, have the worst pros-
thetic prognosis. Paradoxically, immobility of
the tongue creates a minor anatomic advantage
in that it often permits a more aggressive exten-
sion of the lingual flange on the nonsurgical
side, thus facilitating stability and retention. As
in normal patients, the position of the tongue is
also an important prosthodontic prognostica-
tor. Resection of a base-of-tongue lesion often
results in a retruded tongue position, making it
difficult to obtain peripheral seal. More lateral
and anterior resections of the mandible and
t?ngue often leave it in a more favorable posi-
tion.
Impressions are developed using convention-
al prosthodontic principles and techniques.
Centric and lateral registrations and occlusal
schemes should take into consideration the
altered pattern of mandibular movements. De-
livery and follow-up are accomplished in the
usual way. Denture extensions can be verified
with a disclosing wax and excessive tissue dis-
placement eliminated with the aid of pressure-
indicating paste. These patients require con-
tinued encouragement and support during the
prolonged adjustment period to help them
adapt to their new prosthesis.
Facial Defects
Restoration of facial defects is a difficult chal-
lenge for both the surgeon and the prosthodon-
tist. Surgical reconstruction and prosthodontic
restoration both have distinct limitations. The
surgeon is limited by the availability of tissue,
the damage to the local vascular bed in tumor
patients, the need for periodic visual inspection
of an oncologic defect, and the physical condi-
tion of the patient. The prosthodontist is limited
by movable tissue beds, the difficulty in retain-
ing large prostheses, and the patient's willing-
ness to accept the result. Whatever the mode of
rehabilitation, the patient should be fully in-
formed of future problems and of the expected
quality of the final result. In patients with ex-
tensive facial tumors requiring resection, the
method of facial restoration should be con-
sidered before surgery. The patient should be
involved in this discussion and should partici-
pate in the decision-making process. A well-
informed patient with realistic expectations is
the objective to be achieved prior to surgical
resection of large facial tumors.
SURGICAL RECONSTRUCTION VERSUS
PROSTHETIC RESTORATION
The choice of surgical reconstruction versus
prosthetic restoration of large facial defects is
difficult, complex, and depends on the size and
etiology of the defect as well as the wishes of the
patient. Surgical reconstruction of small facial
defects is possible in most cases and is usually
preferable. Many patients prefer masking a de-
fect with their own tissue rather than with a
prosthetic restoration. It is safe to assert that it
is difficult or impossible for the surgeon to
fabricate a facial part that has the appearance of
a well-made prosthesis. However, acceptance of
an artificial part is not universal, and many
would rather have a permanent, even less es-
thetic, nose or ear. In general, younger pa-
tients prefer to have a permanent reconstructed
facial part rather than an artificial one.
The group who are most often candidates for
prostheses are the elderly with neoplasms that
have been extirpated. Advanced or recurrent
tumors of the lips and skin of the face, although
often benign in behavior, may require aggres-
sive surgical removal for control. These lesions
result in extensive loss of facial structure, in-
cluding portions of the nose, upper lip, cheek
and orbital contents, and ear, sometimes in
combination with oral structures such as the
teeth and portions of the maxilla, mandible, and
buccal mucosa. In large oncologic defects, re-
construction is difficult and the final cosmetic
and functional results are often limited and un-
predictable.
A variety of circumstances may dictate pros-
thetic restoration of large facial defects:
1. When a large resection is necessary and re-
currence of tumor likely, it is advantageous to
 23. PROSTHETIC MANAGEMENT
A B
FIGURE 23-14. Prosthetic restoration of a midface de-
fect. (A) Large midfacial defect secondary to removal
of extensive tumor. (B) Prosthesis in position.
be able to monitor the surgical site closely. A
prosthesis permits this observation, whereas
primary surgical reconstruction may make it
impossible.
2. Surgical restoration of large defects is tech-
nically difficult and requires multiple proce-
dures and hospitalizations. The group usually
confronted with this type of defect is general-
ly older and unable or unwilling to tolerate
the multiple procedures required for surgical
reconstruction.
3. Increasing numbers of these types of tumors
are being treated with radiation. Reduced vas-
cularity, increased fibrosis, and scarring of
tissue beds bordering the defect increase the
risk of complications associated with recon-
struction. In many patients, full-course radia-
tion therapy precludes successful surgical re-
construction.
Even when surgical reconstruction is deemed
possible, significant delay may be necessary to
467
ensure control of the tumor. Most surgeons
prefer to wait at least one year after a large re-
section before beginning surgical reconstruction
of a facial defect that results from removal of a
malignant tumor.
PROSTHETIC FACIAL RESTORATIONS
The challenge to the prosthodontist is to fabri-
cate an esthetically pleasing restoration (figure
23-13). A conspicuous prosthesis may produce
more anxiety and permit less social readjust-
ment than a simple facial bandage or eye patch.
Since successful use of the restoration may de-
pend upon the patient's psychological accep-
tance of it, it is beneficial to have the patient seen
by a social worker during rehabilitation period.
The most critical period occurs during the first
2-3 days after delivery of the prosthesis. The
conflicting emotional responses of the patient
should be anticipated and discussed before de-
livery. In some cases, a patient will not wear, a
facial prosthesis because of unrealistic expecta-
tions. Since all facial restorations are detectable
under close scrutiny, the patient must under-
stand that the prosthesis has two different roles.
468 V. SUPPORTIVE CARE
For family, close friends, or business associates,
it can cosmetically replace the tissues excised.
For the public at large, however, it generally
provides enough concealment to render the re-
constructed defect inconspicuous.
MATERIALS USED FOR FACIAL PROSTHESES
A number of materials have been used for facial
prostheses: wood, wax, metals, and, in recent
times, polymers. Current materials exhibit some
excellent properties, but also some frustrating
deficiencies, and all possess some undesirable
characteristics. The materials most often used
today include the acrylic resins, polyurethane
elastomers, and silicone elastomers. The acrylic
resins are used as temporary or interim prosthe-
ses. During the initial phases of healing, they
can be relined or adjusted to suit the changing
configuration of the defect. The polyurethanes
and the silicones are most commonly employed
for the definitive restoration. These latter two
materials are elastic, and easily processed and
colored, but unfortunately are not color stable.
A new silicone, MDX-4-4210, has been intro-
duced, however, whose color stability has been
extended. A prosthesis of this material remains
acceptable for up to one year, whereas the poly-
urethane prostheses are only useful for approx-
imately three months.
RETENTION
A variety of retention systems have been em-
ployed to keep facial prostheses in position.
Biphase tape is useful in rigid materials and in
patients in whom the defect demonstrates little
or no movement. Most facial prostheses are
retained with medical-grade adhesive. A great
number are available and selection depends
upon patient tolerance, ease of application and
removal, and compatibility with the material
used for facial prosthesis. Acrylic resin pros-
theses, particularly those restoring orbital
defects, can be connected to an eyeglass frame.
While the details concerning fabrication of
facial prostheses are beyond the scope of this
review, a few basic principles should be men-
tioned. A presurgical moulage can be very help-
ful, especially if a total rhinectomy or auric-
ulectomy is anticipated. Impressions of the
defect are usually obtained with elastic impres-
sion materials, taking care not to displace the
tissues of the defect. The contours of the pros-
thesis are sculpted in wax, both on the cast and on
the patient. Surface characteristics, appropriate
contour, coloration, and margin placement are
equally important factors to be considered. Pro-
cessing the materials used in facial restoration is
complicated and requires special instrumenta-
tion. Special large flasks are necessary for pro-
cessing large prostheses.
COLORATION
Coloration of the prosthesis varies with the
materials used and the preference of the clini-
cian. Basic skin tones should be developed into
a shade guide for each material. The base shade
selected for a patient should be slightly lighter
than the lightest skin tones of the patient, be-
cause as color is added the prosthesis will
darken. Color may be applied either intrinsical-
ly or extrinsically. Intrinsic coloration is longer-
lasting and is therefore preferred, but is more
difficult to accomplish than extrinsic coloration.
COMBINATION ORAL AND
FACIAL DEFECTS
Large combination defects of the oral cavity and
the external face create innumerable problems
for the patient and the prosthodontist. When
the integrity of the oral cavity has been de-
stroyed, food and air escape during swallowing,
speech is unintelligible, and saliva control is
difficult. It is necessary, but extremely difficult,
to adapt the margins of the prosthesis so that
tissue contact will be maintained during facial
and mandibular movements. Successful adjust-
ment depends on the patient's having a realistic
understanding of the degree of potential reha-
bilitation afforded by the future restoration.
Surgical reconstruction is usually not consid-
ered in large defects because of their size, pre-
vious radiation therapy, and the probability of
recurrence. Retention of maxillary teeth or a
portion of the hard palate improves the pros-
thetic prognosis. Surgical modifications such as
skin- grafts to decrease tissue contraction and
creation of undercut areas for retention improve
the prosthetic prognosis.
Patients will experience less depression if as
many functions as possible are restored im-
mediately after surgery with a temporary
prosthesis. These functions include the ability
to swallow food (thereby eliminating the need
for a nasogastric tube), the ability to control
saliva, and the ability to speak intelligibly. The
temporary prosthesis is constructed of acrylic
resin and/or silicone, and formed so that contact
is established with healthy tissues adjacent to
 23. PROSTHETIC MANAGEMENT
the defect. Functional contact with the remain-
ing portions of the lips allows the patient to
seal the oral cavity effectively. Tissue-bearing
surfaces of the prosthesis are relined with tem-
porary denture reliner at frequent intervals to
accommodate for tissue changes.
In constructing a definitive midface pros-
thesis, a custom tray is used for the master
impression. Movable portions of the defect are
recorded with a thermoplastic material. Record
bases are fabricated and centric relation records
enable casts to be mounted on an articulator.
Eyeglass frames, adhesives, straps, teeth, and en-
gagement of defect undercut suppy retention.
The finished restoration usually provides the
patient with acceptable appearance and function
(figure 23-14).
Radiation Therapy
RISK FACTORS
The histopathologic changes in the oral mucous
membranes and bone and the changes in the
amount, physical properties, and biologic effec-
tiveness of saliva have caused some radiothera-
pists and dentists to be uncertain whether ir-
radiated patients should ever wear partial or
complete dentures. Recent studies reveal, how-
ever, that the risk of developing an osteoradio-
necrosis is minimal in patients who had been
edentulous for some time before radiation ther-
apy. A recent study [6] found that no bone
exposures developed in 92 such patients who
received complete maxillary and mandibular
dentures and in whom a portion of the bearing
surface was within the radiation field. In 87 of
these patients, the bearing surface of the man-
dibular denture was within the radiation field.
The risk of bone necrosis is significant, how-
ever, in those patients who have had teeth re-
moved just before or after radiotherapy. In
the same report, three cases of bone necrosis
attributed to dentures developed (all in extrac-
tion sites) in a group of 36 patients rendered
edentulous by preradiation or postradiation
extractions. All three healed within six months
without surgical intervention.
The recent literature reveals few cases of bone
necrosis associated with dentures leading to re-
section of the mandible. Investigators in Texas
[7] reported five cases of osteoradionecrosis
among 82 patients receiving intraoral prostheses
after radiotherapy to the head and neck region;
469
64 patients received complete dentures and 18
received removable partial dentures. Four
healed by conservative treatment and one was
still unhealed at publication. It was not stated
whether these cases were related to recent ex-
traction.
PLACEMENT OF DENTURES-TIMING
Some controversy exists as to when dentures
can be safely constructed for irradiated patients
who have completed therapy. Recommended
insertion times have ranged from one to three
years after surgery [8-10]. The University of
California study [6] sheds some light on this
clinical dilemma. In 92 patients who were eden-
tulous before onset of disease (87 of whom re-
ported previous experience with complete den-
tures), prostheses were inserted on the average
of 15.4 months after radiation was completed.
Eliminating nine patients who waited longer
than 50 months from the end of therapy to de-
livery reduces the average to 8.9 months. There
were 45 patients received dentures within six
months after radiation therapy. None in the
group of 92 developed an osteoradionecrosis
associated with the use of their dentures.
Those patients who had teeth extracted in
conjunction with radical alveolectomies before
radiotherapy seem to need a more conservative
approach. In the same report, 23 such patients
received dentures on the average of 22.2 months
after completion of therapy. Two bone necroses
developed in this group.
The efficacy of the alveolectomies and the
status of the residual ridge are also important
clinical factors to appraise. An irregular man-
dibular ridge in which the entire body of the
mandible was within the radiation field may
prompt the clinician to defer dentures indef-
initely. On the other hand, a smooth, well-con-
toured mandibular-bearing surface may permit
the clinician to insert dentures soon after
therapy.
As to the question of when dentures should
be placed for the irradiated patient, the data dif-
fer for those who were edentulous and experi-
enced denture wearers before therapy and those
who have had teeth extracted within the field
just before therapy and who are not experienced
denture wearers. The former have little risk of
developing significant complications from den-
ture wear, and it seems justified in most in-
stances to place dentures in these patients 6-12
months after radiation therapy. In the latter
470 V. SUPPORTIVE CARE
group, the risk of bone necrosis is higher, and
placement of dentures should depend on the
status of the mucosal and bony-bearing sur-
faces, the amount and fields of radiation, and
the degree of patient cooperation. Some patients
in this group may never be candidates for com-
plete dentures.
PROSTHODONTIC PROCEDURES-
COMPLETE DENTURES
Clinical manifestations of the radiation treat-
ments important to note include (a) appearance
of oral mucous membranes, (b) scarring and
fibrosis at the tumor site, (c) degree of trismus,
and (d) status of salivary function. Translucent
mucosa with prominent telangiectasia implies
that prosthodontic restorations will be poorly
tolerated and mucosal integrity is at risk. Where
there are severe mucosal changes, dentures may
be postponed or precluded altogether. Scarring
at the tumor site may be prominent, especially if
interstitial therapy was employed. In the case of
floor-of-mouth lesions, it may be prudent to
limit extension of the lingual flange of the man-
dibular denture somewhat. Such scar tissue is
most unyielding, and the slightest overextension
can result in a mucosal perforation and perhaps
lead to an osteonecrosis or soft-tissue necrosis.
Excessive trismus is occasionally observed in
patients whose radiation fields included the
temporomandibular joint and muscles of mas-
tication. If there is severe trismus, it may be
necessary to reduce the vertical dimension of
occlusion of the complete dentures. This will
make intake of food easier and may reduce the
forces exerted on the supporting mucosa during
closure. The amount and viscosity of saliva is an
important determinant of prosthodontic suc-
cess. Impaired salivary function leads to more
friction at the denture-mucosa interface, in-
creasing the chance of mucosal irritation. The
less saliva, the more difficult it is for the patient
to tolerate dentures.
Impressions. Conventional border molding
using a custom tray and modeling plastic is
advocated. If xerostomia is particularly pro-
found, a thin coating of petrolatum may be ap-
plied over the soft modeling plastic to prevent
its sticking to dry mucosa. Displacement of the
tissues of the floor of the mouth in an attempt to
obtain peripheral seal is not advocated. Efforts in
developing the lingual flange should be directed
toward gaining stability and support rather than
retention. In all other extension areas, attention
should be paid to attaining maximum stability
and support. The elastic impression materials
are most suitable in refining the impression.
Vertical Dimension. The completed impres-
sions are boxed and poured in dental stone. Con-
ventional record bases are prepared and used to
determine the vertical dimension occlusion. The
usual methods of determining vertical dimen-
sion apply, such as phonetics, closest speaking
distance, swallowing, neuromuscular percep-
tion, and recording vertical dimension of rest.
Centric relation records are obtained in the
usual manner. Wax, plaster, and zinc oxide
paste are suitable media for obtaining the final
registrations. Graphic recording devices can
likewise be successfully employed.
Occlusal Forms. On theoretical grounds, we
have come to favor monoplane occlusal schemes
with bilateral balance obtained with posteriorly
situated balancing ramps. In arranging posterior
teeth, careful attention should be given to
attaining proper buccal horizontal overlap; in
some patients, edema of the tongue and buccal
mucosa is prominent, predisposing them to
tongue and cheek biting. In dentures constructed
with anatomic posterior teeth, bilateral balance
during function is mandatory.
Delivery and Postinsertion Care. Occlusal
discrepancies due to processing errors should be
eliminated before dentures are removed from
the cast. Pressure-indicating paste is used to
identify areas of excessive pressure, and disclos-
ing wax is useful in verifying extension of den-
ture flanges. Remounting on a suitable articu-
lator with new maxillo/mandibular records
taken at the time of delivery is mandatory.
The patient is given an instruction sheet
detailing possible problems and precautions.
Instructions concerning the need to remove the
dentures if soreness develops, to return for
periodic visits, and to initially limit use of the
prosthesis for mastication are provided. Such
restorations should never be worn during sleep-
ing hours. The care rendered after delivery of
dentures is critical and requires an understand-
ing patient if untoward complications are to be
avoided. During the first week, 24-h and 48-h
recall appointments are recommended regard-
less of. how well the patient is tolerating his
dentures.
 23. PROSTHETIC MANAGEMENT
It must be emphasized that the risk of serious
postradiation sequelae in denture wearers is
small. At the same time, it must not be forgotten
that individual reactions to radiotherapy can
vary greatly, and good judgment and sound
techniques are factors that can never be ignored
in placing prostheses. Cooperation of the pa-
tient is a necessity; without it, the best inten-
tions of the dentist may result in bone or soft-
tissue necrosis. The patient must understand the
tissue changes resulting from radiation treat-
ments and be available for close follow-up.
References
1. Ordway, D: The crises of cancer: challenge to
change. J Prosthet Dent 37:184-189, 1977.
2. Lang BR, Bruce RA: Presurgical maxillectomy
prosthesis. J Prosthet 17:613-619, 1967.
3. Desjardins RP: Obturator prosthesis design for
acquired maxillary defects. J Prosthet Dent
39:424-435, 1978.
4. Aramany M, Myers E: Dental occlusion and
arch relationship in segmental resection of the
mandible. In: Sisson GA, Tardy ME (eds) Plastic
and reconstructive surgery of the face and neck:
proceedings of the Second International Sym-
posium. New York, Grune and Stratton, 1977.
5. Robinson J, Rubright WC: Use of a guide plane
for maintaining the residual fragment in partial
or hemimandibulectomy. J Prosthet Dent 14:
992-999,1964.
6. Beumer J III, Curtis TA, Morrish RB Jr: Radia-
tion complicatiohs in edentulous patients. J
Prosthet Dent 36:193-203,1976.
7. Daley TE, Drahe JB: Management of dental
problems in irradiated patients. Austin, Uni-
versity of Texas Press, 1972.
8. Krajicek DD: Oral radiation in prosthodontics.
J Am Dent Assoc 78:320-322, 1969,
9. Rahn AO, Matalon V, DraneJB: Prosthetic eval-
uation of patients who have received irradiation
to the head and neck regions. J Prosthet Dent
19:174-178,1968.
TABLE 23-1. Percent occurrence of pathogenic organisms in denture specimens taken from 16 cancer patients at
the University of Maryland Cancer Center [9).
Entero- gram-
Pseudomonas Klebsiella Escherichia bacter negative
Sample aeruginosa spp. coli spp.
Dentures 20.0 60.0 6.6 13.3
Denture
containers 57.1 57.1 14.3 28.6
Total 31.8 59.0 9.0 18.2
471
10. King RE, Elzay RP, Prentiss DM: Effects of
ionizing radiation in the human oral cavity and
oropharynx. Radiology 91:1001-1007, 1968.
Recommended Reading
Beumer J, Curtis T, Firtell D (eds): Maxillofacial
rehabiliation: prosthodontic and surgical con-
siderations. St Louis, CV Mosby, 1979.
II. DENTURE MANAGEMENT OF
THE CHEMOTHERAPY PATIENT
This section describes management techniques
for denture patients undergoing myelosuppres-
sive chemotherapy. Care of such patients ne-
cessitates careful attention to the effects of the
underlying disease and its treatment on the oral
mucosa, as well as proper denture adaptation to
the oral tissues.
Chemotherapeutic agents lack the cytotoxic
specificity to destroy only cancer cells and can
adversely affect normal tissue. The rapidly rep-
licating tissues of the oropharyngeal mucosa
are therefore often affected, resulting in mucosi-
tis with denudation and ulceration [1-4]. Thus,
the oral mucosa of the patient undergoing can-
cer chemotherapy no longer represents a natural
protective barrier against infection. In addition,
poorly fitting dentures in these patients are ca-
pable of producing inflammation and ulceration
(denture sores), as in the normal, noncancer
population [5, 6]; in the myelosuppressed
population, adverse mechanical forces generated
by poorly fitting dentures increase the probabil-
ity of developing exaggerated tissue responses
and infection. Furthermore, retention of com-
plete dentures requires adequate salivary flow,
which is decreased with administration of many
antineoplastic agents [2]. The resultant xerosto-
Other
Staphylo- Staphylo-
coccus coccus Candida Torulopsis
bacilli aureus epidermidis spp. glabrata
13.3 6.6 66.6 73.3 13.3
14.3 42.9 71.4 85.7 14.3
13.6 18.2 68.2 77.3 13.6
472 V. SUPPORTIVE CARE
FIGURE 23-15. Growth (total viable count) of microorganisms recovered from denture-soaking containers after
96 h of incubation at room temperature [10]
mia reduces the ability of the myelosuppressed
patient to function properly with dentures.
Thus, there is an intimate relationship between
the stomatotoxic effects of the chemotherapy
and denture adaptation to the oral tissues.
Many antineoplastic agents suppress bone
marrow function, thereby increasing the risk of
infection. Friable, ulcerated oral tissues become
susceptible to microbial colonization and the
patient is at risk for development of systemic
infection [7, 8]. In the edentulous patient this
situation is further complicated by the presence
of a denture that is supported by the oral mu-
cosa. Dentures and denture-soaking containers
used by these patients can be contaminated with
large numbers of potential pathogens [8] (table
23-1). In addition, bedside denture-soaking
containers are capable of supporting micro-
bial growth and can serve as reservoirs for
pathogens in the hospital environment [9, 10]
(figure 23-15).
Therefore, every possible precaution to mini-
mize trauma, irritation, and microbial growth
related to dentures should be taken, since intact
oral mucosa may lessen the possibility of
microorganisms invading tissue and disseminat-
ing systemically. Patients could remove their
dentures during chemotherapy, but this can
severely compromise their self-image, mastica-
tory function, and nutritional needs. Prompt
evaluation and correction of faulty existing
dentures or fabrication of new dentures helps
improve patient function, self-esteem, and the
quality of life at a stressful time [11].
Principles of Prosthodontic Care
MOUTH PREPARATION
Prior to the dental examination, the overall
medical treatment plan should be reviewed with
the oncologist to provide information as to the
type, dose, and duration of the chemotherapy to
be used. Following this consultation, all teeth
should be "!valuated for retention versus extrac-
tion. The state of health of the teeth and
periodontium as well as the overall medical con-
dition of the patient will usually dictate the
 23. PROSTHETIC MANAGEMENT
FIGURE 23-16. When not in use, dentures should b~
placed in a disposable soaking container and im-
mersed in an appropriate cleansing agent. Denture-
soaking containers should be discarded and replaced
daily.
most appropriate treatment plan. Sound, vital
teeth well supported by bone and surrounded
by health gingival tissues that can be maintained
free of inflammation by the patient should be
retained. Patients requiring extraction of teeth
and contruction of dentures should have these
procedures performed prior to chemotherapy if
at all possible. It is important that the extraction
sites be permitted to heal for (ideally) ten days
before chemotherapy is initiated. Once che-
motherapy has begun, dental procedures are
limited and must be timed to correspond with
maximal granulocyte and platelet values [12].
Particular attention should also be given prior
to chemotherapy in educating the patient in pre-
ventive measures for maintaining oral health.
Teaching the patient correct methods for re-
moval of plaque from the teeth is indicated at
this point. In addition, sources of tissue irri-
tation, such as sharp edges of denture teeth or
denture base, should be smoothed in keeping
with the objective of eliminating all sources of
irritation.
PATIENTS WITH EXISTING DENfURES
Patients already wearing dentures present a
slightly different set of needs. Their dentures
should be evaluated to determine adequacy of fit
and function prior to chemotherapy. Problems
of stability, retention, or occlusion should be
corrected if possible. Excessive movement of
473
dentures in function because of lack of reten-
tion and stability can often be corrected by re-
lining. Instability and excessive movement with
potential for irritation from an unbalanced
occlusion may sometimes be corrected by a
remount procedure to refine the occlusion. If
such adjustments are not successful, the den-
tures should be removed from the patient and
new dentures constructed.
As with all denture patients about to undergo
chemotherapy, a program of scrupulous oral
hygiene should be performed. Cleanliness of the
mouth, dentures, denture-soaking containers,
and soaking solutions is extremely important as
part of a program of prevention against infec-
tion for these patients. Denture-soaking con-
tainers should be disposable, and containers and
soaking solutions used therein should be dis-
carded and replaced daily (figures 23-16 and
23-17). Sodium-perborate-containing denture
cleaners such as EFFERDENT (Warner Lambert
Company, Morris Plains, NJ 07950) have been
found to inhibit microbial growth in denture
containers. CHLORHEXIDINE glucognate (Stuart
Pharmaceuticals, Wilmington, DE 19897), LIS-
TERINE Antiseptic (Warner Lambert Company),
and Chloraseptic (Norwich-Eaton Pharma-
ceuticals, Norwich, NY 13815) also inhibit
pathogenic growth on soaking dentures. Any
soaking agent employed, however, must be
changed daily [13].
On occasion, the dentist is consulted regard-
ing a possible denture~related complication
occurring during chemotherapy. The evaluation
of the denture patient in whom chemotherapy
has been initiated must account for numerous
474 V. SUPPORTIVE CARE
factors related to this therapy. Since oral epithe-
lium may be more susceptible to denture irri-
tation, mucosal ulceration may be present.
Trauma from dentures, such as cheek biting, can
exacerbate mucosal bleeding; ulcerative lesions
may predispose the patient to systemic infection
secondary to the increased number and type of
gram-negative organisms in the oral cavity.
Appropriate antimicrobial therapy should be
instituted in these cases [8]. Candidiasis,
evidenced as white patches on the oral mucosa,
frequently occurs in the myelosuppressed
patient in association with dentures; this infec-
tion may be controlled by having the patient use
oral antifungal agents, such as clotrimazole (10
mg five times daily) or nystatin vaginal supposi-
tories (100,000 U four times daily). Dentures
must also be treated and should be soaked in
nystatin oral suspension 100,000 U/ml for 6-8
h. Treatment should continue for at least two
weeks. Cheilitis is frequently seen in association
with the denture patient whose vertical dimen-
sion of occlusion is overclosed in combination
with the presence of Candida overgrowth. The
corners of the mouth may be coated with a fun-
gicidal ointment such as MYCOLOG (Squibb and
Sons, Princeton, NJ 08540) for relief.
The oral mucosa often becomes so sensitive
following initial administration of chemother-
apy that the patient should not attempt to wear
dentures at all. This situation is unfortunate, be-
cause food intake is compromised and the pa-
FIGURE 23-17. This denture-soaking container was
allowed to remain in use for approximately five days.
Microbial growth in this solution approached 107
organisms/ml, many of which are highly pathogenic
in myelosuppressed cancer patients.
tient's dentures may be an important factor in
hislher self-image. Should denture irritation or
mucositis be severe, however, dentures should
be withdrawn from use until oral ulcerations
have epithelialized. Painful ulceration may be
treated palliatively with a rinse of 2% viscous
XYLOCAINE (Astra Pharmaceutical Products,
Worcester, MA 01606) or a 50:50 mixture of
elixer of BENADRYL (Parke-Davis, Division of
Warner Lambert, Morris Plains, NJ 07950) and
KAOPECTATE (Upjohn Company, Kalamazoo,
MI 99001); (see chapter 24).
Drug-induced xerostomia, although not
common, can impair denture function because
of reduced lubrication. An artificial saliva such
as XERO-LUBE (Scherer Laboratories, Dallas,
TX 75234) may provide palliative relief in these
cases.
Denture Evaluation and Fabrication
PATIENTS WITH EXISTING DENTURES
As previously discussed, the primary objective
in denture management for the chemotherapy
patient is to minimize irritation and trauma to
the supporting tissues (figure 23-18), as well as
provide masticatory function and improve
 23. PROSTHETIC MANAGEMENT 475

FIGURE 23-18. Irritation from a poorly fitting den-

ture caused this lesion in a myelosuppressed cancer
patient. Proper evaluation of the denture before and reduce the risk of infection. This therapy
chemotherapy could have prevented the occurrence should continue until hematologic parameters
of this lesion. Pathogenic microorganisms rapidly stabilize either during or following chemother-
colonize lesions of this nature, resulting in serious apy, when new dentures can be constructed.
systemic infection. From De Paola et al. [11]. Having established acceptable stability, the
vertical dimension should be checked prior to
chemotherapy to ensure sufficient interocclusal
patient self-image. Prior to chemotherapy, ex- space during function. This may be accom-
isting dentures should be evaluated for stability, plished phonetically using "5" sounds while
retention, vertical dimension, and occlusion.
Patient habits in cleansing their dentures should
be reviewed and denture hygiene stressed. An
unstable or unretentive denture will have ex-
cessive movement with potential for tissue ir-
ritation or ulceration. Chemotherapy-induced
xerostomia may further decrease retention and
increase the possibility of irritation. Pressure-
indicator paste (Mizzy, Clifton Forge, VA
24422) (figure 23-19) and disclosing wax (Kerr
Manufacturing Company, Romulus, MI 48174)
should be carefully used following manufac-
turers' directions, to evaluate tissue-bearing
surfaces and denture borders respectively.
Dentures should be adjusted where indicated to
achieve stability. If stability cannot be achieved,
consideration should be given to either relining
the dentures or using a tissue-conditioning soft
liner (Coe Laboratories, Chicage, IL 60658)
FIGURE 23-19. Pressure-indicator paste should be
to reestablish stability. Soft liners should be used to detect areas of the denture base that can im-
changed daily, if feasible, but at least every third pinge on soft tissue. Relief of these areas can mini-
day throughout the course of chemotherapy. mize tissue irritation and ulceration with both old
This will help to minimize microbial growth and newly constructed dentures.
476 V. SUPPORTIVE CARE
FIGURE 23-20. Disclosing solution painted on the
tissue surfaces of the denture helps demonstrate the
effectiveness of the patient's denture hygiene.
observing whether the denture teeth contact
during this function, thereby giving an indica-
tion of interocclusal space present. A slightly
overclosed vertical dimension of occlusion is
usually not a problem since biting force is
generally reduced by overclosure. However, if
the patient has little or no interocclusal space,
the dentures can be mounted in centric relation
on an articulator and the occlusion adjusted on
all contacting tooth surfaces to close the vertical
dimension of occlusion, thereby creating more
interocclusal space. An overopened vertical
dimension of occlusion in dentures will cause
excessive force on supporting bone and mucosa,
resulting in irritation and possible ulceration;
thus, it is contraindicated in this population.
Other precautions must also be taken. Occlu-
sion of denture teeth should be evaluated clini-
cally. When the teeth do not contact evenly in
centric and eccentric positions, remounting on
an articulator to refine the occlusion for even
force distribution is necessary. Finally, denture
cleanliness should be evaluated using a disclos-
ing solution on the dentures to demonstrate the
effectiveness of the patient's denture hygiene
habits (figure 23-20). Patients must be thor-
oughly indoctrinated in scrupulous denture care
procedures to minimize microbial growth that
might result in systemic complications. Instruc-
tions should be given the patient to remove den-
tures while sleeping as well as at other times
when possible, to provide rest periods for the
mucosa.
Should existing dentures not be amenable to
correction of existing defects, they should be re-
moved from the patient until new ones can be
constructed. The patient's physician should be
notified of removal of dentures, as the patient's
diet may need alteration and supplementation.
PATIENTS REQUIRING NEW DENTURES
Patients may be rendered edentulous by ex-
traction of acutely involved teeth prior to che-
motherapy to reduce the possibility of infection
during myelosuppression. Also, edentulous
patients often present for cancer treatment
without dentures, or their existing dentures are
clinically unacceptable and must be removed. In
each instance, prosthodontic intervention can
be useful; however, certain preventive measures
must be followed to minimize adverse sequelae.
Postextraction sites in this population must
be monitored carefully for signs for infection
[11, 12]. Healing is often delayed and tissue
quality can be poor in these patients. Therefore,
before prosthodontic treatment begins, closure
of extraction sites is necessary to reduce the
possibility of infection. Primary closure is
generally completed within 2-3 weeks. For this
reason, immediate dentures (denture[ s] inserted
at the time of tooth extraction) are not recom-
mended for these patients. Denture construc-
tion should be delayed until epithelialization is
complete.
New denture construction is most easily
completed prior to the initiation of chemother-
apy. Although denture construction can on
occasion be accomplished during chemother-
apy, the patient's ability to withstand dental
manipulation at this time must be considered.
Many patients are gravely ill at the time of or
shortly after initiation of chemotherapy. While
simple adjustments may be possible for these in-
dividuals, poorly fitting dentures should be
withdrawn from use and new denture construc-
tion deferred until there is an improvement in
the overall status.
When constructing new dentures, every
means possible should be employed to mini-
mize irritation or trauma during denture con-
struction. Impressions should employ as pres-
sure free a technique as possible, using a spaced
custom tray with free-flowing material such as
zinc oxide, light-bodied rubber, or silicone. The
tray should be border molded carefully to pre-
vent overextension of the denture base, yet pro-
vide maximal coverage of supporting structures
 23. PROSTHETIC MANAGEMENT
by the denture. The same precautions relating to
vertical dimension apply as were noted pre-
viously with existing dentures. Nonanatomic
teeth should be used to maintain more evenly
distributed occlusal forces for a longer period of
time (figure 23-21). At the time of insertion,
pressure-indicating paste and disclosing wax
should be used repeatedly to assure an even dis-
tribution of contact between denture base and
mucosa. Denture borders should be smooth and
checked carefully for overextensions that might
cause ulceration. A remount procedure on the
articulator should be routine to refine accurate-
ly the occlusion for the broadest possible dis-
tribution of occlusal force during function. Fol-
lowing occlusal refinement in centric relation, a
protrusive record should be made to set hori-
zontal condylar guidance elements on the arti-
culator so that the nonanantomic occlusion can
be further refined in eccentric positions.
DENTURE MAINTENANCE DURING
CANCER CHEMOTHERAPY
Since pathogenic organisms, particularly gram-
negative bacilli, are more prevalent in the oral
cavity of chemotherapy patients, cleanliness of
the mouth and the dentures takes on heightened
importance [7-10]. Newly constructed or
relined dentures should be gas sterilized in
ethylene oxide or soaked in an antimicrobial
bath (CIDEX, Johnson & Johnson, East Windsor,
NJ 08520) for 12 h to reduce laboratory con-
tamination prior to insertion. After delivery,
daily mechanical cleansing of dentures with a
denture brush, antimicrobial detergent (HIBIC-
FIGURE 23-21. Occlusion should be refined for the
broadest possible distribution of occlusal force
during function.
477
LENS, Stuart Pharmaceuticals), and water can be
quite effective in reducing microbial growth if
performed properly. The denture brush should
be treated in a bacteriocidal bath (ClDEX) fol-
lowing each use. Many of these patients are
unable to use their dentures because of severe
mucositis, pain and/or bleeding from the oral
mucosa. When this situation exists care must
be taken that denture soaking containers for
storing the dentures are clean, replaced daily
and contain a solution such as EFFERDENT or
KLEENITE (Vicks Toiletry Products, Wilton, CT
06897) also renewed daily. Some patients re-
quire a soft-tis sue-conditioning lining in their
dentures because their friable mucosa cannot
tolerate a hard acrylic denture base. When this
approach is necessary, it is important that, in
addition to the cleansing procedures already
discussed, the soft liner be replaced daily, if
possible, to reduce microbial growth.
Newly delivered or relined dentures should
be clinically evaluated daily for the first week
after insertion. Patients should then be followed
as needed until the dentures are comfortable and
functioning well clinically. As these patients
often receive monthly regular cycles of che-
motherapy for prolonged periods of time,
complaints of denture irritation and pain often
occur when the patient becomes profoundly
granulocytopenic. Dentures should be carefully
evaluated at this time for occlusal dysharmony or
overextension. Often, none can be detected, and
the symptoms can be attributed to the cytotoxic
effects of the chemotherapy. These denture
irritations usually resolve without adjusting the
denture-base material after 24-48 h of restricted
use or total removal of the dentures.
The administration of chemotherapy over
long periods of time also means that prob-
lems associated with denture use will persist
throughout the course of cancer treatment.
Dentures should be evaluated frequently for
overextensions, pressure areas, and occlusal
dysharmony by methods previously described.
Three-month recall examinations are satisfac-
tory for most patients, but some patients ex-
hibiting severe oral complications during
chemotherapy may require more frequent re-
examination.
Most denture patients claim that their teeth
do not seem to fit as well shortly after che-
motherapy is initiated, and upon withdrawal of
chemotherapy this phenomenon does not seem
to reverse. The cause for this change in denture-
478 V. SUPPORTIVE CARE
bearing tissues is unknown, but it is a common
complaint that must be recognized and appro-
priate action taken. Dentures that are relined
or constructed after introduction of chemother-
apy seem to remain clinically acceptable to the
patient, but close follow-up at least every three
months is required.
Summary
Dentures for the chemotherapy patient require
great care in their construction and mainte-
nance, utilizing sound basic principles of
denture construction and tissue management
inherent in the highest level of prosthodontic
treatment. The objective of removable prosth-
odontic therapy is to improve the cancer pa-
tient's quality of life and enhance nutrition
by reducing oral irritation and ulceration, as
well as controlling the oral microbial popula-
tions associated with chemotherapy and the
wearing of a denture.
References
1. Dreizen S: Stomatoxic manifestions of cancer
chemotherapy. J Prosthet Dent 40:650-655,
1978.
2. Bottomley WK, Perlin E, Ross GE: Antineo-
plastic agents and their oral manifestations. Oral
Surg 44:527-534,1977.
3. Guggenheimer J, Verbin RS, Appel BN,
Schmutz J: Clinicopathologic effects of cancer
chemotherapeutic agents on human buccal mu-
cosa. Oral Surg 44:58-63,1977.
4. Lockhart PB, Sonis ST: Alterations in the oral
mucosa caused by chemotherapeutic agents. J
Dermatol Surg OncoI7:1019-1025, 1981.
5. Lytle RB: Management of abused oral tissues in
complete denture construction. J Prosthet Dent
7:27-42, 1957.
6. Lytle RB: Complete denture construction based
on the study of the deformation of the under-
lying soft tissues. J Prosthet Dent 9:539-551,
1959.
7. Lindquist SF, Hickey AF, Drane JB: Effect of
oral hygiene on stomatitis in patients receiving
cancer chemotherapy. J Prosthet Dent 40:312-
314,1978.
8. Dreizen S, Bodey GP, Brown LR: Opportunis-
tic gram-negative bacillary infections in leuke-
mia. Postgrad Med 55:133-139, 1974.
9. De Paola LG, Minah GE, Elias SA: Isolation of
pathogenic microorganisms from dentures and
denture soaking containers of myelosuppressed
cancer patients. J Prosthet Dent 49:20-24,1983.
10. De Paola LG, Minah GE: Growth of potential
pathogens in denture soaking fluid of myelosup-
pressed cancer patients. J Prosthet Dent 51 :554-
558,1984.
11. De Paola LG, Leupold RJ, Peterson DE, Over-
holser CD: Prosthodontic considerations for
patients undergoing cancer chemotherapy. J Am
Dent Assoc 107:48-51, 1983.
12. Overholser CD, Peterson DE, Bergman SA,
Williams LT: Dental extractions in patients with
acute nonlymphocytic leukemia. J Oral Marillo-
fac Surg 40:296-298, 1982.
13. De Paola LG, Minah GE, Elias SA: Evaluation
of agents to reduce microbial growth on dental
prothesis of myelosuppressed cancer patients.
Clin Prev Dent 6:9-12,1984.
 24. STANDARDS FOR NURSING
CARE OF THE ORAL CAVITY

Lisa T. Williams
Noel E. Slotke
Jane Daly
Douglas E. Peterson

Radiation, chemotherapy, and/or surgery used
to treat cancer can induce profound changes in
the oral cavity, leading to pain, secondary infec-
tion, and functional defects. Understanding the
patient's systemic and oral condition and utiliz-
ing preventive and palliative therapy can save
the patient from unnecessary discomfort and
deformity.
The principles of and complications associ-
ated with each treatment have been described in
previous chapters. This chapter discusses the
roles and interactions of the nurse and the den-
tal hygienist, and the preventive, palliative, and
supportive care plans for the cancer patient.
Pretreatment Assessment and Care
for Radiation, Chemotherapy,
and Surgery Patients
Oral care should be considered as soon as the
cancer diagnosis has been made and the treat-
ment modality determined. The patient should
be promptly referred for this care prior to
cancer therapy, to identify and treat foci of in-
fection and to initiate preventive and palliative
self-care instruction (table 24-1).
The majority of head and neck cancer patients
who receive radiation are scheduled on an out-
patient basis. Most patients with head and neck
carcinoma receive between 5000 and 7000 cGy as
a "cure dose" [1] typically delivered in fraction-
ated doses five days a week over 4-8 weeks.
Such treatment can result in major complica-
tions involving the oral cavity [2-4] (table 24-2).
Many of these complications can be totally
Peterson et al., HEAD AND NECK MANAGEMENT OF THE CANCER PATIENT.
©> 1986. Martinus NijhoJf Publishing. AU rights reserved.
prevented; others can be minimized through
patient education and proper pretreatment
preparation [3, 5].
Patients receiving chemotherapy are usually
treated according to various protocols designed
specifically for each tumor type. Protocols vary,
but usually involve treatment with several drugs
in combination. Side effects of the drugs often
depend upon the particular combination, dos-
age, and schedule of drugs used, and include in-
fection, hemorrhage, anemia, and mucositis [6]
(table 24-2). The nurse has an excellent oppor-
tunity to assess, monitor, and interact with the
patient prior to and during therapy, and thus
represents a key health-care provider.
Surgical treatment of the head and neck
oncology patient is also very complex and re-
quires a multidisciplinary approach to care.
Surgical procedures often result in major body
image changes, disfigurement, functional im-
pairment, and/or distorted speech (table 24-2).
The patient and family require considerable
emotional and physical support to cope with
his/her new self-image and change in lifestyle
[7] (see chapter 25). The nurse and primary
health team must assess the patient's under-
standing of the disease and treatment, to best
help the patient.
DATA COLLECTION
Important data should be collected prior to
radiation, chemotherapy, or surgery. These data
include (a) cancer classification and treatment
modality (diagnosis, location, and classification
of the tumor; schedule and portals of radiation;
type of chemotherapy, as well as associated
479
480 V. SUPPORTIVE CARE

TABLE 24-1. Dental appointment series for the cancer therapy patient

Oral
evaluation
Dental exam Preventive care during Frequency of post-cancer
and treatment during cancer course of therapy comprehensive
Treatment plan Immediate dental treatment therapy treatment dental care

Radiation 2 weeks prior Oral surgery: 2 wks prior to Oral hygiene Weekly Months 1-3: at least once
therapy to initiation RTa care per month
of radiation Restorative: prior to RT Fluoride Months 4-6: at least every
therapy Endodontics: prior to RT therapy six weeks
Periodontics: prior to RT Diet manage- Months 6 +: at least
(cleaning) ment every four months
Oral hygiene instructions:
prior to RT
Fluoride: prior to RT
Diet counseling: prior to
RT
Chemo- 2 weeks prior Oral surgery: 2 wks prior to Oral hygiene 2-3 times Care begins immediately
therapy to initiation CTb care weekly following recovery of
ofchemo- Restorative: prior to myelo- bone marrow
therapy suppression
Periodontal (cleaning):
prior to myelosuppres-
sion
Oral hygiene instruction:
prior to CT
Surgery 1 week prior Oral surgery: prior to or at Oral hygiene Daily while Frequency of care to be de-
to surgery time of surgery care inpatient termined by patient'S
Restorative: prior to Diet manage- needs; ego prosthetics
surgery ment
Endodontics: prior to
surgery
Prosthetics: prior to surgery
Periodontics (cleaning):
prior to surgery
Oral hygiene instruction:
prior to surgery

• RT, radiotherapy.
b CT, chemotherapy.

severity and duration of myelosuppression;
extent of surgery) and (b) a detailed patient
history (medical, dental, and psychosocial).
Understanding these issues will permit the
dentist to develop a dental treatment plan, and
make appropriate referrals to other health-care
providers. These concepts are discussed below.
Assessing Cancer Classification and Treat-
ment Modality. Treatment will be influenced
by the cancer type as well as its site(s). For ex-
ample, the clinician can predict the radiation-
induced effects on underlying structures (e.g.,
salivary glands, bone, and muscle) by assessing
the classification, staging, and radiation portals.
The patient's complications throughout and fol-
lowing radiation treatment can thus be pre-
dicted. Portals involving the maxilla are more
likely to involve the parotid and thus decrease
the major source of serous salivary flow, caus-
ing xerostomia and subsequent dental problems
[8]. Portals involving the mandible cause a
greater risk of the patient developing osteo-
radionecrosis.
For the chemotherapy patient, the type of
chemotherapy and degree and duration of bone
 24. STANDARDS FOR NURSING CARE OF THE ORAL CAVITY
TABLE 24-2. Oral complications of cancer therapy
Occurrence with:'
Chemo-
Problem Radiation therapy Surgery
Infection + ++
Mucositis ++ ++
Hemorrhage + +
Xerostomia ++ + +
Rampant caries ++ 0/+
Osteonecrosis + 0/+
Neuropathy 0/+ + +
Decreased
vascularization ++ 0/+
Limitation of
function + +
Impaired nutrition ++ ++
a ++. often; +, sometimes; and 0/+, rardy.
marrow suppression are considerations impor-
tant to the head and neck treatment plan.
Patients experiencing profound (less than 100
cells/mm3) and prolonged (greater than two
weeks) granulocytopenia are at high risk for
serious infection [9]. In addition, many patients
receive multiple chemotherapeutic courses. The
patient thus may be repeatedly placed at risk for
various complications of chemotherapy, includ-
ing infection and hemorrhage [6].
Surgery may be used singly or in combination
with prior chemotherapy and/or radiation; such
chemotherapy and radiation therapy often re-
sults in complications that can alter the surgical
course. Patients who present with a history of
radiation therapy or osteoradionecrosis may
have an altered oral micro flora that can cause
postoperative infections. Complications in sur-
gical patients with previous cancer therapy
include immediate fistula, wound dehiscence,
soft-tissue desquamation, laryngospasm, delayed
cervical esphogeal stenosis, trachesotomy
stomal stenosis, osteomyelitis of the mandible,
and carotid rupture [7].
Assessing Patient Histories. Medical history
must also be carefully assessed. For example,
conditions such as acquired and congenital heart
defects may necessitate antibiotic premedication
prior to dental services being rendered; dosing
of medications such as coumadin or prednisone
may also need altering prior to dental treatment;
platelet transfusions may be necessary for the
thrombocytopenic patient [10].
481
Assessing the emotional history and status
of the patient is also important. The support
systems a person has may make the difference
between failure and success with self-care. Kubler-
Ross defined the stages of denial, anger, bar-
gaining, depression, and acceptance [11], all of
++ which can be observed throughout the treat-
0/+ ment series. Understanding and working with a
++ patient experiencing such emotions will facili-
tate comprehensive care of the patient.
0/+
0/+ The patient's social history may reveal prac-
tices not conducive to preventive health care.
For example, history of alcoholism and/or
++ heavy tobacco use may identify an individual
who will not comply with daily preventive care
++ regimens. Assessing the dental history will also
++ permit insight into the patient's attitude toward
preventive care, as well as susceptibility to den-
tal disease. Oral pathology will likely be pre-
sent if the patient has not been evaluated recent-
ly by a dentist. The clinician needs to address
the need for preventive self-care with emphasis
on prevention of pain, infections, facial de-
formity, and financial burden.
An accurate dental history is critical to pre-
vention of oral complications during subse-
quent therapy. A few brief questions as listed
below can elicit frequency of both dental infec-
tions and preventive dental care:
-When was patient's last dental visit and what
type of procedures were performed?
-How often does the patient seek dental care?
-Does the patient have any recent history of
1. gum swellings, drainage or "boils"?
2. toothache or sensitivity of teeth to hot,
cold, or chewing?
-Does the patient have any loose teeth?
-Does the patient have loose, ill-fitting den-
tures or recurring problem of denture sores?
This type of assessment can screen for current
or potential dental problems and generate a
prompt referral.
Dental Examination and Treatment Plan.
A recorded oral assessment by the nurse will
help facilitate identification of obvious oral
disease. This examination must include sys-
tematic and thorough inspection of hard and
soft oral tissues (figure 24-1). A good light
source, gloves, and an instrument for retrac-
tion (i.e., tongue blade) should be used. Areas
not readily accessible to direct vision should
482
 D

E F

FIGURE 24-1. (a) Examination of labial mucosa, vestibule, anterior dentition, and gingiva is accomplished by
retracting the lips. (b) Retraction of the cheeks allows examiner to view the buccal mucosa, vestibule, posterior
dentition, and gingiva. (c) Evidence of periodontal disease or dental caries may be noted on careful inspection of
the dentition and gingiva. (d) Inspection of the dorsum and lateral surfaces of the tongue is accomplished by
grasping tip of the tongue, using a 2" x 2" gauze for retraction. (e) Have patient lift tongue to palate to allow
examination of the floor of the mouth and lingual frenum. (f) Tilt patient's head back, with chin up with mouth
open wide, to inspect hard palate and lingual aspects of maxillary dentition and gingiva. From Williams LT,
O'Dwyer JL: Guidelines for oral hygiene, denture care and nutrition in patients with oral complications
from Peterson D, Sonis S (eds) Oral complications of cancer chemotherapy (Boston, Martinus Nijhoff, 1983),
pp 151-168.

483
484 v. SUPPORTIVE CARE

FIGURE 24-3. Draining fistula (arrow) associated

A with chronic periapical dental infection of maxillary
incisor, visualized only after retraction of lip.

FIGURE 24-2. (a) The dentition appears to be in good

health on initial inspection. (b) Closer examination
reveals a decayed and fractured crown (arrow) with
retained root tip. This condition represents a poten-
tial for acute infection. Photographs courtesy of Dr.
H. Richter, Baltimore College of Dental Surgery,
Dental School, University of Maryland at Baltimore.

not be overlooked, including the lateral borders

of the tongue, floor of mouth, vestibule, hard
and soft palate, and (for the prosthetic patient)
denture-bearing surfaces. Grossly decayed teeth,
severe gingival recession, or hypertrophy are
easily recognized and important to note. Less
obvious but equally important findings are ex-
posed root tips (figure 24-2), fistulas (figure
24-3), and denture sores (figure 24-4).
Most patients do not understand the impor-
tance of dental procedures in the control and
prevention of infection; the nurse or physician FIGURE 24-4. (a) Patient with ill-fitting mandibular
may need to explain in rationale for such pro- partial denture creating irritation to vestibular
cedures during a time when the patient is focused mucosa. (b) denture ulceration (arrow) is readily
on his/her cancer diagnosis. Constant reinforce- apparent when partial denture is removed and lip re-
ment of the importance of dental treatment and tracted.
 24. STANDARDS FOR NURSING CARE OF THE ORAL CAVITY 485

preventive care is essential. mize pain and infection, facial deformity,

A dental treatment plan should be formulated and expense.
after assessing the tumor data, the respective
histories, and the results of the dental examina- Edentulous patients are not exempt from the
tion. In general, the oral plan should reflect oral examination. Root tips may be present in
both the patient's present and future dental the absence of clinical crowns, and could lead to
needs. This is also the appropriate time to con- infectious complications. If the patient wears a
sider postoperative prosthetic appliances. dental prosthesis, a dentist should evaluate the
Ideally, all corrective dental procedures should fit of the denture to assure that the denture base
be completed prior to initiation of cancer will not irritate the mucosa. Otherwise, further
treatment. complications, such as osteoradionecrosis, mu-
cosal ulcerations or infection may ensue [12].
THE PREVENTIVE DENTAL PLAN Patient education regarding the care and wear-
The preventive dental plan is an integral part of ing of the prosthesis during xerostomia or
the overall treatment plan. The preventive plan periods of bone marrow suppression is essential
for the dentulous patient should include initial [13].
periodontal preparation (scaling, root planing),
oral hygiene instructions, nutritional counseling
to limit sucrose intake, impressions for dental Care of the Patient Receiving
casts to fabricate fluoride trays (for the radiation Radiation Therapy
patient), and patient education. This preventive
care should be performed prior to cancer ther- ORAL COMPLICATIONS AND
apy. Emphasis should be placed on self-care on PALLIATIVE TREATMENT
the part of the patient. After patient education is Radiation effects are not tumor cell selective.
given, the patient ideally should be able to: Prevention of all side effects is not possible, but
delivery of treatment to minimize the risk of
1. Perform scrupulous oral hygiene, using mul- secondary infection and palliative treatment is
tiple self-care techniques (brushing, flossing, important and necessary. Assessment of side
and other oral hygiene aids (infra vide). effects should be at weekly intervals throughout
2. Discuss the side effects of cancer therapy, treatment (table 24-1).
their duration during and after therapy, and
palliative treatment. ACUTE RADIATION MORBIDITY
3. Discuss the role of diet on dental health and Mucositis. Radiation-induced mucositis is a
general health, including the need for bal- frequently occurring acute problem. Radiation
anced diet with increased calories but de- impairs mitosis nonspecifically, affecting both
creased sucrose. normal and cancer cells; clinically, inflamma-
4. Understand the need for continued dental
care during and after cancer therapy, to mini- TABLE 24-3. Percentage of alcohol in
commercial mouthwashes
Ethanol
Product
(Manufacturer) % Proof
LISTERINE
(Warner Lambert) 26.9 53.8
SCOPE
(Proctor & Gamble) 18.5 37.0
SIGNAL
(Lever Brothers) 14.5 29.0
LISTERMINT
(Warner Lambert) 14.2 28.4
CEPACOL
(Merrell National
Laboratories) 14.0 28.0
FIGURE 24-5. Radiation-induced mucositis. From Geopferd [20], with permission.
 486 V. SUPPORTIVE CARE

TABLE 24-4. Pain medications, antibacterial and antifungal agents, and oral hygiene preparations

Dose/schedule Manufacturer

Topical anesthetics
XYLOCAINE 15 ml swish and expectorate; not
(lidocaine) viscous to exceed 120 ml in a 24 hour
period
DYCLONE (dyclonine 5-10 ml, swish and expectorate,
hydrochloride) q6h
BENADRYL (diphenhydramine) Mixed 1:1 with KAOPECTATE 30 ml,
PRN, swish and expectorate
TESSALON PERLES (benzonatate 100 mg/perle 1 tab, bite to express
NF) liquid, swish and expectorate, 1
perle tid, max. 6 perles in 24
hours
CETACAINE 2% solution in spray, spray for 1
second; not to exceed 2-second
spray
ORABASE with benzocaine Dab amount on lesion PRN
Astra Pharmaceutical Products,
Worcester, MA 01606
Astra Pharmaceutical Products,
Worcester, MA 01606
Parke-Davis, Division of Warner
Lambert Morris Plains, NJ
07950
DuPont Pharmaceutical,
Wilmington, DE 19898
Cetylite Industries, Pennsauken,
NJ 08110
Hoyt Laboratories, Norwood,
MA02062

Antifungal agents
MYCOSTATIN oral suspension
(nystatin)
MYCOSTATIN vaginal tablets
(nystatin tablets)
Nystatin popsicle (nystatin
powder universal syrup-80%-
85% sucrose/100 ml yields 12
popsicles)
MYCELEX TROCHE (clotrimazole)
LOTRIMIN 1% solution
(clotrimazole)
NIZOROL tablets (ketoconazole)
4-6 ml (100,000 V/ml) 4 times E.R. Squibb, Princeton, NJ 08540
daily; retained in mouth as long
as possible before swallowing;
continue treatment at least 48
hours after symptoms resolve or
cultures are normal
100,000 V tabs; 1 tab 4-6 times a E.R. Squibb, Princeton, NJ 08540
day, use as lozenge; dissolve in
mouth as long as possible before
swallowing
I-oz. popsicle q 4 h 'while awake Prepared by pharmacy
10-mg tabs; 1 tab dissolved slowly Miles Pharmaceuticals, West
5 times a day for 14 consecutive Haven, CT 06516
days
Apply topically to affected area Schering Corporation,
twice a day, A.M and P.M Kenilworth, NJ 07033
200-mg tabs; 1 tab a day; if no Janssen Pharmaceuticals, New
response within expected time, Brunswick, NJ 08903
increase to 2 tabs a day

- Hemostatic agents
GELFOAM (absorbable gelatin
sponges)
THROMBOSTAT (topical thrombin)
SURGICEL (oxidized regenerated
cellulose)
Various sizes; apply sponges Vpjohn Company, Kalamazo, MI
topically w/gauze pressure 49001
packingPRN
Soak "2 x 2" gauze sponge with Parke-Davis, Morris Plains, NJ
thrombin solution and apply 07950
with pressure to bleeding site;
leave on for extended time
period if necessary
Cut appropriate-sized strip of Johnson & Johnson Products,
SURGICEL and apply against New Brunswick, NJ 08903
bleeding site until hemostasis
occurs
 24. STANDARDS FOR NURSING CARE OF THE ORAL CAVITY 487

TABLE 24-4 (Continued)

Oral hygiene rinses
GLY-OXIDE liquid (carbamide
peroxide 10%)
HzO z + saline
Baking soda and salt solution
Dose/schedule Manufacturer
Place several drops on affected Marion Laboratories, Kansas City,
area, expectorate after 2-3 M064137
minutes or rinse 10 drops for 1
minute and expectorate
50 cc HzO z + 50 cc normal saline; Prepared by pharmacy
apply to dry gauze place over
wound site for wound care
In sterile water; used for oral Prepared by pharmacy
irrigation

Fluorides
(ADA approved)
Topical sodium fluoride
Rinse
Sodium fluoride Swish 5-10 cc for 5 minutes daily; Young Dental, Maryland Heights,
solution 2% expectorate NPO 30 minutes M063043
following
Gel
THERA-FLUR N Fill dry tray( s) with enough Hoyt Laboratories, Norwood,
(neutral) fluoride to reach gumline when MA02062
placed over teeth (usually 1f3
full); apply on arch(es) for 5
minutes daily; NPO 30 minutes
following
Topical stannous fluoride
gel
FLO-GEL 0.4% Sabra Dental Products Inc., N.
Miami Beach, FL 33179
GEL-KAM 0.4% Place 3/, in. gel on wet tooth brush: Scherer Laboratories, Dallas, TX
brush all tooth surfaces for 5 75240
minutes; swish 2-3 times,
working gel into interproximal
spaces
OMNnO.4% or Dunhall Pharmaceuticals, Inc.
Gravette, Arkansas 72756
Stannous fluoride 8.0% Using wet carriers, follow same Young Dental, Maryland Heights,
directions as sodium fluoride M063043
STOP 0.4% CooperCare, Fairfield, NJ 07006

Salivary substitutes
MOl-STIR 4-oz. spray bottles, spray PRN Kingswood Laboratory, Carmel,
IN 46032
OREX 16-oz. squeeze bottle, rinse PRN Young Dental, Maryland Heights,
M063043
SALIVART 50-ml spray cans, spray PRN Westport Pharmaceuticals,
Westport, CT 06881
XEROLUBE 6-oz. spray or squeeze bottle, Scherer Laboratories, Dallas, TX
spray or rinse PRN 75240

tion and ulceration of the labial and buccal
mucosa, ventral surface of tongue, and palate is
observed (figure 24-5). Symptoms are usually
pain, burning, and sloughing tissue. The condi-
tion is irritated by spicy foods and commercial-
ly-available mouthwashes containing alcohol
(table 24-3). Mucositis can develop and persist
to a degree that radiation treatment must be
temporarily discontinued.
Patient responses to mucositis are varied;
some patients may not be aware of newly-form-
ing lesions whereas other patients are sensitive
488 V. SUPPORTIVE CARE
to many changes. New lesions should be de-
tected early in their development during regular
oral examination; they should be noted careful-
ly as to size, shape, location, and appearance.
Progress or deterioration can thus be con-
sistently followed. Cultures or smears of new
lesions are often indicated so that superinfection
can be documented and promptly treated.
Palliative treatment for mucositis includes
rinses and topical anesthetics (table 24-4).
Numerous rinses have been used with varying
degrees of success. Sodium bicarbonate (one
teaspoon of baking soda in 32 ounces of water or
normal saline) should be used initially at least
six times a day. In addition, topical anesthetics
may be considered; use should progress from
the least potent and toxic to more potent and
toxic topical agents. At each level, the patient
should use the drug for a specific duration prior
to advancing to the next topical anesthetic. It
is therefore recommended that practitioners
develop sequential palliative protocols to maxi-
mize objectivity and organization in approach.
The following is an example of one such
approach:
Days }-3: 1. XYLOCAINE (Astra Pharmaceu-
tical Products, Worcester, MA 01606),
viscous 2%
Days 4-6: 2. DYCLONE (Dow Pharmaceuti-
cals, Indianapolis, IN 46268) and BENADRYL
(Parke-Davis, Detroit, MI 48232), 0.5%
Days 7-9: 3. DYCLONE and BENADRYL, 1%
Solutions such as "3-2-1" mouthwash (3 parts
KAOPECTATE (Upjohn Company, Kalamazoo,
MI 49001), 2 parts BENADRYL elixir, 1 part
saline) have been used palliatively to manage
mucositis with debatable benefit. The clinician
should be aware that, although KAOPECTATE
may be soothing to ulcerated mucosa, its white
chalky appearance can adhere to tissue; recogni-
tion of infection (e.g., candidiasis) is thus more
difficult to assess. If the "3-2-1" mouthwash
is selected, the KAOPECTATE must be removed
daily from the oral cavity. Other agents that
have been suggested are DYCLONE, TESSALON
PERLES (DuPont Pharmaceuticals, Wilmington,
DE 19898) (crushed, swished intraorally, and
expectorated), and CETACAINE (Cetylite Indus-
tries, Pennsauken, NJ 08110) (table 24-4).
ORABASE with BENZOCAINE (Hoyt Laborato-
ries, Needham, MA 02194) is effective for pal-
liative relief from pain for isolated ulcera-
tions. However, ORABASE with KENALOG (Hoyt
Laboratories) should not be used. KENALOG is a
synthetic corticosteroid that should not be used
in presence of fungal, viral, or bacterial infection
[14]. Due to the shift of oral flora seen in
radiation-induced xerostomia, KENALOG can
potentiate an evolving fungal problem.
All agents must be used with care according
to package instructions. Many topical anesthet-
ics produce undesirable effects if swallowed;
e.g., the gag reflex may be suppressed, causing
an increased risk of aspiration. With intense oral
pain, systemic pain medications may be indi-
cated in lieu of, or in combination with, topical
agents. It should be noted that, although topical
agents may be efficacious, controlled prospec-
tive studies are needed with new generations
of dru.g~ to improve the management of oral
mUCOSItis.
Pain and discomfort need not automatically
limit oral hygiene practices. Topical anesthetics
can be used to control pain so that oral hygiene
procedures can be performed comfortably. Oral
hygiene must be stressed as a means to prevent
further infection in the mouth, as accumulation
of plaque and debris will lead to superinfection
and subsequent delayed healing of the oral
lesions. Brushing and flossing are optimal
methods of plaque control in the noncancer
patient [15]; under careful supervision, these
measures are recommended as the primary
means of performing oral hygiene in the mu-
cositis patient. With adequate pain control,
these techniques can usually be effective. Tooth-
paste, which can be irritating to open lesions,
is not necessary for plaque control.
At times, however, extensive oral ulcerations
and pain will prevent even the most cooperative
patient from brushing and flossing. In these
cases, less effective methods of plaque control
can be substituted. Gentle swabbing of oral
hard and soft tissues with moistened gauze
removes debris, although effective plaque con-
trol is not accomplished. Supplies (e.g., lemon
glycerine swabs and sponge swab sticks) com-
monly found in the hospital, although easy for
the patient or clinician to use, do not appear to
be effective overall for removal of plaque from
the gingival sulcus.
Many patients prefer the use of supplemental
rinses or mouthwashes in addition to standard
oral hygiene practices (table 24-4). Bland or
mild rinses with normal saline or water are
advisable where painful mucositis is a problem.
Antibiotic and/or antiseptic mouthwashes,
such as nystatin rinses or BETADINE (Purdue
 24. STANDARDS FOR NURSING CARE OF THE ORAL CAVITY 489

Frederick Company, Norwalk, CT06856) mouth-

wash, are often incorporated into the oral care
protocols.
Oral ulcerations frequently will bleed in the
setting of low platelets, resulting in crusted and
oozing sores. Oral hygiene in this setting is
severely limited. As noted above, gentle and
frequent swabbing with moist gauze to remove
crusts is effective, combined with irrigation us-
ing a dilute hydrogen peroxide solution (1:5
peroxide and water) followed by thorough rins-
ing with sterile water.
FIGURE 24-6. Oral candidiasis of the hard palate.
Infection. Oral infections in the radiation pa-
tient may be of viral, bacterial, or fungal origin.
Clinical examination, supplemented by viral
titers, microbial cultures and antibiotic sensitiv-
ity, smears, and/or biopsy should be considered
to document infection etiology.
One of the most common acute infections
seen in the radiation patient is moniliasis, which
can be painful to the degree that radiotherapy
may need to be discontinued. As discussed
previously, the infection is caused by radiation-
induced changes in the oral flora. Classically,
white patches that wipe off are seen, leaving red
burning tissue (figure 24-6). Several antifungal
topical and systemic agents are available to treat
moniliasis (table 24-4). It should be noted that
MYCOSTATIN suspension (E.R. Squibb and Sons,
Princeton, NJ 08540) contains as much as 50%
sucrose [14] to make the drug more palatable.
Considering the agent is used 3-4 times a day,
this amount of sucrose may promote caries
formation; thus, a non-sucrose-containing anti-
fungal agent (e.g., MYCOSTATIN vaginal tablets
dispensed as a lozenge; nystatin popsicles with
sorbitol) is recommended in cases of prolonged
use. Alternatively, MYCELEX troches (Miles
Pharmaceuticals, West Haven, CT 06516) (10-
mg clotrimazole lozenge that is sucrose-free) can
be dissolved in the mouth five times a day for 14
consecutive days. If the patient wears a dental FIGURE 24-7. Radiation dermatitis.
prosthesis, it must be removed from the oral
cavity nightly for 8 hand emersed in an antifun-
gal agent to avoid reintroduction of fungal reluctant to provide oral self-care. Palliation of
organisms into the oral cavity. this condition is limited. During the treatment
phase, the patient should not use petroleum
Radiation Dermatitis. Radiation dermatitis products, as they will potentiate the beam of
is an acute condition characterized by a "sun- radiation on the skin; any type of soap or cleans-
burned" appearance, resulting from the radia- ers should also be discouraged until comple-
tion inhibiting mitosis of epithelial cells within tion of therapy. Postradiation cocoa butter and
the portals of radiation (figure 24-7). Because A & D ointment (Schering Corporation, Kenil-
this condition is painful, the patient may be worth, NJ 07033) may be used for relief.
490 V. SUPPORTIVE CARE
Miscellaneous Complications. Other effects
of radiation include anorexia, lethargy, and
alteration in taste (dysgeusia); these complica-
tions may be related. Every patient undergoing
radiation for head and neck cancer should thus
be seen prior to, during, and after radiation by
a registered dietitian who is familiar with this
patient population.
The effects of diet and nutrition have signifi-
cant impact during therapy on both dental and
general health. The problem of weight loss
should be anticipated during therapy; however,
weight-loss problems continue to appear after
radiation, being maximal at three months and
remaining virtually unchanged by six months
after treatment [16]. Treatment-related morbid-
ity, radiation portal size, and treatment site all
influence this weight loss and prevent patient
recovery immediately following radiation ther-
apy. Thus, the nutritional support of these
patients needs to be considered for at least six
months after treatment.
The dietitian must guard against recommend-
ing ad lib sucrose intake as a facile way to boost
calories. Water, tea without sugar, or vegetable
juice is preferred for hydration. Sugarless gums
and mints are acceptable, as are foods contain-
ing non sucrose sweeteners such as saccharin and
aspartame (NUTRA-SWEET), (G. D. Searle, Chica-
go, IL 60680). The dietitian can recommend an
appropriate diet in consultation with the dental
hygienist.
CHRONIC SIDE EFFECTS OF RADIATION
Xerostomia. Xerostomia is caused by radia-
tion-induced sclerosis of the acini of the sali-
vary gland [2]. The resultant quantitative and
qualitative salivary changes can cause general-
ized, severe oral disease.
Saliva normally has multiple effects, including
regulation of the pH of the oral cavity, anti-
microbial immune properties, lubrication, and
cleansing [17]. The oral pH can become more
acidic when salivary flow decreases. An en-
vironment conducive to caries formation is pro-
duced, with an increase in Streptococcus mutans,
a major caries-forming organism [5, 18]. The
change in the oral eco-system due to the xeros-
tomia, combined with a high-sucrose diet and
poor oral hygiene, results in radiation caries.
Periapical infection and osteoradionecrosis may
occur if this destruction continues.
A major complaint of most patients is per-
TABLE 24-5. Risk factors in radiation caries
development
Failure of patient to:
Brush and floss effectively
Use fluoride daily
Wait 30 min after fluoride before rinsing
Perform oral hygiene after sucrose intake
Continue fluoride after radiation
Avoid sucrose intake
Seek frequent dental evaluations
sistent dryness. Palliation of this dryness is
achieved by frequent hydration with noilSU-
crose liquids (ideally water) and commercial
salivary substitutes (table 24-4). Most salivary
substitutes consist of sodium carboxymethyl-
cellulose combined with other agents, including
fluoride. The addition of fluoride is beneficial
as an anticaries agent and will be discussed in
further detail (infra vide).
Radiation Caries. Radiation caries are rapidly
forming lesions seen in conjunction with
radiation-induced xerostomia, poor oral hy-
giene, and frequent sucrose intake. Table 24-5
represents a guide to determine whether a
patient is likely to develop radiation caries.
Dental caries can be seen forming within 2-3
months versus several months for normal caries
formation [4]. Radiation caries classically de-
velop in areas that normally are self-cleansing,
such as incisal edges of anterior teeth, cusp tips
of posterior teeth, and the cervical area of the
tooth at the gingival margin (figure 24-8). A
slight stickiness can be initially detected with a
dental explorer. As the lesion progresses, frank
FIGURE 24-8. Radiation caries classically presents as
decay on cervical areas of the tooth (near gum line)
and as well as cusp tips and incisal edges that fracture.
 24. STANDARDS FOR NURSING CARE OF THE ORAL CAVITY
A tooth, move floss subgingivally. Short venical strokes
FIGURE 24-9. (a) (Lateral view) Soft nylon-bristled
brush with bristles placed at a 45° angle at the gingival
margin. (b) (Frontal view) Light pressure and a small
circular motion will sweep bristles into the sulcus.
caries may develop that may ultimately lead to
pain, infection, and osteoradionecrosis.
The preventive regimen for radiation caries
has four basic segments: periodontal care, oral
hygiene instructions, daily fluoride applica-
tions, and limited sucrose intake. These facets of
care are described below.
PERIODONTAL CARE. After the dental treat-
ment plan has been formulated, the patient
should have a thorough dental prophylaxis
prior to radiation. This includes scaling and root
planing the crowns and roots of the teeth to
mechanically debride supra- and subgingival
bacterial plaque and calculus.
ORAL HYGIENE INSTRUCTION. Effective oral
hygiene techniques must be taught on an indi-
vidual basis to each patient. It is not the fre-
quency but quality of brushing and flossing that
is important. The patient should utilize a sulcu-
491
FIGURE 24-\0. Directing floss in a "en shape around
from contact area to sulcus cleanses tooth surface.
Repeat process on adjacent tooth and throughout
mouth.
FIGURE 24-\1. Floss-holder devices allow easier
flossing for patients with less dexterity or in patients
with intravenous sites who have inhibited hand
movement.
lar brushing technique with a soft-nylon even-
bristled toothbrush (figure 24-9). Commercial
toothpastes are contraindicated once radiation
begins since toothpaste contains abrasives and
alcohol that might be irritating to the mucosa.
However, a bland monofluorophosphate den-
tifrice is acceptable [19]. Baking soda, which
has a low abrasivity and is nonirritating, can
also be used to clean the teeth, as can plain
water. Undiluted mouthwash should not be used
due to the high alcohol content [20], which may
have an astringent effect on mucosa (table 24-3).
Flossing can be accomplished by the hand-
held method or the holder device. The hand-
held method requires slightly more dexterity.
One correct flossing technique is shown in
figure 24-10. Alternatively, a floss holder such
as FLOSS FINGER II (Preventive Dentistry, Corona
492 V. SUPPORTIVE CARE

TUFT brushes (Preventive Dentistry) may b~ in-

dicated. The dental hygienist is well tramed
in their uses and should be utilized. to teach
health-care professionals as well as patients.
DAILY FLUORIDE APPLICATIONS. The third seg-
ment of the preventive regimen is the daily use
of fluorides. Fluoride is an anticaries agent that
remineralizes the enamel and has antibacterial
properties. Three types of fluoride preparations
are available: acidulated phosphate fluoride
(APF), neutral sodium fluoride, and stannous
fl uoride. The fluoride of choice is one that is
nonirritating to the mucosa, convenient, and
readily available. We recommend a neutral
A sodium or stannous fluoride in gel rather than
rinse form. The acidulated phosphate fluoride
can be very irritating to the ulcerated mucosa in
the radiation therapy patient and therefore
should not be prescribed.
A distinction must be made between sodium
and stannous fluorides when giving instructions
in fluoride use. Sodium fluoride ideally should
be applied over dry teeth; comparatively, stan-
nous fluoride requires water on the toothbrush
or fluoride carrier to activate the agent. Fluoride
can be applied by brush-on or fluoride-filled
carrier technique (figure 24-12). Consideration
of patient compliance and whether the fluoride
£I gel will contact the tooth surface for the
specified time is essential when selecting the
method of delivery. The fluoride contact must
FIGURE 24-12. (a) Custom fluoride carrier trays are
filled with fluoride gel prescribed by dentist. (b) Cus-
remain in contact with the tooth surface for at
tom fluoride trays are placed over dry teeth, held in least 5 min.
place for at least 5 min. Fluoride is expectorated after During episodes of severe mucositis and
tray removal; there should be no rinsing, eating, or xerostomia, the brush-on technique is usually
drinking for 30 min. Repeat procedure daily or as effective for the patient who cannot manipulate
prescribed by a dentist. the tissue to place the carriers. Discussion with
the patient will guide the clinician in developing
an individualized treatment regimen.
Del Mar, CA 92625) and FLOSSMATE (John o. Regardless of the type of fluoride or method
Butler Company, Chicago, IL 60611) may be of delivery, fluoride must be used daily and
used (figure 24-11). The floss must be wrapped continuously, beginning with radiation. A list
tightly between the prongs of the floss holder, of the American Dental Association's accepted
following package directions carefully. The type fluorides is outlined in table 24-4.
of floss is not as important as the patient's com- Chlorhexidine is another agent that has pro-
pliance. Although unwaxed floss is preferred, mise for future use as an anticaries agent [21,
waxed floss can be used for patients who have 22]. S mutans, a component of caries-producing
difficulty passing the floss through interprox- dental plaque, is very sensitive to chlorhexidine
imal contacts. The mechanical action of moving [21]. Tonelli et al. state that "the effectiveness of
vertically against the tooth is responsible for chlorhexidine in preventing the initial formation
disrul'.tion of bacterial colonization. of plaque, and in dispersing preformed plaque,
Other oral hygiene aids, such as PROXA- has made use of the drug appealing in numerous
BRUSHES (John Butler Company), PERIO AIDS clinical situations where daily conventional oral
(Marquis Company, Aurora, CO 80011), END- hygiene procedures are temporarily impossible
 24. STANDARDS FOR NURSING CARE OF THE ORAL CAVITY
FIGURE 24-13. Exposed necrotic mandible in patient
with osteoradionecrosis.
or difficult" [22]. Mouthrinses with 0.1% or
0.2% aqueous solution of chlorhexidine used
twice a day have proved to be effective in plaque
inhibition. One percent chlorhexidine-con-
taining toothpastes have also been tested, as
well as chlorhexidine gel containing 0.8%-
1.0% concentrations used in conjunction with
stent delivery trays [22]. These three different
vehicles are available in Canada and Europe.
Despite its value, chlorhexidine has not yet
been approved by the Food and Drug Adminis-
tration for general use in the United States.
Chlorhexidine produces an easily removable
brown stain on the teeth and soft tissues. In
addition, desquamation of epithelial cells has
been a concern [22-24]. However, opinions dif-
fer on the severity of this problem [21, 23] and
further research is needed.
LIMITED SUCROSE INTAKE. The fourth compo-
nent of the preventive regimen, dietary coun-
seling regarding limited sucrose intake, has pre-
viously been discussed in detail in relation to
xerostomia.
Osteoradionecrosis. The most devastating of
all postradiation sequelae from head and neck
radiation is osteoradionecrosis (figure 24-13).
This condition is intensely painful and can be
both disfiguring and expensive to treat.
The pathogenesis of osteoradionecrosis of the
jaws has been classically accepted as radiation,
trauma, and infection [3, 25]. Marx feels that a
more accurate description involves the bioche-
mical and cellular pathology: "Osteoradione-
crosis is not a primary infection of irradiated
bone. It is a complex metabolic and tis§ue
homeostatic deficiency created by radiation-
induced cellular injury" [25]. Microorganisms
493
play only a contaminant role in osteoradione-
crosis and trauma appears to be only one factor
leading to tissue breakdown. Marx suggests the
following sequence: radiation; hypoxic, hypo-
cellular, hypovascular tissue; tissue breakdown;
cellular death and collagen lysis that exceed
synthesis and cellular replication; and a non-
healing wound (a wound in which energy,
oxygen, and metabolic demands exceed supply)
[3, 25]. The mandible, with its single-source
blood supply, is more susceptible and has a
higher incidence of osteoradionecrosis than
the maxilla, which has a broadly based blood
supply [3, 26].
The nurse plays an important role in the
prevention of osteoradionecrosis. Of major
importance are the postradiation follow-up
appointments for which the patient may be re-
luctant to return. The schedule for regular post-
radiation examinations should be presented to
the patient prior to the end of radiation therapy
as essential, nonoptional visits. At these visits,
the nurse should question the patient concern-
ing chronic postradiation oral ulcerations, pain,
defective restorations, or poorly fitting pros-
theses. Affirmative responses to these questions
should prompt the nurse to refer the patient for
a dental examination. Concurrent medical-
dental appointments should be made at every
reexamination appointment (table 24-1).
Treatment for osteoradionecrosis includes
irrigation, high-dose antibiotics for extended
periods of time, hyperbaric oxygen, and surgical
procedures that may be as extensive as hemi-
mandibulectomy [3]. More detailed discussion
of treatment of this complication has been
presented in previous chapters. Certainly,
prevention is imperative.
Care of the Chemotherapy Patient
Some oral complications induced by head and
neck radiation therapy can also be observed in
the chemotherapy patient. It is essential that the
etiology of oral lesions be defined clearly when
possible so that appropriate care is delivered.
The oral changes can occur rapidly; frequent
examinations are necessary to detect the onset
of oral disease.
INFECTION
The frequency and severity of infectious com-
plications in the oncology patient have been de-
scribed previously (see chapters 9,19,21). Bone
494 V. SUPPORTIVE CARE
marrow suppression produced by underlying
disease and its treatment results in increased in-
cidence of infection. Infection remains one of
the leading causes of morbidity and mortality
in patients undergoing profound, prolonged
myelosuppression [27] in spite of antibiotic
therapy [28, 29]. Preventive techniques also
have significantly reduced infectious complica-
tions; these techniques include use of antibiotics
to reduce the number of opportunistic organ-
isms in the gastrointestinal tract, use of low-
microbial cooked food diet and, more recently,
the screening and selected treatment of oral
disease prior to chemotherapy [27, 30]
Periodontal Infection. Because periodontal
disease is chiefly infectious in nature, it must
also be considered as a potential source of
bacteremia for the aplastic patient (see chapter
19). Acute exacerbations of chronic disease have
been observed to frequently occur in severely
myelosuppressed patients [31]. These acute in-
fections are characterized by pain within the
periodontium, and fever, but only minimal
signs of inflammation.
In a patient without hematologic compro-
mise, both the treatment and prevention of
periodontal disease consists of (a) thorough and
consistent oral hygiene to eliminate bacterial
plaque, the local etiologic factor, (b) regular
dental scaling and polishing to further control
plaque and calculus accumulation, and (c)
corrective periodontal surgery if indicated
[15]. However, techniques to prevent acute
periodontal exacerbations of preexistent peri-
odontal disease in patients with altered host
defenses are still under investigation [31]. Oral
hygiene procedures (brushing and flossing) in
the granulocytopenic, thrombocytopenic pa-
tient have been controversial. There is concern
that dental manipulations such as brushing and
flossing in a myelosuppressed patient may cause
bacteremia and/or hemorrhage; for this reason,
many oncologists and dentists have restricted
the use of oral hygiene devices such as tooth-
brush and floss. However, given the known fre-
quency of chronic periodontal infection and in-
cidence of acute periodontal exacerbation in an
aplastic host (approximately 25% of all infec-
tions in acute nonlymphocytic leukemia pa-
tients) [31], some method of thorough plaque
removal appears to be indicated. Brushing and
flossing, correctly performed, remain the best
methods of plaque removal and have therefore
FIGURE 24-14. Culture-positive recurrent herpes
simplex lesions (arrows) on hard palate of granulo-
cytopenic leukemia patient. Early vesicular lesions
rapidly become ulcerated and coalesce to form larger,
necrotic painful lesions.
been utilized with careful supervision at some
cancer centers [32]. Oral hygiene treatment
plans must be tailored carefully to each patient's
abilities and needs. We do not feel that hygiene
procedures (toothbrush and floss) should be
automatically eliminated in the aplastic host.
Positive results of oral hygiene are increased pa-
tient comfort and well-being, possible reduction
of incidence of acute periodontal infection, and
possible reduction of oral mucositis.
Management of an acute periodontal infec-
tion should be approached systemically and
locally. Systemic antibiotic therapy with broad-
spectrum coverage is usually indicated. Local
therapy includes (a) pain control (topical or sys-
temic as indicated) (table 24-4); (b) continued
oral hygiene (brushing and flossing if possible,
less aggressive oral hygiene if necessary), and (c)
oral rinses (i.e., GLY-OXIDE [Marion Labora-
tories, Kansas City, MO 64137] [31, 32]; table
24-4).
Nonperiodontal Viral! Bacterial! Fungal In-
fections. Viral (figure 24-14), bacterial (figure
24-15), and/or fungal infections (see figure 24-6)
are frequently encountered in the myelosup-
pressed host [27, 33]. The oropharyngeal flora
of chronically ill patients shifts toward in-
creased number of gram-negative organisms
[34]. Frequent and long-term antibiotic therapy
will predispose to fungal overgrowth [27, 29].
Also, long periods of immunosuppression
secondary to radiation, chemotherapy, or dis-
ease may predispose to viral infections [27].
Infections in the compromised host will
 24. STANDARDS FOR NURSING CARE OF THE ORAL CAVITY 495

FIGURE 24-15. Infected periodontal lesion (arrow) in

granulocytopenic patient; cultures grew Pseudomo-
nas spp.
usually present in mucosa already affected by
chemotherapy [28-30]. Various antibacterial
and antifungal rinses (table 24-4) are used
selectively to suppress oral and gastrointestinal
flora in some institutions. These may include
such preparations as nystatin, vancomycin,
gentamycin, ketoconazole, amphotericin B,
and trimethoprim sulfamethoxasole delivered
in "swish and swallow" rinses or pills. Mouth-
wash preparations (i.e., BETADINE) are on
occasion incorporated into the oral regimen.
Oral infections are still a major problem in
spite of the availability of such regimens. The
high cost of antibiotic regimens, poor patient
compliance, and lack of prophylactic measures
for viral infections still result in a large number
of oropharyngeal lesions. As with lesions in the
radiation patient, the key to effective therapy of
such lesions is early detection and documenta-
tion of lesions in the medical chart, including
description, size, and location of lesions. Care-
ful observation is essential, since myelosuppres-
sed patients have altered inflammatory signs
and presentation of infection [35]. Diagnostic
tests such as culture, smear, and microbial sensi-
tivity of all lesions may be indicated.
Effective treatment regimens can be designed
once correct diagnosis is established. Topical
agents should not be overlooked, either singly
or in combination with systemic therapy. Anti-
biotic mixed in ORABASE has been used on occa-
sion to deliver topical antibiotics to the oral
mucosa; the efficacy of this approach remains
to be determined.
Pain control and oral hygiene procedures are
a crucial part of the oral treatment of these
lesions. The reader is referred to the section on
mucositis and acute periodontal infection for
further discussion.
XEROSTOMIA
Chemotherapy-induced xerostomia IS usually
transient and is not generally as severe as
radiation-induced xerostomia. Simple palliative
techniques such as use of salivary substitutes
and frequent hydration will usually provide the
necessary relief. Management of xerostomia is
especially important for a patient with mucosi-
tis, in whom dryness can further irritate
damaged tissues.
MUCOSITIS
Mucositis is a direct result of the cytotoxic
effects of many cancer drugs on the mucosa.
Normal tissue (i.e., alimentary tract) as well as
neoplastic cells may be very susceptible to
chemotherapy-induced changes [36]; in this re-
gard, pathogenesis is similar to the previously
discussed radiation mucositis.
FIGURE 24-16. Chemotherapy-induced mucositis in
patient who received 5-f1uoruracil.
496 V. SUPPORTIVE CARE
erythematous patches, sloughing tissue, ulcera-
tions, or necrosis on any soft-tissue surface of
the mouth (figure 24-16). The pain and discom-
fort associated with these lesions often marked-
ly impair nutrition, oral hygiene, speech, and
ability to take oral medication or swallow. The
disruption of the mucosal barrier also may pre-
dispose the patient to opportunistic infection
[28-30].
Protecting the mucosa from the toxic effects
of chemotherapeutic drugs could therefore be
an effective method of preventing mucositis in
patients; however, no preventive techniques
have yet been utilized effectively. The increasing
numbers of new tumoricidal drugs being de-
veloped may eventually yield a drug with less
oral toxicity. Other forms of prevention may be
possible in the nature of "rescue agents," which
are agents that can be delivered topically or
by intravenous infusion. This approach would
limit the adverse effects of the chemotherapy on
the host cells, such as leucovorin rescue used in
high-dose methotrexate therapy.
On occasion, oral complications may be
severe enough as to limit the dosage of the drugs
that can be given in subsequent courses. At best,
any preventive therapy for mucositis is limited
and clinicians are forced to treat the unpleasant
effects of mucositis. This treatment then must
take the form of (a) palliation of pain and (b)
prevention of secondary infection. The same
techniques discussed previously for palliation
and cleansing of radiation-induced mucositis
can be used.
HEMORRHAGE
Hemorrhage resulting from thrombocytopenia
or coagulopathy is another complication in the
chemotherapy patient (see chapter 19). Recent
advances in platelet support therapy have con-
siderably minimized this complication of che-
motherapy and marrow aplasia [37]. However,
simple preventive practices remain crucial to
nursing care for the thrombocytopenic patient.
Specifically, invasive procedures in the mouth
are limited during the periods when platelet
levels are below 50,000 cells/mm3, and should
be completely avoided with platelet counts
less than 20,000 cells/mm 3 [38]. Procedures
that must be performed during profound
thrombocytopenia may require prophylactic
platelet transfusions or immediate availability of
platelet transfusions as needed. This reinforces
the importance of early dental consultation and
treatment so that invasive oral procedures (ex-
tractions, scaling, etc.) can be completed before
the patient experiences significant thrombocy-
topenia.
Trauma to the oral tissue (poorly fitting
dentures, improper brushing, or use of a hard-
bristled toothbrush) should be avoided so as not
to induce bleeding. Infected mucosal areas have
an increased tendency to bleed. Gentle but thor-
ough oral hygiene (brushing and flossing) to re-
duce plaque levels and subsequent oral infection
may therefore be helpful in reducing spon-
taneous hemorrhage from infected oral tissues.
Oral hemorrhage still occurs in spite of pre-
ventive measures and prior transfusion therapy.
The following local measures may be useful in
promoting clot formation:
-If a bleeding point is isolated, gauze packing
should be used with firm constant pressure
for extended periods of time so that clots may
form and adhere to the wound without being
disturbed.
-Hemostatic agents such as thrombin may be
used topically to promote clot formation.
- Avoidance of vigorous rinsing, spitting, or
use of drinking straws following oral surgery
procedures or in the presence of oral bleed-
ing, as the clot may be dislodged.
Adequate levels of circulating, functioning
platelets and prevention of mucosal injury re-
main the best techniques for control of hemor-
rhage.
Care of the Head and Neck
Surgery Patient
The nurse serves as the primary health-care pro-
vider to the patient and family pre- and post-
operatively. The primary roles of the nurse in-
clude (1) preoperative tests and consultations
(including prosthodontic evaluation), (2) man-
agement of fluid and electrolytes, (3) airway
management, (4) pain control, (5) assessment
and care of surgical site, (6) oral hygiene, and (7)
emotional support and discharge preparation.
PREOPERATIVE TESTS AND
CONSULTATIONS
Head and neck surgical patients undergo a wide
range of procedures, varying from a simple ex-
cisional biopsy to radical neck dissection result-
ing in gross disfigurement and loss of function.
 24. STANDARDS FOR NURSING CARE OF THE ORAL CAVITY
FIGURE 24-17. (a) Surgical defect ot hard an soft pal-
ate that produces impaired speech and swallowing.
(b) Prosthetic device used to correct palatal defect.
(Photographs courtesy of Dr. W. Ramsey, Baltimore
College of Dental Surgery, Dental School, University
of Maryland at Baltimore.)
Support of the latter category of patients is
particularly critical, and multiple tests and
consultations are usually indicated. In addition
to working with the surgeon in perfortning the
diagnostic tests, the nurse should facilitate
obtaining the prosthetic consultation.
Prosthetic replacement can be used to correct
a large void in tissue and substructures resulting
from existing surgery. Planning of prosthetics
should begin preoperatively if prosthetics are to
be part of the patient treatment. The patient
needs to be evaluated by the prosthodontist,
who will examine, plan treatment, and fabricate
initial diagnostic casts (see chapter 23).
When the prosthetic device is delivered post-
operatively, the nurse must work with the pa-
tient, teaching him insertion, removal, and the
care of both prosthesis and tissue. The prosthe-
sis should be removed daily and cleaned with a
mild detergent or as specifically prescribed. The
497
tissues should be cleansed with normal saline,
soap and water, or diluted peroxide on gauze or
cotton swabs. The physician and dentist should
be made aware of any tissue irritation or dis-
comfort as the patient continues to wear the
appliance; if signs of irritation are noted in a
patient receiving ongoing chemotherapy or ra-
diation therapy, use of the prosthesis must be
discontinued until the treatment is completed.
The head and neck region is especially impor-
tant to the patient's self-image. Restoration of
esthetics and function can be helpful to the pa-
tient in coping with the diagnosis and treatment
of head and neck cancer (figure 24-17).
MANAGEMENT OF FLUID
AND ELECTROLYTES
When the patient is able to advance to a liquid
diet, the nurse should assist the patient and
family in diet planning and preparation. Occa-
sionally, these patients must learn to take food
through nasogastric or gastrostomy tubes. A
blenderized diet or a liquid processed diet can
then be used. The patient and family should be
taught proper care and methods of tube feeding
in this instance.
498 V. SUPPORTIVE CARE
The first procedure that the patient or family
member responsible for care should demon-
strate is the ability to check the position of the
tube before each feeding. The simplest way is to
place the end of the tube in a glass of water; air
bubbles may indicate that the tube has dis-
lodged into the lungs. The patient in this case
should be instructed to seek medical care for
reinsertion of the tube. The patient should not
insert any food in the tube until proper position
has been established and verified. Correct feed-
ing technique should be demonstrated by the
patient or family member before discharge.
After verification of the tube position, the
feeding should be placed in a feeding bag or
large syringe held approximately 6 inches above
the patient's head. The temperature of the tube
feeding should be approximately 70°-72°F. The
average tube feeding tolerated is approximately
400 cc every 4 h followed by 60-100 cc of water
to prevent food obstruction in the tube. A sched-
ule of six small feedings should be adhered to
daily, with a total intake of 2500-3000 cc. The
patient should record his weight daily and in-
crease the caloric value of his diet if necessary
to maintain adequate weight and a positive
nitrogen balance.
In addition to proper feeding techniques, nare
care is a necessary aspect of patient treatment.
Such care results in (a) prevention of erosion of
TABLE 24-6. Nare care procedures
1. Assemble the equipment.
2. Tear off approximately 3 in. of the silk tape.
3. Take the 3-in. piece of tape and tear it 2/3 of the
way lengthwise.
4. Tear off strip of tape 11/2 in long.
S. Place both pieces of tape in an easily accessible
area.
6. Open 2 alcohol swabs, H 20 2 , and applicators.
7. Hold nasogastric tube in place with one hand and
remove old tape carefully.
8. Clean nose with alcohol.
9. Clean nose area with applicator; if there is dried
mucus on the tube or in the nose area, clean with
H 20 2 on an applicator.
10. Apply skin prep to nose. Allow to dry for a few
seconds.
11. Retape the nasogastric tube
12. Do this procedure every day and prn while
patient has the nasogastric tube in place.
13. Chart nare care on activity and treatment record
or flow sheet. Any noted abnormalities require a
"SOAP" note, progress/nurses note.
tissue from the indwelling tube, (b) prevention
of displacement of the tube, (c) prevention of
bacteria accumulating on the tape, and (d)
improved comfort for the patient. The steps
in the procedure for nare care are outlined in
table 24-6 [39].
AIRWAY MANAGEMENT
Airway management is a serious concern for the
head and neck surgical patient. Breath sounds,
vital signs, lung compliance and consistency,
color, odor, and amount of secretions should be
assessed. The patient may be placed on oxygen
therapy postoperatively, in which case blood
gases should be evaluated if clinically indicated.
Postoperative respiratory therapy should be
included in the patient's treatment. This often
includes chest physiotherapy, coughing and
deep-breathing exercises when sitting, incentive
spirometry, and heated humidity oxygen ther-
apy. The patient should be encouraged to
ambulate as soon as possible. This approach is
designed to prevent postoperative pneumonia, a
serious concern for the head and neck surgical
patient due to the stasis of secretions. Also, sur-
gical patients with extensive defects usually have
had a tracheostomy performed during surgery
to establish a patent airway. The nurse is re-
sponsible for routine tracheostomy care until
the patient is able to assist in his own care. Such
care includes frequent changes of the inner tube
as well as wound care. Occasionally (except for
laryngectomy patients), these patients leave the
hospital with the tracheostomy; it is the nurse's
role to teach the patient and family member
to perform routine stoma and tracheostomy
care, removing and replacing both the inner
and outer cannulas and suctioning adequately
(table 24-7) [40].
PAIN CONTROL
Pain control is a primary role of the nurse. Pre-
scribed medications should be given promptly
and efficacy in pain control monitored. The
dose of medication often must be initially
titrated for sufficient pain control; it can then
be gradually tapered during the postoperative
course. All dosing must considered carefully, to
avoid overdosing and respiratory suppression.
ASSESSMENT AND CARE OF SURGICAL SITE
The surgical site and procedure will be deter-
mined by the specific lesion and extent of dis-
ease. General considerations of postoperative
 24. STANDARDS FOR NURSING CARE OF THE ORAL CAVITY 499

TABLE 24-7. Tracheostomy care. Often the patient will be discharged with a tracheostomy tube in place. The
patient or family must demonstrate the ability to suction secretions and perform accepted tracheostomy care
procedures as described.

1. Wash inner cannula with a small test-tube brush and a cold solution of 1/2 strength H 2 0, sterile normal saline
solution, or sterile sodium bicarbonate solution.
2. Use cold running water and pipe cleaners to clean inside of tube.
3. Clean the inner cannula with soap and hot water. After cleaning the tube, look through the lumen to be
certain it is clear. Next, submerge the cannula in 70% alcohol and place on a sterile gauze to dry. Replace the
cannula when dry.
4. If cleaning both inner and outer cannulae, clean as above. Suction the stoma and trachea with low-pressure
flexible suction tubing. Insert the outer cannula and tie in place with a clean tracheostomy tie or tape.
Reinsert the inner cannula and lock securely.

TABLE 24-8. Wound care

Type of
dressing Wet-to-wet dressing Wet-to-dry dressing Packed dressing Dry dressing

Purpose Cleanses skin of Debrides wounds by Maintains a passage- Protects the wound
exudates and debris a combination of way for the en- from mechanical
Maintains drainage of its capillary action trance of antiseptic injury and bacteria
infected areas by entwining of and debriding Absorbs drainage and
Reduces inflamma- necrotic debris agents fluid wastes
tion by producing within its mesh Allows wound to heal Promotes homeo-
vasoconstriction Acts as passageway by secondary in- stasis as with a
Creates and maintains and storage point tention pressure dressing
a normal phys- for the drainage Prevents contamina-
iologic environ- Provides a physio- tion from bodily
ment logic environment discharge
Allows wound to heal
by secondary in-
tention
Instructions All dressing changes All dressing changes All dressing changes All dressing changes
and wound care are and wound care are and wound care are and wound care are
sterile procedures sterile procedures sterile procedures sterile procedures
Assess wound and Cleanse intact sur- Assess wound and Remove previous
surrounding skin rounding skin with surrounding skin dressing and assess
Open sterile barrier, normal saline be- and document any healing
place stack of 4" x fore each dressing changes Cleanse area as
4" s on barrier Open sterile 4" X 4" s Open sterile 4" x 4"s ordered. Cover
Pour prescribed solu- and place on sterile drop onto sterile wound with 4" x
tion on 4" X 4"5 barrier and pour barrier, pour pre- 4"5
Cleanse wound and solution on 4" X scribed solution Pressure dressings
surrounding skin 4"5 onto 4" X 4"5 should be occlusive
Place wet gauze in Wring out wet 4" x Cleanse wound area and taped com-
wound, loosely 4"s, fluff and place as ordered by pletely at periphery
pack overwound physician (i.e., elastoplast)
Apply dry 4" X 4" Apply dry 4" x 4" Loosely fill entire Tape, date, time
over wet 4" X 4" to overwet41f X 4"s wound with gauze and initial dressing
keep dressing in Tape, date, time or packing material
place and initial dressing Apply dry 4" x 4"s
Tape, date, time over wet 4" X 4"5
and initial dressing Tape, date, time
and initial dressing
500 V. SUPPORTIVE CARE
surgical treatment include evaluation of the sur-
gical sites for inflammation, swelling, drainage,
or dehiscence of the surgical incision. The graft
site should be observed for inflammation, infec-
tion, necrosis, and color if a flap or graft proce-
dure has been performed; a dusky color often
indicates flap failure or inadequate blood flow.
Blanching and subsequent return of color
should occur when slight pressure is applied
and removed. The donor site should be moni-
tored for adequate healing. Pressure should be
avoided over the donor and recipient sites and
suture lines. As noted, proper patient position-
ing is imperative for patient comfort as well as
optimal healing.
Specific wound care will vary with the proce-
dure and healing of the site. General wound
care procedures and rationales are presented
in table 24-8 [39].
The patient should be taught to evaluate the
wound for adequate healing and signs and
symptoms of infection and necrosis. The goal of
wound care is to keep the surgical site as clean
and aseptic as possible. The patient should be
taught to cleanse the site, using a "clean tech-
nique" with normal saline and H 2 0 solution
(50:50); this solution should be applied with a
cotton-tip applicator with a light sweeping mo-
tion away from the excision to debride the area.
An antibiotic ointment such as BACITRACIN
(American Pharmaceutical Company, Passaic,
NJ 0755) can be applied to the incision line. If
a dressing is required, sterile gauze should be
applied and taped lightly.
ORAL HYGIENE
Specific oral hygiene techniques for the head
and neck surgical patient can vary according to
the surgical procedure; when the surgery in-
volves the oral cavity, high levels of oral hygiene
must be maintained. If teeth remain, a light
brushing and flossing technique should be initi-
ated within 24 h postoperatively if possible. Salt
and baking-soda rinses or warm normal saline
rinses are used frequently and have been de-
scribed previously.
The surgical site must be kept free of debris to
facilitate adequate healing and prevent infection.
When grafting is used at the oral site, vigorous
debriding should be avoided, as it can result in
graft failure. Some techniques for debriding that
may be used include (a) enema bag rinses, which
flow gently through tubing placed in the
patient's mouth; the bag is held approximately
8-10 inches above the patient's head; and (b)
use of a 60-cc syringe with a 3-inch length of
oxygen tubing; rinses are gently syringed into
the patient's mouth. The rinses should be
allowed to flow from the patient's mouth into a
basin, and spitting should be avoided. These
rinses should be performed approximately six
times a day and the area should be evaluated for
adequate healing.
If necessary, TOOTHETTES (Hal Brand, Wil-
loughby, OH 44094) swabs or gauze pads
(although not routinely advised for plaque re-
moval) can be used to swab the area and remove
debris. The tongue and mucosa should be
cleansed (even if not included in the surgical
site), as normal salivary flow and stimulation are
frequently reduced in these patients. The teeth
and gingival tissues should be cleansed with
routine oral hygiene techniques if possible.
For the patient with a nasogastric tube, it is
important to (a) prevent infections such as par-
otitis, (b) dilute the secretions in the oral cavity,
(c) prevent periodontal disease and tooth decay,
and (d) aid in patient comfort. A suggested oral
rinse is one teaspoon each of salt and baking
soda, in one quart of tap water. If the patient is
capable, he/she should gargle with the solution
2-3 times, or irrigate with a syringe and ex-
pectorate the secretions [39].
The tracheostomy patient should also be
taught to evaulate the oral cavity for signs and
symptoms of infection. Accepted oral hygiene
techniques include [39] rinsing as previously de-
scribed for the patient with a nasogastric tube,
or use of pulsating devices and suctioning with
a tonsil tip. If the patient has natural teeth,
brushing and flossing as described earlier should
be performed.
DISCHARGE PREPARATION AND
EMOTIONAL SUPPORT
The preparation for discharge should begin as
the patient progresses through the postoperative
course of treatment. The nurse has a primary
role in educating the patient and family in
coping with the demands following surgery.
The primary-care person must accept the
head and neck cancer patient's appearance and
physical limitations, since the changes in body
image created by surgery can be extensive. The
nurse can help verbalize feelings and questions
by teaching the patient and family about the dis-
ease and aspects of treatment. This can best be
achieved when an open and comfortable atmo-
 24. STANDARDS FOR NURSING CARE OF THE ORAL CAVITY
sphere has been established. Appointment for
follow-up care should be scheduled before dis-
charge and need for maintenance of continuing
care reinforced.
Summary
The focus of providing head and neck care to
the cancer patient should be to provide an orga-
nized, sequential approach to nursing care. This
chapter has emphasized the needs for thorough
oral evaluation, treatment, and preventive care
at all stages of cancer therapy. Specific attention
to the prevention of oral problems whenever
possible is crucial to patient comfort and well-
being. The nurse is instrumental in coordinating
and reinforcing this well-planned approach; the
utilization of the dental team can significantly
support such management.
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 25. PSYCHOSOCIAL EFFECT OF
CANCER ON THE PATIENT AND
THE FAMILY
Nathan Schnaper
Tamar Koren Kellner
An Overview of the Emotional
Problems of the Patient with Cancer
Any real understanding of the emotional prob-
lems of the patient with facial involvement
secondary. to cancer and its management re-
quires an understanding of the emotional prob-
lems universal to all patients with cancer. This is
not to say that all patients with cancer react to
the disease and the threat of death in the same
manner. Nor is cancer the only life-threatening
illness; others exist, including cardiovascular
and neurologic diseases, renal disorders, and
physical trauma. However, members of the
oncology team in a cancer center are concerned
with the emotional problems of the patient with
cancer and, on occasion, specifically the patient
with cancer of the head and neck. In addressing
these emotional concerns, the patient cannot be
considered in pure culture, as he/she has family,
friends, and professionals who help. For pur-
poses of discussion in this chapter, however, the
patient, family, and professionals are artificially
separated, while keeping in mind that there is an
ongoing interaction between them.
THE PATIENT
The diagnosis of "cancer" evokes a shock reac-
tion in the patient and his family. The media
supports this response despite the fact that,
statistically, more people die of cardiovascular
disease than cancer. The news strikes the patient
and his family as stress-a stress that seems
to have little possibility of resolution. The pa-
tient frequently seeks an explanation (e.g., sin
[aggression, sexual], falls, bee stings), usually to
expiate guilt for falling ill to cancer [1]. The pa-
tient can experience progressive fears: the fear
Peterson et ai., HEAD AND NECK MANAGEMENT OF THE CANCER PATIENT.
© 1986. Martinus Nijhoff Publishing. All rights reserved.
of the unknown, a basic death anxiety; the fear
of loneliness or separation, particularly from
family and friends; fear of body image change
such as in mutilation (especially genital, breast,
head, mouth, extremity); fear of loss of control;
fear of regression; and a fear of loss of identity
[2].
However, the patient has techniques to cope
with these stress-engendered fears. Just as man
at all times seeks to maintain both an outer
equilibrium with his environment and an inner
homeostasis, he also copes with the anxieties in
his environment and inside himself with a sys-
tem of defenses. Anxiety is an unpleasant feeling
of apprehension with its well-known somatic
symptomatology. In a situation where one
experiences conflict or threat of loss of love,
security, self-esteem, or personal injury, anxiety
signals the defensive process. This process can
be healthy or pathologic, constructive or de-
structive; the defenses begin in earliest childhood
and develop experientially [3].
The defense mechanisms stem from a con- .
scious awareness of a difficult or unpleasant
situation and for the most part are normal. The
predominant and most effective defense utilized
by patients with cancer is denial. Denial is an
unconscious defense that prevents one from
seeing the unpleasant, particularly about onself.
There are various techniques used by patients in
this regard, including: intellectualizations (as in
the case of sophisticated patients referring to
their illnesses in "clinical" terms), humor (in
which the "joke" is on oneself), and anger
toward everyone and everything except the
disease. Denial can spare the individual of pain,
as in the case of the physician who is himself be-
ing treated for cancer. He cannot arrive at the
503
504 V. SUPPORTIVE CARE
correct diagnosis, despite the reality of his
treatment. It can also be used pathologically,
as in the case of the woman who feels a breast
lump, but delays diagnosis and treatment.
A second defense is projection, whereby one
attributes a true feeling to another, false, feeling.
This is a common mechanism in the dental pa-
tient as well as the patient with cancer. Both fear
their professional helper, yet complain only in-
directly while wishing to "get even" and "hurt"
the helper who "doesn't like me and is deliber-
ately hurting me."
Other mechanisms of defense are: repression
(unconscious forgetting); suppression (conscious
forgetting); regression (reversion to an earlier
life stage, e.g., the "mature" patient who fol-
lowing therapy becomes childlike in his de-
pendency); and magical thinking (fantasies of
omnipotence of self or others, e.g., expecting
the professionals to be all-powerful and guaran-
tee a cure).
Some patients simply withdraw, their attitude
being "Do whatever you want, I don't give a
damn." It is neither unusual nor abnormal for
people to entertain suicidal ideas. This includes
patients with cancer. When a patient does com-
mit suicide (a relatively rare occurrence), it is
indicative of giving up all hope and at times, a
way of "cheating" death.
Thus, the cancer patient approaches the criti-
cally threatening period associated with cancer
with self-protective resources that he can use
constructively or destructively. Also available
to him, kindly or cruelly, are his own develop-
mental history and life experiences, notably his
experiences with friends and relatives in similar
situations [4].
THE FAMILY
As previously discussed, it is difficult to deal
with the patient separately from the family.
Some families press to keep the diagnosis a
"secret." Frequently, there is anger at the di-
agnosing professional-a reaction to the guilt
felt for being spared.
Some families, in an effort to preclude later
guilt, move too close to the patients, over-
whelming him and the staff. Others abandon
him, as "he is dead already" at the time of
diagnosis. Both techniques are doomed, as
mourning virtually always ensues.
The family (and the patient's) immediate
problem is the threat of loss or separation. This
anticipation evokes the familiar grief reactio'n.
While grief is a response to loss or threat of loss,
it can be a response to any separation, such as
surgical amputation or financial catastrophe.
How the family grieves will have a positive or
negative effect on the patient as he moves
through the various phases of his illness and its
treatment.
Grief and its expression, mourning, have
phases that overlap, skip, or fixate. It usually
begins with shock and a sense of unreality. This
can give way to expressions such as emotional
release (tears), covert hostility, utter depression,
physical symptoms (anorexia, insomnia, panic,
guilt, overt hostility), and finally readjustment
to reality. All these phases, in varying intensi-
ties, can be expected. They can be summed up as
"shock," "turmoil," and "resolution" [5].
There are also pathologically morbid grief
reactions, such as delayed or inhibited grief,
chronic grief, overdependency, foolish behav~
ior, and physical illness. These reactions require
the intervention of the psychotherapist, and
need to be recognized early by the profes-
sional helpers [6].
THE PROFESSIONAL
By definition, the term professional asserts that
the helpers are a stable, rich source of support
for the patient with cancer. However, the pro-
fessional is also a human with his own defenses
and personality; some find it impossible to
work with patients with cancer, some find it
difficult, while some establish a comfortable
clinical distance and even experience grati-
fication with the work.
When the professional's sense of omnipo-
tence intrudes itself into the therapy, however,
the patient can suffer. At this point, the helper is
concerned more about curing than caring. Any
setback on the part of the patient is experienced
as a failure of omnipotence. This is unconscious,
but manifests itself in subtle ways such as anger
toward the patient, avoidance, or patronization.
When it becomes evident that the patient will
fare poorly or die, the "omnipotent" profes-
sional is compelled by unrealistic guilt and
accountability to abandon the patient before he
dies, thus avoiding retribution.
It is fortunate that most professionals who
have chosen to labor in the field of cancer are
emotionally mature and have come to terms
with their omnipotence.
 25. PSYCHOSOCIAL EFFECT OF CANCER ON THE PATIENT AND THE FAMILY
The Head and Neck Cancer
Patient: a Special Case
The patient with head and neck cancer, by
virtue of his severe and permanent facial dis-
figurement, closely resembles the burn patient.
In both patients, the face and neck, which
are usually unprotected, are subject to trauma
with subsequent massive scarring. Whether or
not these individuals are actually disfigured,
they are approached with a high degree of
revulsion-much as one would feel toward a
leper. This is based in the fact that we greet the
world with our face and the world judges us by
our facial appearance. Weare either beautiful,
ordinary, or ugly. We thus equate our self-
image with our physical appearance; when we
suffer facial disfigurement, the world reacts to
us (or we believe it reacts to us) with horror,
fear and, at times, disgust.
THE PATIENT'S REACTIONS
For the most part, the patient afflicted by a
malignancy of the head and/or neck is treated
surgically. This experience in itself engenders
potential for added emotional trauma; when
one considers that the patient is a person with a
unique personality, defense system, and history
of life successes and failures, the complexity of
reaction becomes clear. The patient has an
illness modulated by emotional factors, and he
brings to this illness and/or treatment his own
personality as well as his anxieties and defenses
[7].
Undergoing anesthesia for surgical interven-
tion for cancer is a unique experience, akin to
death and resurrection. It brings up both realis-
tic fear and infantile (unreal) anxiety. For adults,
there is often the fear of awakening prematurely
or not at all, as well as losing control with sub-
sequent embarrassment. The experience can be a
terrifying one for children, followed by night-
mares, neurosis, and neurotic symptoms [8].
Surgery of the head and neck also entails a
life-and-death threat. Distortions of body image
playa significant role in any surgical experience.
Ordinarily, body image is a picture or concept
one has of the physical appearance of his/her
body (the face particularly), both consciously
and unconsciously. However, body image can
include one's automobile, clothes, or even
perception of the environment, all contributing
to a sense of identity [9].
505
It is during the postoperative period that the
patient feels body image is shattered. It is a time
that body image suffers, as with amputees, para-
plegics, women with mastectomies, violinists
who have lost fingers, and track athletes who
have lost toes. The young woman who has lost
her tongue to cancer, or the congressman whose
mandible has been removed, feels his/her body
image is devastated; they can no longer face
society and, as a part of distorted body image,
feel that society can no longer face them.
As with the "burn" patient, the patient after
surgery of the head and neck feels shame, im-
potent rage, withdrawal, depression, and/or
stigmatization. Some will regress to infantile
behavior [10]. Many carry the constant aware-
ness of their disfigurement, always anticipating
a social confrontation that must be avoided;
some wear surgical masks, others cover their
faces with scarves. Bitterness and quibbling
with family is frequent (as it is with many
patients with cancer of any kind). Some, in
'their apathy, experience "social death," by
which the patient withdraws from all treatment
as well as from society [11]. Those who have
chemotherapy and/or radiation therapy also
must suffer the added humiliation of attendant
complications, including nausea, vomiting, and
hair loss.
THE FAMILY, SOCIETY, AND
PROFESSIONAL STAFF
In general, families of patients with head and
neck cancer respond to the patient as do families
of patients with cancer of any type; shock, anxi-
ety, anger, and grieving are common. However,
added to this reaction are feelings of revulsion
that engender guilt, efforts to conceal reactions,
and detachment. Some will join the patient in
his isolation. Many families patiently suffer
through the experience until they can be sup-
portively direct with the patient by conveying
to him their realistic expectations of his abilities.
Unfortunately, families will share the general
stereotype of the physically disfigured person as
deviant and handicapped [10]. People can offer
an uncomfortable silence or stare at the patient.
Friends unintentionally can make the patient
feel abnormal and unwanted.
. Professionals are not excluded in regarding
these patients as unwelcome. The slang pejora-
tive term "get out of my emergency room"
(GOMER) is used by some physicians in de-
506 V. SUPPORTIVE CARE
scribing these individuals. By definition, it ap-
plies to the old, low socioeconomic, incurable,
unattractive, usually alcoholic, tobacco-stained
person who takes a long time to die regardless
of diagnosis and is therefore considered a waste
of treatment time and medications.
This intolerant attitude sometimes colors the
staff's perception of the patient with head and
neck cancer, who is frequently physically dis-
figured and aged. As noted previously, many
health-care personnel find it difficult, if not im-
possible, to work with or around patients with
such cancer [12]. Some oncologists are "turned
off" by the unattractiveness and mutilation of
these patients. Threats to their omnipotence are
more prevalent in that the diseased or disfigured
sites are readily apparent in patients with head
and neck cancer. Some physicians and dentists
will occasionally treat the aged, the non-"VIP,"
the unattractive person, and/or the patient with
a "nonappealing" diagnosis such as cancer, but
most clinicians generally avoid these indi-
viduals.
As a rule, families, professionals, and people
tend to regard the cancer patient as if he were
some repulsive "thing." The healthy viewer's
own body image feels threatened by identifica-
tion. There is frustration in efforts to communi-
cate, as facial expression is limited by the dis-
figurement; neither joy nor sorrow can be
reflected.
A study by Sigall and Landy demonstrates
the reluctance that people have in being in-
volved with these patients [13]. Participants in
the study observed individuals accompanying
a contrived "ugly" or "unattractive," but not
necessarily handicapped, person. The observers
suggested that the partners of these socially un-
appealing people possessed underlying poor
traits (e.g., low I.Q. or no talent). Thus, the
partners were judged by the people with whom
he/she was associated. A manifestation of this
attitude is the necessity some men feel when
they must have two attractive female models,
one on each arm, when they enter a restaurant
or attend a party.
A more controversial aspect that directly im-
pacts on the family and society is the issue of
whether a patient's personality makes him/her
cancer-prone. Theoretically, this suggests that
emotional states function etiologically. Unfor-
tunately, it also implies that patient's "sins" also
contribute. This feeling that the patient's alchol-
ism and lack of ambition are causative and con-
trolling factors in the development of head and/
or neck cancer is reinforced in the minds of
others, given the patient's lower economic
status, older age, and appearance.
A recent study reviewed the cancer-prone
personality research and questions this concept
[14]. The authors conclude that "the evidence
does not support the concept and is at best in-
conclusive." We agree. In our experience, per-
sonality types can be useful in predicting how
one will cope, not whether they will have can-
cer, coronary occlusion, renal disease, etc. As an
example, aggressive men three months after a
myocardial infarction will run upstairs, insisting
their doctors had misdiagnosed. Dependent pa-
tients will ask their physicians for permission to
shower. "Courageous, feisty, angry" cancer pa-
tients do not live longer, but do have a better
quality of life during their illness.
Management
It is hoped in this time of crisis that the profes-
sionals, the patient, and his family will establish
a relationship based on mutual trust. This trust
will provide the strength to withstand the
immense psychological devastation associated
with cancer and its management.
For example, the patient with cancer, like any
patient, will manifest boredom and irritability
as a reflection of his anxiety. Visits and discus-
sions with family and medical and paramedical
personnel are to be encouraged. Care should be
taken when at the bedside that medical jargon
does not confuse or frighten the patient.
Pain medications, tranquilizers, and anti-
depressants should be part of the medical
armamentarium. When antidepressants are in-
effective, a referral to a psychotherapist can be
useful. When no further therapy is indicated
and the patient is indeed terminal, all efforts
should be made to make him comfortable.
Mourning by the patient and/or his family de-
mands concern on the part of professional staff.
It is incumbent upon the staff to recognize that
the grieving process is "normal"; however,
when it interferes with patient care (e.g., family
burdening the patient), the staff must intercede.
Tranquilizers should not be used to inhibit
mourning, but sleeping medication is appropri-
ate to ward off terror in the lonely night.
Can the patient have hope ? Yes. Hope is
realistic. Weare not too far from the days when
diabetes was treated with black coffee and more
 25. PSYCHOSOCIAL EFFECT OF CANCER ON THE PATIENT AND THE FAMILY
black coffee. Insulin was then introduced, and
tremendous success in management followed.
Ten years ago, the survival for children with
leukemia was measured in months; now it is
measured in years. Obviously, advancements in
care of the ill patient have been striking in the
past decades. However, we are not omnipotent
and no mortal can predict when anyone will die.
Therefore, management requires the profession-
al to walk a thin line between denial and reality.
If reality is emphasized, the patient may lose all
hope and feels abandoned. If emphasis is placed
on denial, the patient feels inadequate to cope
with the demands of his illness. In this sense,
constructive denial equates with hope.
Professionals must be aware that they too are
vulnerable humans and subject to "burnout"
from the stress of their work [12]. An alertness
to feelings of depression is important; too much
self-medication, alcohol, and/or fatigue suggest
an imminent "burnout." This is the time for
vacation, hobbies, "talking it out" with a peer
group or psychotherapist, or considering an
occupational change.
As noted earlier, many patients defer and
delay seeking treatment with early symptoms;
in these cases, denial is used in a destructive
manner, diminishing prospects for successful
treatment and rehabilitation. However, the
mental mechanism of denial can be very useful
for the head and neck cancer patient and his
family. This defense permits the cancer patient
to have hope for something better in the future,
if not a cure, and reflects his capacity to use
this defense constructively. It is difficult, but
still possible, for the patient with head or neck
cancer after surgery to regain his premorbid
attitude.
Other coping techniques that equate with
therapy are important. The individual whose
premorbid personality was flexible, aggressive,
and embodied a sense of self-worth and humor
may view the disfigurement as a hurdle or chal-
lenge to overcome [15]. He will work, and will
seek group and individual relationships and
activities. It is important to recognize that each
patient, having a unique personality, will cope
in his own way with his own assets or liabilities.
Family support and affection are essential.
This does not imply overprotectiveness and
oversolicitiousness, but rather a gentle, firm
"you can do it." In essence, having the expecta-
tion that the patient can succeed permits the pa-
tient to experience a vote of confidence from
507
family members. The professional staff must do
likewise and not personally absorb the patient's
anger and bitterness toward his illness. Family
and staff must recognize and accept that the
period of adjustment can be prolonged and that
support must continue and be consistent. This is
important, since with chronic illnesses and in-
juries, friends tend to fall off in their visiting as
time goes on indefinitely.
Physical rehabilitation may include plastic
surgery, prostheses, and occupational and phy-
sical therapy in addition to the antitumor ther-
apy. In addition, group therapy with other pa-
tients can be useful, although individual therapy
may be preferred by the facially disfigured pa-
tient. Antidepressant and pain medications may
be useful.
A great deal of responsibility for management
obviously falls on the professional. In addition
to his/her medical management of the patient,
emotional care is included. This demands that
the professional listen to the patient. Sitting and
listening gives the patient the feeling of care and
compassion on the part of the professional. The
task of listening is not an easy one, but can be
gratifying. By listening, the patient is given the
opportunity to freely talk about his ideas, anx-
ieties, family, work, illness, and death. In this
way, where cure is not possible, suffering can be
ameliorated.
As professionals, we need to know that the
patient's physical and emotional well-being are
inextricably linked, and the care provided must
account for the entire range of patient-family-
professional reactions described above. The
medical-biological and psychological-socio-
logical-philosophical models are important and
necessary for understanding the work with pa-
tients with cancer. But these very patients need
ordinary, calm, un angry , unfrightened human
contact. In this manner, we gain as much as we
hope our suffering fellow human will benefit
[16].
References
1. Abrams RD, Finesinger JE: Guilt reactions in
patients with cancer. Cancer 6:474-482,1953.
2. Pattison EM: Experience of dying. Am J
Psychother 21 :32-43, 1967.
3. Schnaper N: Care of the dying patient. Med
Times 93:537-545,1965.
4. Schnaper N: Psychosocial aspects of the manage-
ment of the patients with cancer. Med Clin
North Am 61:1147-1155,1977.
508 V. SUPPORTIVE CARE
5. Schnaper N, Legg-McNamara C, Dutcher J,
Kellner TK: Emotional support of the patient
and his survivors. In: Wiernik PH (ed) Suppor-
tive care of the cancer patient. Mt Kisco NY,
Futura, 1982, pp 1-15.
6. Schnaper N: Management of the terminally ill
patient and his family. In: Balis GU, Wurmser L,
McDaniel E, Grenell RG (eds) Psychiatric prob-
lems in medical practice. In: The psychiatric
foundations of medicine, vol 6. Boston, Butter-
worth, 1978, pp 231-249.
7. Schnaper N: What preanesthetic visit? Anesthe-
siology 22:486-488,1961.
8. Schnaper N: Emotional responses of the surgical
patient. In: Tice F (ed) Tice's practice of medi-
cine. Hagerstown MD, Harper and Row, 1969,
pp 1-14.
9. O'Connor GJ, Knorr NJ: Acute trauma from
a psychological viewpoint. In: Ballinger W,
Rutherford RB, Zuidema GD (eds) Management
of trauma. Philadelphia: WB Saunders, 1968,
pp 745-768.
10. Bernstein NR: Emotional care of the facially
burned and disfigured. Boston, Little Brown and
Company, 1976.
11. MacGregor FC, Abel TM, Bryt A, Lauer E,
Weissman S, et al. (eds): Facial deformities and
plastic surgery: a psychosocial study. Spring-
field, Charles C Thomas, 1953.
12. Schnaper N, Hahn AP, De Vries RA: Psycho-
social roles in the cancer drama: speciality
rounds. Am J Med Sci 276:248-261, 1978.
13. Sigall H, Landy D: Radiating beauty: effects of
having a physically unattractive partner or per-
son perception. J Pers Soc Psychol 28:218-224,
1973.
14. Wellisch DK, Yager J: Is there a cancer-prone
personality? CA 33:145-153,1983.
15. Schnaper N, Cowley RA: Overview: psychiatric
sequelae to multiple trauma. Am J Psychiatry
133 :883-890, 1976.
16. Schnaper N: Death and dying: has the topic been
beaten to death? J Nerv Ment Dis 160:157-158,
1975.
 26. NUTRITION IN THE PATIENT
WITH COMPROMISED ORAL
FUNCTION
E George Elias
Deborah L McCaslin
Nutrition and the Cancer Patient
Patients with good nutritional status can be ex-
pected to withstand cancer treatment, including
surgery, chemotherapy, irradiation, or a com-
bination of these, better than those who are
malnourished. A previously active patient who
has been able to eat a well-balanced diet should
have good muscle mass and a reasonable, but
not excessive, amount of subcutaneous tissue.
On the other hand, patients who are suspected
to be marginally malnourished may have bor-
derline protein intake and diets leading to iron
and vitamin deficiencies; these abnormalities
can be evaluated in a systematic and careful
screening by a registered dietitian.
The dietitian plays a major role in the care of
the seriously malnourished cancer patient by
estimating the ideal calorie and protein intake
according to the level of stress, disease state,
presence of infection or fever, and by calculat-
ing the patient's actual, rather than assumed,
protein and caloric intake. Formulation of diet,
identifying need for enteral or parenteral nutri-
tion, determining types of solutions and
methods for their use, and monitoring response
to nutritional therapy are areas where a knowl-
edgeable clinical dietitian can be of value in
assisting the treating physician in caring for the
patient, both in the hospital and at home.
Many cancer patients lose weight at some
point during their disease. Some are under-
nourished at the time of diagnosis. Disturbances
produced by the cancer itself can affect the
proper utilization of nutrients and the mainte-
nance of a normal nutritional status. Other pa-
Peterson et aI., HEAD AND NECK MANAGEMENT OF THE CANCER PATIENT.
© 1986. Martinus Nijhoff Publishing. All rights reserved.
tients seem to be in a normal nutritional state,
but maintaining such nutritional status is a
problem while these patients are undergoing
cancer treatment. This is because all three ther-
apeutic modalities-surgery, radiotherapy, and
chemotherapy-have the potential to limit
caloric intake for extended periods of time.
The majority of patients with head and neck
cancer are malnourished and emaciated. For ex-
ample, in 33 patients with squamous cell carci-
noma of the head and neck that received one
course of chemotherapy consisting of cis-
platinum, bleomycin, and methotrexate with
folic acid rescue, the median weight loss was 4
kg on day 28 after initiation of therapy in spite
of enteral nutrition [1]. The demonstration of
weight loss in these patients reflects on their
immunologic status and performance status
which, in turn, reflects the response to therapy
and survival.
The nutritional complications of cancer are
exceedingly common. Anorexia has been
blamed for malnutrition in cancer patients in
general [2]. Patients with head and neck cancers
also can develop direct, obstructive effects of
their tumors limiting food intake. Use of
narcotics for the control of pain may depress the
patient's appetite, thereby limiting food intake
and adding to their poorly nourished condition.
Abnormalities in taste may result in poor intake
[3]; however, total enteral nutrition and
parenteral hyperalimentation may not always
improve patient status [4]. Therefore, cancer
cachexia can be blamed not only on diminished
nutritional intake but also on tumor factors.
These may include direct tumor utilization of
509
510 V. SUPPORTIVE CARE
metabolites [5], as well as tumor release of
toxins or hormones that may cause loss of
protein and a negative nitrogen balance. Exact
mechanisms are still unknown.
Although such observations have led some
investigators to attempt restoration of the nutri-
tional state of these patients prior to and during
the treatment of their cancer, it is becoming evi-
dent that the best nutritional support is success-
ful response to cancer therapy. Parenteral or en-
teral alimentation of a depleted patient receiving
cancer treatment may not always reverse the
nitrogen balance from negative to positive;
however, the net nitrogen losses can be greatly
reduced, similar to patients with severe burns
[6]. It should also be kept in mind that some
patients with head and neck cancer are chronic
alcoholics with liver cirrhosis and vitamin de-
ficiencies, mainly folates. Some of these patients
are" starving" and, in such cases, the liver plays
an important role in the adaptive mechanisms
designed to derive energy from adipose tissue
and to conserve protein. If this does not take
place, large quantities of protein must be cata-
bolized to supply glucose for muscle function.
Nutritional support is aimed at rebuilding the
body protein first and then, to a lesser extent,
the fat stores. Nutritionists have generally felt
that a positive caloric balance is necessary for
nitrogen retention. Therefore, it has been sug-
gested that infusion of amino acids alone would
be used by the body to restore protein [7]. Even
though it may be possible to achieve a positive
nitrogen balance without glucose or fat under
certain conditions, caloric intake is critical in
most instances. Therefore, even if infusion of
amino acids is supplemented by adequate calor-
ic intake in the form of glucose and fat, it be-
comes clear that the ability to achieve nitrogen
retention depends not only on sufficient
nitrogen intake, but also on the condition of
the patient. We strongly feel that patients who
lack exercise and who are bedridden with low
performance status will probably remain in
negative nitrogen balances. These patients
cannot retain nitrogen and will excrete it in
the urine.
Carbohydrates are the primary source of
energy in the normal human being. However,
limited storage of carbohydrates in the body
combined with inadequate food intake leads to
fat and protein consumption. A starving person
can utilize fatty acids, which are excellent
sources of energy. On the other hand, some dis-
ease conditions both initiate a series of metabo-
lic events characterized by increased urinary
nitrogen excretion, glucose intolerance, and in-
creased resting metabolic expenditure as well as
limit the body's ability to utilize fat. Alteration
in tissue fuel utilization makes the fatty acid and
glycerol shift less effective, with subsequent loss
of protein. Such lean tissue loss not only repre-
sents an inefficient fuel compared with fat, but
also impairs function, in many ways resulting in
a vicious cycle. Therefore, the resulting de-
mands on body protein must be met by a well-
designed oral or intravenous (i.v.) nutritional
program.
Immunosuppression is very common in head
and neck cancer patients as well as in patients
with other malignancies. In fact, the more ad-
vanced the stage of the disease, the greater is the
immunosuppression. Furthermore, all cancer
treatment also depresses immunity. Surgery has
the shortest immunosuppressive period, with an
estimated length of 7-10 days. Radiation ther-
apy has a prolonged effect that can last for
months, even if irradiation was directed to a
localized area and did not involve the total
body. Some chemotherapeutic agents such as
cis-platinum can induce severe and prolonged
immunosuppression. It has been suggested that
i.v. alimentation may reconstitute general im-
munity [8], and may offer nutritional support
and promote wound healing in head and neck
patients [9]. However, there is no proof today
that parenteral alimentation is superior to the
enteral route of nutritional support; in a con-
trolled prospective randomized study of 69
patients, results revealed that total parenteral
hyperalimentation was not superior to enteral
feeding with regard to weight gain, wound heal-
ing, reconstitution of immunity, and survival
[10].
It should be recalled that each of the nutri-
tional approaches has its use. While patients
with no gastrointestinal problems (i.e., no
nausea, vomiting, stomatitis, diarrhea, or im-
paired absorption) can receive enteral nutrition,
other patients with any of these problems are
candidates for total parenteral nutritional sup-
port. In patients with short-lived gastrointesti-
nal complications, initiation of i.v. nutritional
support with the gradual introduction of de-
fined formula/elemental solutions via naso-
duodenal tube would be appropriate. With this
approach, it is important to avoid overfeeding
or underfeeding the patient. The total daily
 26. NUTRITION IN THE PATIENT WITH COMPROMISED ORAL FUNCTION
caloric goal should be met via the combination
of the parenteral and enteral calories. Gradually
increasing the concentration and subsequently
the volume of the enteral solution will necessi-
tate the gradual decrease of the parenteral
volume. Only when the patient is tolerating
the enteral formula and receiving virtually all
required calories via this route should the
parenteral support be discontinued.
Compromised oral function may playa major
role in the nutritional status of the patient. As
noted previously, this compromise can be the
direct result of the tumor, whether primary or
metastatic, to the head and neck area. For exam-
ple, a tumor may interfere functionally with
oral feeding by inhibiting the opening of the
mouth, or it may interfere with mastication
and salivation. Tumors in the oral cavity,
oropharynx, and related areas can become
ulcerated, infected, bleed easily, and cause pain
and loss of taste sensation, which will further
impair oral intake. On the other hand, ther-
apeutic intervention may lead to temporarily or
permanently compromised oral function. For
example, surgery may result in mechanical de-
fects in the form of deformity, scarring, or fistu-
lization. Radiation therapy may result in acute
mucositis and later in decreased salivation and
taste for prolonged periods of time. Patients
receiving systemic chemotherapy may develop
mucositis, which may indicate more widespread
gastrointestinal toxicity. Therefore, mucositis
may not only compromise oral function, but
may also interfere with intestinal absorption of
nutrients.
Nutritional Assessment of the Patient
Evidence of malnutrition can be easily noted by
loss of subcutaneous tissue and skin elasticity
as well as atrophy of muscle mass. Peripheral
edema may also be present, resulting from
decreased serum albumin; this edema may clini-
cally mask the above physical findings. Further
physical and laboratory examination may reveal
signs and symptoms of protein, vitamin, andlor
mineral deficiencies.
The history of weight loss and duration is im-
portant. A loss of 10% or more of actual body
weight without dieting over 2-3 months is an
indication for further investigation of the need
for nutritional support. The patient may give a
history of a loss of appetite, relating it to a de-
crease in the taste sensation. History of nausea,
S11
vomltlng, andlor diarrhea may also play an
important part in the evaluation.
EVALUATION OF A PATIENT'S
ADIPOSE TISSUE AND MUSCLE MASS
Adipose tissue, which is the primary energy re-
serve, can be assessed by measuring the triceps
skinfold thickness using the Lange caliper. This
is accomplished by first measuring the length of
the right upper arm between the acromian of the
scapula superiorly and the tip of the olecranon
of the ulna inferiorly and marking the midpoint.
The skin and the subcutaneous tissues are gently
pinched just below the midpoint, and the thick-
ness is measured at the midpoint with the Lange
skinfold caliper (figure 26-1). A reading is taken
after 3 s, repeated twice, and an average thick-
ness is recorded. Percentiles are determined by
correlating the skinfold thickness value with the
patient's agfC and sex as shown in table 26-1 [11].
LABORATORY EVALUATION
If the patient is dehydrated, i.v. hydration
should be carried out first to prevent erroneous
findings such as elevated hemoglobin, hemato-
crit, or serum proteins and low creatinine clear-
ance. After the patient becomes hydrated and
stable, several additional tests should be per-
fonned. Complete blood counts with indices
and differential white cell counts should be
obtained; anemia and lymphocytopenia may
FIGURE 26-1. Lange skinfold caliper to measure the
thickness of the subcutaneous tissues.
512 V. SUPPORTIVE CARE

TABLE 26-1. Age- and sex-specific reference values for the triceps skinfold thickness'

Percentile
Age group
(years) 5 10 25 50 75 90 95

American men
18-74 4.5 b 6.0 8.0 11.0 15.0 20.0 23.0
18-24 4.0 5.0 7.0 9.5 14.0 20.0 23.0
25-34 4.5 5.5 8.0 12.0 16.0 21.5 24.0
35-44 5.0 6.0 8.5 12.0 15.5 20.0 23.0
45-54 5.0 6.0 8.0 11.0 15.0 20.0 25.5
55-64 5.0 6.0 8.0 11.0 14.0 18.0 21.5
65-74 4.5 5.5 8.0 11.0 15.0 19.0 22.0
American women
18-74 11.0 13.0 17.0 22.0 28.0 34.0 37.5
18-24 9.4 11.0 14.0 18.0 24.0 30.0 34.0
25-34 10.5 12.0 16.0 21.0 26.5 33.5 37.0
35-44 12.0 14.0 18.0 23.0 29.5 35.5 39.0
45-54 13.0 15.0 20.0 25.0 30.0 36.0 40.0
55-64 11.0 14.0 19.0 25.0 30.5 35.0 39.0
65-74 11.5 14.0 18.0 23.0 28.0 33.0 36.0
:I. Developed from data collected during the Health and Nutrition Examination Survey of 1971-1974.
b Values are in millimeters.
From GrantJP et a1. [11].

signify malnutrition or could be due to an ad-
vanced stage of cancer. Urinalysis may rev.eal
protein, sugar, and electrolytes losses. Fastmg
blood sugar and, if needed, a 2-h postprandial
blood sugar are indicated to rule out diabetes
mellitus. Blood urea nitrogen assesses the renal
function and, if extremely low, may indicate
poor nutrition. Serum albumin and transferrin
are reliable indicators for protein nutrition as
well as liver status. These proteins have shorter
half-lives and can respond more rapidly to pro-
tein depletion or repletion. Liver and renal
function tests will rule out hepatic or renal dys-
function.
The immune status can be evaluated clinically
by recall skin test antigens to PPD (intermediate
strength), monilia, mumps, and dermatophy-
ton. A positive reaction is indicated by 1 cm or
more of erythema and induration at the site of
intradermal injection. This test is obtained in
addition to the absolute lymphocyte count.
INDICATIONS FOR
NUTRITIONAL SUPPORT
Specific indications include
1. Weight loss of 10% or more of actual body
weight, without dieting, over 2-3 months.
2. Hypoalbuminemia, i.e., serum albumin less
than 3.5 gm%.
3. Inability to ingest food, or an undesired
caloric intake of less than 20 kcallkg body
weight/day.
4. Poor wound healing with absence of tumor
at the wound site.
5. Long-standing infection that tends to spread
or is uncontrollable, with no actual tumor
involvement.
6. Immunosuppression.
To estimate whether the patient is actually in
nitrogen negative balance and is in need of nu-
tritional support, a simple formula can be used:
The dietitian can calculate the 24-h nitrogen
intake in the diet and in the i.v. nutrition. The
24-h urine urea nitrogen is obtained to which
1.5-2.0 g (in females) or 2-3 g (in males) is
added. Relating nitrogen intake to excretion
gives a fairly good estimate of daily nitrogen
loss. It should be emphasized that 24-h accurate
urine collection is of utmost importance;
inaccurate sampling could lead to a major error
in calculation of the nitrogen balance. A clini-
cally useful balance between intake and output
can then be obtained. Since nitrogen in grams
X 6.25 = grams protein, protein balance is
 26. NUTRITION IN THE PATIENT WITH COMPROMISED ORAL FUNCTION
easily calculated. The objective is to at least
minimize negative nitrogen balance if not main-
tain balance or achieve a 2-4 g/day positive
nitrogen balance during therapy.
Nutritional Support: Enteral
If it can be used, enteral nutrition offers the best
method of providing the energy plus protein re-
quirement of all patients. The ingested food
must be digested and absorbed by the gastro-
intestinal tract. Patients with compromised oral
function may not be capable of ingesting a diet
orally, and a variety of approaches have been
established to bypass such a defect. These can be
used as long as the patient has normal digestive
and absorptive capabilities. These include naso-
gastric tubes or nasoduodenal, esophagostomy
tubes or gastrostomy tubes. A variety of diets
can be administered through these feeding
tubes:
BLENDERIZED FORMULA DIET
Such a diet is readily available at home, and can
be prepared from table foods or purchased
ready-made, such as COMPLEAT B (Doyle Phar-
maceuticals, Minneapolis, MN 55416). If made
from regular foods, however, this diet must be
freshly prepared and not stored, since bacterial
flora may proliferate, causing risk of gastritis,
gastroenteritis, or even botulism. Also, salt and
water or milk must be added; the patient should
receive additional water between feedings. This
diet is usually more applicable for gastrostomy
tube feeding, since it is usually of thick con-
sistency and will not pass readily through the
smaller-caliber nasogastric tubes. The gastros-
tomy tube, as with all feeding tubes, should be
flushed after each feeding. The patient should be
started on small multiple feedings per day, and
then slowly advanced to three regular meals.
The diet should be brought to room tempera-
ture before being gradually dripped through the
tube, to avoid patient cramps and diarrhea.
LACTOSE-FREE FORMULAS
One must remember that a large number of
patients may have lactase deficiency in the
mucosa, resulting in lactose intolerance in the
form of an osmotic cathartic effect with bloat-
ing, gas, cramps, and diarrhea. Therefore, such
patients should receive one of the many lactose-
free formulas available. Several commercial
preparations of this formulation are available:
513
ENSURE (Ross Laboratories, Columbus, OH
43216), ENSURE-PLUS (Ross Laboratories),
ISOCAL (Mead Johnson Nutritional Division,
Evansville, IN 47721), and ISOCAL HCN (Mead
Johnson) are but a few of the ready-to-use
preparations. They vary from 1 to 2 callcc and
require digestive and absorptive abilities. When
administered through the smaller (no. 7, 8, or
9.6) feeding tubes, it is important to flush the
tube with water at least every 6 h to maintain
patency. Usually, these patients are on a 24- or
12-h continuous infusion of formula via an en-
teral feeding pump since this is the administra-
tion route that is best tolerated. If diarrhea de-
velops, the formula should be diluted 1: 1 with
water and gradually brought back to full
strength over 3-4 days. An antidiarrheal agent
may also be administered if symptoms persist.
Elemental and/or peptide formulations are
diets that are beneficial in patients with gas-
trointestinal pathology [12]. They are lactose
free, require minimal pancreatic stimulus, and
are absorbed in the upper gut. There are many
preparations available commercially: VIVONEX
(Norwich Eaton Pharmaceuticals, Norwich,
NY 13815), HIGH NITROGEN VIVONEX (Norwich
Eaton Pharmaceuticals), CRITICARE HN (Mead
Johnson), and VITAL HIGH NITROGEN (Ross
Laboratories) are the most widely used. These
consist of essential and nonessential amino
acids, or of pep tides or combinations of amino
acids and peptides, carbohydrates, minimal fat,
minerals, and vitamins. They have high osmo-
larity and must therefore be given by slow con-
tinuous gravity drip or, preferably, using a
pump to ensure accurate delivery. These diets
are very thin in consistency and can be infused
easily through the small feeding tubes. They re-
quire refrigeration to avoid bacterial and fungal
contamination.
Complications of enteral alimentation are as
follows:
1. Nausea, vomiting, diarrhea. These sequelae
can be corrected by further dilution, by
slower rate of feeding, or by the use of anti-
diarrheals.
2. Aspiration. This is usually occurs because of
large amounts of fluid in the stomach, which
can be corrected by keeping the head of the
bed elevated to 30°, or by using gravity drip
or a pump for continuous, slow infusion
over a longer period of time.
3. Hyperglycemia and fluid plus electrolyte im-
514 V. SUPPORTIVE CARE
balance. Blood sugar should be observed and
corrected by insulin, if so needed. Serum
electrolytes and urea nitrogen should also
be monitored. Additional water must be
provided for fluid requirements.
4. Water retention. Water retention can be
corrected by diuretics.
5. Hypoprothrombinemia. This can be cor-
rected by the addition of vitamin K 10 mg
every other day intramuscularly if needed;
1 mg of folic acid should also be added to the
diet daily.
Nutritional Support: Parenteral
Total parenteral nutrition (TPN) is the i.v.
administration of total nutritional requirements
to patients with gastrointestinal tracts deficient
in function because of disease or treatment such
as radiation or chemotherapy [13]. As already
discussed, patients with compromised oral func-
tion frequently and preferably can meet nutri-
tional needs with enteral rather than paren-
teral nutrition, since their alimentary tracts
are otherwise functional. The main purpose of
parenteral nutrition is to provide essential and
nonessential amino acides, carbohydrates, and
fats for a period of time, in quantities sufficient
to meet the nutritional requirements of the
patient while achieving nitrogen balance and
an anabolic state. Vitamins, minerals, and
trace elements as well as electrolytes are added
according to each patient's requirements. TPN
can be successfully administered in the home for
those patients requiring long-term therapy, but
who are medically stable [14].
TPN solutions are hypertonic and must be
administered through a central venous catheter
or Hickman catheter that has been placed in the
innominate vein or the superior vena cava. The
most commonly used solutions for adults con-
sist of 500 ml of 40%-50% dextrose in water
and 500 ml of 8.5% amino acids. Mixed amino
acids have been utilized in lieu of protein hy-
drolysates such as casein and fibrin hydrolysates,
as they contain more essential amino acids and
(1 -amino acids, which are necessary for protein
synthesis. In addition, the following substrates
are usually added to each liter:
1. 40-50 meq sodium in the form of chloride or
acetate, 20-40 meq potassium (chloride or
acetate), 10-18 meq magnesium sulphate,
and 15-25 meq potassium phosphate.
2. 4.5-9.0 meq calcium gluconate, and a multi-
vitamin preparation and trace elements
should be added to one of the liters/day.
3. Twice weekly, the patient must also receive
10 mg vitamin K.
4. 0.5 ml iron-dextran can be added daily, if
indicated by the patient's serum chemistries.
5. Insulin use varies from 5 to 80 U/liter of
solution, depending on the individual needs.
Modifications of the standard adult formula are
required for patients with infections or cardiac,
liver, or renal diseases.
Administration of the therapy outlined above
is to be initiated at a rate of approximately 42
cc/h (about 1 liter/day) and increased daily by 1
liter to the amount required by the patient to
meet metabolic needs. The infusion is usually
given over a 24-h period, but can be given in as
little as 12 h for a home patient. Cardiac status is
a consideration for this shorter infusion time.
The administration of 500 ml of 10% or
20% fat emulsion derived from soybean oil,
3-7 times a week, satisfies the requirement
for essential fatty acids and provides additional
(9 callg fat) calories. The fat emulsion has the
advantage of being suitable for peripheral vein
infusion [15], but can also be piggybacked into
the TPN line.
Complications of TPN include the following.
CATHETER-RELATED COMPLICATIONS
Hickman catheters can be utilized for pro-
longed infusions. If percutaneous insertion of a
central catheter is required for a limited period,
however, sterile technique and knowledge of
anatomy will minimize accidential pneumo-
thorax (chest x-ray must be done after the
insertion of the catheter), hemothorax, injury
to brachial plexus, or brachial artery and bleed-
ing. Placing the patient in a flat position will
prevent air embolism. The catheter should
never be pulled back after its insertion while the
needle is in the vein as this may cause sheering
and may precipitate catheter embolism.
The maintenance of the catheter is extremely
important. We have been using heparin irriga-
tion of the catheter once a day to prevent its
clotting, using 6 ml of sterile physiologic saline
with 300 U of heparin. This will also prevent or
minimize venous thrombosis. Aseptic technique
is essential. The puncture site in the skin should
be cared for daily by cleansing and antibiotic
ointment dressing. Fever and infection in a pa-
 26. NUTRITION IN THE PATIENT WITH COMPROMISED ORAL FUNCTION
tient prior to insertion of the catheter are not
contraindications to its use; however, if the
catheter is suspected of being the cause of infec-
tion, it should be removed and cultured. The
catheter infection rate is about four incidences
per 1000 days of use, and seems to be primarily
due to seeding by systemic bacteria. Therefore,
the use of systemic antibiotics is highly recom-
mended.
Another source of sepsis can be avoided to a
large extent by utilization of sterile technique in
the preparation of the TPN solution and daily
changing of the delivery tubing and filter.
METABOLIC-RELATED COMPLICATIONS
Metabolic complications can largely be avoided
by careful monitoring of the patient, especially
during the initiation of the TPN.
1. Fluid overload. The patient should be
weighed daily. Accurate recording of intake
and output every 8 h should be maintained
until the patient is in stable condition. If the
patient is gaining more than 1 pound124 h,
the rate of infusion should be reduced and
diuretics may be used.
2. Glucose intolerance (hyperglycemia). This
is the most common complication of TPN.
Periodic examination of the urine for glyco-
suria is extremely important. Patients with
normal renal function may expel a trace to 1+
sugar by the nitroprusside reaction. This indi-
cates that the patient has reached the limit of
tolerance to metabolize glucose. At no time
should a 3+ reaction or more be allowed, as
this indicates excessive glycosuria that may
result in water and electrolyte imbalances,
hyperosmolar state, and may lead to hyper-
glycemic nonketotic coma (HNC) if not im-
mediately corrected. HNC can be corrected
by reducing the rate of alimentation infusion,
administering isotonic solution, and aggres-
sively treating the hyperglycemia with in-
sulin. On the other hand, patients with com-
promised renal function should be monitored
by blood sugar levels rather than urinary
sugars. Diabetic patients can receive their
insulin routinely via the subcutaneous route,
and/or insulin can be added to the TPN
solution.
Hypoglycemia is rare, but can occur in pa-
tients who have had sudden discontinuation
of infusions. Constant infusion pumps must
be used to ensure steady delivery. If the TPN
515
is to be discontinued, it must be tapered
down slowly over a few days to avoid hypo-
glycemia symptoms.
In addition, serum electrolytes and blood ure.a
nitrogen should be obtained daily until stable,
then twice per week. Hepatic and renal function
tests should be evaluated weekly until stable,
and then every two weeks. Periodic determi-
nations of serum osmolarity, urine specific
gravity, and serum zinc and magnesium can be
helpful in correcting these deficiencies early, if
they occur.
Conclusions
Nutritional support has two main purposes: to
prevent a catabolic state from developing in
nutritionally normal patients, and to correct
or minimize a catabolic state in a nutritionally
depleted patient. Patients with compromised
oral function can be nutritionally supported by
enteral or parenteral alimentation. The daily
caloric requirements are 30-45 kcal/kg body
weight/day. Nutritional support is required
during the illness and therapy, and more so
if fever, infection, or wound complications
develop. If the patient is to undergo surgery,
alimentation will be needed for a minimum
of 2-3 weeks preoperatively or until there is
an evidence of reversal of the catabolic state.
Postoperatively, nutritional support will be
necessary until the patients are capable of sup-
porting themselves nutritionally. Nutritional
support of the bedridden patient seems to be
of very little value, unless accompanied by
passive and active exercise to promote tissue
and protein synthesis.
Patients who are receiving nutritional support
must be monitored for two reasons: first, to
prevent complications and, second, to ensure
nutritional improvement and gain.
References
1. Elias EG, Cretien PB, Monnard E, Khan T,
Bouchelle WH, Wiernik PH, Lipson SD, Hande
KR, Zentai T: Chemotherapy prior to local ther-
apy in advanced squamous cell carcinoma of the
head and neck. Cancer 43: 1025-1 031, 1979.
2. De Wys WD: Anorexia as a general effect of
cancer. Cancer 43:2013~2019, 1979.
3. De Wys WD: Changes in taste sensation and
feeding behavior in cancer patients. ] Hum Nutr
32:447-453, 1978.
516 V. SUPPORTIVE CARE
4. Terepka AR, Waterhouse C: Metabolic observa-
tions during forced feeding of patients with can-
cer. AmJ Med 20:225-238,1956.
5. Bozetti F, Pagnoni AM, Delvecchio M: Exces-
sive caloric expenditure as a cause of malnutri-
tion in patients with cancer. Surg Gynecol
Obstet 150:229-234, 1980.
6. Wilmore DW, Curreri PW, Spitzer KW, Spitzer
ME, Pruitt BA Jr: Supra-normal dietary intake
in thermally-injured hypermetabolic patients.
Surg Gynecol Obstet 132:881-886, 1971.
7. Blackburn GL, Flatt JP, Clowes GHA, O'Don-
nell TE: Peripheral intravenous feeding with
isotonic aminoacid solutions. Am J Surg 125:
447-454, 1973.
8. Copeland EM, MacFadyen BV, Dudrick SJ:
Effect of intravenous hyperalimentation on
established delayed hypersensitivity in cancer
patients. Ann Surg 184:60-64, 1976.
9. Copeland EM, MacFadyen BV, MacComb WS,
Gillamondegui 0, Jesse RH, Dudrick SJ: In-
travenous hyperalimentation in patients with
head and neck cancer. Cancer 35:606-611,1975.
10. Sako K, Lore' JM, Kaufman S, Razack MS,
Bakamjian V, Reese P: Parenteral hyperali-
mentation in surgical patients with head and
neck cancer: a randomized study. J Surg Oncol
16:391-402, 1981.
1l. Grant JP, Custer PB, Thurlow J: Current tech-
niques of nutritional assessment. Surg Clin
North Am 61 :437-463, 1981.
12. Winitz M, Seedman J, Graf J: Studies in metabo-
lic nutrition employing chemically defined diets.
I. Extended feeding for normal human adult
males. AmJ Clin Nutr 23:525-545,1970.
13. Dudrick SJ, Wilmore DW, Vars HM, Rhoads
JE: Can intravenous feeding as the sole means of
nutrition support growth in the child and restore
weight loss in an adult? An affirmative answer.
Ann Surg 169:974-984, 1969.
14. Dudrick SF, Englert DM, VanBuren CT, Row-
lands BJ, MacFayden BV Jr: New concepts of
ambulatory home hyperalimentation. J Parenter
Enter Nutr 3:72-76,1979.
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travenous nutrition. Postgrad MedJ 43:307-316,
1967.
 APPENDIX: STAGING OF HEAD
AND NECK NEOPLASIA
I. Staging system for primary
tumors (T) of the lip and
oral cavity
Tx Minimum requirements to assess
the primary tumor cannot be met
To No evidence of primary tumor
Tis Carcinoma in situ
T1 Greatest diameter of pnmary
tumor 2 cm or less
T2 Greatest diameter of pnmary
tumor more than 2 cm but not
more than 4 cm
T3 Greatest diameter of pnmary
tumor more than 4 cm
T4 Massive tumor more than 4 cm
in diameter with deep invasion to
involve antrum, pterygoid mus-
cles, base of tongue, skin of neck
II. Staging system for primary
tumors of the pharynx
OROPHARYNX
Tx Minimum requirements to assess
the primary tumor cannot be met
To No evidence of primary tumor
Tis Carinoma in situ
Tl Tumor 2 cm or less in greatest di-
ameter
T2 Tumor more than 2 cm but not
more than 4 cm in greatest dia-
meter
T3 Tumor more than 4 cm III
greatest diameter
T4 Massive tumor more than 4 cm
III diameter with IllvaSlOn of
bone, soft tissues of neck, or root
(deep musculature) of tongue
NASOPHARYNX
T x Minimum requirements to assess
the primary tumor cannot be met
To No evidence of primary tumor
Tis Carcinoma in situ
Tl Tumor confined to one site of
nasopharynx or no tumor visible
(positive biopsy only)
T2 Tumor involving two sites (both
posterosuperior and lateral walls)
T3 Extension of tumor into nasal
cavity or oropharynx
T4 Tumor invasion of skull, cranial
nerve involvement, or both
HYPOPHARYNX
T x Minimum requirements to assess
the primary tumor cannot be met
To No evidence of primary tumor
Tis Carcinoma in situ
Tl Tumor confined to one site
T2 Extension of tumor to adjacent
region or site without fixation of
hemilarynx
T 3 Extension of tumor to adjacent
region or site with fixation of
hemilarynx
T4 Massive tumor invading bone or
soft tissues of neck
III. Staging system for primary
tumors of the larnyx
SUPRAGLOTTIS
Tx Minimum requirements to assess
the primary tumor cannot be met
To No evidence of primary tumor
Tis Carcinoma in situ
Tl Tumor confined to region of ori-
gin with normal mobility
T2 Tumor involving adjacent supra-
glottic site(s) or glottis without
fixation
T3 Tumor limited to larynx with
fixation or extension to involve
517
518 APPENDIX: STAGING OF HEAD AND NECK NEOPLASIA
postcricoid area, medial wall of
piriform sinus, or preepiglottic
space
T4 Massive tumor extending be-
yond the larynx to involve oro-
pharynx, soft tissues of neck,
or destruction of thyroid cartilage
GLOTIIS
T x Minimum requirements to assess
the primary tumor cannot be met
To No evidence of primary tumor
Tis Carcinoma in situ
TI Tumor confined to vocal cords(s)
with normal mobility (includes
involvement of anterior or pos-
terior commissures)
T2 Supraglottic or subglottic exten-
sion of tumor with normal or im-
paired cord mobility, or both
T3 Tumor confined to the larynx
with cord fixation
T 4 Massive tumor with thyroid car-
tilage destruction or extension
beyond the confines of the
larynx, or both
SUBGLOTIIS
T x Minimum requirements to assess
the primary tumor cannot be met
To No evidence of primary tumor
Tis Carcinoma in situ
TI Tumor confined to the subglottic
region
T2 Tumor extension to vocal cords
with normal or impaired cord
mobility
T3 Tumor confined to larynx with
cord fixation
T 4 Massive tumor with cartilage
destruction or extension beyond
the confines of the larynx, or
both
IV. Staging system for primary
t,!mors of the paranasal
smuses
Tx Minimum requirements to assess
* Significant local extension is defined as evidence of tumor
involvement of skin, soft tissues, bone, or the lingual or
facial nerves
the primary tumor cannot be met
To No evidence of primary tumor
TI Tumor confined to the antral
mucosa of the infrastructure with
no bone erosion or destruction
T2 Tumor confined to the supra-
structure mucosa without bone
destruction or to the infrastruc-
ture, with destruction of medial
or inferior bony walls only
T3 More extensive tumor invading
skin of cheek, orbit, anterior
ethmoid sinuses, or pterygoid
muscle
T4 Massive tumor with invasion
of cribriform plate, posterior
ethmoids, sphenoid, naso-
pharynx, pterygoid plates, or
base of skull
V. Staging system for primary
tumors of the major salivary
glands
Minimum requirements to assess
the primary tumor cannot be met
No evidence of primary tumor
Tumor 2.0 cm or less in greatest
diameter without significant lo-
cal extension"
Tumor more than 2.0 cm but not
more than 4.0 cm in greatest dia-
meter without significant local
extension
Tumor more than 4.0 cm but not
more than 6.0 cm in greatest dia-
meter without significant local
extension
Tumor over 6.0 cm in greatest di-
ameter without significant local
extension
Tumor of any size with sIg-
nificant local extension"
VI. Staging system for cervical
nodes (N) (except for primary
major salivary gland tumors)
Cervical Node Classification. The fol-
lowing regional node classification is
 APPENDIX: STAGING OF HEAD AND NECK NEOPLASIA 519

applicable to all squamous cell No No evidence of regional lymph

carcinoma of the upper aerodigestive node involvement
tract. In clinical evaluation, the actual Nt Evidence of regional lymph node
size of the nodal mass should be involvement
measured and allowance should be
made for intervening soft tissues. It
is recognized that most masses over VII. Distant metastasis (M):
3 em in diameter are not single nodes, Mx Minimum requirements to assess
but are confluent nodes or tumor the presence of distant metastasis
in soft tissues of the neck. There are cannot be met
three stages of clinically positive Mo No evidence of distant metastasis
nodes: Nt> N 2, and N 3. The use of M t Distant metastasis present
subgroups a, b, and c is not required, Specify _ _ _ _ _ _ _ _ _ __
but is recommended. Midline nodes Specify sites according to the follow-
are considered homolateral nodes. ing notations:
N x Minimum requirements to assess Pulmonary PUL
the regional node cannot be met Osseous ass
No No clinically positive node Hepatic HEP
Nt Single clinically positive homo- Brain BRA
lateral node 3 cm or less in Lymph nodes LYM
diameter Bone marrow MAR
N2 Single clinically positive homo- Pleura PLE
lateral node more than 3 cm but Skin SKI
not more than 6 cm in diameter Eye EYE
or multiple clinically positive Other OTH
homolateral nodes, none more
than 6 cm in diameter
N2a Single clinically positive homo- VIII. Stage grouping (except for
lateral node more than 3 cm but primary major salivary gland
not more than 6 cm in diameter
N 2b Multiple clinically positive homo- tumors)
lateral nodes, none more than Stage I Tt> Na,Mo
6 cm in diameter Stage II Tz, No, Mo
N3 Massive homolateral node(s), bi- Stage III T 3, No, Mo
lateral nodes, or contralateral T t orT2 orT3; Nt> Mo
nodes(s) Stage IV T 4, No or Nt> Mo
N3a Clinically positive homolateral Any T, N2 or N 3, Mo
node(s), one more than 6 cm in Any T, any N, M t
diameter
N 3b Bilateral clinically positive nodes
(in this situation, each side of Stage grouping (primary
the neck should be staged separ- major salivary gland tumors)
ately, i.e. N3b: right, N 2a ; left, Stage I Tt> No, Mo
Nt) T 2, No, Mo
N3c Contralateral clinically positive Stage II T 3, No, Mo
node(s) only Stage III Tb T2;NbMo
T4a, T4b; No, Mo
Staging system for cervical Stage IV T3, NhMo
nodes (primary major salivary T4a, T4b, Nb Mo
gland tumors) Any T, any N, M t
N x Minimum requirements to assess From American Joint Committee on Cancer Manual for
the regional nodes cannot be met staging of cancer 2nd edition (Philadelphia, JB Lip-
pincott, 1983.) Next edition to be published 1986)

Acinic cell carcinoma
parotid gland, 218
salivary gland, 262, 292
Acquired immune deficiency syn-
drome (AIDS), 113
cervical lymph node enlargement
and,264
tumor incidence in, 107
Acyclovir, 136, 153,355
Adenine arabinoside, 136
Adenocarcinoma
brain metastases with, 364
cervical lymph node enlargement
and,265
maxillary sinus, 257
metastatic, 30, 33
minor salivary gland tumors, 222
nasal fossa, 256
nasopharyngeal, 194
parotid gland, 218-219, 262
salivary gland, 21-22, 262, 292, 341,
342
thyroid, 262
tongue, 222
Adenocystic carcinoma, 185
Adenoid cystic carcinoma
chemotherapy for, 225-226, 321
nasopharyngeal, 194
perineural invasion of, 22
salivary duct, 18,321,341,342
submandibular gland, 220-221
variations in behavior of, 21-22
Adenoma
minor salivary gland tumors, 222
parathyroid, 263
parotid gland, 215, 216
Adenomatoid odontogenic tumor,
251-252
Adenovirus, 111, 136, 152,406-408
Adriamycin (ADR), 226
combination chemotherapy with,
116,305,306,308,321
mucositis with, 352
response rate to, 302
salivary gland cancer with, 321, 342
squamous cell cancer with, 299, 305,
306,308
AIDS, see Acquired immune deficien-
cy syndrome (AIDS)
Albright's syndrome, 238
Alcohol use and alcoholism
head and neck cancer and, 108
herpes simplex virus and, 114
intraoral neoplasms and, 165
Alkylating agents, 92, 94; see also
specific agents
Allopurinol, 86, 373
Alpha-fetoprotein,7
Ameloblastoma, 250-251
INDEX
computerized tomography (CT) of,
192
multi cystic, 251
unicystic, 251
Amikacin, 148
Aminoglutethimide,93
Aminoglycosides, 148
Amphotericin B, 150, 151,435
Anaplastic carcinoma
cervical lymph node enlargement
and,265
nasopharynx, 256
salivary gland, 292
thyroid, 263
Anemia, 359
Aneurysmal bone cyst, 245
Angiography, 199
Animal models of cancer, 10-14
Anthracyclines, 89
Antibiotic drugs, 93, 94, 495
granulocytopenia and, 144, 147-
148,148-149,150
see also Specific drugs
Antilymphocyte serum (ALS), 11
Antimetabolites, 92-93, 94; see also
specific agents
Asparaginase, 89,93,378,380
Aspiration pneumonitis, 154
Auditory canal, external, 185-186
Azlocillin, 148, 149
Bacillus Calmette-Guerin (BCG)
animal model studies of, 11
head and neck carcinoma with, 116
immunotherapy with, 115
melanoma and, 345
squamous cell cancer with, 308, 313
Bacteremia, in granulocytopenia, 142,
144-145,147,149
Basal cell carcinoma, 47
head and neck, 186
parotid gland, 215
pinna, 185
BCNU, 92, 381
combination chemotherapy with,
305
encephalopathy with, 384
squamous cell cancer with, 302, 305
Benzydamine hydrochloride, 410
Biopsy, 24, 72-73
Birthmarks, maxillofacial, 241
Bladder carcinoma, 52
Bleeding, see Hemorrhage
Bleomycin (BLM), 93
combination chemotherapy with,
116,304,305,307,308,310-311,
314-318
mucositis with, 352
number and timing of courses of,
316-318
oral cavity cancer with, 333
radiotherapy with, 312, 318
response rate to, 299, 301, 314, 315,
317
squamous cell cancer with, 299,
301-302,304,305,307,308,309,
310-311,312,313,314-318,338-
339
toxicity of, 89, 316
Blood-brain barrier, and chemother-
apy, 86
B-lymphocytes, 101
Epstein-Barr virus and, 112-113
humoral immunity and, 101
identification of populations of, 103
markers for, 103
tests of function of, 103-104
Bone marrow transplantation, 129-
136
chemoirradiation toxicity in, 136,
404-406
donor selection in, 130-131
ear, nose, and throat complications
in, 411-413, 416-417, 419
early work in, 129-130
graft rejections after, 132-133
graft-versus-host disease (GVHD)
in, 133-134,408,413-417,418
head and neck complications of,
401-422
infections in, 134-136, 156,354,
402-403,406-408,410-411
malignancy risk after, 421
neurologic complications in, 412-
413,417,419
ocular complications in, 413, 417,
419-420
oral complications in, 403-404,
404-411,414-416,417-419
patient preparation in, 131-132
patient selection in, 130
phases of, 401-403
phase I in, 403-404
phase II in, 404-413
phase III in, 413-417
phase IV in, 417-422
principles of, 129-136
procurement of marrow and
engraftment in, 132
recurrence of leukemia after, 421-
422
relative frequency of complications
in,405
scalp and cutaneous complications
in, 413, 417, 420
Brain
cerebral atrophy in, 384
521
522
encephalopathy of, 381-384
malignant invasion of, 363-386
drug neurotoxicity of, 378-386
Brain metastases, 363-372
clinical findings in, 365-367
diagnosis of, 367-369
incidence of, 364-365
treatment of, 370-372
tumors prone to, 364
Breast cancer, 4, 6, 376
brain involvement in, 366, 368, 369,
386
tumor desmoplasia in, 52-53
Brown tumor of hyperparathyroidism,
231
diagnosis of, 232
histology of, 234-235
treatment of, 238
Buccal cancer
chemotherapy for, 334
radiotherapy in, 281
surgical management of, 257, 259
Burkitt's lymphoma
Epstein-Barr virus in, 37, 42,110,
111-113
maxillary sinus, 257
maxillofacial, 246
oncogenes in, 37
treatment of, 246
Busulfan, 92, 132, 136
Cafe-au-lait spots, 238
Cancer, 3-14
animal models in, 10-14
chemical causing, 5, 6
classification of, 18, 19
diagnosis of, 5-7
epidemiology of, 4-5
etiology of, 4-5
host resistance and,S
markers for, 6-7
medical problems due to, 7-10
mortality from, 3
multistep theory of,S
pathology of, 17-42
phases of development of, 4
screening methods for, 6
significance of, 3-4
staging of, 29-30
treatment and prognosis in, 7
use ofterm, 17-18
see also Neoplasms and specific
types and sites of cancer
Candidiasis
granulocytopenia and, 145, 150-151
oral, 354, 356, 418
Capillary hemangioma, 18
Carbenicillin, 148,375
Carcinoembryonic antigen (CEA), 6,
105, III
Carcinoma
grading, 24-29
lymphatic spread of, 31
Carcinoma ex pleomorphic adenoma,
216
INDEX
Caries, postirradiation, 436-437, 444-
445, 490-493
Carotid body tumors, 293
Cataracts, 419-420
CCNU,92
combination chemotherapy with,
116,305,308
squamous cell cancer with, 302, 305,
308
Cefoperazone, 148, 149
Cefotaxime, 148, 149
Ceftazidine, 148, 149
Cell-mediated immunity (CMI)
animal model studies of, II
head and neck cancer and, 107-110
infections associated with, 152-153
in vitro tests of, 109-110
in vivo tests of, 108-109
Cellular immunity, 101, 102-103
Cementifying fibroma, 252
Cementoma, 252
Central nervous system (CNS) infec-
tions, 152, 153, 154
Cephalothin, 148-149
Cervical lymph node enlargement,
264-265
staging, 518-519
submandibular gland tumor and,
221
Chemicals, carcinogenic, 5, 6
Chemodectoma
computerized tomography (CT) of,
198
radiotherapy for, 293-294
Chemotherapy, 299-321
adjuvant, 313-314
administration guidelines in, 94-96
appointment series for, 480
hone marrow transplantation with,
136.404-406,412-413
cell-cycle-nonspecific agents in, 84
cell-cycle-specific phase-nonspecific
agents in, 84
cell-cycle-specific phase-specific
agents in, 84
classification and characteristics of
(table), 92-93
clinical trials in, 96-97
combination, see Combination che-
motherapy
definition of, 83
denture management in, 471-478
drug delivery, distribution, and
metabolism in, 86
drug dose and schedule in, 87-88
drug resistance in, 86-87
drug toxicity in, 88-92
hemorrhage with, 496
immunotherapy with, 308
initial therapy with, 314-318
intraarterial, 309
in vitro screening for, 98
investigational agents in, 303-304
log cell kill hypothesis in, 85
long-term complications of, 89-92
mucositis and, 351-353, 355, 495-
496
neurotoxicity of, 353, 378-386
number and timing of courses in,
316-318
nursing care in, 493-496
optimal timing of, 97-98
oral complications and, 486-487
palliative, 74, 75
performance status scale for, 96, 97
pharmacology of, 85-92
previously untreated squamous cell
cancers, 309-318
principles of, 83-98
ratiotherapy response prediction
and, 318
recurrent and systematic squamous
cell cancers, 299-309
regional, 98
response criteria in, 95
response rate factors in, 299-300,
309-310,318-320
salivary gland cancer with, 320-321
selectivity of, 85-86
side effects of, 10
survival rate and, 300, 310, 319-320
therapeutic index in, 85-86
tumor cell biology and, 83-85
tumor cell sensitivity to, 54
see also Specific drugs and Classes of
drugs
Cherubism,240-241
Children
bone marrow transplantation in,
421-422
capillary hemangioma in, 18
melanotic neuroectodermal tumor
of, 249
mineralizing microangiopathy in,
383-384
salivary gland tumors in, 222-224
Chlorambucil, 92
Chondrosarcoma, 21,29, 197
maxillary sinus, 257
nasal fossa, 256
Cigarette smoking, see Tobacco
Cis-platinum (CDDP), 92, 94, 226
combination chemotherapy with,
305-308,314-318,321
neurotoxicity of, 378, 385-386
number and timing of courses of,
316-318
radiation response and, 318
response rate to, 302, 314, 317, 318
salivary gland cancer with, 321, 342
squamous cell cancer with, 299,
302-303,305-308,309,313,314-
318,339-340
toxicity of, 316
Clear cell parotid tumor, 219
Clinical trials of drugs
phases in, 96-97
surgery and, 71
Coagulopathy
factors affecting, 375
neurologic complications with, 373-
376

platelet transfusions in, 376
Collagen
basement membrane specific, 51
cell source of, 52
example demonstration of human,
48-51
tumor biologic activity and, 51-52
tumor invasion of, 47-48
Colon cancer, 4, 30, 33
Combination chemotherapy, 116
granulocytopenia and, 148-149
principles of, 88
rationale for, 88
squamous cell cancer with, 304-307
Complement, 102
Computerized tomography (CT), 71,
191-199
brain metastases on, 367-369
lymph node pathology on, 198
mandible on, 191-194
nasopharynx, paraphyngeal space,
and infratemporal fossa on, 194-
195
neck on, 198-199
oral cavity and oropharynx tumors
on, 193-194
paranasal sinuses on, 196-198
salivary glands on, 195-196,212
techniques in, 191-192, 193, 194,
195,196,198
thyroid gland pathology on, 198-
199
ConcanvalinA (Con A), 103-104
Corticosteroids, 93, 370, 377
Coxsackie virus, 208, 408
Cryoprecipitate, 115-116
CT, see Computerized tomography
(CT)
Cushing's syndrome, 7, 370
Cyclophosphamide (CY), 92
bone marrow transplantation with,
132,134,421
combination chemotherapy with,
304,305,306
metabolism of, 86
response rate to, 302, 303, 304
salivary gland cancer with, 321
scheduling of, 88
squamous cell cancer with, 299, 304,
305,306
toxicity of, 89
Cyclosporin, 136,409,412,417
Cylindroma
nasal fossa, 256
oral cavity, 258-259
parotid gland, 217-218
Cystic lesions, salivary gland, 209
Cytobarine, 88
Cytomegalovirus (CMV), 152, 154,
208
bone marrow transplantation with,
135,136,354,406,412,413
head and neck tumors and, 113
Cytosine arabinoside, 86, 93, 303, 378,
379,381,382
Cytoxan,342
INDEX
Dacarbazine (DTIC), 92, 94
Dactinomycin, 93, 94
Daunorubicin, 93, 94
Dentures
complete, 465-466, 470-471
prechemotherapy management tech-
niques for, 471-478
partial, 463-465
timing of placement of, 469-470
Dermatitis, radiation, 489
Desmoplasia, 46, 52-53
Dexamethasone, 370
Diagnosis of cancer, 5-7
Dimethylbanzathracene (BMBA)-
induced cancer, 11-13
Disseminated intravascular coagula-
tion (DIC), 374-375
DNCB testing, 108-109
Doxorubicin, 86, 93, 94
Ear
bone marrow transplantation and,
411-412,416-417,418
examination of, 185-186
melanoma of, 185, 343-344
Emergencies, surgical, 75
Encephalopathy, drug-induced, 379,
380,381-384
Environmental factors, 42
Eosinophilic granuloma, maxillofacial,
245-246
Epidermoid carcinoma
cervical lymph node enlargement
and, 265
computerized tomograph (CT) of,
192-193
hard palate and gingiva, 279
hypopharynx, 260
intraoral, 163
larynx, 260
moderately differentiated, 28
nasopharynx, 288
oropharynx, 259, 260
poorly differentiated, 27
well differentiated, 40
Epithelial dysplasia, 37-38
clinical appearance of, 39
lesions similar to, 38-39
Epithelial hyperplasia, 21
Epithelial tumors, maxillofacial, 245-
246
Epstein-Barr virus (EBV), 152, 154
B-lymphocytes and, 112-113
bone marrow transplantation with,
136
Burkitt's lymphoma and, 37, 42,
110,111-113
head and neck tumors and, 110,
111-113
nasopharyngeal carcinoma and, 42,
113,179
Erythroplakia
intraoral neoplasms and, 167
surgery for, 72, 255-256
Esophageal cancer, 376
523
Esophagitis, 142, 147 /
Esthesioneuroblastoma, nasal cavity,
290
Ethnic factors in cancer, 4
Etoposide, 93, 94
Ewing's sarcoma, 257
Extraoral neoplasms, 179-188
clinical presentation in, 180
etiologic factors in, 179
evaluation of, 180
staging of, 180
treatment of, 181
see also Specific carcinomas
Facial nerve
anatomy in, 201-202
salivary gland neoplasia and, 225,
226
Fibroma
cementifying, 252
ossifying, 240
Fibronectin,47
Fibroosseous lesions, maxillofacial,
238-241
Fibrosarcoma
metastatic cell behavior in, 56-57,
60
tumor cell heterogeneity in, 55-56
Fibrous dysplasia, 238-240
Flaps in reconstructive surgery, 267-
269
Floxuridine, 86
5-fluorocytosine,151
5-fluorouracil (5-FU), 92, 226
combination chemotherapy with,
304,306,307,315-316
mucositis with, 352
neurotoxicity of, 378, 380, 381
number and timing of courses of,
316-318
radiotherapy with, 312, 318
response rate to, 302, 303, 315
salivary gland cancer with, 321, 342
squamous cell cancer with, 299, 304,
306,307,309,312,315-318,339-
340
5-FUDR,302
Follicular thyroid carcinoma, 187,
262-263
Follow-up to surgery, 74, 272-273
Fordyce spots, 216
Fungal infections, 152
bone marrow transplantation and,
406,411
chemotherapy and, 494-495
granulocytopenia and, 145, 151
radiotherapy and, 434-435
Gamma-globulin preparations, 150
Ganglioneuroma, maxillofacial, 249
Gastrointestinal tract
lymphoma, 74
metastases to, 220
Genetic factors in cancer, 4, 34, 104,
524
105-106
Gentamicin, 148
Gestational choriocarcinoma, 97
Giant cell lesions, 231-238
diagnosis of, 231-233
histology of, 234-235
treatment of, 233-238
Giant cell reparative granuloma
(GCRG),234
diagnosis of, 231-232, 233, 234, 241
treatment of, 233-238
Giant cell tumors, 231
diagnosis of, 232-233
histology of, 234-235
treatment of, 233-238
Gingival tumors
metastatic to, 351
radiotherapy in, 281-283
Gingivitis, 355-357, 434
Grading
grades in, 24
prognostic value of, 25-29
Graft-versus-host disease (GVHD)
bone marrow transplantation and,
129,130,131,133-134,408,413-
417,418
chronic, 134, 136
infectious complications of, 135-
136
ocular complications with, 413
oral complications with, 414-416
prevention of, 133-134
reactions seen in, 133
Granulocytic sarcoma, 372
Granulocytopenia
diagnostic approach to, 145-146
fungal infections in, 150-152
granulocyte count in, 141-142
granulocyte transfusions in, 149
infections associated with, 141-152
inflammatory response in, 144-145
pathogens in, 143-144
persistent, 150
pneumonia and, 146-147
sites of, 142-143
therapy for, 147-149
Hand-Schuller-Christian disease, 245,
246
Hard palate defects, 453-458
Hard palate tumors
minor salivary gland tumors in, 293
radiotherapy in, 281-283
surgical management of, 259
Head and neck cancer
animal models in, 10-14
assessment of treatment success in,
331-346
collagenase activity of, 52
estimated new cases and deaths
(1983),17
geneticfactors in, 105-106
immunologic aspects of, 104-06
immunotherapy in, 116-117
lymph node metastases and, 31-32
INDEX
primary sites for, 29
psychosocial effect of, 505-506
tumor-associated antigens in, 105
Hemangioma
capillary, 18
children and, 222-224
maxillofacial, 243
Hematologic neoplasms
disease-associated complications
with, 351
treatment-related complications
with, 351-359
Hematopoietic-reticuloendothelial
tumors, maxillofacial, 245-246
Hemorrhage
bone marrow transplantation and,
406,411
chemotherapy and, 496
intracranial, 375-376
mucosal, 358-359
nasal, 411
neurologic complications with, 373-
376
surgical emergency with, 75
Hepatitis, 152, 153, 154
Herpes simplex virus (HSV), 152
bone marrow transplantation with,
136, 354, 406, 412, 413, 417
granulocytopenia and, 142
head and neck tumors and, 114
immune response to, 110
intraoral neoplasms and, 165, 173
mucositis with, 355
prevention of, 153
Herpesviruses, 111
Herpes zoster infection, 355
Hexamethylenamine, 93
Histiocystosis, maxillofacial, 245-246
Hodgkin's lymphoma
chemotherapy in, 87,92
immunodeficiency and, 107
infections in, 152
Human leukocyte antigen (HLA), in
bone marrow transplantation,
129,130-131
Humoral immunity
head and neck cancer and, 110-111
infections associated with, 153
principles of, 101-102
Hydroxyurea, 93, 373
salivary gland cancer with, 342
squamous cell cancer with, 302, 311
Hypercalcemia
neurologic complications with, 376-
377
parathyroid tumors and, 263
Hyperparathyroidism, brown tumor
of, 231, 232, 234-235, 238
Hypopharynx tumors
assessment of treatment success,
335-336
common tumors in, 260
detection and evaluation of, 183
radiotherapy in, 285-286
squamous cell carcinoma in, 335-
336
staging, 517
surgical management of, 260
Immune-reactive proteins (IRP), 110-
111
Immunoglobulin A (IgA), 102
head and neck cancer and, 11 0, 111
herpes simplex virus and, 114
Immunoglobulin D (IgD), 102, 110,
111
Immunoglobulin E (IgE), 102, 110
Immunoglobulin G (IgG), 101
Epstein-Barr virus and, 112
head and neck cancer and, 110
Immunoglobulin M (IgM), 101
Epstein-Barr virus and, 112
head and neck cancer and, 11 0
herpes simplex virus and, 114
Immunology
aging and increased malignancy and,
106
fundamentals of, 101
genetics and, 104
head and neck carcinoma and, 104-
106,107-111
identification of populations in, 103
principles of, 101-117
tests offunction in, 103-104
treatment modalities and, 117
see also Specific types of immunity
Immunosuppression
animal model studies of, 11
chemotherapy and, 89, 494-495
Immunotherapy
head and neck carcinoma and, 116-
117
melanoma and, 344-345
principles of, 114-116
squamous cell cancer with, 308
Immunotoxins,115
Immunovirology, 111
Indomethacin, 375, 377
Infection
bone marrow transplantation with,
134-136,156,354,402-403,406-
408,410-411
cell-mediated immunity and, 152-
153
central nervous system, 154
chemotherapy and, 493-496
compromised host and, 141
granulocytopenia and, 141-152
humoral immune deficiency and,
153
iatrogenic procedures and, 154
infusions and, 154
management of, 141-156,410-411
mucosal, 353-355
obstruction of natural passages and,
154
oral complications with, 489
periodontal, 355-357, 494
postoperative care and, 272
predisposing factors to, 141
prevention of, 154-156

radiotherapy and, 430-432, 436-438
Infiltrating salivary duct carcinoma,
218-219
Influenza vaccine, 155
Interferon, 106, 115
Interleukin 2, 106, 115
Intraoral neoplasms, 163-175
anatomic considerations in, 163-165
biopsy in, 169-171
clinical evaluation of, 173-174
clinical presentation of, 167-168
diagnosis of, 168-173
examination in, 166-167
incidence of, 165
metastatic, 351
patient history in, 165-166
radiographic evaluation of, 174-175
sites in, 165
survival rates for, 163
Isoniazid, 153, 156
Kaposi's sarcoma, 107, 113
Karnofsky performance status scale,
96
Keratoacanthoma, 24
Keratocyst, odontogenic, 252
Kidney metastases, 220
Lamin,47
Large cell lung carcinoma, 364, 376
Larynx carcinoma, 183-184
assessment of treatment success in,
336-337,338-339
benign, 261
chemotherapy for, 338-339
classification of, 184
common tumors in, 261
evaluation of, 180, 184
lymphoma and plasmacytoma, 264
metastatic carcinoma to, 261
minor salivary gland tumors in,
221-222,261
mononuclear cell infiltrate in, 107
radiotherapy in, 286-288, 336-337
squamous cell carcinoma in, 336-
337
staging, 517-518
surgical management of, 260-261
Lenerer-Siwe disease, 245, 246
Leucovorin, 86
Leukemia, acute, 351, 372
bone marrow transplantation in,
130, 132, 133
chemotherapy in, 87, 97, 156
infections and, 141, 152, 156
neurologic manifestations of, 363,
372,373,381-383
Leukoplakia
intraoral neoplasms and, 167
radiotherapy and, 278
surgery for, 72, 255
Leukostasis,372-373
Levamisole, 115, 116-117,314
Lichen planus, 38
INDEX
Linear energy transfer (LET), 78
Lip cancer
radiotherapy in, 278
staging, 517
surgical management of, 257-258
Lipoma, 209
Liposarcoma, 73
Liver metastases, 31, 74
Lung cancer, 4
large cell, 364, 376
small cell, 79, 87, 368, 386
Lung infections, 152
Lung metastases, 31, 74, 220
Lymphangioma, 224
Lymph node metastases
computerized tomography (CT) of,
198
head and neck cancer and, 31-32
radical neck dissection for, 73-74,
265-266
salivary gland neoplasia and, 226
Lymph node system
cervical, 264-265
computerized tomography (CT) of,
198
extraoral neoplasms and, 179
granulocytopenia and, 143
intraoral neoplasms and, 167
malformations of, 243
preoperative status of, 269, 271
radiotherapy and, 276-277
spread of tumors through, 30-31
tongue lesions and, 284
Lymphoblastic leukemia, acute (ALL),
130, 386, 412
Lymphoepithelioma, nasopharynx,
288
Lymphoma ..
cervical lymph node enlargement
and, 264
chemotherapy in, 87, 97
computerized tomography (CT) of,
198
Epstein-Barr virus and, 112, 113
extranodal, 264
gastrointestinal, 74
infections associated with, 154
intraoral, 167
maxillofacial, 245
nasal cavity, 290
nasal fossa, 256
nasopharynx, 256-257
oropharynx, 259, 260, 279
parotid gland, 219
thyroid gland, 264
Maxillary sinus tumors
common tumors in, 257
surgical management of, 257
Maxillofacial region neoplasms, non-
mucosal,231-252
benign nondontogenic, 231-249
classification of, 231, 232
malignant nonodontogenic, 249
odontogenic, 249-252
525
Medullary thyroid carcinoma, 72,187,
263
Melanoma, 186
assessment of treatment success in,
342-345
brain involvement with, 364, 366,
367,386,389
cervical lymph node enlargement
and, 265
depth of dermal invasion in, 22
external auditory canal and, 185,
343-344
larynx, 261
levels of tumor involvement in, 342
metastatic cell behavior in, 56-60
mucosal,345-346
nasal fossa, 256
parotid gland metastases and, 220
radiation therapy for, 344, 346
recurrence of, 345-346
surgery for, 73, 342-343
tumor cell heterogeneity in, 54, 55,
56
Melanotic neuroectodermal tumor of
infancy, 249
Melphalan, 92
Meninges
drug neurotoxicity and, 378-381
malignant invasion of, 386-393
6-mercaptopurine, 93
Mesenchymal tumors, benign, 231-
241
Metastases
cervical lymph node enlargement
and, 265
extraoral, 180
intraoral, 168
larynx, 261
nasal fossa, 256
oral cavity, 258
parotid gland, 217-218, 220
significance of, 32
sites of, 31
spread of tumor through, 30-31
staging, 519
Metastatic cells
biology and biochemistry of, 45-61
collagen degradation and, 47-48
collagenase activity in human
tumors and, 48-52
desmoplasia and, 52-53
heterogeneity of, 53-56
primary tumor invasion by, 45-47
selective and clonal nature of, 56-61
steps in growth of, 45
three-step hypothesis for, 47
Methotrexate (MTX), 226
adjuvant, 313-314
blood-brain barrier and, 86
bone marrow transplantation with,
134,136,404,412,417,421
combination chemotherapy with,
304,306,307,310-311
leukemic prophylaxis with, 421
leukoencephalopathy of, 382-383,
385
526
meningeal invasion and, 390-391
mucositis with, 352
neurotoxicity of, 378, 379, 381-384
radiotherapy with, 311
randomized trials of, 307-308
response rate to, 300, 301
salivary gland cancer with, 321, 342
scheduling of, 88
squamous cell cancer with, 299,
300-301,304,306,307-308,309,
310-311,313-314
Methyl-CCNU,305
Mezlocillin, 148, 149
Mineralizing microangiopathy, 383-
384
Misonidazole, 80
Mithramycin, 93, 94, 375, 377
Mitomycin, 93, 94, 304-305, 306
Mixed tumor
parotid gland, 214, 341
submandibular gland, 221
Monoclonal antisera, 103
Moxalactam, 148, 149,375
Mucoepidermoid tumors
maxillofacial, 249
parotid gland, 217
salivary gland, 262, 292, 341
submandibular gland, 221
Mucormycosis, 151-152
Mucosa, see Oral mucosa
Mucositis
bone marrow transplantation and,
406,407
chemotherapy and, 351-353, 355,
495-496
management of, 432-435
prevention of, 444
radiotherapy and, 429-430, 432-
435,444,485-490
Multiple myeloma, 376, 377
Myelogenous leukemia, chronic, 130
Myelosuppression, in chemotherapy,
10,89,494-495
Myxoma, 236-237, 238
Nasal cavity carcinoma
development of, 39
examination in, 184-185
lymphoma and plasmacytoma, 264
minor salivary gland tumors, 293
radiotherapy in, 290
treatment of, 185
Nasal fossa tumors
common tumors in, 256
surgical management of, 256
Nasal vestibule, radiotherapy in, 289-
290
Nasopharynx carcinoma, 181-182
assessment of treatment success in,
337-338
clinical presentation in, 181
combination chemotherapy in, 307
common tumors in, 194,256-257,
288
computerized tomography (CT) of,
INDEX
194-195
Epstein-Barr virus in, 42, 113, 179
examination in, 181-182
lymphoma and plasmacytoma, 264
radiotherapy in, 288-289
squamous cell carcinoma in, 337-
338
surgical management of, 256-257
treatment of, 182
Natural cell-mediated cytotoxicity
(NCMC),106
Natural killer (NK) cells, 106
Neck
computerized tomography (CT) of,
198-199
mass of, 187-188
see also Head and neck cancer
Necrotizing sialometaplasia, 39-42,
209
Neoplasms
classification of, 17
clinical history or pattern in, 21
depth of dermal invasion in, 22-24
development of, 32-42
distinction between benign and
malignant in, 18, 34
evaluation of, 24
morphologic exceptions in, 18-21
spread of, 30-32
variations in behavior at same site in,
21-22
Neurilemmoma, 247
Neuroblastoma, olfactory, 256
Neurofibroma, maxillofacial, 247, 248
Neurogenic tumors
maxillofacial,247-249
nasal fossa, 256
Neurologic complications
bone marrow transplantation and,
411-413,417,419
malignancy and, 363-393
see also Brain
Neurotoxicity of chemotherapy, 353,
378-386
Nitrogen mustard, 381
combination chemotherapy with,
116,308
squamous cell cancer with, 308
Nitrosaureas
blood-brain barrier and, 86
combination chemotherapy with,
305
squamous cell cancer with, 305
see also specific drugs
Non-Hodgkin's lymphoma
chemotherapy in, 87
immunodeficiency and, 107
Nonlymphocytic leukemia, acute
(ANLL), 353, 356
Nonmucosal neoplasms, maxillofacial,
see Maxillofacial region neo-
plasms, nonmucosal
N onodontogenic tumors, benign,
231-249
classification of, 231, 232
fibroosseous lesions, 238-241
hemangioma, 243
mesenchymal,231-238
myxoma, 236-237
neurogenic, 247-249
vascular lesions, 241-243
vascular malformations, 243-247
Nonodontogenic tumors, malignant,
249
Nosocomial infection, 154
Nuclear magnetic resonance (NMR),
174-75,369
Null cells, 10 1
Nutrition, 509~515
cancer patient and, 509-11
enteral, 513-514
indications for support in, 512-513
nutritional assessment for, 511-513
parenteral,514-515
postoperative nursing plan for, 497-
498
Nystatin, 156
Oat cell carcinoma, 261, 364
Odontogenic tumors, 249-252
adenomatoid,251-252
ameloblastoma, 250-251
cementoma, 252
classification of, 249
keratocyst, 252
squamous, 41, 42
Olfactory neuroblastoma, 256
Ommaya reservoir, 391
Oncocytoma, parotid gland, 214-215
Oncofetal antigens, 104
Oncogenes, 34-37,111
Oncovin, see Vincristine (Oncovin)
Oral cancer
carcinoembryonic antigen (CEA) in,
105
computerized tomography (CT) of,
193-194
herpes simplex virus in, 114
immune response in, 110
mononuclear cell infiltrate in, 107
screening techniques in, 6
Oral cavity complications
bone marrow transplantation and,
403-404,404-411,414-416,417-
419
dental examination and treatment in,
481-485
infection and, 489
medications for (table), 486-487
nursing care for, 479-501
patient history in, 481
pretreatment assessment for, 479-
485
preventive dental plan in, 485
radiation dermatitis in, 489
radiotherapy and, 429-447, 485-493
table summary of, 481
Oral cavity tumors
assessment of treatment success in,
332-334,338-339
chemotherapy for, 338-339

evaluation of, 180
floor-of mouth lesions in, 258-259
radiotherapy in, 278-283
squamous cell carcinoma in, 332-
334
staging, 517
surgical management of, 257-259
Oral mucosa
hemorrhage in, 358-359
infection of, 353-355
sarcoma of, 29
verrucous carcinoma of, 21
Oropharynx carcinoma, 182-183
chemotherapy for, 338-339
common tumors in, 260, 283
computerized tomography (CT) of,
193-194
evaluation of, 180, 182
radiotherapy in, 283-285
surgical management of, 259-260
Ossifying fibroma, 240
Osteoblastoma, maxillofacial, 241, 242
Osteoid osteoma, maxillofacial, 241
Osteomyelitis, 237, 240
Osteoradionecrosis, 438-441, 493
Osteosarcoma, 197,257
Palliative surgery, 74, 272
Papillary thyroid adenocarcinoma,
187,262
Papillomaviruses, 114
Papovaviruses, 111
Paraganglioma
radiotherapy for, 293-294
Paranasal sinus carcinoma
computerized tomography (CT) of,
196-198
development of, 39
examination in, 184-185
minor salivary gland tumors in, 293
radiotherapy in, 290-292
staging, 518
treatment of, 185
Parathormone, 7
Parathyroid carcinoma, 7
common tumors in, 263
surgical management of, 263-264
Parotid gland tumors, 212-220
acinic cell, 218
adenocarcinoma, 218-219, 262
anatomy in, 201-202
assessment of treatment success in,
340-342
carcinoma ex pleomorphic adeno-
ma,216
children and, 224
clear cell, 219
cylindroma, 217-218
cystic lesions and, 209
lymphoma and plasmacytoma, 219,
264
metastases from, 217-218
metastases to, 220
mixed tumor, 214
monomorphic adenoma, 215
INDEX
mucoepidermoid,217
oncocytoma, 214-215
papillary cystadenoma lymphoma-
tosuffi,214
physical examination in, 211
physiology of, 205
radiotherapy for, 225, 341-342
recurrence rates for, 341
sebaceous tumors, 215-216
squamous cell, 219
survival rate for, 226
Penicillins, 148-149, 375
Periapical cemental dysplasia (PCD),
252
Periodonitis, 142, 145,355-357,430-
432,494
Pharynx carcinoma
lymphoma and plasmacytoma, 264
radiotherapy in, 286
staging, 517
Phenytoin sodium, 370-371
Phorbol esters, 32-34
Piperacillin, 148, 149
Plasmacytoma
extraosseous, 264
maxillary sinus, 257
nasal fossa, 256
Pleomorphic adenoma
children and, 224
minor salivary gland tumors, 222
parotid gland, 214
salivary gland, 224, 261-262
Pneumonia, 135-136, 144, 146-147,
152,153,154
Pneumonitis, 146, 153, 154
Polyoma virus, Ill, 114
Polyps, benign, 256
Pontine abnormalities, 384
Porfiromycin, 302, 303
Port-wine stain, 243
Procarbazine, 86,93,381
Prostate cancer, 4
Prosthetic management, 453-478
chemotherapy and denture manage-
ment in, 471-478
classification in, 453
combination oral and facial defects
in, 468-469
complete dentures in, 465-466, 470-
471
definitive obturator prosthesis in,
455-458
definitive soft-palate prosthesis in,
458-459
facial defects in, 466-469
mandibular defects in, 459-466
maxillary defects in, 453-459
partial dentures in, 463-465
radiotherapy and, 469-471
surgical reconstruction versus, 466-
467
surgical resection needing, 453-469
Pseudoepitheliomatous hyperplasia,
40
Psychological factors in treatment, 10
Psychosocial effect of cancer, 503-507
527
family and, 504
head and neck cancer and, 505-506
management of, 506-507
medical professional and, 504
overview of, 503-504
patient and, 503-504
Pyriform sinus lesions
assessment of treatment success in,
335-336,338-339
chemotherapy for, 338-339
detection of, 183
radiotherapy in, 285-286, 335-336
squamous cell carcinoma in, 335-
336
Radiation dermatitis, 489
Radiation pneumonitis, 146
Radiotherapy, 275-294
appointment series for, 480
biologic aspects of, 77-78
bone marrow transplantation with,
132,136,421-422
brain metastases with, 371-372
caries prevention in, 444-445, 490-
493
cell cycle effects in, 79
cell survival considerations in, 78
chemodectoma in, 293-294
dental management in, 445-447
dose/time/fractionation in, 80-81,
275
fibrous dysplasia transformation
after, 240
general considerations in, 275-277
hypopharynx in, 285-286
infection with, 430-432, 436-438
larynx in, 286-288
linear energy transfer (LET) in, 78
melanoma and, 344, 346
meningeal invasion and, 392
mucositis and ulceration and, 429-
430,432-435,444,485-490
nasal cavity in, 290
nasal vestibule in, 289-290
nasopharynx in, 288-289
nursing care in, 485-493
oral cavity in, 278-283
oral complications of, 429-447,
485-493
oropharynx in, 283-285
osteoradionecrosis with, 438-441,
493
palliative, 74
paraganglioma in, 293-294
paranasal sinuses in, 290-292
physics of, 77
postoperative, 277
postradiation problems in, 435-443
potentially lethal damage repair
(PLDR) in, 79
pretreatment evaluation in, 443-444
primary tumor in, 275-276
principles of, 77-81
prosthetic management and, 453,
528
469-471
radiocurability and radiosensitivity
in, 78-79, 79-80, 81
regional lymph nodes in, 276-277
relative biologic effectiveness (RBE)
of, 78
repair of damage in, 79
risk for malignancy with, 421-422
salivary glands in, 206, 208-209,
224-225,227,292-293
sensitizers in, 80
side effects of, 10, 385, 490-493
specific sites in, 278-293
squamous cell cancer with, 311-312
sublethal damage repair (SLDR) in,
79
surgery combined with, 277, 331-
332
taste alteration with, 441
treatment planning in, 77, 443-447
trismus with, 441-443
tumor cell sensitivity to, 54
tumor size and, 81
xerostomia with, 435-436, 444, 490
Reconstructive surgery, 266-269
Regional chemotherapy, 98
Rehabilitation, see Prosthetic manage-
ment
Relative biologic effectiveness (RBE),
78
Reserve cells, 34
Reticulum cell sarcoma, 57
Rifampin, 151
Salivary duct, adenoid cystic carcino-
rna of, 18
Salivary gland tumors, major, 179,
201-227,249
adenocarcinoma, 21-22
adenoid cystic, 321
adjuvant chemotherapy for, 342
anatomy in, 201-203
assessment of treatment success in,
340-342
benign, 261
biopsy in, 212
carcinoembryonic antigen (CEA) in,
105
chemotherapy for, 225-226, 320-
321
children and, 222-224
classification of, 201, 207, 261-262
common tumors in, 206-208, 292
computerized tomography (CT) in,
195-196,212
diagnosis of, 186-187,209-212
disorders mimicking, 208-209
epidemiology of, 206
Epstein-Barr virus and, 113
histogenic scheme for, 207
histology in, 206
history in, 209-211
malignant, 262
mixed tumors of, 261-262
physical examination in, 186, 211
INDEX
physiology in, 204-206
postradiation, 42
radiography in, 211-212
radiotherapy in, 224-225, 227, 292-
293
recurrence of, 226
staging of, 207-208, 518
surgical management of, 261-262
survival ratefor, 226-227, 341
treatment in, 186-187, 226-227
Salivary gland tumors, minor, 221-222
anatomy of, 203
hard palate and. gingiva, 279
intraoral neoplasms and, 167, 170
larynx and, 221-222, 261
nasal cavity, 290
radiotherapy in, 293
survival rate for, 227, 341
tongue and, 279
treatment of, 222
Sarcoma
grading, 24
granulocytic, 372
lymphatic spread of, 31
of oral mucosa, 29
postradiation, 42
Scar reaction, 46
Schwannoma,247-249
Screening techniques for cancer, 6
Sebaceous tumors, parotid gland, 215-
216
Sensitizers, radiation, 80
Sepsis, postoperative, 75
Severe combined immunodeficiency,
129,130
Sialadenitis, 208, 211
Sialometaplasia, necrotizing, 39-42,
209
Skin cancers, 186
Small cell lung carcinoma, 79, 87, 368,
386
Smoking, see Tobacco
Soft palate defects, 453-454, 458-459
Soft palate tumors
radiotherapy in, 284
surgical management of, 260
Soft-tissue sarcoma
larynx, 261
nasal cavity, 290
Somnolence syndrome, 384
Spindle cell carcinoma of tongue, 28
Splenectomy, 75, 153
Squamous cell carcinoma
animal models of, 10-11
assessment of treatment success in,
332-340
buccal mucosa, 281
carcinoembryonic antigen (CEA) in,
105
chemotherapy in, 299-320, 338-340
erythroplakia and, 72
external auditory canal and, 185
extraoral, 179, 181
floor of mouth, 278
grading, 24
hard palate and gingiva, 279
humoral immunity in, 110
hypercalcemia with, 376
hypopharynx-pyriform sinus, 335-
336,338-339
intraoral, 163
larynx, 286, 336-337, 338-339
lip, 278
maxillary sinus, 257
maxillofacial, 249
multiple primary, 37, 332
nasal cavity, 290
nasal fossa, 256
nasopharynx, 194,256,288,337-
338
odontogenic, 41, 42
oral cavity, 332-334
oropharynx, 283
parotid gland, 219, 220
pinna, 185
salivary gland, 187, 292
soft palate, 284
spread of, 31
tongue, 259, 279
tonsillar region, 334-335
upper respiratory system, 30, 42,
179
Staging of cancer, 29-30, 517-519
surgery decisions and, 74, 255
surgical or pathologic, 30
survival rates and, 320
treatment and, 30, 331
Stem cells, 34
Stomach cancer, 4
Streptozotocin, 92
Sturge-Weber syndrome, 243
Sublingual gland tumors, 221
anatomy of, 203
diagnosis of, 221
Submandibular gland tumors, 220-221
adenocarcinoma, 262
anatomy of, 202-203
lymphoma and plasmacytoma, 264
survival rate for, 226
Sulfhydryl compounds, 80
Surgery, 255-273
airway management in, 498
appointment series for, 480
clinical trials and, 71
diagnosis and staging and, 72-73,
74,255-256
discharge preparation in, 500-501
emergencies and, 75
fluid and electrolyte management in,
497-498
follow-up to, 74, 272-273
goals of, 71
nursing care in, 496-501
operative approach in, 271-272
pain control in, 498
palliative, 74-75,272
postoperative care after, 272
preoperative preparation in, 269-
271,496-497
prevention and early detection with,
72
principles of, 71-75

prosthetic management after, 453-
469
prosthetic reconstruction versus,
466-467
radical neck dissection in, 265-266
radiotherapy combined with, 277,
331-332
reconstructive, 266-269
role of, 71-72
by site, 256-265
wound care in, 498-501
Tamoxifen, 93
Temporal bone tumors
evaluation of, 185-186
radiotherapy in, 293
Testicular carcinoma, 88, 97
Therapeutic index, 85-86
6-thioguanine, 93
Thrombocytopenia
factors affecting, 375
neurologic complications with, 373-
376
platelet transfusions in, 376
Thymosin,116
Thyroid gland carcinoma, 179, 187
anaplastic, 263
computerized tomography (CT) of,
198-199
follicular, 187,262-263
lymphoma of, 264
medullary, 72, 187,263
metastatic spread of, 31
papillary, 187
postradiation, 42
surgical management of, 72, 262-
263
types of, 262-263
Ticarcillin, 148
T-lymphocytes, 101
bone marrow transplantation and,
130,133
cellular immunity and, 102-103, 109
identification of populations of, 103
immunotoxins and, 115
tests offunction of, 103-104
TNM classification, 29, 331
Tobacco
cancer prevention and, 72
extraoral neoplasms and, 179
head and neck cancer and, 108
INDEX
herpes simplex virus and, 114
intraoral neoplasms and, 165
Tobramycin, 148
Tongue carcinoma
adenocarcinoma in, 222
base of tongue, 182-183,222,284-
285,335
common neoplasms in, 279
computerized tomography (CT) of,
193-194
disabilities after surgery for, 459-
461
evaluation of, 182
granulomatous growths on, 414
lymphoma and plasmacytoma, 264
oral tongue, 279
radiotherapy in, 279-281, 284-285
spindle cell, 28
surgical management of, 259
Tonsillar tumors
assessment of treatment success in,
334-335
lymphoma and plasmacytoma, 264
radiotherapy in, 283--284
squamous cell carcinoma in, 334-
335
surgical management of, 260
Total parenteral nutrition (TPN), 514-
516
Transitional cell carcinoma,
nasopharynx, 288
Transplantation, see Bone marrow
transplantation
Trimethoprim-sulfamethoxazole, 136,
148,153,156
Tumor-associated transplantation
antigens (TATA), 104
Tumor cells
cycle stages of, 83-84
chemotherapy and, 83-85
growth patterns of, 84-85
radiation therapy and, 78, 79
see also Metastatic cells
Tumor markers, 6-7,105-06
Tumor-necrotizing factor (TNF), 115
Tumors, see Neoplasms and Specific
cancers
Tumor-specific transplantation
antigens (TSTA), 104
Ulcerative mucositis, 406, 407
529
Uterine cancer, 4
Vaccines, 114-115, 155
Varicella zoster virus (VZV), 136, 152,
155,406,413,417
Vascular lesions, maxillofacial, 241-
243
Vascular malformations, maxillofacial,
243-249
Venous malformations, maxillofacial,
243-245
Verrucous carcinoma
oral mucosa, 21
tongue, 279
Vinblastine (VLB), 86,93,94
combination chemotherapy with,
305,306
neurotoxicity of, 385
response rate to, 302
squamous cell cancer with, 299, 305,
306
toxiciry of, 89
Vincristine (oncovin), 86, 93, 94
combination chemotherapy with,
116,304,305,306,308,310-311
neurotoxicity of, 378, 379-380, 385
squamous cell cancer with, 304, 305,
306,308,310-311,315,339
toxicity of, 89, 316
Viral infection, 152
bone marrow transplantation and,
406-408,410-411
chemotherapy and, 494-495
head and neck tumors and, 111-114
immunology and, 111
oral,354-355
reactivation of, 156
see also Specific viruses
Warthin's tumor, 214, 261
Waterhouse-Friderichsen syndrome,
153
Xerostomia, 353, 405-406
bone marrow transplantation and,
405-406
chemotherapy and, 353
management of, 436
prevention of, 444
radiotherapy and, 435-436, 444, 490