Shear’s Cysts of 

the Oral and Maxillofacial Regions

Shear’s Cysts of the Oral and Maxillofacial Regions

Fifth Edition

Paul M. Speight, BDS, PhD, FDRCPS (Glasg), FDSRCS (Eng), FDSRCS (Edin), FRCPath
Professor Emeritus in Oral and Maxillofacial Pathology
School of Clinical Dentistry
University of Sheffield, UK
This fifth edition first published 2022
© 2022 John Wiley & Sons Ltd

Edition History
1e (1976); 2e (1983); 3e (1992); 4e (2007)

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Library of Congress Cataloging-­in-­Publication Data

Names: Speight, P. M. (Paul M.) author. | Shear, Mervyn. Cysts of the oral
and maxillofacial regions.
Title: Shear’s cysts of the oral and maxillofacial regions / Paul M. Speight.
Other titles: Cysts of the oral and maxillofacial regions
Description: Fifth edition. | Hoboken, NJ : Wiley-Blackwell, 2022. |
Preceded by Cysts of the oral and maxillofacial regions / Mervyn Shear
and Paul Speight. 4th ed. 2007. | Includes bibliographical references
and index.
Identifiers: LCCN 2022000536 (print) | LCCN 2022000537 (ebook) | ISBN
9781119354994 (cloth) | ISBN 9781119354932 (adobe pdf) | ISBN
9781119354949 (epub)
Subjects: MESH: Jaw Cysts | Jaw Diseases–physiopathology. | Mouth
Diseases–physiopathology
Classification: LCC RC815 (print) | LCC RC815 (ebook) | NLM WU 140.5 |
DDC 617.5/22–dc23/eng/20220127
LC record available at https://lccn.loc.gov/2022000536
LC ebook record available at https://lccn.loc.gov/2022000537

Cover Design: Wiley

Cover Images: Courtesy of Paul M. Speight

Set in 9.5/12.5pt STIXTwoText by Straive, Pondicherry, India

Mervyn Shear
1931–2017
 vii

Contents

Preface to the Fifth Edition  viii

Foreword  x
Acknowledgements  xi

1 Classification and Frequency of Cysts of the Oral and Maxillofacial Regions  1

2 General Considerations  6

3 Radicular Cyst  20

4 Inflammatory Collateral Cysts  47

5 Dentigerous Cyst  62

6 Eruption Cyst  83

7 Odontogenic Keratocyst  87

8 Lateral Periodontal Cyst and Botryoid Odontogenic Cyst  140

9 Gingival Cysts  155

10 Glandular Odontogenic Cyst  164

11 Calcifying Odontogenic Cyst  182

12 Orthokeratinised Odontogenic Cyst  201

13 Nasopalatine Duct Cyst  214

14 Nasolabial Cyst  230

15 Cysts of the Salivary and Minor Mucous Glands  237

16 Surgical Ciliated Cyst  262

17 Pseudocysts of the Jaws: Simple Bone Cyst and Stafne Bone Cavity  270

18 Developmental Cysts  288

Bibliography  309
Index  357
viii
Preface to the Fifth Edition
It is an honour to have prepared this fifth edition of
Mervyn Shear’s classic text on cysts of the maxillofacial
regions. This edition is dedicated to his memory and
I am grateful to the publishers for agreeing to make the
book eponymous and have his name in the title. Mervyn
Shear wrote the first edition in 1976  in an attempt to
record, in a single volume, all published knowledge on
the subject. Subsequent editions were published after
7 years (1983), 9 years (1992), and 15 years (2007), and
each continued to attempt to be a comprehensive record
of the literature. I was first honoured in this venture
when I was asked to assist Professor Shear in the prepa-
ration of the fourth edition that was published in 2007.
Even as we wrote it, we realised that the task was getting
more difficult because of the massive proliferation of
new publications. The text was lengthened considerably,
but the extra information was additive and we soon real-
ised that it was no longer possible to continue to try to
present a definitive account of the entire literature.
Feedback from colleagues, and in particular students,
reported that the book had become too detailed and
that much of the research reviewed had little relevance
to the day-­to-­day practicalities of diagnosis and manage-
ment of cysts.
We agreed that a new approach was needed and in late
2012 I was able to meet with Mervyn at his home near Cape
Town. At that time he was no longer able to participate in a
new edition, but together we outlined a basic plan for the
changes that we felt were necessary. This new fifth edition
is a complete rewrite of the book, but still maintains the
basic aim of providing an understanding of the pathogen-
esis of each cyst type as well as recording the clinical, radi-
ological, and histological features. The overall aim is to
assist pathologists and clinicians in making a correct diag-
nosis and informing management, but we also wanted to
make the book more accessible to students and trainees at
all levels, as well as to non-­specialist clinicians and general
pathologists faced with an individual lesion that requires
diagnosis and management. This new edition maintains
the same basic layout, but is restructured to present the
most common lesions first. Each chapter now includes
more detailed histopathology with more photomicrographs
and sections on radiological or histological differential
diagnosis. There are also more detailed discussions of the
historical aspects of the classification and naming of cysts
that I hope will be of general interest, but also provide
some context for the global variation in terminology and
explain why there may be so much confusion in the litera-
ture about some cyst types. We agreed not to include,
and to remove, detailed accounts of research findings
that do not advance our understanding of the pathogen-
esis or assist in diagnosis. The applies especially to the
odontogenic keratocyst, where there has been a massive
increase in publications in the last two decades, but little of
relevance to the practicalities of routine diagnosis and
treatment.
At the outset, I had aimed to reduce the number of
references and especially to remove references to some
of the ‘old’ literature that current students and trainees
may not appreciate as relevant. In the final outcome
about 250 references have been removed, but about
450  new references have been added. I hope that all
these are relevant and helpful. Many younger students
may be surprised to find that I have retained many ‘old’
papers, including some landmark studies going as far
back as the early 1900s, but also studies carried out in
the two to three decades after 1950. Many of these papers
are freely available online and report unparalleled obser-
vational studies that will never be repeated, but are
invaluable because of their original detailed observa-
tions relating to the pathogenesis and histological fea-
tures of many of the cyst types.
As in all previous editions, I have attempted to produce
a book that is useful to students and trainees at all levels,
but also to practising clinicians, whether specialists or
general practitioners. Because the final diagnosis of most

lesions lies in the hands of a pathologist, I have enhanced
the sections on pathology, histological features, and dif-
ferential diagnosis, and hope this will assist non-­specialist
pathologists as much as oral and maxillofacial patholo-
gists. I have made greater use of subsections, so that
Preface to the Fifth Edition ix
information is more accessible, allowing the reader to
rapidly ‘dip in’ to the book to find the information they
need. In this respect, the book may be a useful bench book
for the diagnostician, as well as a gripping read for the
keen student.
x
Foreword
­It is an honor to acknowledge and welcome the fifth edi-
tion of Cysts of the Oral and Maxillofacial Regions, or in
today’s vernacular, Cysts of the Oral and Maxillofacial
Regions 5.0. The oral and maxillofacial region, because of
its anatomic complexity, is home to a variety of cysts and
tumors unique to this site. Many of these arise from the
epithelial components that form our teeth and are known
as odontogenic cysts. Many of these cysts have proved to be
more biologically complex than originally thought as the
molecular pathogenesis has been investigated and reported.
This has blurred the distinction between cysts and cystic
neoplasms and the significance of the molecular landscape
characterizing some of these cysts is widely and energeti-
cally debated today.
The evolution of Cysts of the Oral and Maxillofacial
Regions has been remarkable: first edition (1976), second
edition (1983), third edition (1992), fourth edition (2007),
fifth ed (2022); from a concise text focusing on clinical/
radiographic features and standard histologic descriptions
illustrated in black and white, to an exhaustive review of
every aspect of these cystic lesions richly illustrated in
color. Some of the historical literature has been elimi-
nated, particularly where it lacked clinical relevance. The
current literature is extensively recorded, as is the diver-
sity of the histologic spectrum, including immunohisto-
chemical phenotypes and molecular/genetic alterations.
Two of the world’s most experienced and respected oral
pathologists are responsible for this text. The text was ini-
tiated by Professor Mervyn Shear from Johannesburg, and
Professor Paul Speight of the UK joined as a co-­author in
2007, and he currently continues the legacy of this major
contribution.
Cysts of the Oral and Maxillofacial Regions has become
the definitive source of information about this complex
group of lesions. No other contribution covers this topic
more extensively and accurately than this text and there is
something here for everyone. Clearly it is applicable for
students, both predoctoral and postgraduate, as well as to
radiologists, pathologists, researchers, surgeons, and other
clinicians.
As scientific inquiry has exploded in recent years and the
publication interval of the WHO series of classification of
tumors has been shortened significantly, so too is it likely
that the sixth edition of this text might be just over the hori-
zon. But a lot has been learned since 2007, and detailed
description and analysis of this new knowledge are finally
available. One of the primary functions of a textbook is­
not just to convey what is new, but to analyze what has­
been published and then condense and summarize that
information with an aim toward diagnostic and clinical­
relevancy. Professor Speight has done a masterful job of
condensing our knowledge of these cysts into a readable
and relevant format. This text is a must for anyone involved
in the diagnosis and treatment of cysts of the head and
neck. Improving our understanding of this group of lesions
improves the quality of care we can provide our patients.
And ultimately, that is what it’s all about.
John M. Wright, DDS, MS
Regents Professor
Diagnostic Sciences
Texas A&M University College of Dentistry
Dallas, Texas
USA

Acknowledgements
This edition is dedicated to the memory of Mervyn Shear,
who must first be acknowledged for his research and schol-
arship over many years that laid the foundations for all the
editions of this book. For this edition I specifically acknowl-
edge Mervyn’s support and permission to restructure the
book and to undertake a complete rewrite of the text, with
an increased emphasis on some basic principles and on
histopathology and differential diagnosis that may broaden
the scope of the book, making it more accessible to a wider
range of students and clinicians.
As in previous editions, we have relied heavily on the sup-
port and assistance of colleagues and on the research and
scholarship of our predecessors. In particular, I would like to
draw attention to a number of outstanding giants of the sub-
ject on whose shoulders we stand, and who are heavily cited
in the text or with whom, over many years, we have shared
and discussed cases: Mario Altini, Jerry Bouquot, Roger
Browne, Roman Carlos, Geoff Craig, Ricardo Gomez, Robert
Gorlin, Malcolm Harris, Jos Hille, Fumio Ide, Ivor Kramer,
TieJun Li, Hans Philipsen, Jens Pindborg, Finn Prætorius,
Peter Reichart, Paul Stoelinga, Takashi Takata, Paul Toller,
Willie van Heerden, Pablo Vargas, and John Wright. Some of
these are no longer with us, some I have never met, but most
have become good friends and colleagues.
For the preparation of this fifth edition I would like to
thank my colleagues, past and present, in the Unit of Oral
and Maxillofacial Pathology, University of Sheffield, for
xi
their patience, for many discussions and critical com-
ments on the text, and for their assistance in retrieving
and photographing cases. Daniel Brierley, Geoff Craig,
Lisette Collins, Paula Farthing, Keith Hunter, and Ali
Khurram have commented freely on my thoughts and
ideas about cysts and have also provided assistance in find-
ing appropriate cases for the illustrations. Chris Franklin
and Adam Jones have allowed me access to their data on
the incidence of cysts and oral biopsies.
Many colleagues have selflessly provided clinical pic-
tures, radiographs, and photomicrographs, and a number
of publishers have allowed us to reproduce figures that
have been previously published. For this we are very
grateful, and each has been acknowledged in the relevant
figure legends.
A major aim of this new edition was to broaden the
readership and make the text more accessible to stu-
dents, trainees, and non-­specialist pathologists and cli-
nicians. A number of colleagues have been kind enough
to read early drafts of chapters and freely provided very
helpful and constructive comments that have facilitated
this aim: Daniel Brierley, Lisette Collins, Paula Farthing,
Ali Khurram, Liam Robinson, Willie van Heerden, and
John Wright.
I am also especially grateful to my colleague and friend
Professor John Wright, who very kindly agreed to write the
forward to this edition.
 1

Classification and Frequency of Cysts of the Oral and Maxillofacial Regions

CHAPTER MENU
Classifications, 2
Cysts of the Jaws, 2
●● Odontogenic Cysts,  2
–– Odontogenic Cysts of Inflammatory Origin,  3
–– Odontogenic Cysts of Developmental Origin,  3
●● Non-­odontogenic Cysts and Pseudocysts,  3
–– Non-­odontogenic Cysts of the Jaws,  3
–– Pseudocysts of the Jaws,  3
Cysts of the Salivary and Minor Mucous Glands, 3
●● Cysts of the Major and Minor Salivary Glands,  3
●● Cysts of the Maxillary Sinus,  3
Developmental Cysts of the Head and Neck, 3
Frequency of Cysts of the Oral and Maxillofacial Regions, 4

There is no single satisfactory classification of cysts of
the head and neck region. In part this is because terminol-
ogy varies across the world, but also because classification
systems may be developed to serve different purposes.
Some authors have tried to subdivide lesions into multiple
variants based on histological or clinical features, but this
has little clinical utility in terms of planning management.
Detailed classifications that include variants are neverthe-
less useful for research, and occasionally a reported variant
may eventually emerge as a new entity. A well-­known
example of this is the reporting of an orthokeratinised vari-
ant of the odontogenic keratocyst (Wright  1981), which
over time was shown to have distinctive clinicopathologi-
cal features and is now recognised as an entity  – the
orthokeratinised odontogenic cyst. Other variants, how-
ever, such as the bay or pocket variant of the radicular cyst,
have little bearing on clinical management and are of aca-
demic interest only. There is a tendency for classifications
to be overcomplicated by pathologists, who often describe
subtle histological variations as new ‘entities’. The most
useful classifications should be simple, should use globally
recognised terminology, and should be easy to use and
relevant for clinicians who treat the lesions. A straightfor-
ward uniform nomenclature facilitates communication
between clinical specialties and enables precise reporting
of lesions for statistical and research purposes.
International standards for classifications were first
developed by the World Health Organization (WHO),
which set up a global project for the histological classifica-
tion of tumours in 1952 (reviewed by Sobin 1971). The pro-
ject involved collecting samples of lesions that were
reviewed by groups of international experts, who agreed a
uniform nomenclature and established practical and clini-
cally relevant diagnostic criteria. The first classification of
cysts of the jaws was published in 1971  in Histological
Typing of Odontogenic Tumours, Jaw Cysts and Allied
Lesions (Pindborg and Kramer 1971). This first edition was
deliberately inclusive and provided a comprehensive clas-
sification of jaw lesions so that all neoplasms and cysts of
the odontogenic tissues could be considered in context,
allowing pathologists and clinicians to make an informed
diagnosis. The second edition, published in 1992, also
included cysts of the jaws (Kramer et al. 1992), but the third
edition (Barnes et al. 2005) omitted cysts and restricted the

Shear’s Cysts of the Oral and Maxillofacial Regions, Fifth Edition. Paul M. Speight.
© 2022 John Wiley & Sons Ltd. Published 2022 by John Wiley & Sons Ltd.
2 Classification and Frequency of Cysts of the Oral and Maxillofacial Regions
classification to tumours and a range of ‘tumour-­like’
lesions. Subsequently, the fourth (El-­Naggar et al. 2017) and
fifth editions (WHO  2022a,  b) have included the odonto-
genic cysts and have restored the status of the book as a
complete classification of lesions of the odontogenic tissues.
It is important to note that the WHO classifications still
maintain the original principles of simplicity, relevance, and
a uniform and well-­recognised terminology. Thus the WHO
books should be regarded as a guide to terminology, defini-
tions, and diagnostic criteria. They are not comprehensive
and do not include detailed considerations of variants, unu-
sual features, or differential diagnosis. In this book we have
adopted a simple working classification of the odontogenic
cysts using the WHO terminology. We do not include
detailed subdivisions or variants in the classifications, but in
each chapter we discuss terminology and classification, and
include details of variants of each lesion where this might
have a bearing on diagnosis or management.
A further consideration is the use of the term ‘cyst’,
which still causes disagreement and some controversy. In
pathology dictionaries and general pathology textbooks, a
cyst is usually defined as a closed capsule, cavity, or sac-­like
structure that may be empty or have fluid or semi-­fluid
contents. There is no requirement for a defined lining.
Most contemporary oral pathology textbooks, however,
choose to define a cyst as a pathological cavity lined by epi-
thelium. Cyst-­like spaces not lined by epithelium have been
described as pseudocysts and diagnostic terms such as ‘cav-
ity’ have been used. Kramer (1974) defined a cyst as ‘a
pathological cavity having fluid, semifluid or gaseous con-
tents and which is not created by the accumulation of pus’.
He discussed the terminology and was bemused by the
requirement for an epithelial lining, stating that he was puz-
zled by ‘the definition that demands an epithelial lining’ and
said: ‘I am not sure how, or why, the presence of an epithelial
lining became included in the definition: clearly it creates
difficulties, because so many lesions that have been accepted
for generations as “legitimate” cysts must now be termed
pseudocysts, or false cysts, or “cysts” in quotation marks’.
The requirement for an epithelial lining probably became
enshrined in oral pathology because the vast majority of
cysts of the oral and maxillofacial tissues are odontogenic in
origin and are lined by epithelium. Thus, the use of alterna-
tive terms such as ‘pseudocyst’ or ‘cavity’ clearly distin-
guishes cystic lesions without epithelium from odontogenic
cysts. Although we recognise the term pseudocyst for lesions
that are not lined by epithelium (see Chapter 17), we also
agree with Kramer and suggest that ‘cyst’ can be used as a
diagnostic term for lesions that are clinically or radiologi-
cally cystic. This is in keeping with common usage and
understanding among clinicians and radiologists. For exam-
ple, most clinicians, especially paediatric dentists, use the
term cyst to describe mucoceles, whether they have an
epithelial lining or not, and we therefore retain the diagnos-
tic term mucous extravasation cyst for the non-­epithelial
lined cystic lesion caused by spillage of mucus into the
­tissues (see Chapter 15). Similarly, we are content to use the
well-­recognised diagnostic term simple bone cyst for the non-­
epithelial lined bone cavity that clinically and radiologically
presents as a cystic lesion (Chapter 17). It should be noted
that the definition of cyst does not include a cavity caused by
an accumulation of pus, which is defined as an abscess.
In this book we do not attempt to suggest a definitive
classification of cysts of the oral and maxillofacial regions,
but we divide them into cysts of the jaws, cysts of the salivary
and minor mucous glands, and developmental cysts of the
head and neck. We discuss cysts that are specific to the
maxillofacial regions, and cysts that are not peculiar to
these regions are not included unless they have distinctive
features that must be considered in the differential diagno-
sis. Cystic neoplasms such as unicystic ameloblastoma are
not included either, although the possibility of a neoplastic
origin of some of the odontogenic cysts is considered.
Our classification is intended to be simple and to be par-
ticularly useful to pathologists and clinicians who must share
and understand definitions and terminology. Many other
classifications have been published and may well be perfectly
satisfactory. Although readers may use any classification they
find valuable as an aid to memory and understanding, they
are encouraged to facilitate communication by using the
WHO terminology and definitions (WHO 2022a, b).
­Classifications
In this edition of the book, the cysts are classified under
three broad categories:
Cysts of the jaws
●● Odontogenic cysts (Chapters 3–12)
●● Non-­odontogenic cysts (Chapters 13, 14, 16, and 17)
Cysts of the salivary and minor mucous glands (Chapter 15)
Developmental cysts of the head and neck (Chapter 18)
­Cysts of the Jaws
Odontogenic Cysts
The odontogenic cysts have been divided into cysts of
inflammatory origin and cysts of developmental origin.
These are convenient categories, since it is clearly under-
stood that the inflammatory odontogenic cysts arise as a
result of proliferation of odontogenic epithelium driven by
chronic inflammation, resulting from either pulpitis or
pericoronitis. The pathogenesis of the developmental cysts
is less well understood, however, and in some cases there is

evidence for a neoplastic origin. The pathogenic mecha-
nisms involved in cyst development are discussed in
Chapter 2, and details for each cyst type are presented in
each chapter. Although these categories are widely used,
they are not definitive, since some cysts classified as devel-
opmental may have an inflammatory origin. In particular,
a variant of dentigerous cyst may be inflammatory in
nature (see Chapter 5). In each category the cysts are listed
in order of their approximate frequency (Tables 1.1–1.3).
Odontogenic Cysts of Inflammatory Origin
Radicular cyst
●● Residual cyst
Inflammatory collateral cysts
●● Paradental cyst
●● Mandibular buccal bifurcation cyst
Odontogenic Cysts of Developmental Origin
Dentigerous cyst
●● Eruption cyst
Odontogenic keratocyst
Lateral periodontal cyst
●● Botryoid odontogenic cyst
Gingival cyst of adults
Gingival cyst of infants
Glandular odontogenic cyst
Calcifying odontogenic cyst
Orthokeratinised odontogenic cyst
Non-­odontogenic Cysts and Pseudocysts
Non-­odontogenic cysts of the jaws are mostly developmen-
tal in origin and arise from vestigial epithelial remnants of
ductal structures or from inclusions at the line of fusion of
the palatal shelves. The nasolabial and mid-­palatal raphe
cyst actually occur in the soft tissues, but are so closely
apposed to the maxillary bone that they are included in the
classification of jaw cysts. The surgical ciliated cyst is
included here because it arises within the alveolar bone of
the maxilla. Pseudocysts are not epithelial lined, but are
included because they are important in the radiological dif-
ferential diagnosis of cystic jaw lesions. As discussed above,
we are content to use ‘cyst’ as a diagnostic term for the sim-
ple bone cyst, since this is clearly understood and widely
used by clinicians who recognise that they present clini-
cally and radiologically as a cystic lesion. Stafne bone cav-
ity is neither a cyst nor a pseudocyst, but is an anatomical
anomaly causing an indentation of the mandible that
appears as a cystic lesion on radiology or imaging. It is
often included in classifications and we include it here
because of its importance in the radiological differential
diagnosis of cystic lesions. Osteoporotic bone marrow
defects are controversial lesions, but they present as cystic
­Cysts of the Jaw  3
radiolucencies and must also be considered in the differen-
tial diagnosis.
Non-­odontogenic Cysts of the Jaws
Nasopalatine duct cyst
Nasolabial cyst
Mid-­palatal raphe cyst of infants (Epstein pearls)
Surgical ciliated cyst
Pseudocysts of the Jaws
Simple bone cyst
Stafne bone cavity
Osteoporotic bone marrow defects
Cysts of the Salivary and Minor Mucous Glands
Cysts affecting the salivary and minor mucous glands of the
head and neck are common and may be developmental or
reactive in nature. Retention and extravasation cysts
(mucoceles) are the most common and may arise at any site
associated with minor glands that are found throughout the
submucosa of the upper aerodigestive tract and paranasal
sinuses. Here we include cystic lesions of the major salivary
glands as well as cysts associated with minor glands of the
oral cavity and maxillary sinus. Ranula is included as a sepa-
rate lesion because it has distinctive and specific clinical fea-
tures and problems of management. Cystic neoplasms are
not included. Intraoral lymphoepithelial cysts are included
in this category even though their origin is uncertain. Some
arise from intraoral tonsillar tissue, while others appear to be
associated with dilated ducts of minor salivary gland.
Cysts of the Major and Minor Salivary Glands
Mucoceles
●● Mucous extravasation cyst
●● Mucous retention cyst
●● Ranula
Salivary duct cyst (of the major glands)
Intraoral lymphoepithelial cyst
Lymphoepithelial cysts of the parotid gland
Polycystic disease of the parotid gland
Cysts of the Maxillary Sinus
Mucoceles
Retention cyst
Pseudocysts
Developmental Cysts of the Head and Neck
These cysts are mostly congenital and are usually pre-
sent at birth, although some may grow slowly and not
become clinically apparent until later in childhood or
adolescence. The majority arise from epithelial
4 Classification and Frequency of Cysts of the Oral and Maxillofacial Regions

remnants entrapped during fusion of the facial processes Although the actual frequencies vary, the relative frequencies
or due to incomplete obliteration of the branchial clefts and the rank order of the lesions are very similar. In these
or pouches. studies, and in all studies worldwide (Table  1.3), the most
common odontogenic cyst is the radicular cyst, followed by
Dermoid and epidermoid cysts dentigerous cyst and then odontogenic keratocyst. The naso-
Cysts of foregut origin palatine duct cyst is the most common non-­odontogenic cyst
●● Heterotopic gastrointestinal cyst and in some studies has a similar frequency among all jaw
●● Bronchogenic cyst cysts to the odontogenic keratocyst (Table 1.1). All the other
Branchial cleft cysts cyst types are relatively rare.
Thyroglossal duct cyst These data show the relative frequency of each cyst as a
Nasopharyngeal cyst proportion of all cyst types, but do not allow a clinician to
Thymic cyst determine how likely it is that they will encounter a cyst
in everyday practice. Jones and Franklin (2006a) reviewed
over 44 000 histologically diagnosed oral and maxillofa-
­ requency of Cysts of the Oral
F cial lesions in adults over a 30-­year period. Their data
and Maxillofacial Regions show that all the cyst types described in this book repre-
sent about 20% of all biopsies received (n  =  8354).
Frequency statistics differ from incidence studies in that Odontogenic cysts were by far the most commonly
they are not standardised against known population data, encountered (n  =  6052) and the overall most common
such as age, sex, and ethnicity. For data to be comparable cyst type in the maxillofacial regions was the radicular
between populations and internationally, age-­standardised cyst. They found 3793 radicular cysts (including residual
incidence rates per 100 000 are compared with a standard cyst), representing 8.6% of all biopsy specimens received.
world population. Incidence data are a requirement for all
national cancer registries, but most benign lesions, includ- Table 1.1  Distribution of 3481 jaw cysts according
ing cysts, are not registered and thus incidence data is not to diagnosis.
available for the odontogenic cysts. Epidemiological data are
therefore presented as the relative frequency of each cyst % of
type as a proportion of the total number of cysts encoun- n % of group all cysts
tered within a population, or of the total number of speci-
Odontogenic cysts
mens received. This gives clinicians an estimate of the
Radicular/residual cyst 1825 60.6 52.4
likelihood of encountering these lesions in everyday practice.
Frequency studies are rarely based on the general popula- Dentigerous cyst 599 19.9 17.2
tion, but are usually derived from archival records of diagno-   Eruption cyst 27 0.9 0.8
ses made in a hospital department, usually pathology Odontogenic keratocyst (including 355 11.8 10.2
departments. While these provide useful data on the behav- orthokeratinised odontogenic cysts)
iour and treatment of different diseases, they are of limited Inflammatory collateral cysts 109 3.6 3.1
use in international comparative studies. Table 1.3 shows the Calcifying odontogenic cyst 28 0.9 0.8
wide variation in the frequency of the three most common Lateral periodontal cyst 24 0.8 0.7
odontogenic cysts in different parts of the world. Almost Gingival cyst of adults 21 0.7 0.6
without exception, these data are derived from retrospective
Unclassified 18 0.6 0.5
analyses of pathology records and the frequency of each cyst
Glandular odontogenic cyst 6 0.2 0.2
type may depend on local protocols for patient referral and
3012 100.0
management, or even on individual pathologists’ criteria for
diagnosis. For example, a high frequency of radicular cysts Non-­odontogenic cysts
may reflect a high caries rate in the local population, or a high Nasopalatine duct cyst 404 86.1 11.6
rate of referral of periapical lesions. Conversely, a low fre- Simple bone cyst 35 7.5 1.0
quency of radicular cysts may arise if the local practice is not Nasolabial cyst 21 4.5 0.6
to submit periapical lesions for ­histological analysis. In Surgical ciliated cyst 5 1.1 0.1
Chapter 4 we discuss the very low frequency of paradental Mucosal cyst of maxillary antrum 4 0.9 0.1
cysts in some countries, where the lesion does not seem to be
469 100.0
recognised as an entity and is therefore not diagnosed.
Total 3481 100.0
Tables 1.1 and 1.2 present our experience of the frequen-
cies of jaw cysts in South Africa and the United Kingdom. Source: Data courtesy of Prof. M. Shear, University of Witwatersrand.
 ­Frequency of Cysts of the Oral and Maxillofacial Region  5

Dentigerous cysts represented 2.5% (n = 1081) of all biop- encountering a cyst. Common diagnoses included 6458
sies, and odontogenic keratocyst was 1.3% (n = 591). By cases of fibrous hyperplasia (14.7%), 2973 cases of lichen
comparing these data to other commonly encountered planus (6.8%), and 1901 epulides (4.3%; fibrous epulis,
lesions, a clinician can estimate the likelihood of pyogenic granuloma, or giant cell epulis). During the
same period, there were 3547 periapical granulomas,
Table 1.2  Distribution of 7121 odontogenic cysts in a United showing that the frequency of periapical granulomas
Kingdom population. (8.1%) and radicular cysts (8.6%) is similar. This was also
suggested by Koivisto et  al. (2012), who reviewed 9723
Cysts n % radiolucent lesions associated with the teeth (dentigerous
cysts and lesions in the ramus were excluded) and found
Radicular cyst 3724 52.3 that 73% were periapical granulomas or cysts. There were
  Residual cyst 573 8.0 3215 (33.1%) radicular cysts and 3931 (40.4%) periapical
Dentigerous cyst 1292 18.1 granulomas. The next most common lesion was the odon-
  Eruption cyst 15 0.2 togenic keratocyst (8.8%; n = 857).
Odontogenic keratocyst (including 828 11.6 Among other cyst types, Jones and Franklin (2006a)
orthokeratinised odontogenic cysts) found that the most common were mucoceles (3.9%;
Inflammatory collateral cysts 402 5.6 n = 1720), while all other cysts were rare (less than 1.0%).
Unclassified odontogenic cysts 210 2.9 These data show that cysts are relatively common and
Lateral periodontal cyst 28 0.4 that the most commonly encountered are the radicular
cyst, dentigerous cyst, and mucoceles. They also suggest
Calcifying odontogenic cyst 21 0.3
that when a periapical radiolucency is seen, about 50% will
Gingival cyst of adults 16 0.2
be a radicular cyst and 50% will be a periapical granuloma.
Glandular odontogenic cyst 11 0.2 Details of the frequency and incidence of each cyst type are
Gingival cyst of infants 1 0.0 illustrated and discussed in the following chapters.
Total 7121 100.00

Source: Data from Jones et al. (2006).

Table 1.3  Frequency (%) of the three most common odontogenic cysts in selected case series with a wide geographical distribution.

References Country N Radicular cysta Dentigerous cystb Odontogenic keratocyst Other Males (%)

Daley et al. (1994) Canada 6847 65.2 24.1 4.9 5.8 NR

Mosqueda-­Taylor et al. (2002) Mexico 856 42.1 33.0 21.5 3.4 53.1
Meningaud et al. (2006) France 695 58.2 22.3 19.1 0.5 65.0
Jones et al. (2006) UK 7121 60.3 18.4 11.6 8.1 55.9
Ochsenius et al. (2007) Chile 2944 61.9 18.5 14.3 5.3 52.8
Grossmann et al. (2007) Brazil 2812 63.0 26.1 7.4 3.5 50.0
Tortorici et al. (2008) Italy (Sicily) 1273 84.5 11.4 1.3 2.8 53.9
Ali (2011) Kuwait 196 52.6 26.0 15.3 6.1 57.6
Sharifian and Khalili (2011) Iran 1227 45.8 24.7 19.4 10.1 57.1
Ramachandra et al. (2011) India 252 50.3 22.4 27.4 NI 61.2
Manor et al. (2012) Israel 285 56.1 28.8 8.0 7.0 59.7
Soluk Tekkesin et al. (2012b) Turkey 5003 65.6 10.6 20.9 2.9 57.6
Tamiolakis et al. (2019) Greece 5165 73.2 14.8 8.4 3.6 61.5
Bhat et al. (2019) India 125 60.8 22.4 13.6 3.2 67.9
Kammer et al. (2020) Brazil 406 53.4 14.0 15.0 17.5 56.7
Aquilanti et al. (2021) Italy 2150 57.0 23.5 13.0 6.5 63.3

N, total number of odontogenic cysts – frequencies are proportions of odontogenic cysts only; NI, not included – proportions only given for the
three main cyst types; NR, not reported.
a
 Data for radicular cyst includes residual cysts.
b
 Data for dentigerous cyst includes eruption cysts.
6

General Considerations

CHAPTER MENU

Pathogenesis of Cysts, 6
The Cyst–Tumour Interface, 10
An Approach to the Diagnosis of Cysts of the Jaws, 12
●● Radiology of Cysts of the Jaws,  12

●● Histopathological Examination of Cysts,  15

–– Immunohistochemistry and Molecular Pathology,  15

Cysts of the oral and maxillofacial regions are common

and represent about 20% of all lesions encountered in an
oral and maxillofacial pathology department (Jones and
Franklin  2006a,b; discussed in Chapter  1). Clinicians are
often therefore called upon to make an informed diagnosis
and implement correct management. Of all the cysts dis-
cussed, those within the jaw bones are the most challenging
to diagnose. Overall the most common jaw cyst is the radicu-
lar cyst, which presents as a periapical radiolucency and is
probably the most common cause of a bony swelling in the
tooth-­bearing areas of the jaws. The challenge is to accurately
make a diagnosis and exclude other possible causes of a
swelling or of a radiolucency. In most cases, a final diagnosis
usually requires histological examination of the cyst, and it is
the histopathologist who often takes responsibility for bring-
ing together the clinical, radiological, and histological fea-
tures and reporting the final diagnosis to the surgeon. Each
cyst type has characteristic features and these are discussed
and illustrated in each chapter of this book. In this chapter
we consider general issues that help inform a careful and
accurate approach to the diagnosis of cysts, and we summa-
rise specific radiological and histological features that have
diagnostic utility in the diagnosis of different cyst types.
­Pathogenesis of Cysts
The formation of a cyst requires three elements and can
be considered to develop in three phases: a phase of initia-
tion, a phase of cyst formation and a phase of growth and
Box 2.1  Pathogenesis: The Phases of Cyst Formation
Three elements are needed:
●● A source of epithelium
●● A stimulus for epithelial proliferation
●● A mechanism of growth and bone resorption
The cyst develops in three phases:
●● Phase of initiation  – a source of epithelium and
stimulus for proliferation
●● Phase of cyst formation – a cyst cavity develops and
becomes lined by epithelium
●● Phase of growth and enlargement – the cyst enlarges,
and growth is accompanied by tissue remodelling
and bone resorption
enlargement (Box  2.1). For the inflammatory odontogenic
cysts, the processes of cyst formation and expansion are well
understood and are considered in detail in Chapters 3 and 4,
but for the developmental cysts the mechanisms are not so
clear and many theories have been suggested, including aber-
rant developmental processes, underlying genetic abnormali-
ties, and neoplasia. These are discussed in detail for each cyst
type in the following chapters. For most cysts, the lining is
derived from epithelial remnants or inclusions that remain in
the tissues after developmental processes are complete.
Table 2.1 shows the source of epithelium for each cyst type
and summarises the developmental origin. To fully under-
stand the pathogenesis of cysts, it is therefore essential to have

Shear’s Cysts of the Oral and Maxillofacial Regions, Fifth Edition. Paul M. Speight.
© 2022 John Wiley & Sons Ltd. Published 2022 by John Wiley & Sons Ltd.

Table 2.1  Sources of the epithelial lining of cysts of the head and neck.
Odontogenic cysts
Radicular cyst
Dentigerous cyst
Eruption cyst
Inflammatory collateral cysts
Odontogenic keratocyst
Lateral periodontal cyst
Botryoid odontogenic cyst
Gingival cyst of infants
Gingival cyst of adults
Glandular odontogenic cyst
Calcifying odontogenic cyst
Orthokeratinised odontogenic cyst
Non-­odontogenic cysts
Nasopalatine duct cyst
Nasolabial cyst
Mid-­palatal raphe cyst (Epstein
pearls)
Surgical ciliated cyst
Cysts of the salivary and minor mucous glands
Mucous retention cysts
Salivary duct cyst
Lymphoepithelial cysts
Intraoral lymphoepithelial cysts
Developmental cysts of the head and neck
Intraoral dermoid and
epidermoid cysts
Source of epithelial lining
Cell rests of Malassez
Reduced enamel
epithelium
Cell rests of the dental
lamina (‘glands of
Serres’)
Remnants of the
nasopalatine duct
Nasolacrimal duct
Epithelial inclusions
Remnants of respiratory
epithelium
Ducts of minor mucous
glands
Intraparotid ducts
Tonsillar crypt
epithelium
Epithelial inclusions
­Pathogenesis of Cyst  7
Developmental origin
Remnants of the epithelial root sheath of Hertwig lie in the
periodontal ligament (Figure 3.6)
Reduced enamel epithelium forms from the internal and
external enamel epithelium and embraces the fully formed
crown of an unerupted tooth. This gives rise to the dentigerous
(and eruption) cyst (Chapters 5 and 6, Box 5.3, Figures 5.18 and
5.19). The reduced enamel epithelium also forms the junctional
or sulcular epithelium during tooth eruption and this gives rise
to inflammatory collateral cysts (Chapter 4)
After tooth formation is complete the dental lamina
disintegrates, but residual islands are retained in the gingival
mucosa and alveolar bone. Cell rests are particularly common
in the posterior mandible, where they may also be found in the
gubernacular cord or canal (discussed in detail in
Chapters 7, 8, 9, and 12; see Figures 7.12, 8.3, 9.7, and 9.9)
The nasopalatine duct is a fetal structure and involutes at about
10 weeks of intrauterine life. Residual epithelial remnants,
however, may remain in the incisive canal after birth and in
adults (Chapter 13, Figure 13.1, Box 13.1)
The nasolacrimal duct forms after 6 weeks of intrauterine life
and drains tears from the lacrimal sac to the lower aspect of the
lateral nasal wall. Residual epithelial remnants may persist at
the inferior portion of the duct (Chapter 14)
The palatal shelves fuse at about 7–8 weeks of intrauterine life.
The epithelial coverings fuse and then break down into many
small islands, many of which form small ‘microcysts’ (Figure 9.7).
Most involute before birth, but up to 80% of newborns may have
cysts up to 3 months of age (Chapter 9). There is some evidence
that inclusions may arise in the bone and give rise to an
intraosseous ‘median palatal cyst’ (discussed in Chapter 13)
Fragments of sinus epithelium become implanted into a wound
following surgery involving the maxillary sinus (Chapter 16)
The ducts of minor mucous glands become blocked and dilated,
most often as a result of trauma (Figures 15.5, 15.6, and 15.10)
The pathogenesis is uncertain, but blockage of ducts associated
with sialadenitis may cause cystic dilatation (Figure 15.12)
The opening of intraoral tonsils may become blocked, causing
cystic dilatation of the crypt. Some intraoral lymphoepithelial
cysts may be retention cysts arising from a superficial duct of
minor salivary glands
Epithelial remnants are sequestered into the tissues during
fusion of facial processes. Oral dermoid and epidermoid cysts
are found in the anterior oral cavity at sites of fusion of the
mandibular processes (Box 18.1)
(Continued)
8 General Considerations

Table 2.1  (Continued)

Source of epithelial lining Developmental origin

Intraoral cysts of foregut origin
Branchial cleft cysts
Thyroglossal duct cyst
Epithelial inclusions
Epithelial inclusions
Remnants of the
thyroglossal duct
Oral foregut cysts arise from epithelial remnants following
fusion of the tuberculum impar (first branchial arch) and the
posterior one-­third of the tongue (second to fourth arches)
(Box 18.2)
Branchial cleft cysts arise from epithelial remnants that become
entrapped or persist due to incomplete obliteration of the
branchial clefts or pharyngeal pouches (Box 18.3)
The thyroid gland develops at about 4 weeks of intrauterine life
in the dorsum of the tongue. The developing gland descends
downwards into the upper neck forming the thyroglossal duct,
which then disintegrates. However, residual epithelial
remnants are found in the midline of the upper neck and
tongue in about 40% of people (Box 18.4)

an understanding of the embryology and development of the
head and neck. With regard to the odontogenic cysts (and
odontogenic tumours), a thorough knowledge of tooth devel-
opment is also needed to understand the pathogenesis, since
the complex interactions between epithelium and mesen-
chyme that underpin normal morphogenesis and tooth erup-
tion provide good models for the processes that drive cyst
formation and growth. In addition, the histology of many
lesions may recapitulate the features of the developing tooth
and knowledge of these features facilitates the ability to reach
an accurate diagnosis. A detailed consideration of embryol-
ogy and development is beyond the scope of this book, but
factors relevant to each cyst type are summarised in each
chapter. For up-­to-­date and expert knowledge relating to
development, readers should consult expert texts or reviews
(Wise et  al.  2002; Nel et  al.  2015; Nanci  2017; Seppala
et al. 2017; Diniz et al. 2017; Hovorakova et al. 2018; Bastos
et al. 2021).
In the majority of odontogenic cysts, the epithelial lining is
derived from epithelial remnants of the dental lamina
(Table 2.1). Early in the development of the jaws, the surface
epithelium thickens and grows downwards into the mesen-
chyme of the future dental arches to form the dental lamina.
This extends around the arch as a band that maps the future
sites of tooth bud formation for both primary and secondary
dentitions. The teeth develop as a result of complex epithe-
lial–mesenchymal interactions that result in epithelial thick-
enings or placodes, which then form the enamel organs that
pass through the well-­described bud, cap, and bell stages dur-
ing formation of the fully developed tooth (Nanci 2017). The
dental lamina remains as a thin band that joins the surface
oral epithelium to the enamel organ and only disintegrates at
the late bell stage of tooth development. Disintegration of the
dental lamina results in the formation of small epithelial
islands that lie over unerupted teeth, but also remain in the
tissues adjacent to the teeth after eruption. The disintegrating
vdental lamina is illustrated in Figure 9.9. The epithelial cell
rests of the dental lamina give rise to most of the odontogenic
cysts (Table  2.1) as well as to most odontogenic tumours.
Dental lamina rests are particularly numerous at the poste-
rior aspect of the dental arches and in the tissues overlying
unerupted teeth and in the dental follicle. This accounts for
the fact that the angle of the mandible is a common site for
many cyst types, and that many cysts (and tumours) may
arise in the dental follicle and embrace or surround an
unerupted tooth and lie in a dentigerous relationship. This
especially affects the mandibular third molars, since these
are the most commonly impacted teeth (Brown et al. 1982).
Although most types of odontogenic cyst arise from den-
tal lamina, the most common cyst (radicular cyst) takes its
origin from the rest cells of Malassez that lie in the perio-
dontal ligament as remnants of Hertwig’s root sheath (see
Figure 3.6). The second most common cyst, the dentiger-
ous cyst, arises from the reduced enamel epithelium that
embraces the fully formed crown of a tooth prior to erup-
tion. In the case of the radicular cyst, the phases of cyst
formation and growth are well understood and are driven
by inflammation that is initiated by bacterial factors ema-
nating from a non-­vital pulp. This process is described in
detail in Chapter 3. In developmental cysts, however, the
processes are less clear, but are almost certainly driven by
epithelial–mesenchymal interactions that initiate the
molecular signalling pathways that underpin normal tooth
development, morphogenesis, and eruption. Thus, the
mechanisms of formation of developmental cysts can be
regarded as the aberrant expression of normal processes.
Normal tooth eruption provides a good model of the
epithelial–mesenchymal interactions that regulate tissue
remodelling, including cell proliferation and bone resorp-
tion, and involve complex cascades and networks of

cytokines, chemokines, and growth factors (Wise et al. 2002;
Nel et al. 2015; Bastos et al. 2021). These biological factors
are discussed in detail in the context of the radicular cyst
(Table 3.2), where the cascade is started by bacterial infec-
tion, but the same factors are involved in normal develop-
ment and tooth eruption and contribute to the pathogenesis
of developmental cysts. For example, Il-­1α is a pivotal pro-­
inflammatory cytokine that can be activated by bacterial
endotoxins, but it also has an important role as a paracrine
signalling molecule in the dental follicle where, along with
other factors (e.g. parathyroid hormone–related protein) it
mediates tissue remodelling and bone resorption during
tooth eruption via its role as an activator of osteoclasts.
These basic mechanisms of cytokine-­mediated tissue
remodelling are involved in the growth and expansion of
all types of cyst. These same biological factors are also
responsible for proliferation of the reduced enamel epithe-
lium that merges with the overlying oral epithelium during
normal tooth eruption. It is thought that proliferation of
the reduced enamel epithelium, in the absence of normal
eruption, may be involved in the pathogenesis of the denti-
gerous cyst, but proliferation of rest cells of dental lamina
within follicular tissue may also drive the formation of
other lesions that are commonly associated with unerupted
teeth. This would include some odontogenic tumours (e.g.
ameloblastoma, adenomatoid odontogenic tumour) as well
as the odontogenic keratocyst and orthokeratinised odon-
togenic cyst. The role of these biological factors in the
pathogenesis of dentigerous cyst, the odontogenic kerato-
cyst, and the orthokeratinised odontogenic cyst is discussed
in Chapters 5, 7, and 12, respectively.
As well as activation of cytokines and other biological
factors, there is good evidence that activation of oncogenic
signalling pathways is a common feature in the pathogen-
esis of odontogenic cysts and tumours (Diniz et  al.  2017;
Bilodeau and Seethala 2019). These pathways are involved
in the normal development and morphogenesis of the
teeth, but aberrant activation may drive pathological pro-
cesses. The most widely studied pathway is the hedgehog
(HH) signalling pathway, which is a fundamental feature
of normal development with crucial roles in cell fate, dif-
ferentiation, and patterning. HH activation through bind-
ing of the Sonic hedgehog (SHH) ligand is a fundamental
feature of odontogenesis, regulates the development of the
dental lamina, and is responsible for tooth morphogenesis
and patterning (Diniz et  al.  2017; Seppala et  al.  2017;
Hovorakova et al. 2018; Sasai et al. 2019). The pathway is
regulated by the PTCH protein, which is a receptor for
SHH and under normal conditions controls and regulates
epithelial–mesenchymal interactions, cell proliferation,
and differentiation. The HH signalling pathway is dis-
cussed in detail in Chapter 7 and is illustrated in Figure 7.13.
­Pathogenesis of Cyst  9
Constitutive or aberrant activation of the HH pathway
can be caused by reduced expression or loss of the PTCH
protein at the cell surface, and this is an important mecha-
nism in the pathogenesis of the odontogenic keratocyst.
Loss of PTCH most often results from loss of heterozygo-
sity (LOH) or point mutations in the PTCH gene, and this
is seen in up to 80% or more of keratocysts (see Table 7.6).
However, although PTCH gene alterations are important in
keratocysts, they are not specific, since mutations or LOH
of PTCH or activation of the HH signalling pathway may
be seen in other odontogenic lesions, including orthokerati-
nised odontogenic cyst (Vered et al. 2009; Diniz et al. 2011),
glandular odontogenic cyst (Zhang et al. 2010), and denti-
gerous cyst (Levanat et al. 2000; Pavelić et al. 2001; Barreto
et al. 2002; Vered et al. 2009; Zhang et al. 2010). The role of
PTCH and the HH signalling pathway in these cysts is dis-
cussed in Chapters  5 (dentigerous cyst), 10 (glandular
odontogenic cyst), and 12 (orthokeratinised odontogenic
cyst). The role of the B-­catenin gene (CTNNB1) and the
WNT signalling pathway in calcifying odontogenic cysts is
discussed in Chapter 11.
Overall, it appears that alterations in the PTCH gene or
activation of HH signalling are common features of a num-
ber of lesions and may represent an initiating event in the
formation of developmental odontogenic cysts, possibly in
a progenitor epithelial cell, which then gives rise to the
entire epithelial lining and drives growth and expansion. It
has been suggested that the PTCH gene may act as a gate-
keeper gene and that further genetic events result in the
formation of different cysts or tumours (Gomes and
Gomez 2011). This would explain a role for PTCH in a wide
range of cyst types, but does not exclude a role for further
specific PTCH mutations in keratocysts.
Another unifying feature involved in the pathogenesis of
jaw cysts and probably also of soft tissue cysts is the role of
hydrostatic pressure. With few exceptions (odontogenic
keratocyst, botryoid odontogenic cyst, glandular odonto-
genic cyst), cysts in the jaws tend to be round or spherical
on radiology or imaging, suggesting that they grow slowly
in a regular and centripetal manner. It is widely accepted
that hydrostatic pressure due to osmosis provides the
evenly distributed internal forces that result in this growth
pattern. Osmotic pressure across the cyst wall is caused by
the accumulation of soluble proteins in the cyst lumen, so
that the concentration of molecules inside the cyst is
greater than in the adjacent tissues. This causes passage of
fluid (water) into the cyst lumen and results in a high intra-
luminal pressure that drives cyst expansion and growth.
The mechanisms of hydrostatic pressure and its role in the
radicular cyst are discussed in detail in Chapter 3, but there
is good evidence that hydrostatic pressure due to osmosis is
involved in the expansion of most, if not all, cyst types.
10 General Considerations
Although the odontogenic keratocyst grows in a multicen-
tric pattern associated with cell proliferation in the wall,
there is also evidence of an increased intracystic pressure,
suggesting a role for osmosis in its expansion (Toller 1970b;
Kubota et  al.  2004). Kubota et  al. (2004) suggested that
increased hydrostatic pressure was particularly important
in the initiation and early growth of the keratocyst, while
cell proliferation was more important as the cyst enlarged.
This is in keeping with the observation that keratocysts
tend to be unilocular when they are small, while larger
cysts and lesions in older individuals are more often multi-
locular or scalloped (Forssell  1980; Stoelinga  2001;
MacDonald-­Jankowski and Li 2010; Boffano et al. 2010; see
Chapter 7). Interestingly, Kubota’s research group (Kubota
et al. 2004; Oka et al. 2005) also showed that the increased
pressure stimulated secretion of cytokines, including
IL-­1α, suggesting another common mechanism for activa-
tion of biological factors that promote tissue remodelling
and bone resorption. These data are discussed in detail in
Chapter 7.
­The Cyst–Tumour Interface
The pathogenesis of the developmental odontogenic cysts
is still poorly understood and this has led to much debate
regarding the possible neoplastic nature of some of the
cysts. This applies mostly to the odontogenic keratocyst,
but there is also debate regarding the nature of the calci-
fying odontogenic cyst and glandular odontogenic cyst.
As discussed in Chapter 7, the odontogenic keratocyst in
particular has generated an enormous literature that has
increased more than fivefold since the last edition of this
book. Many papers have explored the expression of vari-
ous markers in an attempt to show that the keratocyst is a
neoplasm. A common suggestion is that expression of
proliferation markers at a higher rate than seen in other
cyst types is evidence that the lesion is a neoplasm. Of
more value are studies exploring aberrant gene expres-
sion or activation of oncogenic signalling pathways.
However, at the present time there is no clear marker of
neoplasia and the definition of a neoplasm has become
uncertain. It is not uncommon for the finding of a single
genetic mutation to be taken as evidence of neoplasia
regardless of the behavioural characteristics of the lesion.
It must be pointed out that a single point mutation or
genetic aberration may be the cause of developmental
anomalies and is not sufficient to designate a lesion as
neoplastic.
At the present time, most pathology textbooks still define
neoplasia in the terms first used by Willis in 1960, as ‘an
abnormal mass of tissue, the growth of which exceeds and
is uncoordinated with that of normal tissues, and persists
in the same excessive manner after cessation of the stimuli
that evoked the change’. No cyst described in this book
meets these criteria and in terms of clinical behaviour none
of the cysts can therefore be described as neoplastic.
Nevertheless, in the 2005  World Health Organization
(WHO) classification (Barnes et al. 2005), two cysts that
had hitherto been regarded as developmental in origin
were renamed ‘tumours’, with the clear intention that
they should be designated as benign neoplasms. The
odontogenic keratocyst was renamed keratocystic odonto-
genic tumour and the calcifying odontogenic cyst was
renamed calcifying cystic odontogenic tumour. With regard
to the keratocyst, the designation as a neoplasm was based
on its ‘aggressive, infiltrative behaviour’ and the role of
the PTCH gene in its pathogenesis. However, keratocysts
do not meet the criteria for neoplasia suggested by Willis,
since there is no evidence of uncoordinated independent
growth. It is ironic that since the lesion was designated as
a neoplasm in 2005, there have been almost 50 publica-
tions reporting marsupialisation (or decompression) as
an effective treatment compared to only 10 papers before
2005. A number of publications have shown that marsu-
pialisation is effective and that it may result in regression
of the typical keratocyst lining to an epithelium indistin-
guishable from that seen in normal oral mucosa. This
cannot be regarded as the behaviour of a neoplasm.
A further consideration is the use of the term ‘aggres-
sive’. It is common for authors to assert that the odonto-
genic keratocyst is aggressive because it has a propensity
for recurrence. While there is no doubt that the keratocyst
(and a number of other cysts) has a tendency to recur, we
do not support the well-­used assertion that ‘recurrence’
and ‘aggressive’ are synonymous. The recurrence rate is
almost entirely associated with the pattern of cyst growth
and the type of treatment (see Chapter 7) and is similar to
that seen in other cysts that have a multilocular growth
pattern (botryoid odontogenic cyst, glandular odontogenic
cyst). Inadequate removal may lead to residual cyst ele-
ments being left in the tissues and these may proliferate to
form new cysts. It is also true that occasionally a kerato-
cyst, especially a recurrent lesion, may spill into the soft
tissues and cause considerable clinical problems. However,
other cysts that are known to be difficult to remove, and
may have very high recurrence rates, are not described as
aggressive or thought to be neoplastic. For example, inad-
equately treated ranulas have a recurrence rate of up to
about 65% (see Chapter  15) and thyroglossal duct cysts
recur in up to 50% of cases if residual ductal elements are
not also removed (see Chapter  18). We believe that the
term ‘aggressive’ is overused and may be over interpreted
to suggest an invasive lesion or a behaviour similar to that

associated with truly aggressive lesions such as malignan-
cies. In this context, none of these cysts behaves in a way
that can be described as truly aggressive.
A more compelling argument for the neoplastic nature
of cysts is the finding of genetic aberrations. A key point in
this discussion, as already mentioned, is the finding of
PTCH gene alterations and activation of the HH signalling
pathway in a range of developmental cysts. The finding of
a single point mutation or LOH in the PTCH gene is insuf-
ficient to designate the keratocyst as a neoplasm. However,
more recent studies (Stojanov et al. 2020) have confirmed
earlier work that has shown that some keratocysts show
biallelic loss of both copies of the PTCH gene (Levanat
et  al.  1996; Sun et  al.  2008; Pan et  al.  2010).
In their study, Stojanov et al. (2020) found that 80% of spo-
radic keratocysts showed biallelic loss of PTCH1. Biallelic
loss of the gene means that both copies have been lost or
mutated and meets the ‘two-­hit’ hypothesis of Knudson
(Knudson  1971,  1996), which suggests that loss of both
copies of a tumour suppressor gene causes neoplasia.
However, Knudson’s hypothesis related to hereditary can-
cer (retinoblastoma), and it is now thought that two hits
may not always cause neoplasia and that further genetic
aberrations may be necessary (Tomlinson et al. 2001).
Notwithstanding this argument, the finding of biallelic
loss of the PTCH gene in some keratocysts provide some
evidence that at least a subset of odontogenic keratocysts
may be neoplastic. However, the line of demarcation
between aberrant development and neoplasia is blurred
and it seems that the keratocyst may sit on a spectrum
between a developmental cyst and a benign cystic neo-
plasm. At the present time it is difficult to make a clinico-
pathological distinction between cysts showing different
genetic changes and there are no defining criteria for
which, if any, keratocysts might be neoplastic. Further
research is needed to clearly define neoplasia and to deter-
mine if there are any behavioural differences between cysts
with different genotypes or clinicopathological phenotypes.
These issues and the debate about the neoplastic nature of
the odontogenic keratocyst are discussed in detail in Chapter 7.
Other lesions that sit on the cyst–tumour interface include
the calcifying odontogenic cyst and the glandular odontogenic
cyst. In 2005, the WHO renamed the calcifying odontogenic
cyst the calcifying cystic odontogenic tumour, and designated
all odontogenic ghost cell lesions as neoplasms (Barnes
et al. 2005; Prætorius and Ledesma-­Montes 2005). However,
more than 85% of ghost cell lesions are simple cysts and do
not recur, with little evidence of behaviour that would sug-
gest a neoplastic origin (Ledesma-­Montes et al. 2008). It has
been shown, however, that ghost cell lesions, including calci-
fying odontogenic cysts, are characterised by mutations in
the β-­catenin gene (CTNNB1) and may be driven by
­The Cyst–Tumour Interfac  11
activation of the WNT signalling pathway (reviewed by
Gomes et al. 2019). The presence of this CTNNB1 mutation
has led to suggestions that the calcifying odontogenic cyst is
a neoplasm. However, this mutation and the resulting intra-
cellular expression of β-­catenin are seen in a range of lesions
and a single mutation is not sufficient to justify designation
as a neoplasm. Further research is needed, but at the present
time there is little evidence to suggest that the calcifying
odontogenic cyst behaves as a neoplasm.
The relationship between the glandular odontogenic cyst
and neoplasia has been speculative and is based largely on
its histological similarity to intraosseous mucoepidermoid
carcinoma. This is discussed in detail in Chapter 10. This
histological similarity can make it very difficult to reach a
definitive diagnosis and may result in misdiagnosis of
lesions. A number of papers have reported lesions with his-
tological features of a glandular odontogenic cyst that have
recurred as mucoepidermoid carcinomas, but some of
these are poorly illustrated and in others the diagnostic cri-
teria are not clear. Nevertheless, this has led to suggestions
that the glandular odontogenic cyst may be a precursor
lesion, or a ‘benign variant’ of mucoepidermoid carcinoma.
The debate is further fuelled by the observation that the
glandular odontogenic cyst has a high recurrence rate,
leading some authors to label it ‘b­iologically aggressive’
(Greer et al. 2018). Mucoepidermoid carcinoma is charac-
terised by specific rearrangements of the MAML2 gene and
large studies have shown that glandular odontogenic cysts
do not show this change, suggesting that the two lesions
are distinct and that the cyst is not a precursor to the carci-
noma (Bishop et al. 2014). More recently, two studies have
reported lesions with the features of glandular odontogenic
cyst that have recurred as MAML2 positive mucoepider-
moid carcinomas, and have suggested that this is further
evidence that mucoepidermoid carcinomas can arise from
glandular odontogenic cysts (Greer et  al.  2018; Nagasaki
et al. 2018). In both cases, an alternative explanation is that
the primary lesions were also mucoepidermoid carcino-
mas, but were either misdiagnosed or were histologically
indistinguishable from cysts. Taken together, however,
these studies raise a number of questions and provide
sufficient evidence to justify further research into the
relationship between glandular odontogenic cyst and
mucoepidermoid carcinoma. The two possibilities to be
explored are that glandular odontogenic cyst is a benign
variant or precursor of mucoepidermoid carcinoma or,
more likely, that in some cases the two lesions are histo-
logically indistinguishable. Until these issues are clarified,
care must be taken to use strict criteria for diagnosis and
histological assessment must be accompanied by careful
assessment of the clinical and radiological features (see
Boxes 10.1 and 10.2, Tables 10.3 and 10.4).
12 General Considerations

­ n Approach to Diagnosis of Cysts

A In most cases, the clinical features of cysts are not specific,
of the Jaws
An accurate diagnosis of a cyst requires knowledge, com-
mon sense, and a logical approach to the assimilation of all
the information available about each lesion. With few
exceptions, it is not possible to reach a correct diagnosis
without considering the clinical, radiological, and histo-
logical features. This is especially relevant to histopatholo-
gists, who may be called upon to make a diagnosis on a
small biopsy. To do so without considering the clinical and
radiological features often leads to diagnostic errors and
incorrect management (Barrett et al. 2017). In each chapter
of this book we present all the features of each cyst type in
context and discuss the differential diagnoses and potential
errors that might occur if only small biopsies are examined.
Throughout we advise on the importance of correlating
clinical, radiological, and histological features and suggest
that a diagnosis of an intraosseous lesion should never be
made without considering the radiology. We also recom-
mend that a diagnosis should never be made on a small
biopsy if there is any uncertainty  – when in doubt, the
pathologist should request a further biopsy. In this chapter,
we briefly discuss an approach to making a correct diagno-
sis and summarise the key features that can assist in mak-
ing a diagnosis of cysts of the maxillofacial regions
(Tables 2.2–2.4). With regard to the odontogenic cysts, an
accurate diagnosis is facilitated by an understanding of
tooth development and the pathogenesis of each cyst type
(see ‘Pathogenesis of Cysts’ and Table 2.1)
since the most common presenting feature is a swelling with
few other symptoms. The surgeon therefore must rely on
additional features to assist in making a provisional diagnosis.
For example, a swelling associated with an absent tooth may
suggest a dentigerous cyst, and a small, bluish-­coloured swell-
ing on the lower lip of a child is almost certainly a mucocele.
Ultimately, however, a final diagnosis is usually made on his-
tological examination, but before this both the clinician and
the pathologist should examine the radiographs or imaging.
Radiology of Cysts of the Jaws
The characteristic radiological feature of all cysts of the jaws
is a well-­demarcated radiolucency with a well-­defined and
often corticated margin. Further features that assist in diag-
nosis include the shape and size of the lesion and the site, but
in most cases it is the relationship to the teeth that provides
the best indication of the type of cyst. A conventional plane
radiograph is usually sufficient to determine the extent and
relationships of jaw cysts, but computed tomography (CT)
and magnetic resonance imaging (MRI) are often useful and
may be essential for planning surgery of larger lesions. These
relationships are discussed and illustrated in each chapter,
but here we present an overview of characteristic radiological
signs and the basic principles of an approach to interpreting
the radiology. Table 2.2 shows the cyst types that have charac-
teristic radiological features, provides a cross reference to the
figures in each chapter, and summarises the diagnostic utility
of each feature.

Table 2.2  Characteristic radiological features that assist in the diagnosis of cysts of the jaws.

Cyst type Radiological sign Diagnostic utility Figure references

Radicular cyst A radiolucency at the apex of
a tooth
Paradental cyst A radiolucency superimposed
over the distobuccal aspect of
an impacted third molar. The
distal follicular space and
lamina dura are intact
Dentigerous Radiolucency surrounds the
cyst crown of an unerupted tooth
All radicular cysts are located at the opening of the root Figures 2.2 and 3.4
canal, almost always at the apex. This feature can be
considered diagnostic of radicular cyst if the tooth is
also non-­vital. The radicular cyst also lies within the
lamina dura. If the tooth is vital then other lesions must
be considered, but are rare. This may include cemental
lesions (cementoblastoma, cemento-­osseus dysplasia)
or, in the anterior maxilla, nasopalatine duct cyst
This feature is diagnostic of paradental cyst. If an intact Figures 4.2 and 4.5
follicular space cannot be seen, then the radiolucency
may be due to a hyperplastic follicle or pericoronitis
All dentigerous cysts show this feature. However, it is Figures 5.5–5.12, 5.14
not specific, since it may be seen in about 30% of (dentigerous cyst), 7.7
keratocysts, up to 50% of orthokeratinised odontogenic (odontogenic keratocyst),
cysts, and occasionally in calcifying odontogenic cysts 12.3 (orthokeratinised
odontogenic cyst)
Table 2.2  (Continued)
Cyst type Radiological sign
Odontogenic Mesiodistal extension with
keratocyst minimal buccolingual
expansion
A well-­demarcated unilocular
radiolucency in the ascending
ramus not associated with a
tooth
Lateral Well-­defined, round corticated
periodontal radiolucency lateral to the
cyst tooth root. Periodontal space
and lamina dura are intact
Glandular Large multilocular
odontogenic radiolucency crosses the
cyst midline of the mandible in a
symmetrical pattern
Calcifying A cystic radiolucency
odontogenic associated with irregular
cyst calcifications
A cystic radiolucency with a
peripheral band of
calcifications
Nasopalatine A radiolucency in the midline
duct cyst of the anterior maxilla
A heart-­shaped radiolucency
in the midline of the anterior
maxilla
Nasolabial cyst An upward or posterior
convexity of the inferior
margin of the nasal aperture
or anterior floor of the nose
Simple bone A scalloped margin at the
cyst superior aspect of a
mandibular cyst, which rises
up and embraces the roots of
multiple teeth
A cone-­shaped margin at the
anterior aspect of a
mandibular cyst
Stafne bone A corticated unilocular
cavity radiolucency at the angle of
the mandible below the
inferior dental (ID) canal
A radiolucency that, in a
coronal view, is open on the
lingual aspect of the mandible
Diagnostic utility Figure references
This appearance is almost pathognomonic for keratocysts in Figures 7.6 (odontogenic
the mandible. Note however that glandular odontogenic cyst keratocyst), 10.4, 10.5
may also show this growth pattern (see below). Other cyst (glandular odontogenic
types and ameloblastomas show ballooning expansion. The cyst, ameloblastoma)
feature is best visualised on computed tomography (CT) scans
Such a radiolucency is most likely to be an odontogenic Figure 7.11
keratocyst. If the cyst is associated with an unerupted
tooth a dentigerous cyst cannot be excluded, and if it is
multilocular an ameloblastoma must be considered.
A keratocyst is even more likely if there is little
buccolingual expansion (see above)
This feature is characteristic of lateral periodontal cyst. Figure 8.2
Lesions are rarely greater than 10 mm in diameter. If the
lamina dura surrounds the cyst, or cannot be seen, a lateral
radicular cyst must be considered. If the radiolucency is
larger than 10 mm or is multilocular, an alternative
diagnosis must be considered: possibly botryoid
odontogenic cyst, keratocyst, or glandular odontogenic cyst
This is not diagnostic, but is typical of the glandular Figures 10.3 and 10.4
odontogenic cyst. In some reports up to 85% of cases are
located in the anterior mandible. Keratocysts and
ameloblastoma may be multilocular, but are more often
located in the posterior mandible
About 25% of calcifying odontogenic cysts are Figures 11.4 and 11.5
associated with an odontoma and show irregular
radiopacities either in or adjacent to the cyst. Note that
simple bone cyst is occasionally associated with
calcifications, but these are usually multiple and
represent florid cemento-­osseous dysplasia (Chapter 17)
About 50% of calcifying odontogenic cysts contain
dentinoid in the wall or show dystrophic calcification in
the lining. A peripheral band of calcification is
characteristic and is best seen on CT scans
Almost diagnostic of nasopalatine duct cyst. Very rarely Figures 13.7 and 13.8
a radicular cyst may be in the midline. Occasional
nasopalatine duct cysts are displaced laterally, in which
case a radicular cyst must be considered. Note that the
nasopalatine duct cyst is not associated with the
periodontal ligament and the lamina dura may be intact
This appearance is diagnostic of nasopalatine duct cyst Figure 13.7
and is seen in about 20% of cases
Nasolabial cyst is a soft tissue cyst, but it may distort the Figure 14.3
margin of the nasal aperture. This ‘distorted anchor
appearance’ is diagnostic of nasolabial cyst. It is only
seen on an anterior occlusal radiograph
This feature is typical and almost diagnostic of simple Figure 17.1
bone cyst and is seen in 50% or more of cases. It has
been described as the tooth roots ‘hanging’ into the cyst
cavity (Chapter 17)
This feature is specific to simple bone cyst. The margins Figure 17.1
converge at a 45° angle to form a cone. However, it is
only seen in about 10% of cases
85% of Stafne bone cavities are located in the posterior Figure 17.5
mandible and are always below the ID canal. This
excludes a lesion of odontogenic origin. The feature can
be regarded as diagnostic
This feature is best visualised on CT and is diagnostic of Figure 17.6
Stafne bone cavity
14 General Considerations
Figure 2.1  In the posterior region of the mandible, the course of
the inferior dental (ID) canal (hashed lines) allows the tooth-­
bearing areas (the alveolar bone) to be clearly distinguished from
the basal bone of the mandible. Radiolucencies below the ID
canal are not odontogenic in origin (see text for details).
In the first instance, the site of the cyst in the jaws can
suggest an initial diagnosis. Odontogenic cysts arise in the
tooth-­bearing areas of the jaws in the alveolar bone and in
the mandible are always situated above the inferior dental
(ID) canal (Figure  2.1). The cyst displaces the ID canal
downwards towards, and sometimes beyond, the lower
border of the mandible. Examples of this feature can be
seen in Figures  5.5, 5.11 (dentigerous cyst), 7.6, 7.7
(odontogenic keratocyst), 10.4 (glandular odontogenic
cyst), 11.3 (calcifying odontogenic cyst), 12.2, and 12.3
(orthokeratinised odontogenic cyst). A cystic radiolucency
located below the ID canal is not an odontogenic cyst and
when such a feature is seen, an alternative diagnosis must
be considered. Figure 17.5 shows a Stafne bone cavity pre-
senting as a radiolucency below the ID canal, excluding
the possibility of an odontogenic origin. In the posterior
region of the mandible, this judgement is easy to make
(Figure 2.1), but in the anterior mandible and in the max-
illa, the distinction between alveolar bone and basal bone
is less clear. Although radiolucencies below the ID canal
cannot be odontogenic, the converse is not true and a
number of radiolucent lesions of non-­odontogenic origin
may arise above the ID canal. Figure 17.1 shows an exam-
ple of a simple bone cyst that is not odontogenic, but char-
acteristically lies within the alveolar bone and embraces
the roots of multiple teeth. Other lesions that may arise in
the alveolar bone and be associated with tooth roots
include giant cell granuloma, Langerhans cell histiocyto-
sis, and ossifying fibroma. Non-­cystic odontogenic lesions,
including periapical granulomas, odontogenic tumours,
Root canal
Periodontal ligament
Lamina dura
Cyst lining
Cyst lumen
Figure 2.2  Diagrammatic representation of a radicular cyst.
The cyst develops from rest cells of Malassez within the
periodontal ligament, and lies within the lamina dura. The
corticated margin of the cyst is continuous with the lamina
dura (see text for details).
cemento-­osseous dysplasias, and cementoblastoma, must
also be considered in the differential diagnosis of lesions
in the tooth-­bearing area. Overall, however, odontogenic
cysts and in particular radicular cysts are by far the
most common.
The defining feature of the radicular cyst is of a radiolu-
cency associated with the apex of a non-­vital tooth
(Table 2.2; Figure 3.4). The radicular cyst arises within the
periodontal ligament from the rest cells of Malassez, and
an important sign is that the cyst lies within the lamina
dura that surrounds the root of the tooth. Furthermore, the
corticated margin of the cyst is continuous with the lamina
dura (Figure 2.2). Although this feature is helpful in diag-
nosing a radicular cyst, it is of more value in excluding a
radicular cyst when another cyst type appears to be associ-
ated with a tooth root. If a cystic radiolucency is associated
with the root of a tooth, but the lamina dura is intact, then
a radicular cyst can be excluded and another diagnosis
must be considered. This feature is especially helpful in the
diagnosis of inflammatory collateral cysts (Figures 4.2 and
4.3), lateral periodontal cyst (Figure  8.2), nasopalatine
duct cyst (Figures  13.7 and 13.8), surgical ciliated cyst
(Figure 16.2), and simple bone cyst (Figure 17.1).
It must be noted, however, that other lesions arise
within the periodontal ligament and may lie within the
lamina dura. In particular, a periapical granuloma may

have an identical radiological appearance to a radicular
cyst, and it is not possible to reliably distinguish between
a granuloma and a cyst (discussed in detail in Chapter 3).
Although cysts are often larger (see Table  3.1), when a
radiolucency is encountered at the apex of a tooth there is
an equal chance that the lesion is a periapical granuloma
or a radicular cyst (Jones and Franklin 2006a,b; Koivisto
et al. 2012; discussed in Chapter 1). Cemental lesions also
arise within the periodontal ligament and, especially
when small and not fully calcified, may present as a radio-
lucency identical to radicular cyst. This feature may be
seen in lesions of cemento-­osseous dysplasia, cemento-­
ossifying fibroma, and cementoblastoma. The dentiger-
ous cyst embraces the crown of an unerupted tooth and
cannot be confused with radicular cyst, but the corticated
margin is continuous with the lamina dura (Figures  5.5
and 5.6).
Histopathological Examination of Cysts
In most cases the responsibility for a final diagnosis lies
with the histopathologist who must examine samples of
tissue. As stated above, it is important that the pathologist
does not make a final diagnosis without first considering
the clinical and radiological features of the lesion. These
may be stated on the pathology request form, but often
the pathologist should read the radiology report, consult
with the radiologist, or personally examine the radio-
graphs. Many cysts may reach a large size and it is good
practice to establish a diagnosis before definitive surgery.
This means that the histopathologist is often presented
with a small incisional biopsy of a large lesion. In most
cases, consideration of the radiological and histological
features together is sufficient to establish a diagnosis. The
key features summarised in Tables  2.2 and  2.3 should
assist decision making in most cases. Occasionally a
definitive diagnosis is not possible on a small biopsy and
a final diagnosis must await examination of the whole
specimen. Pathologists must not be afraid to withhold a
final diagnosis until it has been possible to examine suf-
ficient tissue.
Histopathological examination of a cyst begins with
examination and sampling of the whole specimen. If an
associated tooth is also removed, then the relationship of
the cyst to the tooth can be directly observed and is of par-
ticular value in the diagnosis of a radicular cyst (located at
the tooth apex), dentigerous cyst (attached at the cemen-
toenamel junction; Figure  5.18), and paradental cyst
(attached to the disto-­buccal aspect of the tooth; Figure 4.6).
In all cases it is of value to examine the cyst in its entirety
and also to dissect it and examine the cut surface and the
lumen. Most cysts are unilocular with a thin regular lining,
­An Approach to Diagnosis of Cysts of the Jaw  15
but careful examination of the gross specimen will show
evidence of multilocularity and reveal areas of thickening
or luminal nodules if present. Cysts that are typically mul-
tilocular on gross examination include the botryoid odon-
togenic cyst (Figures  8.3, 8.9, and 8.10) and glandular
odontogenic cyst (Figure 10.6). Thickening of the wall or
luminal nodules are seen in lateral periodontal cyst
(Figure 8.6), glandular odontogenic cyst (Figures 10.6 and
10.8), and calcifying odontogenic cyst (Figures  11.8 and
11.9). Calcifying odontogenic cyst may also have calcified
material in the wall or be associated with an odontoma.
Representative samples of the cyst wall, including any
areas of thickening, should be taken for histological exami-
nation and any hard tissue should be decalcified and sam-
pled for histology.
On dissection, most cysts contain small amounts of sero-
sanguinous fluid, but the odontogenic keratocyst and
orthokeratinised odontogenic cyst usually contain a
‘cheesy’ or ‘buttery’ keratinaceous material that is cream or
yellow coloured, and may have a characteristically unpleas-
ant odour. Such contents will be familiar to many patholo-
gists as a characteristic feature of epidermal cysts of
the skin.
The histological features of each cyst and the histological
differential diagnosis are described in detail in each chap-
ter. Very few cysts have histological features that are abso-
lutely diagnostic or pathognomonic, and diagnosis is
usually made by considering a combination of features in
the context of the radiology. The only possible exception to
this is the odontogenic keratocyst, which shows a thin reg-
ular lining of parakeratinised epithelium with features that
are unique to this cyst type (see Figures  7.15–7.17).
Table 2.3 provides an overview of characteristic histologi-
cal features and their diagnostic utility for different
cyst types.
Immunohistochemistry and Molecular Pathology
There are very many publications reporting the expres-
sion of different proteins in odontogenic cysts. In most
cases the purpose has been to shed light on the pathogen-
esis and mechanisms of growth of the lesions, but many
papers have attempted to determine whether particular
patterns of expression can provide accurate diagnostic
markers for each cyst type. Studies of keratin expression
and proliferation markers are particularly numerous and
the odontogenic keratocyst has been the subject of the
majority of studies. Overall, however, immunohistochem-
istry has only a very small role to play in the diagnosis of
cysts of the maxillofacial regions. Although each cyst type
may show a different pattern of cytokeratins, the expres-
sion demonstrated by immunohistochemistry merely
reflects the type of keratinisation that is easily and clearly
16 General Considerations

Table 2.3  Characteristic histological features that assist in the diagnosis of cysts of the maxillofacial regions.

Histological feature Cyst type(s) Diagnostic utility Figure references

Proliferative Radicular cyst Typical feature of radicular cyst and of inflammatory collateral Figures 3.7, 3.12
epithelium with an Inflammatory cysts (radicular cyst), 4.7
arcading pattern collateral cysts But proliferative arcading epithelium may be seen in any (paradental cyst), 5.22
odontogenic cyst that is secondarily inflamed (dentigerous cyst)
The epithelial lining is Dentigerous Virtually diagnostic of dentigerous cyst. This feature may be Figures 5.18 and 5.19
attached to an cyst seen on macroscopic examination of an intact specimen or in
unerupted tooth at the decalcified sections
cementoenamel Note: there have been reports of odontogenic keratocyst or
junction orthokeratinised odontogenic cyst attached at the
cementoenamel junction, but this is very rare and is thought
to be due to a tooth ‘erupting’ into a cyst (see discussion in
Chapter 12)
Thin regular Odontogenic Diagnostic of odontogenic keratocyst. This typical epithelium Figures 7.15–7.17
parakeratinised keratocyst is not seen in any other jaw cyst
epithelium with a
corrugated surface and
prominent basal layer
Epithelial plaques or Lateral Epithelial plaques are seen in all cases of lateral periodontal Figures 8.6, 8.7 (lateral
thickenings with a periodontal cyst cyst and are diagnostic if the cyst is unilocular and no other periodontal cyst), 8.9
whorling pattern Botryoid features are noted (botryoid odontogenic
odontogenic cyst If the cyst is multilocular, then diagnostic for botryoid cyst), 9.4 (Gingival
Gingival cyst of odontogenic cyst cyst), 10.8 (glandular
adults Gingival cyst shows similar features but is extraosseous odontogenic cyst)
Glandular Glandular odontogenic cyst may show plaques in about 65% of
odontogenic cyst cases, but must be accompanied by other features (see
Table 10.3)
Cuboidal or columnar Glandular Typical feature and seen in up to 100% of glandular Figures 10.7 and 10.8
cells at the luminal odontogenic odontogenic cysts. Diagnostic when accompanied by other
aspect of the cyst cyst features (see Table 10.3). Similar cells are occasionally seen in
lining other cyst types, including dentigerous cyst, but these lack
other features
A simple cyst with Calcifying This feature is diagnostic of calcifying odontogenic cyst. Note Figures 11.8–11.10
ghost cells in the wall odontogenic that the lining is ameloblastomatous and if ghost cells are not
cyst seen, a diagnosis of cystic ameloblastoma must be considered.
Ensure the whole lining is examined (see discussion in
Chapter 11). If the lesion is solid, then consider dentinogenic
ghost cell tumour. Ghost cells may be seen in odontomas and
rarely in ameloblastomas
Hyaline bodies Various Hyaline (Rushton) bodies are often stated as being typical Figures 3.15 (radicular
odontogenic of radicular cyst. They are seen in about 10% of radicular cyst), 7.20
cyst types cysts, but also in up to 10% of odontogenic keratocysts and (odontogenic
dentigerous cysts (see discussion in Chapter 3). However, keratocyst)
hyaline bodies are specific and diagnostic of odontogenic
cysts
Cholesterol clefts Radicular cyst Cholesterol clefts result from an accumulation of cholesterol Figure 3.16
crystals as a results of long-­standing inflammations. They are
therefore typical of radicular cyst and are seen in 30% or more
of cases (Table 3.3)
But they are not specific and may be seen in any cyst that has
become chronically inflamed, in particular in inflamed
dentigerous cysts or keratocysts
 ­An Approach to Diagnosis of Cysts of the Jaw  17

Table 2.3  (Continued)

Histological feature Cyst type(s) Diagnostic utility Figure references

Mucous cells Various cyst Mucous cells have been described in most types of odontogenic Figures 3.14 (radicular
types cyst and are not diagnostic. They are a result of metaplastic cyst), 5.23 (dentigerous
change and are seen in about 20% of radicular cysts, 25% of cyst), 10.10, 10.11
dentigerous cysts, and 2% of odontogenic keratocysts (glandular odontogenic
Note that mucous cells are not a diagnostic requirement for cyst), 13.10
glandular odontogenic cyst and are seen in only about 70% of (nasopalatine duct cyst),
cases (Table 10.3). Mucous cells are seen in surgical ciliated 14.5 (nasolabial cyst)
cysts and in about 50% of nasopalatine duct cysts and
nasolabial cysts
Sebaceous glands Dermoid cyst Sebaceous glands are rare in jaw cysts and when seen a Figures 18.2 and 18.3
diagnosis of dermoid cyst should be considered. If sweat (dermoid cyst)
glands and hair follicles are also present, then this is
diagnostic for dermoid cyst. Sebaceous glands have rarely
been reported in odontogenic keratocyst and orthokeratinised
odontogenic cyst
Respiratory epithelium Nasopalatine Among cysts in the jaws, respiratory epithelium is a typical Figures 3.14 (radicular
duct cyst feature of nasopalatine duct cyst and is seen in about 50% of cyst), 13.9 (nasopalatine
Various cyst cases duct cyst), 14.5
types However, this is not specific. Surgical ciliated cyst is lined by (nasolabial cyst), 16.5
respiratory epithelium and metaplastic respiratory epithelium (surgical ciliated cyst),
has been described in radicular cysts 18.5 (bronchogenic
Among soft tissue cysts, nasolabial cyst, bronchogenic cyst, cyst), 18.6 (branchial
and thyroglossal duct cyst are lined by respiratory epithelium, cyst), 18.8 (thyroglossal
and respiratory epithelium may be seen in cysts of foregut or duct cyst)
branchial cleft origin (Boxes 18.2–18.4)

visible on examination of a routine H&E (haemotoxylin
and eosin)-­stained section. The best example of this
conundrum is the odontogenic keratocyst. Many studies
have been undertaken to compare the cytokeratin profile
of keratocysts with other cysts, but almost without excep-
tion, the specimens used have been selected as typical his-
tological examples of each cyst type. It is not surprising
therefore that if the features are typical, there is no need
for any additional staining beyond a good H&E-­stained
section to make the diagnosis. One key area of diagnostic
difficulty is when the pathologist must examine a small
biopsy of an inflamed cyst. When heavily inflamed, any
cyst type, including a keratocyst, may become lined by
proliferative epithelium identical to that seen in a radicu-
lar cyst. The lining becomes non-­keratinised and studies
have not been able to identify immunohistochemical
markers that can differentiate between an inflammatory
cyst and an inflamed developmental cyst. This issue is dis-
cussed in detail in Chapter 7. Our experience, supported
by a number of studies (Rao et al. 2015), suggests that a
good H&E-­stained section is the most specific marker for
patterns of keratinisation and is usually sufficient to make
an accurate diagnosis.
Despite these limitations, there are a few instances where
immunohistochemistry can help establish a diagnosis and
differentiate between lesions with similar histological fea-
tures. A number of diagnostically useful applications are
summarised in Table 2.4.
Molecular studies have provided much useful and inter-
esting information relating to the pathogenesis of odonto-
genic lesions, especially with regard to the role of the PTCH
gene in the odontogenic keratocyst and to the role of the
SHH (hedgehog), WNT, and MAPK signalling pathways in
a variety of cysts and tumours (Diniz et al. 2017; Bilodeau
and Seethala 2019). Molecular tests, however, have not yet
proven to be useful in routine diagnosis of cysts. The main
exception to this is the identification of MAML2 rearrange-
ments that can be helpful in differentiating between the
glandular odontogenic cyst and intraosseous mucoepider-
moid carcinoma (discussed in Chapter 10). Table 2.4 sum-
marises a number of molecular techniques that may show
some value as diagnostic markers.
18 General Considerations
Table 2.4  Immunohistochemical and molecular markers that might have diagnostic utility in the differential diagnosis of cysts.
Immunohistochemistry
Antibody Target
CK10 Type I keratin, found mainly in
cornified epithelia
CK18 and CK19 Keratin intermediate filaments. Both
are widely expressed, but CK19 is seen
typically in odontogenic epithelium
Calretinin Calretinin, a widely expressed
calcium-­binding protein
Maspin Maspin, a member of the serine
protease inhibitor superfamily
β-­catenin Cell surface protein important in cell
adhesion, but also in the regulation of
the WNT signalling pathway
p16 p16 is a cyclin-­dependent kinase
inhibitor, involved in regulation of the
cell cycle
Diagnostic utility
CK10 stains keratinising epithelium and is positive in the
superficial layers of odontogenic keratocyst and
orthokeratinised odontogenic cyst. Of little value in
histological sections, but has some utility in cytological
smears from aspiration biopsies. Cells from keratocyst and
orthokeratinised odontogenic cyst are positive, but
dentigerous cysts and ameloblastomas are negative (August
et al. 2000). Pan-­cytokeratin antibodies (AE1/AE3) may also
stain keratin in smears from inflamed cysts (Vargas
et al. 2007) (Figure 7.22)
Use of both antibodies together has been shown to be useful
to distinguish a glandular odontogenic cyst from central
mucoepidermoid carcinoma (Pires et al. 2004; discussed in
Chapter 10). Glandular odontogenic cyst is CK19+/CK18-­.
Mucoepidermoid carcinoma is CK19-­/CK18+
Calretinin has been shown to be positive in up to 100% of
ameloblastomas, including unicystic ameloblastoma.
Odontogenic cysts including keratocysts are negative. Useful
to differentiate cystic ameloblastoma from other cysts,
especially in small biopsies from the posterior mandible
region (Altini et al. 2000; Coleman et al. 2001; De Villiers
et al. 2008; Jeyaraj 2019; Rudraraju et al. 2019; discussed in
Chapters 5 and 7)
May be useful in the differentiation of glandular
odontogenic cyst from central mucoepidermoid carcinoma,
especially in small biopsies where not all features may be
apparent. Maspin is widely expressed, but studies have
shown much greater expression in the mucous cells of
mucoepidermoid carcinoma than in glandular odontogenic
cyst. Note that the differences relate only to mucous
cells – other epithelial cells of the cyst lining are positive
(Vered et al. 2010; Chapter 10, Table 10.4)
Intracellular expression of β-­catenin (cytoplasmic and
nuclear) is characteristic of calcifying odontogenic cyst (and
other ghost cell lesions – see CTNNB1 gene below) and is
seen in all cases. However, it is not diagnostic, since it may
also be seen in ameloblastomas
p16 antibodies are useful in the differentiation of branchial
cleft cyst from a cystic metastasis in the lateral neck. p16 is
activated by human papillomavirus (HPV) infection and
strong expression, interpreted in context, is almost
diagnostic of HPV-­associated oropharyngeal carcinoma. The
majority of cystic metastases come from HPV-­associated
squamous cell carcinomas and are p16 positive, but
branchial cysts are negative. Note that positive staining must
be carefully interpreted and the correct criteria must be used
(Pai et al. 2009; Cao et al. 2010; Müller et al. 2015;
Chapter 18, Figure 18.7)
 ­An Approach to Diagnosis of Cysts of the Jaws 19

Table 2.4  (Continued)

Molecular markers

Gene Alterations Diagnostic utility

PTCH Mutations or loss of heterozygosity Alteration or loss of PTCH gene is seen in up to 80% of
(LOH) of PTCH gene odontogenic keratocysts, but is not diagnostic because
altered PTCH may be seen in other cyst types. However,
biallelic loss of PTCH has been recorded in keratocysts and
not in other odontogenic cysts, and this may be diagnostic
MAML2 Rearrangements of MAML2 gene, MAML2 rearrangements are seen in mucoepidermoid
usually with CRCT1 or 3 carcinomas and their presence helps differentiate
intraosseous mucoepidermoid carcinoma from glandular
odontogenic cyst, which does not show the translocation
(Bishop et al. 2014)
CTNNB1 Mutations in the CTNNB1 (β-­catenin) CTNNB1 mutations are seen in a wide range of neoplasms,
gene but within the jaws are almost unique to ghost cell lesions
(calcifying odontogenic cyst and dentinogenic ghost cell
tumour). However, molecular analysis has not been used for
diagnostic purposes. CTNNB1 mutation results in aberrant
intracellular (cytoplasmic and nuclear) expression of
β-­catenin protein (see β-­catenin above) (Gomes et al. 2019;
Chapter 11)
20

Radicular Cyst

CHAPTER MENU
Clinical Features, 20
●● Frequency, 20
●● Age, 21
●● Sex, 22
●● Site, 22
●● Clinical Presentation,  23
–– Radicular Cyst,  23
●● Residual Cyst,  24
­Radiological Features, 25
­Pathogenesis, 26
●● Pathology of Periapical Periodontitis,  27
●● Phase of Initiation,  28
●● Phase of Cyst Formation,  31
●● Growth and Enlargement of the Radicular Cyst,  33
–– Role of Hydrostatic Pressure,  33
–– Epithelial Proliferation,  35
–– Degradation of the Connective Tissues and Bone Resorption,  35
Histopathology, 36
●● Cellular and Metaplastic Changes,  38
●● Hyaline Bodies,  40
●● Accumulation of Cholesterol,  42
●● Residual Cyst,  44
●● Pocket Cyst (Bay Cyst),  44
Malignant Change in Radicular Cysts, 45
Treatment, 46

The inflammatory odontogenic cysts arise as a result of epithe-
lial proliferation within an inflammatory focus due to a num-
ber of causes. Radicular cyst is the most common inflammatory
cyst and arises due to proliferation of epithelial remnants in
the periodontal ligament as a result of periapical periodontitis
following death and necrosis of the pulp. Radicular cysts are
most commonly found at the apex of the involved tooth, but
may arise on the lateral aspect of the root in relation to a lateral
root canal. Quite often a radicular cyst remains behind in the
jaws after removal of the offending tooth and this is referred to
as a residual cyst (Speight and Soluk-­Tekkeşin 2022a).
Inflammatory cysts may also occur on the lateral aspect
of a tooth as a consequence of an inflammatory process in
pericoronal tissues. This lesion has been referred to as a
paradental or inflammatory collateral cyst (Main  1970;
Craig 1976; Speight and Soluk-­Tekkeşin 2022b). Radicular
and residual cysts are considered in this chapter. The
inflammatory collateral cysts are considered in Chapter 4.
­Clinical Features
Frequency
Radicular and residual cysts are by far the most common
cystic lesions of the jaw bones, probably accounting for

Shear’s Cysts of the Oral and Maxillofacial Regions, Fifth Edition. Paul M. Speight.
© 2022 John Wiley & Sons Ltd. Published 2022 by John Wiley & Sons Ltd.
 ­Clinical Feature  21

more than half of all cystic lesions and about 60% of odon-
togenic cysts. In an analysis of nearly 10 000 radiolucent
jaw lesions, Koivisto et al. (2012) found that 73% were peri-
apical granulomas or cysts. Of these, 40.4% were granulo-
mas and 33.0% were cysts.
In Shear’s South African series, radicular and residual
cysts comprised 52.2% of cystic jaw lesions (Table 1.1) and
62% of odontogenic cysts. This is similar to the frequency
in a Sheffield study (Jones et al. 2006), where 4297 radicu-
lar and residual cysts were diagnosed over a 30-­year period,
representing 60.3% of all odontogenic cysts (Table 1.2).
Data from other countries vary (Table 1.3), with a range
from 42.1% in Mexico (Mosquedo-­Taylor et  al.  2002) to
84.5% in Sicily (Tortorici et  al. 2008). The reason for the
global variation in frequency is not clear, but probably
relates to variations in the prevalence of dental caries and
to methods of data collection. For example, in Mexico
Mosquedo-­Taylor et  al. (2002) suggest that the low fre-
quency is due to a large proportion of their studied popu-
lation being treated in the private sector where caries is
less prevalent. Conversely, Tortorici et al. (2008) believed
that the high frequency in Sicily was related to a high prev-
alence of caries in the studied population. The low
­frequency in Iran was ascribed to the fact that caries and
periapical lesions are common and are not routinely sub-
mitted for histological diagnosis (Sharifian and Khalili
2011). Overall, however, these data show that radicu-
lar  (including residual) cysts are consistently the most
common cystic lesion of the jaws, with a frequency of
about 60%.
In presenting these data, radicular and residual cysts
have been included together, but where the information is
stated, almost all the studies show that residual cysts
account for between 5% and 15% of odontogenic cysts and
between 10% and 20% of radicular cysts (Mosquedo-­Taylor
et al. 2002; Jones et al. 2006; Sharifian and Khalili; 2011;
Soluk Tekkeşin et  al.  2012b; Lo Muzio et  al.  2017;
Tamiolakis et al. 2019; Kammer et al. 2020)
Age
The age distribution of 948 patients in South Africa is
shown in Figure  3.1. Very few cases are seen in the first
decade, after which there is a fairly steep rise, with a peak
frequency in the third decade and large numbers of cases
in the fourth and fifth decades. In a Sheffield study of 1970
cases, Jones et al. (2006) found cysts in older age groups,
with a peak in the fourth decade and a mean age of
37.3 years (Figure 3.2). Similar data were found in French
(Meningaud et al. 2006), Australian (Johnson et al. 2013),
Italian (Lo Muzio et  al.  2017), and Greek (Tamiolakis
et al. 2019) studies, with mean ages of 40.8, 50.5, 38.2, and
41.2 years, respectively. The older ages of these patients
compared with the South African patients was noted in
previous editions of this book and suggests that the South
African patients may have been exposed to the relevant
aetiological factor, mainly dental caries, at a slightly
younger age than the other groups.
The wide age range of lesions, the very low frequency in
the first decade, and a peak in the fourth decade have been

Figure 3.1  Age distribution of 948 350

South African patients with
radicular cysts.
300 289

250
225
131
No. of cases

200 Women
77
146 Men
150 131
54
100 61 83
158 148
41 41
50 92
16 70 15 14
42 3
26
0 8 8
0-9 10-19 20-29 30-39 40-49 50-59 60-69 70-79 80-89
Age
22 Radicular Cyst

600 Figure 3.2  Age distribution of 1970

517 patients with radicular cysts from
Women Sheffield, England, 1990–2004 (n = 1970).
500 Men Source: Based on Jones et al. (2006).
430

400 372
257
No. of cases

308
197
300
196
129
200
144
124
260
233 56
100 56 179 59
176
6 10
68 88 33
0 5 26 5
0-9 10-19 20-29 30-39 40-49 50-59 60-69 70-79 80-89
Age

confirmed in a number of studies (Tortorici et  al. 2008;
Sharifian and Khalili 2011; Ramachandra et al. 2011; Soluk
Tekkeşin et  al.  2012b; Lo Muzio et  al.  2017; Tamiolakis
et al. 2019). These studies also indicate that although dental
caries is very common in children, radicular cysts are not
often associated with deciduous teeth. Soluk Tekkeşin et al.
(2016) identified 596 odontogenic cysts in a paediatric pop-
ulation (age 0–17 years), of which 387 (65%) were radicular
cysts (including 17 residual cysts). Of these, only 3 arose in
subjects less than 6 years old, 113 were found in the mixed
dentition (age 6–12 years), and 271  were associated with
permanent teeth (age 13–17 years). In a similar study in
Brazil, da Silva et al. (2018) reviewed 294 odontogenic cysts
in subjects younger than 20 years. They identified 145 radic-
ular cysts, but only 9 arose in subjects younger than 10 years.
Residual cysts are very unusual in the first, second, or
third decades and peak at a slightly older age, usually in the
fifth decade. Lo Muzio et  al. (2017) found a mean age
Box 3.1  Radicular Cyst: Epidemiology – Key Facts
●● Radicular cysts are the most common cystic lesion
of the jaws
●● They comprise about 60% of all odontogenic cysts
●● Residual cysts account for 10–20% of radicular cysts
●● Overall radicular cysts are the most common cause
of bony swellings
●● They are slightly more common in males
(M : F = 1.4 : 1)
●● Peak age is the third and fourth decades
(20–40 years)
●● Rare in children
●● Very rare on deciduous teeth
of  49.4 years (n  =  218; range: 17–90) and, in their large
Greek series, Tamiolakis et al. (2019) found a mean age of
50.5 years (n = 749; range 11–93) for residual cysts.
Sex
Almost all studies show that all odontogenic cysts are
slightly more common in males than in females (Table 1.3).
With regard to radicular cysts in the South African series,
555 (58.5%) were in males and 393 (41.5%) in females
(M : F 1.41 : 1), a statistically significant difference
(P < 0.002). In the Sheffield study, 1914 (51.5%) were in
males and 1801 (48.5%) in females (M : F 1.06 : 1; Jones
et al. 2006), but this difference was not significant.
Site
Figure 3.3 shows that radicular cysts may arise at any site
in the jaws, but are more common in the maxilla (60%)
than the mandible, with a particularly high frequency
in  the anterior maxilla, with about 40–50% of all cases
occurring in this region. There are a number of possible
reasons for this. First, in addition to the hazard posed by
dental caries, maxillary incisors have in the past, perhaps
more frequently than other teeth, had silicate restorations
placed in them, with consequent high risk to their pulps. If
this were the cause, then the prevalence of cysts at this site
might reduce in future ­generations. Second, there is a high
prevalence of palatal invaginations in the maxillary lateral
incisors and a high frequency in which pulp death super-
venes in these teeth. Third, maxillary anterior teeth are
probably more prone than others to traumatic injuries,
which may lead to pulp death.

Figure 3.3  Site distribution of radicular cysts.
A comparison of 1111 cases from South Africa
(Johannesburg) and 1974 cases from England
(Sheffield).
Percentage of cases
S = Sheffield series, n=1974. J = Johannesburg series, n=1111
Recent studies, however, show that this site distribu-
tion is seen across the world and has not changed in the
last two decades, suggesting that trauma and susceptibil-
ity to caries may be the main reasons. The proportion of
radicular cysts associated with the maxillary incisors has
been reported to  be 54.4% in India (Ramachandra
et al. 2011), 52.8% in England (Jones et al. 2006), 47.8% in
Turkey (Soluk ­Tekkeşin et  al.  2012b), 37.3% in Iran
(Sharifian and Khalili 2011), 36.4% in Sicily (Tortorici
et al. 2008), and 43% in Brazil (Tavares et al. 2017). Most
studies agree that the mandibular molar area is the next
most common site.
Clinical Presentation
Radicular Cyst
An essential criterion for the diagnosis of a radicular cyst is
that it is always associated with a tooth with a non-­vital
pulp, usually as a result of dental caries.
Many radicular cysts are small and symptomless and are
discovered by chance during radiological examination of
caries or non-­vital teeth. Overall, however, radicular cysts
are probably the most common cause of swelling of the
jaws and a slowly enlarging swelling is a common present-
ing complaint. At first the enlargement is bony hard, but as
the cyst increases in size, the cortical plate is resorbed and
only a thin layer of subperiosteal new bone covers the
lesion. The swelling then exhibits ‘springiness’ or ‘egg-­shell
crackling’. Only when the cyst has completely eroded the
bone, often due to secondary infection, will the lesion be
fluctuant. In the maxilla there may be buccal or palatal
enlargement, whereas in the mandible it is usually labial or
buccal and only rarely lingual.
­Clinical Feature  23
S
Mandible
J Maxilla
53
39 S J J
S
11 13
7 8
11 7 11 11
12
17
Anterior Premolar Molar
Radicular cysts may occasionally be associated with pain,
but this is usually pulpal in origin, or is due to secondary
infection, when there may be a sinus leading from the cyst
cavity to the oral mucosa. However, even infected lesions
may be symptomless. In a histological examination of 25
radicular cysts, Vier and Figueiredo (2002) showed that 21
contained abscess cavities that disrupted the epithelial lin-
ing. This suggests that although secondary infection may be
quite common, it is not often a cause of pain. Conversely,
some patients complain of pain, although no evidence of
infection is found clinically and no evidence of acute inflam-
mation is seen histologically after the cyst has been removed.
Quite often, a patient may have multiple radicular cysts.
Usually this is clearly associated with dental caries in mul-
tiple teeth, but the fact remains that radicular cysts are
relatively rare in relation to the vast numbers of grossly
carious teeth with dead pulps. This has led a number of
authors to believe that there are cyst-­prone individuals
who show a particular susceptibility to developing radicu-
lar cysts (Oehlers 1970). It is possible that in most people
periapical infections are suppressed and cyst formation is
inhibited, but that cyst-­prone subjects have a defective
immunological surveillance and suppression mechanism.
Multiple radicular cysts may also be seen in patients with
hereditary dental defects (e.g. multiple dens-­in-­dente or
dentinogenesis imperfecta), but in these cases this is
because of morphological defects resulting in increased
caries or early exposure and death of the pulp.
Radicular cysts arising from deciduous teeth appear to be
very rare. Shear found that of 1300 radicular cysts recorded
in his department at the University of the Witwatersrand
over a 25-­year period, only 7 were associated with decidu-
ous teeth (0.5%). In an extensive review of the literature
from 1898 to 1985, only 28 cases were found (Lustmann
24 Radicular Cyst
and Shear  1985). Subsequent reviews have recorded 112
cases up to 2004 (Nagata et al. 2008) and a total of 122 up to
2010 (Shetty et al. 2010).
The frequency is probably higher than these figures
would suggest, because many lesions may not be diagnosed
before the deciduous teeth are extracted or exfoliate, and
lesions may not be submitted for histological examination.
Nevertheless, the frequency is substantially lower than of
radicular cysts associated with permanent teeth and one may
speculate on the reasons for this. It may be due to the fact that
pulpal and periapical infections in deciduous  teeth tend to
drain more readily than those of permanent teeth. Caries is
almost always the aetiological factor, although in over half of
all cases reported there has been previous pulp therapy, sug-
gesting that medicaments used in pulpotomy may be an
additional aggravating factor by perpetuating chronic
inflammation (Grundy et al. 1984; Shetty et al. 2010)
In the study of Lustmann and Shear (1985), 23 person-
ally observed cases were reported. The patients’ ages
ranged from 4 to 12 years, with one exceptional case aged
19 years. The M : F ratio was 1.6 : 1. The mandible was
affected more frequently than the maxilla and the decidu-
ous molars were the teeth most often involved. In 9 cases
buccal expansion was noticed and in 8 cases the permanent
tooth buds were displaced. Mass et al. (1995) gave a detailed
account of 36 cases, of which 22 (61%) were associated
with mandibular molars. They also noted that the lesions
are not associated with the apices of the teeth, but usually
present as a periradicular radiolucency overlying the
crowns of the unerupted permanent premolars. This makes
diagnosis uncertain, since it may be difficult to differenti-
ate a deciduous radicular cyst from a hyperplastic follicle
or even a dentigerous cyst of the permanent successor,
which in this context may be inflammatory in origin (the
inflammatory dentigerous cyst is discussed in Chapter 5).
Residual Cyst
Residual radicular cysts are those that remain in the jaws
after removal of the cause of the lesion  –  the offending
non-­vital tooth. Although the reasons for the persistence of
cysts are contentious, there have been relatively few publi-
cations on the subject and the whole notion of the exist-
ence of such cysts has been challenged on the basis that a
persistent radiolucency after removal of the offending
tooth may merely represent an ongoing healing process
(Walton  1996; Lee et  al.  2014). High and Hirschmann
(1986, 1988) studied a series of asymptomatic and sympto-
matic residual cysts. They were interested in the factors
that decide whether a radicular cyst will resolve or persist
after tooth removal and the natural history and behaviour
of these cysts once established. With regard to the asymp-
tomatic cysts, they showed that there was a decrease in size
with increasing duration of the cyst (r  = 0.5; P < 0.005;
High and Hirschmann 1986). There was an unexpectedly
large number in the mandibular premolar region and there
was a direct relationship between the age of the cyst and
the radiological and histological evidence of mineralisa-
tion (P < 0.001). There was an overall reduction in epithe-
lial thickness with cyst age and all cysts showed minimal
chronic inflammatory changes. Their results support the
notion that the vast majority of residual cysts are slowly
resolving lesions. Nevertheless, they do persist and the
authors did not provide evidence of complete healing.
In their second paper, High and Hirschmann (1988)
showed that symptomatic cysts were larger than asymp-
tomatic lesions, and that the negative correlation of size
with cyst duration was not as strong (r  = 0.39; P < 0.05).
Cyst ages varied from 1 month to 20 years and there was
again a perplexingly high frequency in the mandibular pre-
molar region. Acute and chronic inflammatory cell infiltra-
tion showed variable intensity and there was an inverse
relationship between the presence of acute inflammation
and cortication of the cyst wall radiographically (P < 0.001).
There were no obvious causes for the inflammation in
deeply positioned residual cysts. The authors suggested
that in symptomatic cases chronic inflammation could per-
sist and gradually worsen, and that acute inflammatory
episodes may be triggered by release of pro-­inflammatory
factors from dead or dying cells.
Nair (1998, 2003, 2006) considered that the type of cyst
was important with regard to persistence after treatment.
Although he discussed non-­healing cysts after endodontic
treatment, his conclusions are relevant to residual cysts. He
confirmed the work of Simon (1980), who showed that
there were two types of radicular cyst. These are discussed
in more detail later in this chapter but, to summarise, there
is the true radicular cyst, which contains a closed cavity
entirely lined by epithelium, and the periapical pocket cyst
(also called bay cyst), in which the epithelium is attached to
the margins of the apical foramen in such a way that the
cyst lumen is essentially a pouch or pocket, which commu-
nicates directly with the affected root canal. Thus, it is
expected that the pocket cyst would heal after treatment or
tooth extraction, while the true cyst, being completely
enclosed, is ‘self-­sustaining’ and may therefore persist in
the absence of the cause. Nair et al. (1996) suggested that
only 15% of periapical lesions were radicular cysts, but of
these 61% were true cysts and 39% were pocket cysts. If
only true cysts persisted after removal of the offending
tooth, this may account for the relatively low frequency of
residual cysts.
Regardless of the finer details of the biology of these
lesions, from the clinical point of view it is evident that a
radiolucent lesion may persist and may produce symptoms,
for a substantial period of time after extraction of the

offending tooth. On biopsy, many show the typical features
of a cyst and residual cyst remains an appropriate term for
these lesions.
­Radiological Features
The classic description of the radiological appearance of
radicular cysts is that they are round or ovoid radiolucen-
cies surrounded by a narrow, radiopaque or corticated mar-
gin that extends from the lamina dura of the involved tooth
(Figure  3.4; see also Figure  2.2). In infected or rapidly
enlarging cysts, the corticated margin may not be present.
A residual cyst is usually round to oval with a well-­
demarcated and often corticated margin. They are found
within an edentulous area of the jaws, at a site of a previous
tooth extraction (Figure  3.5). With a residual cyst, the
­differential diagnosis of keratocyst must be considered.
A radicular cyst on the lateral margin of a root in associa-
tion with an accessory root canal must be differentiated
from a lateral periodontal cyst. Root resorption is not often
seen on routine radiographs, but it may occur.
Despite these well-­described features, many studies have
shown that it is not possible to reliably differentiate
­radiologically between a radicular cyst and a periapical
Figure 3.4  Radiograph of a radicular cyst. The lesion is a
well-­defined radiolucency associated with the apex of a
non-­vital root-­filled tooth.
­Radiological Feature  25
granuloma. In one of the largest studies, which has not
been repeated, Mortensen et al. (1970) examined histologi-
cal material of 396 periapical lesions with a diameter of
5 mm or more, that had been classified pre-­operatively as
cysts or granulomas on radiological evidence. A correct
preliminary diagnosis had been made in 81% of 232 granu-
lomas, but in only 48% of 164 cysts. They also showed that
the relative number of granulomas decreased with increas-
ing size of the lesion, whereas the relative number of cysts
increased. Table  3.1 summarises their data and shows
that if a lesion measured between 10 and 14 mm in radio-
graphic diameter, there was an equal chance of it being
a granuloma or a cyst. About one-­third of lesions measur-
ing 5–9 mm were cysts and one-­third of lesions measuring
15 mm or more were granulomas. However, they found
that very large lesions, over 20 mm, were almost always
cysts, a finding confirmed by others (Natkin et al. 1984).
Mortensen et al. (1970) also noted that many cysts had a
diffuse radiographic margin and therefore lacked the
Figure 3.5  Radiograph of a residual cyst. The lesion is at the
site of a previously extracted tooth. The lesion must be
differentiated from an odontogenic keratocyst.
Table 3.1  The relationship between the size of a lesion on
radiological examination and the histological diagnosis of a cyst
or granuloma. The arrow illustrates the increasing chance of a
lesion being a cyst.
Size (mm) Granulomas (%) Cysts (%)
20+ <10 90+
15–19 35 65
10–14 50 50
5–9 65 35
Source: Based on Mortenson et al. (1970).
26 Radicular Cyst
cortication often described as typical for radicular cysts.
This suggested that a corticated margin, although com-
mon, was not a specific diagnostic criterion for a cyst, a
finding supported by others. Ricucci et  al. (2006a) exam-
ined 57 periapical radiolucent lesions and found that of
10  lesions with a corticated outline, only 3  were cysts.
Conversely, 40 of the 47  lesions without cortication were
granulomas.
Shrout et al. (1993) used radiometric methods to analyse
the grey levels on digitised images of periapical lesions.
In a pilot study of only 10 mandibular lesions, they showed
that analysis of grey levels could correctly identify 4 of 6
granulomas and all 4 cysts. They concluded that it may be
feasible to differentiate between radicular cysts and peria-
pical granulomas on the basis of radiographic density. With
the advent of digital radiography and powerful software to
routinely analyse images, it would be interesting to see if
these findings could be confirmed. Early studies examining
grey levels on images from cone beam computed tomogra-
phy (CBCT) suggest that this may provide an accurate diag-
nosis (Simon et  al.  2006). Measurement of conventional
parameters on CBCT, however, have proved to be no more
accurate than conventional X-­rays (Guo et al. 2013).
Although teeth may be resorbed by radicular cysts, there
is a poor correlation between radiological evidence of
resorption and actual tooth resorption on histology. Laux
et  al. (2000) compared the radiological and histological
findings in 114 periapical lesions. Ninety three (81%)
showed histological evidence of tooth resorption, but only
21 (19%) showed evidence of resorption on the radiographs.
It should be noted, however, that only 30 of the 93 lesions
with histological resorption showed dentine involvement.
In the majority (63 cases) only cementum was involved
and it was acknowledged that this would not normally be
visible on a plain radiograph.
The data from these studies suggest that there are no spe-
cific radiological features that can be used to distinguish
between a radicular cyst and a periapical granuloma.
Clinicians know that it is useful in treatment planning to
Box 3.2  Clinical and Radiological Features: Key Facts
●● Always associated with a non-­vital tooth
●● Most commonly found on upper anterior teeth
●● Often symptomless and found on radiological
examination
●● Firm or hard swelling, but large lesions may show
‘egg-­shell’ crackling
●● Residual cysts are found at sites of a previous tooth
extraction
●● Radiology shows well-­demarcated, corticated lesion
●● Rarely greater than 30 mm in diameter
have an indication, a priori, whether a periapical lesion is a
cyst or a granuloma. There are a number of key features that
together can identify that a lesion is odontogenic and can be
highly suggestive of a cyst (Box 3.2). Both granulomas and
cysts are associated with a heavily restored or carious tooth
and lie within the periodontal ligament. Cysts are more often
over 15 mm in diameter, more often have a corticated margin,
and show a greater degree of radiopacity.
­Pathogenesis
For any type of cyst to develop, three elements are needed:
a source of epithelium, a stimulus for epithelial prolifera-
tion, and a mechanism of growth and bone resorption. In
the case of a radicular cyst, the process is driven by an
inflammatory response at the apex of a tooth (Box  3.3).
Although trauma, instrumentation, and irritation from fill-
ing materials may cause inflammation, in reality this is
usually short lived and the chronic inflammation needed
to initiate cyst formation almost always follows microbial
infection in a dead pulp following caries. The presence of
bacteria and their products in the root canal then leads to
periapical inflammation and the formation of a periapical
granuloma, which may then lead to cyst formation.
It must be noted, however, that although cysts are a
direct sequela of periapical inflammation, cyst formation is
not inevitable and radicular cysts are in fact quite rare rela-
tive to the prevalence of caries and periapical lesions. In an
analysis of 256 periapical lesions, Nair et al. (1996) showed
that only 15% were actually cysts, although a further 37%
were granulomas with proliferating epithelium. Their cri-
teria for diagnosis of a cyst was unusually stringent and
depended on the ability to examine, in multiple serial sec-
tions, the entire specimen and to be able to visualise a
Box 3.3  Pathogenesis: Key Facts
Three elements are needed:
●● A source of epithelium
●● A stimulus for epithelial proliferation
●● A mechanism of growth and bone resorption
The cyst develops in three phases:
●● Phase of initiation – rest cells of Malassez are stim-
ulated to proliferate within a periapical granuloma
●● Phase of cyst formation – a cavity within the granu-
loma becomes lined by proliferating epithelium
●● Phase of growth and enlargement  –  growth and
enlargement are driven by increased osmotic pres-
sure, and are associated with inflammation, cell
proliferation and bone resorption

distinct epithelial-­lined cavity. Few studies have under-
taken such meticulous examination of lesions using serial
sections, but those that have have confirmed the findings
of Nair et al. (1996) that cysts form the minority of periapi-
cal lesions. The actual frequencies reported have been
17.1% (Simon 1980), 15.2% (Nair et al. 1996), 32.0% (Ricucci
et al. 2006b), and 24.2% (Ricucci et al. 2020).
It is convenient first to consider the pathology of periapical
periodontitis and then to discuss the pathogenesis of radicu-
lar cysts in three phases: the phase of initiation, the phase of
cyst formation, and the phase of growth and enlargement.
Pathology of Periapical Periodontitis
Radicular cysts develop within a pre-­existing periapical
granuloma where proliferation of the epithelial cell rests
of  Malassez is initiated by inflammation caused by
the  necrotic debris and bacterial factors derived from
the  dead pulp. One can think of this process as part of
­normal healing, where the host response acts to prevent
dissemination of bacteria and stimulates epithelial regen-
eration. Histologically a periapical granuloma is composed
of granulation tissue at various stages of development
and maturation. Early lesions may show clear evidence of
acute inflammation with polymorphonuclear leukocytes
(PMNs), while later lesions become dominated by lympho-
cytes and plasma cells and may develop a fibrous outer cap-
sule. The process involves many cell types that give rise to
a massive array of pro-­inflammatory mediators, cytokines,
chemokines, and growth factors, which work together in
complex interactions to pursue the final goal of elimina-
tion of the cause and healing. However, as well as being
protective to the host, these immunomodulatory pathways
are also destructive, especially if the bacterial insult per-
sists, as is often the case in periapical periodontitis (Marton
and Kiss  2014). Many studies have examined periapical
lesions to determine which cells and pro-­inflammatory
mediators may be important in the development of cysts,
and it is difficult and unnecessary to review them all. For
example, Bernardi et al. (2015) undertook a review of the
literature and identified 187 references to epithelium in
periapical lesions between 1975 and 2014. After removing
duplicates and simple case reports, they found 42 publica-
tions that reported the expression of various biological
­factors that might be involved in the formation of radicu-
lar  cysts. Because the overall biological process is one of
inflammation and the immune response, the factors are
not specific to radicular cysts, and the whole field is
­constantly evolving. Readers interested in the finer points
of the associated immunopathological processes should
search for relevant up-­to-­date papers. There are a number
of detailed reviews that have helped to inform the follow-
ing discussion of the key points (Nair 2004; Silva et al. 2007;
­Pathogenesi  27
Lin et  al.  2007; Graves et  al.  2011; Graunaite et  al.  2012;
Marton and Kiss 2014; Bernardini et al. 2015).
It is now well accepted that the whole process is started
by bacterial infection in the necrotic pulp, and that the
key  initiating event is the action of bacterial endotoxins
(lipopolysaccharides, LPS) on periodontal ligament fibro-
blasts, which then secrete a range of pro-­inflammatory
cytokines and chemokines. Meghji et  al. (1996) studied
cyst fluids and cultured cyst explants from radicular cysts,
keratocysts, and follicular cysts. They showed high levels
of endotoxins in radicular cysts compared with negligi-
ble  levels in the other cyst types. These endotoxins were
LPS derived from Actinobacillus actinomycetemcomitans,
Porphyromonas gingivalis, and Escherichia coli. Wayman
et al. (1992) were able to cultivate bacteria from 51 periapi-
cal lesions, 23 of which had had previous endodontic ther-
apy. They found a total of 50 different species, of which
over 90% were anaerobes. Bacteria were cultured from both
granulomas and cysts with equal frequency, but were seen
histologically in only 8 (13%) cases. Tek et al. (2013) were
only able to culture bacteria from about one-­third of peri-
apical lesions. Nair (1987), however, in a detailed ultras-
tructural analysis, found bacteria in 100% of the root canals
of teeth affected by periapical lesions, but in only 4 of
31 cases were bacteria found in the extraradicular tissues.
In these cases, 1  was infected with Actinomyces and in 3
the bacteria were isolated on the dentinal wall close to the
foramen and were associated with abscess formation with
accumulations of PMNs. In a later review of the literature,
Nair (2004) concluded that periapical lesions rarely har-
bour bacteria unless secondarily infected. This is supported
by Ricucci and Siqueira (2010), who studied 106 biopsy
specimens of tooth roots with apical lesions. They found
evidence of bacteria in only 6% of extraradicular lesions.
However, bacterial biofilms were found in 77% of the root
canals and were more common in untreated (80%) than
treated canals (74%). These authors also showed that
­biofilms were significantly associated with epithelialised
lesions, with a frequency of 95%, 83%, and 69.5% in cysts,
abscesses, and granulomas, respectively.
Taken together, these data indicate that periapical perio-
dontitis is a result of endodontic infection, following death
of the pulp due to caries. Although bacteria proliferate
within the root canal, they are rarely encountered in the
periapical lesions, confirming the view that cyst formation
is initiated by leakage of endotoxins through the apical
foramen.
With regard to the host response, all the expected
immune cells have been reported in periapical granulo-
mas, with most studies indicating that T lymphocytes
predominate and that among these, T-­helper cells (CD4)
predominate over cytotoxic/suppressor cells (CD8) (Skaug
et al. 1984; Nilsen et al. 1984; Liapatas et al. 2003). However,
28 Radicular Cyst
the proportions of different cell types may vary between
sites in the same lesion, or may depend on the stage (or
‘age’) of the lesion (Matthews and Browne 1987). Of par-
ticular importance, especially in the balance between pro-
tective and destructive tissue responses, is the relative
number of the T-­helper cell subsets Th1, Th2, Th17, and
regulatory T cells (Tregs) (Marton and Kiss  2014). Th1
cells, which secrete a range of pro-­inflammatory cytokines,
always predominate in periapical granulomas. Th17 cells
are the primary source of interleukin (IL)-­17, which is
also pro-­inflammatory (Graunaite et al. 2012; Marton and
Kiss  2014), but their action is moderated by Treg cells,
which are a major source of anti-­inflammatory transform-
ing growth factor (TGF)-­β. The Th17/Treg ratio seems to be
an important regulator of the intensity of the inflammatory
response and may thus determine the extent of tissue
destruction (Marton and Kiss  2014). Kontiainen et  al.
(1986), Babál et al. (1987), and Gao et al. (1988a) found that
suppressor/cytotoxic cells (CD8) dominated. Gao et  al.
(1988a), however, also noted that although suppressor/
cytotoxic cells outnumbered T-­helper cells in periapical
granulomas, T-­helper cells predominated in the cysts that
they examined. A more recent study (Liapatas et al. 2003)
has confirmed most of these findings. It showed that T cells
predominated and that helper cells predominated over
cytotoxic/suppressor cells in most periapical granulomas
and cysts. In cysts, however, they found increased numbers
of plasma cells, suggesting that humoral immune reactions
may take on a more important role in cysts. These studies
illustrate the complex nature of the immune interactions
in periapical lesions and may explain the discrepancy in
the results reported by different workers.
The proportion of B lymphocytes has been reported to
be about 20% (Kontiainen et al. 1986), with plasma cells
varying from 2% (Kontiainen et  al.  1986) to 13% (Stern
et al. 1982). As would be expected, the vast majority (over
75%) of plasma cells express immunoglobulin (Ig)G, with
15–20% IgA and very few IgE or IgM (Stern et  al.  1981;
Smith et  al.  1987). Other cell types that play a role in
­periapical lesions include macrophages, mast cells, and
Langerhans cells (Pulver et al. 1978; Kontiainen et al. 1986;
Drazic et al. 2010). Langerhans cells may be of particular
interest because they have been found in the epithelial lin-
ings of radicular cysts (Contos et al. 1987; Matthews and
Browne 1987; Gao et al. 1988a; Liapatas et al. 2003) and
are most prominent in areas of heavy inflammation.
Although they are known to be important in antigen pres-
entation, it has been suggested that they may also be asso-
ciated with epithelial proliferation (Carillo et  al.  2010).
Non-­immune cells, including fibroblasts, endothelial
cells, and epithelial cells, are also present and may be
involved in producing relevant cytokines and growth fac-
tors. Lesions also contain PMNs and primary or secondary
abscess formation may be a key factor in cyst formation
(see later in this chapter).
Although the main initiating factor of a periapical lesion
is bacterial LPS, the lesions are then sustained by a com-
plex network of inflammatory mediators, including
cytokines, chemokines, and the eicosanoids (mainly pros-
taglandins). These have multiple roles in cell activation
and migration, in epithelial proliferation, and in bone
resorption. In early lesions there is good evidence that the
chemokine CXCL8/IL-­8 is important since it is absent in
normal pulp, but found in about 95% of periapical lesions.
LPS stimulates periodontal ligament fibroblasts to secrete
CXCL8/IL-­8, which has a pivotal role in PMN migration
and therefore in lesion initiation (reviewed in Silva
et al. 2007; Graunaite et al. 2012; Marton and Kiss 2014).
This chemokine is also  important in bone resorption.
Other pivotal cytokines are  the interleukins, especially
IL-­1 and IL-­6, which have roles in activating PMNs and
lymphocytes, and in bone resorption (reviewed in
Graunaite et al. 2012). Table 3.2 lists a number of selected
biological factors that may be involved in the pathogene-
sis of radicular cysts. Mostly this list is derived from the
reviews mentioned previously (Bernardini et  al.  2015;
Marton and Kiss  2014; Graunaite et  al.  2012; Graves
et  al.  2011; Silva et  al.  2007; Lin et  al. 2007; Nair  2004).
The actions of those factors thought to have important or
specific roles in the formation of radicular cysts are dis-
cussed in the sections that follow.
Phase of Initiation
It is generally agreed that the source of epithelium for a
radicular cyst is the epithelial cell rests of Malassez. During
tooth development the epithelial root sheath of Hertwig
maps out the shape of the roots and initiates dentine for-
mation. When tooth formation is complete, the sheath
­disintegrates and epithelial remnants remain in the perio-
dontal ligament as the rest cells of Malassez. There are two
common misconceptions about these cells: first, that they
are small islands; and second, that they have no normal
function. It is now clear that the epithelial remnants form
a network or mesh that lies in the periodontal ligament and
surrounds or embraces the tooth root. Only in histological
sections do they appear to be isolated islands (Figure 3.6).
It is now also apparent that the cell rests of Malassez
have a number of important functions in normal periodon-
tal homeostasis, including cementogenesis, healing and
regeneration (Keinan and Cohen 2013; Xiong et al. 2013).
They are thus important in maintaining periodontal
health during all the normal challenges of tooth move-
ment and function as well as in responses to trauma, ortho-
dontic tooth movement, and periodontitis. These properties
are being exploited in the development of therapeutic
 ­Pathogenesi  29

Table 3.2  Biological factors that have a role in the pathogenesis of radicular cyst.

Factors Cell(s) of origin Target cell (ligand(s)) Key function

Bacterial factors
LPS Bacteria Fibroblasts and many Induces a wide range of mediators, including
(endotoxin) cell types (CD14/ CXCL8/IL-­8, TNF-­α, IL-­1, RANKL, OPG. Indirectly
TLR) stimulates bone resorption
Cytokines
IL-­1α Macrophages, PMN, Attracts and activates PMNs; stimulates production
osteoclasts, epithelial cells, of prostaglandins, proteolytic enzymes, cytokines
dendritic cells IL-­6, IL-­8; stimulates bone resorption and inhibits
bone formation (originally called osteoclast-­
activating factor, OAF)
IL-­1β Macrophages Monocytes Inhibits osteoclast formation and bone resorption
IL-­6 Macrophages, epithelial Activates and stimulates PMNs and T cells;
cells, PMN, Th2 cells, B stimulates differentiation of B lymphocytes into
lymphocytes, endothelial plasma cells; stimulates osteoclasts and bone
cells, fibroblasts resorption; down-­regulates production of IL-­1
TNF-­α Macrophages, Th1 cells, Activates lymphocytes and macrophages; stimulates
PMN, fibroblasts bone resorption
IL-­17 Th17 Up-­regulates secretion of IL-­1, IL-­6, TNF-­α, and IL-­8
secretion; attracts PMNs; stimulates osteoclasts and
bone resorption
GM-­CSF Macrophages, T Functionally activates macrophages and PMNs
lymphocytes, endothelial
cells, PMN
TGF-­β Lymphocytes (Treg), PMNs, macrophages Anti-­inflammatory; suppresses T and B lymphocytes;
macrophages, fibroblasts, down-­regulates production of IL-­1, IL-­6, TNF-­α, and
osteoblasts, osteoclasts, IFN-­γ; blocks production of nitric oxide by
epithelial cells macrophages; inhibits bone resorption; inhibits Th17
and promotes Treg formation
IFN-­γ Th1 cells, dendritic cells Th lymphocytes Activates macrophages; induces IL-­1 production;
inhibits RANKL and bone resorption
IL-­12 Th1 cells, macrophages, Up-­regulates IL-­1 and IFN-­γ; stimulates Th1
dendritic cells differentiation; suppresses Th2 differentiation
IL-­10 Macrophages, dendritic cells, Anti-­inflammatory; down-­regulates IL-­1 and IFN-­γ;
lymphocytes (Treg) inhibits action of RANKL and bone resorption
IL-­4 Th2 cells Inhibits bone resorption; inhibits Th17 formation;
down-­regulates IL-­1
RANKL Normally present on Osteoclasts and Activates osteoclasts; positively regulates bone
osteoblasts; also Th1cells, precursors (RANK) resorption
endothelial cells, fibroblasts,
PMNs, epithelial cells; may
be soluble
OPG Osteoblasts, some epithelial Osteoblasts (RANKL) Decoy receptor for RANKL and blocks RANK/
cells, endothelial cells, B RANKL pathway; inhibits osteoclastogenesis and
cells negatively regulates bone resorption
Chemokines
CXCL8 (IL-­8) Macrophages, PMN, Th1 CXCR1-­2 Attracts PMNs and macrophages; chemotaxis and
cells, Th17 cells differentiation of osteoclasts
CXCL12 Endothelial cells Osteoclast precursors Chemotaxis and differentiation of osteoclasts;
(SDF-­1α) (CXCR4); PMNs attracts PMNs; up-­regulates MMPs
CCL7 (MCP-­3) Endothelial cells, Osteoclasts and Chemotaxis and differentiation of osteoclasts
lymphocytes, fibroblasts, precursors
plasma cells

(Continued )
30 Radicular Cyst

Table 3.2  (Continued)

Factors Cell(s) of origin Target cell (ligand(s)) Key function

CCL5 T cells, fibroblasts, Osteoclasts and Chemotaxis and differentiation of osteoclasts

(RANTES) osteoclasts, osteoblasts precursors (CCR1,
CCR5)
CCL-­2 Osteoblasts Osteoclasts and Chemotaxis and differentiation of osteoclasts
(MCP-­1) precursors (CCR2)
CCL3 Fibroblasts, osteoclasts, Macrophages Chemotaxis and differentiation of osteoclasts;
(MIP-­1α) osteoblasts (CCR1), attracts macrophages
lymphocytes/Th1
(CCR5)
CCL4 Th1 cells Chemotaxis and differentiation of osteoclasts;
(MIP-­1β) activates macrophages
Prostaglandins
Prostaglandins Macrophages, fibroblasts, Osteoclasts Stimulates osteoclasts and bone resorption
(PGE2) inflammatory cells, epithelial (receptors EP1–EP4)
cells, endothelial cells

GM-­CSF, granulocyte-­macrophage colony-­stimulating factor; IFN, interferon; IL, interleukin; LPS, lipopolysaccharides; MCP, monocyte
chemoattractant protein; MIP, macrophage inflammatory protein; MMP, matrix metalloproteinase; OPG, osteoprotegerin; PMN,
polymorphonuclear leukocyte; RANK, receptor activator of nuclear factor kappa B; RANKL, receptor activator of nuclear factor kappa B ligand;
RANTES, regulated upon activation, normal T cell expressed and presumably secreted; SDF, stromal cell-­derived factor; TGF, transforming
growth factor; TLR, Toll-­like receptor; TNF, tumour necrosis factor; Treg, regulatory T cell.

approaches to promote periodontal regeneration in the

Figure 3.6  Rest cells of Malassez appear as multiple small
islands of epithelium (arrows) within the periodontal ligament.
management of periodontal diseases (Xiong et al. 2013).
There is no doubt that the start of the process of cyst for-
mation involves the proliferation of the epithelial cell rests
within the inflamed tissues of a periapical granuloma. As
discussed previously, LPS is the key factor that initiates the
inflammatory and immune response, but it may also
directly cause epithelial proliferation. In their study of flu-
ids and explants from radicular cysts, keratocysts, and fol-
licular cysts, Meghji et al. (1996) showed high levels of LPS
in radicular cysts and demonstrated that it could directly
stimulate epithelial proliferation in a dose-­dependent man-
ner. They proposed that bacterial LPS, derived from the
necrotic pulp, is the key initiating factor in the pathogene-
sis of radicular cysts. In this same study they also provided
evidence that cytokines can directly stimulate epithelial
proliferation. All cysts contained IL-­1α and IL-­6, but radic-
ular cyst explants produced significantly more IL-­6 than
either keratocysts or follicular cysts. Further experiments
showed that IL-­1 and IL-­6, and culture supernatants from
cyst fibroblasts, were able to stimulate epithelial prolifera-
tion in a dose-­dependent manner. Significantly, this activ-
ity was further enhanced by the addition of LPS.
In earlier experiments, the same research group (Meghji
et al. 1989; Bando et al. 1993) used immunocytochemistry
to localise cytokines and adhesion molecules in the walls
 ­Pathogenesi  31

of radicular cysts. All cysts showed positive staining for 1) Central necrosis or nutritional deficiency theory. This
IL-­1α, IL-­1β, and IL-­6 in the epithelial lining and in vascu- proposes that a cyst cavity forms within a proliferating
lar endothelial cells. Tumour necrosis factor (TNF) and mass of epithelial cells due to loss of nutrition followed
CXCL8/IL-­8 were occasionally seen in macrophages. The by degeneration and death of cells in the centre of
cell adhesion molecules ICAM-­1 and ELAM-­1 (E-­selectin) the mass.
were also identified in all lesions and were localised to 2) Abscess theory. This postulates that the proliferating epi-
endothelial cells, epithelium, and inflammatory cells. thelium surrounds an abscess cavity, in effect walling
Kusumi et  al. (2004) produced further evidence that off the central focus of inflammation. Essentially this
IL-­6 has an important role. They used reverse transcriptase represents the process of normal wound healing, where
polymerase chain reaction (RT-­PCR) to study a number of epithelium proliferates to cover denuded connective
cytokines in tissues from 19 radicular cysts and compared tissues.
expression with normal gingivae and periodontal ligament. 3) Merging epithelial strands theory. This proposes that the
They found variable expression of cytokines in all tissues, proliferating epithelium forms a three-­dimensional ‘ball
but most cysts expressed IL-­1β, IL-­6, CXCL8/IL-­8, TNF-­α, mass’ (Lin et al. 2007), which entraps inflamed connec-
interferon (IFN)-­γ, and TGF-­β1, and most of these showed tive tissue. This connective tissue then breaks down due
increased expression compared with normal tissues. All to loss of a blood supply and a cyst cavity forms.
the cytokines were expressed at low levels except for IL-­6,
Proponents of each process often promote their favoured
which showed high levels of secretion from fibroblasts
theory, while suggesting that others are not tenable (Lin
extracted from the radicular cysts.
et al. 2007; Nair et al. 2008; Huang 2010), but in fact they
These studies confirmed that the walls and epithelial lin-
are not mutually exclusive and all three have a similar
ing of radicular cysts synthesise a range of cytokines and
premise  –  that epithelium proliferates to surround and
growth factors that are known to be involved in epithelial
encase a focus of inflamed and degenerating or necrotic tis-
proliferation (Table 3.2).
sue. There is little difference, for example, between an
The role of abscess formation in the formation of a cyst
abscess (theory 2) and necrotic connective tissue (theory
will be discussed below, but there is good evidence that an
3), apart perhaps from the degree or stage of necrosis and
acute inflammatory cell infiltration may be directly associ-
the types of cells present. Similarly, the necrotic centre
ated with epithelial proliferation, since many early studies
of  an epithelial mass (theory 1) may contain PMNs and
were able to demonstrate large numbers of PMNs in the
essentially become an abscess, a feature familiar to tumour
proliferating epithelium (Shear 1963a, 1964; Cohen 1979;
pathologists in the form of comedo necrosis. Thus on histo-
Johannessen  1986). As mentioned above, LPS from the
logical examination, the presence of an abscess cavity lined
root canal stimulates CXCL8/IL-­8 secretion from perio-
by epithelium may support theory 1 or 2. Also, in the
dontal fibroblasts via the co-­receptors CD14 and Toll-­like
receptor (mainly TLR4). In addition, epithelial cells in peri-
apical lesions have been shown to express CD14/TLR4
(Leonardi et al. 2015), and there is evidence that CXCL8/
IL-­8  may directly cause epithelial proliferation as well as
being a chemoattractant for PMNs (Silva et al. 2007; Marton
and Kiss 2014). This would explain the association of pro-
liferating epithelium and PMNs in early lesions.

Phase of Cyst Formation

The next phase in the pathogenesis of a radicular cyst is
the  process by which a cavity comes to be lined by the
­proliferating odontogenic epithelium. Many will think it
astonishing that the actual process of cyst formation is so
poorly understood, and although a number of theories
have been debated for decades, there are very few observa-
tional or experimental data to support or refute any of
Figure 3.7  Arcades and rings of proliferating epithelium in a
them. There are three proposed mechanisms of cyst forma-
periapical granuloma. The epithelium surrounds islands of
tion (Shear  1963a; Summers  1974; Valderhaug  1974; Lin inflamed connective tissue that may break down to initiate early
et al. 2007; Nair et al. 2008; Huang 2010): cyst formation.
32 Radicular Cyst
previous edition of this book we showed a photomicro-
graph (Figure  3.7) of arcading epithelium surrounding
inflamed connective tissue in support of theory 1 – but in
fact this pattern of proliferating epithelium, with entrap-
ment of connective tissue, is very similar to the merging
epithelial strands theory of Lin et al. (2007) (theory 3).
In support of theory 1, there is some histological evi-
dence for central necrosis or nutritional deficiency. In
some periapical lesions, distinct clefts may be seen in
sheets of epithelial cells (Shear  1963a) (Figure  3.8), and
the proliferating epithelial masses often show considerable
intercellular oedema. These intercellular accumulations
of  fluid coalesce to form microcysts containing epithelial
and inflammatory cells, including PMNs (Figure  3.9).
These central areas have been shown to contain high lev-
els of  acid  phosphatase activity and proteolytic enzymes
­consistent with autolysis or necrosis (Lutz et  al.  1965;
Summers 1972, 1974). Microcysts may increase in size by
coalescence with adjacent microcysts and, once established,
the cyst increases in size by mechanisms that are dis-
cussed later.
Most information regarding cyst formation is taken
from histological observation of biopsy specimens taken
from humans and there are very few longitudinal studies.
In  experiments that have not been repeated, Valderhaug
(1972) induced radicular cysts in monkeys. Because of the
rarity of such experiments, it is worth considering some of
the details of his findings. He induced pulpal necrosis
sequentially in 39 teeth in 4 animals and was able to histo-
logically examine periapical inflammation and cyst forma-
tion for up to 360 days after the pulps were removed. Of
interest is that he did not observe any cysts until after
200 days, although proliferating epithelium was observed
Figure 3.8  Sheet of epithelial cells in a periapical lesion. A
distinct cleft has formed and this may initiate a radicular cyst.
in earlier lesions. In lesions examined after 200 days, 11 of
16 (69%) developed cysts. Even after 300 days, 3 of 8 lesions
showed no inflammation, but 4 had developed into cysts.
Of relevance to the proposed mechanisms of cyst forma-
tion is that he did not see evidence of intraepithelial
degeneration with formation of microcysts, but observed
long strands of proliferating epithelium lining surfaces of
granulation tissue, or arcades surrounding cores of vascu-
larised or degenerating granulation tissue. These observa-
tions support the merging epithelial strands theory (theory
3). However, in most cases Valderhaug also observed that
the proliferating epithelium was associated with PMNs,
but he did not describe frank abscess formation. He also
showed that in most cysts the epithelial lining was closely
connected to the roots around the apical foramen, sup-
porting the notion that the epithelium is reforming an
intact integument, and that the cysts are pocket or bay
cysts. In a very similar study, Valderhaug (1974) examined
52 primary teeth, and although periapical inflammation
was common, he found small cysts only in ‘a few cases
with long observation periods’. Of relevance to the theo-
ries of cyst formation is that he found that abscess forma-
tion, often with oral fistulas, was common and more
frequently seen than in his previous study on permanent
teeth (Valderhaug  1972). His findings, however, did not
support the abscess theory, since ‘proliferating epithelium
was not observed in the periapical area in connection with
abscess formation’.
Despite this, as described previously, there is good
­evidence that PMNs are a prominent feature of periapi-
cal  granulomas and are associated with epithelial
Figure 3.9  Degeneration of cells in the centre of a mass of
proliferating epithelium in a periapical granuloma. There is an
intense infiltration of lymphocytes and polymorphonuclear
leukocytes. Accumulations of intercellular fluid coalesce to form
a microcyst.

proliferation  (Valderhaug  1972; Shear  1963a,  1964;
Cohen 1979; Johannessen 1986; Marton and Kiss 2014). In
their examination of 256 periapical lesions, Nair et  al.
(1996) showed that 90 (35%) were an ‘abscess’ and that
two-­thirds of these contained epithelium. However, the
definition of an abscess was of a collection of PMNs in a
pre-­existing periapical granuloma – making distinction of
a primary abscess from a collection of PMNs in a necrotic
lesion difficult. In  support of the abscess theory, Nair
et  al. (2008) were able to demonstrate that epithelium
implanted into experimentally induced abscesses could
form cysts. However, the relevance of these experiments
is uncertain, since the abscesses were induced in the skin
of experimental rats, and cysts only developed in 2 of 16
animals (6%). In addition, it is known that implanted epi-
thelium may cause cysts even in the absence of infection
or abscess formation. Nevertheless, we have seen cases of
abscess formation in periapical granulomas where the
abscess cavity has become encased in epithelium to form
a cyst filled with PMNs (Figure  3.10). This supports the
abscess theory, but not to the exclusion of the other pos-
sible mechanisms.
It seems, therefore, that there is little difference between
the three proposed mechanisms  –  cyst formation occurs
due to a ‘walling-­off’ of inflamed connective tissue by a
process of epithelial proliferation similar to healing at an
epithelial surface. This is due to the innate property of epi-
thelium to form an external protective integument. The
cyst lumen therefore represents the external environment,
and in the case of a pocket or bay cyst (see later in this
chapter) is continuous with the outside through the root
canal. All three theories are thus tenable and not mutually
Figure 3.10  A periapical granuloma at the apex of a molar
tooth root. There is a central focal accumulation of
polymorphonuclear leukocytes that has become surrounded by
epithelium (inset).
­Pathogenesi  33
exclusive. There is good observational or experimental evi-
dence for each but, conversely, there is little evidence to
refute any of them.
Growth and Enlargement of the Radicular Cyst
Role of Hydrostatic Pressure
The third phase in the pathogenesis of the radicular cyst is
its growth and enlargement, which must involve a mecha-
nism for expansion and for resorption of alveolar bone.
Almost without exception, radicular cysts, especially when
small, are seen as round or spherical radiolucencies on
radiographs and on 3D imaging (CT or CBCT). This implies
that growth of the cyst is regular and centripetal, and it is
widely accepted that hydrostatic pressure, due to osmosis,
provides the slow and evenly distributed forces necessary
to achieve this growth pattern. This was first noted by
Warwick James in 1926 in an address to the Royal Society
of Medicine. He also reported that he had measured the
increased pressure in cysts and was probably the first to
suggest that ‘The increase in tension may be partly due to
osmosis’ (Warwick James 1926). (Many of these very early
papers are freely available online and are recommend for
their clarity, insight, and the quality of the scientific
observations.) The evidence for this was provided by early
experiments carried out by Paul Toller, more than half a
century ago, which have never been repeated or bettered
(Toller 1948, 1966b, 1967, 1970a, 1970b). In his first paper,
Toller noted that early surgeons had observed that when
opened, jaw cysts appeared to be under pressure, and that
marsupialisation checked further growth and led to a
reduction in size of the lesions (Toller  1948). He quoted
Potts, who in 1927 had noted that cysts displaced the roots
of teeth ‘as if by pressure’. This led to his experiments to
measure the hydrostatic pressure in jaw cysts. Using a can-
nula and a manometer, he showed that the intracystic pres-
sure in radicular and dentigerous cysts averaged 65–70 cm
of water, which was considerably higher than capillary
blood pressure, which was estimated to be lower than
10 cm of water (Toller  1948). In the same paper, he sug-
gested that this increased pressure was a result of ‘osmotic
tension’ and then went on to test whether the cyst lining
acted as a semi-­permeable membrane. He used freshly
­dissected walls from radicular cysts and clamped them
between two cylinders of Ringer’s solution with 5% albu-
min added to one side. In all cases fluid passed through the
cyst wall towards the albumin, showing that the wall acted
as a semi-­permeable membrane.
In later studies, Toller (1970b) showed that the mean
osmolality of the fluid from 21 apical and residual cysts
was 290 ± 14.93 mOsm and was greater than the mean
serum osmolality of 279 ± 4.68 mOsm (P < 0.01). Lytic
34 Radicular Cyst
products of the epithelial and inflammatory cells in the
cyst cavity provided the great numbers of smaller mole-
cules that raised the osmotic pressure of the cyst fluid.
Toller believed that the upper limit of permeability in most
cysts was close to the molecular size of albumin (molecular
weight 69 kDa) and that particles of larger size would find
difficulty in diffusing across a cyst lining. These findings
were confirmed by Skaug (1976a), who conducted similar
experiments and showed that the intracystic pressure
ranged from 25 to 66 mmHg and that these pressures were
restored 3–7 days after aspiration, suggesting that there was
constant movement of fluid into the cyst lumen.
This pioneering work on the role of hydrostatic pressure
in the growth of odontogenic cysts was mostly undertaken
during the 1970s, but it has not been superseded or refuted
by more contemporary experiments. Nair (1998, 2004) has
suggested that osmotic pressure as a factor in the develop-
ment of radicular cysts has been ‘eliminated’. As evidence
for this he cites the fact that the lumen of pocket or bay
cysts is open to the root canal, and cannot therefore sus-
tain an increased internal pressure. He suggests that cyst
growth is sustained by molecular mechanisms. This is
undoubtedly correct – a cascade of biological factors under-
pins the processes of epithelial proliferation, extracellular
matrix destruction, and bone resorption, but there is still
good evidence that there is increased pressure within the
cyst lumen, and that osmosis is the driving force. This does
not exclude other factors, although it should be noted that
even in pocket cysts it is unlikely that the root canal
remains empty and that the lumen is truly open to the oral
cavity. It is also well recognised that release of this pres-
sure, through decompression, has long been and still is a
common and effective form of treatment (Castro-­Núñez
2016). More recently this issue has been re-­evaluated, but
the outcome remains that hydrostatic pressure is still con-
sidered to be of primary importance in the growth of all
cyst types. Kubota et  al. (2004) measured the intracystic
fluid pressure of odontogenic keratocysts, dentigerous
cysts, and radicular cysts. They confirmed the earlier
results of Toller (1970b) and Skaug (1976a), that the pres-
sure was greater than the local blood pressure and that
there were no differences between the three cyst types.
They also measured cyst volume and showed that volume
correlated to the area of the cysts measured on panoramic
radiographs. They correlated the pressure to the areas of the
cysts and found pressures of 337.6 ± 126.0, 258.2 ± 160.9,
and 254 ± 157.3 mmHgcm−2 for keratocysts, dentigerous
cysts, and radicular cysts, respectively. Furthermore, these
authors showed that the intracystic pressure in all cyst
types was inversely correlated to the cyst size. They there-
fore concluded that increased pressure played a pivotal
part in early cyst growth.
Ward et al. (2004) used mathematical modelling to simu-
late odontogenic cyst growth. They assumed a spherical
cyst lined by a semi-­permeable membrane and with a
­central osmotic pressure as a result of accumulation of
degraded cellular material. The model supported the con-
clusions of the early experimental work, that osmotic pres-
sure played an important part in cyst growth. Interestingly,
the model also confirmed the findings of Kubota et  al.
(2004), and suggested that as the cyst became larger,
osmotic pressure played a lesser part and cell proliferation
became more important.
Osmotic pressure must be maintained by a high concen-
tration of soluble proteins in the cyst fluid. Electrophoretic
studies (Toller and Holborow 1969; Toller 1970a) demon-
strated that radicular cyst fluids contained small molecular-­
sized albumin and β1-­globulin in quantities comparable
with the patient’s serum, but had fewer, if any, of the larger
protein molecules. α-­and β2-­globulins were greatly dimin-
ished or absent, and γ-­globulins (mainly immunoglobu-
lins) varied greatly in quantity, but were most often found
in inflamed cysts. They showed that more than half display
levels of immunoglobulins much higher than the patient’s
own serum. In 19 cyst fluids in which levels of IgG, IgA,
and IgM were measured independently, all three were sig-
nificantly raised in most of the non-­keratinising cysts.
Immunofluorescent staining showed that lymphoid cell
aggregates in the walls of radicular cysts often included
numerous plasma cells.
Skaug (1973,  1974,  1976b,  1977) confirmed that fluid
from non-­keratinising jaw cysts contained high concen-
trations of proteins, including immunoglobulins, but
supported the view that accumulation of cyst fluid
resulted essentially from inadequate lymphatic drainage
of the cyst cavity. He suggested that plasma protein exu-
date and hyaluronic acid, as well as the products of cell
breakdown, contributed to the high osmotic pressure of
the cyst fluid.
These data suggest that the accumulation of proteins in
the cyst lumen is a combination of a serum exudate, an
inflammatory exudate, and breakdown products of cells,
including luminal epithelial cells and inflammatory cells.
It is likely therefore that the luminal pressure, necessary
for cyst expansion, is greatest when the cyst is most
inflamed, at earlier stages of development. As a cyst gets
larger and matures, inflammation may subside, the rate of
growth will slow, and a state of equilibrium may be reached.
This is supported by the study of Kubota et al. (2004) and
the model proposed by Ward et al. (2004), who both show
that pressure and the rate of growth decrease with size of
the lesion.
Although osmotic pressure may provide the stimulus for
expansion, it does not operate alone and, as mentioned

above, a complex cascade of molecular events is responsi-
ble for growth. Growth must be accompanied by further
epithelial proliferation, and by degradation of adjacent
connective tissues and bone resorption.
Epithelial Proliferation
The stimuli for epithelial proliferation have been discussed
previously, but in an established cyst LPS plays a less
important role, and epithelial growth is sustained by
cytokines and growth factors resulting from the inflamma-
tory response (Table  3.2) (Bernardini et  al.  2015; Silva
et al. 2007; Lin et al. 2007; Nair 2004). However, as the cyst
matures and inflammation subsides, the rate of cell prolif-
eration may be relatively low. Soluk ­Tekkeşın et al. (2012a)
showed that only about 1.0% of cells were positive for
Ki-­67 in the epithelial lining of radicular cysts, compared
to 2.0% or more in odontogenic keratocysts. They also
found that radicular cysts showed higher levels of the pro-­
apoptotic protein Bax and low levels of bcl-­2, suggesting
that low levels of proliferation are accompanied by high
levels of apoptosis. Others have identified apoptotic mark-
ers in radicular cysts and have suggested that this contrib-
utes to their slow growth (Loreto et al. 2013). As the cyst
continues to expand, this slow proliferation and high levels
of apoptosis probably lead to the thinning of the epithelial
lining that is seen in long-­standing and residual cysts
(Figure 3.11).
Figure 3.11  A long-­standing radicular cyst. The cyst wall has
become fibrous with little inflammation and the epithelial
lining is relatively thin and regular. Note the considerable
cellular and proteinaceous debris in the lumen (top left).
­Pathogenesi  35
Degradation of the Connective Tissues
and Bone Resorption
The next crucial element of cyst growth is degradation of
the connective tissues. Among the most important and
widely studied factors are the matrix metalloproteinases
(MMPs). These are a large family of calcium-­dependent
and zinc-­containing proteases, capable of degrading a wide
range of extracellular matrix proteins. A number of studies
have shown expression of MMPs in odontogenic cysts,
including the gelatinases (MMP-­2 and MMP-­9; Teronen
et  al.  1995a; Kubota et  al.  2000; D’addazio et  al.  2014;
Alvares et al. 2017; Andrade et al. 2017) and collagenases
(MMP-­1, MMP-­8, and MMP-­13; Teronen et al. 1995b; Lin
et  al.  1997; Wahlgren et  al.  2001; D’addazio et  al.  2014;
Andrade et al. 2017), suggesting a role for these enzymes in
cyst growth and development. Furthermore, MMP activity
increases with the intensity of inflammation and is often
more prominent in periapical granulomas than in estab-
lished cysts (Lin et al. 1997; Andrade et al. 2017). In keep-
ing with this, inflammatory cytokines, especially IL-­1,
up-­regulate active MMP-­9  in odontogenic cysts (Kubota
et al. 2000) and increased numbers of mast cells are associ-
ated with MMP activation in odontogenic cysts (Teronen
et  al.  1996; Rodini et  al.  2008; Andrade et  al.  2017).
Inflammation in radicular cysts is also associated with
secretion of neutrophil collagenase (MMP-­8) and with
increased expression of plasminogen activator (Tsai et al.
2004), which indirectly forms plasmin that may also acti-
vate MMPs.
All odontogenic cysts are encased in the bone of the jaws,
and therefore any expansion must be associated with bone
resorption. Normal bone undergoes continuous remodel-
ling controlled by a number of factors, the most important
of which are receptor activator of nuclear factor kappa B
(RANK), its ligand (RANKL), and osteoprotegerin (OPG,
also known as osteoclastogenesis inhibitory factor). These
form the RANKL/RANK/OPG system, which is primarily
responsible for bone homeostasis (Graves et al. 2011; Kular
et  al.  2012). RANK is expressed on the surface of osteo-
clasts and their precursor cells and when bound by
RANKL promotes osteoclast formation and maturation.
OPG secreted by osteoblasts acts as a decoy receptor and
binds RANKL to prevent activation by RANK. RANKL is
primarily cell bound on the surface of osteoblasts and in
normal bone osteoblast–osteoclast interactions is the main
method of bone turnover regulation. In pathological condi-
tions, however, RANKL may be secreted by osteoblasts and
a number of other cell types, including Th1 lymphocytes,
endothelial cells, and epithelial cells, and may function as
a soluble receptor. It should also be noted that RANKL is
the only cytokine that can stimulate osteoclastogenesis,
although a number of other factors support recruitment of
36 Radicular Cyst
osteoclast precursors, or promote osteoclast maturation
and activation (Table 3.2).
Perturbation of the RANKL/RANK/OPG system is
involved in all pathological conditions associated with
bone resorption, and many studies have now provided evi-
dence for its role in increased osteoclast activity in many
odontogenic lesions, including radicular cysts (Tay et  al.
2004; Menezes et al. 2006; da Silva et al. 2008; de Moraes
et al. 2011; Graves et al. 2011; Soluk ­Tekkaşin et al. 2011;
Belibasakis et al. 2013).
Tay et  al. (2004) were the first to demonstrate that
RANKL was expressed in osteolytic lesions of the jaws,
including radicular cysts. RANKL was expressed in the
fibrous wall of radicular cysts, and its association with oste-
oclast recruitment was confirmed by the demonstration of
tartrate-­resistant acid phosphatase (TRAP) and calcitonin-­
receptor positive osteoclasts adjacent to the RANKL-­
positive cells. In a more detailed analysis, Menezes et  al.
(2006) confirmed these findings, but were also able to dem-
onstrate that RANKL and OPG were expressed by a range
of cell types, including PMNs, lymphocytes, macrophages,
endothelial cells, and the epithelial lining of radicular
cysts. They found that RANKL was more highly expressed
than OPG and that expression was greater in cysts than
granulomas. Other studies have shown similar levels of
expression, but have also shown, as would be expected,
that RANKL expression is not specific to radicular cysts
and is also found at similar or even greater levels in denti-
gerous cysts, odontogenic keratocysts, and ameloblastomas
(Tay et al. 2004; Menezes et al. 2006; de Moraes et al. 2011;
Soluk ­Tekkaşin et  al.  2011). It is likely that the level of
expression at any moment in time will be related to the
degree of ‘maturation’ of the cyst or to the extent of inflam-
mation. Kawashima et  al. (2007) studied the kinetics of
RANKL, RANK, and OPG expression in experimentally
induced periapical lesions in rats. They showed that all
three factors peaked at between two and three weeks, but
that the greatest increase was in RANKL, with the highest
RANKL/OPG ratios at this time. They also found that
RANKL was expressed in a range of cell types, but these
were close to the alveolar bone and were associated with
activated osteoclasts. The up-­regulation of the RANKL/
RANK/OPG system also correlated to increased expression
of pro-­inflammatory cytokines, known to be able to acti-
vate RANKL, including IL-­1α and IL-­1β. Similar data have
been presented in a number of subsequent studies (reviewed
in da Silva et  al.  2008; Graves et  al.  2011; Belibasakis
et al. 2013), confirming the role of inflammatory cytokines
and the close association between the inflammatory
response and bone resorption.
The most important cytokines involved in the process are
indicated in Table  3.2, and include IL-­1α (which was
originally called osteoclast-­activating factor, OAF), IL-­6,
and TNF-­α. A range of chemokines are also responsible for
chemotaxis of osteoclast precursors and differentiation of
osteoclasts, including CXCL8/IL-­8, which has been men-
tioned previously as an important initiator of the process,
since it is up-­regulated by LPS and also chemotactic to
PMNs. Prostaglandins have also been shown to be impor-
tant mediators of bone remodelling and may act to stimu-
late both bone deposition and resorption. There are
a  number of prostaglandins, but PGE2 is particularly
important in bone resorption, since it stimulates expres-
sion of RANKL and inhibits OPG on osteoblasts (Blackwell
et al. 2010). Early studies by Harris and his research group
(Harris and Goldhaber 1973; Harris et al. 1973; Harris 1978;
Meghji et al. 1989) were the first to demonstrate that cul-
tures of cyst walls had potent bone-­resorbing activity, and
identified prostaglandins as a key factor. Matejka et  al.
(1985a,b, 1986) confirmed these findings and also demon-
strated that the granulation tissue and the inflammatory
cells in the wall of radicular cysts were the main source
of  PGE2. Further studies from Harris’s group (Bando
et  al.  1993; Meghji et  al.  1996) reinforced these findings
and also showed that IL-­1 and IL-­6 were the predominant
cytokines with bone-­resorbing activities. In immunocyto-
chemical studies, Bando et  al. (1993) showed that these
cytokines appeared to be synthesised primarily by the epi-
thelial cells of the cyst lining. Kusumi et  al. (2004) also
showed that IL-­6 was the predominant cytokine in radicu-
lar cysts and found evidence for synthesis by fibroblasts in
the cyst wall.
­Histopathology
From the foregoing account of pathogenesis, it is clear that
on histological examination a periapical lesion may show a
wide variety of features. Over 100 years ago Thoma (1917)
described five types of lesion that may be encountered
in  association with a non-­vital tooth. To paraphrase his
descriptions into contemporary terminology, the five lesions
were periapical granuloma, periapical abscess, periapical
granuloma with proliferating epithelium, periapical gran-
uloma with early cyst formation, and radicular cyst.
However, we should not regard these as individual lesions,
but as a continuum of changes that reflect the pathogenic
pathway, with a fully developed cyst as the end result.
Some have suggested that a diagnosis of a cyst can
only be made after examination of multiple serial sections
to confirm the presence of a true cavity with an epithe-
lial  lining (Simon  1980; Nair et  al.  1996; Ricucci and
Bergenholtz 2004), but this is not practical or sustainable
in routine clinical practice. The diagnostic histopathologist

rarely receives an intact specimen, or a specimen still in
continuity with the offending root apex. This is because a
periapical lesion is often surgically removed during an api-
cectomy operation, where the apex of the tooth and associ-
ated soft tissue are removed and a filling material is placed
in the root canal, thus enabling preservation and restora-
tion of the affected tooth. Therefore, the pathologist often
receives the lesion as a fragmented or irregular curettage
specimen from which the diagnosis of a cyst must be
deduced, in the context of the orientation of the tissues and
the clinical and radiological findings. An intact specimen
may be a spherical or ovoid cystic mass, but often they are
irregular and collapsed. Lesions are usually 10–15 mm in
diameter and rarely exceed 30 mm. The walls vary from
extremely thin to a thickness of about 5 mm. As with all
cystic lesions, it is important to examine the inner surface
of the cyst. This may be smooth or corrugated, but mural
nodules or thickenings may be seen, which often represent
accumulations of cholesterol or hyaline (Rushton) bodies
projecting into the lumen. The fluid contents are usually
watery and brown from the breakdown of blood, but when
cholesterol crystals are present they impart a shimmering
gold or straw colour. Pathologists must also recall that a
radicular cyst is always associated with a non-­vital tooth. If
this is not the case, then an alternative diagnosis must be
sought, usually needing careful correlation with clinical
and radiological findings.
On histological examination, the key diagnostic criterion
is to identify a variably inflamed fibrous cyst wall lined
wholly or in part by stratified squamous epithelium
(Figure 3.12). The epithelial lining may be discontinuous
and ranges in thickness from 1 to 50 cell layers. The major-
ity are 6–20 cell layers thick. The nature of the lining may
Figure 3.12  Radicular cyst. The cyst has a thick fibrous wall.
The lumen is lined by proliferating and arcading epithelium.
­Histopatholog  37
depend on the age or stage of development of the cyst, or
on the intensity of the inflammation. In early cysts, the epi-
thelial lining may be proliferative and show a characteristic
arcading with an intense associated inflammatory process
(Figure  3.12), but as the cyst enlarges the inflammation
may subside and the lining becomes thin and regular, with
a certain degree of differentiation to resemble a simple
non-­keratinised stratified squamous epithelium. In well-­
developed cysts, the lining may vary. At sites of heavy
inflammation, often adjacent to the tooth root, the epithe-
lium may be proliferative and thickened, but away from the
tooth the wall is often less inflamed and the lining becomes
thin and regular (Figure  3.11). Long-­standing cysts and
residual cysts in particular may be lined by a thin, regular
lining of stratified squamous epithelium (Figure 3.13).
The inflammatory cell infiltrate in the cyst wall and the
epithelial lining may vary considerably, since it reflects
a  single moment of the pathogenic pathway caught in a
histological section. Thus any of the inflammatory cells
involved in the development of the lesion may be seen.
In  early lesions the proliferating epithelial lining usually
contains many PMNs, whereas the adjacent fibrous cap-
sule is infiltrated mainly by chronic inflammatory cells
(Shear  1963a,  1964; Cohen  1979; Matthews and Browne
1987). The proliferating epithelial lining shows a consider-
able degree of inter-­ and intraepithelial oedema or
spongiosis.
The cyst wall is essentially composed of granulation
­tissue at various stages of maturation, depending on the
age of the lesion and on the proximity to the source of the
inflammation. The wall is therefore often zoned, with
heavily inflamed granulation tissue adjacent to the epithe-
lial lining, less inflamed maturing granulation tissue cen-
trally, and collagenous fibrous tissue at the peripheral
margin adjacent to the bone (Figure 3.12). Inflammation is
also more prominent adjacent to the root apex  –  where
Figure 3.13  Quiescent epithelium lining a mature, long-­
standing residual cyst.
38 Radicular Cyst
accumulations of polymorphs may be seen, even in long-­
standing lesions. The predominant cell population, how-
ever, is of chronic inflammatory cells, mostly lymphocytes;
plasma cells are also seen, and on occasion may predomi-
nate or may form dense focal accumulations.
Remnants of odontogenic epithelium and occasional sat-
ellite microcysts may be found in the fibrous capsule and
there have been reports of examples where epithelial pro-
liferation is so extensive that it resembles squamous odon-
togenic tumour (Wright  1979; Simon and Jensen  1985;
Unal et al. 1987; Chrcanovic and Gomez 2018a). These pro-
liferations are reactive in nature and should not be inter-
preted as a co-­existent neoplasm. The behaviour is that of
the cyst of origin and no further treatment is required if
this observation is made during histological examination
of the cyst wall (Chrcanovic and Gomez 2018a).
Some cyst walls are markedly vascular. Haemorrhage is
invariably present and haemosiderin deposits are seen in
many specimens (Shear  1963c). Calcifications of various
kinds may also be seen. Dystrophic calcifications associated
with necrotic and degenerative material in the cyst lumen
are a particular feature of residual cysts that  have been
present for a long time (High and Hirschmann  1986).
Hyaline bodies may also calcify either within the epithelial
lining or among deposits that have extruded into the lumen
or into the wall. In curettage specimens, trabeculae of reac-
tive woven bone and occasionally lamellar bone are often
found at the periphery of the lesion. Occasionally a well-­
formed rim of woven bone may be seen.
Although well-­formed colonies of actinomycosis are well
described in case reports, this is a rare finding. Hirschberg
et al. (2003) found colonies of Actinomyces in only 17 of 936
(1.8%) periapical lesions examined, 4 of which were radicu-
lar cysts. Nair (2006) found a similar frequency in a review
of the literature, and postulated that established colonies
of Actinomyces may persist and be an important cause
of  endodontic failure and persistent or recurrent lesions.
Ricucci and Siqueira (2008), however, found no evidence
for this and suggested that provided the root canal was
properly cleaned, the presence of actinomycosis was not
associated with treatment failure.
Cellular and Metaplastic Changes
Radicular cysts may show variable histological features
due to reactive changes and to metaplastic changes of
the lining epithelium. These additional features are charac-
teristic and occasionally assist in diagnosis (Table  3.3,
Figure 3.14).
Keratin formation may occasionally be seen in radicu-
lar  cysts, but when present it affects only part of the cyst
wall (Figure 3.14a). Browne and Smith (1991) stated that 2%
Table 3.3  Characteristic histopathological features found
in radicular cysts, with their approximate frequency (see text
for explanation).
Feature Frequency (%)
Keratinisation 2
Ciliated cells 10
Hyaline bodies 10
Foamy histiocytes 10
Mucous cells 20
Cholesterol 30
of radicular cysts may show some keratinisation and that
orthokeratin with evidence of a granular cell layer is most
common. More recently, Maheswaran et al. (2014) analysed
38 radicular cysts and 9 residual cysts using Papanicolaou
stain and found evidence of keratinisation in 12 (31.6%)
radicular cysts and 6 (66.7%) residual cysts. Orthokeratin
was only found in 1 residual cyst and only 2 cysts showed
typical parakeratin. In all other cases the keratin was
described as focal. However, little detail was given and the
findings were not illustrated. We interpret this to mean that
the Papanicolaou technique revealed occasional superficial
orange-­stained cells. Although this may suggest early
keratinisation, it should be noted that this technique is pri-
marily a cytological stain and may not be as reliable as a
routine haematoxylin and eosin (H&E) stain for identifica-
tion of keratin in histological sections (Rao et  al.  2015).
A more cautious interpretation of Maheswaran et al.’s data
may suggest that only three of their cysts showed clearly
identifiable keratinisation (6.4%). Our experience would
support this, since we rarely see true keratinisation in radic-
ular cysts, and when present it affects only a small section
of the lining. This, and attention to the clinical and radio-
logical findings (association with a non-­vital tooth), should
prevent the lesion being misinterpreted as odontogenic
keratocyst. Also, when present the parakeratin seen in a
radicular cyst is different morphologically from that seen
in keratocysts, since it lacks the typical corrugated surface
and affects only a small portion of the lesion.
Metaplastic changes, in the form of mucous cells or
­ciliated cells, are frequently found in the epithelial linings
of radicular cysts (Table  3.3; Shear  1960b; Browne  1972;
Browne and Smith  1991; Slabbert et  al.  1995; Takeda
et al. 2005; Tsesis et al. 2016). Mucous cells are seen in the
surface layer of the stratified squamous epithelial lining,
either as a continuous row (Figure  3.14d) or as scattered
cells (Figure  3.14c). Ciliated cells may also be seen, but
are  always found in association with mucous cells and
together they sometimes form quite well-­developed

(a)
(c)
Figure 3.14  Cellular changes in the lining of radicular cysts. (a) A portion of the lining showing a focal area of orthokeratinisation.
(b) Respiratory-­type epithelium with cilia and occasional mucous (goblet) cells. (c, d) Mucous cells in the surface layer may be
scattered (c) or may form a continuous row (d).
respiratory-­type (pseudostratified columnar ciliated) epi-
thelium (Figure 3.14b).
Browne (1972) examined 402 radicular cysts and found
mucous cells in 159 (39.6%), but cilia were only found in
3 cases (0.7%). Takeda et al. (2005) found mucous cells in
18% of radicular cysts, and in most cases they were arranged
along the surface of the epithelium, but occasional intraep-
ithelial gland-­like structures were also noted, most often
in  areas where the epithelium was hyperplastic. Browne
(1972) found no difference in frequency of mucous cells
between mandibular and maxillary lesions, but Takeda
et al. (2005) found that they were more common in maxil-
lary lesions (21%) than mandibular lesions (14%). In an
analysis of 711 radicular cysts, Tsesis et  al. (2016) found
mucous cells in 5.3% and 7.4% of mandibular and maxil-
lary lesions, respectively, but this difference was not signifi-
cant. They also found that mucous cells were significantly
more likely to be found in residual (23.5%) than radicular
­Histopatholog  39
(b)
(d)
(5.8%) cysts, and were also more frequent in asymptomatic
cysts and in cysts with well-­demarcated radiographic mar-
gins. This suggests that metaplasia takes time and is more
likely to be encountered in well-­established or older cysts.
This view is supported by the observation of Browne (1972)
that there was an increasing frequency of mucous cells
with age, at the rate of 7% per decade.
Slabbert et  al. (1995) studied 154  mandibular radicular
and residual cysts and found unequivocal mucous meta-
plasia in 15 (10%). In many cases they found that the
mucous cells were associated with vacuolated cells, many
of which were empty, but some contained fine granules or
networks of periodic acid–Schiff (PAS)–positive material.
The authors observed that the vacuolated cells resembled
those described by Fell (1957) in the process of metaplasia
from stratified squamous to ciliated epithelium in explants
of chick embryo skin grown under the influence of excess
vitamin A. By analogy to Fell’s findings, Slabbert et  al.
40 Radicular Cyst
(1995) suggested that the vacuolated cells represented an
intermediate stage in the process of mucous metaplasia.
Takeda et  al. (2005) found similar clear cells and agreed
with Slabbert et al. (1995) that mucous cell differentiation
is a process of metaplasia. This view is also supported by
the fact that mucous cells are found in mandibular lesions.
Some have suggested that an origin from antral mucosa
(see below) may explain mucous cells in radicular cysts.
This may happen on occasion, but the mucous cells in
mandibular lesions are almost certainly explained by true
metaplasia, and provide good evidence for the metaplastic
potential of odontogenic epithelium. Browne (1972) also
found mucous cells in dentigerous cysts and lateral perio-
dontal cysts, with a similar frequency between mandibular
and maxillary lesions.
Cilia are found in radicular cysts with reported frequen-
cies of 0.7% (Browne 1972), 11.4% (Takeda et al. 2005), 4.8%
(Tsesis et  al.  2016), and 8.2% (Ricucci et  al.  2014). In his
careful ultrastructural studies, Nair examined 39 cysts
and  found 3 (7.6%) that were lined by ciliated columnar
epithelium (Nair et al. 2002). All were found in the maxilla
and he suggested that the cyst linings were derived in part
from cell rests of Malassez, but also from antral mucosa.
However, although cilia do appear to be more common in
the maxilla, ciliated epithelium has also been found in
cysts in the anterior and posterior regions of the mandible.
In the study of Takeda et  al. (2005), ciliated cells were
found overall in 11% of radicular cysts, but in 12% and 9%
of maxillary and mandibular lesions, respectively. Tsesis
et  al. (2016) found cilia in 4.8% of 711 cysts, but only in
2 (0.2%) mandibular lesions compared to 32 (8.9%) maxil-
lary lesions. Furthermore, 16 were found in the maxillary
molar regions, 12 in the anterior region, and 4 associated
with premolars. Browne (1972) also found that cilia were
more frequently encountered in the maxilla, with 2 of 3
being of maxillary origin.
Gao et  al. (1988b) and Lu et  al. (2002) investigated
cytokeratin (CK) expression in radicular cysts. Gao et  al.
showed strong CK19 expression in rest cells of Malassez
and in the epithelium of periapical granulomas and radic-
ular cysts, supporting an odontogenic origin for the cyst
lining. As an early change, proliferating epithelium in peri-
apical granulomas also uniformly and strongly expressed
CK14 and subsequently CK13 and CK4. Further epithelial
changes to form a cyst lining were associated with a more
clearly differentiated phenotype of non-­keratinised strati-
fied squamous epithelium expressing CK8 and CK18. Lu
et  al. (2002) confirmed some of these findings and also
showed that most cysts expressed CK8 and CK18, as well as
CK13. Of relevance to the above discussion, they compared
keratin protein and mRNA expression in radicular cysts to
normal nasal and oral epithelium. They showed that a
CK18+/CK8+/CK13– phenotype was only found in nasal
epithelium. Only three cysts showed this phenotype and
all  three were large maxillary lesions protruding into the
maxillary sinus. They concluded that occasional maxillary
radicular cysts may not be odontogenic in origin, but that
their epithelium may derive from nasal or antral respira-
tory mucosa.
From these studies, it seems certain that some maxillary
cysts may derive at least part of their epithelial lining from
the antral mucosa, and this may explain the occurrence of
mucous and ciliated cells or respiratory-­type epithelium
found in maxillary cysts. Such an occurrence could also be
deduced from the radiological appearance of large maxil-
lary cysts, which often clearly protrude into the maxillary
sinus. However, the presence of secretory and ciliated epi-
thelium in mandibular radicular cysts also confirms that
mucous and ciliated cells may arise as a result of metaplasia.
Hyaline Bodies
In approximately 10% of radicular cysts, hyaline bodies are
found in the epithelial linings (Figure 3.15). Although ini-
tially noted by Dewey in 1918, they were first described in
detail by Rushton (1955) and are often referred to as
Rushton bodies. They measure up to about 0.1 mm and are
described as having two morphological patterns. The first
pattern appears like linear, straight, or curved rods, some-
times with a ‘hairpin’ shape (Figure  3.15b). These may
have a pale centre and a darker eosinophilic or basophilic
periphery. Serial sections, however, will show that these
are not actually rods, but are folded sheets. The second pat-
tern is of circular or polycyclic bodies (Figure 3.15), which
often have a clear or pale centre, surrounded by concentric
laminations that are variably eosinophilic or basophilic.
Both patterns may exist together, as can be seen in
Figure 3.15. Hyaline bodies are brittle and frequently frac-
ture during histological processing, so that only small frag-
ments may be seen. Occasionally they may form masses
that protrude into the cyst lumen (Figure 3.15a), but only
very rarely are they seen in the fibrous capsule. The pres-
ence of hyaline bodies may be suspected if, on examination
of the gross specimen, the pathologist sees small, smooth,
white, dome-­shaped swellings of the epithelial surface pro-
truding into the cyst cavity.
Although they are typically seen in radicular cysts, they
may also be encountered in dentigerous cysts or odonto-
genic keratocysts, but are always associated with areas of
inflammation. Lam and Chan (2000) reported hyaline
­bodies in 7% of a series of 69 odontogenic keratocysts and
Lin et al. (2013) found them in 11% of dentigerous cysts.
Ide et  al. (1996) reported an unusual glandular odonto-
genic cyst with hyaline bodies, and Takeda et  al. (1985)

(a) (b)
Figure 3.15  Hyaline bodies in the epithelial lining of a radicular cyst. (a) The bodies accumulate in the epithelial lining and form
nodules that protrude into the lumen. (b) The bodies are eosinophilic and form circular, folded, and curved ‘rod’ shapes.
described their presence in a plexiform ameloblastoma.
They are, however, specific to odontogenic epithelium and
have not been reported in non-­odontogenic cysts.
Occasionally similar structures may be found associated
with epithelial rests in dental follicles.
Hyaline bodies are intriguing and enigmatic, but they
have little diagnostic or prognostic significance. More than
100 years after they were first noted, the origin and patho-
genesis of these bodies is still debated and no consensus
has been reached. There have been two competing theories
of their origin: first, that they derive from epithelium; and
second, that they are of haematogenous origin. Rushton
(1955) believed that the hyaline bodies resembled, in
appearance and the liability to fracture, the keratinised sec-
ondary enamel cuticle of Gottlieb. Wertheimer (Wertheimer
et  al.  1962; Wertheimer  1966) directly compared enamel
cuticle and hyaline bodies and showed similar staining
for a number of histochemical stains, also concluding that
the bodies represented a keratin-­like epithelial product
equivalent to dental cuticle.
A number of other studies, which have included electron
microscopy and X-­ray microanalysis, have also supported
an epithelial origin (Allison  1974,  1977a,  1977b; Jensen
and Erickson  1974; Morgan and Johnson  1974; Morgan
and Heyden 1975; Rühl et al. 1989; Philippou et al. 1990).
Morgan and Johnson (1974) also found cell debris and par-
ticulate matter and concluded that the bodies are a secre-
tory product of odontogenic epithelium that is deposited
on a hard surface in a manner analogous to the formation
of dental cuticle on the unerupted portions of enamel
­surfaces. X-­ray microanalysis and scanning electron
­Histopatholog  41
microscopic studies (Rühl et al. 1989; Philippou et al. 1990)
also found that the bodies were associated with cell debris,
suggesting that foreign material may irritate the epithe-
lium to form a cuticle-­like substance. These findings are
consistent with the observation that hyaline bodies are
always associated with areas of chronic inflammation. In a
rarely cited paper dating back to 1943, Bauer described the
histology of  the enamel cuticle associated with an
unerupted third molar overlying the carious roots of the
second molar (Bauer 1943). There was a periapical granu-
loma containing proliferating epithelium that was in conti-
nuity with the reduced enamel epithelium of the unerupted
tooth. Within the epithelium Bauer described ‘bands, rods,
rings, and spherically shaped bodies’, which were continu-
ous with the primary enamel cuticle of the unerupted tooth
and with the ‘dental cuticle’ surrounding the cementum of
the decayed roots. He referred to these structures as ‘horny
hyaline-­like bodies’ and his illustrations show structures
identical to what we now regard as hyaline bodies. Bauer
also noted that these bodies were associated with prolifer-
ating epithelial strands that were a ‘product’ of chronic
inflammation. These simple, but careful, observations are
consistent with the more detailed later studies described
above and provide good evidence that hyaline bodies can
derive from odontogenic epithelium and are similar to
enamel cuticle.
Others, however, have believed that hyaline bodies are
of  haematogenous origin (Bouyssou and Guilhem  1965;
Sedano and Gorlin  1968; El-­Labban  1979). Although the
mechanism is not clear, these studies suggest that the
­bodies derive from thrombi or degenerate red blood cells
42 Radicular Cyst
within vessels that have become entrapped in the prolifer-
ating epithelial lining of the cyst. Browne and Matthews
(1985) tested this hypothesis using immunohistochemistry
to stain cysts for keratin, factor VIII-­related antigen, hae-
moglobin, and fibrinogen. The hyaline bodies were nega-
tive for all these antigens, but fibrinogen was detected in
the cores of some circular and polycyclic forms. Browne
and Matthews concluded that hyaline bodies were not
keratinous in nature, nor did they arise from erythrocytes
or capillary endothelium. They tentatively proposed that
the presence of fibrinogen in the cores of some hyaline
bodies could support the notion of a haematogenous origin.
Although we agree that the circular or polycyclic forms
are sometimes of a morphology that suggests a transversely
sectioned blood vessel, there are some puzzling features
about their distribution if they were of vascular or haemo-
togenous origin. For one thing, they are often seen in epi-
thelium overlying connective tissue devoid of any blood
vessels. For another, they are very rarely found in the
fibrous capsules, and we have never seen them in this situ-
ation. Third, if their pathogenesis is as described, it is most
surprising that they are only found in lesions of odonto-
genic origin.
More recently a novel solution to the debate has been
suggested. Sakamoto et  al. (2012) proposed that hyaline
bodies are of both haematogenous and epithelial origin.
They carried out immunohistochemistry for anti-­hair kera-
tin (CK40; AE13), CK17, CK19, and anti-­haemoglobin
alpha chain on 10 cysts containing hyaline bodies. They
found that hair keratin and haemoglobin alpha chain were
specifically expressed in all the hyaline bodies, but not
in adjacent epithelium. Hyaline bodies were also positive
for orcein and Congo red and occasionally for Prussian
blue. Sakamoto et al. suggested that dysregulated epithelial
differentiation results in the formation of hair keratin,
and that keratins and haemoglobin released from dead epi-
thelial cells and red blood cells may aggregate to form hya-
line bodies. They further proposed that these aggregates
undergo β-­sheet conversion to form Congo red–positive
amyloid, and that hyaline bodies are therefore a new and
novel amyloidogenic protein. This unifying hypothesis was
further developed by Sarode et  al. (2016), who proposed
that inflammation and osmotic pressure drive an inflam-
matory exudate and red blood cells into the epithelium.
Degenerated red cells and accumulations of fibrinous exu-
date may then calcify and initiate production of enamel
cuticle. This is an attractive hypothesis and is founded on
the previous observations described, in particular that hya-
line body production is analogous to secretion of cuticle
onto a surface. It is also known that hair keratin may be a
component of enamel (Duverger et al. 2016). Further stud-
ies of keratins and enamel proteins in these structures may
allow this hypothesis to be properly tested and provide
­further clues to the origin of hyaline bodies.
Accumulation of Cholesterol
Deposition of cholesterol is a characteristic feature of long-­
standing chronic inflammation at any site and is due to
deposition and crystallisation of lipids, probably derived
from degenerating cell walls. It is, for example, a ­prominent
feature in atherosclerotic plaques, arthritis, appendicitis,
and cholecystitis.
Deposits of cholesterol crystals are found in many radic-
ular cysts, but by no means in all. The reported frequency
varies from study to study and appears to be between about
10% and 45%. In one of the largest studies, Browne (1971b)
examined 402 radicular cysts and found evidence of
­cholesterol deposition in 43.5%. In other studies, the fre-
quencies have been 9.4% (Lin et  al.  2010), 28.5%
(Shear 1963b), and 30% (Trott and Esty 1972). However, it
is likely that if entire cyst linings were examined instead of
random sections, the frequency would be higher. Browne
(1971b) showed that there was a statistically significant
correlation (P < 0.01) between the presence of cholesterol
and haemosiderin, and suggested that the main source of
cholesterol was from disintegrating red blood cells in a
form that readily crystallises in the tissues. This was con-
firmed by Arwill and Heyden (1973), who showed that the
crystals may form in congested capillaries in the inflamed
areas as they appear to be enveloped by endothelial cells.
Trott et  al. (1973) also found a close correlation between
the occurrence of cholesterol and haemosiderin-­
containing macrophages as well as free haemosiderin in
the tissues. However, their regression analysis showed that
only 35% of the cholesterol may be formed from this asso-
ciation, suggesting that accumulation of cholesterol may
also derive from degenerating lymphocytes, plasma cells,
and macrophages.
Cholesterol crystals are small, rectangular or rhomboid
plate-­like crystals, which characteristically have one cor-
ner  notched or cut off. They can be visualised in fresh
smears of fluids or cyst contents, where they are strongly
birefringent, producing an array of colours from red/
orange to pale blue. Once the cholesterol crystals have been
deposited in the tissues, they behave as foreign bodies and
excite a foreign body giant cell reaction. They cannot, how-
ever, be seen in routine histological sections, because they
are dissolved out of the tissues by the solvents used during
processing. This leaves characteristic cholesterol clefts, sur-
rounded by fibrous tissue and dense aggregations of multi-
nucleate giant cells (Figure  3.16b). In radicular cysts the
cholesterol masses form in the fibrous wall and are associ-
ated with heavily inflamed granulation tissue, and are
 ­Histopatholog  43

(a) (b)

Figure 3.16  Cholesterol clefts in a radicular cyst. (a) An accumulation of cholesterol has formed a nodule that ruptures the cyst
lining and protrudes into the lumen. (b) Multinucleate foreign body giant cells on the surface of cholesterol clefts in the wall of a
radicular cyst.

sometimes referred to as ‘cholesterol granulomas’. These

masses are often extruded from the fibrous wall through
the epithelial lining into the cyst lumen and appear mac-
roscopically and microscopically as a ‘mural nodule’
(Figure  3.16a). Once the entire mass has passed into the
cavity, the epithelial breach may heal and cholesterol crys-
tals may lie free in the cyst lumen (Shear 1963b).
Occasionally isolated or scattered clefts may be seen
within the cyst wall. High-­power examination shows that
each cleft is surrounded by one or more large multinucle-
ated giant cell (Figure 3.16b), an indication that the crys-
tals are recognised as foreign bodies. The persistence of
cholesterol crystals in the tissues and the accumulation of
macrophages may be an important cause of persistent
chronic inflammation, and is thought to be a major factor
in the persistence of non-­healing periapical lesions after
Figure 3.17  A focal accumulation of plump, foamy histiocytes
endodontic treatment of the offending tooth (Nair  2006).
in the wall of a radicular cyst.
Slutzky-­Goldberg et  al. (2013) compared the incidence
of  cholesterol in periapical lesions in young and elderly
patients, and found that the elderly (over 60 years) had a radicular cysts and noted a correlation with cholesterol and
significantly higher incidence of cholesterol than young also with accumulation of foamy histiocytes. Haemosiderin
(13–21 years) patients. They suggested that this may be is often found within histiocytes and Lin et al. (2010) found
associated with increasing serum cholesterol with age, and haemosiderin-­laden and foamy histiocytic in 6.0% and
that it may also be a factor in non-­healing of periapical 6.8% of radicular cysts, respectively (Figure 3.17). Buchner
lesions in older age groups. It is equally likely, however, and David (1978) demonstrated the presence of pigmented
that the increased frequency in the elderly is associated cells in 42% of radicular cysts. However, in this study the
with the length of time the lesion, and associated chronic pigment was not haemosiderin, but was identified as lipo-
inflammation, has been present. fuscin. It was found in association with haemosiderin
A number of other features are typically seen in radicu- deposits and cholesterol, and Buchner and David suggested
lar cysts, but these are not specific and are also associated it was also associated with the inflammatory process in the
with long-­standing chronic inflammation. As noted above cyst wall. Lipofuscin is pale yellow-­brown in colour, is posi-
(Browne  1971b), deposition of haemosiderin pigment is tive with PAS stain, negative for Perls Prussian blue, and
common. Browne (1971b) found haemosiderin in 61.4% of shows a yellow autofluorescence under ultraviolet (UV)
44 Radicular Cyst

light. It can thus be differentiated from haemosiderin,

which is dark brown in colour, PAS negative, and positive
for Perls Prussian blue.
As mentioned above, foamy histiocytes are also com-
monly seen in the walls of radicular cysts (Figure  3.17).
Most often they are scattered or form small focal accumula-
tions in areas of inflammation or are associated with cho-
lesterol clefts. Occasionally, however, sheets of large, pale
foamy histiocytes may be encountered, which appear dis-
concertingly like a xanthogranulomatous reaction.

Residual Cyst
The histopathological features of the residual cyst are simi-
lar to those described above for conventional radicular
cysts. However, because the cause of the cyst has been
removed, residual cysts may progressively become less
inflamed so that eventually the cyst wall is composed of
uninflamed collagenous fibrous tissue (Figures  3.11
and  3.13). The epithelial lining may be thin and regular
and indistinguishable from a developmental cyst, such as a
dentigerous cyst or lateral periodontal cyst. In these cases,
it is important to establish the relationship of the lesion to
the teeth and recall that a residual cyst must arise at a site
of an extracted tooth.

Figure 3.18  A low-­power view of a pocket cyst. The cyst lining

Pocket Cyst (Bay Cyst)
With regard to the relationship between the tooth and the
cyst lining, there is some evidence that there are two distinct
histological types of radicular cyst. Brief mention has already
been made of work by Simon (1980), who found that in
some lesions a cavity may be present that is open to the root
canal and is lined by epithelium that is attached to the root
apex. Simon examined 35 extracted teeth with apical lesions
still attached. Each specimen was decalcified and serial sec-
tioned through the whole block. He found that the majority
of lesions (27 cases: 75.2%) were periapical granulomas and
that 8 (22.9%) of these contained strands of proliferating epi-
thelium without evidence of cyst formation (e.g. see
Figure  3.7). Only 6 cases (17.2%) were diagnosed as cysts.
Three cysts showed an epithelial lining that was attached to
the root apex, so that the root protruded into the cyst lumen,
and the lumen was in direct continuity with the root canal,
forming an open ‘pocket’ (Figure 3.18). Simon (1980) called
these lesions bay cysts. The remaining cysts showed cavities
entirely lined by epithelium with an inflamed fibrous wall,
with no epithelial connection to the root apex. These were
regarded as true cysts. Simon’s data also suggest that cysts
only comprise about 17% of periapical lesions and that bay
cysts and true cysts have an equal frequency. This has been
confirmed in a number of more recent studies that have
is attached to the apex of the tooth (inset). Although in this
plane of section the apical foramen is not visible, it can be seen
that the tooth apex protrudes into the cyst lumen.
shown that pocket cysts comprise about 50% of all periapi-
cal cysts. The actual frequencies reported have been 50.0%
(Simon  1980), 38.5% (Nair et  al.  1996), 56.3% (Ricucci
et al. 2006b), and 52.2% (Ricucci et al. 2020).
In the largest study, Nair et al. (1996) undertook meticu-
lous serial sectioning of 256 periapical lesions and found
that only 39 (15%) were radicular cysts. They also confirmed
Simon’s observations and showed that of the 39 cysts,
24 (61.5%) were true cysts and 15 (38.5%) were pocket cysts.
In further detailed examination of these lesions, Nair
(1998,  2003) showed that in pocket cysts the epithelium
was attached at the root apex, so that the lumen formed an
extension of the root canal, and the intact epithelium acted
as a barrier to seal off the contents of the infected root
canal from the adjacent tissues (Figure  3.18). The cyst
grows through accumulation of debris and necrotic tissue
in the thus-­formed ‘bay’ or ‘pocket’. Simon (1980) and Nair
(1998, 2003) attached considerable clinical significance to
the distinction of the two cyst types and suggested that
pocket cysts were likely to heal after tooth extraction or
endodontic treatment, whereas a true cyst may be

Box 3.4  Histopathology: Key Features
●● The cyst is lined by proliferating non-­keratinised
stratified squamous epithelium
●● In long-­standing and residual cysts, the epithelium
may become thin and regular
●● The cyst wall is composed of inflamed fibrous and
granulation tissue
●● Cholesterol clefts and deposits of haemosiderin
are often seen
●● Hyaline bodies are characteristic, but only seen in
about 10% of lesions
●● Other features include mucous cells, cilia, focal
keratinisation, and accumulation of foamy histiocytes
self-­sustaining and can persist after treatment. From his
data, Nair (1998) suggested that apical true cysts only
account for about 10% of all periapical lesions, and this
may explain the frequency of about 10% of persistent peri-
apical lesions after conventional root canal treatment, and
the low prevalence of residual cysts. Ricucci and
Bergonholtz (2004) consider that the pocket cyst may be
problematic for the endodontist, because the cyst fluid may
be under pressure and may continuously wet the root
canal, making instrumentation and filling difficult.
More recently, however, it has been suggested that true
cysts and pocket cysts do not differ in any clinically signifi-
cant way, and that the management can be the same.
Ricucci et al. (2020) undertook a detailed clinicopathologi-
cal analysis of 11 true cysts and 12 pocket cysts and found
no significant differences in any of the clinical or histologi-
cal features studied, including signs and symptoms, sex,
location, size, or degree of acute inflammation. They also
examined the presence of bacteria in the root canal or the
cyst lumen and found no differences. The authors con-
cluded that there are no clinically important differences
between the two cyst types and that there is no real need to
draw a diagnostic distinction between true cysts and pocket
(bay) cysts. Furthermore, they also found that both pocket
cysts and true cysts were infected, and suggested that there
is little evidence for the idea that true cysts may be self-­
sustainable independent of the infected root canal.
­Malignant Change in Radicular Cysts
Primary intraosseous squamous cell carcinoma is defined
as a central lesion in the jaw bones, which cannot be
­categorised as any other type of carcinoma (Koutlas and
Sloan 2022). To establish the diagnosis, an oral lesion that
has invaded the jaws, or metastatic lesions to the jaw bones,
­Malignant Change in Radicular Cyst  45
must be excluded. Intraosseous carcinomas are derived
from odontogenic epithelium and may arise de novo, with
no identifiable precursor lesion, or may be preceded by an
odontogenic cyst or a benign odontogenic tumour. In a
review of the world literature, Thomas et  al. (2001) were
only able to identify 35 cases of de novo lesions, suggesting
that the majority of intraosseous squamous carcinomas
arise in a pre-­existing lesion and most probably arise in
odontogenic cysts. Eversole et al. (1975) reviewed series of
cases of central squamous cell carcinoma and found that
75% were associated with a cyst lining. In a detailed review
of the literature, Gardner (1969) examined the evidence
presented with each of 63 cases reported during the period
1889–1967 and concluded that 25 (39.7%) fulfilled the crite-
ria for an origin from odontogenic cyst.
Bodner et al. (2011) reviewed 116 cases of primary intra-
osseous squamous cell carcinomas that had arisen in odon-
togenic cysts. Of these, 70 cases (60.3%) were associated
with radicular or residual cysts, 19 (16.4%) with dentiger-
ous cysts, and 16 (13.8%) with an odontogenic keratocyst.
Only 1 lesion was found to be associated with a lateral peri-
odontal cyst and 10 could not be classified. The majority of
cases (92, 79.3%) were found in the mandible and there was
a male : female ratio of 2 : 1.
Before the diagnosis of carcinoma arising from a cyst lin-
ing can be established, a number of alternative possibilities
must be excluded (Bodner et al. 2011; Woolgar et al. 2013;
Koutlas and Sloan  2021). It is possible that a benign cyst
and the carcinoma may have developed independently
adjacent to one another and ultimately fused in some parts.
Careful questioning of the patient and clinical examination
are necessary to exclude the possibility that the neoplasm
arose primarily from the oral mucosa, or that it is a meta-
static deposit in the jaw. A further possibility to be consid-
ered is that the lesion was initially an epithelial neoplasm
that underwent secondary cystic change. To be certain of
the diagnosis, histological evidence of frank squamous cell
carcinoma directly in transition from a typical odontogenic
cyst lining is regarded as the gold standard diagnostic crite-
rion, but in some cases the malignancy may have over-
grown and effaced the precursor lesion. It is also important
not to overinterpret an inflamed or proliferating cyst lining
as malignant. On occasions, the arcading epithelium of a
radicular cyst may give a pseudoepitheliomatous appear-
ance and islands of odontogenic epithelium in the wall are
not uncommon. Attention to the cytology of the islands is
helpful. Often the epithelium is bland and resembles squa-
mous odontogenic tumour rather than the atypical epithe-
lium of malignancy (Parmar et  al.  2011; Chrcanovic and
Gomez 2018a).
Despite the undoubted examples that occur from time to
time, the frequency of neoplastic change is exceptionally
46 Radicular Cyst
rare in relation to the large numbers of cysts that are seen.
There is no evidence, however, that cyst epithelium is at
particular risk and there is therefore no justification for
regarding cysts as pre-­cancerous lesions. The pathogenesis
of malignant change is not known, but some have specu-
lated that it is induced by the long-­standing chronic inflam-
mation (Bodner et  al.  2011; Jain et  al.  2013). This would
explain the higher frequency of malignant change in radic-
ular cysts, and is in keeping with the now well-­established
association between carcinogenesis and inflammation
(Crusz and Balkwill 2015).
­Treatment
Radicular cysts may be removed by conservative surgery
involving simple curettage of the lesion. Often this is carried
out by an apicectomy procedure involving removal of the
cyst and the root apex and sealing of the apical portion of the
root canal. Occasionally the offending tooth may be removed,
but if the cyst is not curetted, then a residual cyst may arise.
Many periapical radiolucencies are treated non-­surgically
by endodontic procedures that remove the necrotic pulp
and disinfect and seal the root canal. In this way, about
95% or more of apical lesions heal or do not progress. In
this case, however, the lesion is not removed for histologi-
cal examination and, as discussed above, the majority will
be periapical granulomas. In this respect, the lesion heals
because the causative root canal infection has been
removed and it is not necessary to make any distinction
between periapical granulomas and cysts, nor between
true cysts and pocket cysts (Ricucci et al. 2020).
Useful analyses or reviews on the non-­surgical treatment
of periapical lesions have been presented by Natkin et al.
(1984), Nair (2003, 2004, 2006), Santos-­Junior et al. (2019),
and Ricucci et  al. (2020), and in systematic reviews by
Sathorn et al. (2005), Torabinejad et al. (2005), and Glynis
et al. (2021).
 47

Inflammatory Collateral Cysts

CHAPTER MENU

Classification and Terminology of Inflammatory Collateral Cysts, 47

Clinical Features, 49
●● Frequency, 49
●● Age,  52
●● Sex, 52
●● Site, 52
●● Clinical Presentation,  53
Radiological Features, 54
●● Radiological Differential Diagnosis,  56
Pathogenesis, 58
●● Relationship of the Paradental Cyst to the Dentigerous Cyst,  60
Histopathology, 61
Treatment, 61

Inflammatory collateral cysts are cysts of inflammatory ori-
gin that are found towards the buccal aspect of the roots of
partially or recently erupted teeth. They arise as a result of
inflammation in the pericoronal tissues, but the pathogen-
esis and the epithelium of origin remain uncertain.
Although it is possible for a collateral cyst to arise on any
erupting tooth, the vast majority are associated with man-
dibular molars, with about 60% on third molars and most of
the remainder seen on the buccal aspect of first or second
molars. Thus, two main types of inflammatory collateral
cyst are recognised: the paradental cyst, found predomi-
nantly on mandibular third molars, and the mandibular
buccal bifurcation cyst, found on first or second molars
(Speight and Soluk Tekkeşin 2022b). In some respects the
collateral cysts remain controversial, since it is clear that in
some quarters their very existence is questioned. There are
a number of papers reporting lesions associated with
impacted third molars that do not include a single case of
paradental cyst (Curran et al. 2002; Stathopoulos et al. 2011),
while other series of pericoronal lesions on mandibular
third molars have suggested that more than 50% may be
paradental cysts (Costa et  al.  2014). One reason for these
discrepancies may be the very nature of the cyst itself. The
lesion presents as a ballooning of the pericoronal tissues to
form a pocket (Ackermann et  al.  1987; Slater  2003) that
some may not regard as a true cyst, while others regard it as
a simple variant of a dentigerous cyst. Nevertheless, the
clinical and radiological features are those of a cystic lesion
and the inflammatory collateral cysts are widely accepted as
an entity and are included in the World Health Organization
(WHO) classification of jaw cysts (WHO 2022a; Speight and
Soluk ­Tekkeşin 2022b).
­ lassification and Terminology
C
of Inflammatory Collateral Cysts
In 1970 Main proposed a classification of jaw cysts based
on a review and analysis of 274 odontogenic cysts. He
found eight cysts (2.9%) that arose ‘alongside a vital tooth
involved in pericoronitis’, which he called an inflammatory
collateral cyst, in recognition of their association with
chronic inflammation and a location on the lateral aspect
of a tooth. This term also distinguishes it from a radicular

Shear’s Cysts of the Oral and Maxillofacial Regions, Fifth Edition. Paul M. Speight.
© 2022 John Wiley & Sons Ltd. Published 2022 by John Wiley & Sons Ltd.
48   Inflammatory Collateral Cysts
cyst associated with a lateral accessory root canal of a non-­
vital tooth, and from a developmental lateral periodontal
cyst. Seven of his eight cases arose on mandibular third
molars, and one on an impacted upper canine (Main 1970).
Main’s 1970 paper is often cited as the first report of this
cyst, but Philipsen et  al. (2004) found that Hofrath in
1930  had reported several jaw cysts on mandibular third
molars affected by pericoronitis. Hofrath called these cysts
‘marginal wisdom tooth cyst’, but all the features were con-
sistent with the inflammatory collateral cyst described by
Main (1970) and the paradental cyst as currently defined.
The first detailed account of inflammatory collateral
cysts was by Craig (1976), who described a cyst of inflam-
matory origin that occurred on the lateral aspect of the
roots of partially erupted mandibular third molars where
there was an associated history of pericoronitis. He recog-
nised that these cysts were the same clinicopathological
entity as the inflammatory collateral cyst described by
Main (1970), but he was the first to suggest the term
paradental cyst. He felt this was more appropriate for this
lesion because it emphasised the odontogenic associations
of the cyst and its location adjacent to a tooth.
Craig’s series consisted of 49 cysts in 48 patients, which
represented about 5% of odontogenic cysts seen in his
department over a 21-­year period. In all cases the involved
tooth was partially erupted and was associated with a his-
tory of pericoronitis. In terms of location, 26 cysts were on
the buccal aspect of the roots, 19 were distal, and 4 were
mesial, but Craig was of the opinion that there was some
buccal involvement even in those cysts designated clini-
cally as of mesial or distal location. Macroscopically, the
cysts were firmly attached to the bifurcation area on the
buccal aspects of the roots, and extended up to the cemen-
toenamel junction. Craig’s description of the paradental
cyst associated with third molar teeth has become the
defining feature of this lesion.
Craig’s paper on the paradental cyst was, for a number of
years, the only detailed account of the entity. Subsequently,
however, Ackermann et al. (1987) described 50 cases, all of
which arose on impacted third molars and had similar fea-
tures to those described by Craig. This was soon followed
by a report of 6 cases by Fowler and Brannon (1989) and 15
cases by Vedtofte and Praetorius (1989), and then by
numerous case reports and a number of case series or
reviews (de Sousa et al. 2001; Colgan et al. 2002; Philipsen
et al. 2004; Mohammed et al. 2019).
In 1983, Stoneman and Worth described 17 cases of a
lesion that was similar to the inflammatory collateral cyst
(Main 1970) and the paradental cyst (Craig 1976), but that
arose primarily on the buccal aspect of mandibular first and
second molars in children. They named this entity the man-
dibular infected buccal cyst to emphasise its origin in
inflamed periodontal tissues of partially or fully erupted
molars. Stoneman and Worth (1983) did not refer to the
reports of Main or Craig and although they emphasised
their lesion as being on first and second molars, three of
their cases involved the third molar region. It seems there-
fore that the mandibular infected buccal cyst and paraden-
tal cyst share similar clinical and histological features and
should be regarded as variants of the same lesion. This is
suggested by more recent papers that have reappraised
these cysts and consider them to be the same entity (Packota
et al. 1990; Wolf and Hietanen 1990; Thurnwald et al. 1994;
Pompura et  al.  1997; Thompson et  al.  1997; Chrcanovic
et al. 2011; Ramos et al. 2012). Pompura et al. (1997) sug-
gested the term mandibular buccal bifurcation cyst for these
lesions, since it described the location of the cyst and
reflected the fact that not all lesions are overtly infected.
None of these cysts appeared in the first (1972) edition of
the WHO classification of odontogenic tumours and cysts,
but they were included in the second edition (Kramer
et  al.  1992). The 1992  WHO classification used the term
paradental cyst, but included inflammatory collateral cyst
and mandibular infected buccal cyst as synonyms. The clas-
sification did however make a distinction between cysts aris-
ing in association with third molars and a distinctive variant
arising on the buccal aspect of first molars in children.
In a review of the world literature, Philipsen et al. (2004)
concurred with this view, but found that the literature
included at least 16 names for these cysts, including marginal
wisdom tooth cyst (Hofrath  1930), inflammatory collateral
cyst (Main 1970), paradental cyst (Craig 1976), mandibular
infected buccal cyst (Stoneman and Worth 1983), and man-
dibular buccal bifurcation cyst (Pompura et al. 1997). Slater
(2003) had suggested eruption pocket cyst, which nicely
describes the association with an erupting tooth as well the
morphological feature of a pocket cyst. Nevertheless, this
name was never used again in the literature. Philipsen et al.
(2004) preferred to use the term inflammatory paradental
cyst to encompass all the collateral cysts of inflammatory ori-
gin. They pointed out, however, that differences in clinical
presentation and appearance justify separating the cyst into
clinicopathological variants. In the literature up to 2004 they
identified reports of 342 patients with 377 cysts. The most
common lesions, representing 61.4% of cysts, arose in adults
and were associated with a mandibular third molar. The sec-
ond group, comprising 35.9% of cysts, were related to the
first and second molars and arose in younger individuals
with a characteristic clinical presentation. A further 10 cysts
(2.7%) were described as occurring in the gobulomaxillary
region between the second incisor and canine. Eight of these
ten cases were reported by Vedtofte and Holmstrup (1989).
There are also reports of four cysts arising in association
with mandibular premolars (Morimoto et al. 2004) and one
case arising on a maxillary second molar (Vedtofte and
Praetorius 1989).

It is apparent from this discussion that all these terms
refer to a similar lesion and have been used synonymously
to describe an inflammatory collateral cyst that arises
towards the buccal aspect of a partially, or recently, erupted
tooth. It is also clear that the vast majority of cysts (about
97%) fall into two main groups  – those associated with
third molars and those associated with first or second
molars. In the previous edition of this book we suggested
that these two variants should be called paradental cyst,
using the criteria of Craig (1976), for lesions associated
with third molars and juvenile paradental cyst for lesions
in younger individuals associated with mandibular first or
second molars. Subsequently, however, the 2017  WHO
classification (Speight and Soluk Tekkeşin  2017) adopted
the term inflammatory collateral cysts for all cysts found
towards the buccal aspect of the roots of partially or
recently erupted teeth, and described the two main types as
paradental cyst and mandibular buccal bifurcation cyst.
This terminology has been retained in the latest edition of
the WHO classification (WHO  2022a; Speight and Soluk
­Tekkeşin 2022b).
Although the paradental cyst is usually defined as aris-
ing on mandibular third molars, identical lesions have
occasionally been described on second permanent molars
when the third molar is absent and the second molar is
the last standing tooth (Vedtofte and Praetorius  1989;
Maruyama et  al.  2015). Thus the definition of the para-
dental cyst might more appropriately refer to the ‘last
standing mandibular molar tooth’. The vast majority,
however, are located on third molars. The key features of
the two main variants are summarised in Box  4.1 and
later Tables 4.2 and 4.3.
Box 4.1  Key Features of the Two Main Clinical Variants of Inflammatory Collateral Cysts
Paradental cyst
Site Mandibular third molar
a
% of ICC 61%
b
% of OC 4%
Location Distal or disto-­buccal
Proportion in males 70%
Proportion bilateral 4%
Clinical features History of pericoronitis on a partially
erupted tooth. Cyst is continuous with
the pericoronal pocket
Radiology Well-­demarcated disto-­buccal radiolu-
cency, superimposed over roots. Distal
follicular space preserved
a
 Frequency as a proportion of inflammatory collateral cysts.
b
 Frequency as a proportion of all odontogenic cysts.
­Clinical Feature  49
­Clinical Features
Most descriptions of inflammatory collateral cysts are to be
found in single case reports or in small case series. In a
review of the world literature, Philipsen et al. (2004) found
23 case reports and 18 case series reporting 377 cysts in 342
patients. More recently, Ramos et  al. (2012) reviewed 16
reports (57 cases) of buccal bifurcation cyst. Selected case
series, and the review of Philipsen et al. (2004), reporting
paradental cysts and mandibular buccal bifurcation cysts
are summarised in Tables 4.2 and 4.3, respectively.
Frequency
Table 4.1 summarises the reported frequencies of inflam-
matory collateral cysts in selected series from a wide geo-
graphical distribution. Data are taken from the same
references shown in Table 1.3 (Chapter 1) and from the
frequencies encountered in the larger series shown in
Table 4.2. Almost without exception, the authors of the
papers cited in Table  1.3 used ‘paradental cyst’ as a
generic term for all inflammatory collateral cysts, so
these frequencies include both paradental cysts and
mandibular buccal bifurcation cysts.
The frequency ranges from 0 to 13.6% of odontogenic
cysts (Table  4.1). Those authors who presented series of
paradental cysts found that they comprised between 3.0 and
4.7% of odontogenic cysts encountered in their departments
(Craig 1976; Ackermann et al. 1987; de Sousa et al. 2001).
In Shear’s large series of 3496 jaw cysts from South Africa
(see Table  1.1), there were 109  inflammatory collateral
cysts representing 3.1% of all jaw cysts and 3.6% of
Mandibular buccal bifurcation cyst
Mandibular first or second molar
36%
0.2%
Buccal
55%
25%
Swelling, painful. May be signs of infection
and suppuration. Tooth tipped buccally,
deep pockets in continuity with cyst lumen
Well-­demarcated radiolucency over buccal
aspect of roots, buccal expansion with cor-
ticated outline
50   Inflammatory Collateral Cysts

Table 4.1  Selected papers, with a wide geographical odontogenic cysts. These data suggest that paradental cysts
distribution, showing the frequency of inflammatory collateral are about 10–20 times more common than mandibular buc-
cysts as a proportion of total odontogenic cysts. Based on
Philipsen et al. (2004). cal bifurcation cysts.
Overall, the data from these studies (Table 4.1) suggest
Country n ICC (%)
that inflammatory collateral cysts represent about 4% of
odontogenic cysts. It is probable, however, that they are
Data from references in Table 1.3 under-­reported, because many cases received within
Meningaud et al. (2006) France 695 0 pathology departments may have insufficient clinical or
Tortorici et al. (2008) Italy (Sicily) 1273 0 radiological information to establish the diagnosis and
many may have been diagnosed as inflamed dentigerous
Ali (2011) Kuwait 196 0
cysts, pericoronitis, or inflamed follicles. In departments
Ramachandra et al. (2011) India 252 0
where the diagnosis is made on a regular basis, the para-
Manor et al. (2012) Israel 285 0 dental cyst appears to be a common lesion. In the series of
Bhat et al. (2019) India 125 0 Colgan et  al. (2002), paradental cysts comprised 15 of 60
Soluk Tekkeşin et al. (2012b) Turkey 5003 0.2 (25%) cystic lesions associated with lower third molars.
Daley et al. (1994) Canada 6847 0.5 This was the second most common diagnosis after denti-
Grossmann et al. (2007) Brazil 2812 0.7 gerous cyst (30%).
Tamiolakis et al. (2019) Greece 5165 1.1 In an analysis of pericoronal tissues from extracted third
molars, Costa et  al. (2014) found that 73.5% (83 of 113)
Mosqueda-­Taylor et al. (2002) Mexico 856 1.4
showed pathological changes and of these, 55 (66.2%) were
Aquilanti et al. (2021) Italy 2150 1.5
diagnosed as paradental cysts and 21 (25.3%) as dentiger-
Sharifian and Khalili (2011) Iran 1227 1.8
ous cysts. It should be noted, however, that the majority of
Ochsenius et al. (2007) Chile 2944 3.8 lesions were associated with erupted or partially erupted
Jones et al. (2006) UK 7121 5.6 teeth (85.5%), and only seven teeth were unerupted, sug-
Kammer et al. (2020) Brazil 406 13.6 gesting that a number of dentigerous cysts were diagnosed
Data from references in Table 4.2 in association with partially erupted impacted third molars.
Ackermann et al. (1989) South Africa 1852 3.0 Mohammed et  al. (2019) undertook a similar study and
Craig (1976) UK 1051 4.7
examined 407 tissue specimens associated with impacted
teeth from 390 patients. The most common diagnosis was
De Sousa et al. (2001) Brazil 1256 4.3
dentigerous cyst (56.5% of lesions; n  =  230), followed by
ICC, inflammatory collateral cysts; n, total number of odontogenic odontogenic keratocyst (6.1%) and then paradental cyst
cysts in each study.
(5.7%; n = 23).
It is interesting that these figures contrast starkly with
odontogenic cysts. In Craig’s original series (Craig  1976), data from other studies that have shown that paradental
paradental cysts comprised 4.7% of 1051 odontogenic cysts, cysts are exceedingly rare or are not diagnosed at all. Six of
and in a recent study from the same department (Jones the studies shown in Table 4.1 did not record any inflam-
et al. 2006), a diagnosis of paradental cyst was made on 402 matory collateral cysts. Costa et al. (2014) also reviewed 11
occasions over a 30-­year period (1975–2004), representing studies that reported histological findings associated with
5.6% of 7121 odontogenic cysts. third molars in 8464 patients. The most common finding
Few studies have determined separately the frequencies of was of normal dental follicle (76%), but the most common
paradental cysts and mandibular buccal bifurcation cysts. lesions were dentigerous cysts, found in 410 cases (11%).
Tamiolakis et  al. (2019) reviewed 5165 odontogenic cysts Only one paper (Al-­Khateeb and Bataineb 2006) reported
and found only 57 (1.1%) inflammatory collateral cysts. Of finding any paradental cysts and there were only 2, sug-
these, 53  were paradental cysts on third molars and only gesting an overall prevalence of 0.05%. In a systematic
4 were mandibular buccal bifurcation cysts in children, sug- review of the prevalence of odontogenic cysts and tumours
gesting frequencies of 1.0% and 0.1%, respectively. Jones associated with impacted third molars, Mello et al. (2019)
et  al. (2006) used the term paradental cyst to encompass reviewed 16 studies reporting histological diagnoses asso-
both types of inflammatory collateral cyst, but found only 15 ciated with more than 50 000 teeth. There were 1371 cysts,
cases in their paediatric population (patients 16 years), rep- of which 783 (57.1%) were dentigerous cysts, 400 (29.2%)
resenting 2.7% of odontogenic cysts in children (n  =  553) radicular cysts, and 150 (10.9%) odontogenic keratocysts.
and only 0.2% of all odontogenic cysts (n = 7121). Paradental These authors also found the same single study (Al-­
cysts in adults comprised 376 cases, representing 5.2% of Khateeb and Bataineb  2006) that had reported only 2
 ­Clinical Feature  51

Table 4.2  Paradental cysts. Age, sex, and site distribution from selected reports, and from the review of 222 cases by Philipsen
et al. (2004).

References n Mean agea Age range Male (%) % Bilateral

Craig (1976) 48 3rd decade NR 83.0 2.1

Ackermann et al. (1987) 50 3rd decade 17–62 70.0 6.0
Vedtofte and Praetorius (1989) 15 24.4 18–34 60.0 0.0
b
de Sousa et al. (2001) 54 3rd decade 13–47 39.0 NR
Colgan et al. (2002) 15 27.4 18–43 46.6 6.6
Jones et al. (2006) 376 29.6 17–74 57.3 NR
Philipsen et al. (2004) 11 29.9 18–46 63.6 18.0
Tamiolakis et al. (2019) 53 29.3 18–56 52.8 NR
Mohammed et al. (2019) 23 30.2 11–51 69.5 NR
Philipsen et al. (2004) 222c 27.6 18–47 70.6 4.1

n, number of patients; NR, not reported.

a
 In some reports, the mean age is not given, so the peak decade is included.
b
 Includes three cases on first or second molars.
c
 Total cases reviewed, n for each parameter varies.

Table 4.3  Mandibular buccal bifurcation cysts. Age, sex, and site distribution from selected reports, and from the review of 110 cases
by Philipsen et al. (2004) (see text for discussion).

References First molars Second molars

n % Male % Bilateral n Mean age Age range n Mean age Age range

Vedtofte and Praetorius (1989) 12 33.3 16.6 5 8.0 7–9 7 13.3 11–15
Wolf and Hietanen (1990) 6 16.6 NR 3 7.3 6–9 3 13.0 12–14
Thurnwald et al. (1994) 10 70.0 40.0 10 7.7 5–9 – – –
Pompura et al. (1997) 32 43.7 37.5 32 7.5 5–11 – – –
Philipsen et al. (2004) 110a 55.2 23.9 36 8.7 5–47 13 17.4 10–40

n = number of patients; NR, not reported.

a
 Total cases reviewed, n for each parameter varies.

paradental cysts. These data are similar to other studies
that have examined tissues associated with impacted third
molars and have not reported a single paradental cyst (e.g.
Curran et al. 2002 [USA]; Stathopoulos et al. 2011 [Greece];
Patil et al. 2014 [India]).
These data cannot be taken to represent the true preva-
lence of paradental cysts because many studies were based
in surgical units, the criteria for diagnosis are not given,
and although most report ‘impacted’ teeth, it is rarely
stated whether the tooth is fully unerupted or partially
erupted. These studies do, however, suggest that many cli-
nicians may not recognise or diagnose paradental cysts.
There is some evidence that many clinicians and pathol-
ogists in the United States may not recognise the paraden-
tal cyst as an entity, but rather regard it as a variant of
dentigerous cyst. One of the best and most widely used
textbooks on oral and maxillofacial pathology (Neville
et al. 2016) recognises the buccal bifurcation cyst in chil-
dren, but is uncertain about the paradental cyst. Its authors
agree that the features may be due to chronic pericoronitis,
but suggest that most are probably diagnosed as examples
of inflamed dentigerous cysts. Two other excellent and
widely used textbooks take a similar stance and suggest
that the paradental cyst is an inflamed dentigerous cyst
that has become buccally or distally displaced, presumably
as a result of eruption of the tooth (Woo  2016; Regezi
et al. 2017).
In a study from the United States of 2646 pericoronal
lesions associated with impacted teeth, Curran et al. (2002)
did not identify a single case of paradental cyst. They
reported that 67% (1776 lesions) were diagnosed as normal
follicular tissue and of the remaining pathologically
52   Inflammatory Collateral Cysts
significant lesions (n  =  872), 86.6% (n  =  752) were diag-
nosed as dentigerous cysts. This suggests that in this cen-
tre, paradental cysts were not recognised as an entity and
were probably diagnosed as dentigerous cysts. The paper
was challenged on this issue by Slater (2003), who sug-
gested in correspondence that some of the dentigerous
cysts diagnosed by Curran et al. (2002) may in fact be para-
dental cysts. It is not stated, however, how many of their
impacted teeth were unerupted or partially erupted.
These discrepancies in frequency or prevalence are almost
certainly due to uncertainty about the criteria for diagnosis
and the fact that pericoronal radiolucencies associated with
partially erupted third molars are often given a clinical or
radiological diagnosis of ‘dentigerous cyst’, ‘pericoronitis’, or
‘hyperplastic follicle’. The pathologist may receive only frag-
ments of inflamed tissue that may be consistent with any of
these diagnoses, and paradental cyst may not be considered.
The differential diagnosis of the paradental cyst and criteria
for diagnosis will be discussed later in this chapter.
Age
The mean age of presentation of inflammatory collateral
cysts correlates well with the chronological stage of erup-
tion, with lesions most often presenting a few years after
the eruption of the associated tooth. The mandibular buc-
cal bifurcation cyst presents in children, but the mean age
of presentation depends on the tooth affected (Table 4.3).
Lesions on first molars are found at a mean age of about
8 years, with most studies showing a narrow range between
5 and 11 years. Cysts on second molars are found at a mean
age of about 13 years. In their review of more than 40
papers, Philipsen et al. (2004) found limited demographic
data, but showed a wider age range than suggested in the
literature. The age range for lesions on first molars and sec-
ond molars was reported as 5–47 years and 10–40 years,
respectively. However, careful reading of their paper shows
that there was only one first molar cyst in a patient over
11 years (a male age 47) and this was from their own files.
They also found only three cases over the age of 16 on sec-
ond molars, and two of these were from their own files.
Philipsen et al. (2004) also suggested that the ages differ
for males and females, with males affected slightly later.
They showed that lesions on the first molar affect individu-
als with a mean age at presentation of 9.0 years for males
(range 5–47; n = 24) and 8.1 years for females (range 6–11;
n = 12). Lesions on the second molar presented with mean
ages of 19.8 years for males (range 10–40; n  =  8) and
13.6 years for females (range 12–16; n = 5). These differences
were not shown to be significant and the higher mean age in
males is almost certainly due to outlying single cases at an
older age. Nevertheless, the data show that occasional cysts
may persist undetected into later adulthood.
Paradental cysts on third molars present in an older age
group (Table 4.2). The mean age of presentation is about
28 years and all studies show a peak in the third decade.
Two-­thirds (66.7%) of the cases in Craig’s (1976) series
arose in the third decade. In the study by Ackermann et al.
(1987), 48 of the 50 cysts occurred between the ages of
10 years and 39 years, with 34 cases (68%) in the third dec-
ade. There was only one case in the fifth decade and one
patient aged 62 years. Five of the six cases in the study of
Fowler and Brannon (1989) affected patients in the third
decade. In their review of the world literature, Philipsen
et al. (2004) reported similar age distributions with a peak
in the third decade (38% of cases) and a mean age of
27.6 years. The age range of lesions associated with third
molars is wide, overall ranging from 11 to 74 years
(Table  4.2), again suggesting that occasional lesions may
remain undetected and symptomless for long periods.
Inflammatory collateral cysts arising at other sites also
reflect the age of eruption of the associated teeth: the four
premolar cases reported by Morimoto et  al. (2004) pre-
sented at ages 9 or 10 years, and 7 of the 8 cases reported
in the globulomaxillary region were found between the
ages of 10 and 19 years (Vedtofte and Holmstrup 1989).
Sex
Inflammatory collateral cysts show a slight preponderance
for males, but this is most apparent for paradental cysts
(Table  4.2), where about 70% of cases overall affected
males. Mandibular buccal bifurcation cysts affecting chil-
dren show a more even distribution between males and
females (Table 4.3), with only one series reporting a male
preponderance (70%: Thurnwald et  al.  1994). Philipsen
et al. (2004) found 87 cases where sex had been recorded,
with a slight male preponderance of 55%. In their analysis
of odontogenic cysts, Jones et al. (2006) found 14 cases in
children where sex was recorded and showed a male :
female ratio of 1.33 (57% males).
Site
Inflammatory collateral cysts are almost exclusively found
in the mandible and over 60% are paradental cysts involv-
ing a mandibular third molar. Only a handful of cases
have been reported in the maxilla. In the original descrip-
tion of the lesion, Main (1970) described 1 case associated
with an upper canine and Vedtofte and Holmstrup (1989)
subsequently reported a series of 8 cases arising between
the upper canine and second incisor (globulomaxillary
region). In their large review, Philipsen et al. (2004) found
that 97.3% of cases arose in the mandible, with only 10
(2.7%: including the 8 cases of Vedtofte and Holmstrup) in
the maxilla. Jones et  al. (2006) found 402  inflammatory

collateral cysts in their files, but only 1 case was recorded
in the maxilla, associated with a third molar. Ochsenius
et al. (2007) found 113 paradental cysts in their series of
odontogenic cysts, 6 (5.3%) of which were associated with
maxillary third molars. The 4 premolar cases reported by
Morimoto et al. (2004) were all in the mandible.
Paradental cysts are located almost exclusively on man-
dibular third molars, but 2 cases have been recorded on sec-
ond molars when the third molar is absent and the second
molar is the last standing tooth (see later Figure 4.2; Vedtofte
and Praetorius 1989; de Sousa et al. 2001 [2 cases]; Maruyama
et al. 2015). These unusual examples arose at an average age
of 14.5 years (range 13–17 years), but were otherwise identi-
cal to paradental cysts encountered on third molars.
Mandibular buccal bifurcation cysts are located on the
first or second molar teeth, but the relative frequency of
occurrence on each tooth is rarely reported. In the review by
Philipsen et al. (2004), cysts on the first and second molars
were usually reported together, but for 49 cases the site dis-
tribution was known. Of these cases, 36 (73.5%) were
located on first molars and 13 (26.5%) on second molars.
This suggests that mandibular buccal bifurcation cysts are
about twice as common on first molars as on second molars.
Inflammatory collateral cysts may be bilateral, but this is
more common for the mandibular buccal bifurcation cyst
than for paradental cysts. Case series have shown that
between about 16 and 40% of mandibular buccal bifurca-
tion cysts present as bilateral lesions (Table  4.3), while
bilateral lesions are only seen in about 4% of patients with
paradental cysts (Table 4.2)
Clinical Presentation
Over 60% of all inflammatory collateral cysts are paradental
cysts involving mandibular third molar teeth with a history
of recurrent or persistent pericoronitis, although lesions
may be symptomless at presentation. The third molar is
always partially or recently erupted and most are impacted.
In Craig’s (1976) series of 48 patients, all cases were associ-
ated with a history of pericoronitis, but bony expansion or
swelling was not a feature and most lesions were chance
findings on extraction of the impacted tooth. Ackermann
et al. (1987), Fowler and Brannon (1989), and Colgan et al.
(2002) found that all their cases were associated with a par-
tially erupted third molar with a history or presence of peri-
coronitis. Symptoms of pain or swelling were rarely
encountered, although there may be signs of persistent
infection. On examination, all lesions are found on the buc-
cal side of the tooth and most are orientated towards the
distal aspect. On probing, the cyst lumen is usually found to
communicate with the associated periodontal pocket or
with the pericoronal space beneath the inflamed opercu-
lum. As mentioned previously, a paradental cyst may arise
­Clinical Feature  53
on a second molar when it is the last standing tooth in the
mandible. This is rare, but when it occurs the clinical and
radiological features are identical to a paradental cyst aris-
ing on a third molar (Vedtofte and Praetorius 1989; de Sousa
et al. 2001; Maruyama et al. 2015).
In contrast to the paradental cyst, the mandibular buccal
bifurcation cyst usually presents with symptoms  – most
often a complaint of swelling, with pain or tenderness.
Stoneman and Worth (1983) first reported this lesion as
‘mandibular infected buccal cyst’, and although some cases
produced few or no clinical symptoms, they felt that the
lesion was characterised by signs of infection, including
discomfort, pain, tenderness, and painful occlusion. Rarely,
there may be suppuration with formation of a facial abscess
that may point (Figure 4.1). Swelling and pain are the clini-
cal features most likely to induce the patient to seek advice.
Pompura et al. (1997) reported 32 patients with cysts on
mandibular first molars and found that all cases presented
with pain or tenderness in the affected area. Only
14 patients (43.7%) were aware of swelling of the cheek,
but in the remaining 18 cases intraoral swelling of the alve-
olus was evident on clinical examination. A foul-­tasting
discharge consistent with infection was reported by 20
patients (62.5%). Vedtofte and Praetorius (1989) reported
12 cases associated with first or second molars and found
that the most common symptoms were pain and swelling
associated with discharge of pus. In all cases the cyst lumen
communicated with the periodontal pocket on the buccal
aspect of the tooth. Philipsen et  al. (2004) reported that
buccal swelling was rarely associated with cysts on the sec-
ond molar, but is a characteristic feature of lesions on the
first molar.
The mandibular buccal bifurcation cyst is always situated
on the buccal aspect of the root of the affected tooth and the
tooth is usually tilted buccally so that the apices are
adjacent to the lingual cortical plate, a feature that is best
Figure 4.1  Young boy with mandibular buccal bifurcation cyst
involving a recently erupted mandibular first permanent molar.
Infection has extended through the bone, resulting in a facial
abscess. Source: Courtesy of Dr D.W. Stoneman.
54   Inflammatory Collateral Cysts

seen in occlusal radiographs (Figure  4.4) or cone-­beam
computed tomography (CBCT). The tooth is always vital,
which allows a lateral radicular cyst to be excluded.
With regard to inflammatory collateral cysts presenting
at other sites, the clinical features are very similar to the
mandibular buccal bifurcation cyst. Morimoto et al. (2004)
found that all four of their cases on lower premolars pre-
sented with swelling and three were also painful.
Inflammatory collateral cysts in the globulomaxillary
region probably arise in association with the erupting
canine and present as an inverted pear-­shaped radiolu-
cency between the incisor and canine teeth, which are vital
and show divergent roots. Of the eight cysts in the globulo-
maxillary region reported by Vedtofte and Holmstrup
(1989), five were asymptomatic chance findings and three
presented with signs of acute infection.
­Radiological Features
The clinical features of inflammatory collateral cysts are
not specific and an accurate diagnosis can only be made
after consideration of the radiological features, which are
characteristic (Box 4.2).
The paradental cyst shows a number of quite specific but
subtle features, which were first described by Craig (1976).
On conventional radiographs the cyst presents as a well-­
demarcated radiolucency, usually with a corticated mar-
gin. This is well illustrated in Figure  4.2, which shows
radiographs from the paper by Vedtofte and Praetorius
(1989). Of note is that the case illustrated in Figure 4.2a is
of bilateral paradental cysts associated with second molars,
in a 13-­year-­old girl where the third molars are absent. The
cyst is usually displaced distally, but in all cases the radio-
lucency is superimposed over the buccal aspect of the tooth
and overlies the roots and bifurcation area. Most paraden-
tal cysts are 10–15 mm in diameter (Philipsen et al. 2004)
and rarely exceed 20 mm. Larger lesions may appear to be
periapical, but it is important to note that the periodontal
ligament space is not widened and the lamina dura is intact
around the roots (Figures 4.2 and 4.3). Most cysts extend
distally, but the distal element is well defined and is dis-
tinct from the distal follicular space (Figure 4.2). This fea-
ture was first noted by Craig (1976) and was confirmed by
Colgan et al. (2002), who identified it in 9 of their 15 cases
and considered it to be an important and helpful diagnostic
criterion, since it indicates that the dental follicle is not
involved in the development of the cyst.

Box 4.2  Inflammatory Collateral Cysts: Key Features and Diagnostic Criteria

Paradental cyst
●● Arises on the last standing mandibular molar – almost always a third molar
●● There is a history or presence of pericoronitis
●● May be swelling and discomfort, but often symptomless
●● The associated tooth is vital
●● Well-­demarcated and corticated radiolucency
●● Usually 10–15 mm in diameter
●● Lies on the buccal aspect of the tooth root and bifurcation, but often orientated distally
●● An important diagnostic feature is that the distal follicular space is intact and distinct from the cyst
●● The periodontal space and lamina dura are intact
Mandibular buccal bifurcation cyst
●● Arises on mandibular first or second molars
●● Often has symptoms – swelling, pain, and there may be suppuration
●● The associated tooth is vital
●● Well-­demarcated and corticated radiolucency
●● 10–20 mm in diameter
●● Lies on the buccal aspect of the tooth root and bifurcation
●● The periodontal space and lamina dura are intact
●● Buccal expansion is common
●● Subperiosteal new bone (visible especially on occlusal radiographs) may be deposited in a laminated pattern
●● The tooth is tilted buccally and the root apices may abut onto the lingual cortical plate
 ­Radiological Feature  55

(a)

(b)

Figure 4.2  Paradental cysts. (a) Bilateral cysts in a 13-­year-­old associated with recently erupted second molars. The third molars
were absent. (b) Two cysts in different patients associated with partially erupted (left) and recently erupted (right) third molars. In all
cases, the cysts are distal and buccal to the involved teeth. The distal part of the cyst is separate from the distinct distal follicular
space (arrows in a) and the periodontal ligament space and lamina dura are intact (arrowheads). Source: Vedtofte P 1989, p. 182–188 /
with permission of Elsevier. Courtesy of CV Mosby Co.

Although most lesions are located in a buccal or disto-­
buccal location (Figure 4.2), Colgan et al. (2002) suggested
that the precise site of the cyst may depend on the angle of
impaction of the associated tooth. A distoangular impac-
tion was shown in 10 of their 15 teeth and all had cysts
located towards the distal aspect. Two of their cysts were
located towards the mesial aspect of the teeth, but both
showed mesioangular impactions. Two teeth that were ver-
tically impacted had cysts located purely on the buccal
aspect. The vast majority of reports of paradental cysts
record that cysts are located towards the distal aspect of the
teeth and that a mesial orientation is rare (Craig  1976;
Ackermann et  al.  1987; Vedtofte and Praetorius  1989;
Philipsen et al. 2004). Since most impacted third molars are
mesioangular, these data suggest that a distally impacted
tooth is more likely to give rise to a paradental cyst than a
mesially angled tooth.
Radiological examination of the mandibular buccal
bifurcation cyst should include occlusal and panoramic
radiographs or CBCT. The cyst presents as a well-­
demarcated and usually corticated radiolucency overlying
the buccal aspects of the roots of an erupting or recently
erupted first or second molar tooth (Figure 4.3). The infe-
rior margin of the cyst is concave and rarely the cyst may
extend to the inferior border of the mandible, but does not
lead to distortion of the lower border or to an external
deformity (Figure 4.3a). There may be involvement of the
bone in the furcation and inter-­radicular bone may be lost.
56   Inflammatory Collateral Cysts
(a)
Figure 4.3  Mandibular buccal bifurcation cysts involving (a) an erupting first permanent molar and (b) a second permanent molar.
The cysts are well demarcated and corticated and overly the buccal and periapical aspects of the tooth roots. The periodontal
ligament and lamina dura are intact (arrows). Sources: (a) Courtesy of Dr Douglas W Stoneman. (b) Courtesy of Prof Paul Speight
(Previously published: El-Naggar AK 2017, Courtesy of IARC).
In the inter-­radicular region, therefore, the lamina dura
may be lost, but the periodontal ligament space and the
lamina dura are intact on the mesial and distal aspects of
the roots (Figure  4.3), a feature that enables distinction
from a radicular cyst.
Buccal expansion is often apparent and with involve-
ment of the periosteum new bone may be laid down, either
as a single linear band or in a laminated pattern (Figure 4.4).
This pattern of laminated new bone is seen as a result of
periostitis and is also seen in chronic osteomyelitis. Wolf
and Hietanen (1990) noted this feature and suggested that
clinically and radiographically, the mandibular buccal
bifurcation cyst may be similar to osteomyelitis, and that in
some cases the cyst may be a cause of chronic osteomyeli-
tis, (sometimes referred to as Garré’s osteomyelitis or peri-
ostitis ossificans).
CBCT is especially useful in the diagnosis of mandibular
buccal bifurcation cysts because it allows the buccal expan-
sion and extent of the lesion to be fully visualised (Ramos
et al. 2012; Bautista et al. 2019; Dave et al. 2020). Magnetic
resonance imaging (MRI) can also be useful, but although
it has the advantage of lower radiation dosage, it has very
limited use in routine examination of jaw lesions in den-
tistry. CBCT shows a hypodense, well-­demarcated, and
often spherical cystic lesion with a corticated outline,
which is always located on the buccal aspect of the tooth.
CBCT and occlusal radiographs show that the affected
tooth is tilted buccally and transverse views show the api-
ces abutting and occasionally eroding the lingual cortical
plate (Figure 4.4; Bautista et al. 2019).
(b)
Inflammatory collateral cysts at other sites show similar
radiological features. The four cases associated with pre-
molars, reported by Morimoto et al. (2004), showed well-­
demarcated radiolucencies overlying the buccal aspect of
erupting and incompletely formed premolars. There was
buccal expansion and in all cases the teeth were displaced
lingually. Cysts in the globulomaxillary region present as a
well-­demarcated radiolucency between the lateral incisor
and the canine tooth. The cyst has an ‘inverted pear’ shape
and the tooth roots are displaced and diverge. All eight
cases reported by Vedtofte and Holmstrup (1989) showed
these features and in all cases both the canine and incisor
tooth were fully erupted.
Radiological Differential Diagnosis
The histological features of inflammatory collateral cysts
are not specific, but taken together the clinical and radio-
logical features should allow an accurate diagnosis
(Box 4.2). In virtually all cases the cysts arise on the buccal
or disto-­buccal aspect of a partially erupted or recently
erupted tooth with characteristic radiological features.
The associated tooth is vital. Nevertheless, as discussed
previously, there is great variation in the relative frequency
of these cysts in different studies and it is apparent that
some workers do not recognise it as an entity. For the most
part this is probably due to lack of clear diagnostic criteria
and uncertainty about the pathogenesis. The key features
of these lesions and diagnostic criteria are suggested
in Box 4.2.

Figure 4.4  Occlusal view of a mandibular buccal bifurcation
cyst on a mandibular first molar tooth. There is resorption of
bone on the buccal aspect of the tooth and buccal expansion.
Subperiosteal new bone has been deposited buccally, giving a
laminated appearance. Note also the displacement and tilting of
the tooth, so that its apices abut onto, and appear to erode, the
lingual cortical plate. Source: Courtesy of Dr Douglas W
Stoneman (Previously published: Dental Radiography and
Photography (1983) 56, 1–14. Courtesy of Eastman Kodak Co.)
With regard to the paradental cyst, the presence of a
pericoronal radiolucency associated with a partially
erupted third molar is not specific, since a similar
(a)
Figure 4.5  Differential diagnosis of the paradental cyst. (a) The cyst is well demarcated and corticated (arrows) and is distinct from
the distal follicular space (arrowhead). (b) Chronic pericoronitis on a vertically impacted and partially erupted third molar. The distal
follicular space is dilated (arrowhead) and there is evidence of alveolar bone loss, but there is no cyst.
­Radiological Feature  57
radiolucency may result from an inflamed or hyperplastic
dental follicle or pericoronitis (Figure 4.5). In such a case,
the pathologist may be presented with fragments of
inflamed tissue and a clinical diagnosis of ‘pericoronitis’,
and therefore a diagnosis of paradental cyst may not be
considered. In addition, some workers consider that a per-
icoronal radiolucency distal to a partially erupted third
molar may arise as a result of lateral displacement of a
dentigerous cyst during tooth eruption, or that a cyst that
arises in a pericoronal relationship is a mere variant of
dentigerous cyst. In this case, the final diagnosis may be of
an ‘inflamed dentigerous cyst’.
However, careful examination of radiographs will show
that the paradental cyst is distinct from the pericoronal fol-
licular tissues and the criteria for diagnosis must include
the finding of a well-­demarcated cyst that is distinct from
the distal aspect of the dental follicle (Figures 4.2 and 4.5a).
If the follicular space is merely expanded, then the lesion
may be a hyperplastic dental follicle, or bone loss associ-
ated with chronic pericoronitis. Figure  4.5b shows an
expanded pericoronal space associated with a partially
erupted but vertical third molar. There is also evidence of
pocketing with alveolar bone loss. This appearance is con-
sistent with chronic long-­standing pericoronitis, but with-
out cyst formation. The relationship to the dentigerous cyst
is discussed further below.
Both the paradental cyst and mandibular buccal bifurca-
tion cyst overly the tooth roots and may resemble a periapi-
cal radicular cyst, or a radicular cyst lying lateral to the root
associated with a lateral root canal. However, in the case of
an inflammatory collateral cyst, the periodontal space and
(b)
58   Inflammatory Collateral Cysts
the lamina dura remain intact (Figures 4.2 and 4.4), a fea-
ture that excludes an inflammatory cyst of endodon-
tic origin.
A number of other cysts may on occasion arise on the
lateral aspect of a tooth, including odontogenic keratocyst
and glandular odontogenic cyst. However, these do not
embrace the crown of partially erupted teeth, are not asso-
ciated with pericoronitis, and have characteristic features
that clearly distinguish them from inflammatory collateral
cysts (see Chapters 7 and 10). Developmental lateral peri-
odontal cysts may also be considered, but the clinicopatho-
logical features are quite different (see Chapter 8). Although
lateral periodontal cysts are most common in the mandi-
ble, they are found in the canine/premolar region and they
lie lateral to the roots of fully erupted teeth in middle-­aged
adults. They are not associated with inflammation.
A number of workers have drawn attention to the fact
that the clinical and radiological features of mandibular
buccal bifurcation cyst may be similar to the chronic form
of osteomyelitis often referred to as Garré’s osteomyelitis or
periostitis ossificans (Stoneman and Worth 1983; Wolf and
Hietanen 1990). This is typified by buccal expansion with
laminated depositions of new subperiosteal bone – a fea-
ture that is also seen in cases of mandibular buccal bifurca-
tion cyst (Figure 4.4). Periostitis ossificans of the mandible
is most often seen in association with first molars in young
people and is usually secondary to periapical infection. The
mandibular buccal bifurcation cyst is of inflammatory ori-
gin and it is probable that in some cases, persistent chronic
inflammation may give rise to a low-­grade osteomyelitis
with periostitis. However, a diagnosis of collateral cyst can
be made on the basis of a vital tooth, a well-­defined buccal
radiolucency, and evidence of continuity between the buc-
cal periodontal pocket and the cyst lumen.
­Pathogenesis
There is no unanimity with regard to the pathogenesis of
inflammatory collateral cysts. Craig (1976), however, pro-
posed a pathogenic process that has become widely
accepted. He suggested that the cyst arises within a focus of
inflammation associated with pericoronitis around a par-
tially erupted tooth. In this respect the pathogenesis is sim-
ilar to the radicular cyst, in that chronic inflammation
initiates the cyst and is the stimulus for proliferation of the
epithelial lining. Craig (1976) is widely cited as having pro-
posed that the epithelium of origin is the reduced enamel
epithelium, but in fact his proposal was more nuanced
than this. The reduced enamel epithelium embraces the
crown of an unerupted tooth and is derived from the rem-
nants of the inner and outer enamel epithelium. As the
tooth erupts, the reduced enamel epithelium fuses with the
oral epithelium and forms the dentogingival junction or
the early epithelial attachment, which is composed of the
junctional epithelium that binds to the tooth crown and
the sulcular epithelium towards the opening of the gingival
sulcus. Since inflammatory collateral cysts are associated
with partially or recently erupted teeth, Craig (1976) actu-
ally proposed that the epithelium of origin was the early
epithelial attachment that is derived from the reduced
enamel epithelium. Thus the cyst is derived from the epi-
thelium that lines the inflamed periodontal or pericoronal
tissues associated with pericoronitis. Although classified as
an odontogenic cyst, it probably does not arise directly
from odontogenic remnants, but rather from pocket or per-
icoronal epithelium that is itself of odontogenic origin.
Craig (1976) and others (Main 1970; Ackermann et al. 1987;
Fowler and Brannon 1989; Vedtote and Praetorius 1989; de
Sousa et al. 2001; Philipsen et al. 2004) also considered the
rest cells of Malassez as a potential source of epithelium, but
this has largely been dismissed on the basis that, when seen
in histological sections, the rests of Malassez always appeared
inactive, and such an origin would not account for the con-
sistent buccal distribution of the lesions (Craig 1976; Fowler
and Brannon 1989).
Ackermann et  al. (1987) agreed with Craig (1976) that
the paradental cyst arises as a consequence of inflamma-
tory destruction of bone that is followed by proliferation of
epithelium and cyst expansion. They also discussed an ori-
gin from reduced enamel epithelium or from sulcular (or
crevicular) epithelium, and suggested that cyst formation
occurs as a result of unilateral expansion of the dental fol-
licle secondary to inflammatory destruction of periodon-
tium and alveolar bone. This, they proposed, was different
from the histogenesis of a dentigerous cyst, which is not
inflammatory and where expansion of the follicle is the
primary event with consequent bone destruction.
Vedtofte and Praetorius (1989) agreed that inflammatory
collateral cysts are of inflammatory origin, and are associ-
ated with pericoronitis on third molars or with a deep and
inflamed periodontal pocket when found on first or second
molars. While accepting that the paradental cyst was an
entity, Fowler and Brannon (1989) suggested that it may be
a variant of the dentigerous cyst, in that it is derived from a
cystic expansion of follicular reduced enamel epithelium
secondary to pericoronitis.
Fowler and Brannon (1989) also proposed that the para-
dental cyst may arise as a result of expansion of an occluded
periodontal or pericoronal pocket. This is consistent with
the proposal of Craig (1976) and others, if one recalls that
the epithelium lining a pocket or pericoronal tissues
around a partially erupted tooth are derived from the same
source – the reduced enamel epithelium.

More recently, Maruyama et al. (2015) found that inflam-
matory collateral cysts consistently expressed cytokeratins
K13, K14, and K19, and perlecan and UEA-­1. Dentigerous
cysts showed similar expression, but also expressed K10,
which was negative in the collateral cysts. Other cyst types
(odontogenic keratocyst and radicular cyst) showed minor
differences in keratin expression, but the expression of the
markers in lateral periodontal cyst and in normal junc-
tional or sulcular epithelium was similar to the collateral
cysts. Overall, the expression of cytokeratins was variable
and the results of this study cannot be regarded as conclu-
sive. Nevertheless, the similarity of expression patterns
between the inflammatory collateral cysts and junctional/
sulcular epithelium supports the view that the cysts arise
from the epithelium lining a periodontal or pericoronal
pocket. The authors suggest that their results contradict
the findings of Craig (1976), who they say proposed an ori-
gin from ‘reduced enamel epithelium’, but the findings
actually support Craig’s proposal that the epithelium of
origin is from the early epithelial attachment (i.e. the junc-
tional or sulcular epithelium) that derives from the reduced
enamel epithelium.
An origin from pocket or pericoronal epithelium is fur-
ther supported by the observation that the cyst lining is
often continuous with junctional or sulcular epithelium, or
with the periodontal or pericoronal pocket around the asso-
ciated tooth (Figures  4.6 and  4.7; Craig  1976; Ackermann
et al. 1987; de Sousa et al. 2001; Colgan et al. 2002; Philipsen
et al. 2004). The cyst therefore presents as a dilated pocket,
whereby a probe can be placed into the lumen through the
(a)
Figure 4.6  Gross specimen of a paradental cyst on the buccal aspect of a partially erupted third molar, which has been received
intact. (a) The cyst is attached to the cementoenamel junction and involves the distal and buccal surfaces of the roots. (b) Careful
probing shows that the lumen is open towards the coronal aspect and is in continuity with the lining of the pericoronal pocket.
Source: Courtesy of Prof G.T. Craig.
­Pathogenesi  59
opening of the associated periodontal pocket or from
beneath the operculum (Figure 4.6b). Some workers require
an opening to the surface as a diagnostic criterion (de Sousa
et al. 2001). A number of workers (Craig 1976; Ackermann
et al. 1987; de Sousa et al. 2001) have obtained sections of
the cyst in continuity with the associated teeth and showed
that the cyst linings were attached at the cementoenamel
junction and were continuous with the oral epithelium
(Figure 4.6).
These studies suggest that inflammatory collateral
cysts are equivalent to a dilated follicle or pocket lined by
hyperplastic and proliferative epithelium derived from
reduced enamel (follicular) epithelium. Thus, a descrip-
tive designation of ‘inflammatory pocket cyst’ may be
appropriate, and Slater (2003) has suggested that the
third molar lesions should be called ‘eruption pocket
cysts’. It is possible that swelling associated with inflam-
mation leads to occlusion of the opening of the pocket,
thus allowing accumulation of debris and cyst growth by
osmotic pressure in a similar process to that described for
radicular cysts.
From this discussion it can be seen that there is agree-
ment that collateral cysts are of inflammatory origin and
that the initiating factor is inflammation within the peric-
oronal tissues of an erupting or partially erupted tooth.
However, pericoronitis is common and this pathogenic
process does not easily explain why paradental and man-
dibular buccal bifurcation cysts are so rare.
Craig (1976) was able to examine the teeth in 28 of his
49 cysts. In 20 of the 28 cases (71.4%) he found a
(b)
60   Inflammatory Collateral Cysts
developmental enamel projection or spur extending from
the cementoenamel junction towards the bifurcation of
the roots on the buccal aspect of the tooth. He suggested
that the downwards extension of the reduced enamel epi-
thelium at the site of an enamel spur may provide a site of
stagnation or focus of inflammation, and predispose to
the development of a paradental cyst at this site. Fowler
and Brannon (1989) found enamel projections on two of
the three teeth they were able to examine and agreed with
Craig that such projections may localise inflammation
and cyst formation on the buccal aspect. In their study,
Ackermann et al. (1987) were only able to examine eight
of the associated teeth. In all cases the cyst was attached
at the cementoenamel junction, and two showed enamel
spurs. Others, however, have been unable to show an
association between these cysts and enamel spurs, but
often this is because the associated teeth were not availa-
ble for examination (Vedtofte and Praetorius  1989; de
Sousa et al. 2001). Studies have shown that enamel pro-
jections may be seen on up to 70% of teeth and are more
common on mandibular molars (Chan et al. 2010). Risnes
(1974) found that 11.7% of third molars had enamel pro-
jections and that 99% occurred on the buccal aspect.
These data may explain in part why lesions are found pre-
dominantly on the buccal aspect of mandibular molars.
Colgan et al. (2002) suggested that food impaction may
have an important part to play. In 13 of their 15 cases the
associated tooth was opposed by a maxillary molar and
they proposed that the angulation of the affected tooth
(usually distal) could promote food impaction into the per-
icoronal tissues around the crown. As further evidence for
this they showed that four cases contained giant cells con-
sistent with a foreign body reaction.
With regard to the mandibular buccal bifurcation cyst,
studies have shown that the affected tooth is almost always
tilted buccally (Figure 4.4), giving prominence to the lin-
gual cusps and often associated with increased pocket
depth on the buccal aspect (Pompura et al. 1997; Philipsen
et al. 2004). Stoneman and Worth (1983) suggested that the
mesio-­buccal cusp of the first molar is the first to penetrate
the oral mucosa during eruption, and that this would
explain the buccal location of the cyst, but this explanation
is at odds with the fact that the lingual cusps may erupt
first in the buccally displaced tooth. However, it is not
known whether this buccal inclination occurs as a result of
displacement of the tooth by the cyst, or is present at erup-
tion and may thus predispose to cyst formation. Since the
cysts are rare, it is most likely that the associated tooth is
buccally displaced at eruption and that this predisposes to
inflammation in a buccal pocket and subsequent cyst for-
mation. It is possible that the prominence of the lingual
cusps and the buccal inclination may predispose to food
impaction on the buccal aspect.
Relationship of the Paradental Cyst to the
Dentigerous Cyst
As discussed previously (see ‘Frequency’), there is evidence
that some clinicians and pathologists do not recognise the
paradental cyst as an entity, but rather regard it as a variant
of dentigerous cyst. Ackermann et al. (1987) suggested that
although the paradental cyst may arise from follicular
(reduced enamel) epithelium, the histogenesis is quite dif-
ferent and it should not be regarded as a variant of denti-
gerous cyst. They believed that the dentigerous cyst should
be defined as a cyst enclosing the crown of a completely
unerupted tooth.
Despite this, many clinicians and pathologists diagnose
collateral lesions associated with partially erupted third
molars as ‘inflamed dentigerous cysts’. Fowler and Brannon
(1989) agreed with Ackermann et al. (1987) that a dentiger-
ous cyst is, by definition, associated with an unerupted
tooth, but also believed that the paradental cyst is a variant
of dentigerous cyst. In this respect, a relationship to the
dentigerous cyst may be suggested on the basis of a com-
mon origin from epithelium lining the dental follicle, with
intraosseous (dentigerous cyst) and extraosseous (paraden-
tal cyst) variants associated with totally unerupted and par-
tially erupted teeth, respectively.
One possible pathogenic mechanism for the paradental
cyst is that it represents a developmental dentigerous cyst
that has become laterally (and buccally) displaced by the
eruption of the associated tooth, with subsequent inflam-
mation. This seems unlikely, however, since the typical
radiology of the paradental cyst (see Figures 4.2 and 4.5a)
suggests that the dental follicle remains intact and is not
dilated, and such a mechanism would not explain the con-
sistent buccal location. An alternative proposal is that the
paradental cyst is simply an inflammatory type of dentiger-
ous cyst that arises as a result of inflammation of the peri-
coronal tissues surrounding the partially embedded crown
of an impacted or erupting tooth. This would be a perfectly
acceptable proposal, but for the fact that an inflamed and
expanded pericoronal follicle would be indistinguishable
from pericoronitis associated with inflammatory osteoly-
sis. Yet paradental cysts show a very distinctive radiology
with a buccally orientated radiolucency that is quite dis-
tinct from an expanded dental follicle (see ‘Radiological
Differential Diagnosis’ and Figures 4.2 and 4.5). For these
reasons, we believe that inflammatory collateral cysts and
dentigerous cysts show distinctive diagnostic features and
should be designated as separate entities (Box 4.2).
 ­Treatmen  61

­Histopathology

Paradental cysts associated with third molars are removed

by enucleation of the cyst along with extraction of the asso-
ciated tooth. Occasionally, the whole specimen is received
intact (Figure 4.6) and will show that the cyst is a sac-­like
mass attached at the cementoenamel junction and located
on the buccal aspect of the tooth roots. This is in contrast to
a dentigerous cyst, which is also attached to the cementoe-
namel junction, but surrounds the crown of the tooth (see
Figures  5.18 and 5.19). Careful examination with a probe
will show that the lumen of the cyst is continuous with the
periodontal or pericoronal pocket (Figure 4.6b). This appear-
ance is virtually diagnostic of an inflammatory collat-
eral cyst.
Mandibular buccal bifurcation cysts are usually removed
by enucleation or curettage and the tooth is left in situ.
In this case the pathologist will often receive fragments of
soft tissue that in places may resemble a cyst wall.
Histological examination shows non-­specific features
that are indistinguishable from radicular cyst and it will
be impossible to make a diagnosis without consideration
of the clinical findings and review of the radiology. The
cysts are lined by a hyperplastic, non-­keratinised, strati-
fied squamous epithelium, which may be spongiotic and
of varying thickness. There is an intense chronic or mixed
inflammatory cell infiltrate associated with the hyper-
plastic epithelium and in the adjacent fibrous capsule
(Figure 4.7). As in radicular cysts, haemosiderin deposits,
hyaline bodies, or accumulations of cholesterol crystals Figure 4.7  Paradental cyst adjacent to the root of an impacted
may be seen. An opening into the cyst lumen may also be mandibular third molar. The cyst is lined by non-­keratinised
stratified squamous epithelium of variable thickness and
seen and the epithelial lining may be continuous with
showing areas of proliferation and inflammation in the wall.
sulcular or gingival epithelium at the periphery. Source: Courtesy of Prof G.T. Craig.
Occasional cases may show focal accumulations of for-
eign body–type giant cells, consistent with impaction of
food particles (Fowler and Brannon  1989; Colgan
et al. 2002).
normally. Nevertheless, removal of the cyst may not be
necessary, since there is good evidence that it may resolve
­Treatment after more conservative treatment. Marsupialisation of the
cyst has been found to be effective and has resulted in com-
Inflammatory collateral cysts are simple cysts and there is pete regression, with normal eruption of the associated
no evidence to suggest that recurrence is a problem. tooth and restoration of a normal gingival profile (Lizio
Paradental cysts associated with third molars are usually et  al.  2011). Cysts have also been shown to resolve after
enucleated along with the offending tooth. However, if the simple probing and irrigation, or even to heal spontane-
tooth is not impacted or angulated and appears to be erupt- ously as the tooth erupts (David et  al.  1998; Gomez
ing, it may be preserved and should continue to erupt into et  al.  2001; Zadik et  al.  2011). That these cysts are self-­
a normal occlusion. limiting and may resolve spontaneously is supported by the
Mandibular buccal bifurcation cysts are often enucleated fact that they rarely reach a large size and they do not occur
without removal of the associated tooth, which then erupts in adults.
62

Dentigerous Cyst

CHAPTER MENU
Clinical Features, 63
●● Frequency, 63
●● Age, 63
●● Sex, 65
●● Site, 66
●● Clinical Presentation,  67
Radiological Features, 67
●● Radiological Differential Diagnosis,  70
●● Distinguishing Dilated Follicles from Dentigerous Cysts,  71
Pathogenesis, 72
●● Source of Epithelium and Phase of Initiation,  72
●● Phase of Cyst Formation,  73
●● Growth and Enlargement of the Dentigerous Cyst,  73
–– Degradation of the Connective Tissues and Bone Resorption,  74
●● Dentigerous Cysts and the PTCH Gene,  74
●● Inflammatory Dentigerous Cyst,  75
●● ‘Extrafollicular Dentigerous Cyst’,  76
●● Dentigerous Cyst as a Potential Ameloblastoma,  76
Histopathology, 78
●● Immunohistochemistry and Biomarker Studies,  80
●● Malignant Change in Dentigerous Cysts,  81
Treatment, 82

A dentigerous cyst is an odontogenic cyst that encloses the
crown of an unerupted tooth and is attached to the cervical
region at the cementoenamel junction (Nelson and
White 2021; see later Figures 5.18 and 5.19). The cyst devel-
ops as a result of expansion of the dental follicle and
follicular cyst has been used as a synonym. There has been
debate with regard to terminology, but the term dentigerous
is most widely used and is preferred since it is unique to
this lesion, asserts an association with the teeth, and avoids
any confusion with follicular cysts at other sites such as the
ovary, or hair follicles (Browne and Smith  1991; Nelson
and White 2022).
Unfortunately, the term dentigerous is also used in a
broader sense, especially in radiology, as a descriptive name
for any radiolucent lesion that envelops the crown of an
unerupted tooth. The lesion is referred to as being in a ‘den-
tigerous relationship’ and the radiological differential diag-
nosis may be quite wide, but would include an odontogenic
keratocyst, an orthokeratinised odontogenic cyst, or an
ameloblastoma, all of which are commonly encountered at
the angle of the mandible and may envelop the crown of an
unerupted third molar (Müller 2021). It is important there-
fore that the diagnosis of dentigerous cyst is not made
uncritically on radiographic evidence alone. The criteria for
diagnosis will be discussed later in this chapter.
An eruption cyst is a variant of dentigerous cyst that is
found in the soft tissues overlying an erupting tooth.
Eruption cysts will be considered in Chapter 6.

Shear’s Cysts of the Oral and Maxillofacial Regions, Fifth Edition. Paul M. Speight.
© 2022 John Wiley & Sons Ltd. Published 2022 by John Wiley & Sons Ltd.
 ­Clinical Feature  63

­Clinical Features
Frequency
Dentigerous cyst is the second most common cyst of the
jaws and comprises about 20% of odontogenic cysts. In a
large series of cysts recorded over a 46-­year period at the
University of the Witwatersrand, Shear found that 17.1%
(599) of 3498 jaw cysts were dentigerous cysts (Table 1.1).
If only odontogenic cysts are included, dentigerous cysts
represented 19.7% and were the second most common
odontogenic cyst. This is similar to the frequency of 18.1%
found in a large series of 7121 odontogenic cysts in the
United Kingdom (Jones et al. 2006; Table 1.2).
The frequency varies between series and countries
(Table  1.3), with a range from 10.6% in Turkey (Soluk
Tekkeşin et  al.  2012b) to as high as 33.0% in Mexico
(Mosqueda-­Taylor et al. 2002). Three studies found that the
frequency of dentigerous cysts was lower than that of odonto-
genic keratocysts (Soluk Tekkeşin et al. 2012b; Ramachandra
et al. 2011; Kammer et al. 2020), but this is unusual and no
clear explanation has been given. In a pooled analysis of 17
studies, Kammer et  al. (2020) found that dentigerous cysts
represented 22.9% of odontogenic cysts compared to 12.0%
for odontogenic keratocysts (and 54.3% for radicular cysts).
A number of studies have shown that the relative fre-
quency of dentigerous cysts is greater in paediatric popula-
tions (16 years and less). In an Israeli study of 57 paediatric
patients with odontogenic cysts, Bodner (2002) found that
31 (54.3%) were dentigerous cysts and a further 15 (26.3%)
were eruption cysts. Only 9 cysts (15.8%) were radicular.
Soluk Tekkeşin et al. (2012b) found that 21.3% of cysts were
dentigerous in their paediatric population, compared to only
9.1% in adults. Other studies have shown a frequency of den-
tigerous cysts of 53.8% and 19.3% (Manor et al. 2012), 66.4%
and 12.5% (Ochsenius et  al.  2007), and 30.3% and 17.5%
(Jones et al. 2006) in children and adults, respectively. These
data appear to suggest that children may be more susceptible
to dentigerous cysts, but a more probable explanation is that
children are less susceptible to radicular cysts, resulting in a
relatively higher frequency of dentigerous cysts.
Age
Dentigerous cysts show a wide age distribution, but most
reports suggest a mean age of between 30 and 40 years.
However, there is some variation between studies and coun-
tries. This is illustrated in Figures 5.1 and 5.2, which show
contrasting data from two different countries. In Shear’s
series of 343 patients from South Africa (Figure 5.1), most
cases arose in the second to fourth decades, but with a slight
peak in the 20–29-­year age group, followed by a gradual
decline. A large Sheffield series of 1274 cases shows a similar
wide age range (Figure  5.2), but with most cases in the
fourth to sixth decades and a slight peak in the 40–49-­year
age group. The mean age was 40.8 years (Jones et al. 2006).
Both series showed that the frequency of dentigerous cysts
in the first decade was considerably lower than in the sub-
sequent three decades. This is because the most frequently
affected teeth are the mandibular third molars and maxillary
permanent canines, which are more likely to be impacted in
adolescents and young adults. Figure  5.3 illustrates the

Figure 5.1  Age and sex distribution of 343 100

patients with dentigerous cysts (South
African series). 90 86

80 76

70 34

59 Females
60
No. of cases

41 Males
50 18

40 38

32 8
30 28
10 52
11 20
20 41
4
35
30
10 22
17 16
3
1
0
0-9 10-19 20-29 30-39 40-49 50-59 60-69 70-79 80-89
Age
64 Dentigerous Cyst

300

Females
252
250 Males
230
218

200 90
78 66
No. of cases

166
158

150 141
61
60
56
100
162

152 152
50 49
50 105 98
14 85 20

36 10
29
4
0 6
0-9 10-19 20-29 30-39 40-49 50-59 60-69 70-79 80-89
Age

Figure 5.2  Age and sex distribution of 1274 patients with dentigerous cysts (Sheffield series).

0-9 10-19 20-29 30-39

Tooth Tooth Tooth Tooth
8 7 6 5 4 3 2 1 8 7 6 5 4 3 2 1 8 7 6 5 4 3 2 1 8 7 6 5 4 3 2 1

12
10
5 5
3 2
1 1 1 1 1
1

2 1 1 6 1 1 1 1
4 4
6 8 8

23 22

40-49 50-59 60-69 70-79

Tooth Tooth Tooth Tooth
8 7 6 5 4 3 2 1 8 7 6 5 4 3 2 1 8 7 6 5 4 3 2 1 8 7 6 5 4 3 2 1

5
2 1 2 2
1

1 1 1 1
2
4

10
12

Figure 5.3  Distribution of the location of dentigerous cysts in different decades (n = 174). The distribution closely follows the
chronology of tooth development and eruption.
 ­Clinical Feature  65

Table 5.1  Age and sex distribution from selected large series

Box 5.1  Dentigerous Cyst: Epidemiology and Key Facts of dentigerous cysts.
●● Dentigerous cysts are the second most common
cystic lesion of the jaws Mean Peak
References n age decade(s) Male (%)
●● They comprise about 20% of all odontogenic cysts
●● They are more common in males. Overall about 60% Daley et al. (1994) 1662 NR 3rd 59.9
are found in males (M : F 1.5 : 1)
Ledesma-­Montes et al. 108 NR 2nd 64.8
●● Peak age is in the third and fourth decades (2000)
(20–40 years)
Meningaud et al. (2006) 154 44.9 NR 70.0
●● Upto about 70% are associated with impacted lower
Jones et al. (2006) 1292 40.8 5th 65.1
third molars
Ochsenius et al. (2007) 546 23.5 2nd 63.0
●● Very rare on deciduous teeth
Tortorici et al. (2008) 149 31.0 2nd 61.1
Zhang et al. (2010) 2082 35.0 2nd 61.0
distribution of 174 cases from the South African series for Sharifian and Khalili 303 21.5 2nd and 3rd 57.3
which both age and the involved tooth had been recorded. (2011)
No cases were recorded on deciduous teeth. Only 17 cases Soluk Tekkeşin et al. 529 32.8 NR 60.4
(2012a,b)
occurred in the first decade and these were found most
commonly on mandibular premolars. Maxillary canines Lin et al. (2013)a 338 33.0 2nd 63.8
are the second most affected tooth and these were found to Tamiolakis et al. (2019) 766 38.7 4th–6th 65.3
be involved mostly in the second (12 cases) and third (10 Lo Muzio et al. (2017) 806 34.8 3rd and 4th 60.5
cases) decades. Mandibular third molars were found to be Karabas et al. (2020) 114 NR 5th 66.0
affected predominantly in the third and fourth decades
NR, not reported.
(23 and 22 cases, respectively). Dentigerous cysts were a
 Lin et al. reported a second peak for males in the fourth to sixth
rarely encountered in the seventh or eighth decades, but decades.
even then impacted third molars or canines were found to
be involved.
Most studies that have reported large a number of denti- with 213 (62%) in males and 130 (38%) in females, a ratio of
gerous cysts show a similar wide age range and a mean age 1.6 : 1. In the Sheffield sample (Figure 5.3; Jones et al. 2006),
of between 30 and 40 years, with a peak incidence in the 819 (64%) cases were in males and 455 (36%) in females
second or third decades (Table  5.1). Three studies have (M : F 1.8 : 1).
reported dentigerous cysts in slightly older age groups, with Figures 5.1 and 5.2 show that the proportions of males
mean ages of 44.9 (Meningaud et al. 2006) and 38.7 years in each decade are approximately the same and most
(Tamiolakis et al. 2019), or with peaks in the fourth to sixth studies that have undertaken this analysis have a found
decades (Tamiolakis et al. 2019). In the Sheffield data there a similar distribution (Ochsenius et  al.  2007; Zhang
is a small peak in the fifth decade (Figure 5.2), but overall et al. 2010; Tamiolakis et al. 2019). Tamiolakis et al. (2019)
there was a wide age range, with the majority of cases found also found no significant differences in the mean ages of
between 30 and 59 years. male and female patients (39.8 and 36.6 years, respec-
These data also show that dentigerous cysts may arise tively). Lin et al. (2013), however, found a significant dif-
in children. At this age, many may be inflammatory in ference between males and females, with mean ages of
origin and are associated with maxillary canines or 35.2 and 29.1 years, respectively. They also showed that
lower premolars (see ‘Inflammatory Dentigerous Cyst’). although the frequency in both sexes peaked in the sec-
The youngest reported case is in a 1-­year-­old child ond decade, there were further peaks among male patients
(Suresh et al. 2011). in the fourth to sixth decades. Their overall proportion of
males was 63.8% (M : F 1.8 : 1), but in the fourth, fifth, and
sixth decades the proportions of males were 68.9%, 75.0%,
Sex
and 72.5%, respectively.
Without exception, the literature shows that there is a Although it might be suggested that the more frequent
male predilection for dentigerous cysts, with males affected occurrence in males is because they have a higher preva-
in about 60% of cases (M : F 1.5 : 1; Table  5.1). The fre- lence of unerupted or impacted teeth, there is mixed evi-
quency of dentigerous cysts in the South African sample dence for this in the literature. In a recent study in Canada,
(Figure 5.1) was significantly greater in males than females, MacDonald and Yu (2020) examined 6252 consecutive
66 Dentigerous Cyst
dental panoramic radiographs and found that the most com-
mon incidental finding was the presence of impacted teeth.
These were found in 1470 patients (23.5%), with a slight
male predilection of 797 cases (12.7%) compared to 673
(10.8%) in females. The proportion of males with impacted
teeth was 54.2% and the proportion with impacted third
molars was 54.4%. These authors also identified 18 inciden-
tal dentigerous cysts, of which 61.0% (11 cases) arose
in males.
A Greek study, however, showed the opposite findings
(Gisakis et al. 2011). These authors identified 425 patients
with impacted teeth from consecutive panoramic radio-
graphs. A total of 940 impacted teeth were identified, of
which 91.6% (841) were third molars, and of these 508 were
in the mandible, representing 54.0% of all impactions. Of
interest, however, is that of all the impacted teeth only 441
(46.9%) were found in males and 499 (53.1%) in females.
Of the 425 patients with impacted teeth, 202 (47.5%) were
male and 223 (52.5%) were female (M : F 0.9 : 1). Considering
only lower third molars, 46.3% were found in men.
These data support previous large series of radiographs
that have found no evidence of sex differences in the fre-
quency of impacted teeth (Mourshed  1964a,b; Brown
et al. 1982). With regard only to third molars, Carter and
Worthington (2016) undertook a systematic review and
identified 49 studies that had investigated the prevalence of
third molar impaction. Worldwide, the prevalence was
24.4%, but ranged from only 3.1% in a Nigerian population
to 68.6% in Singapore. The odds ratio of impaction in males
versus females was examined in 14 studies. Interestingly, 9
of the 14 studies showed that the odds of having an
impacted tooth were greater in females, but the 95%
Tooth
8 7 6 5 4 3 2 1
42
11
Numbers of cases
8 7
2 1 2 Maxilla
3 5 0 2
10 10
16
119
confidence intervals were wide and overall there were no
significant differences between males and females.
These data show that the higher frequency of dentiger-
ous cysts in males cannot be explained simply by a higher
rate of impacted teeth, and suggest that other, unknown
factors may influence the development of dentigerous cysts.
Site
The anatomical distribution of 245 dentigerous cysts, in
relation to the tooth involved, is shown in Figure  5.4. A
substantial majority (119 cases: 48.6%) involved the man-
dibular third molar. The maxillary permanent canine was
next in order of frequency with 42 cases (17.1%), followed
by the mandibular premolars and the maxillary third molar.
Similar distributions have been reported in other large
series. The proportions of dentigerous cysts affecting the
mandibular third molar and maxillary canine regions, respec-
tively, have been reported as 77.0% and 6.6% (Daley and
Wysocki 1995), 73.2% and 10.6% (Jones et al. 2006), 77.0% and
5% (Zhang et al. 2010), and 45.3% and 11.2% (Lin et al. 2013).
Dentigerous cysts may be associated with supernumerary
teeth, but the overall frequency appears to be between 1 and
5% (Lustmann and Bodner  1988). In Shear’s series that
contributed to Figure  5.4, there were 2 additional cysts
associated with supernumerary teeth (<1%). In their series
of 2082 cysts, Zhang et al. (2010) found only 11 on supernu-
merary teeth (0.5%). Lin et  al. (2013) found 46 of 338
dentigerous cysts (13.6%) associated with supernumerary
teeth, but this appears to be an unusually high frequency.
Lustmann and Bodner (1988), in a review of 42 such cases
from their own material and those reported in the
Figure 5.4  Anatomical distribution
of 245 dentigerous cysts.
7
Mandible

literature, found that about 90% were associated with a max-
illary mesiodens. In a more recent review, Anthonappa et al.
(2018) identified more than 40 case reports of dentigerous
cysts associated with supernumerary teeth. In this study, 41
out of 64 (64.1%) reported cases were found in the anterior
maxilla, and only 5 were found at any site in the mandible.
Dentigerous cystsvmay also be associated with odontomas.
In their large Canadian series, Zhang et al. (2010) found 5
cases (0.25%) associated with odontomas. Kaugars et  al.
(1989b) reported a series of 351 odontomas and found that
27.6% were associated with dentigerous cysts.
Occasional patients present with dentigerous cysts at
multiple sites (see later Figure  5.11). Most occurrences
have been recorded as single case reports and have most
often been found in patients with syndromes associated
with impacted teeth, including cleidocranial dysplasia and
the mucopolysaccharidoses. Non-­syndromic cases can be
seen, however. In the Canadian, Taiwan, and Turkish
series (Zhang et al. 2010; Lin et al. 2013; Karabas et al. 2020),
the proportion of patients with multiple cysts was 2.5%
(51 cases), 1.8% (6 cases), and 1.7% (3 cases), respectively.
Devi et al. (2015) reviewed the literature and recorded 19
case reports of bilateral dentigerous cysts between 1943
and their own case in 2015. Of these, 8 involved bilateral
mandibular third molars, 2  involved maxillary third
molars, and 1 reported a case involving bilateral upper
canines. Other teeth involved included mandibular premo-
lars and second molars, and 9 cases were in children,
including 6 under 10 years. A number of single case reports
continue to be published, including 2 involving 10-­year-­olds
(Khandeparker et al. 2018; Pant et al. 2019).
More recently, Boussouni et al. (2020) reviewed the litera-
ture and found 36 papers reporting 43 cases of multiple or
bilateral dentigerous cysts between 2009 and 2019. Of these,
23 cases (53.5%) involved the mandible, 12 (27.9%) the
maxilla, and in 8 patients (18.6%) both jaws were affected.
Bilateral mandibular third molars were affected in only 12
patients (27.9%), with mandibular premolars affected in 14
cases (32.6%) and maxillary canines in 13 (30.2%).
There have been five patients reported with bilateral den-
tigerous cysts involving all four quadrants (Devi et al. 2015;
Jeon et  al.  2016; Boussouni et  al.  2020) and one patient
reported with five cysts affecting a maxillary incisor and
premolar, and mandibular canine and second and third
molars (Moturi and Kaila 2018).
Clinical Presentation
The vast majority of dentigerous cysts are symptomless
and are discovered on radiographs that have been taken
because a tooth has failed to erupt, or is missing, or because
teeth are tilted or are otherwise out of alignment.
­Radiological Feature  67
Denti­gerous cysts may occasionally be painful, particularly
if infected. Patients may give a history of a slowly enlarging
swelling, and this is the common form of presentation
with edentulous patients when unerupted teeth have
inadvertently been retained. Occasionally a cyst may grow
to a large size before it is diagnosed. This is particularly the
case in maxillary lesions, which may expand and displace
the maxillary antrum. Lesions in the mandibular third
molar region, as they grow, may quickly become trauma-
tised during mastication or may become continuous with
the oral cavity through a periodontal pocket distal to the
second molar. They may therefore be inflamed or infected
at presentation and give rise to pain or discomfort, and
occasionally may be associated with a purulent discharge.
­Radiological Features
A dentigerous cyst, by definition, is found in a dentigerous
relationship with an unerupted tooth. Radiographs there-
fore show a radiolucent area enveloping the crown of an
unerupted tooth (Figure 5.5). The unerupted tooth may be
impacted as a result of inadequate space in the dental arch
or as a result of malpositioning, for example a horizontally
impacted mandibular third molar or an inverted tooth.
The typical radiological appearance of a dentigerous cyst
is illustrated in Figure 5.5. The lesion envelops the crown of
an impacted tooth and is attached at the neck or cervical
region (where the tooth crown meets the root), so that
only the crown of the tooth protrudes into the cyst lumen.
Dentigerous cysts are unilocular and have a corticated
margin. The corticated outline of the cyst is continuous
with the lamina dura surrounding the tooth roots (Figure 5.5),
indicating that the cyst arises and is contained within the
dental crypt of the developing tooth. Cysts may grow to a
large size and cause considerable buccal or lingual expan-
sion of the cortical plates (Figures 5.6 and 5.8).
Box 5.2  Clinical and radiological Features: Key Facts
●● Always associated with an unerupted or impacted tooth
●● Most commonly found on lower third molars and
then upper canines
●● Often symptomless and found on radiological
examination
●● Slowly growing swelling, may cause bucco-­lingual
expansion
●● Radiology shows well-­demarcated, corticated lesion
enveloping the crown of the affected tooth
●● A pericoronal space greater then 10 mm is highly
suggestive of a dentigerous cyst
68 Dentigerous Cyst

Figure 5.5  Radiograph of a typical dentigerous cyst, associated

with a lower third molar. The cyst is well defined and has a
corticated margin attached at the cementoenamel junction (arrow).

Figure 5.6  Computed tomographic scan of a central type of

dentigerous cyst, showing the extent of bucco-­lingual expansion
and clear evidence of a corticated margin.

(a) (b) (c) Figure 5.7  Diagram illustrating the manner in which

the cyst may expand to produce the radiographic
appearances of (a) central, (b) lateral, and
(c) circumferential types of dentigerous cyst.

This typical radiological appearance is referred to as the

central type of dentigerous cyst (Figure  5.7). In this type
the crown is enveloped symmetrically and the pressure of
cyst growth is applied to the crown of the tooth and may
push it away from its direction of eruption. In this way,
mandibular third molars are often displaced towards the
angle or lower border of the mandible or into the ascend-
ing ramus (Figure  5.8), and a maxillary canine may be
forced into the maxillary sinus. A maxillary cyst may dis-
place the antrum and impinge on the floor of the nose
(Figure 5.9).
More often, and especially when third molars are
involved, a dentigerous cyst becomes displaced as the tooth
tries to erupt and may be found lateral to the tooth, or the
whole cyst may envelop the tooth in a circumferential pat-
tern (Figure  5.7). The lateral type of dentigerous cyst
(Figures 5.10 and 5.11) is a radiographic appearance that Figure 5.8  A central type of dentigerous cyst has displaced the
results from dilatation of the cyst on one aspect of the third molar into the ascending ramus. This large cyst has
expanded bucco-­lingually, but on this plain radiograph only a
crown, or if the cyst is displaced by the tooth as it tries to shadow can be seen (arrows). Bucco-­lingual expansion is best
erupt (Figure 5.10). seen on computed tomography (Figure 5.6).

The so-­called circumferential type of dentigerous cyst,
in which the entire tooth appears to be enveloped by the
cyst (Figure  5.12), results when the cyst expands in the
manner illustrated in Figure 5.7c. It is important that this
variety be differentiated from other lesions that may
envelop a tooth.
Dentigerous cysts appear to have a greater tendency than
other simple jaw cysts to produce some resorption of the
roots of adjacent teeth. In a radiographic study of root
resorption produced by jaw cysts, Struthers and Shear
Figure 5.9  Computed tomographic scan of a maxillary
dentigerous cyst extending to, and impinging on, the floor of the
nose. Source: Courtesy of Dr Mark Cohen.
Figure 5.11  A rare example of bilateral
dentigerous cysts in a child, affecting
both developing second molars. Both
cysts are large, but have been displaced
in a medial direction to the lateral aspect
of the teeth.
­Radiological Feature  69
(1976) observed root resorption in 11 of 20 dentigerous cysts
(55%) (Figures  5.12 and  5.13), compared to only 6 of 33
radicular cysts (18%), and in none of their sample of 26
odontogenic keratocysts. They suggested that the dentiger-
ous cyst potential for root resorption may be due to its origin
from dental follicle and the ability of the follicle to resorb
the roots of the deciduous predecessors of the affected teeth.
Most dentigerous cysts can be diagnosed on plain radio-
graphs, but computed tomography (CT) is useful and is now
widely used since the accessibility of cone beam computed
tomography (CBCT). CT is especially useful to appreciate
the three-­dimensional extent of a lesion in a bucco-­lingual
direction (Figure  5.6), or to determine the relationship of
the cyst to the complex anatomy of the maxilla (Figure 5.9)
(MacDonald 2016; Allison and Garlington 2017).
As discussed above, the majority of dentigerous cysts are
associated with impacted lower third molars followed by
maxillary canines, so it might be expected that cysts are
commonly encountered when radiographs are taken for
routine diagnostic purposes or for orthodontic surveillance.
However, this is not the case and overall the prevalence of
Figure 5.10  Radiograph of a lateral type of dentigerous cyst.
The cyst is displaced to the medial aspect of the tooth, which is
now partially erupted.
70 Dentigerous Cyst
Figure 5.12  Radiograph of a circumferential type of
dentigerous cyst associated with a mandibular third molar. The
cyst has enveloped the tooth so that both the crown and roots
appear to be in the lumen. Note also that the cyst wall has
resorbed part of the root of the adjacent molar.
cysts on routine radiographs appears to be low. MacDonald
and Yu (2020) undertook a retrospective review of 6252 con-
secutive panoramic radiographs and found that 32% showed
at least one incidental finding. In 1470 (23.5%) cases this
was an impacted tooth, but evidence of a widened pericoro-
nal space suggestive of a dentigerous cyst was only found in
18 cases (1.2%). The prevalence of possible dentigerous
cysts in the total cohort was only 0.3%.
In a similar study, Karabas et  al. (2020) reviewed 6758
CBCTs and found that only 5.9% (400 images) showed evi-
dence of a radiolucent lesion (a pericoronal space of >2.5 mm)
around impacted teeth. Of these, 190 were examined histo-
logically and 114 dentigerous cysts were confirmed. Thus,
only 1.6% of patients from the whole cohort were confirmed
to have a dentigerous cyst.
In a systematic review of the prevalence of odontogenic
cysts and tumours associated with impacted third molars,
Mello et al. (2019) identified 16 studies where lesions had
been noted on radiographs and the diagnosis confirmed by
histological examination. A total of 50 969 impacted third
molars were identified and meta-­analysis showed a pooled
prevalence of cysts and tumours of 5.3% and a prevalence
of dentigerous cysts of only 2.1%.
Radiological Differential Diagnosis
Although the radiographic features of a dentigerous cyst are
characteristic, other lesions may also envelop a tooth and it
is not possible to give a definitive diagnosis on radiology
Figure 5.13  A dentigerous cyst wall with resorption of the
contiguous root of an adjacent tooth.
alone, without histological confirmation. The most impor-
tant lesions that must be considered, and that are frequently
associated with unerupted third molars, are odontogenic
keratocyst, orthokeratinised odontogenic cyst, and amelo-
blastoma. These arise from remnants of the dental lamina
that may be found in the connective tissues overlying the
dental follicle, within the gubernacular canal or the dental
crypt. Thus, as the cyst or tumour expands, it may envelop
the tooth and appear radiologically to be in a dentigerous
relationship with the crown (Figure 5.14).
In their systematic review of lesions associated with
third molars, Mello et  al. (2019) found that 5.3% were
affected by odontogenic cysts or tumours. Dentigerous
cysts were found in 2.1% of cases, odontogenic keratocysts
in 0.5%, and ameloblastomas in 0.4%. Other lesions that
were occasionally encountered included calcifying odonto-
genic cyst and odontogenic myxoma.
In a series of 5486 impacted third molars (in 4133 patients),
Patil et al. (2014) found 132 dentigerous cysts (2.4%) as well
as 16 odontogenic keratocysts (0.3%) and 31 ameloblastomas
(0.6%). Overall, dentigerous cysts, odontogenic keratocysts,
and ameloblastomas comprised 67%, 8%, and 16%, respec-
tively, of the 197  lesions detected. Other lesions included
calcifying odontogenic cyst (2), hyperplastic follicles (5),
odontogenic fibroma (3), and odontomas (6).
Curran et al. (2002) reported a sample of 2646 pericoro-
nal lesions over a six-­year period, and found that 1776
(67%) were follicular tissue with no evidence of pathology.
Of the remaining cases, 752 (28.4%) were dentigerous cysts,
71 (2.7%) were odontogenic keratocysts, and 13 (0.5%) were
ameloblastomas. The remaining lesions included odon-
toma, squamous carcinoma, calcifying odontogenic cyst,
calcifying epithelial odontogenic tumour, and odonto-
genic myxoma.
At other sites, an important lesion to consider is adenoma-
toid odontogenic tumour, up to 75% of which may be found,

Figure 5.14  A cyst envelops the crown of a lower third molar, and on radiology is in a dentigerous relationship with the tooth.
Histology, however, showed an odontogenic keratocyst.
on radiographs, to be in a dentigerous relationship with an
impacted tooth – most often an upper canine (Reichart and
Philipsen 2004; Chrcanovic and Gomez 2019b).
Diagnostic errors can be avoided if the criteria for diag-
nosis are followed (see later Box 5.4) and the clinical, radio-
logical, and histopathological features are reviewed and
correlated (Barrett et al. 2017; Müller 2021). Barrett et al.
(2017) showed that histological features of dentigerous
cyst, keratocyst, and cystic ameloblastoma may be similar,
especially in small incisional biopsies. In a review of
101  lesions diagnosed histologically as dentigerous cysts,
they found that five keratocysts and four ameloblastomas
had been missed because of a lack of knowledge of the cor-
rect histology, or failure to properly consider the radiologi-
cal features.
Distinguishing Dilated Follicles
from Dentigerous Cysts
All unerupted or impacted teeth show a zone of radiolu-
cency around the crown that represents the soft tissues of
the dental follicle. In the differential diagnosis, therefore, it
is important to be able to distinguish between a normal or
hyperplastic dental follicle and a dentigerous cyst. There is
much debate about the size or width of a normal pericoro-
nal space, but most authors suggest that a space of greater
than 3–5 mm is abnormal. An additional consideration is
that some erupting teeth have a dilated or hyperplastic fol-
licle in the pre-­eruptive phase.
Daley and Wysocki (1995) have pointed out that it can be
difficult to distinguish between a small dentigerous cyst
and a large dental follicle, despite the availability of both
radiographic and histological information. Their compara-
tive study of 1662 dentigerous cysts and 824 dental follicles
showed considerable overlap in age distribution and site
­Radiological Feature  71
predilection. They concluded that a pericoronal space of
4 mm or greater was suggestive of a dentigerous cyst, but
that distinguishing reliably between a small dentigerous
cyst and a large dental follicle may be resolved only by
identifying a cyst cavity at the surgical operation.
The approach taken by Damante and Fleury (2001) was
to correlate the relationship between the width of the
pericoronal space and the microscopic features of the
follicular tissue. Their sample comprised 130 unerupted
and 35 partially erupted teeth that were radiographed and
then extracted. The pericoronal spaces were measured on
the radiographs and the widths were compared with the
results of the histological examination of the removed tis-
sue. The width of the pericoronal space ranged from 0.1 to
5.6 mm. The most frequently observed lining of the folli-
cles was a reduced enamel epithelium in 68.4% of
unerupted teeth, and a hyperplastic stratified squamous
epithelium in 68.5% of the partially erupted teeth.
Inflammation was present in 36.1% of the unerupted
teeth and 82.8% of the partially erupted group. There was
a statistically significant association between the pres-
ence of stratified squamous epithelium and pericoronal
space enlargement for unerupted teeth. They also found a
trend in the association between inflammation and
enlargement of the pericoronal space.
Surgically, the authors detected no bone cavitation or
luminal cystic contents, and were unable to diagnose any
dentigerous cysts in pericoronal spaces smaller than
5.6 mm. They proposed that a pericoronal space up to 3 mm
in width corresponds to a normal dental follicle and a
width between 3 and 5.6 mm suggests an inflamed and
hyperplastic dental follicle. They agreed with Daley and
Wysocki (1995) that the criteria for diagnosis of a dentiger-
ous cyst must include the presence of a cystic cavity and
luminal contents. Some regard the presence of stratified
72 Dentigerous Cyst
squamous epithelium as diagnostic, but both these studies
(Daley and Wysocki  1995; Damante and Fleury  2001)
found non-­keratinised stratified squamous epithelium lin-
ing normal or hyperplastic dental follicles.
Stathopoulos et al. (2011) examined 417 ‘lesions’ (defined
as a pericoronal space >3 mm) in a consecutive series of
7782 impacted third molars. Of these, 202 (48.4%) proved
to be normal follicles and 138 (33%) were dentigerous cysts.
Other detected lesions included 29 odontogenic kerato-
cysts (7.0%) and 21 (5.0%) ameloblastomas.
More recently, Namgyel et al. (2020) compared the his-
tological features of pericoronal tissues from follicles
measured on radiographs as being less than 2.5  mm or
2.5 mm and above. Of the 206 specimens less than 2.5 mm,
105 (51%) showed normal dental follicle and 101 (49%)
showed pathological changes. There were 92 specimens
from spaces greater than 2.5 mm, of which 41% were normal
follicles and 59% pathological. There were no significant
correlations between the width of the pericoronal space
and pathological changes.
Edamatsu et al. (2005) compared 80 dental follicles with
27 dentigerous cysts and found that 76% (61) of the follicles
were less than 3 mm in width and the remainder were
between 3 and 10 mm. There were no follicles greater than
10 mm. In contrast, 20 of the cysts (74%) were greater than
10 mm and 7 (26%) were between 3 and 10 mm. No cysts
were less than 3 mm.
Taken together, these studies suggest that the width of
the follicle is not a reliable indicator of pathological
change. Although a pericoronal space of greater than
2.5–5 mm is suggestive of pathological change, it may also
be an enlarged follicle. Only pericoronal spaces of 10 mm
or more are most likely to be dentigerous cysts.
­Pathogenesis
In Chapter  3, the pathogenesis of the radicular cyst was
discussed in detail and was presented in three phases: the
phase of initiation, the phase of cyst formation, and the
phase of growth and enlargement (including bone resorp-
tion). These three phases are the basis for the pathogenesis
of all cysts, but whereas the initiating phase of inflamma-
tory cysts is quite well understood, the initiating factors
behind the formation of dentigerous cysts are poorly
understood or even unknown. The pathogenesis of odonto-
genic cysts has not been of great interest to researchers and
little new knowledge has been added to the literature since
the seminal studies of Harris and Toller in the 1960s and
1970s (reviewed in Harris and Toller 1975) and of Browne
and colleagues (reviewed in Browne  1991a; Browne and
Smith 1991).
Source of Epithelium and Phase of Initiation
The epithelial lining of the dentigerous cyst arises from the
reduced enamel epithelium that overlies the crown of a
tooth after enamel formation is complete, but before erup-
tion. Apart from the histological appearance of the lining
of some cysts (see ‘Histopathology’), the evidence for this
comes from animal studies, mostly carried out in the 1970s,
that are unlikely to be repeated (reviewed by Harris and
Toller  1975; Browne  1991a). These early studies largely
aimed to investigate the possibility of tooth transplants, but
it soon became apparent that implanted teeth often devel-
oped cysts around the crowns – a serendipitous model of
dentigerous cyst formation.
The work of two research groups was especially informa-
tive. Atkinson (1972, 1976, 1977) and Al-­Talabani and
Smith (1980) transplanted tooth germs subcutaneously
into mouse skin or hamster cheek pouches, and found
cystic change as early as 7 days after transplantation. Cyst
formation only occurred after enamel formation was com-
plete and was preceded by hyperplasia of the reduced
enamel epithelium and the formation of intraepithelial
clefts overlying the occlusal surfaces of the teeth. Cystic
degeneration within the hyperplastic epithelium produced
cavities lined with a thick, parakeratotic, stratified squa-
mous epithelium, but as the cysts enlarged, the lining
changed to a thin, non-­keratinised, stratified squamous
epithelium. After about 50 days the cysts may envelop the
tooth crown and extend to the cementoenamel junction.
Al-­Talabani and Smith (1980) found that many of the
affected teeth showed enamel hypoplasia. They went on to
examine teeth associated with human dentigerous cysts
and found that in 50% of cases there was evidence of
enamel hypoplasia on the occlusal surfaces or incisal edges
of the affected teeth. They proposed that there was a direct
relationship between the development of cysts and the
occurrence of enamel hypoplasia, and suggested that there
may be two types of dentigerous cyst, with different causes
and arising at different stages of tooth development. One
type would arise by cystic degeneration of the stellate retic-
ulum at an early stage of development and is likely to dis-
rupt amelogenesis and cause enamel hypoplasia. In the
second type, cyst formation commences after completion
of the crown and is initiated by accumulation of fluid,
either between the layers of the reduced enamel epithe-
lium or between the epithelium and the tooth crown.
Enamel hypoplasia would not be a significant feature of
this variety. This association of dentigerous cyst with
enamel hypoplasia of the contained tooth is an interesting
one, since it would explain the frequent finding of enamel
hypoplasia on affected teeth. However, another explana-
tion that was not considered by Al-­Talabani and Smith

(1980) may be that the presence of enamel hypoplasia
reduces the adhesion of reduced enamel epithelium to the
crown and provides the starting point for cyst development.
Great care must be taken in extrapolating animal experi-
ments to the human situation, but these studies do indicate
that the reduced enamel epithelium may give rise to a den-
tigerous cyst and suggest that cleft formation may be an
initiating event. An account of normal tooth eruption is
beyond the scope of this chapter, but an understanding of
the basic mechanisms is helpful (Wise et  al.  2002; Nel
et al. 2015; Bastos et al. 2021). The processes that cause a
tooth to move towards the surface of the alveolus are still
poorly understood, but do involve a complex network of
inductive signals between the tissues involved. The overall
outcome is movement of the tooth that is associated with
pressure on the adjacent structures. As a tooth moves
towards the surface, the reduced enamel epithelium prolif-
erates upwards, merges with the overlying mucosa, and
forms the gingival cleft through which the tooth emerges
into the mouth. If tooth eruption is impeded the epithe-
lium may still proliferate, but without upward movement it
may then degenerate and form clefts that represent the ear-
liest stage of cyst formation. An alternative scenario is that
if eruption is impeded, the reduced enamel epithelium
does not proliferate at all, but becomes separated from the
tooth crown to form a space that then develops into a cyst.
Phase of Cyst Formation
Whether the cyst starts as a cleft within the reduced enamel
epithelium or between the reduced enamel epithelium and
the tooth, it is thought that further cyst development results
from accumulation of fluid as a result of pressure in the
tooth follicle producing a fluid transudate. Main (1970)
suggested that the pressure exerted by an erupting tooth on
an impacted follicle obstructs the venous outflow and
thereby induces rapid transudation of serum across the
capillary walls. The increased hydrostatic pressure of this
pooling fluid separates the reduced enamel epithelium
from the crown. With time, capillary permeability increases
and permits the passage of greater quantities of protein
above the low concentration of the pure transudate. Such a
mechanism is supported by the observation that during
normal tooth development and eruption, there is apoptosis
of cells in the enamel organ and this stimulates the release
of paracrine factors, including interleukin (IL)-­1α, which
are pro-­inflammatory and may mediate capillary permea-
bility as well as osteoclastogenesis (see later; Nel et al. 2015).
Thus in the impacted tooth, rather than facilitating normal
eruption, these paracrine signalling events may promote
cyst formation.
­Pathogenesi  73
Growth and Enlargement of the
Dentigerous Cyst
Once a cystic cavity has formed, the mechanisms of further
growth and enlargement are similar to those described for
radicular cysts. In particular, expansion is almost certainly
mediated by hydrostatic pressure, and the early studies,
especially those of Toller (1948, 1966b, 1967, 1970a,b), have
been described in detail in Chapter 3.
A number of studies have shown that dentigerous cyst
fluids have soluble protein and immunoglobulin (Ig) levels
similar to those in serum, suggesting a simple transudate
(Skaug 1973; Skaug and Hofstad 1973; Browne 1975). There
is also evidence that immunoglobulins are produced in the
capsule of dentigerous cysts, since plasma cells are found
in the cyst wall and there is intense extracellular staining of
IgG, suggesting that the immunoglobulins found in cyst
fluids may be derived from local synthesis in the cyst cap-
sule as well as from a transudate (Smith et al. 1987).
Many dentigerous cysts show evidence of acute and
chronic inflammation in their walls, and in these instances
an inflammatory exudate may contribute to the accumu-
lation of luminal proteins and play some part in the
expansion of the cyst. Moreover, desquamated epithelial
cells and the passage of inflammatory cells into the cyst
cavity must contribute to an increase in luminal osmotic
tension and thereby promote further expansion of the
cyst. Glycosaminoglycans, predominantly hyaluronic
acid, heparin, and chondroitin-­4-­sulphate, have been
found in the fluids and walls of dentigerous cysts (Skaug
and Hofstad  1972; Smith et  al.  1984, 1988), and are also
thought to have an important role in expansile cyst growth
raising the internal hydrostatic pressure.
Toller (1970b) showed that the mean osmolality of denti-
gerous cyst fluid (291 ± 14.42 mOsm) was similar to that
found in radicular cysts (290 ± 14.93 mOsm) and odonto-
genic keratocysts (296 ± 15.16 mOsm). He believed that
raised osmolality of the cyst fluid made an important con-
tribution to expansion of odontogenic cysts. These findings
were supported by Kubota et  al. (2004), who also found
similar fluid pressures in keratocysts, dentigerous cysts,
and radicular cysts. Furthermore, the latter authors showed
that the intracystic pressure in all cyst types reduced as the
cyst increased in size. They concluded that increased pres-
sure played a pivotal part in early cyst growth, but was less
important as the cyst got bigger.
As the cyst expands, there must be some compensatory
epithelial proliferation to cover the greater surface area of
the cyst lumen. Similar mechanisms occur in all cyst types
and studies have shown that the proliferation rate of the
lining epithelium is similar in dentigerous and radicular
cysts (Martins et al. 2011). There is also evidence that the
74 Dentigerous Cyst
PTCH gene and the Sonic hedgehog (HH) signalling path-
way are activated in a number of cyst types, including den-
tigerous cyst (see below), and this may contribute to cell
proliferation and growth.
Degradation of the Connective Tissues
and Bone Resorption
Growth and enlargement of all odontogenic cysts must be
accompanied by degradation of the adjacent connective
tissues and resorption of surrounding bone. Mechanisms
of bone resorption have been considered in detail in
Chapter  3, and these apply equally to bone resorption in
dentigerous cysts. Of particular interest is the role of IL-­1
and prostaglandins, both of which are produced in denti-
gerous cysts and appear to have a pivotal role in mediating
osteoclastogenesis and bone resorption (Harris and
Goldhaber  1973; Harris et  al.  1973; Harris  1978; Meghji
et  al.  1989; Bando et  al.  1993; Meghji et  al.  1996). In the
case of radicular cysts, it is inflammation that produces the
network of biological factors that underpin growth of the
cyst (Table  3.2), but in dentigerous cysts inflammation
plays a lesser role and the initiating factors are less clear.
During normal tooth eruption there is turnover of adja-
cent connective tissues and bone around the erupting
tooth, with bone resorption above the erupting tooth and
redeposition below it. This is thought to be mediated by a
cascade of paracrine signalling events in the follicular tis-
sues surrounding the developing tooth. These events may
be initiated by tissue remodelling and apoptosis of the fol-
licular tissues after enamel formation is complete, result-
ing in production of cytokines, including IL-­1 and
parathyroid hormone related protein (PTHrP), both of
which influence osteoclastogenesis and bone resorption
(Wise et al. 2002; Nel et al. 2015; Bastos et al. 2021). If tooth
eruption is impeded, these events will still occur, but rather
than facilitating tooth eruption, they may result in bone
resorption that allows a developing cyst to grow. This sug-
gests that bone resorption in dentigerous cysts is similar to
the normal bone remodelling that might occur during
eruption, but is perturbed by the impaction of the tooth.
This idea is supported by the observation that there is no
difference in the expression of bone resorption–related
matrix metalloproteinases (MMPs) between dentigerous
cysts and normal dental follicles (Suojanen et al. 2014).
Although dentigerous cysts are developmental in origin,
most become inflamed as they get larger. This may be a
direct result of the signalling events described above,
which will facilitate recruitment of monocytes and other
inflammatory cells, but may also be a result of trauma or
infection. As cysts grow, especially in the third molar
region, they may become continuous with the oral cavity
through a periodontal pocket distal to the second molar, or
Box 5.3  Pathogenesis: Key Facts
Three elements are needed for cyst formation:
●● A source of epithelium
●● A stimulus for epithelial proliferation
●● A mechanism of growth and bone resorption
Dentigerous cysts are developmental in origin and
the initiating factors are poorly understood. However,
cyst development can still be considered in three phases:
●● Phase of initiation – the reduced enamel epithelium
overlying an unerupted tooth proliferates and
forms clefts, either within the epithelium or
between the epithelium and the tooth crown
●● Phase of cyst formation –  accumulation of debris
and proteins in the clefts increases luminal osmotic
pressure, resulting in cyst formation and expansion
●● Phase of growth and enlargement – expansion of the
cyst is associated with epithelial cell proliferation
and bone resorption. These events may be facilitated
by perturbed bone remodelling and by associated
inflammation
they may be traumatised by the occlusion. It is almost cer-
tainly the case, therefore, that inflammation plays a role in
cyst growth and destruction of bone and adjacent tissues.
Dentigerous Cysts and the PTCH Gene
The role of the PTCH gene and the hedgehog (HH) signal-
ling pathway in the pathogenesis of the odontogenic
keratocyst is discussed in Chapter 7. The point is made that
although PTCH alterations are important in keratocysts,
they do not seem to be specific, and there is some evidence
that PTCH may be involved in other odontogenic lesions
(Gomes and Gomez  2011), including orthokeratinised
odontogenic cyst (Diniz et  al.  2011), calcifying epithelial
odontogenic tumour (Peacock et al. 2010), glandular odon-
togenic cyst, and dentigerous cysts (Levanat et  al.  2000;
Pavelić et al. 2001; Barreto et al. 2002; Zhang et al. 2010).
Although much more research is needed, the studies show-
ing loss of heterozygosity (LOH) of the PTCH gene in den-
tigerous cysts (Levanat et al. 2000; Pavelić et al. 2001) have
not yet been repeated and sequencing studies to investigate
mutations have not been performed.
Levanat et al. (2000) examined seven each of dentiger-
ous cysts, radicular cysts, and odontogenic keratocysts for
LOH in two regions of the PTCH gene. Three of seven
dentigerous cysts and four of seven keratocysts showed
LOH in the 9q22.3 region of the gene and one from each
group showed loss at 9q31. LOH was not detected in any

radicular cysts. In a further study, the same group (Pavelić
et al. 2001) confirmed these findings in a larger series and
found LOH in the same region in five of ten dentigerous
cysts. They also used RT-­PCR in two cysts to show that the
PTCH gene was still expressed despite evidence of
LOH. They interpreted this to mean that the remaining
allele must be mutated, otherwise normal PTCH protein
would have blocked the normal signalling pathway.
Inactivation of the PTCH gene and reduced expression of
the PTCH protein may lead to activation of the hedgehog
signalling pathway. This is discussed in detail in Chapter 7
in the context of the odontogenic keratocyst, but there is
good evidence that hedgehog signalling contributes to the
pathogenesis of the dentigerous cyst and may promote
growth and cell proliferation. Vered et  al. (2009) exam-
ined the expression of the hedgehog pathway–associated
proteins PTCH, SMO, and Gli1 in keratocysts, orthokerati-
nised odontogenic cysts, dentigerous cysts, and radicular
cysts. PTCH and Gli1 were expressed strongly in all cyst
types; SMO was found in all keratocysts and in 33% of
orthokeratinised odontogenic cysts and 40% of dentiger-
ous cysts. In a similar study, Zhang et al. (2010) examined
20 dentigerous cysts and found homogeneous expression
of SHH, PTCH, SMO, and Gli1 in the epithelial lining of
all lesions. They also found similar expression in all cases
(n = 12) of glandular odontogenic cyst examined.
These studies suggest that aberrations in the PTCH recep-
tor and activation of the HH signalling pathway are not spe-
cific to keratocysts. PTCH gene alterations may represent a
decisive initiating event in the formation of developmental
odontogenic cysts, possibly in a progenitor epithelial cell,
which then gives rise to the entire epithelial lining. The
resultant activation of the hedgehog signalling pathway may
then drive growth and expansion of the cyst. Such a scenario
could explain a role for HH signalling in many odontogenic
lesions, including dentigerous cysts, but does not exclude a
further role for specific PTCH mutations in keratocysts.
Gomes and Gomez (2011) supported this view and sug-
gested that PTCH1 may act as a gatekeeper gene for many
types of odontogenic lesions, and that further genetic
events drive the formation of different cysts or tumours.
Inflammatory Dentigerous Cyst
As described above, the vast majority of dentigerous cysts
are developmental in origin, and although inflammation
may play a role in growth and enlargement, initiation of the
epithelial proliferation remains speculative. However, in
some cases there is good evidence that cyst development
may be initiated by inflammation, resulting in a true inflam-
matory dentigerous cyst. The pathogenesis of these cysts
involves stimulation of the reduced enamel epithelium of a
­Pathogenesi  75
Figure 5.15  An inflammatory dentigerous cyst. The crown of
the developing first premolar is surrounded by a well-­
demarcated radiolucency associated with the roots of the
overlying deciduous teeth.
developing permanent tooth by periapical inflammation
from a carious, non-­vital deciduous precursor. Thus, inflam-
matory dentigerous cysts arise in children, in the mixed
dentition, and most frequently are associated with develop-
ing premolars (Figure  5.15). Most cases are single case
reports, but some series of inflammatory dentigerous cysts
have been published (Benn and Altini  1996; Shibata
et al. 2004; Marques et al. 2017; Huang et al. 2019).
Benn and Altini (1996) reported 15 patients ranging in age
from 5 to 12 years. In 13 cases the cyst was associated with
periapical inflammation from a non-­vital deciduous prede-
cessor, while in 2 patients there was evidence of osteomyeli-
tis. The mandible was involved in 10 cases and premolars
were the most commonly affected teeth (9 cases), followed
by canines (4 cases). The mandibular second permanent
molars were involved in the 2 cases associated with osteomy-
elitis. Of note is that two-­thirds (10) of the cases presented
with pain and swelling. On pathological examination, all the
cysts were attached to the cervical region of the teeth and
were composed of an inflamed wall lined by non-­keratinised
stratified squamous epithelium, with varying degrees of pro-
liferation and hyperplasia. In most cases part of the cyst lin-
ing, adjacent to the tooth, showed a thin layer of cuboidal
epithelium, which they interpreted as evidence of an origin
from the reduced enamel epithelium.
Shibata et al. (2004) reviewed 70 patients under the age of
16 years who had histologically confirmed dentigerous cysts
that had developed between the central incisors and the sec-
ond premolars. Of these cases, 54 (77%) affected the premo-
lar teeth. In 7 cases the deciduous teeth had been extracted,
76 Dentigerous Cyst
but of the remainder, 44 (94%) showed radiological evidence
of a periapical lesion and 98% (53 of the 54) of cases were
inflamed on histological examination. Marques et al. (2017)
reported similar findings and found that 6 of their 12 cases
affected the maxillary canines and 6 affected the mandibular
second premolars. Radiology showed well-­demarcated radi-
olucencies ranging from 10 to 27 mm in diameter. All cysts
were inflamed and lined by variably hyperplastic non-­
keratinised stratified squamous epithelium.
These studies support the concept of an inflammatory
aetiology in the pathogenesis of some dentigerous cysts.
Nevertheless, individual cases need to be assessed criti-
cally. Attachment of the cyst wall to the neck of the associ-
ated tooth is an essential feature, and microscopically the
cyst lining should demonstrate a readily identifiable com-
ponent of reduced enamel epithelium before a diagnosis of
dentigerous cyst is made.
‘Extrafollicular Dentigerous Cyst’
In 1958, Gillette and Weinmann (1958) reported two cysts
that enveloped the crowns of unerupted teeth and on radi-
ology were seen to be in a ‘dentigerous relationship’. They
proposed that an alternative mechanism for the pathogen-
esis of dentigerous cysts is that they may arise from epithe-
lium outside of the dental follicle (presumably dental
lamina rests) and then envelop the tooth. They introduced
the term ‘extrafollicular dentigerous cyst’. Since their paper,
it has often been reported that a dentigerous cyst may have
an extrafollicular origin. However, examination of their
paper reveals that both of their cysts show the histological
features of what we now recognise as odontogenic kerato-
cyst, and both were separated from the tooth follicle (and
reduced enamel epithelium) by a fibrous cyst wall. As dis-
cussed previously (see ‘Differential Diagnosis’; Figure 5.14),
a number of lesions, including odontogenic keratocysts,
may arise from within the dental crypt and embrace an
unerupted tooth in a dentigerous relationship. Therefore,
there is no evidence for an extrafollicular origin for denti-
gerous cysts.
In this context it is worth reviewing Browne’s definition
of a dentigerous cyst (Browne 1991b) as a cyst that ‘by defi-
nition is one which encloses the crown of an unerupted
tooth lying within bone and cannot be assigned to any
other classification’. Thus the criteria for diagnosis must
include a consideration of the histological features (see
‘Histopathology’ and Box 5.4) and if these show a defined
lesion, such as a keratocyst or ameloblastoma, then the
lesion is not a dentigerous cyst.
A nice historical discussion of this is given by Altini and
Cohen (1982,  1987), who reported 17 cases of odontogenic
keratocyst that presented in a dentigerous relationship with
unerupted teeth (similar to Figure 5.14). In all cases the cysts
showed typical histological features of an odontogenic
keratocyst. In five cases they were able to process the cyst and
tooth in continuity, and in all five they found a keratocyst lin-
ing, but at the point where the cyst joined the cervical region
of the tooth, the keratocyst lining merged with a typical
reduced enamel epithelium. They postulated that the cyst
develops from epithelial rests outside of the dental follicle
and that the tooth then erupts into the cyst and the lining
merges with the reduced enamel epithelium. In their 1987
paper (Altini and Cohen 1987), they demonstrated in animal
studies that this mechanism can occur. An earlier study by
Browne (1971a) had investigated 139 odontogenic kerato-
cysts and found 56 cases associated with an unerupted tooth.
Of these, 8 (14%) were found to have a keratocyst lining that
was attached at the cementoenamel junction of the tooth.
Altini and Cohen (1982) and Browne (1991b) have called
these cysts ‘envelopmental primordial cyst (keratocyst)’
and clearly state that, although they have a dentigerous
relationship with the teeth, they are not dentigerous cysts.
They are odontogenic keratocysts and should be managed
as such. A similar mechanism may give rise to other lesions
being in a dentigerous relationship, including cystic amelo-
blastoma, orthokeratinised odontogenic cyst, adenomatoid
odontogenic tumour, and calcifying odontogenic cyst.
With regard to the inflammatory dentigerous cyst dis-
cussed above, consideration must also be given to the pos-
sibility that these arise due to the crown of a permanent
tooth erupting into a radicular cyst formed at the apex of its
deciduous predecessor. This phenomenon possibly does
occur, but only exceptionally rarely, because radicular cysts
involving the deciduous dentition are so uncommon
(Lustmann and Shear 1985). In such a case, the erupting
tooth may indent rather than penetrate the wall of the
radicular cyst and this should be apparent histologically, if
not macroscopically (Gebhardt and Lenz  1985; Wood
et al. 1988). Figure 5.16 illustrates how this might occur.
Dentigerous Cyst as a
Potential Ameloblastoma
A simple search of the literature will show many case
reports suggesting that dentigerous cysts are a precursor
of various neoplasms, usually ameloblastoma. Ameloblas­
tomas are of odontogenic epithelial origin and therefore it
is possible that they may arise from reduced enamel epi-
thelium or a dentigerous cyst lining, as well as any other
odontogenic epithelium. However, the belief that it com-
monly arises in this situation and that the dentigerous cyst
should be regarded as pre-­ameloblastomatous should be
viewed with caution. Much of the confusion has probably
arisen for three reasons. First, an ameloblastoma (like an

(a)
Figure 5.16  (a) A radicular cyst associated with a deciduous mandibular second molar appears to be in a dentigerous relationship
with the erupting premolar. Source: Courtesy of Dr J. Lustmann. (b) A diagrammatic representation of the probable relationship, where
the erupting tooth has indented the radicular cyst wall.
Figure 5.17  Radiograph of a unilocular
ameloblastoma that appears to be in a
dentigerous relationship with unerupted teeth.
odontogenic keratocyst) may envelop an unerupted tooth,
particularly a third molar at the angle of the mandible,
and this may be incorrectly interpreted as a dentigerous
cyst on radiographs (Figure 5.17). When subsequently the
lesion is removed and diagnosed histologically as an
ameloblastoma, the erroneous conclusion may be reached
that the ameloblastoma developed from a dentigerous
cyst. In this situation, it is considered that the ameloblas-
toma arises from dental lamina rests within the crypt of
the developing tooth and envelops the tooth crown in a
dentigerous relationship.
The second possible reason for believing that many
ameloblastomas develop from a dentigerous cyst is that
biopsies of a radiolucent lesion may be taken of a superficial
­Pathogenesi  77
(b)
expanded locule lined by a thin layer of epithelium. If the
surgeon’s provisional diagnosis is dentigerous cyst because
of the radiological picture, the pathologist may well regard
such histological features as consistent with this diagnosis.
When the tumour is removed entirely and a diagnosis of
ameloblastoma is made, once again this may be misinter-
preted as having developed from a dentigerous cyst.
A third reason may be misinterpretation of epithelial
islands within a cyst wall. Isolated islets or follicles of
odontogenic epithelium are sometimes found in the wall of
a dentigerous cyst some distance from the epithelial lining.
If prominent or enlarged, these may be interpreted as
ameloblastoma, although they bear only a superficial
resemblance to the tumour.
78 Dentigerous Cyst
­Histopathology
Pathologists very rarely receive a specimen where the cyst is
intact and often may not receive the associated tooth.
Usually the thin cyst wall is torn or fragmented during the
surgical procedure. Nevertheless, pathologists should per-
form a careful dissection of the gross specimen and care-
fully examine the associated tooth to determine that the
cyst surrounds the crown of the tooth, and is attached at the
cementoenamel junction. Figure 5.18 shows an example of
a dentigerous cyst attached to the cervical region of the
Figure 5.18  A dentigerous cyst and the associated tooth, in
this case a canine. The cyst is attached to the cervical region at
the cementoenamel junction.
Figure 5.19  A low-­power view of a decalcified section of a dentigerous cyst and its associated tooth. The cyst envelops the crown
and is attached to the tooth at the cementoenamel junction. Source: Courtesy of Prof. Paul Speight (Previously published: El-Naggar AK
2017 / Courtesy of IARC).
tooth at the cementoenamel junction. Thus, the lumen of
the cyst is partially lined by the enamel of the tooth.
If the associated tooth is decalcified with the cyst
attached, histology will show that the cyst is attached at the
cementoenamel junction of the tooth (Figure 5.19). Typical
histology shows a thin, fibrous cyst wall that, being derived
from dental follicle, consists of fine stellate fibroblasts
widely separated by stroma and ground substance to give a
slightly myxoid appearance (Figures  5.20 and  5.21). The
epithelial lining is usually thin, non-­keratinised stratified
squamous epithelium about two to five cell layers thick
(Figure 5.20). This is derived from the reduced enamel epi-
thelium and occasionally, especially in small cysts, a sim-
ple bilayer of cuboidal cells resembling reduced enamel
epithelium may be seen (Figure 5.21).
Although a typical developmental cyst is uninflamed, as
discussed previously inflammation may play a role in cyst
growth and occasional inflammatory cells are seen in the
wall. Often, however, by the time they present clinically,
dentigerous cysts have become traumatised and areas of
heavy inflammation are seen. This is often associated with
epithelial proliferation and the cyst may then resemble, or
be indistinguishable from, a radicular cyst (Figure  5.22).
Similar to radicular cysts, inflammation may be accompa-
nied by accumulation of granulation tissue and cholesterol
clefts are not uncommon. In most analyses about 70–80%
of dentigerous cysts show evidence of inflammation in the
wall (Lin et al. 2013; Huang et al. 2019) and this is more
common and intense in paediatric cases, where an inflam-
matory origin may be apparent (Benn and Altini  1996;
Shibata et al. 2004; Huang et al. 2019). In their analysis of
338 dentigerous cysts, Lin et al. (2013) found that 71% of
dentigerous cysts were inflamed, 26.6% contained choles-
terol clefts, and 30% had foamy or hemosiderin-­laden
macrophages.
 ­Histopatholog  79

Figure 5.20  The wall of a dentigerous cyst lined by a thin epithelium of two to four layers of undifferentiated cells derived from the
reduced enamel epithelium. The fibrous cyst wall is relatively uninflamed and sparsely cellular.

Figure 5.21  The wall of a dentigerous cyst, composed of loose myxoid fibrous connective tissue lined by two-­layered cuboidal
epithelium, resembling the reduced enamel epithelium from which it is derived.

Figure 5.22  An inflamed region of a dentigerous cyst wall, lined by hyperplastic epithelium. The features are indistinguishable from
those seen in inflammatory odontogenic cysts.
80 Dentigerous Cyst
Figure 5.23  A portion of the lining of a dentigerous cyst shows mucous metaplasia.
In some cysts, part of the epithelial lining may contain
mucous-­producing cells (Figure 5.23). Browne (1972) found
them in 36% of mandibular and 53% of maxillary dentiger-
ous cysts, and made the interesting observation that the fre-
quency of such mucous cells increased in proportion to the
age of the patient. In a sample of 130 dentigerous cysts,
Takeda et al. (2005) found mucous cells in the linings of 31
(23.8%) cysts and ciliated cells in 14 (10.8%), indicating that
both can be present together. It has been thought that
mucous and cilia are more likely to be found in maxillary
cysts, and may be associated with proximity to the epithelial
lining of the maxillary antrum. Takeda et al. (2005), how-
ever, found that ciliated cells were more frequently encoun-
tered in the mandible, but overall there were no significant
differences between the mandible and maxilla.
Nests, islands, and strands of odontogenic epithelium
are often seen in the fibrous cyst wall. These are almost
certainly epithelial remnants of the dental lamina and
have been reported in about 20–25% of cases (Lin
et al. 2013; Huang et al. 2019). Wright (1979) reported the
presence of larger epithelial proliferations that resem-
bled squamous odontogenic tumour. In a review of the
literature, Chrcanovic and Gomez (2018b) found reports
of 60 cases of squamous odontogenic tumour–like prolif-
erations in odontogenic cysts. Most were seen in radicu-
lar cysts (51 cases; 85.0%), but 6 dentigerous cysts with
squamous odontogenic tumour–like proliferations had
been reported.
Another rare example of metaplasia in dentigerous cysts
is the occasional presence of sebaceous glands in their
walls (Chi et al. 2007). Hyaline bodies (Rushton 1955) are
also sometimes seen (Lin et  al.  2013). Takeda and
Yamamoto (2001) have reported a case of a dentigerous
cyst containing granules of melanin pigment and dendritic
melanocytes in the basal cells of the lining epithelium.
Immunohistochemistry and Biomarker Studies
Numerous immunohistochemical studies have been
undertaken to compare the expression of cytokeratins (CK)
and other markers in dentigerous cyst epithelium with that
of the odontogenic keratocyst, radicular cyst, and amelo-
blastoma. The purpose of these studies is not always well
articulated, but overall they represent attempts to shed
light on the pathogenesis or to assist in diagnosis. In par-
ticular, many recent studies have used markers in an
attempt to highlight differences between dentigerous cysts
and keratocysts, with a view to establishing the neoplastic
nature of the keratocyst. This is discussed in Chapter 7.
With regard to diagnosis, the clinical, radiological, and
histological features of the individual cyst types are char-
acteristic, and if strict diagnostic criteria are followed
diagnosis is rarely a problem (Box 5.4). A particular diag-
nostic challenge may arise when a pathologist is faced
with a small biopsy from a large radiolucent lesion, and in
this situation a diagnostic marker may be useful.
Furthermore, if the cyst lining is inflamed, then all cyst
types (as well as a cystic ameloblastoma) may show identi-
cal features of a proliferative or hyperplastic epithelial lin-
ing and therefore be indistinguishable from each other.
Overall, however, immunocytochemistry appears to have
a limited role in the diagnosis of odontogenic lesions
(Hunter and Speight 2014).
Bhakhar et al. (2016) investigated the expression of CK18
and CK19  in dentigerous cysts, odontogenic keratocysts,
and radicular cysts, and found that while more dentigerous
cysts than keratocysts expressed both cytokeratins, expres-
sion in radicular cysts was the same as in dentigerous cysts.
These authors also reviewed 5 studies that had investigated
CK18, and 17 studies that had investigated CK19. These
showed either no differences between the different cyst
 ­Histopatholog  81

Box 5.4  Dentigerous Cyst: Criteria for Diagnosis

●● A correct diagnosis is facilitated by careful correlation of clinical, radiological, and histological features. The patholo-
gist should review the radiographs or the radiologist’s report to confirm the relationship of the cyst to the crown of
an unerupted tooth
●● Dentigerous cysts always present as a radiolucency around the crown of an unerupted or impacted tooth
●● The radiolucency, or pericoronal space, is greater than 5 mm, although a space of 10 mm or greater is most likely to
be a dentigerous cyst
●● A cystic cavity or lumen can be demonstrated at surgery or on macroscopic examination
●● The cyst lining is attach to the cervical region of the tooth at the cementoenamel junction. This can be seen on
macroscopic examination or microscopically if the tooth and cyst are processed together
●● On histological examination the cyst is lined by thin, regular non-­keratinised stratified epithelium. Areas of bilayered
cuboidal epithelium resembling reduced enamel epithelium may be seen
●● Inflammation is often present
●● A lining showing features of an odontogenic keratocyst or ameloblastoma excludes a diagnosis of dentigerous cyst,
even if the lining is attached to the tooth. These would be ‘envelopmental’ lesions

types or wide variability within or between the studies.
This degree of variability suggests that the use of cytokerat-
ins as a diagnostic test on a single isolated case would be
inappropriate and grossly inaccurate.
It is also notable that in most studies the specimens are
chosen to show the typical features of each cyst type, in
seeming disregard of the fact that if the features are typical,
then there is no requirement for staining beyond a good
haematoxylin and eosin (H&E) stain to differentiate
between the lesions most commonly encountered around
unerupted teeth (Müller 2021). Few studies have been able
to identify markers that may differentiate between the his-
tologically identical features of an inflammatory cyst and
an inflamed developmental cyst  –  this is because when
inflamed, the histology and CK expression are the same.
Many studies have also investigated proliferation mark-
ers, but rarely for diagnostic purposes. Rather, these stud-
ies have sought to compare the proliferative potential of
the lining of the odontogenic keratocyst to other cyst types
(reviewed by Shear 2002b; Kichi et al. 2005). Almost with-
out exception, studies have shown that keratocyst linings
have a greater proliferation rate than dentigerous or radic-
ular cysts, although they may be similar to cystic amelo-
blastomas. These studies support the role of mural growth
in the expansion of keratocysts, but add little to our under-
standing of the diagnosis or pathogenesis of dentiger-
ous cysts.
An exception to this discussion may be the expression
of calretinin, which in the context of odontogenic lesions
appears to be specific for ameloblastomas and is there-
fore useful in the differential diagnosis of cystic lesions,
especially in small biopsies (Coleman et  al.  2001; De
Villiers et al. 2008; Hunter and Speight 2014). Coleman
et al. (2001) studied a series of 22 keratocysts, 26 residual
cysts, and 20 dentigerous cysts, all of which were nega-
tive for calretinin, compared to 81.5% of unicystic amelo-
blastomas that had been shown to be positive in their
previous study (Altini et al. 2000). Subsequently, a num-
ber of studies have confirmed that odontogenic cysts,
including dentigerous cysts, are negative for calretinin,
but that ameloblastomas (including unicystic ameloblas-
toma) are positive in up to 100% of cases (De Villiers
et al. 2008; Jeyaraj 2019; Rudraraju et al. 2019).
Malignant Change in Dentigerous Cysts
Intraosseous squamous cell carcinoma is a central jaw car-
cinoma that arises from odontogenic epithelium (Koutlas
and Sloan  2022). Although these may arise from odonto-
genic epithelial rests, the majority probably arise from the
epithelium of odontogenic cysts. Overall they are exceed-
ingly rare, but they most commonly arise in radicular cysts
followed by dentigerous cysts and then odontogenic kerato-
cysts. However, this does not reflect a particular propensity
to malignant change within the epithelium of the different
cyst types, but rather their relative frequency.
Bodner et  al. (2011) reviewed the literature and found
reports of 116  intraosseous carcinomas that had arisen in
odontogenic cysts between 1938 and 2010. Of these, 19
cases (16%) arose in a dentigerous and 70 (60%) in a radicu-
lar cyst, and 16 (14%) in a keratocyst. Well or moderately
differentiated squamous cell carcinomas represented 85%
of lesions, and there were no differences in lesions from dif-
ferent cyst types. In their systematic review, Borrás-­Ferreres
et al. (2016) identified 48 reports of carcinomas arising in
odontogenic cysts, but they excluded keratocysts (which
they defined as benign tumours, keratocystic odontogenic
tumour or KCOT). They identified 53 cases of which 27
82 Dentigerous Cyst
(51%) arose in dentigerous cysts, 4  in radicular cysts, and
10 in residual cysts. They found 6 cases in orthokeratinised
odontogenic cysts. In both series, males accounted for
60–70% of the cases, and the average age was about 60 years,
a decade or two older than the average age for benign cysts.
­Treatment
The mainstay of treatment of the dentigerous cyst is enu-
cleation of the cyst with or without removal of the involved
tooth. In the case of impacted third molars, the tooth is usu-
ally extracted, but when canines or premolars are involved
in children, the emphasis is on conservative enucleation,
often combined with orthodontics, in order to retain the
involved tooth and to ensure eruption into normal
occlusion (Bodner 2002; Motamedi and Talesh 2005; Hauer
et  al.  2020). Marsupialisation or decompression may be
used when attempting to preserve the teeth (Koca et al. 2009;
Hyomoto et al. 2003). In their series, Hyomoto et al. (2003)
performed a retrospective investigation into the eruption
of teeth associated with dentigerous cysts involving
47 mandibular premolars and 11 maxillary canines in pre-­
adolescent children. In one group, 81% of the mandibular
premolars and 36% of the maxillary canines erupted suc-
cessfully about 100 days after marsupialisation without
traction. Koca et al. (2009) successfully treated 35 children
with marsupialisation followed by eruption of the associ-
ated tooth. The eruption potential of the teeth was closely
related to root formation, so that teeth with incomplete root
formation had good potential to erupt, whereas those with
fully formed roots may not.
 83

Eruption Cyst

CHAPTER MENU
­Clinical Features, 83
●● Frequency, 83
●● Age, 83
●● Sex, 84
●● Site, 84
●● Clinical Presentation,  84
­Radiological Features, 84
­Pathogenesis, 85
­Histopathology, 85
­Treatment, 86

An eruption cyst is a variant of dentigerous cyst occurring in
the soft tissues overlying an erupting tooth. Whereas the den-
tigerous cyst develops around the crown of an unerupted or
impacted tooth within the bone, the eruption cyst is associ-
ated with a tooth that might otherwise erupt normally.
­Clinical Features
Frequency
Eruption cysts are usually treated conservatively and tissue
is rarely sent for histological examination. Since most
series of cysts are derived from pathology departments, the
reported frequency and prevalence appear, falsely, to be
low. Tables 1.1 and 1.2 show that in our series, eruption
cysts comprised only 0.8% and 0.2% of cysts, respectively.
Of those studies shown in Table 5.1 that reported eruption
cysts, the frequency ranged from 0.1% to 1.0% of odonto-
genic cysts, but all studies only reported cases that had
been ­submitted for histological examination (Daley and
Wysocki 1995; Ledesma-­Montes et  al.  2000; Jones
et al. 2006; Ochsenius et al. 2007; Sharifian and Khalili 2011;
Soluk Tekkeşın et  al.  2012b; Lo Muzio et  al.  2017;
Tamiolakis et al. 2019).
It is likely that eruption cysts are seen much more fre-
quently clinically and because many rupture spontane-
ously, they are not excised and are therefore not submitted
for histological examination. Bodner (2002) reported a
series of 69 paediatric patients with cystic lesions of the
jaws, diagnosed clinically as well as on histology, and found
that 15 (22%) were eruption cysts. In their large series of 66
cases, Şen-­Tunç et  al. (2017) showed that only 10 (15%)
required surgical intervention. This suggests that the true
prevalence of eruption cysts might be 10 times, or more,
higher than that reported from pathology series.
Age
Eruption cysts are found in children and rarely in adults.
In the three largest series reported, the mean ages of the
patients affected were 6.7 years (n  =  27; range 13 months
to  11 years; Aguilo et  al.  1998), 4.4 years (n  =  24; range
1 month to 12 years; Bodner et  al.  2005), and 5.4 years
(n = 53; range 5 months to 11 years; Şen-­Tunç et al. 2017).
Occasional cases have been reported in adults, usually
associated with teeth that had been impacted but erupted
late. Seward (1973) recorded a case in a 21-­year-­old and
Woldenberg et  al. (2004) documented an unusual case

Shear’s Cysts of the Oral and Maxillofacial Regions, Fifth Edition. Paul M. Speight.
© 2022 John Wiley & Sons Ltd. Published 2022 by John Wiley & Sons Ltd.
84 Eruption Cyst
that occurred in a 40-­year-­old woman associated with an
impacted canine erupting ectopically in the buccal mucosa.
Eruption cysts have also been reported at birth, either
associated with natal teeth (Bodner 2002) or presenting as
a swelling in the anterior mandible associated with devel-
oping deciduous incisors (de Oliveira et al. 2018).
Sex
In almost all series, boys have been affected more often
than girls. In the three large series the proportions of males
were 55.6% (Aguilo et al. 1998), 66.6% (Bodner et al. 2005),
and 58.4% ­(Şen-­Tunç et al. 2017).
Site
Deciduous and permanent teeth may be involved, most fre-
quently anterior to the first permanent molar. Aguilo et al.
(1998) found that over 90% of their cases arose in the per-
manent dentition and 80.6% were in the maxilla. This is
unusual, however, and other large series and the majority
of case reports have shown an almost equal distribution
between the primary and permanent dentition. Bodner
et  al. (2005) and Şen-­Tunç et  al. (2017) found 50% and
58.5%, respectively, in the permanent dentition. The teeth
most frequently involved in the permanent dentition have
been maxillary central incisors and first molars, and in the
primary dentition, maxillary first molars and maxillary or
mandibular incisors (Aguilo et al. 1998; Bodner et al. 2005;
Şen-­Tunç et al. 2017).
Multiple eruption cysts are not unusual (Figure  6.1).
Aguilo et al. (1998) found two or more eruption cysts in 6
of their 27 patients, and in 3 of these the lesions were
bilateral, symmetrical, and concurrent. Şen-­Tunç et  al.
(2017) found multiple cysts in 13 of their patients (24.5%),
Figure 6.1  Eruption cysts involving both maxillary permanent
incisors.
10 of which were in the primary dentition and were sym-
metrically bilateral. Kimura et al. (2014) described a child
who had had six eruption cysts. The first two presented
around mandibular central incisors at 7 months old, and
regressed spontaneously. At 18 months the child devel-
oped four cysts simultaneously on all four deciduous
first molars.
Clinical Presentation
The eruption cyst produces a smooth swelling over the
erupting tooth, which in most cases is blue or translucent
and blueish (Figure 6.1). Occasional cases are the colour
of normal gingiva or clear. It is usually painless unless
infected and is soft and fluctuant. In Şen-­Tunç et  al.’s
(2017) series of 53 patients, only 7 (13.2%) reported symp-
toms and these comprised dull aching pain, usually appar-
ent during eating.
There is often a brief history of about three to four
weeks’ duration during which they enlarge to approxi-
mately 1–1.5 cm. They are usually exposed to masticatory
trauma, which causes haemorrhage and the blue colour,
and are sometimes referred to clinically as an ‘eruption
haematoma’ (Figure  6.1). The majority of cases resolve
spontaneously or are ruptured during mastication and
heal uneventfully.
­Radiological Features
The cyst may throw a soft-­tissue shadow, but there is usu-
ally no bone involvement, except that the dilated and open
crypt may be seen on the radiograph.
Box 6.1  Eruption Cyst: Key Facts
●● Eruption cysts may constitute up to 10% of odonto-
genic cysts
●● The clinical features are typical, and radiology and
histopathology play only a minor role in diagnosis
●● They arise in children, with most seen between
5 and 7 years
●● About 60% are found in males, with a M : F ratio of
about 2 : 1
●● Deciduous teeth and permanent teeth are almost
equally affected
●● In the primary dentition incisors and maxillary first
molars are most often affected
●● In the permanent dentition first molars and maxillary
central incisors are most often affected
●● Most lesions present as soft, fluctuant bluish swellings

Figure 6.2  Histological features of an
eruption cyst. The surface epithelium is
at the top right and the cyst lumen at the
bottom of the photomicrograph. The cyst
lining is thin and has become fragmented
(arrows). Focal infiltrates of chronic
inflammatory cells are seen in the wall.
­Pathogenesis
The pathogenesis of the eruption cyst is similar to that of
the dentigerous cyst. The difference is that tooth eruption
in the case of the eruption cyst is impeded in the soft tis-
sues of the gingiva rather than in the bone. As Browne and
Smith (1991) have argued, ‘as the crown of the tooth associ-
ated with an eruption cyst usually projects into the cyst
lumen, it is widely believed that the epithelium is derived
from the reduced enamel epithelium, as in the dentigerous
cyst’. The factors that actually impede eruption in the soft
tissues are not known. It is possible that cyst formation
may be associated with trauma to the overlying alveolus as
a result of mastication. Trauma may cause gingival fibrosis,
and any associated inflammation might initiate epithelial
proliferation and cyst formation, as discussed for dentiger-
ous cyst in Chapter 5.
Interestingly, there is some evidence that fibrosis may
have a role, by showing that the administration of cyclo-
sporine may lead to the development of eruption cysts. The
first article (O’Hara et al. 2002) reported the development of
multiple eruption cysts in neonatal dogs given oral cyclo-
sporine as an immunosuppressant, as part of an investiga-
tion of the efficacy of adenoviral-­mediated gene therapy in
a canine model of Duchenne muscular dystrophy. The cysts
resolved within one month when cyclosporine administra-
tion was discontinued. In the second report (Kuczek
et al. 2003), eruption cysts developed in a boy treated with
cyclosporine A following a heart transplant. The child was
given periodontal treatment and the cyclosporine A was
switched to tacrolimus, following which no further erup-
tion cysts developed. These findings cannot impute any
­Histopatholog 85
general aetiological role in eruption cyst formation, but are
important to note as a possible side effect when cyclosporine
medication is being considered. Cyclosporine is known to
cause gingival fibrosis and it may be that this impedes erup-
tion and has a role in cyst formation.
­Histopathology
There are no specific histopathological features of the
eruption cyst and histological examination plays only a
minor role in diagnosis. Few cysts are actually biopsied and
when tissue is made available it is usually as a result of
surgical treatment, which involves marsupialisation. The
pathologist receives only the superficial part of the cyst
wall (Figure 6.2). This is covered by the keratinised, strati-
fied squamous epithelium of the overlying gingiva, sepa-
rated from the cyst by a strip of dense connective tissue of
varying thickness, which usually shows a chronic inflam-
matory cell infiltrate. Sometimes it is possible to distin-
guish a line of demarcation between gingival and follicular
connective tissues. The gingival connective tissue is rela-
tively acellular and densely collagenous, while the follicu-
lar connective tissue is more cellular, less collagenous, and
may be myxoid with a basophilic hue.
The epithelial lining of the cyst is of reduced enamel epi-
thelial origin and characteristically consists of two to three
cell layers of squamous epithelium, with a few foci where it
may be a little thicker. Invariably, however, the epithelial
lining is fragmented (Figure  6.2). If the cyst is heavily
inflamed, the epithelial lining may be proliferative and
hyperplastic.
86 Eruption Cyst
­Treatment
Eruption cysts should be treated conservatively and in
many cases only reassurance is needed. The cysts often
rupture or may resolve spontaneously and the involved
tooth then erupts normally. When surgical intervention is
required, then simple marsupialisation with removal of
the ‘top’ of the cyst almost always has a satisfactory out-
come. In the series of 24 cases reported by Bodner et  al.
(2005), 12  were treated by marsupialisation, and 10
resolved without treatment. In two cases, involved neona-
tal teeth were extracted. Şen-­Tunç et al. (2017) reported 66
cysts, of which 56 (85%) were treated with no intervention
except for advice to ‘massage’ the area. In all cases the
teeth erupted normally between 15 days and 5 months
later. The other 10 cysts were associated with symptoms
and were treated surgically, and in all cases the teeth
erupted within a few weeks.
 87

Odontogenic Keratocyst

CHAPTER MENU
Classification and Terminology: A Brief Historical Review, 88
Clinical Features, 89
•• Frequency, 89
•• Age, 92
•• Sex, 93
•• Site, 93
•• Clinical Presentation,  95
•• Peripheral (Extraosseous) and Soft-­Tissue Keratocysts,  96
–– Peripheral Odontogenic Keratocyst,  96
–– Soft-­Tissue Keratocyst,  96
Naevoid Basal Cell Carcinoma Syndrome (NBCCS), 98
Radiological Features, 100
•• Computerised Tomography and Magnetic Resonance Imaging,  103
•• Radiological Differential Diagnosis,  104
Pathogenesis, 106
•• Source of Epithelium,  106
–– Rest Cells of Dental Lamina,  106
–– Epithelial Islands Derived from Oral Epithelium,  107
–– Summary and Conclusions,  108
•• Hedgehog Signalling Pathway, PTCH Gene Alterations, and Odontogenic Keratocyst,  108
•• Is the Odontogenic Keratocyst a Neoplasm?,  111
–– Summary and Conclusions,  113
•• Growth and Enlargement of the Odontogenic Keratocyst,  113
Histopathology, 117
•• Odontogenic Keratocysts Associated with Naevoid Basal Cell Carcinoma Syndrome,  124
•• Histological Differential Diagnosis,  125
•• Solid Odontogenic Keratocyst,  125
•• Cytology and Aspiration Biopsy,  129
•• Immunohistochemistry and Biomarker Studies,  131
•• Malignant Change in Odontogenic Keratocysts,  132
Recurrence of Odontogenic Keratocyst, 133
•• Factors Associated with Recurrence,  134
–– Clinical and Radiological Factors,  134
–– Histological Factors,  135
Treatment and Recurrence of Odontogenic Keratocyst, 136
•• Treatment Methods,  136
–– Enucleation and Curettage,  136
–– Marsupialisation and Decompression,  137
–– Resection, 137
–– Adjunctive Methods,  137
•• Evaluation of Treatment Methods,  138
–– Summary and Conclusions,  138

Shear’s Cysts of the Oral and Maxillofacial Regions, Fifth Edition. Paul M. Speight.
© 2022 John Wiley & Sons Ltd. Published 2022 by John Wiley & Sons Ltd.
88 Odontogenic Keratocyst
The odontogenic keratocyst has aroused more interest and
debate than any other cyst of the jaws. This is partly because
it has a particular tendency to recur following surgical
treatment, and because it may grow to a large size before it
manifests clinically. More recently, however, interest has
been fuelled by the debate regarding terminology and the
possible neoplastic nature of the lesion. An internet search
of publication numbers showed that between 1963 and
2006 there was an average of 10 publications per year with
odontogenic keratocyst in the title. Since the last edition of
this book (2007) there have been more than 750 papers
with either odontogenic keratocyst or ‘keratocystic odonto-
genic tumour (KCOT)’ in the title, and the average number
of publications per year rose almost fivefold to 47. This
chapter will start with a brief review of terminology and
will later include a discussion on the evidence that the
odontogenic keratocyst may be a benign cystic neoplasm.
­ lassification and Terminology:
C regarded the primordial cyst and dentigerous cyst as both
A Brief Historical Review
It is well established that any epithelial-­lined cyst of the
jaws may, on occasion and often as a result of metaplasia,
show some evidence of keratinisation of the lining. In the
early literature there was no real distinction between what
we now know as odontogenic keratocyst and any jaw cyst
with a keratinised epithelial lining.
Pogrel (2003a) and Ide et al. (2020) have presented his-
torical reviews of the odontogenic keratocyst and described
how early researchers recognised keratinising cysts in the
jaws, but often used terms borrowed from other anatomical
sites such as cholesteatoma or dermoid cyst. Ide et  al.
(2020) traced the first description of keratocysts to 1855,
when they were referred to as ‘buttery cysts’ by
Maissonneuve, the term ‘buttery’ referring to the thick
keratinaceous contents that resemble butter. The term
‘odontogenic keratocyst’ was introduced by Philipsen
(1956), but in this and a subsequent paper (Pindborg
et al. 1962) the term was still used to describe any jaw cyst
in which keratin was formed to a large extent. Some denti-
gerous, radicular, and residual cysts were therefore
included in the category of odontogenic keratocyst. Browne
(1971a) pointed out that although a few radicular and
residual cyst linings may become keratinised by metapla-
sia, the pattern of keratinisation and the histology of the
linings was distinctly different from the characteristic par-
akeratinised lining epithelium of the odontogenic kerato-
cyst. In early studies he showed that the parakeratinised
cysts occurred at a significantly younger age than other
cysts, making it unlikely that they may have arisen by
metaplasia in long-­standing dentigerous or radicular cysts
(Browne  1970,  1971a). A number of studies also demon-
strated that the site distribution of keratinising cysts dif-
fered from that of non-­keratinised cysts (Browne  1970;
Hjørting-­Hansen et al. 1969; Rud and Pindborg 1969), sup-
porting the view that the odontogenic keratocyst was a
separate and distinct entity.
Before Philipsen introduced ‘odontogenic keratocyst’ in
1956, a variety of terms had been used for keratinising cysts
(Pogrel 2003a; Ide et al. 2020), including the term primor-
dial cyst, which was suggested by Robinson in 1945 when
he proposed a comprehensive classification of cysts of the
jaws (Robinson 1945). He suggested that these cysts were
‘formed through degeneration of the stellate reticulum in
enamel organs before any calcified structures had been laid
down’. In other words, they developed from the tooth ‘pri-
mordium’, replaced a developing tooth, and clinically
would present at a site where a tooth was absent, or at the
site of a putative supernumerary tooth. Robinson did not
however describe any distinctive histological features and
arising from the dental lamina, but before and after hard
tissue formation, respectively. Over time it became appar-
ent that if primordial cysts (cysts found to have replaced a
developing tooth) were examined as a group, the vast
majority were found to be parakeratinised, with cuboidal
or columnar palisaded basal cells (Shear  1960a; Forssell
and Sainio 1979). These authors suggested that these were
‘genuine keratocysts’ and that cysts lined by parakerati-
nised epithelium should not be regarded as ‘primordial
cysts’. The studies of Browne (1970,  1971a) showed that
dentigerous cysts and ‘primordial cysts’ were clinically and
pathologically distinguishable as separate entities, and that
the latter were characterised by a wholly parakeratinised
lining and a higher recurrence rate. He proposed that ‘pri-
mordial cyst’ should be abandoned in favour of the more
appropriately descriptive term ‘odontogenic keratocyst’. It
thus became accepted that ‘primordial cyst’ and ‘odonto-
genic keratocyst’ were in fact the same cystic entity charac-
terised by a parakeratinised epithelial lining. In 1971, the
first edition of the World Health Organization (WHO) clas-
sification of odontogenic cysts described odontogenic
keratocyst and primordial cyst as synonymous and defined
it as being characterised by ‘a thin fibrous capsule and a
lining of keratinized stratified squamous epithelium rarely
exceeding about five cells in thickness and having no rete
processes’ (Pindborg and Kramer 1971). The term primor-
dial cyst (as a synonym for odontogenic keratocyst) gradu-
ally fell out of favour and last appeared in the literature in
1987 (Partridge and Towers 1987). It may, however, still be
found as a synonym for odontogenic keratocyst in some
textbooks and also appeared in the second and third edi-
tions of the WHO classification (Kramer et  al.  1992;

Philipsen  2005). Nevertheless, it does not appear in the
fourth or fifth editions of the WHO classification (Speight
et al. 2017a; Wright and Li 2022), and the term primordial
cyst should no longer be used as a synonym for odonto-
genic keratocyst.
Yet it should be noted that ‘primordial cyst’ is still occa-
sionally used for other categories of odontogenic cyst. In
the 2012 Armed Forces Institute of Pathology (AFIP) fasci-
cle (Robinson and Vincent  2012), a primordial cyst was
defined as an ‘odontogenic cyst of undetermined origin’
and is described as being a non-­keratinised cyst that forms
in place of a developing tooth. They assert that a missing
tooth is not needed for the diagnosis, since the definition
includes supernumerary teeth. They suggest that it is a
diagnosis of exclusion and should be used when a ‘develop-
mental cyst’ cannot be identified as any other defined
cystic entity. More recently, Argyris et al. (2016) suggested
the term primordial cyst for an unusual cystic lesion that
had developed at the site of a congenitally missing second
molar in an 18-­year-­old. This cyst showed evidence of
inductive change and hard tissue formation, suggesting
that it may in fact be an unusual hamartoma or odontoma.
A further change in terminology was initiated by the
debate regarding the possible neoplastic nature of the
odontogenic keratocyst. This is discussed later in this chap-
ter. However, some regarded the evidence that the odonto-
genic keratocyst is a neoplasm to be so compelling that a
change of name was warranted. Thus, in the third edition
of the WHO classification (Philipsen 2005), the term odon-
togenic keratocyst was replaced by ‘keratocystic odonto-
genic tumour (KCOT)’. This change was made on the basis
that the odontogenic keratocyst ‘behaves as a neoplasm’
and may show genetic changes (primarily in the PTCH
gene) that are associated with the naevoid basal cell carci-
noma syndrome and with neoplasia at other sites. Although
the possibility that the odontogenic keratocyst is a neo-
plasm had been long debated, this change in terminology
was controversial and resulted in widespread debate,
which is reflected in the huge increase in publications
mentioned previously. However, KCOT was not adopted
worldwide and the literature continued to be dominated by
the term odontogenic keratocyst (Bhargava et  al.  2012).
Many felt that the evidence of neoplasia was insufficient to
warrant a change in designation. Also, the term odonto-
genic keratocyst is well established and is so widely used by
clinicians and pathologists that a good case can be made
for retaining it even if it is indeed a neoplasm. For the
fourth edition of the WHO classification, the consensus
group felt that odontogenic keratocyst was the most appro-
priate name for this lesion and the term was reinstated
(Speight et  al.  2017a; Speight and Takata  2018) and has
been retained in the latest classification (Wright and
­Clinical Feature  89
Li  2022; WHO  2022a). This is not without controversy
(Stoelinga 2019), but the name does not deny the possible
neoplastic nature of the odontogenic keratocyst, and man-
agement decisions should be based on an understanding of
the pathobiology of the lesion, not on the name alone.
Finally, previous definitions of the odontogenic kerato-
cyst (Wright  1981; Kramer et  al.  1992) have included an
orthokeratinised variant. However, it has long been recog-
nised that this ‘variant’ showed different and characteristic
clinical and pathological features. In the 2005  WHO
classification, it was clearly stated that cysts lined by
orthokeratinised epithelium were not part of the spectrum
of the ‘KCOT’ (Philipsen 2005), and in 2017 the orthokerati-
nised odontogenic cyst was included as a separate entity in
the classification of odontogenic cysts (Speight et al. 2017b;
Speight and Takata  2018). The orthokeratinised odonto-
genic cyst is discussed in Chapter 12.
­Clinical Features
Most descriptions of the odontogenic keratocyst are to be
found in case reports and small case series. In a systematic
review, MacDonald-­Jankowski (2011) found a total of 151
case series of odontogenic keratocyst between 1976 and
2010. In his review, he excluded incomplete descriptions,
referred cases and repetitions, and finally reviewed only 49
papers that reported 4795 cysts. The case series ranged in
size from 3 to 588 lesions. In his analysis of these papers, he
also excluded orthokeratinised cysts and cysts associated
with the naevoid basal cell carcinoma syndrome (NBCCS).
Subsequently there have been a number of large case
series, including a multicentre study of 2497 cases reported
from Brazil (Schuch et al. 2020), Selected case series with a
broad geographical spread and MacDonald-­Jankowski’s
review are summarised in Tables 7.1 and 7.2.
Frequency
The odontogenic keratocyst is the third most common cyst
of the jaws, representing 10.2% of all jaw cysts in our South
African series (Table 1.1) and 11.6% of odontogenic cysts in
the Sheffield study (Table  1.2; Jones et  al.  2006). Studies
from other countries, however, show a wide variation
(Table 1.3), with a range from only 1.3% in Sicily (Tortorici
et  al.  2008) to 27.4% in India (Ramachandra et  al.  2011)
(Table 1.3). A systematic review of frequencies showed an
overall combined frequency of 11.7% (Johnson et al. 2014).
The reasons for the variation are not always clear, but it
must be noted that the studies are not population studies,
but are mostly retrospective analyses of pathology records.
The prevalence and frequency of different lesions may
90 Odontogenic Keratocyst

Table 7.1  Age, sex, and site distribution from selected case series of odontogenic keratocyst, and from the systematic review of Data
from MacDonald-­Jankowski (2011). Wherever possible, data are presented for solitary, non-­syndromic cysts only.

References Country n Mean age Peak decade Male (%) Mandible (%)

Brannon (1976) USA 283 37.8 3rd 56.9 65.4

Ahlfors et al. (1984) Sweden 255 41.0 3rd and 4th 65.5 75.0
Woolgar et al. (1987b) UK 379 40.4 3rd and 4th 61.7 74.0
Crowley et al. (1992) USA 387 39.6 NR 61.9 70.3
Myoung et al. (2001) S Korea 256 30.8 3rd 58.6 76.5
Jones et al. (2006) UK 828 41.3 3rd 56.0 71.1
Jing et al. (2007) China 588 34.9 3rd 63.0 81.5
Habibi et al. (2007) Iran 74 27.1 2nd 59.5 67.5
Gonzalez-­Alva et al. (2008) Japan 183 32.8 3rd 51.3 70.5
Luo and Li (2009) China 507 36.0 3rd 63.7 74.7
Boffano et al. (2010) Italy 241 43.3 4th 67.6 73.2
Jattan et al. (2011) New Zealand 223 37.0 3rd 61.0 65.9
Azevedo et al. (2012) Brazil 158 32.2 3rd 44.7 69.3
Siriwardena et al. (2012) Sri Lanka 431 31.3 3rd 55.5 74.4
Bello (2016) Saudi Arabia 65 31.1 3rd 64.6 84.6
Tamiolakis et al. (2019) Greece 436 42.5 NR 56.7 71.7
Kahraman et al. (2018) Turkey 204 46.6 NR 55.5 81.0
Schuch et al. (2020) Brazil 2497 34.2 3rd 52.2 77.3
MacDonald-­Jankowski (2011) SR 4795a 37.8 3rd 60.0 72.1

n, number of patients affected; NR, not reported; SR, systematic review.

a
 Total cases in review, but n for each parameter varies depending on number of reports.

therefore be affected by local clinical practice. Radicular
cysts, for example, are often a straightforward diagnosis
based on clinical and radiological findings and since the
treatment may often be tooth extraction, the soft tissue may
be discarded and not submitted for histological examina-
tion. This may explain the lower frequency of radicular
cysts and higher frequency of keratocysts in some coun-
tries, including Mexico (Mosqueda-­Taylor et al. 2002), Iran
(Sharifian and Khalili  2011), and India (Ramachandra
et al. 2011) (Table 1.3). Conversely, some countries, includ-
ing Sicily (Tortorici et  al.  2008) and Greece (Tamiolakis
et al. 2019), have shown a low frequency of keratocysts, but
a very high level of radicular cysts, which they ascribed to
high levels of dental caries in the region. The French study
(Meningaud et al. 2006) analysed only cases that had been
operated on under general anaesthesia, which may bias the
results towards greater numbers of larger cysts, including
the odontogenic keratocyst.
Most studies recording the relative frequency of odonto-
genic cysts (Table  1.3) have included orthokeratinised
odontogenic cyst in with odontogenic keratocysts, but this
does not appear to affect the overall frequencies. Six of the
reports in Table 1.3 excluded orthokeratinised odontogenic
cyst, and showed frequencies of 7.4% (Grossmann
et  al.  2007; Brazil), 15.3% (Ali  2011; Kuwait), 8.4%
(Tamiolakis et  al.  2019; Greece), 13.6% (Bhat et  al.  2019;
India), 15.0% (Kammer et  al.  2020; Brazil), and 12.9%
(Aquilanti et  al.  2021; Italy). Early papers that discussed
orthokeratinised cysts as a variant of odontogenic kerato-
cyst suggested that they only represented about 10% of the
total (Brannon 1977; Wright 1981; Crowley et al. 1992; Li
et al. 1998; MacDonald-­Jankowski 2011).
Since 2005, a number of workers have redefined odonto-
genic keratocyst as a neoplasm (KCOT) and have reana-
lysed the frequency of odontogenic cysts without
keratocysts included, or have presented the frequency of
keratocysts (KCOT) among odontogenic tumours (Jaeger
et al. 2017; Gaitán-­Cepeda et al. 2010). This has had little
overall effect on the frequency of cysts, since keratocysts
only represent about 10% of the total and there is great vari-
ation. However, others have suggested that the frequency
of odontogenic tumours doubled after 2005 from about 2.5
to 5% (Gaitán-­Cepeda et al. 2010), or even as high as 11.5%
(Jaeger et  al.  2017), and that the KCOT represented the
most common tumour type with frequencies of 38.9%
(Gaitán-­Cepeda et al. 2010) and 41% (Jaeger et al. 2017). In
Table 7.2  Frequency (%) of clinical features reported in selected case series. Totals may exceed 100% because patients show multiple symptoms. Based on Brannon, 1976; Chow,
1998; Myoung et al., 2001; Chirapathomsakul et al., 2006; González-Alva et al., 2008; Bello, 2016 and Sundaragiri, 2018.

Associated with
Country n Swelling Pain Infection or discharge Incidental finding Paraesthesia NBCCS Multiple cystsa impacted tooth

Brannon (1976) USA 283 41.3 16.7 NR 49.3 1.4 3.9 3.5 26.6
Crowley et al. (1992) USA 387 27.9 15.0 10.3 14.5 2.1 4.7 NR 47.8
Chow (1998) Singapore 70 51.4 9.9 18.5 15.7 1.4 1.4 2.8 52.8
Myoung et al. (2001) S Korea 256 62.5 36 6.6 5.5 0.8 4.3 10.9 27.1
Chirapathomsakul et al. (2006) Thailand 51 72.5 45.0 15.7 13.7 2.0 0 11.8 31.3
Habibi et al. (2007) Iran 74 60.2 13.2 19.3 24.1 NR 6.1 0 33.7
Simiyu et al. (2013) Kenya 22 81.8 13.6 NR 18.2 NR 4.5 0 9.1
Bello (2016) Saudi Arabia 75 75.7 13.7 8.4 10.0 1.1 4.0 9.3 30.8
MacDonald-­Jankowski (2011) SR 4795b 58.3 32.4 12.2 21.0 1.9 6.4 NR 35.2

n, number of patients affected; naevoid basal cell carcinoma syndrome (NBCCS); NR, not reported; SR, systematic review.
a
 Relates to multiple cysts in patients without NBCCS.
b
 Total cases in review, but n for each parameter varies depending on number of reports.
92 Odontogenic Keratocyst

their systematic review, Johnson et  al. (2014) showed an
overall combined frequency of odontogenic keratocyst of
11.7% of odontogenic cysts. However, papers that defined it
as a neoplasm showed a combined frequency of 36.6% of
odontogenic tumours (range 19.5–38.7%), which was simi-
lar to ameloblastoma (37.9%). When interpreting the litera-
ture, it is important to ensure that the classification and
the denominator used for calculating frequencies are
clearly stated.
Age
Odontogenic keratocysts are seen in young adults with a
mean age of about 35 and a peak incidence in the third
decade (Figure 7.1 and Table 7.1). However, there is a wide
age range and cases have been recorded as early as the first
decade and as late as the ninth (Meara et  al.  1996; Jones
et al. 2006; Jattan et al. 2011). Jones et al. (2006) recorded
one case in the tenth decade (female, age 92). In most series
there has been a pronounced peak incidence in the second
and third decades, with 40–60% of patients being in this
age group, but many workers have also demonstrated a
bimodal age distribution with a second, although smaller,
peak in the fifth decade or later (Toller 1967; Vedtofte and
Prætorius  1979; Ahlfors et  al.  1984; Partridge and
Towers  1987; Woolgar et  al.  1987b,c; Jones et  al.  2006;
Azevedo et  al.  2012). This is illustrated by an analysis of
1007 consecutively diagnosed odontogenic keratocysts in
our Sheffield department (Figure 7.1). In this series, 37.3%
of cases arose in the second and third decades, with smaller
peaks in the sixth (13.5%) and seventh (12.7%) decades.
This bimodal distribution may not be apparent in all
populations. In a series of 223 cases from New Zealand,
most cases occurred in the second (40 cases: 18%) and third
decades (59 cases: 26.5%), followed by a gradual decline
with no second peak (Jattan et al. 2011). In a sample of 256
cases in South Korea, Myoung et al. (2001) found a similar
distribution, with 53.9% of cases in the second (25%) and
third (28.9%) decades, followed by a gradual reduction with
no second peak. Very similar data were reported from
Japan, with 53.5% of 183 cases in the second and third dec-
ades, and no second peak (González-­Alva et al. 2008).
To address the question of whether two different types of
keratocyst might exist, one in younger and one in older age
groups, Rachanis et al. (1979) reviewed the clinical and his-
topathological features of a series of odontogenic kerato-
cysts from patients in the age groups 10–29 and 50–64 years,
but no significant differences were observed between the
two groups. The authors concluded that it was unlikely
that these were different varieties of odontogenic kerato-
cyst and agreed with Browne (1975) that the cysts in older
age groups have probably been present but undiagnosed
for many years. This is in keeping with the observation dis-
cussed later in this chapter that keratocysts may involve the
body and ascending ramus of the mandible extensively,
with little or no bony expansion.
Although the odontogenic keratocyst is more common in
young people, it is very rare in the first decade. In our series
(Figure  7.1) we found only 9 of 1007 cases in children
under 10 years. In a Turkish study, Soluk Tekkeşin et  al.
(2016) reviewed 745 odontogenic lesions (including 596
cysts) in patients aged 17 years and under and found

200 Figure 7.1  Age distribution of 1007

odontogenic keratocysts diagnosed in
Males
180 Sheffield.
Females
160
102
140
101

120
No. of cases

100
70 82

59
80 93

53
60
93
40 80
60
55
20 54
35 40 6
5 14 1
0 4

0-9 10-19 20-29 30-39 40-49 50-59 60-69 70-79 80-89 90+
Age

64  keratocysts (10.7% of cysts). All cases were associated
with the mixed or permanent dentition, 44 were found in
the 13–17-­year age group, and 20  in the 6–12-­year age
group. No lesions were found in patients under the age of
6. Similar frequencies have been found in other studies. In
South Korea, Myoung et  al. (2001) found only 11 (4.3%)
cases under the age of 10 years, and only three (1.7%) were
found in the Japanese study, one of which (age 8 years) was
associated with the NBCCS (González-­Alva et al. 2008).
In an analysis of biopsy specimens received over a 30-­
year period, Jones and Franklin (2006b) found 73 odonto-
genic keratocysts in a paediatric population (0–16 years)
compared to 591 cases in the adult population (Jones and
Franklin 2006a). Only two cases were found to be associ-
ated with NBCCS. However, the data also suggested that
keratocysts were relatively more common in children. As a
proportion of the total specimens received, keratocysts
constituted 1.6% of specimens received in the paediatric
group compared to 1.3% in the adult group. As a proportion
of total odontogenic cysts, keratocysts represented 13.8% of
odontogenic cysts in children compared to only 9.8% in the
adult group. This apparent higher frequency in children
arises because radicular cysts are relatively uncommon in
children, but represent a larger proportion of cysts in adults.
Woolgar et al. (1987b) compared the age of patients with
sporadic keratocysts with those arising in association with
NBCCS and suggested that cysts arise at a younger age in
syndromic patients. In patients without the syndrome
(n = 379), the mean age at removal of the first diagnosed
keratocyst was 40.4 years, compared to 26.2 years in patients
with NBCCS (n = 60; P < 0.001). In a systematic review of
14 case series, MacDonald (2015) found that although
NBCCS was diagnosed at a mean age of 29.2 years in East
Asian patients (7 reports; n  =  251) and 36.2 years in
European patients (7 reports; n  =  406), the mean age of
presentation of the first odontogenic keratocyst was 31.4
and 16.9 years, respectively. Rehefeldt-­Erne et  al. (2016)
also found that NBCCS was diagnosed in the fifth decade,
but in a review of four studies (including their own) they
found that the first jaw cyst was always found in the second
decade, with mean ages between 15.5 and 19.8 years.
From these studies it can be concluded that odontogenic
keratocysts in patients with NBCCS arise in a younger age
group, that the age difference is an intrinsic feature of the
syndrome, and that it may be in keeping with the underly-
ing inherited genetic changes known to be associated with
NBCCS (see also later Table 7.5).
Sex
Similar to most odontogenic cysts, keratocysts show a
slight predilection for males, who account for about 60% of
­Clinical Feature  93
cases. In the Sheffield series (Figure 7.1), 571 cases (56.7%)
arose in males, a male: female ratio of 1.3 : 1. Table 7.1 sum-
marises a number of selected studies that show that males
predominate, although there are small variations between
studies and in different parts of the world. Occasional stud-
ies, including from Brazil (Azevedo et  al.  2012) and
Thailand (Chirapathomsakul et  al.  2006), have shown
female predilections of 55.3% and 54.9%, respectively, but
this is unusual and the reasons for the discrepancy are
not clear.
There is some evidence that keratocysts in association
with NBCCS may present more frequently in females.
Rehefeldt-­Erne et  al. (2016) found that 56.6% of their
NBCCS patients were male, but in a review of four other
studies they found that females predominated in three,
with a male : female ratio of 1 : 1.3. Woolgar et al. (1987a)
found that 61.7% of patients with non-­syndromic solitary
cysts were male (Table 7.1; n = 379; M : F 1.63 : 1), but this
was significantly different (P < 0.025) from patients affected
by the syndrome (n  =  60), in which 55.0% were females
(M : F 1 : 1.22). This is in keeping with the evidence that
females may be more frequently affected by
NBCCS. Macdonald’s (2015) systematic review of 14 case
series of NBCCS found that in 3 of 7 East Asian studies,
and in 5 of 7 European studies, there was a predilection for
females.
Site
The mandible is involved far more frequently than the
maxilla (Table  7.1 and Figure  7.2). In his systematic
review, MacDonald-­Jankowski (2011) found that the man-
dible was affected more than twice as often as the maxilla,
although he was able to demonstrate geographical varia-
tions. In studies from East Asia, the mandible was affected
in 77% of cases, compared to 73% in Latin America and
63% in Western studies. In our own material from South
Africa, 149 of 193 cysts (77%) for which data were availa-
ble occurred in the mandible. The high frequency of man-
dibular involvement is borne out in many series from
throughout the world (Table 7.1) and is reported from 65%
(USA; Brannon  1976) to as high as 85% (Saudi Arabia;
Bello 2016).
More recently, Slusarenko da Silva et al. (2019a) under-
took a systematic review and meta-­analysis of 34 studies
that had accurately recorded the site of lesions. Of
3126 keratocysts included, 2376 (76%) were located in the
mandible, and 1401 (44.8% of all keratocysts) of these were
found in the posterior mandible – including the third molar
region, angle, and ramus. Conversely, lesions in the maxilla
were more likely to be found in dentate areas of the jaw. Of
the 750 (24%) maxillary cysts, 75.5% were found anterior to
94 Odontogenic Keratocyst
5%
15% 25%
5%
50
%
20% 75%
5%
the second molar and only 24.5% (184 lesions) were associ-
ated with the third molar or tuberosity. Ali and Baughman
(2003) in an analysis of 398 keratocysts found only 7.5% in
the posterior maxilla, but of the remainder, the majority
(54 lesions: 13.6%) were located in the canine region and
half of these (27 cysts) were in a periapical position, resem-
bling a radicular cyst.
Figure  7.2 illustrates the approximate distribution of
odontogenic keratocysts in the jaws. These data are esti-
mated from the publications in Table  7.1 and from
Slusarenko da Silva et al. (2019a), and figures are rounded
to the nearest 5% for simplicity and to aid recall. The right
side of the diagram shows that about 75% of all keratocysts
arise in the mandible, while the left side illustrates the dis-
tribution in different regions of the jaws. A total of about
50% are located at the angle of the mandible, some of
which may extend into the ramus, and only 20% are found
anterior to the second molars. About 5% of lesions extend
across multiple mandibular sites. In the maxilla, the major-
ity (15%) are located in the dentate regions of the jaw, and
only about 5% of all keratocysts are associated with a max-
illary third molar or the tuberosity. About 5% may extend
across multiple sites.
A number of studies have suggested that the site distribu-
tion of NBCCS-­associated keratocysts is different to sporadic
cysts, with a higher frequency in the maxilla. Woolgar et al.
(1987b) reviewed 164  keratocysts from 60 patients with
NBCCS. Of these, 34 (21%) arose in the posterior maxilla in
patients with NBCCS, compared to only 11% at this site in
patients without the syndrome (n = 379). In addition, 60% of
cysts were found in the posterior mandible in patients
Figure 7.2  The approximate site distribution
of odontogenic keratocysts (see text for
details).
without the syndrome, while only 44% arose at this site in
patients with NBCCS. Of their patients with the syndrome,
18 (30%) initially had only one cyst, but in all except 3 patients
further cysts developed subsequently; 24 syndrome patients
had cysts in two quadrants, 13 of which were bilateral man-
dibular cysts related to third molar teeth; 5 patients had cysts
in three quadrants and 13  had cysts in all four quadrants.
These authors emphasised that the term ‘multiple’, when
applied to cysts occurring in patients with NBCCS, referred
to the lifetime history of the patient and not necessarily that
more than one cyst was present at any one time. More
recently, Karhade et al. (2019) supported these findings, and
found that 13 of 18 (72.2%) syndromic cysts arose in the max-
illa, compared to only 11 of 32 (34.3%) sporadic cysts.
Woolgar and colleagues (Woolgar et  al.  1987b; Rippin
and Woolgar 1991) have also suggested that the finding of
multiple keratocysts is sufficient for a diagnosis of NBCCS
even if other features are not evident, since on full exami-
nation other features of the syndrome, albeit only minor
anomalies, may be revealed. Others, however, do not sup-
port this and have reported multiple (not recurrent) kerato-
cysts in up to about 10% of non-­syndromic patients
(Table 7.2; Brannon 1976; Chow 1998: Myoung et al. 2001;
Chirapathomsakul et  al.  2006; González-­Alva et  al.  2008;
Bello  2016; Sundaragiri  2018). Nevertheless, clinicians
need to be aware of the probability that if a patient has
more than one odontogenic keratocyst, other features of
the syndrome should be investigated. Furthermore, if a
patient, especially a young patient, has a single obvious
keratocyst, careful scrutiny of appropriate radiographs
should be performed to exclude the possibility of other cysts.

Box 7.1  Odontogenic Keratocyst: Clinical Features
and Key Facts
●● Third most common of the odontogenic cysts with a
frequency of 10–15%
●● Mean age is about 35 years, with a peak in the
third decade
●● Slightly more common in males (60%)
●● 75% arise in the mandible
●● 50% arise at the angle and ramus region of the
mandible
●● Lesions in the posterior maxilla are rare (~5%)
●● Up to 10% of patients without naevoid basal cell car-
cinoma syndrome (NBCCS) may have multiple cysts
●● About 5% of keratocysts are associated with NBCCS
●● Keratocysts in patients with NBCCS show a different
profile:
–– Almost always multiple and in multiple quadrants
–– More often female (55%)
–– Often younger (<20 years)
–– More frequently encountered in the posterior max-
illa (up to ~20%)
Clinical Presentation
The clinical features are summarised in Table 7.2. The sin-
gle most common presentation is of a painless swelling,
although a significant number of cases arise as an inciden-
tal finding during radiological examination for other pur-
poses. In one of the largest series (256 patients), Myoung
et  al. (2001) found that 62.5% of odontogenic keratocysts
presented with a swelling and 36% with pain. However,
only 42 patients (16.4%) had both swelling and pain
together. This means that almost half of patients (46%) pre-
sented with swelling only and 20% with pain only. They
also found 17 cases (6.6%) that presented with a discharge
and 5.5% presented as an incidental finding. Only 2 cases
(0.8%) showed signs of paraesthesia.
In a large Italian study of 241 patients (Boffano
et  al.  2010), only 37.2% presented with symptoms, while
the remainder (62.8%) were incidental findings during rou-
tine radiographic examination. In a systematic review of 49
case series, MacDonald-­Jankowski (2011) found that fewer
than 10 papers reported clinical signs and symptoms. The
most common clinical sign, affecting up to about 60% of
patients, was the presence of swelling, with or without
pain. Overall, about 20% of keratocysts were an incidental
finding, either secondary to a pathological fracture or,
more commonly, discovered fortuitously during dental
examination when radiographs are taken. Other features
included infected lesions, which may present with a puru-
lent discharge, in up to 18% of cases. Nerve involvement
­Clinical Feature  95
with numbness or tingling (paraesthesia) has been reported
to occur in less than 2% of cases. Between 10 and 56% of
cysts may be associated with a missing or impacted tooth
and this will be discussed below in the section on radiology.
In most cases, swelling is accompanied by expansion of
the bone. Browne (1970) found that expansion of bone
occurred in about 60% of cases, with about half of man-
dibular lesions causing buccal expansion and one-­third lin-
gual expansion. One-­third of maxillary cysts caused buccal
expansion, but palatal expansion was very rarely seen. In
his systematic review, MacDonald-­Jankowski (2011) found
only two papers that detailed the pattern of expansion, and
these recorded that 62% of cases produced bucco-­lingual
expansion and 71% displaced the lower border of the man-
dible. The review also found that 100% of maxillary lesions
expanded into the antrum. Forssell (1980) observed expan-
sion of bone in 53% of his cases, and this occurred signifi-
cantly more frequently at the angle or ascending ramus of
the mandible than in the maxilla or body of the mandible.
Perforation of bone, as observed in orthopantomograms,
occurred in 39% of his cases. As with other intraosseous
jaw lesions, the enlarging cyst may cause resorption or dis-
placement of teeth (Borghesi et  al.  2018). MacDonald-­
Jankowski and Li (2010) reported tooth displacement and
resorption in 69% and 41% of cases, respectively.
With regard to the incidental presentation of odonto-
genic keratocysts, patients may be remarkably free of
symptoms until the cyst has reached a large size, often with
extensive involvement of the entire ascending ramus,
including the condylar and coronoid processes or with
extension into the maxillary sinus. This occurs because the
odontogenic keratocyst tends to extend antero-­posteriorly
through the cancellous bone and clinically observable
expansion of the jaws occurs late.
Odontogenic keratocysts are often described as showing
‘aggressive’ behaviour, but this must not be overinterpreted
to suggest invasion, or a growth pattern similar to that seen
in truly aggressive lesions such as malignancies. It is cer-
tainly true that keratocysts may grow to a large size and
have a tendency to recur, but even when large, the lesions
are usually well defined on radiology, suggesting slow
growth. We do not support the concept that clinical recur-
rence alone is synonymous with, or a defining feature of,
aggressiveness. The size and extent of the lesion appear to
be associated with late presentation of a cyst that has
grown slowly over time. This may be a feature of the fact
that they tend to grow within the bone of the mandible
with late cortical expansion.
Extensive growth may also occur within the maxilla,
where the lesion can expand unimpeded within the
antrum. Lund (1985) described a large keratocyst involving
the maxillary sinus that led to displacement and
96 Odontogenic Keratocyst
perforation of the floor of the orbit and proptosis of the eye.
Vencio et al. (2006) also reported a case that had extended
into the maxillary antrum, destroying the floor, and a more
recent case has been shown to extend through the posterior
wall of the antrum and involve the pterygoid process of the
sphenoid bone (Goto et  al.  2020). Other authors have
reported on aggressive behaviour of keratocysts to the
extent that they perforated the cortical bone and involved
surrounding soft tissues (Emerson et  al.  1972; Partridge
and Towers 1987). Jackson et al. (1993) reported two cases
that showed extensive growth. One lesion in a 47-­year-­old
male extended from the maxilla and eventually involved
the base of the skull. However, it should be noted that the
lesion recurred over a period of 10 years after first present-
ing as a suppurating infection that was curetted, but not
diagnosed or removed. Subsequently there were multiple
recurrences associated with multiple cysts, infection, and
persistent draining sinuses. There are many similar reports
of extensive lesions, including involvement of the infratem-
poral fossa (Chuong et al. 1982) and the temporalis muscle
(Worrall  1992). These cases are often cited to illustrate
aggressive behaviour, but most are unusual, involving
inadequate initial treatment, multiple recurrences, and
infection. They cannot be regarded as representing the typ-
ical behaviour of a keratocyst, but do illustrate how a recur-
rent lesion can cause significant management problems.
Peripheral (Extraosseous)
and Soft-­Tissue Keratocysts
It is well recognised that a typical intraosseous odonto-
genic keratocyst may recur within the soft tissues adjacent
to the site of initial surgery. In addition, however, there
have been reports of primary keratocysts arising within the
gingivae or in the soft tissues. Lesions in the gingivae are
regarded as peripheral odontogenic keratocysts that arise
from odontogenic epithelium within the alveolar mucosa
or gingivae overlying bone. Lesions with features of a
keratocyst arising within soft tissues away from bone have
also been described, but are of uncertain origin.
Peripheral Odontogenic Keratocyst
Gingival or peripheral odontogenic keratocysts appear to be
rare, with fewer than 20 fully documented cases. The first
well-­characterised case was reported by Dayan et al. (1988),
who described a lesion entirely within the gingiva, which
had the clinical features of a gingival cyst of adults but the
histological characteristics of an odontogenic keratocyst
with the typical parakeratinised lining. They suggested the
term ‘peripheral odontogenic keratocyst’ for this rare pres-
entation of the lesion. Vázquez-­Romero et  al. (2017)
reported a case and reviewed the literature up to 2016.
They identified 23 cases, but 3 were not fully documented
and 3 appeared to be in soft tissues. Data were available for
17 peripheral gingival lesions (Chehade et al. 1994; Fardal
and Johannesssen 1994; Dayan et al. 1988; Ide et al. 2002;
Chi et  al.  2005; Preston and Narayana  2005; Faustino
et  al.  2008; Vij et  al.  2011; Gröbe et  al.  2012; Sakamoto
et al. 2014). Vázquez-­Romero et al. found that peripheral
lesions showed an average age of 51.3 years (range 24–83),
with a slight predilection for females (11 lesions: 65%). The
most common site was the canine/premolar region, with a
slight predilection for the maxilla (9/17  lesions: 52.9%).
Clinically the peripheral odontogenic keratocyst is indis-
tinguishable from the gingival cyst of adults (see Chapter 9)
and presents as a gingival nodule that may be normal or
blue/grey in colour and ranges from 3 to 15 mm in diame-
ter (Chi et al. 2005). All reported lesions have arisen on the
buccal or labial aspect of the gingivae. Only two cases have
been shown to recur. One case has been reported in asso-
ciation with the NBCCS, in a 24-­year-­old female (Sakamoto
et al. 2014)
The peripheral odontogenic keratocyst has a clinical
presentation identical to gingival cyst of adults and proba-
bly has a similar pathogenesis, arising from rest cells of
dental lamina. Some have suggested that they are part of a
spectrum of the same lesion. However, the peripheral
keratocysts are histologically identical to their intraosseous
counterpart and occasionally may show daughter or satel-
lite cysts (Chi et al. 2005). Given its characteristic features,
we would regard the peripheral odontogenic keratocyst as
a separate and distinct entity.
Soft-­Tissue Keratocyst
In addition to peripheral lesions presenting on the gingi-
vae, there are a number of reports of lesions with the typi-
cal histological features of odontogenic keratocyst, but
arising within the soft tissues of the maxillofacial region.
These lesions are of uncertain origin and are often referred
to as soft-­tissue keratocyst.
The total number of cases of soft-­tissue keratocyst reported
is uncertain, but appears to be fewer than 20. A number are
reported under different names or are included in larger
series of other cyst types. Table  7.3 summarises 12  well-­
documented cases. The majority occurred in males (10 cases;
83.3%) and the average age at presentation was 52.5 years
(range 16–74). Although this is older than for intraosseous
odontogenic keratocysts, it is possible that the soft-­tissue
lesions present late because they grow slowly and are embed-
ded deep in the soft tissues. The one case reported in a
16-­year-­old (Ide et  al.  2010) was a chance finding during
microscopic examination of a biopsy of a ‘traumatic fibroma’.
It was only 3 mm in diameter and if left, might well have
grown for a long period before becoming clinically apparent.
 ­Clinical Feature  97

Table 7.3  Soft-­tissue keratocyst: summary of the clinical features of 12 well-­documented cases.

Age Sex Location Max dimension Notes

Precheur and Krolls (2009) 59 M Buccal space 31 mm

Ide et al. (2010) 60 M Buccal mucosa 30 mm Multicystic
16 M Buccal mucosa 3 mm Microcyst associated with ‘traumatic
fibroma’
Gröbe et al. (2012) 52 M Buccal mucosa 20 mm
Yamamoto et al. (2013) 74 M Buccal mucosa 35 mm
Kaminagakura et al. (2013) 37 M Buccal mucosa 20 mm
Abé et al. (2014) 46 M Temporalis muscle 21 mm Extended into buccal mucosa; multicystic
Zhu et al. (2014) 44 F Soft palate, pharynx 40 mm
69 M Buccal mucosa 20 mm Also involved the pterygopalatine fossa
Makarla et al. (2015) 62 M Buccal space 48 mm
Witteveen et al. (2019) 63 M Buccal space 18 mm
48 F Buccal space Not reported

The most common presentation was of an intraoral
swelling of normal colour, varying from about 20 to 40 mm
in diameter. One case presented in the soft palate and
extended into the pharynx (Zhu et al. 2014) and one case
appeared to arise in the temporalis muscle (Abé et al. 2014),
but all the others arose in the ‘cheek’. Those described in
Table 7.3 as presenting in the ‘buccal mucosa’ appeared to
be primarily intraoral and were submucosal, lying deep to
the buccinator muscle (the oral side), and all were located
posterior to the opening of the parotid duct. Those reported
as presenting in the ‘buccal space’, however, were primarily
extraoral and lay superficial to the buccinator muscle,
towards the skin or facial aspect (Precheur and Krolls 2009;
Makarla et al. 2015; Witteveen et al. 2019).
Histologically, all the lesions showed the typical features
of an odontogenic keratocyst, with a thin lining of par-
akeratinised epithelium. Two lesions (Ide et al. 2010; Abé
et al. 2014) were described as multicystic, but others were
simple cysts with no evidence of satellite cysts or epithelial
islands. Occasional lesions were associated with salivary
tissue, but sebaceous glands or dermal appendages were
not seen.
Most authors have noted the similarity of the cysts to
conventional odontogenic keratocyst and assumed there-
fore that they are of odontogenic origin. The presumptive
source of epithelium would be cell rests of dental lamina
that have become displaced during development. This is
perfectly possible and heterotopic odontogenic tumours,
including ameloblastoma and odontomas, have occasion-
ally been reported in the soft tissues.
Others have noted that the parakeratinised lining is simi-
lar to the lining of steatocystoma or sebaceous ducts and
have proposed an origin from sebaceous glands (Ide
et  al.  2010; Makhija  2015). Cutaneous keratocysts are an
occasional finding in NBCCS and show similar histological
features. Makhija (2015) noted this similarity and proposed
that steatocystoma (simplex) and cutaneous keratocysts
should be unified as sebaceous duct cysts. The soft-­tissue
keratocyst of the maxillofacial region may therefore be
derived from sebaceous glands. In this respect it must be
noted that sebaceous glands are commonly found in the
buccal mucosa (‘Fordyce spots’). Against this concept is the
fact that sebaceous glands have never been reported in the
walls of these cysts. On the rare occasions that steatocysto-
mas have been reported in the oral tissues, they have been
associated with sebaceous glands and have shown seba-
ceous differentiation in the lining (Olsen et  al.  1988;
Daley 1993).
These studies suggest that soft-­tissue keratocysts in the
oral tissues are most likely derived from ectopic odonto-
genic epithelium, but some may occur in the subcutaneous
tissues, be analogous to cutaneous keratocysts, and arise
from dermal appendages. Table  7.3 indicates that lesions
may be superficial (facial) or deep (oral) to buccinator mus-
cle, and it may be that these represent two similar cyst
types with different pathogenic mechanisms.
A rare multicystic lesion, called keratocystoma, with fea-
tures resembling odontogenic keratocyst has been
described in the parotid gland (Seifert et  al.  1999).
Histologically the keratocystoma is composed of multiple
cystic spaces lined by stratified squamous epithelium
showing para-­ and orthokeratinisation, but without a
prominent basal or granular cell layer. Solid islands of
squamous epithelium are also seen. The cysts are often
98 Odontogenic Keratocyst

irregular and multilocular. Keratocystoma resembles the
so-­called solid odontogenic keratocyst (see
‘Histopathology’), but the lesion is only found in the
parotid gland. The true nature of the lesion is unknown
and the literature has variously described it as a benign
cyst, a choristoma, or more frequently as a benign neo-
plasm. Only 11 cases have been reported (reviewed by
Aresta et al. 2019; Komatsu et al. 2020) and most authors
regard the lesion as a benign neoplasm that arises from
intercalated ducts that have undergone squamous meta-
plasia. Keratocystoma and soft-­tissue keratocyst are proba-
bly completely unrelated lesions, but their histological
similarity may cause diagnostic difficulties in small biop-
sies. Lesions located in the parotid gland should be diag-
nosed as keratocystoma, not as soft-­tissue keratocyst. The
keratocystoma is discussed further in Chapter 15.
­ aevoid Basal Cell Carcinoma
N keratocysts, however, only about 6% or less are associated
Syndrome (NBCCS)
In 1960, Gorlin and Goltz described a syndrome comprised
of cysts of the jaws, multiple basal cell ‘epitheliomas’, and
bifid ribs, a combination that is frequently referred to as
the ‘Gorlin–Goltz syndrome’, ‘Gorlin syndrome’, basal cell
nevus syndrome, or NBCCS. Gorlin et  al. (1963) and
Meerkotter and Shear (1964) later identified the jaw cysts
as odontogenic keratocysts. Subsequently, numerous clini-
cal and molecular studies have shown that there is a wide
range of possible clinical features with variability in clini-
cal presentation (reviewed by MacDonald 2015). However,
the most commonly encountered clinical manifestations of
the syndrome include odontogenic keratocysts, basal cell
carcinomas, pitting of the palms of the hands or soles of
the feet, and calcification of the falx cerebri. The features of
the syndrome and the criteria for diagnosis are shown in
Table 7.4 (Bree et al. 2011) and Table 7.5 summarises the
prevalence of the key features taken from four representa-
tive large series (Evans et  al.  1993; Shanley et  al.  1994;
Kimonis et al. 1997; Endo et al. 2012) and from a system-
atic review of seven reports from East Asia (n = 251) and
seven reports of patients of European origin (n  =  406)
(MacDonald 2015).
Overall, about 75% of patients present with odontogenic
keratocysts, but this may be higher in East Asian patients.
In the vast majority of cases these are multiple and present
in a synchronous and metachronous manner. The number
of cysts that each patient may have over a lifetime ranges
from 1 to 28, with an average of 4–6. Odontogenic kerato-
cysts are often the first manifestation of the syndrome,
with 75% or more of patients presenting with their first cyst
before the age of 20 years. In the totality of odontogenic
with NBCCS (Table 7.2). Basal cell carcinomas tend to pre-
sent later, with an average age of 21.4 years, but the full
syndrome is often not diagnosed until the middle of the
fourth decade (Table 7.5; Kimonis et al. 1997).
The important fact to note is that dental healthcare work-
ers are in a pivotal position to identify the first and early
signs of the syndrome and refer accordingly. As well as
odontogenic keratocysts, patients may present with frontal
bossing, hypertelorism, or cleft lip or palate. Furthermore,
the basal cell carcinomas are often encountered on the face,
often as clusters around the eyes and nose. There is some
evidence that the prevalence of basal cell carcinomas may
be affected by ethnicity or geographical factors. While the
overall prevalence is about 75%, the prevalence in Japanese
patients was only 38% (Endo et al. 2012) (Table  7.5) and

Table 7.4  Diagnostic criteria for naevoid basal cell carcinoma syndrome. Two major criteria, or one major criterion and two minor
criteria, or one major criterion and genetic confirmation are required for diagnosis.

Major criteria Minor criteria

1)  Multiple basal cell carcinomas (BCCs) or
one BCC in a person younger than 20 years
2)  Odontogenic keratocyst before age 20
3)  Palmar or plantar pitting
4)  Calcification of the falx cerebri
5)  Medulloblastoma
6)  First-­degree relative with basal cell nevus
syndrome (BCNS)
1)  Rib anomalies (bifid, fused, or splayed)
2)  Other specific skeletal and radiological abnormalities (vertebral anomalies,
kyphoscoliosis, short fourth metacarpals, postaxial polydactyly)
3)  Macrocephaly
4)  Cleft lip or palate
5)  Ovarian or cardiac fibroma
6)  Lymphomesenteric cysts
7)  Ocular anomalies (congenital cataract, coloboma, glaucoma, hypertelorism)

Source: Based on Bree et al. (2011).

 ­Naevoid Basal Cell Carcinoma Syndrome (NBCCS  99

Table 7.5  Clinical features of naevoid basal cell carcinoma syndrome (NBCCS) from four representative case series and a large
systematic review. Data from MacDonald 2015.

Evans Shanley Kimonis Endo MacDonald MacDonald

et al. (1993) et al. (1994) et al. (1997) et al. (2012) (2015)a (2015)a

Country UK Australia USA Japan East Asian European

No. of patients 84 118 105 157 251 406
OKC (%) 66 75 74 86 90 70
No of OKC – mean (range) NR 6 (1–28) 5.1 (1–28) 3.7 (1–10) NR NR
Age at first cyst (mean) NR 15.5 17.3 19.8 31.4 16.9
Age at diagnosis of NBCCS NR 35 34.5 33.1 29.2 36.2
(mean)
BCC (%) 47 76 73 38 31 71
Palmar/plantar pitting (%) 71 80 87 69 68 79
Falx cerebri calcification (%) NR 92 65 79 61 78
Rib anomalies (%) NR NR 26 36 37 39
Cleft lip/palate (%) 5.7 NR 2.8 9.0 9 4

OKC, odontogenic keratocyst; BCC, basal cell carcinoma; NR, not reported.
a
 Systematic review.

Kimonis et al. (1997) found only 38% in black patients com-
pared to 80% in whites. In a systematic review, MacDonald
(2015) found a prevalence of 31% in East Asian patients
compared to 71% in patients of European origin (Table 7.5).
The current criteria for diagnosis of NBCCS are shown in
Table 7.4. A diagnosis should be suspected on the basis of
(i) one major criterion confirmed by molecular analysis, or
(ii) two major criteria, or (iii) one major and two minor cri-
teria. If these criteria are met, a patient should be referred
to a medical geneticist (Bree et al. 2011). Furthermore, the
association with odontogenic keratocyst is so strong that
any patient under age 20 years with even a single keratocyst
should ‘trigger’ further investigations following an estab-
lished diagnostic protocol that includes a detailed history
and skeletal and dermatological examinations (Bree et
al.  2011). Karhade et  al. (2019) reviewed odontogenic
keratocysts in 50 children and young adults (18 years and
under), 18 of whom (36%) had NBCCS, 8 with a previously
known family history, and 10 based on further investiga-
tions following diagnosis of the odontogenic keratocyst. Of
the 18 patients who were diagnosed with NBCCS, 8 (44%)
had presented with a single keratocyst. Odontogenic
keratocysts associated with NBCCS may also show charac-
teristic histological features that might alert an examining
pathologist to the possibility that a patient has the syn-
drome. These are discussed later in this chapter (see
‘Histopathology’ and Table 7.8)
NBCCS is an autosomal-­dominant inherited syndrome,
with strong penetrance, but with variable expressivity and
an overall prevalence of about 1 in 60 000 live births. The
most common mutation is in the PTCH1 gene, but muta-
tions in PTCH2 and SUFU have also been implicated. So
far, almost 450 mutations have been identified in PTCH1
(Reinders et al. 2018) and this genetic heterogeneity may
contribute to the lack of genotype–phenotype correlations
and to the variability of clinical presentation. The PTCH
gene encodes a transmembrane protein that acts as a
receptor for the hedgehog family member SHH (Sonic
hedgehog) (Figure 7.13). The function of the PTCH pro-
tein is to inhibit activation of SMO (smoothened). When
SHH binds to the PTCH receptor, SMO is activated and in
turn activates the Gli transcription factors that up-­regulate
cell proliferation and also have roles in development and
normal odontogenesis (Diniz et  al.  2017; Seppala
et  al.  2017; Reinders et  al.  2018). Mutation of PTCH1
results in constitutive activation of the hedgehog (HH) sig-
nalling pathway with a plethora of downstream conse-
quences, including increased cell proliferation or failure
of apoptosis. PTCH1 is thus regarded as a tumour-­
suppressor gene.
It has been suggested that the developmental anoma-
lies associated with NBCCS are caused by a germline
mutation in one allele of PTCH1, while tumours are a
result of mutations in both PTCH alleles (the ‘two-­hit
hypothesis’). The hedgehog signalling pathway and
molecular studies on solitary (sporadic) and syndrome-­
related odontogenic keratocyst are discussed in detail
later in this chapter (see ‘Pathogenesis’ and Figure 7.13).
100 Odontogenic Keratocyst
­Radiological Features
A typical odontogenic keratocyst appears as a well-­
demarcated unilocular radiolucency with a corticated mar-
gin (Figure 7.3). However, a wide variation in appearances
may be seen, resulting in considerable diagnostic difficul-
ties. Cysts range from small, round or ovoid and well-­
demarcated to large, extensive lesions with poorly defined
borders.
Case series show that between about 70 and 85% of
keratocysts are unilocular (Chirapathomsakul et al. 2006;
Boffano et  al.  2010; MacDonald-­Jankowski  2011; Schuch
et al. 2020; Kitisubkanchana et al. 2021) and that 95% or
more are described as well demarcated with a corticated or
sclerotic margin (MacDonald-­Jankowski and Li  2010;
Schuch et  al.  2020). Many unilocular lesions, especially
Figure 7.3  A small odontogenic keratocyst. Radiology shows a
well-­demarcated radiolucency with a corticated margin.
(a)
Figure 7.4  (a) Radiograph of an odontogenic keratocyst that is unilocular but lobulated with scalloped margins. (b) The gross
specimen shows the irregular growth pattern of the lesion that results in the scalloped radiological appearance.
when larger, have a scalloped or lobulated margin and may
show incomplete bone septae within the lesion (Borghesi
et  al.  2018; Figure  7.4). These are sometimes misinter-
preted as multilocular. A truly multilocular lesion is com-
posed of multiple cysts, often described as having a
‘soap-­bubble’ appearance (Figure 7.5; Borghesi et al. 2018;
MacDonald-­Jankowski and Li 2010).
In a series of 75 keratocysts, Stoelinga (2001) was careful
to make this distinction, and carefully defined cysts as uni-
locular, scalloped, multilobular, and multilocular. In par-
ticular, multilobular comprised two or more lobes, but with
Figure 7.5  A large keratocyst at the angle and ramus of the
mandible. This cyst is truly multilocular.
(b)

no bony septae dividing the lobules (e.g. Figure  7.4),
whereas multilocular showed locules or lobules separated
by intact bony septae (e.g. Figure 7.5). He found that only 7
(9.3%) cases were truly multilocular, 35 (46.7%) were uni-
locular, but 15 (20.0%) were scalloped and 18 (24.0%) were
multilobular. All the multilocular cysts were located in the
posterior mandible. A review of many case reports shows
that most authors describe both multilobular and multi-
locular lesions as multilocular, and these combined in
Stoelinga’s series gives a proportion of 33%, in keeping with
other reports.
A number of authors agree with Stoelinga, and have
shown that larger lesions and lesions in the mandible are
more often multilocular. Chirapathomsakul et  al. (2006)
found that 34.8% of mandibular lesions were multilocular
compared to only 14.3% in the maxilla. Browne (1970)
found 19 of 83 cysts (22.9%) to be multilocular, all in the
mandible, and Forssell (1980) observed a frequency of
25.0% in a series of 135, also all in the mandible. Forssell
showed that about 50% of his cysts were 40 mm or more in
diameter and that this was particularly the case with cysts
of the ascending ramus and angle of the mandible, com-
pared with cysts of the maxilla or body of the mandible.
MacDonald-­Jankowski and Li (2010) found that 75.0% of
mandibular cysts were multilocular compared to only
15.4% of maxillary lesions. These authors also found that
multilocular lesions (especially in the mandible) were
larger than unilocular lesions, and that unilocular lesions
presented at a younger age (24.5 years) than multilocular
lesions (36.1 years). Boffano et  al. (2010) also found a
(a)
Figure 7.6  A large odontogenic keratocyst. (a) A conventional radiograph shows the lesion arising at the angle of the mandible, with
extensive mesio-­distal extension from the first molar and almost filling the ramus. (b) The coronal computed tomography (CT) scan,
however, shows relatively little bucco-­lingual expansion.
­Radiological Feature  101
significant association between multilocular lesions and
size greater than 31 mm. Forssell (1980) found that uniloc-
ular cysts that were scalloped or multilobular were also sig-
nificantly larger than unilocular cysts with a smooth margin.
These data suggest that unilocular lesions as they grow
may become scalloped and then multilocular (compare
Figures  7.3–7.5). This is feasible, but difficult to prove.
Multilocular lesions are more common in the mandible
and it is possible that the restricted growth imposed by the
cortical plates results in a multicystic lesion. In the maxilla,
however, growth is relatively unimpeded and the cyst is
enabled to grow centripetally in a ballooning pattern, often
filling the antrum (see later Figures 7.8 and 7.9).
The pattern of growth in the mandible produces a char-
acteristic feature of the odontogenic keratocyst. Lesions
may show marked mesio-­distal extension, but with rela-
tively little evidence of bucco-­lingual expansion
(Figure  7.6). This feature is best visualised on computed
tomography (CT) scans, but is so characteristic that
MacDonald (2016) regarded it as pathognomonic of the
odontogenic keratocyst. This is discussed further later in
this section.
The most common site of presentation of odontogenic
keratocysts is the posterior aspect of the mandible
(Figure 7.2), and both unilocular and multilocular lesions
may involve the body and ascending ramus of the mandi-
ble extensively (Figures 7.4–7.6). Up to 50% of lesions are
associated with an impacted tooth (Table  7.3) and it is
common for the odontogenic keratocyst to present in a
radiological dentigerous relationship, particularly with
(b)
102 Odontogenic Keratocyst
impacted third molars. (Figure 7.7; see also Figure 5.14).
Ali and Baughman (2003) found that 137 of their 398
cysts were located in the posterior mandible, of which 52
(37.9%) were in a pericoronal relationship with an
impacted third molar. Such lesions are frequently misdi-
agnosed as dentigerous cysts and this has given rise to
two misconceptions. One is that dentigerous cysts may
have a keratinised epithelial lining similar to that found
in odontogenic keratocysts; and the second is that denti-
gerous cysts may have an extrafollicular origin (Gillette
Figure 7.7  An odontogenic keratocyst that has enveloped an
unerupted tooth and lies in a ‘dentigerous’ relationship.
(a)
Figure 7.8  Sagittal computed tomography (CT) scans of odontogenic keratocysts in two different patients. (a) The keratocyst has
expanded into the maxillary antrum, but still has a corticated margin (arrows). (b) In this case, the CT scan shows the multilocular
nature of the lesion and buccal expansion.
and Weinmann 1958). The relationship between the den-
tigerous cyst and odontogenic keratocyst is discussed in
detail in Chapter 5.
Downward displacement of the inferior alveolar canal is
almost always seen and about 70% of mandibular lesions
also cause downward displacement of the lower border of
the mandible (MacDonald-­Jankowski  2011; Figure  7.5).
Maxillary lesions displace the floor of the maxillary sinus
upwards, but may still show a corticated margin (Figures 7.8
and 7.9). Displacement of teeth (70% of cases) and perfora-
tion of the cortical plate (50% of cases) are also common
(Chirapathomsakul et al. 2006; MacDonald-­Jankowski 2011).
Resorption of the roots appears to be infrequent and is rarely
mentioned in reports (Struthers and Shear  1976).
Chirapathomsakul et al. (2006) found that only 1 of 67 (1.5%)
cysts showed radiological evidence of root resorption, and
Kitisubkanchana et al. (2021) found resorption in 7 of 100
cases (7%). Others, however, have found a higher incidence.
Forssell (1980) noted varying degrees of root resorption in
24% of his series of 90  keratocysts, but pointed out that a
large proportion of these showed only a slight degree of
resorption. Partridge and Towers (1987) observed resorption
in 9 of their sample of 82 cases (11%), and MacDonald-­
Jankowski and Li (2010) found root resorption in 13 of
32 lesions (40%).
Very rarely (less than 4% of cases) an odontogenic kerato-
cyst may show a mixed radiological pattern with small
areas of radiopacity (Azevedo et  al.  2012; Borghesi
et al. 2018; Schuh et al. 2020). Almost certainly, this is due
to dystrophic calcification within the keratinaceous or
necrotic luminal contents, or within the cyst wall.
(b)

Computerised Tomography and Magnetic
Resonance Imaging
CT and cone beam CT (CBCT) have advantages in the diag-
nosis of odontogenic keratocysts since they allow high-­
resolution three-­dimensional assessment of the lesion. CT
is particularly valuable for visualising the bucco-­lingual
expansion of mandibular cysts and for determining the
extent of maxillary lesions, which may be particularly dif-
ficult to see on conventional radiographs (Figures  7.8
and  7.9; MacDonald  2016; Borghesi et  al.  2018; Alves
et al. 2018). Three-­dimensional imaging is now regarded as
essential for proper surgical planning of large lesions,
although it should be noted that CT is not ideal for evaluat-
ing extension into soft tissues.
MacDonald (2016) showed how CBCT can be used to
visualise the three-­dimensional extent of mandibular
odontogenic keratocysts and to show how marked mesio-­
distal extension may be associated with minimal bucco-­
lingual expansion (Figure  7.6). This was also shown by
Alves et  al. (2018), who compared nine cases each of
ameloblastoma and odontogenic keratocyst by conven-
tional radiographs and CT. Radiographs enabled accurate
evaluation of location, margins, and the relationship to the
teeth, but CT showed a higher resolution and allowed addi-
tional assessment of bucco-­lingual expansion and perfora-
tion of the cortical bone (Figure 7.9). All the ameloblastomas
Figure 7.9  A coronal computed tomography (CT) scan enables
accurate visualisation of the extent of this large keratocyst. The
lesion has filled the antrum with displacement of the lateral
wall of the nose and has raised the floor of the orbit. There is
also evidence of perforation of the cortical bone (arrows). This
lesion was diagnosed as a solid odontogenic keratocyst (see
Figure 7.21).
­Radiological Feature  103
showed a ballooning pattern of expansion with a similar
degree of extension mesio-­distally and bucco-­lingually. In
contrast, four of seven odontogenic keratocysts that had
expanded bone showed a fusiform pattern of expansion,
with mesio-­distal extension much greater than bucco-­
lingual. This pattern is characteristic of odontogenic
keratocyst and has been described as pathognomonic
(MacDonald 2016). It should be noted, however, that a sim-
ilar pattern of growth can be seen in glandular odontogenic
cyst; this is discussed in Chapter 10. Figure 10.5 illustrates
the typical ballooning expansion of an ameloblastoma,
which is not seen in odontogenic keratocysts. Alves et al.
(2018) also found that root resorption was more common
in ameloblastomas and was seen in six cases compared to
only one case of keratocyst. However, both lesions showed
a similar association with unerupted teeth (four of nine
lesions) and with cortical bone resorption (six of nine
lesions)
Magnetic resonance imaging (MRI) is less often used or
necessary, but may complement CT and is especially use-
ful in selected cases to evaluate soft-­tissue extension. By
using selective T1 and T2 weighting, it is also possible to
clearly distinguish between odontogenic keratocysts and
more solid lesions such as ameloblastoma (Borghesi
et al. 2018). The use of MRI to differentiate odontogenic
keratocysts from ameloblastomas and other cysts was the
basis of a study by Minami et  al. (1996). Their sample
included 19 keratocysts, 11 ameloblastomas, and 13 other
jaw cysts. They found that MRI of the ameloblastomas
differed from the keratocysts in displaying a mixed solid
and cystic pattern and irregularly thickened walls in all 11
cases, papillary projections in 7, and strong enhancement
of solid components in 9. Odontogenic keratocysts
showed a purely cystic pattern in 13 of the 19 cases, while
4  were mixed cystic and solid and 2 appeared wholly
solid. The walls of the keratocysts were uniformly thin
with weak enhancement compared to thicker walls and
stronger enhancement in ameloblastomas. These authors
suggested that MRI was able to accurately differentiate
odontogenic keratocysts from ameloblastomas in all their
cases, although some other cysts showed similar findings
to the keratocysts. T1 and T2 weighting of images shows
that keratocysts tend to be heterogeneous, but ameloblas-
tomas are homogeneously hypointense (grey) on
T1 weighting and hyperintense (white) on T2 weighting
(Minami et al. 1996; Van Rensburg et al. 2003; Borghesi
et al. 2018). Figure 7.10 shows a maxillary lesion that has
been visualised using a T2-­weighted MRI image with het-
erogeneous intensity. The lesion is well demarcated and
its extent and lobulated outline can be clearly seen. Such
a clearly demarcated image would not be possible using
conventional radiographs.
104 Odontogenic Keratocyst

Radiological Differential Diagnosis
The clinical features of the odontogenic keratocyst
(Table  7.2; Boxes  7.1 and  7.2) are not diagnostic and the
first opportunity to make a preoperative diagnosis is usu-
ally after examination of radiographs or imaging. The radi-
ological features of a well-­demarcated radiolucency are
shared by many lesions, and for simple unilocular lesions
the differential diagnosis may include a wide range of
benign cysts and tumours of the jaws as well as other
lesions, including giant cell granulomas. For multilocular
lesions the differential diagnosis may be more limited.
Figure 7.10  Coronal magnetic resonance imaging (MRI)
showing the lobularity (arrow) of a large maxillary odontogenic
keratocyst. The image is T2 weighted and shows a
heterogeneous signal intensity. Source: Prof van Rensburg 2003,
p.311-466 / With permission of Elsevier.
The most common single site for odontogenic keratocyst
is the posterior mandible and at this site the three most com-
mon lesions that must always be considered are dentigerous
cyst, keratocyst, and ameloblastoma. About 35% of kerato-
cysts are associated with an unerupted tooth (Table 7.2) and
dentigerous cyst is probably the most common provisional
radiological diagnosis. Myoung et  al. (2001) and Brannon
(1976) found that 27.1% and 25.1%, respectively, of kerato-
cysts were provisionally diagnosed as dentigerous cyst.
Other diagnoses included ameloblastoma (11.6% and 9.5%,
respectively), residual cyst (9.7% and 19.2%), and radicular
cyst (3.1% and 5.3%). Myoung et al. (2001) also found that a
majority of lesions (39.9%) were given a correct preoperative
diagnosis of odontogenic keratocyst (although the term pri-
mordial cyst was also used). Stoelinga (2001) found that
51.2% of his cases presented with radiographic features sug-
gestive of a keratocyst, while the remainder could not be dis-
tinguished from other odontogenic cysts, including 13.4% of
cases that were in a dentigerous relationship.
The differential diagnosis of lesions at the angle of the
mandible and in a pericoronal relationship with impacted
third molars has been discussed in detail in Chapter 5. At
this site dentigerous cysts are by far the most common,
comprising more than 70% of lesions (Curran et al. 2002;
Patil et  al.  2014; Mello et  al.  2019), but the frequency of
odontogenic keratocysts and ameloblastomas may be simi-
lar, reported as about 9.5% and 7.5%, respectively (Mello
et  al.  2019). Patil et  al. (2014), however, reported that
ameloblastomas were twice as common (16%) at this site as
keratocysts (8%), a finding also noted by MacDonald-­
Jankowski and Li (2010). Dentigerous cysts are always

Box 7.2  Odontogenic Keratocyst: Clinical Presentation and Radiology

Clinical presentation
●● Over 50% present with swelling, with or without pain
●● Up to about 20% present as an unexpected incidental finding on radiographs
●● 10–15% may be infected or have a discharge
●● Nerve involvement (numbness or paraesthesia) is rare (<2%)
●● Peripheral lesions are rare, but presentation is indistinguishable from gingival cyst
Radiology
●● A characteristic feature is marked mesio-­distal extension with minimal bucco-­lingual expansion
●● About 75% are well demarcated and unilocular
●● 40–50% are unilocular, but with a scalloped or lobulated outline
●● Most lesions (over 90%) have a corticated margin
●● Only about 10% are truly multilocular
●● Multilocular or multilobular lesions are most frequently seen at the angle of the mandible
●● Larger lesions are more frequently multilobular or multilocular
●● Up to 50% are associated with a missing or impacted tooth
●● About 30% may be in a dentigerous relationship with an unerupted tooth.

unilocular with a corticated margin, and are attached to
the tooth in the cervical region. Larger cysts may become
lobulated, but they rarely show significant extension into
the ramus. They tend to grow in a ballooning fashion and
to show a similar degree of bucco-­lingual and mesio-­distal
expansion. Odontogenic keratocysts may be very similar,
especially while small, and an accurate diagnosis may not
be possible (Figure  7.7; see also Figure  5.14). However,
keratocysts are more often scalloped or lobulated and about
10% are multilocular. Keratocysts may also grow to larger
sizes and mesio-­distal extension often exceeds bucco-­
lingual expansion. As mentioned previously, this fusiform
swelling is so characteristic of the odontogenic keratocyst
that MacDonald (2016) regarded it as pathognomonic.
Odontogenic keratocysts may also grow in the ramus
posterior to the third molars. At this site an ameloblastoma
is the most likely alternative diagnosis. Ameloblastomas,
however, are more often multilocular, and so a unilocular
radiolucency in the ramus of the mandible that is not asso-
ciated with an unerupted tooth is most likely to be an odon-
togenic keratocyst (Figure 7.11).
The differential diagnosis of multilocular lesions is also
problematic, but the number of possible diagnoses is more
limited. Ameloblastoma is the most important, but for
small lesions on plane radiographs it is difficult to accu-
rately differentiate between an ameloblastoma and an
odontogenic keratocyst. The lesions show a similar age,
site, and sex distribution and so a definitive diagnosis will
Figure 7.11  A well-­demarcated unilocular radiolucency in the
ascending ramus, not associated with an unerupted tooth. Such
a lesion is most likely to be an odontogenic keratocyst.
­Radiological Feature  105
often rely on an incisional biopsy. For larger lesions, how-
ever, it may be possible to predict more accurately a diagno-
sis of keratocyst. The fusiform expansile pattern of the
keratocyst has been mentioned above, and this contrasts
markedly with the ball-­like or ballooning expansion of the
ameloblastoma (MacDonald  2016; Alves et  al.  2018;
Kitisubkanchana et  al.  2021). This pattern of growth in
ameloblastoma is illustrated in Chapter  10 (Figure  10.5)
and is so characteristic as to be almost diagnostic. The only
other lesion that may show this pattern is odontogenic
myxoma, but the myxoma tends to be more radiolucent
and may often show incomplete bony septae. To fully
appreciate these features, three-­dimensional imaging
would now be regarded as essential and the role of CT and
MRI has been discussed.
Kitisubkanchana et al. (2021) compared the radiological
features of odontogenic keratocysts (n = 100) and amelo-
blastomas (n = 101) and showed that keratocysts were sig-
nificantly more often associated with an impacted tooth
(47% compared with 19% of ameloblastomas), but less
often caused tooth displacement (29% compared with 53%)
or root resorption (6% compared with 62%). Keratocysts
were also more frequently unilocular (82% compared with
32%) and with a smooth or non-­scalloped outline (60%
compared with 23%).
Other lesions to consider in the differential diagnosis of
a multilocular radiolucency are botryoid odontogenic cyst
and glandular odontogenic cyst. These are discussed in
Chapters 8 and 10, respectively. Botryoid odontogenic cysts
are always lateral to a tooth, present in the canine–premo-
lar region, and rarely reach 40 mm in diameter. The glan-
dular odontogenic cyst may grow to a large size and may
show a multilocular pattern identical to an ameloblastoma
or keratocyst. Its growth pattern is also very similar to the
keratocyst, with extensive mesio-­distal extension and rela-
tively little bucco-­lingual expansion (e.g. see
Figures  10.3–10.5), and 75% arise in the mandible.
However, glandular odontogenic cyst has a predilection for
the midline and canine–premolar region, and the average
age of presentation is about 50 years with a peak in the
sixth decade. They are very rare below 20 years of age.
Finally, a number of authors have drawn attention to the
potential for misdiagnosis of keratocysts as radicular cyst.
Small unilocular lesions in the dentate areas of the jaws
often present in association with the roots of the teeth. The
key diagnostic feature of the radicular cyst is the associa-
tion with a non-­vital tooth, but this is not specific and vital-
ity testing is not always reliable. There are a number of case
reports of the chance finding of keratocysts in the periapi-
cal region, and Ide et al. (2009) estimated that 0.03–0.1% of
periapical biopsies may show an odontogenic keratocyst.
Garlock et al. (1998) reviewed 239 odontogenic keratocysts
106 Odontogenic Keratocyst
and found that 8.8% (21 cysts) were found at the periapex,
and in 12 of these (57.1%) the tooth was either non-­vital or
had undergone prior root canal treatment. Two-­thirds of
patients presented symptoms of pain and/or swelling con-
sistent with pulpal and periapical pathology. Most lesions
were small (less than 20 mm), but presented at an average
age of 56 years. From these data it can clearly be appreci-
ated why keratocyst would not be the most favoured diag-
nosis for a small radiolucency at this site. Ali and Baughman
(2003) found a high frequency of periapical keratocysts in
the maxilla, especially in the canine region. At this site
25.9% of cases were provisionally diagnosed as a radicular
cyst or periapical granuloma, and 27.8% as a lateral perio-
dontal cyst. However, a small majority (31.5%) were still
diagnosed correctly as keratocysts.
From this discussion it can be seen that a preoperative
diagnosis of large multilocular odontogenic keratocysts
can often be made because of their characteristic fusiform
growth pattern and multilocular ‘soap-­bubble’ appearance.
Similarly, a large unilocular lesion in the ramus, not associ-
ated with a tooth, is most likely to be a keratocyst. The most
problematic lesions to accurately diagnose are small uni-
locular lesions in the tooth-­bearing areas of the jaws that
may be indistinguishable from common periapical lesions
(Ali and Baughman  2003; MacDonald et  al.  2013;
MacDonald  2016; Slusarenko da Silva et  al.  2019a).
MacDonald et  al. (2013) showed that lesions that were
diagnosed as keratocysts before surgery were significantly
less likely to recur than lesions that had a provisional diag-
nosis of another cyst type. Ironically, because larger multi-
locular cysts were more likely to get an accurate preoperative
diagnosis, the authors suggested that small, simple uniloc-
ular odontogenic keratocysts are more likely to recur
(MacDonald et al. 2013; MacDonald 2016). Factors associ-
ated with recurrence of the odontogenic keratocyst are dis-
cussed at the end of this chapter.
Pathogenesis
It is now widely accepted that the odontogenic keratocyst is
associated with activation of the HH signalling pathway, most
often as a result of alterations in the PTCH1 gene (reviewed by
Gomes et  al.  2009; Li  2011; Gomes et  al.  2017; Diniz
et al. 2017). Downstream targets of the HH pathway drive cell
proliferation and growth, and this almost certainly acts to ini-
tiate cyst formation in odontogenic epithelial rest cells.
Source of Epithelium
Most authors agree that the odontogenic keratocyst arises
from the odontogenic cell rests of the dental lamina, but
there have been suggestions that some keratocysts may
arise from epithelial islands originating from the basal
aspect of the overlying oral epithelium. The evidence for
each will be briefly reviewed.
Rest Cells of Dental Lamina
The dental lamina begins to form at about 37 days of devel-
opment as a thickening of the epithelium in the early oral
cavity (the stomatodeum). It develops as a series of out-
growths into the underlying mesenchyme, each of which
develops through the bud, cap, and bell stages to give rise
to the enamel organ from which each tooth develops. The
tooth germ is attached to the overlying oral epithelium by
an intact dental lamina, until the late bell stage after which
it begins to disintegrate. Early studies of fetal tissues
(Stoelinga and Peters 1973; Moskow and Bloom 1983) have
shown that as the dental lamina breaks down, multiple
small epithelial islands, often with microcystic change, can
be found overlying the developing tooth. Moreillon and
Schroeder (1982) showed that these ‘microkeratocysts’ are
frequently found in the gingivae or alveolus of infants and
may give rise to gingival cysts of infants (see Chapter 9 and
Figure 9.7). It is thought that after tooth development and
eruption are complete, most of the residues of dental lam-
ina involute, but some rest cells of dental lamina are
undoubtedly retained in the mucosae and in the alveolar
bone adjacent to the teeth.
A number of observations from these studies are perti-
nent to the following discussion. First, the epithelial rests
and small microcysts are often found to be continuous
and fused with the overlying oral epithelium (Stoelinga
and Peters 1973; Moreillon and Schroeder 1982; Moskow
and Bloom  1983). Secondly, the remnants of the dental
lamina typically form strands that lie within the guber-
nacular canal (also referred to as the gubernaculum den-
tis, or gubernacular tract). The gubernacular canal is a
bony channel that lies between the lamina propria of the
oral mucosa and the dental follicle of the developing suc-
cessional (permanent) teeth. The canal contains fibrous
tissue (the gubernacular cord) that provides a pathway for
the erupting tooth. Significantly, a gubernacular canal (or
tract) may also aid eruption of the permanent molars, and
may persist into adult life. CT imaging has shown that it
forms a continuity between odontogenic lesions (amelo-
blastoma, odontogenic keratocyst, and dentigerous cyst)
and the lamina propria of the oral mucosa (Oda
et al. 2018). The gubernacular canal and its contents (rest
cells of dental lamina) have been implicated in the patho-
genesis of the adenomatoid odontogenic tumour
(Philipsen et  al.  1992; Ide et  al.  2011) and odontomas
(Oda et al. 2016), but have not been discussed in the con-
text of the odontogenic keratocyst. Of significance is that

Oda et al. (2018) showed that patent gubernacular tracts
were present in 46 of 50 (92%) odontogenic keratocysts
studied, and were frequently seen just distal to the third
molars, forming a continuity between the fibrous capsule
of the cyst and the lamina propria of the retromolar
mucosa. They also showed that in about 25% of cases the
gubernacular canal was expanded to form a wider com-
munication through the anterior cortical plate of the
ramus. These communications are rarely seen on plane
panoramic radiographs, but when they have been noted,
have probably been interpreted as cortical perforation due
to cyst growth.
Epithelial Islands Derived from Oral Epithelium
Stoelinga and colleagues, in a number of studies
(Stoelinga  1976,  2001,  2005; Stoelinga and Peters  1973;
Stoelinga et  al.  1975), have suggested that odontogenic
keratocysts may also arise from a proliferation of basal cells
of the oral epithelium, which results in islands ‘dropping
down’ into the underlying lamina propria. In their early
studies (Stoelinga and Peters  1973; Stoelinga  1976), they
undertook histological examination of fetal mandibles and
demonstrated that the dental lamina extended distally to
the second primary molars, suggesting that it became ‘sub-
merged’ into the deeper connective tissues where the tooth
germs of the successional teeth were formed. They pro-
posed that dental lamina rests may be found in the gingivae
of dentate areas of the jaws, but that distal to the third
molars, the dental lamina is adherent to the tooth follicle
and cannot give rise to keratocysts in the ascending ramus.
They also examined six keratocysts enucleated from the
third molar region (Stoelinga and Peters 1973). In all cases,
the cysts were attached to the oral mucosa overlying the
anterior aspect of the ascending ramus. These authors
attributed this attachment to the presence of a fenestration
through the cortical plate of the ascending ramus.
Histological examination showed epithelial islands and
occasional microcysts within the connective tissues of the
oral mucosa overlying the cysts. No islands were found in
areas of the cyst walls away from the mucosal aspect. The
islands were described as odontogenic or basal cell like,
although some appeared to be simple squamous epithe-
lium. In a later study (Stoelinga 2001), the author reported
the treatment of 82 keratocysts over a period of 25 years. In
44 cases, the oral mucosa overlying the cysts was excised
and examined, and in 23 (52.3%) he found clusters of epi-
thelial islands or microcysts in the region where the cyst
wall was attached to the mucosa. Occasionally the islands
or microcysts were fused with the oral epithelium. He
showed that the attachment of the cyst wall to the oral
mucosa was via a perforation or fenestration in the bone
just posterior to the third molars.
Pathogenesis  107
From these studies, Stoelinga (2001, 2005) proposed that
odontogenic keratocysts, particularly in the ramus of the
mandible, may not arise from dental lamina rests, but from
epithelial islands derived as offshoots of the basal layer of
the oral epithelium, which are referred to as ‘basal cell
hamartias’. Furthermore, he suggested that these islands
derived from the oral epithelium are a major cause of
recurrences, and advocated that when keratocysts are enu-
cleated, the overlying mucosa should also be excised.
Stoelinga has also discussed the recurrence of odontogenic
keratocysts in bone grafts that had been used to repair the
surgical defects after marginal or segmental resection.
Stoelinga and Slusarenko da Silva (2021) reviewed the lit-
erature and found seven well-­documented cases where a
keratocyst had recurred in a bone graft. The authors sug-
gest that the source of the recurrence must be from the
overlying mucosa and cite such recurrences as further evi-
dence for the role of mucosal epithelial islands in the
pathogenesis of the odontogenic keratocyst.
Most oral pathologists will have encountered proliferat-
ing islands of epithelium within the oral mucosa, espe-
cially in the region of the retromolar area or within the
follicles associated with unerupted or impacted teeth. On
occasion these may be quite prominent and the term basal
hamartia has been used (Ide and Kusama  2002b). An
example of epithelial islands, similar to those described by
Stoelinga and overlying a keratocyst, is shown in
Figure  7.12. Many pathologists, however, would regard
these as proliferating islands of odontogenic epithelium. In
a recent study of 167 biopsies taken from the edentulous
alveolus or retromolar area, Almazyad et al. (2020) found
that 11 (6.6%) contained odontogenic epithelial rests as a
chance finding. Conversely, Diniz et  al. (2009) provided
some support for Stoelinga’s hypothesis. They investigated
PTCH1 splice variants (three isoforms: exons 1b, 1d, and
1e) and found that exon 1b was expressed in 90% of odon-
togenic keratocysts and in 83% of samples of oral mucosa
adjacent to keratocysts. This suggests that the mucosa adja-
cent to a keratocyst may harbour similar alterations in the
PTCH gene and may therefore have the potential to form
new lesions. However, Diniz et al. (2009) were not able to
undertake histological examination of their mucosal sam-
ples, so it remains possible that the source of the exon 1b
was remnants of dental lamina in the mucosa rather than
oral epithelium.
Heikinheimo et al. (2007, 2015) investigated genomic
aberrations in sporadic odontogenic keratocysts using
cDNA expression arrays, comparative genomic hybridi-
sation, or genome wide expression analysis, and found
significant expression of genes associated with tooth
development supporting an origin from dental lamina.
They also found overexpression of genes associated with
108 Odontogenic Keratocyst
Figure 7.12  Islands and cords of epithelium in the oral mucosa
overlying an odontogenic keratocyst. In places these merge with
the oral epithelium and have been referred to as ‘basal cell
hamartias’ (see text). Some islands show peripheral palisaded
cells (arrows), typical of odontogenic epithelial rests. Source:
Courtesy of Dr Adalberto Mosqueda.
keratin 6B (Heikinheimo et al. 2007), as well as enrich-
ment of genes associated with the HH signalling path-
way and with squamous epithelial differentiation
(Heikinheimo et al. 2015), suggesting that the keratocyst
arises from remnants of dental lamina that have not dif-
ferentiated towards formation of the enamel organ. They
found that genes enriched in ameloblastoma were asso-
ciated with later stages of tooth development, including
genes of the WNT pathway. This supports the concept
that odontogenic cysts and tumours may arise from cells
at different stages of tooth development (reviewed by
Diniz et al. 2017).
An origin from dental lamina does not necessarily con-
tradict the findings of Stoelinga. The more recent demon-
strations of a patent gubernacular canal overlying
odontogenic keratocysts in adults (Oda et  al.  2018) are
quite in keeping with Stoelinga’s descriptions of fenestra-
tions in the anterior cortical plate in the retromolar region
of the ascending ramus (Stoelinga and Peters  1973;
Stoelinga  1976,  2005). The gubernacular canal contains
remnants of the dental lamina, which are also seen extend-
ing into the overlying oral mucosa (Moskow and
Bloom  1983; Philipsen et  al.  1992; Ide et  al.  2011;
Nanci  2017). It is possible therefore that the epithelial
islands found on the deep aspect of oral mucosa overlying
primary and recurrent keratocysts arise not from basal cell
buds ‘dropping off’, but from residual rest cells of dental
lamina lying superficial to the opening of the gubernacu-
lar canals.
If this is the case, the advice from Stoelinga that it is wise
to remove the attached overlying oral mucosa after enu-
cleation of a keratocyst is still valid and applicable. Such a
procedure is often used and may have an effect on reducing
recurrence (see later in this chapter).
Summary and Conclusions
Although it is possible that epithelial islands from the oral
mucosa may give rise to odontogenic cysts, this hypothesis
has not gained widespread support and the findings have
not been repeated or described by other workers. Overall,
the accumulated evidence supports the concept that the
odontogenic keratocyst arises from cell rests of the dental
lamina. Initiation of cyst formation is probably early in the
development of the teeth, involving alterations in the
PTCH1 gene (see below) before the dental lamina begins to
disintegrate at the bell stage of tooth morphogenesis. In
this way, the keratocyst lining derives from a clone of
genetically altered epithelial remnants that give rise to the
cyst, but may also explain the frequent presence of satellite
cysts and also the propensity for recurrence if residual epi-
thelial islands remain after surgery (Browne 1975; Browne
and Smith 1991).
Hedgehog Signalling Pathway, PTCH Gene
Alterations, and Odontogenic Keratocyst
Hedgehog (HH) signalling is a fundamental feature of nor-
mal development, with crucial roles in cell fate, differentia-
tion, and patterning. In normal odontogenesis, HH
activation through binding of the SHH ligand regulates the
development of the dental lamina and is responsible for
tooth morphogenesis and patterning. It is likely therefore
that constitutive or aberrant activation of HH signalling in
odontogenic epithelium initiates the formation of kerato-
cysts. An understanding of tooth development and the role
of the dental lamina is helpful for understanding cyst
pathogenesis, and readers are referred to specialist texts or
reviews for up-­to-­date and detailed accounts of odontogen-
esis and the role of HH signalling (Nanci  2017; Diniz
et  al.  2017; Seppala et  al.  2017; Hovorakova et  al.  2018;
Sasai et al. 2019).
A simplified description of the HH signalling pathway is
illustrated in Figure 7.13. The key regulator of the pathway
is the PTCH protein, which is a transmembrane protein that
acts to suppress or inhibit SMO (smoothened) at the cell
surface. PTCH is a receptor for SHH and under normal con-
ditions ligand binding releases SMO and results in con-
trolled and regulated activation of the HH signalling
pathway (Figure 7.13b). The downstream outcomes of sig-
nalling are tissue specific, but in odontogenesis HH signal-
ling regulates epithelial–mesenchymal interactions, cell
 Pathogenesis  109

(a)

H
SH

(b) (c)

SHH
SMO
X SMO
X SMO

PTCH 1 PTCH 1 PTCH 1

Cell membrane Cell membrane Cell membrane

SU
SUFU

SU
FU
GLi

FU
GLi GLi

Gene expression off Gene expression on Gene expression on

Nucleus Nucleus Nucleus

Figure 7.13  The hedgehog signalling pathway. (a) In the absence of ligand binding, the PTCH protein suppresses SMO at the cell
membrane and signalling and gene expression are switched off. (b) Sonic hedgehog (SHH) is the ligand for the PTCH receptor and,
when bound, PTCH inhibition of SMO is released and signalling is switched on in a controlled manner (dashed green arrow). Gli
proteins are destabilised by release from SUFU and are translocated to the nucleus where gene expression is switched on. (c)
Reduction or loss of PTCH protein results in ligand-­independent activation of the HH signalling pathway (solid green arrow). This may
occur as a result of mutation or loss of heterozygosity (LOH) of PTCH1.

proliferation, and cell fate in the dental lamina and tooth
germ, and is crucial for normal tooth morphogenesis. Gene
expression is regulated through the Gli transcription fac-
tors. In the absence of SHH ligand binding, Gli proteins are
inactive and bound to the protein SUFU (Figure 7.13a), but
on activation of SMO, SUFU is released and Gli migrate into
the nucleus (Figure 7.13b). The downstream target genes of
the pathway include the transcription factor SOX2 (impor-
tant in odontogenesis), the anti-­apoptotic protein bcl-­2, and
cell cycle regulatory proteins (including cyclin D1).
Alterations of the PTCH gene cause reduced expression or
loss of PTCH protein at the cell surface and results in ligand-­
independent, constitutive activation of the HH signalling
pathway (Figure 7.13c). As discussed previously, PTCH muta-
tions are the cause of the NBCCS and are also involved in the
pathogenesis of odontogenic keratocysts  – both syndromic
and sporadic. The majority of causative mutations are
frameshift, nonsense, or missense mutations in the PTCH1
gene (Guo et al. 2013; Reinders et al. 2018), but mutations or
alterations in PTCH2, SUFU, and SMO have been implicated
in NBCCS and in sporadic keratocysts (Rui et al. 2014).
In NBCCS, germline mutations are found in one allele of
PTCH and are inherited in an autosomal-­dominant man-
ner. Thus NBCCS patients will have reduced expression
(haploinsufficiency) of PTCH protein, causing activation
of the HH pathway with the resulting developmental
defects. Loss of one PTCH allele predisposes patients to
neoplasia and loss of the second allele is thought to be the
major cause of basal cell carcinomas and other neoplasms
in these patients. Loss of the second allele may be by a sec-
ond (somatic) mutation or, more commonly, due to loss of
heterozygosity (LOH). Mutation or loss of both copies of a
gene is referred to as the ‘two-­hit hypothesis’ of carcino-
genesis, first described by Knudson in 1971 (see
Knudson  1996; Tomlinson et  al.  2001), but it should be
noted that two hits may not always cause neoplasia.
Alterations in the PTCH gene have also been demon-
strated in sporadic odontogenic keratocysts, but in most
cases this has only involved one copy of the gene, resulting
in haploinsufficiency and reduced expression of PTCH
protein at the cell surface, with activation of the HH path-
way. Alterations of the PTCH gene may be by somatic
mutations, LOH, or due to gene silencing by DNA methyla-
tion (Gomes et al. 2009). Table 7.6 summarises a number of
studies that have determined the frequency of PTCH alter-
ations in NBCCS and sporadic cysts. In general, the num-
ber of cysts analysed is small, but the overall findings are
similar and consistent: 80% or more of NBCCS and spo-
radic cysts show mutations or LOH on chromosome 9q at
the PTCH1 gene locus. Two things can be noted from these
data. First, not all NBCCS cysts show a mutation, despite
the fact that in the syndrome the mutations are found in
the germline. This is in part due to technical factors
whereby mutations may not always be detected, but
also because small numbers of cases may harbour muta-
tions not yet found, or may involve mutations in other
110 Odontogenic Keratocyst

Table 7.6  Frequency of PTCH1 gene alterations (mutations or loss of heterozygosity, LOH) in naevoid basal cell carcinoma syndrome
(NBCCS) and sporadic odontogenic keratocysts. Based on Myoung et al. (2001) and Kahraman et al. (2018).

NBCCS cysts Sporadic cysts

PTCH1 alterations PTCH1 alterations

References n Mutations (%) LOH (%) n Mutations (%) LOH (%) Notes

Levanat et al. (1996) 6 – 83.3 14 – 28.6 3 (50%) NBCCS cysts showed

evidence of biallelic loss
Lench et al. (1996) – – – 6 – 50.0
Lench et al. (1997) 16 31.3 0 – – –
Barreto et al. (2000) 3 66.6 – 3 33.3 –
Agaram et al. (2004) – – – 10 – 60.0
Ohki et al. (2004) 4 0 – 9 77.8 –
Gu et al. (2006) 2 100 – 10 30.0 –
Sun et al. (2008) 10 80.0 – 20 25.0 – 2 (20%) NBCCS and 3 (15%) sporadic
cysts showed evidence of biallelic loss
Pan et al. (2010) 15 86.7 46.7 29 31.0 27.6 8 (53%) NBCC and 5 (17%) sporadic
cysts showed evidence of biallelic loss
Guo et al. (2013) 14 78.6 – 29 44.8 –
Shimada et al. (2013) 16 56.3 42.0 20 0 15.0 25% of sporadic cysts showed LOH at
PTCH2 and 15% at SUFU.
Qu et al. (2015) – – – 19 84.2 –
Stojanov et al. (2020) – – – 44 93.2 34.1 35 (80%) showed evidence of biallelic
loss

n, number of cysts analysed.

HH-­related genes, including PTCH2, SUFU, or SMO (dis-
cussed by Li 2011). This may also apply to sporadic cysts
(Rui et al. 2014), so the actual number of cysts with genetic
alterations may be higher than so far discovered. Secondly,
the frequency of mutations found in cysts has increased in
more recent studies. This is due to more advanced tech-
niques (e.g. next-­generation sequencing), and also because
some more recent studies have used microdissection to iso-
late keratocyst epithelium and thus remove stromal con-
tamination (Qu et al. 2015; Stojanov et al. 2020). Ohki et al.
(2004) and Shimada et  al. (2013) found no mutations in
NBCCS and sporadic cysts, respectively, but this is unusual
and the reasons are uncertain.
A number of studies have confirmed that the HH signal-
ling pathway is activated by examining the expression of
HH-­associated genes or proteins. Gurgel et al. (2014) ana-
lysed 23 keratocysts and showed up-­regulation of the HH
pathway–associated genes SMO, PTCH1, and GLI1, as well
as overexpression of the downstream target genes for cyc-
lin D1 and bcl-­2. In their gene expression analysis,
Heikinheimo et  al. (2015) also found up-­regulation of
genes of the HH pathway, including PTCH1, PTCH2, SMO,
GLI1, and GLI2, as well high levels of the downstream tar-
get SOX2.
Ohki et al. (2004) examined 18 sporadic and 4 NBCCS-­
associated keratocysts and found expression of SHH,
PTCH, SMO, and Gli1  mRNA and protein in all cases.
Expression of PTCH and SMO was similar in the epithelial
lining and in the fibrous cyst wall, but expression of SHH
and Gli1 was higher in the epithelium, suggesting an ele-
ment of epithelial–mesenchymal cross-­talk in the signal-
ling process. Hoyos Cadavid et al. (2019) confirmed these
findings and showed immunohistochemical expression of
SHH, PTCH1, PTCH2, SMO, Gli1, Gli2, and Gli3 in both
sporadic and NBCCS-­associated cysts.
In a similar study, Vered et al. (2009) showed PTCH and
Gli1 protein expression in all keratocysts studied (27 spo-
radic and 6 NBCCS associated), with intermediate to high
staining in all layers of the epithelial lining. Expression of
SMO was found mainly in the basal and parabasal layers
in 69% of primary sporadic keratocysts, 54% of recurrent
cysts, and 50% of NBCCS-­associated cysts. However, this
expression was not specific to odontogenic keratocysts,
since a similar pattern of PTCH and Gli1 staining was

found in ameloblastomas and also in orthokeratinised
odontogenic cysts, dentigerous cysts, and radicular cysts.
SMO expression was seen in 22% of ameloblastomas, 58%
of unicystic ameloblastomas, 33% of orthokeratinised
odontogenic cysts, and 40% of dentigerous cysts. SMO
was not expressed in radicular cysts. Vered et  al. (2009)
also examined expression of the anti-­apoptoticprotein
bcl-­2, which is known to be a downstream target of the
HH pathway. Bcl-­2  was strongly expressed in the basal
layers of all the odontogenic keratocysts, but only weakly
expressed in ameloblastoma. Orthokeratinised odonto-
genic cysts, dentigerous cysts, and radicular cysts did not
express bcl-­2.
These findings confirm previous studies showing that
PTCH protein is expressed in a wide range of odontogenic
lesions, including radicular cysts and dentigerous cysts
(Pavelić et al. 2001; Barreto et al. 2002). It is probable that
PTCH is constitutively expressed on the cell surface of the
epithelial linings, but there is an apparent anomaly in that
PTCH protein is still expressed in cysts, even when there is
evidence of a mutation or LOH. This can be explained by
the fact that usually only one copy of the gene is affected
(haploinsufficiency), so the protein is reduced in amount
but is still expressed and detectable. It is also possible that
the mutant protein, although inactive, still has the appro-
priate epitopes for immunohistochemical detection.
Although these data show that PTCH gene alterations
are important in keratocysts, they do not seem to be spe-
cific, and there is evidence that mutations or LOH of the
PTCH gene or activation of the HH signalling pathway may
be involved in other odontogenic lesions (Gomes and
Gomez 2011), including orthokeratinised odontogenic cyst
(Diniz et  al.  2011), calcifying epithelial odontogenic
tumour (Peacock et al. 2010), glandular odontogenic cyst
(Zhang et  al.  2010), and dentigerous cyst (Levanat
et al. 2000; Pavelić et al. 2001; Barreto et al. 2002; Zhang
et  al.  2010). It should also be noted that LOH of other
tumour-­suppressor genes, including p16, p53, MCC,
TSLC1, LTAS2, and FHIT (Agaram et  al.  2004; Henley
et al. 2005), has been found in keratocysts, but the signifi-
cance of these findings remains uncertain, since these
changes may also be seen in radicular and dentigerous
cysts (Malcić et al. 2008). Overall, however, these data sug-
gest that LOH is not uncommon and, although it may pro-
mote cell proliferation and growth, it cannot be regarded as
a specific pathogenetic event. However, these are tumour-­
suppressor genes and their loss is also associated with
many types of neoplasms.
Of particular interest are studies that have shown LOH
at the PTCH1 locus in dentigerous cysts. Levanat et  al.
(2000) examined seven each of dentigerous cysts, radicular
cysts, and odontogenic keratocysts for LOH in two regions
Pathogenesis  111
of the PTCH gene. Three of seven (43%) dentigerous cysts
and four of seven (57%) keratocysts showed evidence of
LOH. LOH was not detected in any radicular cysts. In a
further study, the same group (Pavelić et  al.  2001) con-
firmed these findings and found LOH in the same region in
five of ten (50%) dentigerous cysts, but not in radicular
cysts. They also used reverse transcription polymerase
chain reaction (RT-­PCR) in two cysts to show that the
PTCH gene was still expressed despite evidence of LOH,
suggesting that reduced expression of the PTCH protein
may still lead to activation of the HH signalling pathway.
These studies confirm that aberrations in the PTCH gene
are not specific to keratocysts, but may represent an initiat-
ing event in the formation of developmental odontogenic
cysts, possibly in a progenitor epithelial cell that then gives
rise to the entire epithelial lining. The resultant activation
of the HH signalling pathway may then drive growth and
expansion of the cyst. Such a scenario could explain a role
for PTCH in dentigerous cysts, but does not exclude a fur-
ther role for specific PTCH mutations in keratocysts.
Gomes and Gomez (2011) supported this view and sug-
gested that PTCH1 may act as a gatekeeper gene for many
types of odontogenic lesions, and that further genetic
events drive the formation of different cysts or tumours.
However, more research is needed, since the studies show-
ing PTCH alterations in dentigerous cysts (Levanat
et al. 2000; Pavelić et al. 2001) have not yet been repeated
and sequencing studies to investigate mutations of PTCH
in dentigerous cysts have not been performed.
Is the Odontogenic Keratocyst a Neoplasm?
It has long been thought that the odontogenic keratocyst
may be a benign cystic neoplasm, rather than a develop-
mental cyst. Paul Toller (1967) first suggested that the
keratocyst had ‘some of the potentialities of a benign neo-
plasm’, but the debate was fully initiated by Ahlfors et al.
(1984), who examined 319  keratocysts from 255 patients
and found one or more recurrences in 69 (27%). They also
demonstrated variable histological appearances of the cyst
linings with evidence of a proliferative activity in some
cysts, including budding of the basal layer in 25%, epithe-
lial islands in the cyst wall (23%), satellite cysts (7%), and
mural proliferations (8%). However, these features were
not associated with recurrence and were seen most fre-
quently in cases of multiple cysts or in cysts associated
with NBCCS. Nevertheless, based on these observations
they proposed a mechanism of growth involving down-
growth of the epithelial lining into the cyst capsule, and
suggested that the lesion should be regarded as a benign
cystic neoplasm. These early papers cited a high recurrence
rate, an unusual growth pattern, and increased cell
112 Odontogenic Keratocyst
proliferation as evidence of neoplastic origin. Subsequently,
the neoplastic nature of the odontogenic keratocyst has
been much debated in the literature and has been reviewed
in the previous edition of this book and by others
(Shear  2002a,b,c; Gomes and Gomez  2007; Gomes
et al. 2009; Li 2011; Bhargava et al. 2012).
Most textbooks still define neoplasia in the terms first
used by Willis in 1960, as ‘an abnormal mass of tissue, the
growth of which exceeds and is uncoordinated with that of
normal tissues, and persists in the same excessive manner
after cessation of the stimuli that evoked the change’. This
implies autonomous and uncontrolled growth, and on this
basis the odontogenic keratocyst would not meet the crite-
ria for a neoplasm. The reasons for the high recurrence
potential are discussed later in this chapter, and although
this is suggestive of an element of autonomy, it appears
insufficient to categorise the behaviour of all keratocysts as
neoplastic. A further strong challenge to the concept of
neoplasia is the now commonly reported finding of a good
response to marsupialisation, with regression of the typical
keratocyst lining to an epithelium indistinguishable from
that seen in normal oral mucosa (Marker et  al.  1996;
Ninomiya et  al.  2002; August et  al.  2003; Pogrel  2003b;
Pogrel and Jordan 2004; Zhang et al. 2014). Pogrel (2003b)
treated 13 patients with large or surgically problematic
keratocysts with marsupialisation. The cyst cavities were
kept open and cleaned for follow-­up periods ranging from
1.9 to 6.9 years. In this and in a follow-­up paper (Pogrel and
Jordan  2004), the authors found that all the keratocysts
resolved and histological examination of the retained cyst
wall at the base of the healed cavities showed normal epi-
thelium only, with no signs of cystic remnants, daughter
cysts, or budding of the basal layer. The role of marsupiali-
sation in the management of the odontogenic keratocyst is
discussed later in this chapter (see ‘Treatment and
Recurrence of the Odontogenic Keratocyst’), but it is often
cited as the main argument against a neoplastic origin.
On the other hand, it is known that neoplasia is accom-
panied by (often multiple) genetic aberrations and it is
increasingly apparent that neoplasia is being defined,
rightly or wrongly, on the basis of the findings of genetic
changes. An important driver of neoplasia is thought to be
loss of both copies of a tumour-­suppressor gene following
the ‘two-­hit hypothesis’ of Knudson (Knudson  1996). In
the case of the odontogenic keratocyst, alterations in the
PTCH gene discussed in the previous section have been
taken as unequivocal evidence that the lesion is a neo-
plasm. However, as discussed in a number of excellent
reviews (Gomes and Gomez  2007; Gomes et  al.  2009;
Li  2011), the situation is more nuanced and evidence of
PTCH alterations cannot be taken as unconditional evi-
dence of neoplasia. As discussed in the previous section, it
is widely accepted that the key driver for formation of the
odontogenic keratocyst is activation of the HH signalling
pathway and that in the vast majority of cases this is due to
ligand-­independent activation following alterations in the
levels of PTCH protein receptor secondary to a genetic
aberration. It is also discussed that alterations of the PTCH
gene may not be a simple mutation, but can be due to a
number of genetic events. In NBCCS there is a germline
mutation in one allele of PTCH, which gives rise to the
developmental anomalies and also to NBCCS-­associated
keratocysts. Single mutations have been found in sporadic
keratocysts, but sporadic cases may also be associated with
LOH at the PTCH locus (Table 7.6). In most cases there is
evidence of change in only one allele of PTCH (‘one hit’),
presumably resulting in haploinsufficiency and a reduced-­
level of PTCH receptor protein sufficient to activate the HH
pathway. The important point is that LOH or haploinsuffi-
ciency of PTCH and HH pathway activation is not specific
to the odontogenic keratocyst but, as discussed previously,
may be seen in developmental cysts, including orthokerati-
nised odontogenic cyst and dentigerous cyst (Levanat
et al. 2000; Pavelić et al. 2001; Barreto et al. 2002; Gomes
and Gomez 2011; Diniz et al. 2011). It is also the case that
single-­point mutations cannot define neoplasia, since a
number of disorders thought to be non-­neoplastic or devel-
opmental are known to harbour specific gene mutations,
including fibrous dysplasia (GNAS1; Idowu et  al.  2007),
Cherubism (SH3BP2; Ueki et  al.  2001), and giant cell
lesions of the jaws (KRAS, TRPV4, FGFR1; Gomes
et al. 2020).
Notwithstanding this argument, there remains good evi-
dence that at least a subset of odontogenic keratocysts may
be neoplastic. The most compelling evidence for a neoplas-
tic origin is that a number of studies have shown that
keratocysts may harbour biallelic loss (‘two hits’) of both
copies of the PTCH gene (Table  7.6; Levanat et  al.  1996;
Sun et  al.  2008; Pan et  al.  2010; Stojanov et  al.  2020).
According to Knudson’s two-­hit hypothesis, loss of both
alleles is a crucial step towards neoplasia and in some cases
may be sufficient for neoplastic change. The concept was
first developed to explain the onset of childhood retino-
blastoma. The first hit was a germline (inherited) mutation
in the retinoblastoma gene (RB1), followed by a second
somatic mutation resulting in lesions in early childhood.
Occasional retinoblastomas may arise by two somatic ‘hits’,
usually a mutation followed by LOH. RB1 acts as a tumour-­
suppressor gene and loss of one allele due to a germline
mutation results in an inherited predisposition to cancer.
The second ‘hit’ may involve truncating mutations, LOH,
or DNA silencing by methylation. Although two hits may
initiate neoplasia, multiple genetic events are usually
needed for lesion development. Normal expression of the

PTCH protein receptor supresses activation of the HH sig-
nalling pathway, so PTCH acts as a tumour-­suppressor
gene, and the pathway to neoplasia in the odontogenic
keratocyst may follow the two-­hit process, analogous to
retinoblastoma.
In the very first paper to show PTCH alterations in odon-
togenic keratocysts, Levanat et al. (1996) also provided the
first molecular evidence of a two-­hit mechanism for the
pathogenesis of these cysts. They examined six keratocysts
from four NBCCS patients and fourteen sporadic cysts for
polymorphisms in the PTCH region on chromosome 9. Five
of the six (83.3%) syndrome cysts and four (28.6%) sporadic
cysts showed LOH at two or more loci. Furthermore, three
cysts from two NBCCS siblings showed evidence of two hits
in the form of a germline mutation in one allele and LOH in
the second allele. Subsequently, these findings were con-
firmed in two papers from T-­J Li’s research group (Sun
et al. 2008; Pan et al. 2010). These authors showed evidence
of biallelic loss in up to about 50% of NBCCS cysts and 17%
of sporadic cysts (Table 7.6). Sun et al. (2008) found that two
patients with NBCCS and two sporadic cases showed bial-
lelic mutations, while the third sporadic case showed a
mutation in one allele and LOH at the second allele. In their
second study (Pan et al. 2010), the group found alterations
in PTCH1 in 27 of 44 (61.4%) keratocysts, with evidence of
biallelic loss in 13 cases (8 NBCCS and 5 sporadic cysts), of
which 10 showed inactivation of one allele by mutation and
the second by LOH, and 3 contained two inactivating muta-
tions. Overall, 53.3% of NBCCS cysts and 17.2% of sporadic
cysts were found to harbour two hits, while 33.3% and
31.0%, respectively, showed one hit. It must be noted that 2
(13.3%) NBCCS cysts and 51.7% of sporadic cysts showed no
PTCH1 alterations at all. In these cases, aberrations in other
genes associated with the HH pathway may be involved,
including PTCH2, SMO, and SUFU (Shimada et  al.  2013;
Rui et al. 2014).
A more recent study has suggested that as many as 80%
of sporadic odontogenic keratocysts may show biallelic loss
of PTCH1 (Stojanov et  al.  2020). Using next-­generation
sequencing, these authors found PTCH1-­inactivating
mutations in 93% of 44 cases and LOH in the PTCH1 locus
in 34%. Furthermore, 20 cases showed two biallelic PTCH1
mutations and 15 cases showed a single mutation and LOH
in the second allele. Overall, therefore, 35 of 44 cases
(79.5%) showed evidence of two hits on the PTCH1 gene.
The authors interpreted their findings to support the clas-
sification of keratocysts as a benign cystic neoplasm. They
attributed their high yield of positive cases to dissection of
the cyst epithelium, thus removing contamination by stro-
mal DNA. It is worth noting, therefore, that they found no
evidence of mutations or LOH in any other HH pathway
genes (SMO, SUFU, GLI1, GLI2).
Pathogenesis  113
Summary and Conclusions
The accumulated evidence from these studies shows that
activation of the HH signalling pathway appears to under-
pin the initiation and growth of the odontogenic keratocyst
and that in the vast majority of cases this is associated with
alterations in the PTCH1 gene. However, the line of demar-
cation between aberrant development and neoplasia is
blurred and it seems that the keratocyst may sit on a spec-
trum between a developmental cyst and a benign cystic
neoplasm. The PTCH gene alterations may be brought
about by a one-­hit or a two-­hit mechanism involving muta-
tions or LOH. In NBCCS all cysts are associated with at
least one germline mutation, and the majority of sporadic
cysts show one alteration via a mutation or LOH in one
allele. This suggests that reduced PTCH receptor protein
expression (due to haploinsufficiency) is sufficient to acti-
vate the HH pathway and is an important pathogenic
mechanism in many cysts. As noted previously, this is not
specific to keratocysts, since LOH and HH activation are
also seen in dentigerous cysts and other non-­neoplastic
lesions.
In addition, however, a number of keratocysts are associ-
ated with two hits on the PTCH1 gene, strongly suggesting
that at least a subset of odontogenic keratocysts are truly
neoplastic. In these cases, loss of PTCH protein leads to
constitutive activation of the HH pathway and this may be
associated with a different phenotype or with different
clinical behaviour. Because patients with NBCCS have a
PTCH germline mutation, they are much more likely to
have a second hit and keratocysts in syndrome patients are
probably more likely to be truly neoplastic than sporadic
cysts. It remains to be determined, preferably in controlled
prospective studies, if there are clinicopathological differ-
ences between cysts showing different genetic aberrations.
Retrospective studies have suggested that this is the case,
since there are a number of histological differences
between NBCCS and sporadic cysts and there is evidence
that the genotype may affect rates of cell proliferation, his-
tological features, and recurrence (Yagyuu et al. 2008; Pan
et al. 2010; Shimada et al. 2013). This will be discussed later
in this chapter in ‘Histopathology’ and ‘Recurrence of the
Odontogenic Keratocyst’.
Growth and Enlargement of the
Odontogenic Keratocyst
The odontogenic keratocyst has a different pattern of
growth to most other odontogenic cysts. In particular, the
two most common cysts, the radicular and dentigerous
cysts, grow in a centripetal or ‘ballooning’ pattern (dis-
cussed in Chapters  3 and  5) to produce a characteristic
spherical radiolucency. It is thought that this pattern of
114 Odontogenic Keratocyst

growth is mediated primarily by increased intracystic pres- over 90% of Ki-­67–positive cells found in the suprabasal
sure due to osmosis across the cyst wall. In contrast, the layers (Figure 7.14) and few in the basal layers. In contrast,
odontogenic keratocyst appears to grow in a mesio-­distal about 80% of Ki-­67–positive cells in dentigerous cysts and
direction, with minimal expansion of the cortical plates. radicular cysts were located in the basal layer. Furthermore,
The characteristic appearance on plane radiographs or CT there was no significant difference in the Ki-­67 count
is of a fusiform expansion with large lesions extending between sporadic and recurrent keratocysts, but the num-
through the mandible, but with minimal bucco-­lingual ber of Ki-­67–positive cells in NBCCS-­associated lesions
expansion. This pattern of growth is thought to be mediated (n = 9; 91.8 ± 35.6 cells/mm) was significantly greater than
by increased cell proliferation of the epithelial lining, with in the other groups (Li et al. 1995).
growth of the cyst through the cancellous bone in an irregu- In a more recent discussion of these data, Li (2011) con-
lar lobulated or locular pattern (see ‘Radiological Features’). cluded that their finding of no significant differences in
Many papers have shown that proliferation in the epithe- cell proliferation between sporadic and recurrent kerato-
lial lining of the odontogenic keratocyst is greater than in cysts suggested that incomplete removal, rather than
dentigerous or radicular cysts, but is similar to that seen in intrinsic growth, was likely to be responsible for the
ameloblastoma. The early literature up to 2002  has been reported high rates of recurrence. On the other hand, the
reviewed by Shear (2002a,b). The very first study was by finding that Ki-­67–positive counts in NBCCS-­associated
Toller (1971), who estimated mitotic activity in an autoradio- cysts were almost twice the level of those in sporadic cysts
graphic study following the in vitro incubation of cyst linings indicated a greater level of proliferative activity in syndro-
with tritiated thymidine. He showed mean labelling indices mic lesions. This was reflected in the multiplicity of cysts
of 13.0% for a series of six odontogenic keratocysts, com- and the increased numbers of satellite cysts and epithelial
pared with 1.7% for five other odontogenic cysts and 7.0% for islands in the cysts of NBCCS patients. This suggested
normal oral mucosa. Some of the earliest, but still most com- increased cell proliferation may be related to PTCH altera-
prehensive, immunohistochemical studies were undertaken tions and activation of the HH signalling pathway. This was
by Li and colleagues (Li et  al.  1994,  1995). These authors confirmed in a later study from the same group (Pan and
investigated the expression of proliferating cell nuclear anti-
gen (PCNA) and Ki-­67 in odontogenic keratocysts, dentiger- (a)
ous cysts, and radicular cysts and found that expression was
consistently higher in keratocysts and was also suprabasal.
In their first study (Li et al. 1994), they found that the epithe-
lial linings of keratocysts (n  =  11) contained the highest
number of PCNA-­positive cells, most of which were in the
suprabasal layers, with fewer than 5% in the basal layer (e.g.
see Figure  7.14). The total PCNA count in the keratocysts
had a mean value of 94.4 ± 22.7 cells/mm, and was signifi-
cantly higher than in dentigerous cysts (n = 10; 5.1 ± 3.0 cells/
mm) or radicular cysts (n = 10; 11.0 ± 4.1 cells/mm). These
differences were entirely due to the higher number of PCNA-­
positive cells in the suprabasal layers of the keratocysts,
because there were no significant differences in positive cells
in the basal layers. These authors also found that PCNA (b)
expression in the keratocysts was similar to that seen in nor-
mal oral epithelium.
In their second study, Li et  al. (1995) investigated the
expression of Ki-­67 in 27 odontogenic keratocysts (10 spo-
radic, 8 recurrent, 9 associated with NBCCS), 5 dentigerous
cysts, 5 radicular cysts, and 7 samples of normal oral
mucosa. The number of Ki-­67–positive cells in the sporadic
keratocysts (53.1 ± 17.8 cells/mm) was similar to normal
epithelium (42.5 ± 12.7 cells/mm), but was significantly
greater than in dentigerous cysts (3.9 ± 1.3 cells/mm) or
Figure 7.14  (a) Ki-­67 and (b) proliferating cell nuclear antigen
radicular cysts (6.7 ± 4.8 cells/mm). This study also found (PCNA) expression in odontogenic keratocysts. Most positive
that the pattern of staining was the same as for PCNA, with cells are found in the suprabasal layers.

Li 2009), when it was shown that Ki-­67 labelling in kerato-
cysts with PTCH1 mutations (n = 29; 103.29 ± 35.47 cells/
mm) was significantly higher than in keratocysts with no
mutations (n = 33; 69.82 ± 24.28 cells/mm). The study also
found that the labelling index was higher in lesions with
truncating mutations compared to non-­truncating muta-
tions, and was highest in NBCCS-­associated cysts (n = 20;
115.56 ± 32.33 cells/mm).
Many papers have confirmed these findings and have
consistently shown that cell proliferation-­associated mark-
ers (including Ki-­67, PCNA, p53, and p73) are expressed
suprabasally, and more strongly in keratocysts compared to
other cysts (Ogden et  al.  1992; Thosaporn et  al.  2004; Lo
Muzio et al. 2005; Kolář et al. 2006; de Oliveira et al. 2011;
Soluk Tekkeşın et al. 2012a; Hammad et al. 2020) and are
also more highly expressed in NBCCS-­associated cysts (EI
Murtadi et al. 1996; Lo Muzio et al. 1999). Cyclin D1 has
also been shown to be up-­regulated in keratocysts, with
greater expression in NBCCS cysts and in sporadic cysts
with PTCH gene alterations (Lo Muzio et al. 1999; Shimada
et al. 2013). Studies have further shown that the rate of pro-
liferation in keratocysts is similar to that found in amelo-
blastomas (Thosaporn et  al.  2004; Soluk Tekkeşın
et al. 2012a; Hammad et al. 2020), but the significance of
this is uncertain, since the rate may also be similar to pro-
liferation in normal oral epithelium (Li et al. 1994, 1995).
Bcl-­2 is an anti-­apoptotic protein that promotes growth
and is transcriptionally regulated by the HH signalling
pathway. A number of studies have shown increased
expression of bcl-­2 in odontogenic keratocysts compared to
other cysts (Lo Muzio et al. 1999; Kolář et al. 2006; Vered
et al. 2009; Soluk Tekkeşın et al. 2012a; Shimada et al. 2013)
and have also found that expression is associated with
NBCCS-­associated cysts and with PTCH alterations
(Shimada et  al.  2013). More recently, Zhang et  al. (2018)
found increased Ki-­67, PCNA, and bcl-­2  in keratocysts
compared to dentigerous cysts, and further showed that
increased proliferative and anti-­apoptotic activity corre-
lated to expression of the AP-­1 signalling pathway tran-
scription factors Fra-­1, c-­Jun, and c-­Fos.
To investigate the pattern of growth of the keratocyst,
Kichi et  al. (2005) investigated Ki-­67, p53, and bcl-­2
expression in 20 odontogenic keratocysts and 20 denti-
gerous cysts and compared expression to the location of
apoptotic cells, using the TUNEL method (Terminal
deoxynucleotidyl Transferase Biotin-­dUTP Nick End
Labelling). They showed that apoptotic cells were located
exclusively in the surface layer of the lining epithelium
of both keratocysts and dentigerous cysts, but were far
more common in keratocysts (25.5 ± 2.1% of surface
cells) than in dentigerous cysts (5.5 ± 1.8%). Numbers of
proliferating cells (Ki-­67 and p53 positive) were
Pathogenesis  115
significantly greater in keratocysts and were more often
found in the suprabasal layers. Bcl-­2 was expressed only
in the basal layers, but was significantly greater in kerato-
cysts (99.6 ± 0.5% of basal cells) than in dentigerous cysts
(3.4 ± 2.2%). This confirmed the findings of Lo Muzio
et  al. (1999) that bcl-­2  was almost exclusively found in
the basal cell layer of keratocysts. The authors suggested
that these data explain why keratocysts grow as cystic
lesions rather than a solid mass. They concluded that
apoptosis occurs at a high rate in the superficial layers of
the epithelial lining, while at the same time bcl-­2 inhib-
ited apoptosis to facilitate cellular proliferation in the
basal layer. By such a mechanism, the higher rate of cell
proliferation was regulated by the apoptotic activity, so
that these lesions maintain a cystic lumen and do not
form solid masses (Kichi et al. 2005).
These studies show that there is a higher rate of cell pro-
liferation in odontogenic keratocysts than in other cyst
types that show a typical centripetal or spherical growth
pattern (dentigerous and radicular cysts), and support the
concept that expansion of the keratocyst is primarily driven
by mural growth due to proliferation of the epithelial lin-
ing. Furthermore, it is suggested that a balance between
cell proliferation in the basal and immediate suprabasal
layers is counterbalanced by apoptosis in the superficial
layers, maintaining the integrity of the cyst lumen (Kichi
et al. 2005).
Although cell proliferation may explain growth of the
cyst lining, it may still be insufficient to entirely explain the
expansion or enlargement of the cyst, and there is evidence
that intraluminal pressure may still play a role. In early
studies, Toller (1970b) considered the part played by intra-
luminal pressure and the osmolality of the cyst fluid in
enlargement of odontogenic keratocysts. He showed that
the mean cyst fluid osmolality of odontogenic keratocysts
(296 ± 15.16 mOsm) was similar to that of dentigerous cysts
(291 ± 14.42 mOsm) and radicular cysts (290 ± 14.93 mOsm)
and was higher than the mean serum osmolality
(282 ± 14.75 mOsm). In view of the low total soluble pro-
tein level in keratocysts (Toller  1970a), he suggested that
osmotic differences between sera and cyst fluids may be
the result of the liberation of the products of cell lysis at the
luminal surface. He believed strongly that the raised osmo-
lality has an important role in the expansive growth of all
jaw cysts, including keratocysts.
Main (1970), on the other hand, felt that mural growth in
the form of epithelial proliferation was the essential pro-
cess involved in the enlargement of the odontogenic
keratocyst and that the evidence for osmotic diffusion was
inconclusive. This view was supported by Browne
(1970,  1975) and Kramer (1974). They believed that the
multilocular and loculated outlines exhibited by many
116 Odontogenic Keratocyst
keratocysts were difficult to interpret on the basis of uni-
centric hydrostatic expansion alone. This form of cyst out-
line suggested a multicentric pattern of cyst growth brought
about by the proliferation of local groups of epithelial cells
against the semi-­solid cyst contents.
Kubota et al. (2004), however, have confirmed the find-
ings of Toller and found similar intracystic fluid pressures
in keratocysts, dentigerous cysts, and radicular cysts.
Furthermore, they showed that the intracystic pressure in
all cyst types reduced as the cyst increased in size. They
concluded that increased pressure played a pivotal role in
the initiation of cysts and early growth, but was less impor-
tant as the cyst got bigger.
Previous studies (Kubota et  al.  2000; Ninomiya
et al. 2002) had shown that interleukin (IL)-­1α was strongly
expressed in the epithelial cells of keratocysts, and that the
expression of IL-­1α and cell proliferation were reduced
proportionally by marsupialisation. The authors suggested
therefore that increased intracystic pressure might stimu-
late IL-­1α and prostaglandin secretion in the cyst walls and
play a crucial part in the growth of odontogenic jaw cysts.
Since IL-­1 is also involved in the stimulation of bone
resorption, maintenance of a positive pressure may further
facilitate cyst enlargement.
A later study by this group found further evidence for the
role of intracystic pressure in facilitating growth and
enlargement. Oka et  al. (2005) investigated the effects of
positive pressure on the expression of IL-­1α, matrix metal-
loproteinases (MMPs), and prostaglandin E2 (PGE2). They
found that positive pressure stimulated secretion of IL-­1α
and MMPs in a co-­culture of keratocyst epithelial cells and
fibroblasts. They concluded that positive pressure may up-­
regulate expression of IL-­1α and MMPs in the wall of odon-
togenic keratocysts, and that this may stimulate
osteoclastogenesis and promote connective tissue break-
down and bone resorption. These studies support early
work by Meghji et  al. (1992), who showed that levels of
IL-­1α were significantly higher in the fluids of keratocysts
than in dentigerous or radicular cysts and that IL-­1α medi-
ated the secretion and activation of MMP-­9.
Mechanisms for the degradation of the connective tis-
sues and bone resorption in odontogenic cysts and the role
of cytokines, including IL-­1, and MMPs are discussed in
detail in the pathogenesis of radicular cysts in Chapter 3.
Although inflammation plays a minimal role in the growth
of keratocysts, the basic mechanisms of cytokine-­mediated
resorption are similar.
A number of studies have investigated the presence of
myofibroblasts in the walls of odontogenic cysts, on the
basis that these cells are important in healing and extracel-
lular matrix turnover and are found to be prominent in the
stroma of tumours. Vered et  al. (2005) undertook an
immunohistochemical study to determine the frequency of
stromal myofibroblasts (α smooth muscle actin [αSMA]–
positive cells) in a range of odontogenic cysts and tumours,
including 8 odontogenic keratocysts, 9 orthokeratinised
odontogenic cysts, and 7 dentigerous cysts. Of the odonto-
genic cysts, keratocysts had the highest number of αSMA-­
positive cells (25.7 ± 11.4 cells per high-­power field),
followed by orthokeratinised odontogenic cysts
(12.4 ± 12.3), while the dentigerous cysts had the lowest
(8.7 ± 11.6). The myofibroblasts were located in the superfi-
cial cyst wall, orientated parallel to the basement mem-
brane. The number of myofibroblasts found in keratocysts
was similar to that in ameloblastomas (n  =  7; 29.0 ± 7.0)
and to squamous carcinomas (n = 5; 21.3 ± 5.3), but only
small numbers were found in unicystic ameloblastomas
and ameloblastic fibromas. The authors suggested a posi-
tive link between the occurrence of large numbers of
myofibroblasts in the stroma, and the more “aggressive”
behaviour of the keratocyst and ameloblastomas compared
to the other lesions studied. However, the number of
myofibroblasts was variable, and their density was not cor-
related to histological features or to behaviour.
More recent studies have confirmed these findings.
Syamala et  al. (2016) also showed that the number of
myofibroblasts in odontogenic keratocysts (n  =  20;
22.9 ± 6.5 cells per high-­power field) was greater than in
dentigerous cysts (n = 20; 12.3 ± 4.1), but was not signifi-
cantly different to that in ameloblastoma (n  =  20;
24.8 ± 3.9). However, although the mean numbers were
high, they showed that a small number of keratocysts (10%)
did not express αSMA at all. They did not correlate the den-
sity or presence of myofibroblasts to histological features.
Kouhsoltani et  al. (2016) also found a higher density of
myofibroblasts in keratocysts than in dentigerous and
radicular cysts, but showed that expression was variable, in
that 2 of 15 (13.3%) keratocysts did not express αSMA at all,
and 60% of cases showed only weak expression. Only 4
cases (26.7%) showed strong expression compared to 33.3%
of dentigerous cysts.
Myofibroblasts are derived from fibroblasts under the
influence of TGF-­β1, and secretion of TGF-­β1 by the epithe-
lial lining of odontogenic keratocysts (Piattelli et al. 2004)
suggests a mechanism whereby myofibroblastic differentia-
tion is driven directly by the cyst epithelium. However,
expression may be variable and the true significance of
myofibroblasts remains uncertain. Further work is needed
to correlate myofibroblasts to histological features and to
clinical behaviour. Intriguingly, it has recently been shown
that myofibroblastic activation of lung fibroblasts may be
under the control of SHH and the HH signalling pathway
(Cao et  al.  2020), suggesting another possible avenue for
investigations of the role of myofibroblasts in keratocysts.

A number of studies have suggested that podoplanin
may be important in keratocyst growth. Podoplanin is a
transmembrane glycoprotein normally expressed on lym-
phatic endothelial cells and was thought to be a specific
marker of lymphatic vessels, but it is now known to be
expressed in a range of tissues and in pathological condi-
tions, including squamous cell carcinoma and ameloblas-
toma. The exact function of podoplanin is unknown, but it
is thought to be involved in cell migration and develop-
ment, and has been implicated in tumour invasion.
However, it is also expressed in tooth germs and may have
a role in development, and has been found in the pulp tis-
sue, odontoblasts, and ameloblasts in odontomas
(González-­Alva et  al.  2011). Okamoto et  al. (2010) exam-
ined podoplanin expression in 46 odontogenic keratocysts,
11 orthokeratinised odontogenic cysts, and 15 dentigerous
cysts. Podoplanin was expressed in 42 (91.3%) of the kerato-
cysts but in only 11 (73.3%) dentigerous cysts and 3 (27.2%)
orthokeratinised odontogenic cysts. Expression in the
keratocysts was consistently strong and was located in the
basal and suprabasal layers of the epithelial lining; it was
also seen in areas of basal budding, and in epithelial islands
and satellite cysts in the wall. In contrast, expression in
orthokeratinised and dentigerous cysts was weak and usu-
ally only in the basal layer, and was often associated with
areas of inflammation. Okamoto et  al. interpreted these
findings to suggest that podoplanin contributed to the local
‘invasiveness and neoplastic nature’ of the odontogenic
keratocyst. The same group, however, in their study of
odontomas, interpreted podoplanin expression to be asso-
ciated with epithelial–mesenchymal interactions and cell
differentiation (González-­Alva et al. 2011). Its exact role in
these lesions remains to be determined.
Caetano Ados et  al. (2013) studied podoplanin expres-
sion in a range of odontogenic cysts and tumours, includ-
ing 20  keratocysts. They found a similar pattern of
expression to the previous studies (Okamoto et  al.  2010;
González-­Alva et  al.  2011), with strong expression in the
peripheral or basal layers of the epithelium and in odonto-
blasts. They found strong expression in the epithelium of
odontogenic tumours, including ameloblastoma, adenom-
atoid odontogenic tumour, and calcifying epithelial odon-
togenic tumour. In odontogenic keratocysts they found
strong expression in the basal and suprabasal layers and in
satellite cysts in the wall. These results have been further
confirmed by Oliveira et al. (2014), who found strong podo-
planin expression in the basal and suprabasal cells of all
(n = 18) keratocysts studied. They also found a significant
correlation with ezrin expression, which was strong in the
cytoplasm of basal cells in over 80% of the keratocysts.
Ezrin (also called cytovillin) is a cytoplasmic protein that
interacts with a range of cell surface molecules, including
­Histopatholog  117
podoplanin, and mediates the functions of the actin
cytoskeleton, including its role in cell migration. This sug-
gests a possible role for podoplanin in mediating growth
and cell migration in odontogenic lesions, including the
odontogenic keratocyst.
A further study investigated podoplanin expression in 16
sporadic odontogenic keratocysts before and after decom-
pression surgery (marsupialisation; Zhang et  al.  2014).
Samples obtained at the time of decompression surgery
showed strong podoplanin expression in the basal layers in
15 (93.8%) cases. In the samples obtained at subsequent enu-
cleation, 3 showed similar expression, but in 13 cases podo-
planin expression was significantly decreased, including 1
case in which expression was lost entirely. The linings also
lost the typical features of a keratocyst and took the form of
hyperplastic epithelium with inflammation. The authors
suggested that decompression reduces the processes of cell
proliferative and local growth, a suggestion that is in keeping
with the possible role of intracystic pressure in growth of the
keratocyst, discussed earlier in this section.
­Histopathology
Odontogenic keratocysts are usually removed conserva-
tively by enucleation and/or curettage, so the pathologist
will often receive multiple fragments of cyst wall
(Figure  7.15). The lining is usually thin and folded, and
may be friable with detachment of the epithelium. The
specimen may also include the cyst contents, which are
composed of ‘cheesy’, ‘fatty’ or ‘buttery’ keratinaceous and
necrotic material that is cream or yellow coloured, with a
characteristically unpleasant odour. Similar contents may
be found in orthokeratinised odontogenic cysts, but will
also be familiar to many pathologists as a characteristic fea-
ture of epidermal cysts of the skin.
Smaller cysts may be enucleated intact, but are usually
collapsed with a thin wall, although the irregular growth
pattern that is responsible for the scalloped radiographic
margins may be apparent (see Figure  7.4). On dissection
the cyst may contain a thick keratinaceous material as well
as a thin, watery straw-­coloured fluid. Thickenings of the
wall or multicystic lesions are rare, but when seen may sug-
gest a cyst associated with NBCCS (Figure 7.15b).
The histological features of the typical odontogenic
keratocyst are so characteristic as to be regarded as diag-
nostic (Figures  7.16 and  7.17; Box  7.3). The cyst wall is
loosely collagenous and is lined by a thin regular, par-
akeratinised stratified squamous epithelium that is usually
about 5–8 cell layers thick and without rete ridges
(Figures 7.16a, b and 7.17). The basal layer is well defined
and is composed of palisaded cuboidal to columnar cells,
118 Odontogenic Keratocyst

(a) (b)

Figure 7.15  Low-­power scans of two odontogenic keratocysts. The lining of the cyst is thin and friable, so specimens are often
fragmented. (a) A sporadic cyst. Even at this low power it can be seen that the epithelial lining is thin and regular, the wall is
uninflamed, and there are no satellite cysts or islands. (b) A cyst associated with naevoid basal cell carcinoma syndrome (NBCCS).
Many islands and satellite cysts can be seen in the wall (arrows).

(a) (b)

(c) (d)

Figure 7.16  Characteristic features of the odontogenic keratocyst. (a) The lining is thin and regular, 5–8 cell layers thick. The basal
layer is palisaded with focal areas showing reversal of nuclear polarity (arrows). Areas of hyalinisation are seen in the connective
tissue wall. (b) The parakeratinised surface layer is corrugated. (c) The lining shows prominent folding. (d) The epithelium is separated
from the underlying fibrous wall.

Figure 7.17  A high-­power view shows reversal of nuclear
polarity in the epithelial basal layers and a small cluster of
suprabasal mitotic figures (arrows).
Box 7.3  Odontogenic Keratocyst: Histopathology and
Diagnostic Criteria
●● Lined by a thin, regular stratified squamous epithe-
lium, 5–8 cell layers thick
●● Always parakeratinised
●● 90% show a corrugated surface
●● Well-­defined and palisaded basal layer of cuboidal or
columnar cells
●● Focal areas of reversal of nuclear polarity
●● The lining is irregular and folded, with characteristic
‘hairpin’ bends
●● Up to 25% show satellite cysts in the wall
●● Up to 25% show solid epithelial islands or odonto-
genic rests in the wall
●● Up to 20% show budding of the epithelial basal layers
●● Small focal areas of orthokeratin may be seen
●● Over 60% may be inflamed
●● Focal areas of inflammation bulging into the lumen
are characteristic
●● In areas of inflammation the lining is lost or may be
simple non-­keratinised epithelium
with focal areas where the nuclei are orientated away from
the basement membrane (reversal of nuclear polarity;
Figure 7.16a arrows; Figure 7.17). In the majority of cases
the nuclei are hyperchromatic. In over 90% of cases the epi-
thelial lining shows a characteristic corrugated surface pat-
tern (Figure  7.16b) and is folded to form sharp ‘hairpin
bends’ (Figures  7.15a and  7.16c; Brannon  1977; Cottom
et  al.  2012). The irregular and folded lining may give an
erroneous impression of a multicystic lesion in histological
sections, and care must be taken not to misinterpret cross-­
cut folds as satellite cysts. If necessary, multiple serial
­Histopatholog  119
sections must be examined. Another characteristic feature,
seen in between 50 and 95% of cases, is separation of the
epithelial lining from the underlying connective tissue
(Figure 7.16c, d; Ahlfors et al. 1984; Brannon 1977; Cottom
et al. 2012). Occasionally the epithelium splits suprabasally
to leave an intact layer of basal cells on the cyst wall
(Brannon 1977; Ahlfors et al. 1984; Cottom et al. 2012).
These classic features of the odontogenic keratocyst are
diagnostic and are seen in at least a portion of all lesions.
They are not seen in any other cyst type and serve to distin-
guish the odontogenic keratocyst from other cysts that may
show keratinisation (Box 7.3).
The high proliferation potential of the lining of the odon-
togenic keratocyst has been discussed previously, but on
histological sections this is reflected by the consistent find-
ing of mitotic figures (Figure  7.17; Browne  1971a;
Brannon  1977; Woolgar et  al.  1987a; Cottom et  al.  2012).
Woolgar et  al. (1987a) found mitotic figures in 100% of
cysts, but also noted that they were more prominent and
more often suprabasal in NBCCS cysts. Cottom et al. (2012)
examined 110  keratocysts and found mitotic figures in
93.6%. In 16 cases (14.5%) they were located only in the
basal layers, but suprabasal mitoses were seen in 79.1% of
the cysts and in 56 cases (50.9%) they were found only in
the suprabasal layers.
About 65% of all odontogenic keratocysts are simple
cysts, with no changes in the cyst wall (e.g. Figure 7.15a;
Brannon 1977; Woolgar et al. 1987a). However, a number
of additional histological features may be seen with varia-
ble frequency (Table  7.7). Most striking is the finding of
satellite cysts or epithelial islands within the cyst wall,
which are seen in up to 50% of cases (Figure 7.18; Table 7.7;
Myoung et al. 2001; Kahraman et al. 2018), and have been
shown to be more common in NBCCS-­associated lesions
(Table  7.8; Ahlfors et  al.  1984; Woolgar et  al.  1987a;
Dominguez and Keszler  1988). The variable reporting of
the frequency of these features (Table  7.7) appears to be
due to differences in definition. Review of the papers shows
that some authors do not distinguish between solid epithe-
lial islands and odontogenic epithelial rests, and in some
cases satellite cysts are only included if they have an obvi-
ous lumen, whereas cysts filled with keratin are counted as
solid islands.
Nevertheless, satellite cysts are regarded as a typical fea-
ture of the odontogenic keratocyst (Figure  7.18) and are
seen in up to 25% of sporadic cysts and 50% of NBCCS-­
associated cysts (Tables 7.7 and 7.8). These may show simi-
lar histological features to the main cyst and have a thin,
parakeratinised epithelial lining. Often, however, the wall
shows areas of thickening and the lumen may be small or
filled with parakeratin (Figure  7.18a, b). The distinction
between a satellite cyst and a solid epithelial island is
Table 7.7  Frequency (%) of histological features reported in odontogenic keratocysts in selected case series.

n Satellite cysts Epithelial islands Odontogenic rests Basal budding Inflammation Cholesterol Calcifications Focal OK Hyaline bodies

Brannon (1977)a 266 24.4 ND 33.3 17.2 66.9 12.5 17.0 8.3 11.2
Ahlfors et al. (1984)b 319 7.2 8.2 22.9 24.8 NR NR NR NR NR
Woolgar et al. (1987a) 164 10.7 7.9 25.0 14.0 57.9 11.6 8.5 32.3 9.8
Azevedo et al. (2012)b 177 7.9 ND 4.5 12.4 67.8 5.6 7.9 2.8 2.8
Bello (2016)b 95 23.3 ND 23.3 8.4 57.9 8.4 8.4 NR 5.3
Cottom et al. (2012)b 110 21.8 9.1 21.8 26.4 90.0 9.1 51.8 1.8 17.3

n, number of cysts; ND – not defined, epithelial and odontogenic rests not distinguished; NR, not reported; OK, orthokeratin.
a
 Brannon reported 312 cysts; data are corrected to remove orthokeratinised and syndromic cysts.
b
 These data include a small number of syndromic cysts (<10%).
 ­Histopatholog  121

(a) (b)

(c) (d) (e)

Figure 7.18  Satellite cysts and epithelial islands in the wall of odontogenic keratocysts. The satellite cysts usually resemble the
main cyst, but are often filled with parakeratin (a, b) and may become solid (b, arrows). Epithelial islands (c–e) often show peripheral
palisaded cells and resemble odontogenic cell rests. (d) The islands may proliferate and form branching islands. This pattern has been
referred to as ‘ameloblastomatoid’ (see text).

therefore not always apparent. A cyst may be filled with
parakeratin, and an island may occasionally show micro-
cystic change (Figure  7.18b, arrows). It is probable that
there is a spectrum of change, with islands becoming
increasingly cystic as they grow. Brannon (1977) is proba-
bly correct in his proposal that satellite cysts arise by cystic
change in epithelial islands or odontogenic rests within the
wall. He also noted that satellite cysts were most common
in keratocysts found at the angle and ramus of the mandi-
ble, supporting the concept that the satellite cysts develop
from rests of dental lamina that are most frequently
encountered at this site. The odontogenic rests may prolif-
erate and form branching islands, which resemble
ameloblastoma. Woolgar et  al. (1987a) reported ‘amelo-
blastomatoid’ islands in 7 of 164 (4.3%) NBCCS-­associated
cysts, and Brannon (1977) and Ahlfors et  al. (1984)
described them in 0.6% and 1.5%, respectively. Brannon
(1977) interpreted these islands as transformation to
ameloblastoma, but Ahlfors et al. (1984) and Woolgar et al.
(1987a) did not think they met the criteria for ameloblas-
toma and interpreted them as islands of proliferating odon-
togenic epithelium (Figure  7.18). Review of the
photomicrographs in all three papers show solid islands or
proliferating strands, in all cases consistent with quiescent
or proliferating odontogenic rests and resembling dental
lamina (Figure 7.18 c-e). Similar islands have been reported
in more recent papers and have been interpreted as islands
of odontogenic epithelium, with no suggestions of an asso-
ciation with ameloblastoma (Myoung et al. 2001; Cottom
et al. 2012; Cunha et al. 2016; Naruse et al. 2017).
Many authors assume that all the epithelial islands and
satellite cysts in the wall arise from odontogenic rests, but
some may be a result of budding of the basal layers of the
cyst lining (Ahlfors et al. 1984). Budding of the basal layer
122 Odontogenic Keratocyst

Table 7.8  Frequency (%) of clinical and histological features stratified squamous epithelium (Figure  7.20c). This is
reported in naevoid basal cell carcinoma syndrome (NBCCS) indistinguishable from the epithelium of the radicular cyst
and sporadic odontogenic keratocysts.
or other inflamed odontogenic cysts and in small biopsies
of an inflamed odontogenic keratocyst it may not be possi-
NBCCS Sporadic
n = 164 n = 164
ble to make a diagnosis.
Other reactive changes, more often associated with
Clinical features inflammatory cysts, may also be seen. Cholesterol clefts
Age (mean) 26.2 40.4 and hyaline (Rushton) bodies are seen in about 10% of
Males 45 62 cases (Figure 7.20d). Other changes that may be seen are
mucous cells in the superficial epithelial layers in about 2%
Site: Mandible 66.0 74.0
of cases (Brannon 1977; Cottom et al. 2012) and a report of
Posterior mandible 44.0 60.0
sebaceous cells in three cases (Brannon 1977).
Posterior maxilla 21.0 11.0 A rare finding is the presence of epithelial dysplasia,
Histological features which has been noted in less than 1% of cases
Satellite cysts 54.3 10.7 (Brannon  1977; Ahlfors et  al.  1984; Cottom et  al.  2012).
Solid epithelial islands 33.5 7.9 Basal cell hyperplasia and bulbous rete pegs are a feature of
Odontogenic rests 40.2 25.0 dysplasia in the oral mucosa, but budding and bulbous pro-
Basal budding 14.0 14.0 liferations in the wall of a keratocyst (Figure 7.19) should
not be interpreted as dysplasia unless associated with
Mitotic figures 100.0 100.0
cytological atypia. When dysplasia does occur, it appears
Inflammation 71.3 57.9
as basal cell crowding and loss of stratification, with
Cholesterol 8.5 11.6
cell and nuclear pleomorphism, hyperchromatism, and
Calcifications 19.5 8.5 dyskeratosis.
‘Ameloblastomatoid’ islands 4.3 0 The lumen of odontogenic keratocysts may be full of
Bold – significantly different from sporadic cysts. Source: Data from keratin, but the frequency is uncertain since the luminal
Woolgar et al. (1987a,b) and Rippin and Woolgar (1991). contents are often lost during removal and processing.
Nevertheless, it has been reported that at least 40% may
contain variable amounts of desquamated keratin
occurs in up to 25% of cases (Table 7.7) and is most often (Brannon 1977; Cottom et al. 2012). Keratocysts have also
seen as a focal area of multiple small buds pushing into the been shown to contain a thin straw-­coloured fluid at opera-
superficial connective tissue of the wall (Figure  7.19). tion, but may appear empty on macroscopic or microscopic
Occasionally, however, large buds resembling bulbous rete examination.
pegs may be seen and sometimes these appear to give rise The fibrous cyst wall is usually thin and composed of col-
to satellite cysts or separate islands (Figure 7.19d; Ahlfors lagenous connective tissue, with few distinctive features.
et al. 1984; Myoung et al. 2001; Cunha et al. 2016). Hyalinisation of the connective tissue, usually in a subepi-
Occasionally, satellite cysts and epithelial islands may be thelial band, has been described in up to about 50% of cases
so prominent that the lesion takes on a more solid multi- (Figure  7.16a; Browne  1971a; Brannon  1977; Cottom
cystic appearance. When this occurs, the term solid odonto- et al. 2012). Often the epithelium is missing in areas of hya-
genic keratocyst has been used. This lesion will be discussed linisation and it has been suggested that this may be caused
later in this section. by alterations in the basement membrane, resulting in loss
Over half of odontogenic keratocysts, and in some series of adhesion and separation of the epithelial lining (Cottom
the vast majority, show evidence of inflammation et  al.  2012). Occasional cases show evidence of keratin
(Table  7.7). In some cases this may be due to trauma or within the fibrous wall, with an associated granulomatous
continuity with the oral cavity through cortical and or foreign-­body giant cell reaction. Focal areas of calcifica-
mucosal perforation and infection, but often the cause is tion are occasionally seen. Sometimes these appear to be
not apparent. If the cyst is large and traumatised or infected dystrophic, but often small ‘cementicle’-­like calcifications
then the inflammation may be widespread, but a character- may be seen in association with odontogenic epithe-
istic appearance is of focal areas of inflamed fibrous or lial rests.
granulation tissue pushing into the cyst lumen There have been a number of reports of cartilage within
(Figure 7.20a, b). In areas of inflammation the typical par- the wall of odontogenic keratocysts. The first report was by
akeratinised pattern of the epithelium is lost and the cyst Arwill and Kahnberg (1977), who noted a keratocyst in the
lining is composed of variably hyperplastic, non-­keratinised anterior mandible with an associated ‘chondroma’. A

(a)
(c)
Figure 7.19  (a–d) Hyperplasia of the epithelial lining and budding of the basal layer in odontogenic keratocysts. Sometimes,
epithelial islands appear to ‘drop off’ from the lining to form islands or satellite cysts (d).
further four cases were reported by Kratochvil and Brannon
(1993). These showed the typical features of odontogenic
keratocysts, but with focal areas of quite well-­formed carti-
lage lying just below the epithelial lining. Three of the four
lesions were located in the anterior region of the jaws, two
in the mandible, and one in the ‘globulomaxillary’ region.
The fourth case was located in the premolar region.
Subsequently, a further five cases have been reported
(Mosqueda-­Taylor et  al.  1998; Fornatura et  al.  2001;
Vicente-­Barrero et  al.  2004; Yih and Krump  2005; Ide
et al. 2009). All showed similar features of a typical kerato-
cyst but with focal areas of cartilage formation, usually just
below the epithelium. Interestingly, all the cases arose in
the anterior regions of the jaws, three in the mandible and
two in the maxilla. One of the maxillary lesions arose in the
nasopalatine canal (Yih and Krump  2005). The origin of
the cartilage is open to speculation, but the authors have
suggested that the cartilage might be vestigial rests, or
metaplastic, or a result of unusual inductive change from
the cyst epithelium. In all cases the cartilage has been
bland and essentially normal, so a coincidental neoplastic
process seems unlikely. Vestigial rests of cartilage are
­Histopatholog  123
(b)
(d)
occasionally found in the anterior regions of the jaws, so
this may explain some of the cases, especially that of Yih
and Krump (2005), which was located in the nasopalatine
canal. Other cases are most probably metaplastic in nature.
Early descriptions of the odontogenic keratocyst included
an orthokeratinised variant, but it is now appreciated that
the orthokeratinised odontogenic cyst should be classified
as a separate entity (Speight and Neville 2022); this is dis-
cussed in Chapter 12. Nevertheless, most large series have
described a small number of cysts with focal areas of
orthokeratin (Table 7.7). In Brannon’s (1977) early series of
312 odontogenic keratocysts, he found that 9.7% would
meet the criteria for an orthokeratinised odontogenic cyst,
but that 22 parakeratinised cysts (8.3%) showed focal areas
of orthokeratin. Because the orthokeratin was focal, he
regarded these lesions as odontogenic keratocysts. Crowley
et al. (1992) also found a small number of lesions with both
para-­ and orthokeratin (7 of 449 cases; 1.6%) and also con-
sidered these to be keratocysts. Woolgar et  al. (1987a,c),
however, found that up to 32% of odontogenic keratocysts
may contain areas of orthokeratosis. The reason for this
high figure is uncertain, but Woolgar et  al. (1987a)
124 Odontogenic Keratocyst
suggested that they interpreted keratin squames within the
lumen as indicating orthokeratinisation. This suggests that
their figure of 32% is too high. There are no clear guidelines
for how much orthokeratin must be present to determine a
diagnosis of orthokeratinised odontogenic cyst. The WHO
definition states that the lesion is entirely or predominantly
lined by orthokeratinised stratified squamous epithelium
(Speight and Neville 2022). We would interpret these data
to mean that an odontogenic keratocyst may show small
focal areas of orthokeratin, and that an orthokeratinised
odontogenic cyst may show focal areas of parakeratin.
However, if the lining shows obvious areas of typical par-
akeratinised epithelium (Figure 7.16; Box 7.3), then a diag-
nosis of odontogenic keratocyst should be given
Odontogenic Keratocysts Associated
with Naevoid Basal Cell Carcinoma Syndrome
The pathogenesis of the odontogenic keratocyst and its
relationship to NBCCS has been discussed in detail earlier
in this chapter. It was proposed that the keratocyst may sit
on a spectrum between a developmental lesion and a neo-
plasm, with variable degrees of genetic aberrations
(Table  7.6), but involving activation of the HH signalling
pathway secondary to alterations in the PTCH1 gene. This
would suggest that keratocysts with different degrees of
genetic change may show different phenotypes, and there
is evidence that this may be the case. The differences in the
clinical presentation of sporadic and NBCCS-­associated
cysts has already been discussed (see Box 7.1) and are sum-
marised again in Table 7.8 and Box 7.4.
There is also good evidence that keratocysts associated
with NBCCS show different and characteristic histologi-
cal features and that there may be some genotype–phe-
notype correlations. The most comprehensive studies of
NBCCS cysts were carried out by Woolgar and colleagues
(Woolgar et  al.  1987a,b; Rippin and Woolgar  1991) and
their main findings are summarised in Table 7.8. NBCCS
cysts had a higher frequency of satellite cysts, epithelial
islands, and odontogenic rests in the wall than sporadic
cysts, and overall 67% of NBCCS cysts showed one or
more of these features compared to only 34% of sporadic
cysts. NBCCS cysts were also more likely to be inflamed
and to show evidence of dystrophic calcifications in the
wall. Woolgar et al. (1987a) also found that satellite cysts
in NBCCS cases were more numerous than in solitary
cysts, and often arose in groups of varied sizes, giving an
impression of ‘several generations of cysts’. Islands of
proliferative epithelium resembling ameloblastoma
(‘ameloblastomatoid’ islands) were only seen in syndro-
mic cysts. These authors found no evidence that these
islands develop into true ameloblastomas, and suggested
Box 7.4  Features Suggestive of a Diagnosis of
Naevoid Basal Cell Carcinoma Syndrome (NBCCS) That
Warrant Further Clinical Investigations or Careful
Follow-­up
●● A diagnosis of odontogenic keratocyst (even solitary)
in a patient under 20 years of age
●● Multiple keratocysts, especially involving multiple
quadrants
●● Lesions in the posterior maxilla, especially in
younger people
●● Prominent satellite cysts, epithelial islands, or odon-
togenic rests
●● Numerous satellite cysts, often in groups of varied size
●● High number of mitotic figures, especially in the
suprabasal layers
Caution:
NBCCS cysts constitute less than 10% of the total num-
ber of keratocysts that may be encountered (Table 7.2),
so care must be taken not to overinterpret the histo-
logical findings, since satellites and islands may also be
seen in solitary cysts (Table  7.7). Each cyst should be
evaluated on the clinical, radiological, and histological
findings.
that NBCCS patients may be more susceptible to prolif-
erations of odontogenic epithelium.
Surprisingly, there were no differences between the cysts
with regard to budding of the epithelial basal layers or to
the presence of mitoses. Mitoses were seen in all cysts
examined, although there were significantly more in syn-
dromic cysts than in sporadic cysts. Dominguez and
Keszler (1988) compared keratocysts from NBCCS patients
and sporadic cases and also found that significantly more
NBCCS cysts contained satellite cysts or islands (36.4%;
n = 33) than sporadic cysts (6.1%; n = 33).
The finding of a greater frequency and number of satel-
lite cysts and islands in NBCCS-­associated keratocysts is in
keeping with the concept that in these lesions there is a
germline mutation in the PTCH1 gene that constitutively
activates the HH signalling pathway, resulting in a clone of
genetically altered dental lamina rests that subsequently
proliferate to form cysts with a high frequency of satellite
cysts and proliferating islands. This provides some expla-
nation for how the genetic changes may influence the his-
tological phenotype.
In keeping with the findings of increased mitotic figures,
Li et al. (1995) showed that cell proliferation (Ki-­67–posi-
tive cells) was significantly greater in NBCCS-­associated
cysts than in sporadic cysts. In a later study, the same group
(Pan and Li 2009) found that Ki-­67 labelling in keratocysts

with PTCH1 mutations (n = 29; 103.29 ± 35.47 cells/mm)
was significantly higher than in keratocysts with no muta-
tions (n = 33; 69.82 ± 24.28 cells/mm). Furthermore, they
also found that the labelling index was higher in lesions
with truncating mutations compared to non-­truncating
mutations in both NBCCS cysts (138.04 ± 24.07 cells/mm
vs 99.93 ± 28.18) and sporadic cysts (92.16 ± 22.50 vs
67.82 ± 23.78). The authors concluded that PTCH1 muta-
tions, especially truncating mutations that affect protein
function, may define a subset of keratocysts with a higher
proliferative potential.
Shimada et  al. (2013) investigated the genotype of
16  NBCCS and 20 sporadic cysts and found LOH at the
PTCH1, PTCH2, or SUFU locus in 79% of NBCCS cysts and
42% of sporadic cysts, with PTCH1 being the most com-
monly affected (see Table  7.6). NBCCS cysts showed the
highest frequency of budding of the epithelial basal layers
and of satellite cysts, but across all cyst types LOH at
PTCH1 and SUFU showed a significant correlation with
epithelial budding. Epithelial budding was also associated
with recurrence. Satellite cysts and islands were not associ-
ated with LOH or recurrence.
These studies further demonstrate that odontogenic
keratocysts are genetically heterogeneous, and provide
early evidence that there are genotypic subsets with differ-
ent clinical or histological features. This may explain the
range of behaviours and histological features seen, but fur-
ther research is needed to determine whether the kerato-
cyst can be divided into truly distinctive entities.
Histological Differential Diagnosis
The classic histological features of the odontogenic kerato-
cyst are diagnostic (Figures  7.16 and  7.17; Box  7.3) and
when seen the diagnosis should not be in doubt and few
alternative lesions need to be considered. Occasionally the
typical parakeratinised epithelium may not be prominent
and may only comprise a small portion of the cyst lining.
This may occur in inflamed cysts or in cysts that show
areas of orthokeratinisation. Differentiation from ortho­
keratinised odontogenic cyst has been discussed previously
and is considered in detail in Chapter  12. We have sug-
gested that if the lining shows areas of a typical parakerati-
nised odontogenic keratocyst, then a diagnosis of
odontogenic keratocyst should be given. Occasionally
other odontogenic cysts, especially radicular and dentiger-
ous cysts, may show keratinisation through a process of
metaplasia. This is rare and when it does occur it usually
affects only a small portion of the cyst lining and is typi-
cally orthokeratin. Even if parakeratin is seen, it does not
resemble a typical keratocyst and the overall clinical and
histological features will enable a correct diagnosis.
­Histopatholog  125
As discussed previously, the most common single site for
odontogenic keratocyst is the angle and ramus of the man-
dible, and at this site there are three lesions that may have
a similar radiological appearance and may be considered in
the clinical differential diagnosis – dentigerous cyst, kerato-
cyst, and ameloblastoma. Usually these are easy to diag-
nose histologically, but in a small incisional biopsy,
especially if a lesion is inflamed, it may not be possible (see
below). If a diagnosis cannot be made, then a second biopsy
or conservative excision (enucleation) may be necessary. A
cystic ameloblastoma or a unicystic ameloblastoma may on
occasion show a keratinised surface or eosinophilic surface
epithelial cells that resemble parakeratin. However, promi-
nent basal columnar cells resembling ameloblasts and the
presence of suprabasal stellate reticulum–like areas should
enable a correct diagnosis to be made.
A particular problem may arise if an odontogenic kerato-
cyst becomes heavily inflamed through trauma or infec-
tion. In areas of inflammation, the typical features are lost
and the lining reverts to a simple non-­keratinised stratified
squamous epithelium (Figure 7.20), which may show vari-
able degrees of hyperplasia and rete peg formation.
Histologically such a lining is indistinguishable from radic-
ular cyst or other inflamed odontogenic cysts. If a patholo-
gist is faced with such an appearance, and the clinical and
radiological features suggest a keratocyst, then multiple
blocks and sections must be examined to search for areas of
typical keratocyst lining. Usually these will be present and
a correct diagnosis can be made. Occasionally a cyst may be
entirely inflamed and show a non-­descript epithelial lin-
ing, and even widespread loss of the lining. In these cases a
definitive diagnosis is not possible, and a judgement of the
most likely diagnosis must be made based on the clinical,
radiological, and surgical findings. It should be noted that
immunohistochemistry is not helpful in these cases,
because any biomarkers (usually cytokeratins) considered
typical of parakeratinised keratocyst epithelium are not
expressed in the simple epithelium of the inflamed cyst.
A further diagnostic problem arises when a lesion with
cystic spaces typical of a keratocyst appears solid or
multicystic.
Solid Odontogenic Keratocyst
There are a number of case reports of ‘solid’ odontogenic
keratocysts. All appear to be unusual and show such vari-
able features that the true nature of this lesion remains
uncertain. It is important, however, because the authors of
all the reports have suggested that the solid odontogenic
keratocyst is the ‘link’ that demonstrates the true neoplas-
tic nature of the lesion. As an analogy, a number of authors
(Vered et  al.  2004; Daley et  al.  2007; Shuster et  al.  2012;
126 Odontogenic Keratocyst

(a) (b)

(c) (d)

Figure 7.20  Inflammatory changes in the odontogenic keratocyst. A characteristic feature is focal areas of inflammation pushing into
the cyst lumen (a, b). In areas of inflammation the epithelial lining may be lost (a, b) or may revert to simple non-­keratinised stratified
squamous epithelium (c), with a sharp transition from the more typical parakeratinised surface (c, arrow). (d) Focal accumulations of
hyaline bodies are occasionally seen.

Table 7.9  Reported cases of solid odontogenic keratocyst.

Age Sex Location Radiology

Omura et al. (1997) 70 F Mandible angle/ramus Multilocular

Vered et al. (2004) 52 M Maxilla posterior Multilocular
Daley et al. (2007) 52 M Mandible canine/premolar Unilocular
Iezzi et al. (2011) 52 F Mandible premolar Unilocular
Shuster et al. (2012) 47 M Mandible premolar Unilocular
Kahraman et al. (2018) 42 M Mandible posterior Multilocular
30 F Mandible posterior Multilocular

Kahraman et al. 2018) have suggested that the solid kerato-
cyst is equivalent to the dentinogenic ghost cell tumour,
representing a ‘solid variant’ of calcifying odontogenic cyst
that is a true neoplasm.
Table  7.9 summarises the features of seven well-­
documented cases. The clinical and radiological presenta-
tion is similar to a conventional keratocyst (Table  7.1),
although the age of presentation may be slightly older. The
reports in Table 7.9 are regarded as acceptable because all
were primary lesions and were well documented with radi-
ology, histology showed that at least some cysts were lined
by a parakeratinised epithelium typical of odontogenic
keratocyst, and none reported features suggestive of amelo-
blastoma (see also Box 7.5). The lesions were described as
‘solid’ at surgery or on macroscopic examination, but all
were actually composed of multiple, variably sized cysts

Figure 7.21  A solid odontogenic keratocyst that arose in the
maxilla (see Figure 7.9). The lesion is actually composed of
multiple irregular and variably sized cystic spaces and small
islands in a dense fibrous stroma.
and solid islands in a dense fibrous stroma (Figure 7.21). In
the first report, Omura et  al. (1997) described numerous
variably sized keratocysts lined by parakeratinised epithe-
lium and often filled with desquamated keratin and
necrotic material. Some cysts were lined by non-­keratinised
epithelium, and some of the larger cysts were occasionally
accompanied by smaller satellite cysts. Of note is that they
showed that many small cysts were located within the can-
cellous bone. Subsequent reports have shown similar fea-
tures (Vered et al. 2004), but others have also found many
solid islands and sheets or cords of epithelium (Daley
et al. 2007; Shuster et al. 2012). The case reported by Daley
et  al. (2007) showed a solid tumour mass with multiple
keratocysts, but also with solid islands and branching cords
of epithelium. The cysts were lined by parakeratinised epi-
thelium and many were filled with desquamated keratin
and inflammatory cells. Similarly, the lesions described by
Shuster et  al. (2012) and Kahraman et  al. (2018) showed
multiple keratocysts, but also multiple small solid islands.
Many of these resemble odontogenic epithelium and some
showed microcyst formation. In some cases the keratinised
islands have been described as keratin pearls (Kahraman
et  al.  2018) and feature a flattened epithelium without a
prominent basal layer, lining a cystic space filled with kera-
tin or keratinaceous material with macrophages.
Examination of some of the published histological images
shows a striking similarity to well-­differentiated squamous
cell carcinoma (Daley et  al.  2007; Shuster et  al.  2012;
Kahraman et  al.  2018). A number of cases reported (and
illustrated) islands of epithelium, or small cysts within the
adjacent cancellous bone (Omura et  al.  1997; Vered
et  al.  2004), and this was interpreted as indicating
­Histopatholog  127
aggressive behaviour typical of a neoplasm. Others, how-
ever, found that the lesions were well demarcated with no
bone involvement and suggested that there is no evidence
that the solid variant should be regarded as more aggres-
sive than a conventional cystic odontogenic keratocyst
(Daley et  al.  2007; Iezzi et  al.  2011; Shuster et  al.  2012;
Kahraman et  al.  2018). None of the lesions shown in
Table 7.9 recurred.
These reports demonstrate that the features of the solid
odontogenic keratocyst are quite variable, but also suggest
that there are too few cases reported to draw any firm con-
clusions regarding their true nature. Because the solid
lesions show variably sized multiple cysts, the line of dis-
tinction between a ‘solid’ keratocyst and a conventional
keratocyst with multiple satellite cysts and islands in the
wall is not clear. Kahraman et  al. (2018) examined
204  keratocysts and found that 149 (73.0%) were simple
cysts with no satellite cysts or epithelial islands, 43 (21.1%)
had fewer than 10 mural satellites or islands, and only 12
cases (5.9%) had more than 10 satellite cysts or islands. Only
2 of these 12 cases were regarded as solid (Table 7.9). These
were very similar to the lesion shown in Figure 7.21 and
described as showing multiple, randomly distributed small
cysts and islands within a dense fibrous connective tissue,
and presumably did not have a single large or dominant cyst.
Overall, it seems that the histological features of the
keratocyst may sit on a spectrum from simple cysts with no
mural changes, to cysts with scattered satellite cysts and
islands, to the more solid multicystic lesions described
here. Although there is evidence of an association between
genetic changes and histology, and satellite cysts are more
common in NBCCS-­associated cysts (Table 7.8), there have
been no studies to determine the status of the PTCH gene
in ‘solid’ lesions. None of the lesions in Table 7.9 or reported
as solid in the literature has been associated with NBCCS. As
discussed previously, further studies are needed to under-
stand the genetic changes involved in cysts with different
features and to determine if there are distinctive subsets of
odontogenic keratocyst.
A further area of difficulty is the differential diagnosis of
the solid lesions. Those described have been composed of
multiple cystic spaces as well as solid islands and cords of
epithelium, many of which show slits or microcystic change,
filled with keratin. Although typical parakeratinised areas
should be present, many cystic spaces are filled with lamel-
lae of keratin and resemble keratin pearls. These lesions
often resemble a well-­differentiated squamous cell carci-
noma. In particular, they may resemble carcinoma cunicula-
tum (Fonseca et al. 2013; Barrett et al. 2020; Janardhanan et
al. 2021), which has been shown to permeate the bone
and  form branching crypts and cyst-­like spaces lined
by  keratinised epithelium or filled with keratin squames.
128 Odontogenic Keratocyst
Fonseca et al. (2013) reviewed 10 cases that had perme-
ated the jaw bones and found that 2  had been misdiag-
nosed as odontogenic keratocyst. More recently, Barrett
et al. (2020) described a series of 12 cystic squamous cell
carcinomas within the jaws and highlighted the diagnos-
tic pitfalls, including misdiagnosis as odontogenic
keratocyst. One lesion in particular appeared to be intra-
osseous and had cysts resembling keratocyst, with a par-
akeratinised surface and palisaded basal cells. Review of
the figures in these papers (Fonseca et al. 2013; Barrett
et al. 2020) will show a striking resemblance to a num-
ber of cases reported as solid odontogenic keratocyst.
The key feature of a squamous carcinoma or carcinoma
cuniculatum is that it ‘burrows’ into the bone from the
surface mucosa and usually there is evidence of a surface
lesion. Kawano et  al. (2013) reported a case of a solid
variant of odontogenic keratocyst that showed unusual
features that raise doubt about the diagnosis. This lesion
presented as a moth-­eaten radiolucency in an area of the
mandible where molar teeth had been previously
extracted, but the reason for extractions were not noted.
Clearly the lesion had continuity with the oral mucosa
(via the extraction sites) and histologically resembled a
well-­differentiated carcinoma or carcinoma cunicula-
tum. Clear cells and mucous cells were also noted, and
although the authors suggest the possibility of odonto-
genic origin, the true nature of the lesion could not be
determined. In diagnosing a solid keratocyst, care should
be taken to ensure that the lesion is truly intraosseous
and does not have an origin from surface (or gingival)
epithelium.
A further lesion that may resemble a solid or multicystic
odontogenic keratocyst is the keratoameloblastoma. These
two lesions show an almost identical morphological archi-
tecture and only subtle differences in histological appear-
ance. Both are multicystic, with cysts lined by keratinising
epithelium. The keratoameloblastoma, however, is
thought to be a variant of ameloblastoma and shows basal
ameloblast-­like cells and typical areas of ameloblastoma-
tous epithelium with stellate reticulum. Nevertheless, the
lesions are so similar that it is still debated whether the
keratoameloblastoma is a multicystic keratinising amelo-
blastoma, or an odontogenic keratocyst undergoing amelo-
blastomatous change.
Whitt et  al. (2007) reported a case of keratoameloblas-
toma and reviewed 12 cases reported up to 2007. They sug-
gested that these lesions may show a range of features that
fall into four broad categories: (i) papilliferous, (ii) simple
histology, (iii) simple histology with keratocyst-­like areas,
and (iv) a complex histology. The papilliferous type is
regarded as a separate entity and would not be confused
with an odontogenic keratocyst. Similarly, the simple type
appears to represent a follicular ameloblastoma with exten-
sive keratinisation and cystic change, and is virtually
­indistinguishable from acanthomatous ameloblastoma.
Confusion with odontogenic keratocyst arises when con-
fronted with types iii and iv. These may show areas of cystic
change lined by typical keratocyst epithelium, but with
minimal areas resembling ameloblastoma. The case illus-
trated by Whitt et  al. (2007) showed a complex plexiform
pattern with islands and strands of epithelium in a dense
collagenous stroma. Cystic spaces lined by keratocyst-­like
parakeratinised epithelium were seen and lamellated sheets
of parakeratin were prominent, both within the cysts and
extruding into the stroma. There were only small areas of
peripheral palisading resembling ameloblastoma, but the
authors did not describe or illustrate ameloblastomatous
areas. Whitt et  al. (2007) used the term keratoameloblas-
toma in the title of their paper, but they were uncertain of
its true nature. They speculated that it may be an odonto-
genic keratocyst with focal areas resembling ameloblas-
toma, or a hybrid lesion. Their illustrations, however, are
very similar to other reports describing lesions as solid
odontogenic keratocyst. Geng et al. (2012) reported a very
similar case that showed some features typical of kerato-
cyst, but also areas of ameloblastomatous change, and
called it a solid odontogenic keratocyst with ameloblasto-
matous transformation. This case is not included in
Table 7.9 since it more closely meets the criteria for a type of
keratoameloblastoma.
It is clear, however, that the keratoameloblastoma and
odontogenic keratocyst are related, at least by a similar his-
tology, and some have proposed a histogenetic relationship
whereby a keratocyst may give rise to an ameloblastoma, or
a solid keratocyst may evolve from keratoameloblastoma
(Ide et al. 2012). Ide et al. (2003) are credited with one of
the earliest reports of a solid odontogenic keratocyst, but
their case had originally shown features of keratoamelo-
blastoma and had recurred or persisted over a period of
25 years, finally showing an unusual histology of an infil-
trative lesion composed of cords and islands of epithelium
and irregular cysts filled with parakeratin. Ide and col-
leagues (Ide et  al.  2003,  2012) and others have cited this
case as evidence of transition from (kerato)ameloblastoma
to keratocyst, but because of its unusual features its true
nature remains uncertain.
Because of the known ability of odontogenic epithelium
to show multiple routes of differentiation and to give rise to
a plethora of cysts and tumours, it is perfectly possible for
these lesions to be histogenetically related, with resulting
combinations of features when a lesion is examined histo-
logically at a fixed point in time. As a result, the literature
contains many case reports of very similar lesions under
different names, often depending on the past experiences
 ­Histopatholog  129

of the pathologist or their preferred interpretation. Many Cytology and Aspiration Biopsy

of these lesions probably represent unusual tumours aris-
Toller (1970a) and Kramer and Toller (1973) were the first to
ing from odontogenic epithelium but defying categorisa-
suggest that a preoperative diagnosis of odontogenic kerato-
tion, and should be regarded as oddities rather than
cyst might be made by the examination of aspirated cyst
entities. Nevertheless, there is little doubt that an odonto-
fluid. Toller (1970a) showed that fluids from keratinising
genic keratocyst may show multiple satellite cysts and epi-
cysts had soluble protein levels below 3.5 g per 100 mL (mean
thelial islands, and the evidence suggests that on occasion
2.2 g per 100 mL), whereas the values for non-­keratinising
these may be so prolific as to produce a lesion that appears
cysts were in the range 5.0–11.0 g per 100 mL, with a mean of
solid (see Figures 7.9 and 7.21). Further reports and genetic
7.1 g per 100 mL. Electrophoretic studies corroborated the
studies may, in the future, clarify the true nature of this
finding that keratinising cysts were very low in soluble pro-
lesion. To ensure consistency and to assist future studies,
teins, and Toller postulated that a protein level of less than
we suggest that strict criteria are applied for a diagnosis of
4.8 g per 100 mL indicated a diagnosis of odontogenic kerato-
a solid or multicystic odontogenic keratocyst (Box 7.5).
cyst. A value of over 5.0 g per 100 mL, however, would suggest
We have previously mentioned a multicystic lesion,
a radicular or dentigerous cyst, or even an ameloblastoma.
keratocystoma, with features resembling odontogenic
He suggested that fully keratinised epithelium was impervi-
keratocyst that has been described in the parotid gland
ous to proteins, whereas the non-­keratinised linings of
(Seifert et al. 1999; reviewed by Aresta et al. 2019; Komatsu
radicular or dentigerous cysts would at least slowly transmit
et al. 2020). Histologically the keratocystoma is multicystic
smaller proteins. For a time, it was quite common for special-
and is almost indistinguishable from lesions described as
ist oral pathology laboratories to examine cyst fluid by elec-
solid odontogenic keratocyst. However, the keratocystoma
trophoresis for protein levels (reviewed by Smith 1991), but
arises only in the parotid gland and, despite the histological
with the advent of larger, automated, and highly regulated
similarities, it is not related to the odontogenic keratocyst.
laboratories, infrequently used specialist techniques are now
Lesions located in the parotid gland should be diagnosed as
rarely applied and few if any laboratories examine cyst fluids
keratocystoma, and not as soft-­tissue or solid keratocyst.
for protein content as a diagnostic test.
The keratocystoma is discussed further in Chapter 15.

Box 7.5  Solid Odontogenic Keratocyst: Suggested Criteria for Diagnosis

●● The lesion is histologically multicystic
●● The cysts may be irregular and vary in size, but no single large or dominant cyst should be present
●● At least some of the cysts and in particular larger cysts must be lined by parakeratinised epithelium typical of
odontogenic keratocyst (Figure 7.16)
●● Palisading of the basal cells and reversal of nuclear polarity may be seen
●● Solid epithelial islands and odontogenic rests may be present
●● Branching strands and cords of epithelium may be seen, but these often resemble collapsed cystic structures and
may contain ‘slits’ filled with parakeratin
●● The lesion should be intraosseous
Caution: If these features are present, consider an alternative diagnosis:
●● A single large typical keratocyst surrounded by smaller cysts and islands. This is probably a conventional odonto-
genic keratocyst with prominent satellites. Also consider the possibility of naevoid basal cell carcinoma syn-
drome (NBCCS)
●● Ameloblasts or stellate reticulum. This excludes the diagnosis of keratocyst. Consider a keratinising type of amelo-
blastoma (acanthomatous ameloblastoma) or keratoameloblastoma
●● Prominent burrowing strands, islands, or crypts of keratinising epithelium. Consider carcinoma cuniculatum
●● Prominent keratin pearls or any evidence of cytological atypia. Consider well-­differentiated squamous cell carci-
noma, either primary or a metastasis
●● Any evidence of continuity with the overlying oral mucosa or with gingival epithelium. If perforation of the cortical
plate by an intraosseous lesion can be excluded, consider mucosal or gingival well-­differentiated squamous cell
carcinoma
130 Odontogenic Keratocyst
Cytological examination of cyst aspirates, however, is
included in the repertoire of routinely applied techniques
in most centres, and aspiration cytology may be a useful aid
to preoperative diagnosis. Kramer and Toller (1973) were
the first to report the use of aspiration cytology for the pre-
operative diagnosis of keratocysts. They examined a total
of 53 cystic lesions and subsequent histological examina-
tion showed that 21  were odontogenic keratocysts and
32 were non-­keratinised cysts. Microscopic examination of
smears of the aspirates showed keratinising epithelial cells
(squames) in 17 of the 21 (81.0%) keratocysts, but in only 3
(9.4%) of the 32  non-­keratinising cysts, giving an overall
correct diagnosis in 46 of the 53 cysts (86.8%).
August et  al. (2000) examined fine needle aspiration
biopsies from 18 odontogenic cysts and compared the pre-
operative cytology findings to the gold-­standard histologi-
cal diagnosis. During aspiration, they deliberately contacted
and sampled the wall of the cyst to ensure a yield of surface
epithelial cells. Smears were stained with ‘Diff-­Quik’
(Romanowsky stain) and the Papanicolaou method, and
using immunocytochemistry for CK10. The epithelial cells
of 10 cysts were strongly positive for CK10 and all 10 were
subsequently confirmed to be odontogenic keratocysts,
with strong positivity for CK10 in the superficial parakera-
tin layers. Four dentigerous cysts and four radicular cysts
were negative for CK10 in the aspirates and in the histo-
logical sections. The authors suggested that expression of
CK10 is specific for the odontogenic keratocyst and allows
keratinised epithelial cells to be easily distinguished from
non-­keratinised cells.
(a)
Figure 7.22  Sections from a cell block preparation of an aspirate from an inflamed odontogenic keratocyst. (a) Lamellae of keratin
can clearly be seen among the inflammatory cells. (b) Pan-­cytokeratin (AE1/AE3) highlights the keratin. Source: Courtesy of Prof.
Pablo Vargas.
In a similar study, Vargas et al. (2007) examined aspirates
from eight odontogenic keratocysts and found that
Papanicolaou stain showed positive staining (orange/red)
for keratinised squames in all cases. Cells were also posi-
tive for pan-­cytokeratin (AE1/AE3) and CK19 (Figure 7.22),
but the specificity of the cytokeratin expression was not
determined by comparison with other non-­keratinising
cysts. The authors also prepared cell blocks from the aspi-
rates and were able to show lamellae of desquamated kera-
tin that expressed cytokeratins (Figure 7.22b). Cell blocks
are prepared by centrifugation of the aspirate to produce a
cell pellet that can then be embedded and sectioned using
routine histological techniques. The advantage is that cells
are concentrated and some of the architectural arrange-
ment of the tissue may be preserved. Rivero et  al. (2014)
prepared cell blocks from aspirates of 135 cystic jaw lesions.
Blocks were sectioned and stained with haematoxylin and
eosin (H&E) and the findings were compared to the final
diagnosis made on examination of surgical biopsies.
Examination of the cell blocks showed keratin in 20 cases,
of which 19  were odontogenic keratocysts and 1  was an
orthokeratinised odontogenic cyst. Of the 115 cases that
did not show evidence of keratin, none was diagnosed as a
keratocyst after examination of the surgical specimen. As a
diagnostic test for odontogenic keratocyst, these data sug-
gest a sensitivity of 100%, specificity of 99.1%, and positive
and negative predictive values of 95% and 100%, respec-
tively. The images in this paper (Rivero et al. 2014) show
clearly visible desquamated epithelial cells, evidence of
parakeratin, and lamellae of keratin, even in cases that also
(b)

showed inflammation (see also Figure  7.22a). A more
recent study (Patidar et al. 2015) supported these findings
and showed that epithelial cells could be found in aspirates
from 14 of 15 (93.3%) keratocysts compared to only 3 of 15
(20.0%) non-­keratinised odontogenic cysts.
These studies demonstrate that aspiration cytology, espe-
cially with examination of cell blocks, may provide a useful
and accurate method for a preoperative diagnosis of the
odontogenic keratocyst. However, among all radiolucent
lesions of the jaws, keratocysts are relatively rare and
inflammatory cysts are more common. If aspirates are used
indiscriminately, the vast majority will show inflammatory
cells and some epithelial cells, but will be non-­diagnostic.
A diagnosis of keratocyst can only be made if keratinising
cells or lamellae of keratin are seen. Aspiration biopsies
should only be used when a preoperative diagnosis is clini-
cally indicated and a conventional biopsy may be difficult.
It is most beneficial for large lesions, especially in the pos-
terior mandible, where there may be a wide differential
diagnosis, and large lesions in the posterior maxilla, where
surgical access may be limited.
Immunohistochemistry and Biomarker Studies
There are many studies investigating the expression of
cytokeratins and other biomarkers in odontogenic kerato-
cysts and comparing expression to other cyst types. Most
studies have tried to determine whether particular patterns
of expression could provide accurate diagnostic markers
for the common odontogenic cysts. Other studies have
used markers to explore the pathogenesis and mechanisms
of growth of the keratocyst. Studies of HH signalling path-
way–associated proteins and proliferation markers have
already been discussed in ‘Pathogenesis’.
With regard to cytokeratins, Shear (2002c) and the previ-
ous edition of this book reviewed more than 16 studies
published between 1987 and 2005 and discussed their
potential utility as diagnostic markers. The overall conclu-
sion was that the diagnostic potential appeared to be lim-
ited, due in part to the variability of results from different
laboratories and a lack of standardised methodology. In
particular, many early studies used antibodies that had lim-
ited availability, could only be used on fresh frozen tissues,
and produced results that were widely variable and could
not be compared (Smith and Matthews  1991). More
recently, Bhakhar et al. (2016) investigated the expression
of CK18 and CK19  in dentigerous cysts, odontogenic
keratocysts, and radicular cysts, and found that while more
dentigerous cysts than keratocysts expressed both
cytokeratins, expression in radicular cysts was the same as
in dentigerous cysts. These authors also reviewed 5 studies
that had investigated CK18 and 17 studies that had
­Histopatholog  131
investigated CK19. These showed either no differences
between the different cyst types, or wide variability within
or between the studies. This degree of variability suggests
that the use of these cytokeratins as a diagnostic test on a
single isolated case would be inappropriate and grossly
inaccurate.
A further limitation is that if the clinical, radiological,
and histological features of the individual cyst types are
characteristic and if strict diagnostic criteria (Boxes  7.2
and  7.3) are followed, a histological diagnosis of odonto-
genic keratocyst is rarely a problem and immunocyto-
chemical studies are not needed. It is also notable that in
most studies comparing different cyst types, the specimens
are chosen to show the typical histological features, regard-
less of the fact that if the features are typical, then there is
no requirement for staining beyond a good H&E-­stained
section to make the diagnosis.
Despite these limitations, most studies have shown that
odontogenic keratocysts consistently express cytokeratins
that are associated with a cornified epithelium, in par-
ticular CK1, CK10, and CK11 (Shear 2002c), while these
are not seen in non-­keratinised cyst types. This is of
course consistent with the histological finding of keratin
in keratocysts, and since this can be observed in routine
sections, then the role of these markers is limited.
However, as discussed previously, expression of CK10 was
shown to be a useful diagnostic aid in cytological prepara-
tions of cyst aspirates (August et al. 2000) and expression
of pan-­cytokeratin can also help identify keratin in aspi-
rates of inflamed cysts (Vargas et  al.  2007; Figure  7.22).
Although useful to differentiate keratocysts from denti-
gerous cysts, radicular cysts, and even ameloblastomas,
similar cytokeratin expression may be seen in an
orthokeratinised odontogenic cyst (Aragaki et al. 2010). A
more recent study (Tsuji et  al.  2014), however, found
CK10 expression in the superficial layers of only 3 of 25
odontogenic keratocysts, compared to all of 15 orthokerati-
nised cysts. Conversely, they found that all 25 keratocysts
showed moderate to strong expression of CK17, but all
other cyst types, including orthokeratinised, dentigerous,
and radicular cysts, were negative. Expression of
CK17 has been shown to be associated with neoplastic or
proliferative epithelium, and a number of studies have
suggested that it is strongly expressed in keratocysts
(Meara et al. 2000; Stoll et al. 2005; Cserni et al. 2020b).
Nevertheless, it is not specific, since it may be weakly
expressed in up to one-­third of dentigerous and radicular
cysts (Meara et al. 2000; Stoll et al. 2005). These studies
demonstrate that, on average, keratocysts may show
strong expression of CK17, and this is consistent with the
higher rate of proliferation, but for a single case CK17
cannot exclude other cyst types.
132 Odontogenic Keratocyst
A particular diagnostic challenge may arise when a
pathologist is faced with a small biopsy from an inflamed
cyst. Few studies have been able to identify markers that
can differentiate between the histologically identical fea-
tures of an inflammatory cyst and an inflamed odonto-
genic keratocyst. Cserni et al. (2020a) addressed this by
comparing inflamed and uninflamed areas of 11 kerato-
cysts for expression of bcl2, CK17, CK10, and CK19. In
typical uninflamed keratocyst epithelium, all markers
were positive. Bcl2 was expressed in the basal and supra-
basal layers, CK17 and CK19 showed strong expression
through the whole epithelium, and CK10 was expressed
in the superficial layers, but was often patchy with focal
unstained areas. In areas of inflammation the epithelium
was non-­keratinised and proliferative, but all showed
loss of bcl2 and complete (four cases) or weak and patchy
(six cases) loss of CK17. Similarly, there was complete
loss (three cases) or markedly reduced expression (eight
cases) of CK10. CK19  was reduced in six cases. These
data show that the characteristic keratin profile of the
odontogenic keratocyst is lost when inflamed, suggesting
that immunocytochemistry for cytokeratin is of little
diagnostic value in inflamed lesions. The authors also
noted that inflammation and expression of cytokeratins
may be patchy, indicating that a diagnosis of keratocyst
cannot be excluded if only a small sample is examined.
Their finding of focal and patchy expression for
CK10 may explain the variable results for CK10 expres-
sion in studies on histological sections (Aragaki
et al. 2010; Tsuji et al. 2014), but consistent positivity in
aspirates (August et al. 2000).
In the posterior mandible, the two most common lesions
that must be considered in the differential diagnosis are
dentigerous cyst and ameloblastoma, and a preoperative
diagnosis is always desirable before definitive surgery,
especially for large lesions. At this site an aspiration biopsy
may be useful, but often a small incisional biopsy is taken
in the retromolar area. For typical lesions a biopsy should
be diagnostic, but occasionally a cystic or unicystic amelo-
blastoma may show features similar to a keratocyst, espe-
cially if there is an element of inflammation. In this
context, immunohistochemistry for calretinin may be use-
ful, since it has been shown to be expressed in a high pro-
portion of solid, unicystic, and multicystic ameloblastomas
(Altini et al. 2000; Coleman et al. 2001). Altini et al. (2000)
showed that calretinin was expressed in 22 of 27 (81.5%)
unicystic ameloblastomas and in 29 of 31 (93.5%) solid/
multicystic ameloblastomas. In a subsequent study, the
same authors (Coleman et  al.  2001) studied a series of
22 keratocysts, 26 residual cysts, and 20 dentigerous cysts,
and found that all were negative for calretinin, suggesting
that, in the context of odontogenic lesions, calretinin is
specific for ameloblastomas. In a similar study, De Villiers
et al. (2008) compared 19 ameloblastomas (including 3 uni-
cystic cases) with 17 odontogenic keratocysts and found
that all ameloblastomas showed calretinin expression, but
all keratocysts were negative. These authors and Altini
et al. (2000) also found that calretinin was more strongly
expressed in ameloblastomas with areas of squamous
metaplasia. Subsequently, two further studies have con-
firmed that odontogenic cysts, including keratocysts, are
negative for calretinin, but that ameloblastomas (including
unicystic ameloblastoma) are positive in up to 100% of
cases (De Villiers et  al.  2008; Jeyaraj  2019; Rudraraju
et al. 2019).
These studies suggest that calretinin is useful to distin-
guish ameloblastoma from odontogenic keratocyst, but
none has investigated expression in inflamed lesions. Also,
there are no studies that have investigated the utility of cal-
retinin, or any markers, in distinguishing between a solid
keratocyst and keratoameloblastoma.
Malignant Change in Odontogenic Keratocysts
Intraosseous or odontogenic squamous cell carcinoma is a
central carcinoma of the jaws that arises from odontogenic
epithelium (Koutlas and Sloan 2022). Although they may
arise from odontogenic epithelial rests, the majority prob-
ably arise from the epithelium of odontogenic cysts.
Although about 70% of primary intraosseous carcinomas
arise from cysts, it has been estimated that less than 0.2% of
cysts may show malignant change (Stoelinga and Bronkhorst
1988; Bodner et  al.  2011; Borrás-­Ferreres et  al.  2016).
Because the odontogenic keratocyst shows an increased
rate of cell proliferation and an increased number of
mitotic figures, early papers suggested that they have a
greater tendency to malignant change than other cyst types
(Toller  1967). Others have drawn attention to the occa-
sional finding of epithelial dysplasia in keratocysts, but this
is actually very rare and has not been associated with
malignant change (Brannon  1977; Ahlfors et  al.  1984;
Cottom et al. 2012).
Ye et al. (2020) presented 5 cases of carcinomas arising
in odontogenic keratocysts and reviewed a further
29 well-­documented cases up to 2020. The average age of
presentation was 48.8 years (range 15–81) and 58.6% arose
in males. The majority (69.0%) were in the mandible and
37.9% arose in recurrent cysts. All the cases were squa-
mous cell carcinomas, although one was also described as
verrucous. Only three patients (8.8%) developed cervical
lymph node metastases, but a further three developed dis-
tant metastases and the overall five-­year survival was only
53.2%. Ye et  al. (2020) did not comment on the criteria
applied for diagnosis in the reviewed cases, but in all of

their own cases they demonstrated evidence of a typical
parakeratinised keratocyst lining. In a recent systematic
review, Kumchai et al. (2021) found 34 papers reporting
37 carcinomas arising in odontogenic keratocyst.
However, 9 cases were recorded as arising in an
orthokeratinised ‘variant’, suggesting that these were
associated with orthokeratinised odontogenic cyst. The mean
age was 45.1 years (range 8–81 years). These authors
found that the majority of cases (59.5%) were diagnosed
when there was histological evidence of carcinoma in
continuity with a typical cyst lining (e.g. Figure 7.23).
In the remaining cases (40.5%) the diagnosis was made on
the basis of the carcinoma arising at a site of a previously
diagnosed odontogenic keratocyst.
With regard to the relative frequency of malignant
change in keratocysts, Bodner et al. (2011) reviewed the
literature and found reports of 116 intraosseous carcino-
mas that had arisen in odontogenic cysts between 1938
and 2010. Only 16 (13.8%) arose in keratocysts compared
to 19 (16%) in dentigerous cysts and 70 (60%) in radicular
cysts. Of the lesions, 85% were well or moderately differ-
entiated squamous cell carcinomas, and there were no
differences in lesions from different cyst types. Although
these data suggest that malignant change is far more com-
mon in radicular cysts, they do not take account of the
relative frequency of each cyst type. Since radicular cysts
are about six times more common than odontogenic
keratocysts, then the frequency of reports of carcinomas
arising in odontogenic cysts is proportionate, suggesting
that the actual rate of malignant change in each cyst type
is similar.
Figure 7.23  Malignant change in odontogenic keratocyst.
Islands of squamous cell carcinoma arise in continuity with
the keratocyst lining (left side). Source: Courtesy of Dr Lisette
Collins.
Recurrence of Odontogenic Keratocyst  133
Overall, the accumulated data suggest that malignant
change in the odontogenic keratocyst is very rare and is no
more common than in other cyst types. When it does occur
it presents at a slightly later age than a conventional kerato-
cyst, but the sex and site distribution are similar.
Histologically, the lesion shows areas of conventional
squamous cell carcinoma arising in continuity with a typi-
cal keratocyst epithelial lining (Figure 7.23).
Recurrence of Odontogenic
Keratocyst
It is well established that the odontogenic keratocyst has a
particular tendency to recur after surgical treatment. Many
authors and textbooks state that the keratocyst has the
highest recurrence of all the odontogenic cysts, and cite
this as evidence of its different and more aggressive behav-
iour, but there is so much variability in reported recurrence
rates that it is difficult to provide a definitive probability of
recurrence for any individual lesion. It should also be noted
that the overall recurrence rate for the odontogenic kerato-
cyst is about 20% (Table  7.10), and this is similar to that
reported for glandular odontogenic cyst and botryoid odon-
togenic cyst, both of which are also characterised by a mul-
tilocular morphology and have recurrence rates of between
20 and 30% (see Chapters 8 and 10).
The earliest reports of recurrence suggested rates of
between 50 and 60% (Pindborg and Hansen  1963;
Hansen 1967; Toller 1967), but most later reports and larger
series have found lower rates. In the previous edition of
this book, we tabulated 32 reports that documented recur-
rence rates of between 3% (Voorsmit et al. 1981) and 62%
(Pindborg and Hansen  1963). In a similar, more recent
review, Mendes et al. (2010) reviewed 31 studies that had
correlated treatment and recurrence and found rates of
between 0 and 100%. They showed wide variability in
recurrence rates depending on treatment methods, but also
reported studies with 0% or 100% recurrence where the
number of cases included were three or fewer. Other
reviews have reported similar wide ranges of recurrence
(Kaczmarzyk et al. 2012; Diaz-­Belenguer et al. 2016), but
careful reading of the papers shows that recurrence rates of
50% or even 100% have been taken from studies where the
number of cases was only two.
There are many reviews and small case series that report
widely variable recurrence rates and great care is needed in
interpreting the data. Studies that have investigated clinical
and radiological factors associated with recurrence are
almost all retrospective analyses that compare ‘recurrent’
and ‘non-­recurrent’ cases. However, few authors define the
meaning of ‘recurrent’ and it is not always clear if the data
134 Odontogenic Keratocyst

Table 7.10  Summary of five systematic reviews that have evaluated the effectiveness of treatments and recurrence rates for the
odontogenic keratocyst.

De Castro
Blanas Johnson Al-­Moraissi Chrcanovic and et al. (2018)
et al. (2000) et al. (2013) et al. (2017) Gomez (2017) P = 29;
P = 15; N = 578 P = 8; N = 362 P = 35; N = 2287 P = 94; N = 6427 N = 1321

n R (%) n R (%) n R (%) n R (%) n R (%)

Enucleation and/or curettage 413 28.1 156 25.6 1269 19.9 2639 23.3 1049 20.8
Enucleation and Carnoy’s 60 1.6 63 7.9 549 11.5 319 6.6 – –
Enucleation and cryotherapy 16 31.3 – – 137 14.5 91 23.1 – –
Marsupialisationa 45 24.4 21 4.8 63 32.3 226 24.8 126 18.3
Marsupialisation and – – 76 15.8 141 14.6 102 14.7 146 13.7
cystectomy
Resection 38 0 16 6.3 92 8.4 159 2.5 – –
All treatments 23.2 18.7 16.6 22.8 19.8

N, total number of cysts included; n, number of cysts in each treatment group; P, number of papers included in the review; R (%), proportion (%)
that recurred.
a
 Some studies include decompression as well as marsupialisation.

presented are for primary lesions that have subsequently
recurred, or for the actual recurrent lesions. When consult-
ing the literature, readers are cautioned not to cite the sum-
mary findings presented in abstracts without consulting
definitions and the detailed data in the text of the paper.
Factors Associated with Recurrence
Woolgar et al. (1987c) suggested that the three main causes
of recurrence are incomplete removal of the cyst lining;
growth of a new cyst from satellite cysts or epithelial
islands left behind at the time of surgical removal; and an
apparent recurrence associated with a new cyst developing
at or adjacent to a site of a previous removal. This latter
association is most often seen in patients with NBCCS,
when a new cyst may be interpreted as a recurrence.
With regard to the first two causes, these can be miti-
gated against by using treatment methods that aim to
ensure complete removal of the cyst as well as any satel-
lite cysts or epithelial islands. It is not surprising, there-
fore, that the accumulated evidence from large case
series and from systematic reviews suggests that the rate
of recurrence is primarily associated with the type of
treatment; this is discussed at the end of this chapter.
However, the success of treatment may also be affected
by a number of clinicopathological factors, including the
location and size of the lesion, association with teeth,
cortical perforation, the presence or number of satellite
cysts or islands, association with NBCCS, and the length
of the follow-­up period.
Clinical and Radiological Factors
A number of clinical factors have been shown to be associ-
ated with recurrence, but there is great variability between
studies. For example, Woolgar et al. (1987c) explored fac-
tors associated with recurrence by comparing 228 solitary
non-­syndromic keratocysts, followed for five or more years,
with 44 recurrent cysts for which data were available for
both the primary lesion and the recurrence. They found no
differences in age distribution, sex, or location between the
non-­recurrent and recurrent cysts. In similar studies, Zhao
et al. (2002), Berge et al. (2016), and Naruse et al. (2017)
studied recurrences in 255, 92, and 65 cases, respectively.
They reported overall recurrence rates of 12%, 29%, and
20%, but found no associations with any clinical or radio-
logical parameters. Myoung et al. (2001), however, found
that the highest recurrence rates (82.4%) were found in
patients in the fifth decade and for cysts located in the
mandibular molar region (75%). Chrcanovic and Gomez
(2017) reviewed 94 publications reporting 6427 keratocysts
and found an overall recurrence of 22.8%. Meta-­analyses
showed that clinical or radiological factors significantly
associated with an increased risk of recurrence were an
association with NBCCS (34.3% recurred; n  =  329) and
multilocular lesions (25.7% recurred; n  =  447) compared
with unilocular lesions (14.3% recurred; n  =  1027).
Recurrence was not associated with age, sex, or location
(mandible or maxilla).
MacDonald et  al. (2013) followed patients for a mini-
mum of five years and found that those with cysts that
recurred were significantly older (43.4 years; n = 18) than

patients with non-­recurrent lesions (28.0 years; n = 11), but
there were no differences in sex. There were no significant
associations with size of the cysts, expansion, cortication of
the margins, multilocularity, association with teeth, root
resorption, or involvement of the maxillary antrum. Of
interest, however, is that they did find that keratocysts in
the posterior mandible and lesions with a preoperative
diagnosis of odontogenic keratocyst were less likely to recur.
As discussed previously (see ‘Radiological Features’),
MacDonald (MacDonald et al. 2013; MacDonald 2016) has
suggested that large and multilocular lesions are more
likely to have a preoperative diagnosis of odontogenic
keratocyst and to be treated less conservatively, and thus to
be less likely to recur. Conversely, small unilocular radiolu-
cencies in the dentate areas of the jaws may be indistin-
guishable from common periapical lesions and may be
treated more conservatively, with a higher chance of recur-
rence (MacDonald et al. 2013; MacDonald 2016; Slusarenko
da Silva et al. 2019a). In support of this, MacDonald et al.
(2013) found that small unilocular lesions located in the
premolar region were only seen in the group of keratocysts
that recurred. These data are supported by a number of
other studies that have shown that recurrence may be asso-
ciated with conservative enucleation with retention of
involved teeth (Chirapathomsakul et  al.  2006; Cunha
et al. 2016; Fidele et al. 2019). In their study, Cunha et al.
(2016) treated 18 keratocysts that involved the roots of the
teeth by enucleation. In 9 cases the teeth were removed
and none recurred, but 6 of 9 (66.7%) cases where the teeth
were retained recurred. Fidele et  al. (2019) reviewed
274 keratocysts that had been enucleated. In 56 cases teeth
involved with the cyst were preserved and 42 (75%) of these
recurred, compared to only 6 recurrences (2.8%) among
218 cases where teeth were extracted or not involved.
Furthermore, they found that 19 of the 56 patients with
involved teeth also had cortical perforations and all 19
(100%) recurred, compared to only 23 (62.2%) of the 37
cases without evidence of cortical perforation.
Another reason for the considerable variation in recur-
rence rates reported by different workers may be the wide
variability in the reported follow-­up periods. The majority
of recurrences occur within the first 5 years, but many
keratocysts have recurred 10 years or more after surgery,
with occasional reports of recurrent lesions after 25
(Stoelinga  2001) or even 40 years (Crowley et  al.  1992;
Fidele et al. 2019). Berge et al. (2016) followed patients for
up to 25 years and found that although the mean time to
recurrence was 53 months, the range was between 9 months
and 11.5 years. The risk of recurrence increased up to 7
years after diagnosis and then remained constant at about
40%. The majority of studies have reported follow-­up peri-
ods of between 1 and 5 years, and occasionally less than 1
Recurrence of Odontogenic Keratocyst  135
year, meaning that the true recurrence rates remain uncer-
tain and it is difficult to compare studies.
These studies show great variability in clinical and radio-
logical factors that might predict recurrence of the odonto-
genic keratocyst, and suggest that they may not be helpful for
making management decisions about individual lesions.
Although a number of studies suggest that larger and multi-
locular lesions, especially in the posterior mandible, may be
more likely to recur, this is contradicted by others who have
suggested that smaller lesions in dentate areas show the
highest recurrence rates (MacDonald et  al.  2013;
MacDonald 2016; Slusarenko da Silva et al. 2019a). The dif-
ferent findings probably reflect different treatment
approaches, since it is suggested that the greater risk of recur-
rence for smaller lesions is a lack of appreciation that the
lesion may be a keratocyst, resulting in more conservative
removal and retention of the teeth. A number of studies have
shown that preservation of involved teeth (Chirapathomsakul
et al. 2006; Cunha et al. 2016; Fidele et al. 2019) is associated
with a high risk of recurrence, and suggest that this is due to
the retention of residual fragments of cyst lining or epithelial
islands that reside adjacent to the tooth roots and are not
removed during conservative enucleation.
Histological Factors
A number of papers have investigated histological factors
that may be associated with recurrence, but the findings
have been variable. In a comparison of the histology of 44
cases each of primary, recurrent, and non-­recurrent cysts,
Woolgar et  al. (1987c) found no histological factors that
might predict recurrence. The only significant finding was
less inflammation in the recurrent lesions compared with
the primary cysts. Of note, however, is that satellite cysts,
solid islands, odontogenic rests, or budding did not show
any association with recurrence. Others have confirmed
these findings and have also found no relationship between
recurrence and the presence of satellite cysts or islands in
the wall (Brannon  1977; Yagyuu et  al.  2008; Cottom
et  al.  2012; Shimada et  al.  2013; Naruse et  al.  2017;
Augustine et al. 2021).
Nevertheless, others have shown an increased rate of
recurrence of keratocysts that had satellite cysts or epithelial
islands. Myoung et al. (2001) found that about 75% of cysts
that recurred had satellite cysts and this had a statistically
significant association with a higher rate of recurrence. De
Franca et al. (2020) compared 22 non-­recurrent cysts with 18
that recurred and found that only 1 (4.5%) of the non-­
recurrent group had satellite cysts, compared to 50% of the
cysts that recurred (P = 0.002). There were no differences,
however, between the primary lesions and the recurrence.
In contrast to Woolgar et al. (1987c), they also found signifi-
cantly greater inflammation in recurrent cysts. Similarly,
136 Odontogenic Keratocyst
Cunha et al. (2016) found that epithelial islands or budding
were associated with a higher recurrence rate. Cottom et al.
(2012) found no differences between recurrent and non-­
recurrent lesions with regard to satellite cysts or epithelial
islands, but did find that recurrence was significantly associ-
ated with subepithelial hyalinisation, separation of the epi-
thelium, and the number of basally located mitoses. More
recently, Augustine et al. (2021) also showed that subepithe-
lial hyalinisation was associated with recurrence.
We have previously discussed the work of Stoelinga and
colleagues (Stoelinga  1976,  2001,  2005; Stoelinga and
Peters 1973; Stoelinga et al. 1975; see ‘Pathogenesis’), who
have described epithelial islands and microcysts in the
walls of odontogenic keratocysts and have suggested that
these are located almost exclusively in the superficial por-
tions of the cyst wall and are often seen in areas where the
cyst is continuous with the oral mucosa through fenestra-
tions in the overlying bone. In an early study, seven odon-
togenic keratocysts were examined histologically in serial
sections, and microcysts and islands were only found in the
oral mucosa above the cysts (Stoelinga and Peters  1973).
No islands or microcysts were found in other regions of the
cyst wall. Subsequently, Stoelinga (2001,  2005) has sug-
gested that there is no evidence that microcysts can be
found in the bone surrounding keratocysts and that, for
this reason, surgical resection of keratocysts is not justified.
Furthermore, he proposes that microcysts and islands
overlying the cysts are a major cause of recurrence and
advocates that when keratocysts are enucleated, the overly-
ing mucosa should also be excised. As further evidence of
this, he has discussed the issue of recurrences in bone
grafts used to repair surgical defects after resection
(Stoelinga and Slusarenko da Silva 2021). The authors sug-
gest that the source of the recurrences must be found in the
overlying mucosa that is replaced after surgery.
Studies of cell proliferation markers have been discussed
previously, but it is of note that Li et al. (1995) and, more
recently, Naruse et al. (2017) found no relationship between
the number of Ki-­67–positive cells and recurrence. Both
authors have proposed that recurrence is not associated
with increased proliferation, but is primarily a result of
inappropriate surgery or inadequate removal (Li et al. 1995;
Li 2011; Naruse et al. 2017).
Treatment and Recurrence
of Odontogenic Keratocyst
Treatment and recurrence are considered together because all
studies, including systematic reviews, that have investigated
the effectiveness of treatment have used recurrence as the pri-
mary outcome measure. Evaluation of treatment methods
has been the subject of many hundreds of papers since the
keratocyst was first described in 1956, but more recently there
have been a number of systematic reviews that have attempted
to explore this relationship (Blanas et al. 2000; Kaczmarzyk
et al. 2012; Johnson et al. 2013; Antonoglou et al. 2014; Sharif
et al. 2015; Dias et al. 2016; Diaz-­Belenguer et al. 2016; Al-­
Moraissi et  al.  2016a,b,  2017; Chrcanovic and Gomez  2017;
Tabrizi et al. 2019; Slusarenko da Silva et al. 2019b).
Before considering treatment options, it needs to be stated
that overall, the evidence for or against any method is weak.
This is because of the wide variability or heterogeneity
between studies and a complete lack of any randomised
controlled trials. In a Cochrane systematic review, where
the primary inclusion criterion was randomised controlled
trials, no studies were identified (Sharif et al. 2015), and the
authors had to conclude that they were unable to assess
the effectiveness of any interventions for the treatment
of  the odontogenic keratocyst. Subsequent reviews have
also failed to identify any randomised trials and all authors
have highlighted the need for properly controlled prospec-
tive studies. Nevertheless, systematic reviews have
attempted to assimilate the evidence from case series and
retrospective cohort studies, and some have attempted
meta-­analyses. Overall, however, they have shown great
variability between studies and most comparisons of treat-
ment methods have been inconclusive. The major causes of
heterogeneity have included small numbers of subjects;
inadequate follow-­up period; poor definition of recurrence;
inclusion of orthokeratinised ‘variants’; lack of histological
verification; poor definition of treatment methods; and no
controls for clinicopathological factors such as site or size of
the lesions, involvement of teeth, or association with
NBCCS. For these reasons, a number of the reviews
included very few studies (Kaczmarzyk et al. 2012; Sharif
et al. 2015; Al-­Moraissi et al. 2016b; Dias et al. 2016) or were
unable to reach any conclusions (Antonoglou et  al.  2014;
Diaz-­Belenguer et  al.  2016). Despite this, a number of
authors have reviewed large numbers of keratocysts and
have produced qualitative analyses that suggest differences
between treatments. These are summarised in Table 7.10.
Treatment Methods
The most common treatment is enucleation, but this has
been applied either alone or with other adjunctive meth-
ods, and in some cases is poorly defined. The treatment
methods used in the management of the odontogenic
keratocyst are briefly described.
Enucleation and Curettage
In early studies enucleation and curettage were considered
as two separate methods of surgical management (Blanas

et  al.  2000). Curettage was defined as surgical scraping
(curetting) of the cyst cavity with removal of the contents,
and usually resulted in piecemeal removal of the cyst in
multiple fragments. Enucleation was defined as removal of
the lesion by shelling out, so the cyst was removed intact.
However, the lining of the odontogenic keratocyst is thin
and friable, so true enucleation is rarely achieved.
Simple cyst enucleation without curettage is no longer
advocated, and enucleation and curettage should be
regarded as components of the same method and are often
used synonymously. The cyst is enucleated, intact or piece-
meal, and the underlying bone is curetted. Some authors
regard curettage as an adjunctive method to remove super-
ficial bone in the exposed cavity, with the aim of ensuring
removal of residual lining or any satellite cysts or epithelial
islands. In this respect curettage has occasionally been
used as meaning peripheral ostectomy (see ‘Adjunctive
Methods’).
Marsupialisation and Decompression
These two terms are often used synonymously, since the
objective of both methods is to ‘decompress’ the cyst by
exposing the lumen and releasing the intracystic pressure.
However, the procedures are quite different. Marsupiali­
sation involves removing a wide area of superficial cyst
wall, including overlying bone, and suturing the cyst wall
to the adjacent mucosa. This creates a pouch exposed to the
oral cavity that is left open, allowing the cyst to reduce in
size as the cavity heals. The pouch may be left open for up
to 24 months and must be cleansed by the patient on a reg-
ular basis. Sometimes the lesion resolves with marsupiali-
sation alone, but often the residual cyst lining is enucleated
after the lesion has reduced in size. Marsupialisation is
becoming increasingly used and is particularly useful for
larger lesions, where reduction in the size of the cyst allows
a more conservative enucleation with less risk to vital
structures.
Decompression is similar to marsupialisation in that the
objective is to relieve the intracystic pressure, but in this
case the cyst lumen is exposed through a small hole and
kept patent with a tube or gauze. Decompression is always
followed by enucleation after an appropriate period.
Resection
The term resection is used in the conventional sense to
mean surgical removal of the whole lesion with a surround
of up to 1 cm of adjacent normal bone. Resection may be
segmental, whereby a whole segment of the jaw (usually
the mandible) containing the cyst is removed, or marginal,
where a rim of bone is removed with the cyst, but the lower
or posterior border of the mandible is left intact. In one of
the largest studies, Fidele et al. (2019) reported that 6.19%
Treatment and Recurrence of Odontogenic Keratocyst  137
(n = 35) of their patients over a 12-­year period were treated
with resections. All cases were in the mandible and the
majority (77%) involved the molar–ramus area. Most
(88.6%) were treated with segmental resection. Only one
case recurred. The authors acknowledged that resections
are rarely indicated, but suggested a management protocol
whereby a resection should be considered for large lesions
with evidence of cortical perforations or extension into
adjacent tissues.
Adjunctive Methods
A number of additional methods have been used to accom-
pany the primary treatment with the aim of ensuring com-
plete removal of the cyst along with any satellite cysts or
epithelial islands. Adjunctive methods are used in combi-
nation with enucleation. The most commonly used adjunc-
tive methods are the application of Carnoy’s solution,
cryotherapy, peripheral ostectomy, and excision of the
overlying mucosa.
Carnoy’s solution is a tissue fixative that can be applied to
the cyst cavity to ‘fix’ or render non-­viable any residual cyst
lining or islands. The solution is made up of alcohol, glacial
acetic acid, ferric chloride, and chloroform. In recent years,
however, there has been a ban on the use of chloroform in
some countries (primarily in the USA) and some surgeons
have used Carnoy’s without chloroform, but the compara-
tive effectiveness of each variant is not known (Ecker
et  al.  2016). Carnoy’s solution can be applied to the cyst
lining before it is enucleated, but most often the solution is
applied to the bone cavity after the cyst has been enucle-
ated (Stoelinga 2001, 2005). The solution is applied for up
to 15 minutes and may penetrate about 1.5 mm into the
bone. Care is needed, because Carnoy’s solution will also
damage normal tissues and it should not be applied to
exposed tooth roots or nerves, or when there is cortical per-
foration or involvement of the maxillary sinus.
Cryotherapy serves a similar function to Carnoy’s solution,
but uses a liquid nitrogen cryoprobe to freeze the bone cavity
with the purpose of killing any residual lining or epithelial
islands. Usually the cavity is frozen two or three times for one
minute each. Schmidt and Pogrel (2001) used a combination
of enucleation and liquid nitrogen cryotherapy, and found
that only 3 of 26 (11.5%) cysts recurred over a 10-­year period.
Peripheral ostectomy is used after enucleation to remove
a margin of bone at the periphery of the cyst. The purpose
is to remove between 1 and 2 mm of bone with the aim of
eliminating any residual lining or islands. Ostectomy may
be carried out by firm sharp scraping or curettage of the
bone cavity, but more often is done using a round bone bur.
Sometimes this has been facilitated by dying the surface of
the bone cavity (for example with toluidine blue) and
removing the dye to ensure complete surgical cleansing.
138 Odontogenic Keratocyst
Excision of the overlying mucosa has been championed by
Stoelinga (2001,  2005) on the basis that the superficial
aspect of the cyst wall, in continuity with the overlying
mucosa, is the site of most of the microcysts and epithelial
islands. The process involves removal of the overlying
mucosa in continuity with the enucleated cyst. In the pos-
terior regions this means removal of the mucosa in the ret-
romolar region just posterior to the last standing molar, or
removal of the mucosa of the maxillary tuberosity. If a cyst
is being marsupialised or decompressed, then access to the
cyst lumen should involve removal of the appropriate area
of mucosa.
Evaluation of Treatment Methods
Table 7.10 summarises five of the larger systematic reviews
that have evaluated the most common treatments for the
odontogenic keratocyst. As already mentioned, it is impor-
tant to note that none of these reviews has been able to
identify any randomised controlled trials and that hetero-
geneity across the studies means that quantitative analyses
are difficult, with very few overall significant differences.
Despite this, it can be seen that the most common treat-
ment is enucleation and that in all analyses this results in a
recurrence rate of between about 20 and 30%, which is
similar to or higher than the overall recurrence rate for all
treatments of about 20%. A further consistent finding is
that enucleation followed by the application of Carnoy’s
solution shows the lowest recurrence rates, from as low as
1.6% to 11.5%. In most studies, marsupialisation alone has
a similar recurrence rate to enucleation, but if this is fol-
lowed by cystectomy (enucleation of the cyst) then the rate
drops to about 15%. As would be expected, resection of the
lesion is associated with a very low recurrence rate.
These reviews also suggest that marsupialisation before
enucleation may have a better outcome than enucleation
alone. Slusarenko da Silva et  al. (2019b) considered this
issue specifically and reviewed six studies that had reported
202 keratocysts. The recurrence rate for cysts that had been
enucleated was 28.9% (n  =  135), compared to 16.4%
(n  =  67) when enucleation was preceded by up to
23.5 months of marsupialisation. A meta-­analysis, how-
ever, showed that although this difference was consistent
across all studies, it was not significant. In a similar study,
Tabrizi et  al. (2019) reviewed 192  keratocysts treated by
marsupialisation alone (n  =  118) or by marsupialisation
followed by cystectomy (n = 64) and found recurrences of
27.1% and 10.9%, respectively. In a study by Zhao et  al.
(2002), 255 patients were treated by enucleation (n = 163),
enucleation with Carnoy’s solution (n = 29), marsupialisation
followed by enucleation (n = 11), or resection (n = 52). The
recurrence rates were 17.8%, 6.7%, 0%, and 0%, respectively.
Another study examined the effectiveness of marsupialisa-
tion alone (Zecha et  al.  2010). These authors treated
68 keratocysts, 58 with enucleation alone and 10 with mar-
supialisation alone, with no further cystectomy. The recur-
rence rates were 20.7% and 40%, respectively.
These data support the findings summarised in
Table 7.10, and suggest that marsupialisation alone is not
an effective treatment and should be followed by enuclea-
tion of the cyst lining with or without application of
Carnoy’s solution or cryotherapy.
Al-­Moraissi et al. (2016b) undertook a systematic review
to determine the effectiveness of excision of the overlying
mucosa. They identified two papers (Voorsmit et al. 1981;
Stoelinga 2001), which had reported 90 keratocysts treated
by enucleation alone and 82 treated by enucleation with
excision of the overlying mucosa. The recurrence rates in
the two groups were 14.4% and 4.8%, respectively, suggest-
ing that removing the mucosa reduced recurrence.
However, close examination of the data shows that 78
(95%) of the cysts in the group that had mucosa excised
were also treated with Carnoy’s solution, compared with
only 5 (5.6%) in the enucleation-­only group. It seems there-
fore that the treatment benefit was also due to the use of
Carnoy’s solution and the authors concluded that there is
no evidence to support the beneficial effect of removing the
overlying mucosa. They did however recommend that exci-
sion of the mucosa should be performed, since it is easy to
do and because there is good evidence that epithelial
islands may reside in the mucosa overlying the cyst
(Stoelinga 2001, 2005).
Summary and Conclusions
The accumulated evidence from studies of different treat-
ments shows that resection of the odontogenic keratocyst
is the most effective for the avoidance of recurrence.
However, there is a general consensus in the literature that,
in most cases, resection is an unnecessarily aggressive
treatment for a benign cystic lesion. The most effective
treatment therefore appears to be enucleation with or with-
out peripheral ostectomy, followed by treatment with
Carnoy’s solution. This may result in a recurrence rate of
less than 2% (Table 7.10).
Stoelinga (2001, 2005) proposed a treatment strategy for
the odontogenic keratocyst and Chapelle et  al. (2004)
developed these ideas into decision trees for diagnosis and
treatment of cystic lesions of the jaws. They suggested that
any unilocular cystic lesion in the mandible or maxilla,
except for those in the mandibular third molar or ramus
region, should be enucleated and submitted for histological
examination. If a keratocyst is subsequently diagnosed, a
‘wait and see’ policy, with strict follow-­up, can be applied,
since any recurrences at these sites are easy to treat.

Unilocular lesions that are not dentigerous, in the man-
dibular third molar region or in the ascending ramus, are
likely to be keratocysts and should be treated with careful
enucleation, including excision of the overlying mucosa,
followed by application of Carnoy’s solution or cryotherapy.
If histological examination confirms a keratocyst, then
careful follow-­up is indicated. If the lesion proves to be a
solid ameloblastoma, then further surgery may be indicated.
Multilocular lesions are more difficult to manage and
because of the potential for a wider differential diagnosis,
an incisional or aspiration biopsy is always indicated. If an
odontogenic keratocyst is diagnosed, the cyst should be
enucleated with excision of the overlying mucosa and
application of Carnoy’s solution or cryotherapy.
Although marsupialisation has become a more com-
monly used treatment, the recurrence rates are variable
and there is little objective evidence to support its effective-
ness. Marsupialisation may be particularly useful for the
management of larger lesions, when shrinkage may enable
subsequent enucleation with less risk to vital structures.
Marsupialisation followed by enucleation may have recur-
rence rates similar to enucleation with Carnoy’s solution
Treatment and Recurrence of Odontogenic Keratocyst  139
(Table  7.10; Zhao et  al.  2002; Zecha et  al.  2010; Tabrizi
et al. 2019; Slusarenko da Silva et al. 2019b).
A further consideration is the management of involved
teeth. A number of studies discussed previously
(Chirapathomsakul et  al.  2006; Cunha et  al.  2016; Fidele
et al. 2019) have shown that preservation of involved teeth
is associated with a risk of recurrence, suggesting that teeth
should be removed. However, this is not straightforward,
since the diagnosis of an unsuspected odontogenic kerato-
cyst will not be made until after the lesion has been enucle-
ated. Thus, a second operation for removal of the teeth may
not be justified and, as discussed above, it has been sug-
gested that small lesions, even if thought to be a keratocyst,
can be treated conservatively with a ‘wait and see’ policy,
with removal of recurrences as they arise (Stoelinga
2001, 2005; Chapelle et al. 2004). This appears to suggest a
policy of ‘managed recurrence’. Pogrel (2003a) also noted
this approach in his historical review and quoted a surgeon
as suggesting that repeated removal of recurrences was
‘part of the normal management of jaw cysts’. Such an
approach may in part explain the higher rates of recur-
rence in the older literature.
140

Lateral Periodontal Cyst and Botryoid Odontogenic Cyst

CHAPTER MENU
Lateral Periodontal Cyst, 141
●● Clinical Features,  141
–– Frequency, 141
–– Age, 141
–– Sex, 141
–– Site, 142
–– Clinical Presentation,  142
●● Radiological Features,  142
–– Radiological Differential Diagnosis,  143
●● ­Pathogenesis,  144
–– Phase of Initiation and Source of Epithelium,  144
–– Reduced Enamel Epithelium,  144
–– Cell Rests of Malassez,  144
–– Cell Rests of Dental Lamina,  145
–– Phases of Cyst Formation and Growth and Enlargement,  146
●● ­Histopathology,  146
●● Treatment, 150
Botryoid Odontogenic Cyst, 150
●● Clinical Features,  150
–– Frequency, 150
–– Age, 150
–– Site, 151
–– Clinical Presentation,  151
●● Radiological Features,  151
●● Recurrence of the Botryoid Odontogenic Cyst,  152
●● Pathogenesis, 152
●● Histopathology, 152
●● Differential Diagnosis,  154
●● Treatment, 154

There has been a great deal of confusion about the relation-
ship between the gingival cyst of adults, lateral periodontal
cyst, and botryoid odontogenic cyst, and much of the early
literature described them together as variants of the same
lesion. This appears to have arisen because they all have a
predilection for occurrence in the canine and premolar
region of the mandible and maxilla, and the pathogenesis,
particularly with regard to the cells of origin, is similar
(Browne 1991b). The confusion is further complicated by
the fact that many early papers used ‘lateral periodontal’ in
a generic sense and included any cyst that may have
arisen adjacent to a tooth as a ‘lateral periodontal cyst’
(Fantasia 1979; Eliasson et al. 1989). Thus, some cysts in
the lateral periodontal position are really odontogenic
keratocysts, while others may be lateral radicular cysts or
inflammatory collateral cysts.
The relationship between the gingival cyst, lateral perio-
dontal cyst, and botryoid odontogenic cyst was discussed
by Wysocki et  al. in  1980, and their observations and
thoughtful discussion have not been bettered in the

Shear’s Cysts of the Oral and Maxillofacial Regions, Fifth Edition. Paul M. Speight.
© 2022 John Wiley & Sons Ltd. Published 2022 by John Wiley & Sons Ltd.

intervening four decades. They postulated, on the basis of
histological similarities, that they have a common his-
togenesis but show distinct clinicopathological differences.
They regarded the lateral periodontal cyst and gingival cyst
of adults as intraosseous and extraosseous variants of the
same lesion. Others agree with this interpretation, and also
emphasise the distinct differences in clinical presentation
and management (Shear and Pindborg  1975; Altini and
Shear  1992; Siponen et  al.  2011; de Andrade et  al.  2012;
Chrcanovic and Gomez 2019a).
The botryoid odontogenic cyst is regarded as a variant
of the lateral periodontal cyst, with a similar pathogene-
sis but with distinctive, and important, differences in
clinical and pathological features (Wysocki et  al.  1980;
Altini and Shear  1992; Chrcanovic and Gomez  2019b;
Vargas and White 2022).
In this chapter, we will discuss the lateral periodontal
cyst and botryoid odontogenic cyst as related lesions, but
with distinctive clinicopathological features. Gingival cysts
of adults and infants, which have similar histogenesis and
presentations, will be considered together in Chapter 9.
­Lateral Periodontal Cyst
The lateral periodontal cyst is defined as a developmental
odontogenic cyst that is located at the lateral aspect of a
tooth or between the roots of erupted teeth (Vargas and
White 2022). The cyst has a distinctive histology and other
cysts that may arise in a lateral periodontal position,
including inflammatory cysts and odontogenic keratocyst,
must be excluded (Shear and Pindborg 1975; Browne 1991b).
Clinical Features
Only a small number of case series have been published
(Wysocki et  al.  1980; Cohen et  al.  1984; Rasmusson
et al. 1991; Carter et al. 1996; Jones et al. 2006) and these
Table 8.1  Age, sex, and site distribution from selected series of lateral periodontal cysts and from the systematic review of
Based on Chrcanovic and Gomez (2019b).
References n Mean age
Wysocki et al. (1980) 39 50.0
Cohen et al. (1984) 37 54.0
Rasmusson et al. (1991) 31 55.0
Carter et al. (1996) 25 49.4
Jones et al. (2006) 28 48.2
Chrcanovic and Gomez (2019b) 213 46.8
NR, not reported.
­Lateral Periodontal Cys  141
are summarised in Table 8.1. Most of the publications on
the subject have been short case reports. Siponen et  al.
(2011) and de Andrade et al. (2012) reviewed the literature
and recorded about 270 cases up to 2012. Chrcanovic and
Gomez (2019b) have undertaken a systematic review that
included reports of 213 lateral periodontal cysts.
Frequency
Lateral periodontal cysts are rare and represent less than
1% of all odontogenic cysts. In Shear’s series from the
University of the Witwatersrand, only 24 lateral periodon-
tal cysts were encountered over a 46-­year period, represent-
ing 0.7% of the total (Table 1.1). In the Sheffield series of
7121 odontogenic cysts, only 28 (0.4%) lateral periodontal
cysts were diagnosed (Table 1.2; Jones et al., 2006). Of the
studies shown in Table 1.3, 11 included data for lateral per-
iodontal cysts, with a range from 0.1% (Soluk Tekkeşin
et al. 2012b) to 1.5% (Daley et al. 1994). Daley et al. (1994)
is the only study to record a frequency of greater than 1%.
Age
Lateral periodontal cysts affect adults, with a peak in the
fifth or sixth decades and an overall mean age of about
47 years (Table 8.1). They are almost unknown in children,
with studies showing an age range from 19 to 85 years
(Wysocki et  al.  1980; Cohen et  al.  1984; Rasmusson
et al. 1991; Carter et al. 1996; Jones et al. 2006). A system-
atic review of 213 cases recorded a mean age of 46.8 years
(range 12–81 years), with the greatest number of cases
(40%) in the sixth decade (Chrcanovic and Gomez 2019b).
Figure 8.1 illustrates the age distribution of 114 patients,
including the 24 from Shear’s series pooled with those of
Cohen et  al. (1984), Rasmusson et  al. (1991), and Carter
et al. (1996).
Sex
Wysocki et al. (1980) and Rasmusson et al. (1991) observed
that about 70% of cases arose in males, but this was
Peak decade Male (%) Mandible (%)
6th 70.2 66.6
5th 48.6 78.3
6th 68.0 88.0
5th 52.2 87.5
6th 55.5 NR
6th 52.6 69.8
142 Lateral Periodontal Cyst and Botryoid Odontogenic Cyst
45
41
40
35
30
25
No. of cases
25
20
15
10
6 7
4
5 2
0
0
0-9 10-19 20-29 30-39 40-49 50-59
Age
unusual, since most other studies have reported more
equal sex distribution (Table 8.1; Cohen et al. 1984; Carter
et  al.  1996; Jones et  al.  2006). In their systematic review,
Chrcanovic and Gomez (2019b) found a male to female
ratio of 1.1 (52.6% males : 47.4% females). Some studies
(Carter et al. 1996) have noted that the cysts may occur at a
significantly younger age in females (mean 40.5 years) than
in males (mean 58.4 years), but pooled data from 197 stud-
ies where these data were available showed no difference
in age between the sexes (Chrcanovic and Gomez 2019b).
Site
Overall, 70% of lateral periodontal cysts are found in the
mandible (Chrcanovic and Gomez 2019b), although there
is some variation between the larger series (Table 8.1). All
reported cases have been found anterior to the first molars.
There are no reported cases arising in association with
molars, except for a small number that are sited distal to
the root of a second premolar (Cohen et al. 1984; Rasmusson
et al. 1991; Carter et al. 1996).
The most frequent location of a lateral periodontal cyst is
the mandibular canine/premolar area, followed by the
anterior region of the maxilla. Wysocki et al. (1980) found
that 26 of their 39 cases (67%) occurred in the premolar–
canine–incisor region of the mandible and 7 of these were
located between the first and second premolars. In the
studies of Cohen et al. (1984) and Rasmusson et al. (1991),
all the mandibular cases were in the canine/premolar area.
Carter et al. (1996) found that 21 of 24 cases occurred in the
mandible and 18 of these were in the canine/premolar
Figure 8.1  Age distribution of 114
patients with developmental lateral
periodontal cysts. Source: Based on Cohen
et al. (1984), Rasmusson et al. (1991), and
Carter et al. (1996).
28
1
60-69 70-79 80-89
region. The other three were associated with lateral inci-
sors. Cohen et al. (1984) recorded 3 cases associated with
mandibular incisors, 1 of which was between the central
incisors.
Clinical Presentation
Lateral periodontal cysts are usually symptomless and are
typically discovered fortuitously during routine radiologi-
cal examination of the teeth. Only 12% show symptoms,
although up to 50% may be associated with bone expansion
or erosion of the cortical plate (Chrcanovic and
Gomez 2019b). Lesions always occur on the buccal or labial
aspect of the alveolus and may present as a gingival swell-
ing, which if the bone is perforated may be blueish and
fluctuant. Swelling is never a prominent feature, however,
since the cyst rarely exceeds 10 mm in diameter. The associ-
ated teeth will be vital, unless affected by another unre-
lated pathology.
Radiological Features
The clinical and radiological features are typical and virtu-
ally diagnostic (Box 8.1). The cysts are found on the lateral
aspect of a tooth, or between the roots of two teeth, as a
round or oval, well-­circumscribed radiolucent area, usually
with a corticated, sclerotic margin (Figure 8.2). If the teeth
are displaced, the lesion may become tear-­or pear-­shaped.
The cysts lay somewhere between the apex and the cervical
margin of the tooth, but usually in the middle third. If a
large radiolucency fills the space between divergent teeth,

Box 8.1  Lateral Periodontal Cyst: Clinical
and Radiological Features
●● They are rare – less than 1% of odontogenic cysts
●● Only seen in adults, mean age about 50 years. Peak in
the sixth decade
●● Slightly more common in males
●● 70% are found in the mandible. Most common in the
canine/premolar area
●● Always arise anterior to the second premolars
●● Round,well-­defined radiolucency with corticated margin
●● Very rarely greater than 10 mm in diameter
●● The periodontal space is normal and the lamina dura
is intact
Figure 8.2  Radiograph of a lateral periodontal cyst lying
between the mandibular premolar teeth. The margins are well
demarcated and corticated, indicative of slow enlargement. Note
that the periodontal space is normal, the lamina dura is intact,
and the cyst is superimposed over the root of the tooth (arrow).
Source: Courtesy of the late Professor J.J. Pindborg.
then an alternative diagnosis should be considered. In this
respect the most important lesion to consider is a botryoid
odontogenic cyst, but odontogenic keratocysts may also
present at this site. The old term ‘globulomaxillary cyst’
described an inverted pear-­shaped lesion that filled the
space between a divergent maxillary canine and second
incisor. If small they may be a lateral periodontal cyst, but
many larger lesions are odontogenic keratocysts. The term
‘globulomaxillary’ should be used as a descriptive term
only, or not at all (Dammer et al. 2014).
Lateral periodontal cysts are rarely more than 10 mm in
diameter. In the series reported by Rasmusson et al. (1991)
and Carter et  al. (1996), only four and two cysts, respec-
tively (about 10%) measured more than 10 mm on radio-
graphs. In four cases Rasmusson et al. (1991) were able to
compare serial radiographs over a period of up to 14 years
and estimated that the mean growth rate was 0.7 mm per
­Lateral Periodontal Cys  143
year. In their systematic review, Chrcanovic and Gomez
(2019b) found 144 cases where the size had been measured
and recorded a mean diameter of 10 mm (standard devia-
tion [SD] ±6 mm; range 2–30 mm).
As the cysts grow, they always expand towards the buccal
or labial (facial) aspect of the jaw, and the corticated mar-
gin becomes superimposed over the adjacent teeth
(Figure  8.2). A review of radiographs published in the
many case reports shows that, almost without exception,
the periodontal space is normal, and the lamina dura sur-
rounding the tooth is intact (Figure 8.2, arrow). This is an
important sign that serves to differentiate this developmen-
tal cyst from a lateral radicular cyst that may have arisen at
the opening of a lateral root canal. The teeth may be dis-
placed in up to 40% of cases, but resorption of the roots is
rarely seen (Chrcanovic and Gomez 2019b).
Occasionally lateral periodontal cysts may be multifocal.
Siponen et al. (2011) described four patients with multiple
lesions. In two cases up to four separate lesions were seen
at different sites and all showed histological features of a
lateral periodontal cyst. A further two patients showed two
cysts at the same site. In the first patient, one cyst showed
a well-­demarcated round radiolucency, while the second
was more apically placed and was multilocular. In the sec-
ond case the two cysts abutted onto each other. Although
the lesions showed features of lateral periodontal cysts, the
authors speculated that fusion of multiple cysts may give
rise to a multicystic botryoid odontogenic cyst. Multiple
cysts are rare, however, and in their review Siponen et al.
(2011) could find only three previous reports.
Radiological Differential Diagnosis
A final diagnosis can only be confirmed on histological
examination, but the radiographic features described above
are almost diagnostic. However, caution is needed, because
a number of other lesions may arise at the lateral aspect of
a tooth or between the tooth roots. The most commonly
encountered are a lateral radicular cyst, odontogenic
keratocyst, botryoid odontogenic cyst, and glandular odon-
togenic cyst. Fantasia (1979) examined 46 cysts that had
arisen at the lateral aspect of a tooth and found that only 13
(28.3%) met the histological criteria for lateral periodontal
cyst. The remainder were laterally placed radicular cysts
(20 cases, 43.5%) and 8 (17.4%) odontogenic keratocysts.
Five cysts could not be categorised. In the series of 20 cases
reported by Altini and Shear (1992), a reappraisal shows
that 8 were probably botryoid odontogenic cysts and 3 were
glandular odontogenic cysts.
The key to diagnosis is attention to detail on the radio-
graphs. The lateral periodontal cyst is almost always round,
less than 10 mm in diameter, and does not disrupt the lam-
ina dura. Radicular cysts arise from rest cells of Malassez
144 Lateral Periodontal Cyst and Botryoid Odontogenic Cyst
within the periodontal ligament, and therefore the perio-
dontal space is expanded and the corticated margin of the
cyst is continuous with the lamina dura (see Chapter  3).
Botryoid odontogenic cysts, odontogenic keratocysts, and
glandular odontogenic cysts are rarely round in shape and
may be multilocular or lobulated. They also grow and
exceed 10 mm in diameter. Glandular odontogenic cysts
often affect the anterior mandible, but usually reach a large
size and extend across the midline. Any cyst found lateral to
a tooth, which is greater than 10 mm in diameter or is mul-
tilocular, is almost certainly not a lateral periodontal cyst.
Pathogenesis
Three elements are needed for a cyst to develop: a source of
epithelium, a stimulus for proliferation, and a mechanism
for growth and bone resorption. While these are well
described for radicular cysts (see Chapter 3), the phases of
the pathogenesis of developmental cysts are poorly under-
stood. Although we can speculate on the source of epithe-
lium, the initiating factors or the stimulus for proliferation
are largely unknown.
It is widely accepted that the lateral periodontal cyst and
botryoid odontogenic cyst have similar histological fea-
tures and are almost certainly derived from the same
source of epithelium. In this section the pathogenesis of
these two cyst types will be considered together and we will
attempt to explain how each cyst might develop the distinc-
tive morphological features.
Phase of Initiation and Source of Epithelium
There has been considerable debate about which odonto-
genic epithelium the lateral periodontal cyst and botryoid
odontogenic cyst arise from. Proof of origin from any par-
ticular source is lacking and any hypothesis must therefore
be based on presumptive evidence. There seem to be three
possibilities: reduced enamel epithelium, cell rests of
Malassez, and remnants of dental lamina. The arguments
for and against these three possibilities have been debated
extensively in the literature and in previous editions of this
book. They will be briefly reviewed.
Reduced Enamel Epithelium
Shear and Pindborg (1975), Altini and Shear (1992), and
previous editions of this book have argued that the reduced
enamel epithelium is the most likely source of the lining of
the lateral periodontal cyst. They suggested a mechanism
whereby the follicle overlying an erupting tooth may
expand and develop into an early dentigerous cyst.
Subsequently, the cyst is displaced laterally (for example,
see Figures  5.7 and 5.10) and is then ‘left behind’ as the
tooth erupts, resulting in a cyst lying lateral to the root of
the fully erupted tooth. To explain the development of a
multicystic variant or botryoid odontogenic cyst, they pro-
pose that epithelial plaques may bud off from the cyst lin-
ing and form daughter cysts, which then expand to form a
multicystic lesion (Altini and Shear 1992).
In support of this mechanism, they argued that the lin-
ing of the lateral periodontal and botryoid odontogenic
cyst is composed for the most part of thin, non-­keratinised
epithelium that resembles reduced enamel epithelium.
They also suggested that lateral periodontal cysts tend to
occur in areas where dentigerous cysts are likely to be asso-
ciated with vertically impacted teeth such as mandibular
premolars and maxillary incisors and canines, and that epi-
thelial plaques similar to those seen in the lateral periodon-
tal cyst are occasionally found in dentigerous cysts.
This hypothesis is unsatisfactory in a number of respects.
First, if the enlarged follicle is displaced laterally as the
tooth erupts, then it will develop within the crypt of the
developing tooth and will come to lie within the lamina
dura and will expand the periodontal space. However, as
described above, the lateral periodontal cyst invariably lies
outside of the periodontal ligament, the periodontal space
is not expanded, and the lamina dura is intact. Second,
the hypothesis suggests that lateral periodontal cysts are
associated with those teeth that are also most likely to be
associated with dentigerous cysts that develop over verti-
cally impacted teeth. This is not in fact the case. Lateral
periodontal cysts are most often found in the mandibular
canine/first premolar region, which is a site rarely affected
by dentigerous (or eruption) cysts. Furthermore, such an
association cannot explain why molar teeth, in particular
mandibular third molars, are never affected by lateral peri-
odontal cysts. Finally, it is suggested that the epithelial
plaques and thickenings that are typical of the lateral peri-
odontal cyst may be seen in dentigerous cysts, and that this
implies an origin from reduced enamel epithelium. In fact,
epithelial thickening is rarely seen in dentigerous cysts and
the typical whorled or clear cell plaques of lateral perio-
dontal cysts are not a feature of the lining of dentiger-
ous cysts.
Cell Rests of Malassez
The second possibility is an origin from the cell rests of
Malassez. The rests of Malassez occur in the periodontium
and they are well positioned for a lateral periodontal cyst,
but the support for this theory of origin is scanty. In an
early paper and in the previous edition of this book, we
reported a case (Buckley et al. 1989) in which two separate
developmental odontogenic cysts were associated with an
unerupted lower third molar tooth. We suggested that
these were a lateral periodontal cyst and a dentigerous cyst,
and contended that this provided evidence that the

periodontal cyst may have an origin from the cell rests of
Malassez and not reduced enamel epithelium. This paper
has been cited a number of times as evidence for an origin
from the rest cells of Malassez. However, with the benefit
of experience and a reappraisal, we now refute this idea.
Careful review of the images in Buckley et al. (1989) shows
a laterally (mesial) placed dentigerous cyst and a second
well-­defined cyst overlying the distal root of a mesio-­
angular displaced third molar. This second cyst is superim-
posed over the middle third of the root, but the periodontal
space is normal and the lamina dura is intact. Thus, it does
not appear to have an origin within the periodontal liga-
ment from the rest cells of Malassez. The origin is most
likely to be rests of dental lamina, which are known to be
prominent at this site. Furthermore, this cyst is associated
with a third molar tooth, which is very unusual for a lateral
periodontal cyst. Review of the histology shows typical
whorled plaques, but also mucous cells, small duct-­like
structures, and superficial columnar cells that would be
very unusual for a lateral periodontal cyst, but are now
known to be typical features of a glandular odontogenic
cyst (Fowler et al. 2011; Speight and Rautava 2022).
Cell Rests of Dental Lamina
The third potential source of the epithelium is the cell
rests of the dental lamina. This hypothesis was first put
forward by Wysocki et al. (1980), who provided strong cir-
cumstantial evidence and a logical description of how
such a mechanism might work. They suggested that the
lateral periodontal cyst and gingival cyst of adults are both
derived from rests of dental lamina, and represent intraos-
seous and extraosseous variants of the same entity.
Figure 8.3  A unifying mechanism for
the formation of unicystic and multicystic
lesions. The cysts arise by cystic
degeneration in rest cells of dental
lamina (top). A unicystic lesion arises
from cyst formation in a single rest, but if
multiple rests are involved a multicystic
lesion may be formed. Multicystic lesions,
whether enclosed in a single fibrous
capsule (unilocular) or multilocular,
should be diagnosed as botryoid
odontogenic cysts (see text).
Unicystic, unilocular
Lateral periodontal cyst
­Lateral Periodontal Cys  145
The mechanism they propose is that cyst formation is
initiated by cystic degeneration in rests of dental lamina to
form a small microcyst that then develops into a unilocular
cyst. Dental lamina rests are commonly found in the alveo-
lar bone and gingival tissues (Hodson  1962) and often
show a clear cell appearance, similar to the cells seen in the
lining of lateral periodontal cysts. In their paper, Wysocki
et al. (1980) show that the walls of the lateral periodontal
cyst contain variable numbers of epithelial islands resem-
bling rests of dental lamina, a feature that has been consist-
ently described in these lesions (see “Histopathology”).
They further suggested that a unicystic lateral periodontal
cyst (or gingival cyst) arises through cystic change in a single
dental lamina rest and that a multicystic, botryoid odonto-
genic cyst develops if simultaneous changes occur in several
adjacent cell rests. As noted above, Altini and Shear (1992)
suggested that multicystic lesions arose from a budding or
‘pinching’ off of the epithelial plaques to produce mural
islands that then undergo cystic change. Others (Redman
et al. 1990; Siponen et al. 2011) have proposed that some bot-
ryoid odontogenic cysts may arise by fusion of multiple lat-
eral periodontal cysts at the same site (see discussion under
‘Radiological Features’). These alternative mechanisms for
the formation of a multicystic lesion are possible, but are still
consistent with an origin from dental lamina rests.
An origin from rest cells of the dental lamina is now con-
sidered to be the most logical and likely explanation for the
origin of these cysts (Wysocki et  al.  1980; Rasmusson
et al. 1991; Siponen et al. 2011). This would explain why the
cysts lie adjacent to teeth, but outside of the periodontal liga-
ment, and supports a unifying mechanism for the pathogen-
esis of unilocular and multilocular lesions (Figure 8.3).
Multicystic, unilocular Multicystic, multilocular
Botryoid odontogenic cyst
146 Lateral Periodontal Cyst and Botryoid Odontogenic Cyst
However, if dental lamina rests are the source of the lat-
eral periodontal cyst, this does not easily explain why they
are never found associated with third molars, where dental
lamina rests are abundant. Also, although odontogenic
keratocysts may arise at similar sites in the anterior aspects
of the jaws, they are found more frequently at the angle of
the mandible and, despite a similar origin from dental lam-
ina, they show a quite different histology and pattern of
behaviour. Genetic factors are almost certainly involved,
but Wysocki et al. (1980) also suggested that lateral perio-
dontal cysts arise in older age groups from postfunctional
cells of the dental lamina, whereas the odontogenic kerato-
cyst arises in younger individuals from dental lamina still
possessing marked growth potential.
Phases of Cyst Formation and Growth
and Enlargement
These processes are poorly understood and have not been
described for lateral periodontal cysts. There is little evi-
dence of inflammation, so the inflammatory processes
described for other cyst types, including radicular cyst and
inflamed dentigerous cyst, are not involved. However, cyst
formation may still be promoted by accumulation of cell
debris within the degenerating cell rests or microcysts,
resulting in an increased luminal osmotic pressure that
then drives cyst expansion and growth. Bone resorption
follows as a result of pressure on the surrounding tissues.
Such a process is supported by the observation that the lat-
eral periodontal cyst and gingival cyst are spherical, sug-
gesting a process where intraluminal pressure causes
centripetal growth, similar to that described for radicular
cysts (Chapter 3). Furthermore, the cysts are never large,
suggesting a limited growth potential and consistent with
the findings that osmotic pressure only plays a role in early
cyst growth, after which the osmotic gradient equalises and
intraluminal pressure reduces (Ward et  al.  2004; Kubota
et al. 2004). In other cyst types proliferation of the epithe-
lial lining may promote further growth, but that does not
seem to the case with lateral periodontal and gingival cysts.
In summary, these considerations would support the
view that the lateral periodontal cyst arises from the rest
cells of the dental lamina and that cyst growth is driven by
a high luminal osmotic pressure.
Histopathology
Lateral periodontal cysts are small, with a thin and fragile
lining. They are usually removed conservatively by enu-
cleation with or without curettage. The pathologist often
receives multiple fragments of a collapsed cyst wall.
Sectioning of a collapsed or fragmented cyst may cause a
false impression of a multicystic or multilocular lesion
microscopically. If there is doubt, multiple blocks and sec-
tions should be examined and radiographs should be
reviewed to confirm a simple unilocular lesion. If a lesion
is truly multicystic, then the correct diagnosis is probably
botryoid odontogenic cyst (see below).
On histological examination, lateral periodontal cysts
are composed of a fibrous wall lined by a thin, non-­
keratinising squamous epithelium usually two to five cell
layers thick (Figure 8.4). The epithelial cells are typically
flattened, but may be cuboidal. Quite often the wall
shows dense hyalinisation in the immediate subepithe-
lial area and we have noted that this is usually associated
with an exceptionally thin lining, only one cell thick, that
is friable and separates from the connective tissue
(Figure 8.5)
Figure 8.4  Lateral periodontal cyst is
lined by thin non-­keratinising epithelium.
Epithelial thickening can be seen (left)
and the wall often contains small islands
of epithelium (centre).

Figure 8.5  The wall of the lateral periodontal cyst may show
hyalinisation, and this is often associated with a very thin
attenuated epithelium that separates from the underlying
connective tissue.
A characteristic feature that is seen in all lateral perio-
dontal cysts and botryoid odontogenic cysts is the presence
of localised plaques or thickenings of the epithelial lining
(Figure  8.6). Sometimes only one or two plaques may be
seen, but most cysts contain multiple plaques. The plaques
show a number of different patterns (Figure 8.6). They may
be small and flattened, but others are larger and extend
into the surrounding cyst wall or produce mural bulges
that protrude into the cyst lumen. Most plaques are com-
posed of flattened or cuboidal cells that may form central
whorls (Figure 8.6a, b), but clear cell change is common.
The clear cells may be seen in up to one-­third of cases
(Wysocki et al. 1980; Altini and Shear 1992) and are found
in the thin lining as well as in the plaques (Figure 8.6c, d).
They contain abundant glycogen and are therefore positive
with periodic acid–Schiff (PAS), and are diastase labile.
Glycogen may also be seen in the superficial layers of the
squamous and cuboidal cells of the lining epithelium.
These will also be PAS positive, and can be digested with
diastase. It should be noted that mucous cells are not a fea-
ture of lateral periodontal cysts. If mucous cells are sus-
pected (PAS positive, diastase resistant), these should be
confirmed using other stains and an alternative diagnosis
should be considered, in particular the possibility of glan-
dular odontogenic cyst.
Occasionally the epithelial thickenings are markedly
prominent and may be folded and convoluted (Figure 8.6e).
The wall of the lateral periodontal cyst is composed of
loose collagenous connective tissue and is usually unin-
flamed, although occasional inflammatory cells may be
seen. The wall often contains small islands of odontogenic
epithelium resembling rests of dental lamina (Figure 8.4),
and it was this finding that was originally cited as strong
evidence for an origin from dental lamina rests (Wysocki
­Lateral Periodontal Cys  147
et al. 1980). Altini and Shear (1992) disputed this, however,
and suggested that the islands may arise by ‘pinching-­off’
of extensions of the epithelial plaques (Figure  8.7). Both
mechanisms may apply, but similar islands are seen in
other cyst types and in the alveolar mucosa, and are widely
regarded as residues of the dental lamina. Occasionally
these islands show clear cell change and/or microcystic
degeneration (see later Figure  8.9). The epithelial linings
may be tenuous and may separate from the fibrous cyst
wall, especially in areas of juxta-­epithelial hyalinised col-
lagen (Figure 8.5).
Although plaques and thickenings in the epithelial lin-
ings are a key diagnostic feature of the lateral periodontal
cyst (Box 8.2), they are not specific. They are also seen in
botryoid odontogenic cyst, gingival cyst of adults, and glan-
dular odontogenic cyst. It is not known how or why these
localised epithelial proliferations are formed. However,
they do seem to be a spontaneous process that occurs in the
development of these cysts, although similar whorls can be
seen in some odontogenic tumours. It is possible that the
thickenings represent another of the many examples of
odontogenic epithelium recapitulating stages of tooth
development under pathological conditions. In this
instance, the process seems to be similar to that which
takes place during the early stages of tooth development,
when there is thickening of the oral epithelium to form the
dental lamina.
Examination of histological material at the light micro-
scope level, and particularly study of serial sections, has
suggested a possible mode of formation of these plaques
(Shear and Pindborg  1975; Figure  8.7). The sequence
appears to be proliferation of the flat basal cells, which
produces a slight localised thickening of the epithelium
(Figure 8.7b). At this stage, the thickened epithelium con-
sists predominantly of darkly staining fusiform basal cells.
This early plaque may extend into the fibrous wall of the
cyst or bulge into the lumen (Figure 8.7c, d). The plaque
increases in size both by further basal cell proliferation
and by swelling of these epithelial cells. At this stage there
is a more pronounced bulging into the lumen and also
into the wall (Figure  8.7e). The bulbous nature of the
thickening into the wall sometimes leads to undermining
of the adjacent cyst lining. Complex convolutions of the
epithelium may be seen in the larger plaques (Figures 8.6e
and 8.7f).
Altini and Shear (1992) described the histology of 20
cases of ‘lateral periodontal cyst’. A review of their paper
now suggests that 3 of the lesions they described were actu-
ally glandular odontogenic cysts. Of the remaining 17,
however, they found that 9 were unicystic and 8 were mul-
ticystic. Six of the multicystic group comprised two or more
cystic spaces contained within a single round or ovoid
148 Lateral Periodontal Cyst and Botryoid Odontogenic Cyst

(a) (b)

(c) (d)

(e) (f)

Figure 8.6  Epithelial thickenings and plaques are seen in lateral periodontal and botryoid odontogenic cysts. These may be flattened
(a) or may produce prominent bulges into the lumen or the wall (c, d). Whorling (a, b) and clear cell change are common (c, d). In
botryoid odontogenic cysts, the plaques may be particularly prominent and may become folded (e) or may form papillary processes (f).
 ­Lateral Periodontal Cys  149

Box 8.2  Lateral Periodontal Cyst: Histopathology and Diagnostic Criteria

●● A simple cyst lined by non-­keratinised epithelium two to five cells thick
●● Localised plaques and thickenings are seen in virtually all cases
●● Clear cell change with abundant glycogen (periodic acid–Schiff/diastase positive)
●● Epithelial lining is friable and often separates from the underlying connective tissue
●● The cyst wall is loosely collagenous and is uninflamed. Areas of subepithelial hyalinisation may be seen
●● The wall contains variable numbers of epithelial islands resembling rests of dental lamina. These may show clear
cell and microcystic change.
Caution: if any of the following features are noted, consider an alternative diagnosis:
●● If the lesion is multicystic, consider a botryoid or glandular odontogenic cyst
●● If luminal columnar cells, duct-­like structures, or mucous cells are present, consider a glandular odontogenic cyst
●● If there is evidence of keratinisation, consider an odontogenic keratocyst

Figure 8.7  Diagram illustrating the possible Ep

mode of formation of epithelial plaques by
localised proliferation of cells. (a) Cyst lined by
thin epithelium. (b) Early epithelial thickening Lu
by basal cell proliferation. (c) Basal cells
continue to proliferate. Superficial cells swell by
accumulation of intracellular fluid and glycogen (a) (b)
(c, d) and the plaques protrude into the cyst
cavity and wall (d, e). The epithelial plaques can
become folded and form convolutions (f, see
also Figure 8.6e). Protrusions into the cyst wall
(c–f) may be ‘pinched off’ and develop into
daughter cysts (see text), leading to the
formation of the botryoid odontogenic cyst.
Source: Shear and Pindborg (1975).
(d)
(c)

(e) (f)

fibrous capsule, whereas two were larger, with an irregular
lobulated fibrous wall. The latter had a distinctly botryoid
appearance, consisting of several cystic spaces of varying
size, separated by fibrous tissue. From these observations,
they suggested that there were three variants of the lateral
periodontal cyst (see Figure 8.3): a unicystic variant com-
posed of a single simple cyst, a multicystic variant com-
posed of multiple simple cysts within a single fibrous
capsule, and a multicystic variant composed of multiple
irregular cysts, each separated by fibrous tissue. This third
type they believed was a botryoid odontogenic cyst, while
the first and second types were variants of lateral periodon-
tal cysts.
This proposal therefore suggested that the lateral peri-
odontal cyst may be unicystic or multicystic. However,
we do not now think this is the case. The pathology of
the botryoid odontogenic cyst is discussed in more detail
in the next section, but originally the diagnosis depended
on the gross specimen showing a multilocular (botryoid)
morphology, as well as being multicystic on histology
150 Lateral Periodontal Cyst and Botryoid Odontogenic Cyst
(Weathers and Waldron  1973). A botryoid morphology
may be seen during surgery, or at macroscopic examina-
tion if the cyst has been removed intact. In practice this
rarely occurs and the diagnosing pathologist can rarely
verify a macroscopic botryoid pattern. Furthermore, it is
reported that less than half of botryoid odontogenic
cysts are multilocular on radiographs (Chrcanovic and
Gomez 2019b).
Therefore, we believe that the diagnostic criteria (see
Box  8.2) for lateral periodontal cyst should include the
finding of a single cyst as described above within a thin
fibrous capsule, although the wall may contain islands of
epithelium. A lesion that is multicystic, whether within a
single capsule (unilocular) or separated by fibrous tissue
(multilocular), should be diagnosed as a botryoid odonto-
genic cyst (Figure 8.3; see next section; Siponen et al. 2011).
Treatment
The lateral periodontal cyst is treated by surgical enuclea-
tion with or without curettage of the underlying bone, but
care must be taken not to damage the associated tooth.
Occasional recurrences have been reported, but this is
unusual. In their systematic review, Chrcanovic and
Gomez (2019b) found only two reports of a cyst recur-
ring (2.4%).
­Botryoid Odontogenic Cyst
The botryoid odontogenic cyst is regarded as being a
multicystic variant of lateral periodontal cyst (Vargas
and White 2022). This is because they present at a similar
site and the epithelial linings show the same histological
features. However, the botryoid odontogenic cyst has
distinctive radiological, morphological, and behavioural
characteristics that justify it being regarded as a sepa-
rate entity.
It was first described by Weathers and Waldron (1973),
who reported two examples of a cystic lesion of the jaws
that had a multilocular radiological appearance and, on
examination of the gross specimen, had the appearance
of a small bunch of grapes. They therefore suggested the
term botryoid, meaning ‘like a bunch of grapes’, and
derived from the ancient Greek word for grape: botrus
(βοτρυς).
Subsequently there has been confusion over the precise
definition, with some demanding that the lesion must be
grossly ‘grape-­like’ or multiloculated, while others have
used the term for any multicystic lesion with an epithelial
lining similar to the lateral periodontal cyst. Although
multilocularity is characteristic, it has been shown that
some unilocular lesions are multicystic and, conversely,
that some radiologically and grossly multilocular lesions
are unicystic on histological examination (Greer and
Johnson  1988; Siponen et  al.  2011). In their systematic
review, Chrcanovic and Gomez (2019b) found that only
36.5% of lesions diagnosed as botryoid odontogenic cyst
were found to be multilocular. Of the rest, 42.7% were uni-
locular and in 15.6% the locularity was unknown. This sug-
gests that many pathologists will diagnose a lesion as
botryoid based on a multicystic histology regardless of
locularity.
We would support the view that the term botryoid odon-
togenic cyst should be used for a cyst in a lateral periodontal
position that is multicystic on gross or microscopic exami-
nation (Siponen et  al.  2011; Vargas and White  2022).
Although a variant of lateral periodontal cyst, it is impor-
tant that botryoid odontogenic cyst is used as a diagnostic
term because the cyst has a greater potential for growth
and recurrence.
Clinical Features
Frequency
Botryoid odontogenic cyst is extremely rare. In most series
of odontogenic cysts, it has been included as a variant of
lateral periodontal cyst and therefore the exact frequency is
uncertain. In the series reported in Table 1.3 (Chapter 1),
only two included data for botryoid odontogenic cyst and
these were 0.07% (Grossmann et al. 2007) and 0.03% (Soluk
Tekkeşin et al. 2012b). In the larger series of lateral perio-
dontal cysts shown in Table  8.1, most included botryoid
odontogenic cysts, but the numbers reported were only 3 of
39 (Wysocki et al. 1980), 6 of 27 (Cohen et al. 1984), 6 of 32
(Rasmusson et al. 1991), and 2 of 25 (Carter et al. 1996).
This represents only about 10–20% of lateral periodontal
cysts and suggests an overall frequency of less than 0.1% of
all odontogenic cysts.
In their systematic review, Chrcanovic and Gomez (2019b)
found only 96 reported cases of botryoid odontogenic cyst
and Cunha et  al. (2019) found 98. However, both these
reviews included a number of cases that have subsequently
been shown to be glandular odontogenic cysts.
Age
The literature review published by Ramer and Valauri (2005)
identified 66 cases of botryoid odontogenic cyst, including
the large series of 33 cases of Gurol et al. (1995). The age
distribution of these 66 patients was very similar to lateral
periodontal cyst and is shown in Figure  8.8. The lesion
occurs in adults and has a peak incidence in the sixth and
seventh decades. In the two largest reviews, Chrcanovic

Figure 8.8  Age distribution of 66 patients with 20
botryoid odontogenic cysts. Source: Data from
Ramer and Valauri (2005). 18
16
14
12
No. of cases
10
8 7
6 5
4
2
0 0
0
0-9
and  Gomez (2019b) and Cunha et  al. (2019) both found a
mean age of 54.0 years (ranges 15–85 and 20–85, respec-
tively) and a peak in the sixth and seventh decades.
Site
About 85% of botryoid odontogenic cysts are found in the
mandible (Ramer and Valauri  2005; Chrcanovic and
Gomez 2019b; Cunha et al. 2019). Of the 10 lesions docu-
mented by Greer and Johnson (1988) and by Santos et al.
(2011b), 8 involved the mandible, predominantly the ante-
rior region. The distribution appears to be very similar to
the lateral periodontal cyst, with most lesions arising in the
mandibular canine/premolar area (Gurol et  al.  1995;
Méndez et al. 2007). Occasional cases have been reported
in the midline (Kaugars 1986). The lesion very rarely occurs
posterior to the premolar teeth. In the largest series of 33
cases, only 1 was found to be associated with a molar tooth
(Gurol et al. 1995). Santos et al. (2011b) reported 10 cases,
2 of which were in the mandibular molar region and 1 in
the maxillary molar region. Chrcanovic and Gomez (2019b)
reported the precise location of 92  lesions and recorded
only 6 (6.5%) in the molar regions, but also 6 that were
extensive and involved an entire mandibular quadrant,
including one that extended from the mandibular premo-
lars to the ramus, and enveloped an unerupted third molar
(Vidaković et al. 2016).
Clinical Presentation
The literature suggests that about 55% of patients present
with a swelling or expansion of the bone (Gurol et al. 1995;
Ramer and Valauri 2005; Chrcanovic and Gomez 2019b),
but other symptoms are rare.
­Botryoid Odontogenic Cys  151
18 18
10
6
2
0
10-19 20-29 30-39 40-49 50-59 60-69 70-79 80-89 90-99
Age
Ramer and Valauri (2005) included the data of Gurol
et al. and identified 59 cases with information on clinical
presentation. Of these cases, 30 (50.1%) had evidence of
swelling, but only 7 (11.9%) complained of other symp-
toms, including 3 with pain, 2 with paraesthesia and 2 with
a discharge. In a more recent systematic review, Chrcanovic
and Gomez (2019b) reviewed 96 cases of botryoid odonto-
genic cyst and in those where data were available, 56.9%
showed swelling or bone expansion, but only 15 patients
(15.6%) recorded other symptoms.
Radiological Features
The botryoid odontogenic cyst shows radiological features
similar to lateral periodontal cyst. It is located at the lateral
aspect of a tooth root or between the roots of two teeth. The
lesion is usually well demarcated with a corticated outline
and the periodontal space and lamina dura are typically
intact. Botryoid odontogenic cysts may show two charac-
teristic features not seen in lateral periodontal cysts: they
may be multilocular and larger.
Although multilocularity is thought of as typical, only
46.1% were found to be multilocular (Chrcanovic and
Gomez  2019b). All 3  lesions reported by Kaugars (1986)
showed multilocular radiolucencies, but in the series of
Greer and Johnson (1988), 8 of 10  were unilocular, and
Gurol et al. (1995) found that 15 of 16 cysts with informa-
tion available were unilocular. In their review, Méndez
et al. (2007) found 45 cases with information on the radio-
graphic appearance and reported that only 40% were mul-
tilocular. Cunha et al. (2019) identified 78 cases where data
were available and reported that 52.6% were multilocular.
152 Lateral Periodontal Cyst and Botryoid Odontogenic Cyst
Whereas a lateral periodontal cyst rarely exceeds 10 mm
in diameter, the botryoid cyst may grow to larger sizes. In
Greer and Johnson’s (1988) series the size ranged from 4 to
45 mm, and Altini and Shear (1992) reported that one of
their botryoid cases measured 50 mm in diameter. Santos
et al. (2011b) reported 10 cases, all of which were greater
then 10 mm in size, with a range of 15–80 mm. In their sys-
tematic review, Chrcanovic and Gomez (2019b) found 49
cases where the size had been measured and recorded a
mean diameter of 28 mm (SD ±28 mm. range 3–150 mm).
It has been reported that multilocular lesions may be
larger than unilocular lesions, although the range is quite
large. In their review, Cunha et  al. (2019) identified
34  lesions where size was reported and showed that the
mean size for unilocular lesions was 15.2 mm (range
4–45 mm), while multilocular lesions showed a mean of
27.9 mm (range 2–75 mm).
Recurrence of the Botryoid Odontogenic Cyst
A key feature of the botryoid odontogenic cyst is that it has
a tendency for recurrence. Almost certainly this is due to
its multilocular or multicystic nature, making it more
likely that remnants of cyst lining may be left behind after
enucleation. Overall, it is reported that 21.7% recur, com-
pared to only 2.4% of lateral periodontal cysts (Chrcanovic
and Gomez 2019b).
Of the 10 cases documented by Greer and Johnson
(1988), 3 recurred between 8 and 10 years after surgery.
Follow-­up information on recurrences was available for 11
cases of the 33 reported by Gurol et al. (1995), of which 2
recurred. Further documentation of the tendency for the
botryoid odontogenic cyst to recur has been provided by
Ramer and Valauri (2005).
Méndez et al. (2007) have reviewed these reports and oth-
ers and have identified factors associated with recurrence.
They found 37 cases where follow-­up had been recorded
and of these, 12 (32.4%) recurred. They showed that 81.8%
of recurrent cysts were multilocular compared with only
23.8% of non-­recurrent cysts. Recurrent cysts were also
larger, with a mean size of 31 mm compared to 9.6 mm in
non-­recurrent cases. Recurrent cases also occurred in a
younger age group: 47.8 years compared to 54.9 years.
Cunha et al. (2019) identified 12 recurrent cases, 11 (92%) of
which were multilocular and, as noted above, found that
multilocular lesions were on average larger. Similar find-
ings have been reported by others (Vidaković et al. 2016).
A note of caution is needed. A review of many of these
reports shows that very few botryoid odontogenic cysts
have actually been followed up and the number of those
that recurred is recorded as a proportion of those where
follow-­up data are available. This may overestimate the
proportion, because those that were not followed up may
simply not have returned because they had no further
lesions. Also, Siponen et  al. (2011) have pointed out that
some of the earlier reports (for example Phelan et al. 1988;
Heikinheimo et al. 1989; Öçok et al. 2005) have included
glandular odontogenic cysts, which may have a higher
recurrence rate.
Nevertheless, the data show that the botryoid odonto-
genic cyst may have a recurrence rate of up to 30% and that
multilocular or larger lesions may have an increased risk of
recurrence. Patients treated for a botryoid odontogenic cyst
should be followed periodically.
Pathogenesis
The pathogenesis of the botryoid odontogenic cyst has
been discussed along with the lateral periodontal cyst. A
unifying mechanism is suggested, in which the lateral peri-
odontal and botryoid odontogenic cysts arise from rest cells
of dental lamina (Figure 8.3). It is proposed that the botry-
oid cyst arises due to simultaneous cystic degeneration of
multiple dental lamina rests to produce a multicystic lesion
(Wysocki et  al.,  1980). Altini and Shear (1992) proposed
that a multicystic lesion is formed by ‘pinching-­off’ of the
epithelial plaques to form mural islands, which then
undergo cystic change. As this process is repeated, a multi-
cystic lesion develops. A further mechanism was proposed
by Redman et  al. (1990) and Siponen et  al. (2011), who
described multiple lateral periodontal cysts, some of which
were closely apposed and multilocular. They suggested
that some botryoid odontogenic cysts may arise by fusion
of multiple lateral periodontal cysts. These mechanisms
are not mutually exclusive and some or all may apply in
individual cases. Figure 8.3 illustrates a unifying hypothe-
sis for formation of unicystic and multicystic lesions, and
suggests correct terminology.
Histopathology
The botryoid odontogenic cyst was so named because, on
macroscopic examination, it resembled a small bunch of
grapes (Weathers and Waldron 1973), and some regarded
this as an essential appearance to establish the diagnosis.
However, this is rarely seen, because most lesions collapse
or fragment at surgery and the diagnosing pathologist
receives a folded lesion or multiple fragments. Furthermore,
some lesions are multicystic but not multilocular, since
the cysts are contained within a single fibrous capsule
(Figure  8.3). A correct diagnosis can often only be made
after a full consideration of the clinical, radiological, and
histological features (Box 8.3).
 ­Botryoid Odontogenic Cys  153

Box 8.3  Botryoid Odontogenic Cyst: Key Facts and Diagnostic Criteria
●● They are rare – less than 0.1% of odontogenic cysts
●● Only seen in adults, mean age about 50 years. Peak in sixth decade
●● Always arise anterior to the second premolars
●● 70% are found in the mandible. Most common in the canine/premolar area
●● Well-­defined radiolucency with corticated margin
●● About 50% are multilocular
●● Often greater than 10 mm diameter
●● Histology shows multiple cysts enclosed in a single fibrous capsule or may be multilocular
●● Each cyst is lined by non-­keratinised epithelium with plaques or thickenings similar to lateral periodontal cyst
●● Between 20% and 30% may recur
Caution: if any of the following features are noted, consider an alternative diagnosis:
●● If the radiolucency is large, or crosses the midline, or is posterior to premolars, possibilities include glandular odontogenic
cyst or odontogenic keratocyst
●● If luminal columnar cells, duct-­like structures, or mucous cells are present, consider a glandular odontogenic cyst

Figure 8.9  A botryoid odontogenic cyst. The

lesion is multicystic, with thin fibrous walls lined
by epithelium two to five cell layers thick. Many
epithelial thickenings and plaques can be seen.
Inset: a small island shows clear cell and
microcystic change. Source: Martin and Speight
2017. Reproduced with permission from Elsevier.

The defining feature of the botryoid odontogenic cyst is
that it is multicystic (Figure 8.9), with most reports show-
ing between two and about six cystic cavities, although
additional small microcysts and epithelial islands may be
seen. Occasionally the cysts are rounded and ballooning
(Weathers and Waldron 1973; Rasmusson et al. 1991), con-
sistent with the idea that they expand by hydrostatic pres-
sure, but most often they are collapsed with folded irregular
outlines, producing a multilocular appearance.
The cyst cavities are of varying size, but each one is lined
by epithelium identical to that described previously for the
lateral periodontal cyst (Figures 8.6 and 8.10). The lining is
a thin non-­keratinised epithelium comprising, for the most
part, one to three layers of flattened cells but with plaque-­
like thickenings, showing whorling and clear cell change
(Figure  8.6). The plaques and thickenings are seen in all
cases, and may be more prominent in botryoid lesions than
in unicystic lateral periodontal cysts, and occasionally
154 Lateral Periodontal Cyst and Botryoid Odontogenic Cyst
Figure 8.10  Botryoid odontogenic cyst with numerous small
cysts showing a thin lining with epithelial plaques. Epithelial
islands with clear cell and microcystic change can also be seen
(bottom left).
tangential sectioning may result in the appearance of pap-
illary projections (Figure 8.6f). The fibrous cyst wall is not
usually inflamed and in 70% of cases may show hyalinisa-
tion immediately below the epithelium (Gurol et al. 1995;
Santos et  al.  2011b; see Figure  8.5). Epithelial islands,
resembling rests of dental lamina, are seen in about 50% of
cases and often show clear cell change or cystic degenera-
tion (Figure 8.9, inset).
Altini and Shear (1992) described three morphological
variants of the lateral periodontal cyst (see Figure  8.3).
They suggested that the lateral periodontal cyst may be
unicystic or multicystic, but both types are contained
within a single fibrous capsule. The third variant was
composed of an irregular or lobulated thin-­walled multi-
cystic structure, which they felt was consistent with a
botryoid odontogenic cyst. As discussed previously, it is
often difficult to establish multilocularity on gross or his-
tological examination, and many multicystic lesions are
unilocular on radiographic examination. We believe
therefore that botryoid odontogenic cysts can be diag-
nosed when a lesion is found to be multicystic and that
multilocularity cannot be used as a defining criterion for
diagnosis. Lateral periodontal cysts are unilocular and
unicystic.
Differential Diagnosis
The diagnostic features of botryoid odontogenic cyst are
quite clear and misdiagnoses can be avoided if care is taken
to correlate the clinical, radiographic, and histological find-
ings (Box 8.3). However, one lesion in particular – glandular
odontogenic cyst – may share some features with botryoid
odontogenic cyst and care should be taken to avoid this
pitfall. Both may arise at the same site (anterior mandible),
both may be radiologically multilocular, and both are
multicystic. On radiological examination, botryoid odonto-
genic cysts are located between two teeth, rarely reach a
large size, and are rare in the midline. In contrast, glandu-
lar odontogenic cysts are often apical to the teeth or
embrace multiple teeth, may reach a very large size, and, in
the mandible, have frequently been shown to cross the
midline (see Figures 10.3 and 10.4). Histologically, glandu-
lar odontogenic cysts are often multicystic and do show
epithelial plaques and thickenings, but the lining is thicker
and is characterised by luminal cuboidal or columnar
cells, intraepithelial microcysts or duct-­like structures,
and mucous cells (Fowler et al. 2011; Chapter 10). These
features are not seen in lateral periodontal or botryoid
odontogenic cysts. Note that mucous cells are only seen in
about 70% of glandular odontogenic cysts, so an absence of
mucous does not exclude the diagnosis (Kaplan et al. 2008;
Fowler et  al.  2011). A number of papers have reported
unusual lateral periodontal or botryoid odontogenic cysts,
which on review are in fact glandular odontogenic cysts
(Phelan et  al.  1988; Heikinheimo et  al.  1989; Buckley
et al. 1989; Öçok et al. 2005).
Treatment
Botryoid odontogenic cysts are usually treated conserva-
tively by enucleation, but because they are multicystic and
many are multilocular, care is needed to ensure that all
tissue is removed. Curettage to underlying clean bone is
recommended. As discussed above, the cyst has a propen-
sity for recurrence so cases should be carefully followed
for a number of years, and complete healing should be con-
firmed radiologically.
 155

Gingival Cysts

CHAPTER MENU
­Gingival Cyst of Adults, 155
•• Clinical Features,  156
–– Frequency, 156
–– Age, 156
–– Sex, 156
–– Site, 156
–– Clinical Presentation,  157
•• Radiological Features,  158
•• Pathogenesis, 158
•• Histopathology, 158
–– Differential Diagnosis,  159
–– Microkeratocysts, 159
•• Treatment, 160
­Mucosal Cysts in Infants and Neonates, 160
•• G
­ ingival Cyst of Infants,  160
–– Clinical Features,  161
◦ Frequency and Prevalence, 161
◦ Age and Sex,  161
◦ Site, 161
◦ Clinical Presentation,  161
–– Pathogenesis, 161
–– Histopathology, 162
–– Treatment, 162
•• ­Epstein Pearls – Midpalatal Raphe Cyst,  162
–– Clinical Features,  162
◦ Frequency and Prevalence,  163
◦ Age and Sex,  163
◦ Clinical Presentation,  163
–– Pathogenesis,  163
–– Histopathology,  163
–– Treatment,  163

Gingival cysts are discussed together as a group of lesions
that are extraosseous and arise within the soft tissues. The
lesions to be discussed in this chapter are the gingival cyst
of adults and gingival cyst of infants, which arise in the
tooth-­bearing areas and are of odontogenic origin, and
the midpalatal raphe cyst, which arises in the palate of
infants.
­Gingival Cyst of Adults
The relationship between the gingival cyst of adults and the
lateral periodontal cyst has been discussed in the previous
chapter (Chapter 8). It is believed that they have a similar
pathogenesis and represent intraosseous and extraosseous
variants of the same lesion (Wysocki et al. 1980). Although

Shear’s Cysts of the Oral and Maxillofacial Regions, Fifth Edition. Paul M. Speight.
© 2022 John Wiley & Sons Ltd. Published 2022 by John Wiley & Sons Ltd.
156 Gingival Cysts

this may be the case, there are distinct differences in clini-
cal presentation and management that deserve separate
consideration (Shear and Pindborg  1975; Altini and
Shear  1992; Siponen et  al.  2011; de Andrade et  al.  2012;
Chrcanovic and Gomez 2019a).
Clinical Features
Up to 2019 there have been about 50 papers reporting 157
cases of gingival cyst (Wagner et al. 2015; Chrcanovic and
Gomez 2019a), but most of these have been reports of one
or two cases. There have been few case series, but those of
reasonable size are summarised in Table  9.1. Of the 33
cases reported by Buchner and Hansen (1979), 7  were
found on histological examination to be keratinising cysts
and are best excluded if a critical assessment of the gingival
cyst of adults is to be performed.
Frequency
Gingival cysts are rare and comprise less than 0.5% of all
odontogenic cysts (Tables 1.1–1.3). In the studies summa-
rised in Table 1.3, 8 included data on gingival cyst of adults
and showed a frequency of between 0.03% (Grossmann
et al. 2007) and 0.48% (Daley et al. 1994). In their study of
7121 odontogenic cysts over a period of 30 years, Jones
et  al. (2006) found 16 (0.2%) gingival cysts of adults.
Viveiros et al. (2019) found 20 gingival cysts in a series of
7023 odontogenic cysts (0.3%).
Age
The mean age of presentation of gingival cyst of adults is
about 50 years, with a peak in the fifth or sixth decade
(Table 9.1). The age distribution of 56 cases is illustrated in
Figure 9.1. These data include 10 from Shear (University
of the Witwatersrand), 4 reported by Reeve and Levy
(1968), 26 by Buchner and Hansen (1979), and 16 from
Jones et  al. (2006). This shows only 3 cases occurring
before the age of 30 and a peak frequency in the sixth dec-
ade, with the majority of patients (71.4%) in the fifth and
sixth decades.
Wagner et  al. (2015) reviewed 47 reports and found an
overall mean age of 49.10 years, and a more recent system-
atic review (Chrcanovic and Gomez  2019a) recorded 157
gingival cysts of adults and found a mean age of 48.6 years
(range 7–79), with a peak in the sixth decade.
Ironically, despite the name, a small number of gingival
cysts of adults are found in children (Buchner and
Hansen 1979; Giunta 2002; Richman and Johnston 2020).
The criteria for diagnosis used by these authors was of a
cyst on the gingivae associated with erupted teeth, in con-
trast to gingival cysts of infants that arise on the edentulous
alveolus. Richman and Johnston (2020) reported details of
a case in a 5-­year-­old boy. It presented as a cystic swelling
on the gingiva between a mandibular deciduous second
incisor and the canine. The lesion was lined by a thin non-­
keratinised stratified squamous epithelium.
Sex
Data accumulated from all published cases (n = 157) shows
that females are slightly more often affected than males,
with a male : female ratio of 1 : 1.44 (41% male : 59% female)
(Wagner et  al.  2015; Chrcanovic and Gomez  2019a).
However, the ratio varies considerably between series
(Table 9.1), with the proportion of males ranging from as
low as 12.5% to a high of 55.6%.
Site
Gingival cysts of adults occur much more frequently in the
mandible than in the maxilla (Table  9.1), with the large
reviews showing 76% in the mandible with almost all cases

Table 9.1  Age, sex, and site distribution from selected case series of gingival cyst of adults, and from the systematic review of
Chrcanovic and Gomez (2019a).

References n Mean age Peak decade Male (%) Mandible (%)

Buchner and Hansen (1979) 26 48.2 5th and 6th 42.0 73.0
Wysocki et al. (1980) 10 50.7 5th 55.6 70.0
Nxumalo and Shear (1992) 14 50.0 6th 50.0 57.1
Bell et al. (1997) 8 51.0 NR 12.5 87.5
Giunta (2002) 22 52.0 5th 28.5 88.8
Jones et al. (2006) 16 52.9 6th 25.0 NR
Viveiros et al. (2019) 20 53.5 6th 35.0 60.0
Chrcanovic and Gomez (2019a) 157 48.6 6th 41.6 76.5

NR, not reported.


Figure 9.1  Age distribution of 56
patients with gingival cyst of the adult.
No. of cases
arising anterior to the molar teeth. Overall, about 70% are
found in the anterior mandible or canine/premolar region,
although the single most common site is the mandibular
canine/premolar area with 35% of cases (Wagner et al. 2015;
Chrcanovic and Gomez  2019a). Chrcanovic and Gomez
(2019a) found reports of the precise location in 112 cases
and reported that only 4 (3.5%) were found posterior to the
second premolars.
Clinical Presentation
The gingival cyst of adults is usually symptomless, although
the patient may give a history of a slowly enlarging, pain-
less swelling (Figure 9.2). Many are only found fortuitously
during an oral examination or have been detected in the
Figure 9.2  Gingival cyst of an adult. The lesion is a sessile
swelling of normal colour, about 10 mm in diameter (arrows).
­Gingival Cyst of Adults 157
30
25 24
20
16
15
10
7
5
5
1 2
1
0 0
0
0-9 10-19 20-29 30-39 40-49 50-59 60-69 70-79 80-89
Age
course of histological examination of large numbers of gin-
gival biopsies (Moskow  1966). Ritchey and Orban (1953)
discovered 6 such cysts in 350 gingival biopsies.
In their systematic review, Chrcanovic and Gomez
(2019a) found 56 cases where symptoms had been
recorded, but only 8 (14.3%) reported symptoms. In their
series of 20 cases, Viveiros et  al. (2019) found 12  with
evidence of a swelling or ‘vesicle’, but only 2 cases pre-
sented with symptoms. In 12 cases where size had been
recorded, 3 were over 10 mm in diameter, but the remain-
ing 9  were less than 5 mm. Giunta (2002) recorded an
average dimension of 6 mm and his largest lesion was
12 mm in diameter. Chrcanovic and Gomez (2019a)
found 93 cases where size had been recorded and found a
mean diameter of 6 mm (standard deviation [SD] ±3 mm;
range 2–20 mm).
The cysts are round to oval, well-­circumscribed, usually
less than 10 mm in diameter, and may occur in the
attached gingiva or the interdental papilla, on the buccal
or labial aspect (Figure 9.2). The surface is smooth and is
usually the colour of normal gingiva, but occasional
lesions are translucent or blueish (Viveiros et al. 2019). If
they are traumatised, they may have an ulcerated surface
or may be haemorrhagic. The lesions are soft and fluctu-
ant and the adjacent teeth are vital. During surgical explo-
ration, slight erosion or saucerisation of the surface of the
bone may be observed, without extension into the perio-
dontium. Very rarely, more than one gingival cyst may be
found in a patient (Shade et al. 1987; Giunta 2002; Wagner
et al. 2015).
158 Gingival Cysts
Figure 9.3  Radiograph of a gingival cyst in an adult. There is a
faint radiographic shadow (marked with arrows), indicative of
superficial bone erosion.
Radiological Features
Gingival cyst of adults is a soft tissue lesion, so radiology
may not be helpful in diagnosis. However, a cyst originat-
ing in the gingival soft tissues may enlarge sufficiently to
cause superficial erosion of the cortical plate, with radio-
logical evidence of a faint round shadow (Figure  9.3).
Chrcanovic and Gomez (2019a) found 75 cases where radi-
ological features had been recorded, and 38 (50.7%) showed
evidence of bone erosion. In their review of 157 cases,
Wagner et  al. (2015) found that 35 (22.3%) showed evi-
dence of bone erosion, and described a case of their own
where surgery revealed exposure of a tooth root. However,
only 22 cases (14%) recorded radiographic evidence of bone
resorption.
Pathogenesis
Although a number of suggestions have been made about
the pathogenesis of the gingival cyst of adults, the most
favoured theory of origin is from odontogenic epithelial
cell rests derived from the dental lamina (Wysocki et  al.
1980). Early studies have shown that dental lamina rests
are commonly found in the alveolar bone and gingival tis-
sues and often show evidence of microcystic change (see
Figure  9.7; Hodson  1962; Moskow and Bloom  1983).
Wysocki et  al. (1980) suggested that lateral periodontal
cysts and gingival cysts had the same origin from rest cells
of dental lamina, but from intraosseous and extraosseous
rests, respectively.
Others have suggested an origin from junctional epithe-
lium. In material studied by Nxumalo and Shear (1992),
some cases were observed in which the epithelial lining
resembled reduced enamel epithelium and sometimes
extended to the deep aspect of the specimen, where it lay
close to the junctional epithelium. They suggested a mech-
anism similar to that proposed for lateral periodontal cyst
(discussed in Chapter  8), whereby both cysts are derived
from reduced enamel epithelium (Nxumalo and
Shear 1992). This proposes that an early dentigerous cyst
forms on an erupting tooth and becomes displaced later-
ally, as the tooth emerges into the mouth, to form a lateral
cyst. A gingival cyst may form from junctional epithelium
that is derived from ‘postfunctional’ reduced enamel epi-
thelium. It is possible that a developmental cyst may derive
from a down-­growth of junctional epithelium, but this
mechanism has not gained favour for gingival cyst of
adults.
The rest cells of the dental lamina are now considered to
be the source of gingival cyst of adults and provide a logical
explanation for their location in the gingival tissues and
the histological similarity to lateral periodontal cyst. It  is
now accepted that the gingival cyst of adults, lateral perio-
dontal cyst, and botryoid odontogenic cyst are derived from
the same source of epithelium, and this was discussed in
detail in Chapter 8.
There is no clear explanation as to what the stimulus
for the proliferation of these rests and their subsequent
cystic breakdown might be. It is certainly not an inflam-
matory stimulus, which produces well-­recognised effects
on odontogenic epithelium in radicular cysts, but is prob-
ably similar to that described previously for lateral peri-
odontal cyst (Chapter 8). This suggests that cyst formation
and growth are stimulated by accumulation of cell debris
and increased luminal osmotic pressure that drives cyst
expansion. A detailed discussion of the role of osmotic
pressure in cyst growth can be found in Chapter 3.
Histopathology
The pathologist will often receive an excisional biopsy (a
‘gingivectomy’ specimen) composed of mucosa with the
cyst on the deep aspect. Gingival cysts are small and fragile
and may be spherical, but are usually collapsed and folded,
and may have a thin translucent wall.
Gingival cysts are lined by thin non-­keratinised epithe-
lium, comprising one to five layers of flat to cuboidal cells
containing darkly staining nuclei (Figures  9.4-9.6).
Localised areas of plaques or thickened epithelium are
often seen (Figure 9.4, arrows). Occasionally these may be
whorled or nodular, similar to those seen in a lateral peri-
odontal cyst (see Figure 8.6), but are usually not as promi-
nent and may be smaller and flattened (Figure  9.6).
Nevertheless, the similarities support the commonly held
view that the two cysts originate from the same epithelium.
The attachment of the epithelium to the underlying con-
nective tissue is tenuous and it easily peels off, leaving
 ­Gingival Cyst of Adults 159

epithelial discontinuities (Figure 9.4, asterisks; Figure 9.6).

The fibrous connective tissue wall is usually uninflamed,
except close to the junctional epithelium where a chronic
inflammatory cell infiltrate may occur, or if the lesion has
been traumatised. The wall may contain small epithelial
islands (Figure  9.6). The cyst is almost always unicystic,
but rare multicystic lesions have been reported (Wysocki
et al. 1980; Nxumalo and Shear 1992).

Differential Diagnosis
In most cases the diagnosis should be straightforward
based on the characteristic clinical and histological fea-
tures and radiological evidence that the lesion is extraosse-
ous (Box  9.1). The main lesions to exclude are lateral
periodontal cyst or botryoid odontogenic cyst that may
have perforated the cortical plate. These may be suspected
if the plaques or thickenings are especially prominent or if
the lesion is multicystic. However, these lesions have an
intraosseous origin and the radiographs should be exam-
ined to confirm the site of the lesion. Peripheral odonto-
genic keratocyst may have an identical clinical presentation, Figure 9.4  Gingival cyst of the adult. The cyst lies just below
but this is rare and is defined histologically as having a par- the gingival epithelium (left) and is lined by thin, regular
akeratinised lining (see Chapter 7). non-­keratinised epithelium. Epithelial thickenings can be seen
(arrows), as well as areas of fragility where the epithelium is
separated from the cyst wall (*). Source: Martin and Speight
Microkeratocysts (2015), reproduced with permission of Elsevier.
Buchner and Hansen (1979) described gingival cysts of adults
with an ortho-­ or parakeratinised lining, and suggested that
these should be diagnosed as epidermoid cysts or keratocysts,
respectively. If keratin is seen, then a diagnosis of odonto-
genic keratocyst must be considered, and radiographs should
be examined to ensure that the lesion is not a peripheral
extension of a central cyst. Extraosseous or peripheral odon-
togenic keratocysts have been reported and many of these

Box 9.1  Gingival Cyst of Adults: Key Features

●● They are rare – less than 0.5% of odontogenic cysts
●● Seen in adults, mean age about 50 years. Peak in
sixth decade
●● Slightly more common in females Figure 9.5  The epithelial lining of a gingival cyst of the adult
●● Always arise anterior to the second premolars is thin and regular, two to five cells thick.
●● 75% are found in the mandible. Most common in the
canine/premolar area
●● Round, well-­circumscribed swelling on the attached show features similar to gingival cyst, but with a parakerati-
gingiva nised lining. Most oral pathologists will have, on occasion,
●● Usually normal colour and symptomless encountered islands of odontogenic epithelium in mucosal
●● Very rarely more than 10 mm diameter biopsies, especially from the retromolar region. Sometimes
●● 50% may show erosion of surface bone with slight these show cystic degeneration to form small microcysts
radiolucency (Figure  9.7), which are similar to the microkeratocysts
●● Lined by thin regular epithelium with areas of small described by Moreillon and Schroeder (1982). These arose
plaques or thickenings from dental lamina rests in the alveolus of fetuses and neo-
nates, and are the origin of gingival cysts of infants (see next
160 Gingival Cysts

cysts that affect the oral cavity in newborn infants. The

Figure 9.6  Gingival cyst of the adult, showing a thin epithelial
lining with a central small, flattened plaque. Small islands of
epithelium are seen in the wall, and an area of separation is also
seen (left).
first descriptions of these lesions were by Bohn in 1866 and
Epstein in 1880, but a contemporary classification was first
proposed by Fromm (1967), who undertook an extensive
study of oral lesions in the mouths of newborn infants. He
pointed out that Bohn originally described mucosal cysts
derived from mucous glands, which occurred on the palate
or on the buccal or lingual aspects of the alveolar ridges.
Based on his own observations, Fromm (1967) proposed
that there were three cyst types (Table  9.2). Despite this,
some or all of these terms are used synonymously to
describe any cyst with the characteristic features in a new-
born infant. In particular, the term Bohn’s nodule is fre-
quently used as a clinical term to refer to any cystic nodule
on the alveolar ridges, regardless of origin or histology. The
lesions are rarely biopsied, so a histological diagnosis is not
made and the close proximity of the crest of the alveolus to
the lateral aspects means that a precise anatomical position
is infrequently recorded.
Since most lesions are only diagnosed on their clinical
appearance and treatment is rarely needed, we agree with
Van Heerden and Van Zyl (2010) that a pragmatic approach
to classification is appropriate and that two types of cysts
should be identified. In this section we will categorise them
into two types and discuss the gingival cyst of infants and
the midpalatal raphe cyst.

Table 9.2  A summary of the characteristics of the three types

of developmental cysts found in neonates.
Figure 9.7  A mucosal biopsy from the retromolar area of an
adult contains islands of dental lamina rests that have
undergone cystic change to form ‘microkeratocysts’ (see text). Source of
Site epithelium Other names
section). It is possible that similar ­‘dental lamina cysts’ may be
Epstein Midline palate Epithelial Midpalatal
found in the gingivae of adults. These may be extremely rare, pearls inclusions raphe cyst
or may be common and, regarded as inconsequential, and Palatal cyst
therefore rarely reported. Nevertheless, they are probably
Bohn’s Lateral aspect ?Mucous Gingival cyst
oddities rather than entities and care should be taken not to nodules of alveolus minor salivary of infants
overinterpret them as fully formed odontogenic keratocysts, glands
since this may result in overtreatment. Dental Crest of the Rest cells of Gingival cyst
lamina cyst alveolar ridges the dental of infants
lamina
Treatment
Source: Adapted from Fromm (1967).
The gingival cyst is removed by local surgical excision and
in the majority of cases there is no tendency for recurrence.
In reports of 157 cases, only 1  was recorded as recurring
(Chrcanovic and Gomez 2019a). ­Gingival Cyst of Infants

Here, we define the gingival cyst of infants as an odonto-

­Mucosal Cysts in Infants and Neonates genic cyst found in the edentulous alveolar mucosa of new-
born infants (Vargas and Gomez  2022). Other names for
There is much confusion and misunderstanding around this lesion include dental lamina cyst, alveolar cyst, and
the classification and terminology of the developmental Bohn’s nodules, but we regard these as synonymous.
 Gingival Cyst of Infants 161

Clinical Features Clinical Presentation

The lesions present as small, white or cream-­coloured nod-
Frequency and Prevalence
ules from 1 to 3 mm in diameter (Figure 9.8). They appear
Gingival cysts of infants are rarely biopsied and therefore
to be symptomless and will disappear of their own accord,
their frequency among odontogenic cysts has not been
usually before 3 months of age. They are usually multiple,
recorded. However, studies of oral lesions in newborns
with up to 12 lesions seen in clusters and at more than one
suggests that they are very common and should probably
site. In Perez-­Aguirre et al.’s (2018) study, the average num-
be regarded as a normal occurrence rather than a patho-
ber of lesions per child was 5.4. When found on the crest of
logical change. In his original paper, Fromm (1967) exam-
the ridge, they resemble natal teeth, but the nodules are
ined 1367  newborn infants and found that 75.9% had
not as hard and may be mobile.
evidence of an oral cyst on the alveolus or palate. A high
frequency was also found in a Taiwanese study, in which
420 neonates were examined and palatal or gingival cysts Pathogenesis
were found in 94% of the infants (Liu and Huang  2004).
There is general agreement that gingival cysts in infants
More recently, in a cross-­sectional study of 2216 newborns
arise from remnants of the dental lamina. The epithelial
in Mexico, Perez-­Aguirre et al. (2018) found that 79% had
cell rests of the dental lamina, the so-­called glands of Serres,
gingival cysts, with a total of 11 862 cysts between them.
have the capacity, from as early a stage in development as
Zen et al. (2019) found an overall prevalence of 60.3%, but
10 weeks in utero, to proliferate, keratinise, and form small
also showed that the cysts were significantly more com-
cysts. Moskow and Bloom (1983) noted that as tooth devel-
mon in full-­term than in preterm (born at less than
opment progressed, but prior to separation of the tooth
36 weeks) infants.
germ from the oral epithelium, the dental lamina may pro-
liferate, with the formation of multiple areas of distinct
Age and Sex
microcysts with keratin production. In the late bell stage of
The cysts arise in newborn infants. There is good evidence
tooth development, according to Moskow and Bloom, disin-
from early studies that they begin to develop in early fetal
tegration of the dental lamina occurs and numerous islands
life and are well developed by 22 weeks of gestation
and strands of odontogenic epithelium are seen in the
(Moreillon and Schroeder  1982). After this, they seem to
mucosa just below the oral epithelium (Figure  9.9).
begin to involute and after birth they rapidly rupture or
Moreillon and Schroeder (1982) showed that dental lam-
merge with the overlying mucosa. Most are therefore seen
ina–derived microcysts increased in number between the
in the first few weeks of life and are rare after 3 months.
12th and 22nd weeks of gestation. They called these ‘micro-
Males and females seem to be affected equally (Perez-­
keratocysts’, with histological features very similar to those
Aguirre et al. 2018; Zen et al. 2019).
shown in Figure 9.7. The cysts were seen to fuse with the
overlying epithelium and discharge their keratin contents
Site
into the oral cavity. Just before and after birth, most of these
More than 85% of gingival cysts are encountered in the
inclusions and microcysts atrophy and become resorbed,
maxilla, and usually towards the buccal or labial aspect,
but some persist to produce clinically detectable cysts.
with a slight majority towards the posterior regions. A
number of studies have distinguished between lesions
classified as Bohn’s nodules (on the buccal, palatal, or lin-
gual aspects of the alveolus) and dental lamina cysts (on
the crest of the alveolus). In the most detailed analysis,
Perez-­Aguirre et al. (2018) identified a total of 11 862 cysts
on the alveoli of 2216  newborn infants. They classified
80.4% (9542) as Bohn’s nodules, of which 3516 (84.7%)
were in the maxilla and over 95% were on the buccal
aspect, but evenly distributed between anterior and poste-
rior regions. In the mandible, 62.4% were located buccally
and 37.6% were lingual. Of the 19.6% (2320) located on
the crest of the alveolar ridge (classified as dental lamina
cysts), 91.5% were located on the maxilla and 85.3% of
these were in the posterior region. Only 198 cysts were Figure 9.8  Gingival cysts in an infant. Multiple lesions on the
buccal aspect of the alveolus of a neonate. One lesion is white
found in the mandible, but most of these (84.3%) were and prominent (arrowhead), while others are pale and relatively
anterior. inconspicuous (arrows). Source: Courtesy of Prof. Ian Brook.
162 Gingival Cysts
Figure 9.9  A mucosal biopsy from an infant shows a
fragmenting dental lamina with small residual islands scattered
below the surface epithelium.
It has been suggested that lesions on the lateral aspects of
the alveolus (Bohn’s nodules) are derived from degeneration
of developing glandular tissue, but this does not appear to
have been confirmed histologically, and minor salivary glands
are rarely found on the attached mucosa of the alveolar ridges.
It seems more likely therefore that the primary source of the
epithelium at all sites on the alveolus is the dental lamina.
Histopathology
Most gingival cysts of infants resolve spontaneously very early
in life and it is unusual for a pathologist to receive a specimen
for diagnosis, which is typically made clinically (Box  9.2).
Most reports of the histological features have come from
studies of fetal or infant tissues, or cysts encountered by
chance. The cysts are lined by a thin, regular parakeratinised
stratified squamous epithelium, similar to those described
above (Figure 9.7), and are often filled with whorls of keratin
and debris (Figure 9.10). Occasionally keratin from the cysts
may extrude into the adjacent connective tissues, causing
inflammation and a foreign-­body giant cell reaction. They
Box 9.2  Gingival Cyst of Infants: Key Features
●● They are common and may affect up to 90% of
newborns
●● Only seen in newborns and are rare after 3 months
of age
●● 85% or more are found in the maxilla
●● Round, well-­circumscribed nodules 1–3 mm in
diameter
●● Usually in clusters of 2–12 lesions
●● Usually white or yellowish and may resemble natal
teeth, but are softer and mobile
●● Lined by thin keratinised epithelium
Figure 9.10  Gingival cyst in an infant. The cyst lies just below
the surface epithelium, and is filled with whorls of keratin and
debris. Source: Courtesy of Prof. John Wright.
may fuse with the overlying epithelium and occasionally a
punctum is seen. Although it is suggested that Bohn’s nod-
ules have an origin from glandular tissue, there are no
reports of cysts lined by glandular epithelium.
Treatment
There is no indication for any treatment of gingival cysts
of infants. Once their contents are expelled, they atrophy and
disappear. It has been suggested that massage or ­‘teething
rings’ may help them resolve, but this is not usually necessary.
­ pstein Pearls – Midpalatal
E
Raphe Cyst
Epstein pearls is the widely accepted term for the small
cysts that arise in the centre of the palate in newborn
infants. They arise from epithelial inclusions within the
mucosa along the palatal raphe  – the line of fusion of
the  epithelium of the palatal shelves along the midline
of the palate. The midpalatal raphe cyst must not be con-
fused with the so-­called median palatal cyst, which has
been described as an intraosseous cyst arising at the fusion
of the palatal shelves. The existence of such median cysts is
questionable and is discussed in Chapter 13. Epstein pearls
is the term widely used in paediatric dentistry and is well
understood. Since the diagnosis is almost always made
clinically, we suggest that this common term should con-
tinue to be used.
Clinical Features
Epstein pearls are so common that they are usually regarded
as a normal occurrence in the mouths of neonates. Although

a number of papers record their prevalence, few studies
have reported in detail their clinicopathological features.
Frequency and Prevalence
Numerous studies have recorded the prevalence of oral
lesions in neonates and most report that more than 80% of
newborns have small nodules, or cysts, in the oral mucosa
(Fromm  1967; Liu and Huang  2004; Perez-­Aguirre et  al.
2018; Zen et al. 2019). Most reports have found that Epstein
pearls are the most commonly encountered anomaly. In
their examination of 2216  newborns, Perez-­Aguirre et  al.
(2018) found Epstein pearls in 1463 (66.0%). Other studies
have shown a prevalence of between 38.3% (Niranjan
et al. 2020) and 70.2% (Moosavi and Hosseini 2006).
Age and Sex
Lesions are found in newborn infants and are rarely
encountered after 3 months of age. The largest studies have
not shown any sex predilection (Moosavi and Hosseini 2006;
Monteagudo et  al.  2012; Perez-­Aguirre et  al.  2018; Zen
et al. 2019).
Clinical Presentation
Midpalatal raphe cysts are found along the midline of the
hard palate, often towards the posterior aspect, but not
involving the soft palate. They are small, white or yellowish
nodules usually less than 3 mm in diameter and, true to
their name, resemble small pearls. They often arise in clus-
ters of two to five lesions.
Pathogenesis
Cysts along the midpalatal raphe arise from epithelial
inclusions at the line of fusion of the palatal shelves.
As for many lesions of developmental origin, our under-
standing of their pathogenesis often comes from early
studies of human fetal tissues that are not likely or needed
to be repeated. To appreciate the tissues involved, readers
are encouraged to consult an up-­to-­date text on oral anat-
omy and embryology of the head and neck. The origin
of Epstein pearls has been well described in the early stud-
ies of Burke et al. (1966) and of Moreillon and Schroeder
(1982). Burke et  al. (1966) examined the palates of
32 human fetuses and found cysts in 31. They were mostly
confined to the posterior half of the hard palate and were
most numerus between 3 to 6 months of gestation. After
this, the cysts gradually reduced in number. The cysts
were found in the palatal midline, associated with
­Epstein Pearls – Midpalatal Raphe Cyst 163
epithelial inclusions or down-­growths into the superficial
lamina propria. They were often fused with the overlying
epithelium with a punctum or duct-­like morphology, and
the authors suggested that they may represent abortive
glandular differentiation. However, this seems unlikely,
since glands are rarely found at this site. More likely, they
represent remnants of the surface epithelium of the fused
palatal shelves.
In a meticulous study on serial sections of 32 human
heads, approximately 8–22 weeks of fetal age, Moreillon
and Schroeder (1982) showed epithelial rests of palatal
fusion from 8 to 12 weeks of gestation, with formation of
midpalatal keratinising microcysts between 10 and
22 weeks. The number of cysts in any one individual var-
ied from 1 to 20 and appeared to increase up to 22 weeks
and then decline. The cysts were heavily keratinised and
were often fused with the surface epithelium. The authors
noted that cysts were found in all fetuses and that the
number of cysts (15–20 at 22 weeks) contrasted sharply
with the number of cysts encountered in newborns or
adults. They suggested that as the cysts develop, they fuse
with the oral epithelium, discharge their contents, and
resolve, so that at birth and shortly after the cysts have dis-
appeared. Hence, they are rarely seen in infants over
3 months of age.
Histopathology
There are very few reports of the histopathology of Epstein
pearls in infants, but studies of their development show
that the cysts are round or ovoid, with a thin lining of strat-
ified squamous epithelium and a para-­or orthokeratinised
surface, and keratin fills the cyst cavity, usually in concen-
tric laminations containing flattened cell nuclei (Burke
et al. 1966; Moreillon and Schroeder 1982). The basal cells
are flat, unlike those in the keratocyst. Epithelial-­lined
clefts may develop between the cyst and the surface oral
epithelium. The features have been described as ‘micro-
keratocysts’ (Moreillon and Schroeder 1982) and are very
similar to those described above for gingival cysts of infants
and the small dental lamina cysts occasionally encoun-
tered in the oral mucosa (Figures 9.7 and 9.10).
Treatment
There is no indication for any treatment of midpalatal
raphe cysts in infants. Once their contents are expelled,
they atrophy and disappear.
164

10

Glandular Odontogenic Cyst

CHAPTER MENU
Clinical Features, 165
●● Frequency, 165
●● Age, 165
●● Sex, 166
●● Site, 166
●● Clinical Presentation,  166
Radiological Features, 167
●● Radiological Differential Diagnosis,  168
Recurrence of the Glandular Odontogenic Cyst, 169
Pathogenesis, 169
Histopathology, 170
●● Diagnostic Criteria,  173

●● Histological Differential Diagnosis,  175

–– Central Mucoepidermoid Carcinoma,  176
–– Immunohistochemistry and Molecular Studies,  178
Treatment, 181

Glandular odontogenic cyst is a developmental cyst in
which the epithelium resembles salivary or glandular tis-
sue (Speight and Rautava 2022). It was first mentioned by
Padayachee and Van Wyk (1987), who described two mul-
ticystic lesions with features of both botryoid odontogenic
cyst and ‘central mucoepidermoid tumour’. They named
the lesion sialo-­odontogenic cyst to emphasise the resem-
blance to salivary tissue. Soon after, Gardner et al. (1988)
reported eight cases and introduced the name ­glandular
odontogenic cyst, and this was subsequently adopted as a
new entity in the second edition of the World Health
Organization (WHO) classification of odontogenic
tumours (Kramer et al. 1992). The characteristic features of
the cyst were that it was intrabony and multilocular radio-
logically; that it could recur if not adequately excised; and
that it was composed of multiple cystic spaces lined by a
non-­keratinised epithelium with thickenings or plaques.
Mucous and cylindrical cells also formed an integral part
of the epithelial component.
The lesion has evoked a considerable amount of interest
because of its tendency to recur and its resemblance to, and
possible relationship with, the central mucoepidermoid
carcinoma of the jaws. There have been few case series of
glandular odontogenic cyst, but numerous reports of single
or relatively few cases had been published between its rec-
ognition in 1992 and the fourth edition of this book in 2007
(van Heerden et al. 1992; Semba et al. 1994; Economopoulou
and Patrikiou 1995; Savage et al. 1996; de Sousa et al. 1997;
Magnusson et  al.  1997; Ramer et  al.  1997; Koppang
et al. 1998; Manojlović et al. 1998; Chavez and Richter 1999;
Jose et al. 2000; Lin et al. 2000; Tosios et al. 2000; Barreto
et  al.  2001; Noffke and Raubenheimer  2002; Ertaş et  al.
2003; Osny et al. 2004; Pires et al. 2004; Tran et al. 2004;
Abu-­Id et al. 2005; Qin et al. 2005; Shen et al. 2006). Since
2006 there have been a further 72 case reports. Mascitti
et al. (2014) reviewed 110 reported cases, and Chrcanovic
and Gomez (2018b) reviewed the literature up to 2018 and
found 169 fully documented cases.

Shear’s Cysts of the Oral and Maxillofacial Regions, Fifth Edition. Paul M. Speight.
© 2022 John Wiley & Sons Ltd. Published 2022 by John Wiley & Sons Ltd.
 Clinical Features 165

­Clinical Features
Most publications on glandular odontogenic cyst have
been single case reports or small case series. The largest
series was by Fowler et al. (2011), who described 46 cases.
The few reports of more than 10 cases are summarised in
Table 10.1, along with data from the review of 169 cases by
Chrcanovic and Gomez (2018b).
Frequency
The glandular odontogenic cyst is a rare lesion and consti-
tutes less than 1% of odontogenic cysts. Our data from the
archives of the University of the Witwatersrand for the
period 1992–2004  indicated only six cases in a series of
3498  jaw cysts (0.2%) (Table  1.1). The Sheffield data were
similar, with only 11 cases (0.2%) in a sample of 7121 odon-
togenic cysts over a 30-­year period (Jones et al. 2006). Most
other studies agree with this low frequency, although there
is some variation globally. Table 10.2 shows that the reported
frequencies range from as low as 0.03% up to 1.16%.
Age
Glandular odontogenic cyst presents at an average age of
about 50 years, with a peak in the sixth decade (Table 10.1).
Figure 10.1 illustrates the age and sex distribution of 105
glandular odontogenic cysts that we have pooled from the
review of Koppang et al. (1998) and from subsequent pub-
lications that have recorded age and sex by decade
(Economopoulou and Patrikiou  1995; Savage et  al.  1996;
Magnusson et  al.  1997; Ramer et  al.  1997; de Sousa
et al. 1997; Manojlović et al. 1998; Chavez and Richter 1999;
Lin et al. 2000; Tosios et al. 2000; Barreto et al. 2001; Noffke
and Raubenheimer  2002; Ertaş et  al.  2003; Abu-­Id
et  al.  2005; Kaplan et  al.  2005b; Qin et  al.  2005; Jones
et  al.  2006). There was a distinct peak frequency in the
sixth decade, particularly in males.

Table 10.1  Age, sex, and site distribution from selected reports of glandular odontogenic cysts (where n ≥ 10), and from the review of
169 cases by Chrcanovic and Gomez (2018b).

References n Mean age Male (%) Mandible (%)

Kaplan et al. (2005a) 11 49.0 100 72.7

Jones et al. (2006) 11 48.5 80.0 63.6
Fowler et al. (2011) 46 51.0 48.9 80.0
Soluk Tekkeşin et al. (2012b) 23 47.5 82.6 65.2
Tamiolakis et al. (2019) 19 51.1 68.4 44.4
Chrcanovic and Gomez (2018b) 169 48.1 53.6 73.2

Table 10.2  The frequency of glandular odontogenic cyst reported in selected studies from around the world.

Country Total odontogenic cysts Glandular odontogenic cysts

References n n %

Daley et al. (1994) Canada 6847 3 0.04

Mosqueda-­Taylor et al. (2002) Mexico 856 2 0.10
Meningaud et al. (2006) France 695 2 0.20
Jones et al. (2006) UK 7121 11 0.20
Shen et al. (2006) Japan 7023 12 0.17
Ochsenius et al. (2007) Chile 2944 1 0.03
Grossmann et al. (2007) Brazil 2812 2 0.07
Sharifian and Khalili (2011) Iran 1227 4 0.30
Soluk Tekkeşin et al. (2012b) Turkey 5003 23 0.45
Tamiolakis et al. (2019) Greece 5165 19 0.40
Aquilanti et al. (2021) Italy 2150 25 1.16
166 Glandular Odontogenic Cyst
30
25
20
No. of cases
15
15
7 11
10 9
1 7
5 11
8 8
0 1
0
0-9 10-19 20-29
Figure 10.1  Age and sex distribution of 105 patients with glandular odontogenic cysts.
Table  10.1 summarises data from a number of studies,
including the aggregated data from 169 cases reviewed by
Chrcanovic and Gomez (2018b). Although there is some
variation in age, there have been no cases reported in the
first decade and very few over the age of 79. The youngest
reported cases have been in 11-­year-­olds (Noffke and
Raubenheimer 2002; Faisal et al. 2015).
Sex
The data in Figure  10.1 shows 61  males (58.1%) and 44
females (41.9%). Most studies show a male predilection
(Table  10.1) and although this is variable, the overall sex
difference is not statistically significant (Chrcanovic and
Gomez 2018b).
Site
Glandular odontogenic cyst is found most frequently in the
mandible, with an overall proportion of 73.2% (Chrcanovic
and Gomez (2018b); Table  10.1). In their review of 110
cases, Mascitti et al. (2014) found that 74.8% arose in the
mandible, with 33.3% in the anterior mandible and a
­further 25.2% extending from the anterior to the posterior
region. Chrcanovic and Gomez (2018b) found 60 cases
(35.5%) that affected the anterior/premolar region of the
mandible. Lesions can grow to a large size, and they
recorded 14 cases that filled the body of the mandible, 6
cases that extended across the whole maxilla, and 8 that
extended from the mandibular body to the angle or ramus.
Our experience has shown that lesions in the anterior
25 Females
Males
11
17 17
6
12
5
14 1
7
6 6 2
30-39 40-49 50-59 60-69 70-79 80-89 90+
Age
mandible often cross the midline in a characteristic sym-
metrical pattern (Figures  10.3 and  10.4). In the first 10
reported cases, 6 showed this appearance (Padayachee and
Van Wyk 1987; Gardner et al. 1988). In the series of Noffke
and Raubenheimer (2002), 6 of 9 cases involved the mandi-
ble and 4 of these crossed the midline. Koppang et  al.
(1998) listed the individual locations of 40 cases in both
mandible and maxilla. Most of these (34 cases: 85.0%) were
in the anterior mandible and 6 were in the maxilla. Some
involved the mandible from incisor or canine to the molar
regions. One was described as involving the entire mandi-
ble. Of the 7 cases reported in the study by Kaplan et  al.
(2005b), 4  were in the maxilla, 3  with extensive involve-
ment including the maxillary sinus.
Clinical Presentation
Most cases are symptomless and are discovered by chance
on radiographs, or present as a slowly expanding, painless
swelling. Only about 24% may show symptoms, although
73% had evidence of swelling (Chrcanovic and
Gomez 2018b). All 9 patients of Noffke and Raubenheimer
(2002) presented with swelling of the jaws, as did the 7
patients reported by Kaplan et  al. (2005b), although 6 of
the 7 were painless. One of their maxillary cases showed
facial and nasal swelling with infra-­orbital paraesthesia.
Fowler et  al. (2011) presented 46 cases of which 30  had
information on signs and symptoms; 20 (66.6%) showed
bone expansion, but only 8 had other symptoms, including
5 with pain, 2 with evidence of infection, and 1 with par-
aesthesia. The clinical features are summarised in Box 10.1.

Figure 10.2  Radiograph of a glandular odontogenic cyst in the
maxilla. There is a large unilocular radiolucent area with a
smooth but slightly scalloped corticated margin (arrows). The
histology of this lesion is shown in Figure 10.6a.
­Radiological Features
Glandular odontogenic cysts are well-­defined radiolucen-
cies with a corticated margin (Figure 10.2-10.4). Although
they may be multicystic and are often regarded as charac-
teristically multilocular, in fact up to 60% are unilocular
(Manor et  al.  2003; Mascitti et  al.  2014; Chrcanovic and
Gomez 2018b).
Manor et  al. (2003) reviewed the radiology of 56 cases
and found that 52% had been described as unilocular and
48% as multilocular. Almost all (94.5%) had well-­defined
Figure 10.3  Radiograph of an extensive multilocular glandular odontogenic cyst. The lesions crosses the midline in an almost
symmetrical pattern. Courtesy of Prof. Christoffel Nortjé.
­Radiological Features 167
borders, which were sclerotic in 8% and scalloped in 13%.
Information on cortical plate integrity was available in only
24 cases, half of which reported perforation and 17% ero-
sion or thinning of the cortical plates. Root resorption was
reported in 22% of patients and tooth displacement in 24%.
The size of the lesions ranged from 5 to 120 mm, but uni-
locular lesions were smaller on average (39 mm × 28 mm)
than multilocular lesions (63 mm × 30 mm).
Noffke and Raubenheimer (2002) reported a radiological
study of nine cases. All showed cortical expansion and
those with a diameter of more than 60 mm had perforated
the cortical plate. Seven (77.8%) were unilocular and well
circumscribed: five with smooth borders and two with
irregular borders. Eight cases showed tooth displacement.
The two multilocular lesions showed irregular or scalloped
borders and perforations. Their measurements ranged
from 32 × 20 mm in a 14-­year-­old boy to a multilocular
lesion of 165 × 40 mm in a 53-­year-­old woman. Unlike the
survey by Manor et al. (2003), no significant root resorption
of involved teeth was observed.
These authors suggested that multilocularity might be
a size-­related phenomenon, since lesions over 60 mm
tended to be multilocular and showed bone expansion
and perforation (Noffke and Raubenheimer 2002; Manor
et al. 2003).
In their review of 169 cases, Chrcanovic and Gomez (2018b)
found that 26% showed evidence of perforation of the cortical
plate, 31% were associated with displaced or unerupted teeth,
but only 13.9% showed evidence of tooth resorption.
Occasional cases have been reported to occur in a denti-
gerous relationship with unerupted teeth. Fowler et  al.
(2011) reported that 8 of their 46 cases were in a dentiger-
ous relationship radiographically, but no details were
168 Glandular Odontogenic Cyst

include a wide range of benign cysts of the jaws as well as

Box 10.1  Glandular Odontogenic Cyst: Clinical
other lesions, including giant cell granulomas. For multi-
and Radiological Features
locular lesions the differential diagnosis may be more lim-
●● They are rare – less than 1% of odontogenic cysts ited. We have noted a number of large glandular
●● Seen in adults, mean age about 50 years. Peak in odontogenic cysts that cross the midline of the mandible
sixth decade with a characteristic, almost symmetrical pattern
●● Slightly more common in males (Figures 10.3 and 10.4). Other lesions, in particular amelo-
●● Over 70% occur in the mandible. Most common in the blastoma, may arise at this site and show similar multi-
anterior/premolar area locular features. However, the glandular odontogenic cyst
●● Usually symptomless, but 70% show swelling/bony seems to show relatively little bucco-­lingual expansion
expansion relative to the lateral growth, whereas ameloblastomas
●● Well-­defined radiolucency with corticated margins tend to show a ballooning growth pattern with a similar
●● About one-­third are multilocular degree of bucco-­lingual and lateral expansion. For com-
●● May grow to a large size and be extensive parison, an example of a large ameloblastoma is shown in
●● Crossing the midline in a symmetrical pattern is Figure 10.5.
characteristic Odontogenic keratocyst may show a very similar growth
●● Recurrence rate is about 22% pattern to glandular odontogenic cyst, but a location in the
anterior mandible is unusual.
A further consideration in the differential diagnosis is lat-
given. Ferreira et al. (2019) reported a case in a dentiger- eral periodontal cyst or botryoid odontogenic cyst (see dis-
ous relationship with a mesially impacted mandibular cussion in Chapter 8), both of which are also found in the
third molar, and reviewed a further 22 cases reported since anterior regions of the jaws. All three lesions may arise in a
1996. Of 13 cases where site was specified, 5 were associ- lateral periodontal position with a predilection for the man-
ated with mandibular third molars and 3 with mandibular dible. Glandular odontogenic cyst and botryoid odonto-
canines. genic cyst may also be multilocular. On radiology alone, it
may not be possible to differentiate between these lesions.
However, lateral periodontal cysts are usually round or oval
Radiological Differential Diagnosis
and are rarely greater than 10 mm in diameter, while botry-
Generally, the radiological features of glandular odonto- oid odontogenic cysts have a mean diameter of 15 mm and
genic cyst are not specific. The overall clinical and are rarely greater than 50 mm. Therefore, a glandular odon-
­radiological features suggest a benign process and, for sim- togenic cyst should always be suspected if a lesion embraces
ple unilocular lesions, the differential diagnosis may multiple teeth or is larger than 50 mm (Figure 10.2).

Figure 10.4  Another example similar to Figure 10.3. The cyst crosses the midline from second molar to second molar, but there is
relatively little expansion of the mandible. Source: Prof. Paul Speight (Previously published: El-­Naggar AK, Chan JKC, Grandis JR, Takata
T, Slootweg PJ. World Health Organization Classification of Tumours of Head and Neck. IARC, Lyon, 2017. Courtesy of IARC.)

(a)
Figure 10.5  A radiograph (a) and an axial computed tomography (CT) scan (b) of a large ameloblastoma. In comparison to the
glandular odontogenic cyst (Figures 10.3 and 10.4), the lesion is ‘ballooning’, with considerable expansion of the cortical plates.
­ ecurrence of the Glandular
R reported that 9 (19.6%) cases were known to have recurred
Odontogenic Cyst
The glandular odontogenic cyst has a reputation for
recurrence and many publications tend to label it as
‘aggressive’. The lesion may certainly reach a large size,
but growth appears to be slow, as evidenced by the corti-
cated or even sclerotic margins. Recurrence is probably a
consequence of the size of the lesion and its tendency to
be multilocular and multicystic, making it more likely
that fragments of cyst are left behind after surgery.
The overall recurrence rate from 58 studies reporting
97 lesions where data was available was 21.6% (Chrcanovic
and Gomez 2018b). These authors also undertook an anal-
ysis of factors associated with recurrence. They showed
that lesions that were curetted were less likely to recur than
those with enucleation alone (16.7% vs 25.4%). Other fac-
tors associated with a higher recurrence rate were bone
expansion, cortical bone perforation, and multilocularity.
Histological factors associated with recurrence included
multicystic lesions and the presence of mucous cells or
cilia. However, it must be noted that none of these factors
was shown to have a statistically significant association
with the recurrence rate.
In their review of 45 cases, Koppang et al. (1998) found
information about recurrence in 38, of which 8 (21%)
recurred; 6 of these recurred after 2–8 years, and 2 cysts
recurred twice after 2 and 5 years, and 3 and 5 years. Of 6
recurrent lesions where information was available, 5 were
multilocular. In their series of 46 cases, Fowler et al. (2011)
Pathogenesis 169
(b)
with an average time interval of 8 years (range 3–13 years);
6 cases recurred twice. They found no significant differ-
ences in the histological features between recurrent and
non-­recurrent cysts.
In their analysis of recurrences after treatment, Kaplan
et al. (2005b) reviewed 48 patients, including 7 treated in
their own department. Pooling together patient data that
recorded location, size, radiographic features, different
modalities of primary treatment of the lesions, and length
of follow-­up, they found that recurrences occurred in 13
cases (27.1%); 2 patients had three recurrences each within
2 years. Citing a series of publications, they found recur-
rence rates ranging from 21 to 55%. They also compared
recurrent and non-­recurrent lesions and showed that large
lesions recur (85.6%) more often than small lesions (14.4%)
and that recurrent lesions were more likely to be multiloc-
ular (64.3 versus 41.2%) or associated with perforation or
thinning of the cortical plates (71.4 versus 47.1%; Kaplan
et al. 2005b, 2008).
These studies suggest that about 22% of glandular odonto-
genic cysts may recur, and that recurrence is associated with
larger multilocular or multicystic lesions with evidence of
bone resorption and perforation of the cortical plates.
­Pathogenesis
Very little has been written on the pathogenesis of the glan-
dular odontogenic cyst. Although most authors agree that
170 Glandular Odontogenic Cyst
it is of odontogenic origin and probably arises from rest
cells of the dental lamina, there is still much speculation.
The very first reports described the close similarities
between the lining of the glandular odontogenic cyst and
those of the lateral periodontal and botryoid odontogenic
cysts (Padayachee and Van Wyk 1987; Gardner et al. 1988).
These authors were particularly struck by the similar
­epithelial thickenings and plaques, and the multicystic or
botryoid nature of the lesions. This was so striking that
many early authors regarded the glandular odontogenic
cyst as a variant of the botryoid odontogenic cyst
(Browne 1991b; Noffke and Raubenheimer 2002) and the
two lesions are still often confused (see discussion on dif-
ferential diagnosis below and in Chapter  8). Occasional
cases have been associated with other odontogenic lesions,
including dentigerous cysts and ameloblastomas, and
some have contained hyaline bodies (Gardner et al. 1988;
Ide et al. 1996; Cousin et al. 2017), which has been taken as
further e­ vidence that confirms an odontogenic origin.
Although the lesion shows features of glandular or even
‘salivary’ differentiation, the possibility of an origin from
intraosseous entrapped salivary tissue has not gained any
support. The glandular changes are regarded as metaplastic
in nature and an example of the known pluripotentiality of
odontogenic epithelium.
The possibility that glandular odontogenic cyst is a
benign neoplasm cannot be dismissed without further
research. The relationship between the cyst and the intra-
osseous or central mucoepidermoid carcinoma is discussed
in the next section. These two lesions show a number of
histological similarities (Kaplan et  al.  2008; Fowler
et  al.  2011; Reddy et  al.  2019) and some authors have
shown evidence of similar MAML2 rearrangements, sug-
gesting that glandular odontogenic cyst may be a precursor
to central mucoepidermoid carcinoma (Greer et  al.  2018;
Nagasaki et al. 2018).
The role of the PTCH gene and of the hedgehog signal-
ling pathway in the pathogenesis of the keratocyst is dis-
cussed in detail in Chapter  7. Hedgehog signalling is
activated by interaction between the Sonic hedgehog
(SHH) protein and its receptor PTCH on the cell surface,
although constitutive ligand-­independent activation may
also occur as a result of truncating mutations or loss of het-
erozygosity (LOH) of the PTCH gene. Activation of the
pathway results in downstream expression of factors medi-
ating cell growth, proliferation, and differentiation, and
there is now evidence that SHH/hedgehog signalling is not
unique to keratocysts, but may drive growth and prolifera-
tion of a number of odontogenic cysts and tumours (Gomes
and Gomez  2011), including glandular odontogenic cyst
(Barreto et al. 2002; Zhang et al. 2010). Zhang et al. (2010)
examined 12 glandular odontogenic cysts and found
homogeneous expression of the hedgehog pathway–related
proteins SHH, PTCH, SMO, and Gli1 in the epithelial lin-
ing of all lesions. They also found similar expression in all
cases (n = 20) of dentigerous cysts examined.
­Histopathology
Lesions are usually enucleated with or without curettage,
so the pathologist often receives a fragmented or collapsed
specimen, making it difficult to always appreciate the true
morphology of the lesion. Lesions may be multicystic and
this may not be clearly apparent on a fragmented speci-
men. Larger lesions may occasionally be removed with a
localised block resection and examination of the intact
specimen may show a botryoid, bosselated, or lobular cyst
that, when bisected, has a multicystic appearance on the
cut surface. Examination of the cyst wall will often show
thickenings and papillary projections and the lumen may
occasionally contain mucus.
The first reports of the glandular odontogenic cyst pre-
sented comprehensive and detailed descriptions of the his-
tological features (Gardner et al. 1988; Padayachee and Van
Wyk 1987) that have not been bettered and still provide the
benchmark for diagnosis. The cyst shows a number of
­different features, few of which are specific, but when con-
sidered in combination may be diagnostic. Gardner et al.
(1988) listed more than seven features that may be seen in
the glandular odontogenic cyst, and subsequent authors
(Kaplan et al. 2005a; Fowler et al. 2011) have used these to
develop diagnostic criteria to help differentiate it from
other lesions. Table 10.3 lists the features that may be found
in glandular odontogenic cysts, with their relative fre-
quency as reported in the series of 46 cases of Fowler et al.
(2011) and the review of 169 cases by Chrcanovic and
Gomez (2018b).
Glandular odontogenic cysts are characteristically multi-
locular on radiography or multicystic on histology
(Figure 10.6), although overall, only about 60–70% of cases
have been described as multicystic or botryoid (Fowler
et al. 2011; Chrcanovic and Gomez 2018b).
The cyst may be lined in parts by a non-­keratinised squa-
mous epithelium of variable thickness, which lies on a flat
basement membrane. In places the lining may be only two
layers thick, with a cuboidal or flattened basal layer and a
columnar surface layer (Figure 10.7). The surface layer may
contain occasional mucous cells or show apocrine ‘snout-
ing’ or decapitation secretion. We have seen one case
(Figure 10.7) in which most of the lining had this appear-
ance. However, most cases show epithelial thickenings or
plaques that may be present in the thin epithelium or in the
stratified squamous epithelium (Figure 10.8). The plaques,
 ­Histopathology 171

(a) (b)

Figure 10.6  Two examples of multicystic glandular odontogenic cysts. Even at this low magnification it can be seen that the linings
are mostly thin, but show multiple plaque-­like thickenings and areas with papillary projections (b, lower right). (a) The histology of the
cyst in Figure 10.2. Source: Martin and Speight (2017), reproduced with permission from Elsevier.

Figure 10.7  Glandular odontogenic cyst may have a thin regular lining only two to three cell layers thick. The superficial cells are
cuboidal or columnar and may show apocrine secretion (arrows).

when present, are similar morphologically to those in the
gingival cyst of adults, the lateral periodontal cyst, and the
botryoid odontogenic cyst, and may show spherules or
­whorling (Figure  10.8b). Occasionally these plaques
­protrude into the cyst cavity to form short bulbous ­papillary
projections, that may be numerous and prominent
(Figure 10.8a, d).
In almost all cases (Table  10.3; Fowler et  al.  2011;
Chrcanovic and Gomez 2018b), the epithelial lining has a
superficial layer of columnar or cuboidal cells (Figure 10.8c,
d), sometimes referred to as ‘hobnail’ cells, which often
show cilia or apocrine snouts (Figure  10.9). Superficial
hobnail cells may be seen throughout the ­lining, but may
be most prominent overlying areas of thickening.
A characteristic feature, seen in almost all cases, is glan-
dular or pseudo-­glandular structures within the epithelial
lining. These form microcysts or pools that are lined by
cuboidal or columnar cells, to give an appearance of small
ducts (Figure  10.9). Occasionally these are also lined by
mucous cells (Figure 10.9, arrow). In certain planes of sec-
tion, these microcysts may be seen to open onto the surface
of the epithelium through openings or crypts, giving the
epithelium a papillary or corrugated surface, described by
Fowler et al. (2011) as ‘tufting’. The crypts are sometimes
empty and sometimes contain mucus (positive for periodic
acid–Schiff [PAS] or mucicarmine).
Mucous cells are also characteristic, but it must be noted
that these are not essential for the diagnosis: up to 30% of
172 Glandular Odontogenic Cyst
(a)
(c)
Figure 10.8  Epithelial thickenings and plaques in glandular odontogenic cysts. Sometimes these are prominent and form papillary
projections (a, b, d). Superficial cuboidal or columnar (‘hobnail’) cells can clearly be seen (c, d).
cases may not contain mucous cells and in others they may
be very few in number (Table  10.3; Fowler et  al.  2011;
Chrcanovic and Gomez 2018b). When present, they most
often appear as superficial goblet cells that may be seen
alone as single cells or in groups (Figure  10.10). In some
cases focal accumulations of plump mucous cells have
been seen (Figure 10.11), and these may be admixed with
squamous cells in a pattern similar to that seen in mucoep-
idermoid carcinoma (see below). Most cysts also show scat-
tered or focal accumulations of clear or vacuolated cells.
Occasional clear cells can be seen in the cyst linings shown
in Figures 10.7–10.10 and 10.12.
Islands of odontogenic epithelium and even microcysts
may be present in the connective tissue wall of the cyst.
Fowler et  al. (2011) described three cases with islands in
the wall as ‘mucoepidermoid carcinoma-­like’. In two cases
these islands were found within bone. Small cysts and
islands can be seen in the walls of the cysts shown in
(b)
(d)
Figure 10.6, but some of these may be due to the plane of
section. Irregular calcifications may also be present in the
connective tissue wall, but inflammation is unusual, except
in large lesions that may have been traumatised or perfo-
rated the cortical plate. In one case we have seen small
focal areas of flattened epithelium, with a parakeratinised
surface (Figure 10.12).
There have been reports of glandular odontogenic cysts
associated with ameloblastoma. Cousin et  al. (2017)
reported a single case and reviewed four previous reports.
These suggested ameloblastomatous epithelium within the
lining of the cyst, or islands of ameloblastoma within the
wall of an otherwise typical glandular odontogenic cyst.
However, on review we feel that two of these reports do not
provide sufficient evidence that the lesions meet the crite-
ria for a diagnosis of glandular odontogenic cyst, and one
report is so unusual as to be difficult to diagnose. Thus
there are only two reports that are sufficiently well
 ­Histopathology 173

Figure 10.9  Part of the lining of the cyst shown in Figure 10.6b. An area of a thickened lining with microcysts, lined by cuboidal cells
to give an appearance like small ducts. Mucous cells are also noted (arrow). Inset: duct-­like appearance and cilia.

Table 10.3  Histological features of the glandular odontogenic unicystic ameloblastoma. These lesions appear to be unu-
cyst and their frequency (%). From the series of Fowler et al. (2011) sual oddities and, based on only two cases, the clinical sig-
and the review of Chrcanovic and Gomez (2018b).
nificance of these findings remain uncertain.

Fowler Chrcanovic and

et al. (2011) Gomez (2018b) Diagnostic Criteria

n = 46 cases n = 169 cases (review) It can be seen that there are many and varied histological
features that may be encountered in the glandular odonto-
Superficial 100.0 95.0 genic cyst. Each individual cyst may present some but not
cuboidal cells all of the features and diagnosis may be difficult if key fea-
Microcysts/ 95.7 97.5 tures are absent in any given biopsy. Whenever possible the
duct-­like full specimen should be examined and, with large lesions, it
structures
is necessary to examine multiple blocks. Box 10.2 summa-
Apocrine snouting 91.3 40.4
rises the diagnostic criteria and emphasises the need to also
Clear cells 89.1 45.3 consider the clinical and radiological findings (Box 10.1).
Variable thickness 89.1 96.3 Kaplan et al. (2005a) divided the histological features into
Papillary 84.8 77.6 major and minor categories and suggested that each of the
projections major features must be present for a diagnosis of glandular
(tufting)
odontogenic cyst, while the presence of any of the minor fea-
Mucous cells 71.7 72.0 tures was supportive. The five major features were (i) squa-
Epithelial spheres 67.4 72.7 mous epithelial lining; (ii) variations in thickness of the lining
Multicystic 63.0 70.2 with or without epithelial ‘spheres’ or ‘whorls’ or focal lumi-
Ciliated cells 21.7 61.5 nal proliferation; (iii) cuboidal eosinophilic cells or ‘hobnail’
cells; (iv) mucous (goblet) cells with intraepithelial mucus
pools with or without crypts lined by mucus-­producing cells;
documented to suggest that ameloblastoma and glandular and (v) glandular microcystic or duct-­like structures. The four
odontogenic cyst may co-­exist (Gardner et al. 1988; Cousin minor features were (i) papillary proliferation; (ii) ciliated
et al. 2017). Both cases arose in the premolar/molar region cells; (iii) multicystic or multiluminal architecture; and (iv)
of the mandible and showed islands of quite typical follicu- clear or vacuolated cells in the basal or spinous layer.
lar ameloblastoma in the wall of a glandular odontogenic A significant problem with these criteria is that if a major
cyst. Cousin et  al.’s (2017) case also showed transition of feature is missing, then the diagnosis cannot be made. In
the lining from cyst to ameloblastoma. The authors sug- their own study, Kaplan et al. (2005a) reviewed 29 reports
gested that the features were analogous to a mural type of of glandular odontogenic cyst and showed that no reports
174 Glandular Odontogenic Cyst

Figure 10.10  A periodic acid–Schiff (PAS)-­stained

section of part of the lining of the cyst shown in
Figure 10.6a. Mucous cells were not prominent, but
were seen in the superficial layers, either as single
cells or in small groups.

Figure 10.11  An example of a glandular

odontogenic cyst with prominent mucous cells in
focal accumulations. Plaque-­like thickenings,
whorling, and superficial columnar cells can also
be seen.

Figure 10.12  A portion of a cyst wall from the

lesion illustrated in Figure 10.6a. Note small area
of parakeratinisation (arrows). Clear cells are also
noted in the basal layers.
 ­Histopathology 175

Box 10.2  Glandular Odontogenic Cyst: Diagnostic Criteria and Differential Diagnosis

●● Over 70% occur in the mandible. Most common in the anterior/premolar area
●● Well-­defined radiolucency with corticated margin. About one-­third are multilocular
●● Histology typically shows multicystic lesion, superficial cuboidal/columnar (hobnail) cells, microcysts, mucous
cells, cilia, and plaque-­like thickenings
●● If 6 of 10 features are present (Table 10.3), the diagnosis is almost certain
●● Immunocytochemistry with cytokeratin (CK)19 and CK18 may help. Glandular odontogenic cyst is always CK19+,
but only 30% express CK18
●● Do not show MAML2 rearrangement
Caution: features that suggest an alternative diagnosis:
●● Multicystic lesion with plaques or thickenings, but no hobnail or mucous cells or microcysts: consider botryoid odon-
togenic cyst
●● Unilocular lesion with plaques or thickenings, but no hobnail or mucous cells or microcysts: consider lateral perio-
dontal cyst
●● Cyst with mucous cells, but no microcysts, apocrine secretion, cilia, or thickenings: consider odontogenic cyst with
mucous metaplasia, especially radicular or dentigerous cyst
Mucoepidermoid carcinoma (Table 10.4) shows:
●● Evidence of invasion of bone or the cyst wall
●● Admixture of epidermoid or intermediate cells and mucous cells
●● Solid areas
●● Immunocytochemistry with CK19 and CK18 may help. Mucoepidermoid carcinoma is always CK18+, but only 50%
express CK19
●● Fluorescence in situ hybridisation (FISH) shows MAML2 rearrangement in 50% of cases

recorded the presence of all five features listed as major cri-
teria. For example, only 65.5% recorded the presence of
mucous cells or hobnail cells and only 58.6% reported
microcysts. It is not clear, therefore, why the authors chose
to make these features mandatory.
Fowler et al. (2011) analysed 46 cases and also showed that
not all features were present in all cysts (Table 10.3), and this
was confirmed in a review of 169 cases by Chrcanovic and
Gomez (2018b). It can be seen, for example, that almost all
cysts contain superficial columnar cells and microcysts, but
mucous cells are absent from about 30% of lesions. Therefore,
a common diagnostic error is to exclude a diagnosis of glan-
dular odontogenic cyst if mucous cells are not seen. Fowler
et al. (2011) thus adopted a more pragmatic approach to diag-
nosis and suggested that the presence of six or more of the
features listed in Table 10.3 was highly predictive of a diagno-
sis of glandular odontogenic cyst, and if there were five or
fewer then this diagnosis was less likely. They showed that all
46 cysts had six features or more and that 43 (93.5%) had
seven or more. Only two cysts not diagnosed as glandular
odontogenic cyst had more than seven features, but both
were unusual and the precise diagnosis was not certain.
When compared to 21 lesions with similar features to glan-
dular odontogenic cyst (‘mimickers’), these authors found
that microcysts, epithelial spheres, clear cells, and a
multicystic morphology were statistically more likely to be
found in the glandular odontogenic cyst. Furthermore, they
showed that if microcysts are present, then a multicystic
morphology is most associated with the diagnosis.
These analyses suggest that great care needs to be taken
in diagnosing these lesions. Although the features are char-
acteristic, each is not specific and the diagnosis is made on
consideration of a combination of the features. If 7 of the 10
features described in Table 10.3 are present, then this is vir-
tually diagnostic of glandular odontogenic cyst. However,
in our experience this number of features may not always
be present. The features most commonly seen are superfi-
cial cuboidal (‘hobnail’) cells, and a combination of these
with microcysts, epithelial plaques or spheres, mucous
cells, and a multicystic morphology is usually sufficient to
render a diagnosis of glandular odontogenic cyst. Special
care must be taken when examining small incisional biop-
sies, because multiple features are rarely present. The histo-
logical features should always be interpreted along with the
clinical and radiological features (Boxes 10.1 and 10.2).
Histological Differential Diagnosis
As discussed above, a diagnosis of glandular odontogenic
cyst is made on the recognition of a combination of a
176 Glandular Odontogenic Cyst
number of histological features. However, these varied
appearances may still cause considerable diagnostic diffi-
culty and this cyst is probably the most commonly missed
or misdiagnosed of all the odontogenic cysts. As discussed
in the next section and in Chapter  8, the most common
errors of diagnosis are confusion with central mucoepider-
moid carcinoma and botryoid odontogenic cyst.
In early reports, glandular odontogenic cyst was regarded
as a variant of botryoid odontogenic cyst (Browne 1991b;
Noffke and Raubenheimer 2002) and a number of papers
reported unusual lateral periodontal or botryoid odonto-
genic cysts, which on review are in fact glandular odonto-
genic cysts (Phelan et  al.  1988; Buckley et  al.  1989;
Heikinheimo et  al.  1989; Öçok et  al.  2005). Glandular
odontogenic cyst and botryoid odontogenic cyst may be
multilocular on radiographs and multicystic on histology
and both show typical epithelial thickenings or plaques,
which they also share with lateral periodontal cyst (com-
pare Figures  8.6 and  10.8). However, glandular odonto-
genic cyst also shows microcysts, superficial columnar
cells, apocrine secretion, and mucous cells, which are not
features of lateral periodontal or botryoid cysts. Also, we
have noted that the epithelial plaques are often more prom-
inent in glandular odontogenic cyst and may form bulbous
papillary processes (e.g. Figure 10.8a, d), but these are rare
in lateral periodontal and botryoid cysts. Furthermore, lat-
eral periodontal and botryoid odontogenic cysts lie lateral
to the teeth and are rarely greater than 10 mm or 40 mm in
diameter, respectively. In the differential diagnosis, there-
fore, if lesions are large and microcysts, hobnail cells, or
mucous cells are seen, then a diagnosis of botryoid odonto-
genic cyst is probably incorrect and glandular odontogenic
cyst should be considered.
All pathologists are aware that many types of odonto-
genic cyst may show evidence of metaplasia with mucous
cells, but a common error is the overinterpretation of
mucous cells, especially in dentigerous cysts, to arrive at a
misdiagnosis of glandular odontogenic cyst. Takeda et al.
(2005) examined 130 dentigerous cysts and found mucous
cells and cilia in 23.8% and 10.8%, respectively. Many cases
also showed intraepithelial mucus pools that resemble
microcysts or duct-­like structures. Fowler et  al. (2011)
examined 13 selected dentigerous cysts that showed evi-
dence of metaplastic changes and found evidence of some
overlap with features seen in glandular odontogenic cyst.
The changes seen in dentigerous cysts included superficial
cuboidal cells, microcysts, mucous cells, apocrine snout-
ing, ‘tufting’, and clear cells, but none showed a combina-
tion of features that would lead to a diagnosis of glandular
odontogenic cyst. These authors also pointed out that the
‘microcysts’ seen in dentigerous cysts are usually simple
mucus pools and not true microcysts. We would agree with
this and would suggest that similar pools are also often
seen in radicular cysts with mucous metaplasia. The pools
are small, intraepithelial, and lined by flattened epithelial
cells, which appear to have been ‘pushed aside’ by the
accumulation of mucus (Figure  10.13). In contrast, the
microcysts in glandular odontogenic cyst are often lined by
cuboidal or columnar cells to invoke the appearance of
ductal structures, some of which may open into the cyst
lumen (Figure 10.9). Although cases have been reported, it
should also be noted that it is not common for glandular
odontogenic cysts to be found in a dentigerous relationship
and therefore a pericoronal radiolucency argues against
the diagnosis.
Central Mucoepidermoid Carcinoma
Most histopathologists, faced with histological sections of a
glandular odontogenic cyst, will have noted the similarities
to the central mucoepidermoid carcinoma. The resem-
blance between these two lesions was noted in the first
reported cases by Padayachee and Van Wyk (1987), who
Figure 10.13  A dentigerous cyst with mucous
metaplasia. There are mucous cells, but also mucus
pools lined by flattened epithelial cells (compare
with Figure 10.9).

described their lesions as having features of both botryoid
odontogenic cyst and ‘central mucoepidermoid tumour’.
As early as 1956, however, Hodson had drawn attention to
mucous cells in odontogenic cysts and reported a series of
cases as ‘muco-­epidermoid odontogenic cysts of the jaws’
(Hodson 1956). Most of these showed mucous metaplasia
in radicular or dentigerous cysts, but his illustrations sug-
gest that at least one case could have been a glandular
odontogenic cyst, and he drew attention to the similarities
with ‘muco-­epidermoid salivary tumours’. Since then, cen-
tral (intraosseous) mucoepidermoid carcinoma has been
shown to be the most frequently encountered central sali-
vary gland tumour (Bouquot et  al.  2000; Li et  al.  2008),
with 147 cases reported up to 2018 (de Souza et al. 2018).
There has been much speculation about the origin of this
lesion, but possible sources include intraosseous salivary
tissue entrapped during development, glandular differen-
tiation of odontogenic epithelial rests, or metaplasia in
odontogenic cysts (Eversole et al. 1975; Bouquot et al. 2000;
Li et al. 2008). Most authors favour an odontogenic origin,
since central mucoepidermoid carcinomas have been
shown to arise in association with odontogenic cysts
(Eversole et al. 1975; Chaisuparat et al. 2012).
Because of the histological similarities between glandu-
lar odontogenic cyst and mucoepidermoid carcinoma,
(a)
Figure 10.14  Two examples of central mucoepidermoid carcinoma. (a) Islands of tumour invade the connective tissues. (b) Solid
islands of tumour are seen in the cyst wall. These show a characteristic admixture of epidermoid or intermediate cells with clear cells
and mucous cells (inset).
­Histopathology 177
there is much speculation in the literature about their rela-
tionship, in particular that mucoepidermoid carcinomas
may arise from glandular odontogenic cysts, or that glan-
dular odontogenic cyst is at the benign end of a spectrum
of mucoepidermoid carcinoma (Waldron and Koh 1990).
If care is taken and the diagnostic criteria discussed
above are followed, diagnosis should rarely be a problem
(Box 10.2). However, about 50% of intraosseous mucoepi-
dermoid carcinomas are low grade, and may be cytologi-
cally bland and multicystic, leading to potential confusion.
Mucoepidermoid carcinomas are almost always composed
of multiple variably sized cystic spaces, whereas glandular
odontogenic cysts are multicystic in only 60–70% of cases
(Table 10.3). Both lesions, however, may contain mucous
cells, duct-­like structures, and clear cells. In glandular
odontogenic cyst these features are seen within the lining
of the cyst, whereas in mucoepidermoid carcinoma more
solid islands may be seen, or sheets of tumour may infil-
trate from the cyst lining into the underlying connective
tissue (Figure  10.14) or adjacent bone (Figure  10.15).
Mucoepidermoid carcinomas also show a characteristic
admixture of epidermoid or intermediate cells, with
mucous or clear cells (Figure 10.14b), and may show areas
of keratinisation or keratin pearls (Figure  10.15, inset).
Conversely, glandular odontogenic cysts may show ciliated
(b)
178 Glandular Odontogenic Cyst
Figure 10.15  Central mucoepidermoid carcinoma (same lesion as Figure 10.14a). The lesion is multicystic and small cysts are
invading into the adjacent bone. The cysts are lined by epidermoid and mucous cells (inset) and a small island can be seen with
central keratinisation (inset, arrowhead).
cells and apocrine secretion, and be characterised by super-
ficial hobnail cells, plaque-­like thickenings, whorling, and
epithelial spheres and papillary projections, all features
that are rarely or never seen in mucoepidermoid carcino-
mas. Invasion into adjacent bone is also a feature of
mucoepidermoid carcinoma, but has been rarely described
in glandular odontogenic cyst (Figure  10.15; Fowler
et  al.  2011). Table  10.4 summarises the histological simi-
larities and differences between glandular odontogenic
cyst and mucoepidermoid carcinoma.
Immunohistochemistry and Molecular Studies
A number of studies have been undertaken to examine the
potential role of immunocytochemistry in the diagnosis of
glandular odontogenic cyst, especially expression of
cytokeratins (de Sousa et  al.  1997; Koppang et  al.  1998;
Pires et al. 2004; Shen et al. 2006). However, most studies
have only used one or two cases and have not compared
expression to any potential alternative lesions. Overall they
have shown that glandular odontogenic cysts tend to show
patchy and variable expression of simple cytokeratins, but
in particular most cases have been positive for CK7 and
CK19 and are negative for CK20 (Shen et al. 2006). Pires
et al. (2004) specifically addressed the issue of differential
diagnosis and investigated expression of 11 cytokeratins in
glandular odontogenic cyst and central mucoepidermoid
carcinoma, as well as in a number of salivary mucoepider-
moid carcinomas and a range of other odontogenic cysts
and tumours. Central (n = 6) and salivary (n = 23) mucoep-
idermoid carcinomas showed very similar cytokeratin pro-
files, with consistent expression of CK5, CK7, CK8, CK14,
and CK18. Glandular odontogenic cysts (n  =  10) shared
expression of CK5, CK7, CK8, and CK14 with mucoepider-
moid carcinoma, but only 30% expressed CK18. Conversely,
100% of glandular odontogenic cysts showed CK19 expres-
sion compared to only 50% of central mucoepidermoid car-
cinoma. However, CK19 expression was higher in salivary
tumours, with up to 100% of intraoral lesions (palate and
retromolar) being positive. CK19 expression was also seen
in the majority of other odontogenic lesions.
These results would support the view that glandular
odontogenic cyst and central mucoepidermoid carcinoma
are distinct entities, characterised in particular by high
expression of CK19 and CK18, respectively. When faced
with an individual lesion, immunocytochemistry for a
combination of CK19 and CK18 may be a helpful diagnos-
tic adjunct. It must be noted that although CK 19 is sensi-
tive for glandular odontogenic cyst, it is not specific, and a
positive result is not diagnostic. However, since 100% of
glandular odontogenic cysts are positive for CK19, a nega-
tive result may exclude this diagnosis. The converse is true
for CK18: a negative result would mitigate against mucoep-
idermoid carcinoma. Thus the immunophenotypes that
would support a diagnosis are CK19+/CK18– for glandular
odontogenic cyst and CK19–/CK18+ for central mucoepi-
dermoid carcinoma (Pires et al. 2004; Table 10.4).

Table 10.4  Features that may assist in the differential diagnosis of glandular odontogenic cyst and central mucoepidermoid
carcinoma.
Histological features
Multilocular radiolucency
Multicystic
Perforates cortical plate
Mucous cells
Duct-­like structures
Plaques and thickenings
Surface columnar/cuboidal cells
Ciliated cells
Apocrine secretion
Commonly anterior mandible
CK19+/CK18−a
Solid areas infiltrating cyst wall
Admixture of epidermoid and mucous cells
Invasion into cyst wall and bone
Commonly posterior mandible
CK18+/CK19−a
Maspin+ mucous cells
MAML2 translocation
CK, cytokeratin; N, not seen or very rare; Y, characteristic feature often present.
a
 See text for detailed explanation. Source: Based on Pires et al. (2004).
Other studies have investigated proliferation markers as
potential diagnostic aids. Tosios et  al. (2000) compared
expression of bcl-­2 protein, Ki-­67 antigen, and p53 protein
in three glandular odontogenic cysts with expression in six
dentigerous cysts. The glandular odontogenic cysts showed
homogeneous reactivity for bcl-­2 protein, but the dentiger-
ous cysts were negative or had faint basal cell staining.
Ki-­67  was slightly lower in glandular odontogenic cysts,
but there were no differences in p53 staining. The authors
speculated that the increased expression of the anti-­
apoptotic bcl-­2 may contribute to growth of the cyst; cell
proliferation and p53 status did not seem to play a signifi-
cant role.
Kaplan et al. (2005a) performed a similar study, compar-
ing p53, Ki-­67, and proliferating cell nuclear antigen
(PCNA) expression in a series of 11 glandular odontogenic
cysts, 9 mucoepidermoid carcinomas (only 2 were central),
and 15 radicular cysts showing mucous metaplasia. Only
the Ki-­67 results showed a difference between glandular
odontogenic cyst (mean ± SD: 4.4 ± 4.7%) and the mucoepi-
dermoid carcinomas (0.7 ± 1.6%). Interestingly, Ki-­67
expression in radicular cysts (3.7 ± 6.7%) was similar to
glandular odontogenic cyst and was lowest in the
carcinomas.
­Histopathology 179
Glandular odontogenic cyst Central mucoepidermoid carcinoma
Y Y
Y Y
Y Y
Y Y
Y Y
Y N
Y N
Y N
Y N
Y N
Y N
N Y
N Y
N Y
N Y
N Y
N Y
N Y
These papers demonstrate some differences in prolifera-
tion markers, but given the great range of expression, vari-
ation between lesions, and the overall low proportion of
positive cells, they do not seem promising as diagnostic
aids in differentiating the glandular odontogenic cyst from
the central mucoepidermoid carcinoma.
Vered et  al. (2010) explored expression of maspin as a
potential discriminatory marker. They compared glandular
odontogenic cyst (n = 8) with low-­grade mucoepidermoid
carcinoma of salivary origin (not central; n = 6), and found
that maspin expression was similar in the epithelial cells.
However, they found a significantly greater expression of
maspin in mucous cells of mucoepidermoid carcinoma
(16.5 ± 10.8%) than in glandular odontogenic cyst
(1.5 ± 2%), and suggested that this may be diagnostically
helpful, especially in small biopsies.
More recently there has been a focus on rearrangements
of the MAML2 gene as a potential molecular marker
to  ­distinguish glandular odontogenic cyst from central
mucoepidermoid carcinoma. It is well established that
mucoepidermoid carcinomas are characterised by a
t(11;19) gene rearrangement and associated CRTC1/3/
MAML2 fusion transcript. The MAML2 rearrangement can
be detected by reverse transcription polymerase chain
180 Glandular Odontogenic Cyst
reaction (RT-­PCR) or, more usually, by fluorescence in situ
hybridisation (FISH); a positive result is useful for the diag-
nosis of mucoepidermoid carcinoma and may also assist in
tumour grading. Up to 80% of salivary and about 50% of
central mucoepidermoid carcinomas have been shown to
be positive for the MAML2 rearrangement (Bell et al. 2016;
Cipriani et al. 2019; Reddy et al. 2019).
Bishop et  al. (2014) used analysis of the MAML2
­rearrangement to help clarify the relationship between
glandular odontogenic cyst and central mucoepidermoid
carcinoma. They used FISH to seek evidence of a MAML2
rearrangement in 21 glandular odontogenic cysts and 5
central mucoepidermoid carcinomas. All 5 central mucoep-
idermoid carcinomas were positive for the MAML2 rear-
rangement, whereas all 21 glandular odontogenic cysts
were negative. They noted that FISH demonstrated the
rearrangement in solid areas of mucoepidermoid carcino-
mas, but also in cystic areas that histologically resembled
glandular odontogenic cyst. The authors concluded that
glandular odontogenic cyst is a separate entity to central
mucoepidermoid carcinoma and should not be regarded as
a ‘benign’ form or precursor of mucoepidermoid carci-
noma. Barrett et  al. (2016) described three cystic lesions
where the differential diagnosis was between mucoepider-
moid carcinoma and glandular odontogenic cyst, and
where the demonstration of MAML2 rearrangements was
able to resolve the dilemma.
Subsequently, three papers have suggested that MAML2
may not be so specific and may be found in glandular odon-
togenic and other odontogenic cysts (Argyris et al. 2015b;
Greer et al. 2018; Nagasaki et al. 2018). Because of the topi-
cal nature of this argument, these papers will be consid-
ered in some detail.
Greer et al. (2018) deliberately selected a subset of 11 glan-
dular odontogenic cysts that had recurred (and that they
labelled as ‘biologically aggressive’) for investigation of
MAML2 rearrangements. All 11 cases were histologically
diagnosed as glandular odontogenic cyst and showed at least
6 of the 10 features described by Fowler et  al. (2011)
(Table 10.3). One case showed the MAML2 rearrangement.
The text of the published paper suggests that the rearrange-
ment was found in the recurrent cyst and that the primary
lesion was not available. All the clinical and histological fea-
tures suggest that this recurrent lesion was a typical glandu-
lar odontogenic cyst. The only unique features were the
finding of prominent goblet cells and cilia, almost involving
the entire luminal surface. This case raises two possibilities:
first, that glandular odontogenic cyst, even with typical
­histology, may show the MAML2 gene rearrangement;
or  secondly, that a low-­grade (MAML2-­positive) central
mucoepidermoid carcinoma may be clinically and histologi-
cally indistinguishable from a glandular odontogenic cyst.
Nagasaki et al. (2018) reported a similar case where a typi-
cal glandular odontogenic cyst, showing 7 of the 10 criteria
(Table  10.3), recurred after nine years. The primary lesion
was negative for the MAML2 rearrangement, but PCR
showed a CRTC3/MAML2 fusion in the recurrent lesion,
confirming a mucoepidermoid carcinoma. Review of the
histology illustrated in their paper shows that the recurrent
lesion has features quite unlike glandular odontogenic cyst,
but is more typical of a multicystic and infiltrative mucoepi-
dermoid carcinoma. The authors interpreted these findings
as confirming that mucoepidermoid carcinoma can arise
from a glandular odontogenic cyst. An alternative explana-
tion, however, is that the primary lesion was also a mucoepi-
dermoid carcinoma, but indistinguishable from a glandular
odontogenic cyst, similar to the cases of Greer et al. (2018).
Argyris et  al. (2015b) investigated the presence of
MAML2 rearrangements in odontogenic cysts with evi-
dence of mucous cells. Their study was based on the prem-
ise that many central mucoepidermoid carcinomas have
been shown to arise in odontogenic cysts, and that the
CRTC1/MAML2 fusion transcript may be an early molecu-
lar event in the development of mucoepidermoid carcino-
mas (Bell et  al.  2010). They hypothesised therefore that
some cysts with mucous metaplasia may be precursor
lesions and may harbour the MAML2 rearrangement. They
used FISH to determine the MAML2 status of eight denti-
gerous and one radicular cyst that contained mucous cells,
and found that the radicular cyst and four dentigerous
cysts had the MAML2 rearrangement. The authors
described this as a pilot study and the findings have not yet
been independently repeated, but they are interesting, and
they do raise the possibility that odontogenic cysts with
mucous metaplasia may harbour early molecular events
that precede progression to mucoepidermoid carcinoma.
Taken together, these studies provide some evidence to
support the concept that glandular odontogenic cyst may
be a precursor lesion to central mucoepidermoid carci-
noma, and that the possibility that glandular odontogenic
cyst is itself a benign neoplasm cannot yet be dismissed. A
further interpretation is that, in rare cases, the histological
features of glandular odontogenic cyst may be indistin-
guishable from a low-­grade central mucoepidermoid carci-
noma. Nevertheless, the work of Bishop et al. (2014) still
provides strong evidence that glandular odontogenic cysts
do not have MAML2 rearrangements. In cases of doubt, the
finding of MAML2 should be regarded as diagnostic of cen-
tral mucoepidermoid carcinoma. Conversely, although a
negative result suggests glandular odontogenic cyst, it is
not diagnostic. Faced with a single lesion, pathologists
must consider all the clinical, radiological, and histological
features in reaching a diagnosis (Boxes 10.1 and 10.2). The
differentiating features are summarised in Table 10.4.

­Treatment
Glandular odontogenic cyst is usually treated conserva-
tively, by enucleation with or without curettage. In their
review of 169 cases, Chrcanovic and Gomez (2018b)
reported that the majority had been treated by enucleation
(66.4%) or curettage (22.1%) and only 10% had a marginal
or segmental resection.
Kaplan et al. (2005b) carried out an extensive survey of
the treatment and follow-­up of a sample of 56 patients with
glandular odontogenic cysts, including 3 of their own
cases. The mandible was involved in 41 cases (73%) and the
maxilla in 15 (27%). Of the lesions, 11 were located in the
anterior region, 9 in the posterior, and 36 overlapped both.
The authors suggested that the protocol for treatment
should take into account that small unilocular lesions are
usually enucleated before a definitive histological diagno-
sis has been made, and, if they are completely enucleated,
further surgery is not indicated because recurrence is
unlikely. They recommend, however, that these patients
­Treatment 181
should be followed for at least three years and preferably as
long as seven years.
Large unilocular or multilocular lesions should be biop-
sied before treatment is planned. Kaplan et al. recommended
that as unilocular lesions had a lower risk of recurrence than
multilocular ones, even large lesions can be enucleated with
preservation of vital structures. Peripheral ostectomy in con-
junction with enucleation can reduce recurrence and should
be performed whenever possible. Marsupialisation is an
option if the lesions approach vital structures. If marsupiali-
sation is performed, curettage and peripheral ostectomy are
advised for second-­phase surgery.
For large multilocular lesions, major treatment modali-
ties are indicated. These include peripheral ostectomy,
marginal resection, or partial jaw resection, depending on
the size of the lesion, integrity of the jaw borders, and prox-
imity to vital structures. Kaplan et  al. suggest that if the
lesion lies close to the sinus, pterygoid, or nasal cavity, mar-
supialisation with second-­phase enucleation after reduc-
tion of the lesion can be undertaken.
182

11

Calcifying Odontogenic Cyst

CHAPTER MENU
­Classification and Terminology of the Calcifying Odontogenic Cyst, 182
­Clinical Features, 185
●● Frequency, 185
●● Age, 186
●● Sex, 186
●● Site, 186
●● Clinical Presentation,  187
–– Peripheral (Extraosseous) Calcifying Odontogenic Cyst,  188
­Radiological Features, 188
●● Radiological Differential Diagnosis,  190
­Pathogenesis, 190
●● Ghost Cells and the β-­Catenin Gene (CTNNB1), 191
­Histopathology, 193
●● Histological Differential Diagnosis,  199
●● Ghost Cell Odontogenic Carcinoma and Malignant Progression of Calcifying Odontogenic Cyst,  199
­Treatment, 200

Calcifying odontogenic cyst is an odontogenic cyst, lined
by an ameloblastoma-­like epithelium, and characterised by
focal accumulations of ghost cells that may calcify. It was
first described and named by Gorlin et  al. (1962,  1964),
who were impressed by the presence of the ghost cells
and the cyst’s histological resemblance to the cutaneous cal-
cifying epithelioma of Malherbe (pilomatrixoma). The
lesions they described were simple cysts and, because
­dystrophic calcification in the ghost cells was prominent,
they named them calcifying odontogenic cyst. Since this early
description, however, it has become appreciated that lesions
with similar features can show considerable histomorpho-
logical variation, including solid lesions that may be neo-
plastic. It is now recognised that calcifying odontogenic cyst
is one of a family of odontogenic ghost cell lesions that
includes dentinogenic ghost cell tumour and ghost cell odonto-
genic carcinoma (Ledesma-­Montes et  al. 2008; Wright and
Soluk ­Tekkeşin 2022; WHO 2022a). Nevertheless, over the
six decades since Gorlin et al.’s description, there has been
considerable debate in the literature about the classification
and terminology of the odontogenic ghost cell lesions.
­ lassification and Terminology of the
C
Calcifying Odontogenic Cyst
When Gorlin et  al. (1962,  1964) first described the lesion,
they recognised its characteristic features and named it the
calcifying odontogenic cyst. It should be noted that the term
‘calcifying’ was used primarily because of the prominent
dystrophic calcification of the ghost cells, although dentine-­
like material may also be seen. The lesion became well rec-
ognised and was included in the 1971  World Health
Organization (WHO) classification of odontogenic tumours
and was defined as a ‘non-­neoplastic cystic lesion’ (Pindborg
and Kramer  1971). For reasons that are uncertain, it was
listed under the benign ‘neoplasms and other tumours’
rather than under the developmental odontogenic cysts.

Shear’s Cysts of the Oral and Maxillofacial Regions, Fifth Edition. Paul M. Speight.
© 2022 John Wiley & Sons Ltd. Published 2022 by John Wiley & Sons Ltd.

This categorisation and a number of misunderstandings
(discussed below) seem to have started decades of confusion
about the nature of this lesion. It does seem that several
authors have noted that the cyst is classified under ‘tumours’
and have considered this to be synonymous with a neo-
plasm, often ignoring its designation as ‘non-­neoplastic’.
Subsequent to the 1971 classification, it became apparent
that the nature of the lesion was more varied and that a num-
ber of odontogenic lesions may contain ghost cells. This
included a ‘solid variant’ of the calcifying odontogenic  cyst
that was variously called the ‘calcifying ghost cell odontogenic
tumour’ (Fejerskov and Krogh 1972), the  ‘cystic calcifying
odontogenic tumor’ (Freedman et al. 1975), and the ‘epithelial
odontogenic ghost cell tumor’ (Ellis and Shmookler 1986).
Gorlin and his colleagues revisited the nature of the
lesion in 1981 (Prætorius et  al.  1981) and identified two
types. Type 1  was a simple unicystic lesion with the fea-
tures first described by Gorlin et al. in 1962. Type 2 was a
solid lesion with a growth pattern like ameloblastoma, but
with ghost cells and prominent formation of dentinoid
material. They regarded this solid lesion as a neoplasm and
proposed the name dentinogenic ghost cell tumour. For the
cystic lesion they retained the name calcifying odontogenic
cyst, but also identified three variants (Table 11.1). Type 1A
was a simple calcifying odontogenic cyst as described pre-
viously. Type 1B showed features of a typical calcifying
odontogenic cyst, but with epithelial islands in the wall
and with an associated odontoma. Type 1C was similar
to  1A, but with ameloblastoma-­like proliferations in the
lumen and in the wall. This became the first attempt to
subdivide the ghost cell lesion into categories and became
known as the ‘dualistic’ concept: that the calcifying odon-
togenic cyst represented two entities, a non-­neoplastic cyst
Table 11.1  The first detailed classification of the odontogenic
ghost cell lesions.
Calcifying
Type 1 odontogenic cyst Key features
1A Simple cyst Ameloblastoma-­like lining.
Ghost cells. Calcifications
1B Simple cyst, with As 1A, but with multiple
odontoma forming in tooth-­like structures
the wall
1C Simple cyst, but with As 1A, but with luminal
ameloblastoma-­like and mural proliferations
proliferations in the wall and prominent dentinoid
and lumen
Type 2 Dentinogenic ghost Solid neoplasm with
cell tumour ameloblastoma-­like growth
pattern (may be
multicystic). Prominent
ghost cells and dentinoid
Source: Based on Prætorius et al. (1981).
­Classification and Terminology of the Calcifying Odontogenic Cys 183
and a solid neoplasm. It is a source of some bemusement
that for many years the neoplastic lesion was often referred
to as the ‘solid calcifying odontogenic cyst’. This first clas-
sification is summarised in Table 11.1.
In 1991, two groups reviewed the classification of the
ghost cell lesions and agreed with the dualistic concept that
they fell into a non-­neoplastic cystic group and a solid neo-
plasm (Buchner 1991; Hong et al. 1991). Both continued to
recognise that the cyst had a number of variants, including
an association with odontomas and proliferative types.
They also drew attention to the fact that peripheral lesions
may be encountered. Buchner (1991) furthermore included
a malignant variant in his classification – the lesion that is
now known as ghost cell odontogenic carcinoma.
The next milestone in the story of terminology and classifi-
cation came with the publication of the second edition of the
WHO classification of odontogenic tumours (Kramer
et al. 1992). The terminology used and the subsequent mis-
understanding led to a further period of confusion. In the
1992 classification, the cyst was still (incorrectly in our view)
included under the benign odontogenic ‘neoplasms and
other tumours’, but the authors seemed uncertain about its
nature – they used an almost identical definition to 1971, but
removed ‘non-­neoplastic’ and defined it as a ‘cystic lesion’.
This implied that the calcifying odontogenic cyst should be
defined as a neoplasm, although in the text they stated clearly
that the cyst was ‘non-­neoplastic’, but that a more solid vari-
ant was neoplastic, and used the term ‘dentinogenic ghost
cell tumour’ that had been suggested by Prætorius et al. (1981).
In 1998, Toida attempted a further clarification of the
nature of the calcifying odontogenic cyst and its classifica-
tion. He reviewed the previous classifications described
above and discussed the two concepts of a ‘monoistic’ clas-
sification, which regarded all calcifying odontogenic cysts
as neoplastic, and a ‘dualistic’ classification, which recog-
nised a (non-­neoplastic) cyst and a neoplasm. Toida (1998)
interpreted the 1992 WHO classification as being ‘monois-
tic’ and as meaning that all calcifying odontogenic cysts
‘both cystic and solid are neoplastic in nature’. To resolve
the issue, he proposed a new classification that he called
‘simple and basic’, but it included three types and at least
nine variants, compared to two types and three variants
proposed by Prætorius et al. (1981) (Table 11.1). Toida also
preferred the term ‘calcifying ghost cell odontogenic
tumour’ and proposed that it included cystic and solid neo-
plastic variants. If a non-­neoplastic cyst existed, he favoured
the term ‘calcifying ghost cell odontogenic cyst’.
Subsequent authors have continued to interpret the
1992  WHO classification as indicating that the calcifying
odontogenic cyst may be a neoplasm with a cystic and
solid  variant, but have still continued to describe a non-­
neoplastic (simple cystic) variant under a number of differ-
ent names. Li and Yu (2003) and Reichart and Philipsen
184 Calcifying Odontogenic Cyst
(2004) proposed similar classifications that included a non-­
neoplastic (simple) cyst, a neoplasm that may be solid or
cystic, and a malignant neoplasm. They also recognised
subtypes that may be associated with odontomas, and
peripheral variants. Reichart and Philipsen (2004) pre-
ferred the terms calcifying ghost cell odontogenic cyst and
calcifying ghost cell odontogenic tumour.
For reasons that are still not clear, the third edition of the
WHO classification (Barnes et al. 2005) completely dispensed
with the term ‘calcifying odontogenic cyst’ and with the dual-
istic concept, and redefined the ghost cell lesions into three
types, all of which were neoplasms: the calcifying cystic odon-
togenic tumour (CCOT), the dentinogenic ghost cell tumour,
and the ghost cell odontogenic carcinoma. The 2005 classifica-
tion did not include a classification of cysts, and so from this
time onwards the calcifying odontogenic cyst became known
as the CCOT and was classified as a neoplasm.
A further reappraisal was undertaken in 2008 by a large
multicentre group that included the authors of the WHO
classification (Ledesma-­Montes et  al.  2008). They under-
took a detailed review of 122 ghost cell lesions and their
terminology. They categorised the lesions into three groups
using the 2005 WHO terminology, and divided the calcify-
ing cystic odontogenic tumour into four types:
●● CCOT Type 1: simple cystic
●● CCOT Type 2: CCOT associated with an odontoma
●● CCOT Type 3: with ameloblastomatous-­like proliferation
●● CCOT Type 4: associated with other benign odontogenic
tumours other than odontoma
They found that 87% of their cases were simple cysts,
either alone (Type 1: 65%) or associated with odontomas
(Type 2: 22%). Of the 113  lesions in this category, only 6
(5.3%) recurred. Only 3 cases showed ameloblastomatous
proliferations and only 4 (3.3%) were associated with other
odontogenic lesions. There were 6 cases (5%) that were solid
and could be regarded as true neoplastic dentinogenic ghost
cell tumours. Although the authors used the term CCOT,
they seemed uncertain about its nature. They defined the
CCOT as a ‘cystic lesion’ or ‘cystic tumour’, whereas they
clearly defined the solid dentinogenic ghost cell tumour as
a ‘neoplastic tumour’ or ‘solid neoplastic growth’.
These findings agreed with the previous studies of
Buchner (1991) and Hong et al. (1991), who also showed
that simple cystic lesions rarely recur and have a com-
pletely benign course. As discussed above, most authors up
to 2005 classified this lesion (the CCOT) as a simple cyst
and only regarded the solid lesion as a true neoplasm.
There seems, therefore, to be good evidence that all the
early papers were correct (Pindborg and Kramer  1971;
Prætorius et al. 1981; Buchner 1991; Hong et al. 1991; Li
and Yu 2003; Reichart and Philipsen 2004) and that simple
cystic lesions should be classified as a developmental cyst,
which arises alone or in association with odontomas
(Ledesma-­Montes et al. 2008).
Thus, in 2017, the fourth edition of the WHO classifi-
cation (El-­Naggar et al. 2017) reverted to the original ter-
minology and classified the odontogenic ghost cell
lesions as calcifying odontogenic cyst, dentinogenic ghost
cell tumour, and ghost cell odontogenic carcinoma.
Furthermore, the 2017 classification included the odonto-
genic cysts and the calcifying odontogenic cyst was there-
fore classified as a developmental odontogenic cyst
(Speight et al. 2017a). The latest edition of the WHO clas-
sification also includes the odontogenic cysts and has
retained these definitions and terminology (WHO 2022a;
Wright and Soluk ­Tekkeşin 2022).
It can be seen from this discussion that there has been
considerable debate and confusion over the terminology
and classification of the ghost cell lesions over a period of
more than five decades. We have been able to identify at
least 11 different proposed classifications and numerous
different names for the various lesions, often with complex,
confusing, and similar acronyms, and sometimes with
excessive subclassifications. Details of some of the classifi-
cations have been reviewed and published by Toida (1998)
and Robinson and Vincent (2012), and also by Reichart and
Philipsen (2004), who proposed a further unified classifica-
tion. Ide and colleagues have also published one of their
interesting historical reviews (Ide et al. 2012) cataloguing
the early history of the odontogenic ghost cell lesions.
Although Gorlin et  al. (1962,  1964) are credited with the
first definitive description of the calcifying odontogenic
cyst, Ide et al. (2012) were able to identify 32 cases of jaw
lesions that would meet the criteria for calcifying odonto-
genic cyst or dentinogenic ghost cell tumour published
between 1917 and 1962, and credit Rywkind, a Russian
author, with the first description in 1931. They note that
ghost cell lesions regularly featured in Thoma’s textbooks
between 1917 and 1960, but were categorised as odonto-
mas, as variants of ameloblastoma, or as variants of other
tumours or cysts. Ide et  al. (2012) also identified 40 case
reports of jaw lesion that included ghost cells going as far
back as 1838.
A feature of all the classifications is that a proportion
of  calcifying odontogenic cysts are associated with other
odontogenic lesions, most often odontomas. As will be
noted from other chapters in this book, it is not unusual
for  odontogenic cysts to occasionally occur with other
odontogenic lesions, either as hybrid lesions or due to
­co-­development of two lesions. With regard to calcifying
odontogenic cyst this will be discussed in later sections, but
associations with ameloblastomatous proliferations and
occasional odontogenic tumours are probably unusual
 ­Clinical Feature 185

occurrences that should be regarded as oddities that do
not warrant a separate categorisation (e.g. CCOT Types 3
and 4). However, in relation to the association between cal-
cifying odontogenic cyst and odontoma, this appears to be
a common occurrence seen in up to 25% of cases. So dis-
tinctive is this association that some have suggested it
should be regarded as a separate entity and have proposed
the term odontocalcifying odontogenic cyst (Hirshberg
et al. 1994). This will be discussed in a later section, but it
is such a frequent occurrence that it may be justified to
classify calcifying odontogenic cyst associated with odon-
toma as a distinctive clinicopathological variant.
Based on the latest WHO classification (WHO  2022a)
and from a consideration of the issues discussed above, a
simpler classification of odontogenic ghost cell lesions is
proposed (Table 11.2) that removes complex subcategories
Table 11.2  A simple classification of odontogenic ghost cell
lesions that will be followed in this chapter.
Key features
Calcifying
odontogenic cyst
●● Simple cyst Typical cystic lesion, ameloblastoma-­like
lining with ghost cells. Includes occasional
variants with proliferating epithelium
●● Cyst associated Cyst associated with an odontoma in the
with odontoma wall
Dentinogenic Solid lesion with ameloblastomatous
ghost cell tumour epithelium, ghost cells, and dentinoid
Ghost cell Malignant lesion, ameloblastoma-­like
odontogenic epithelium, ghost cells, and dentinoid
carcinoma
that itemise each histological variant. Each of the three
types may, on occasion, present as peripheral or extraosse-
ous lesions. This classification and terminology will be fol-
lowed in this chapter. Only the calcifying odontogenic cyst
will be considered in detail.
­Clinical Features
There are almost 250 reports of calcifying odontogenic cyst
in the literature, most of which are single reports of unusual
or interesting lesions. There have also been a number of case
series, but many early reports include ‘cystic’ and ‘solid’
lesions, making it difficult to interpret data specifically for
calcifying odontogenic cyst. There have been two substan-
tial multicentre case series, of 113 cases by Ledesma-­Montes
et  al. (2008) and 268 cases by de Arruda et  al. (2018b).
Buchner et al. (1991) reported a detailed review of 215 cases
and de Arruda et al. (2018a) undertook a systematic review
of 367 cases reported up to 2018. These reviews and selected
case series that have provided clinical data specifically for
calcifying odontogenic cyst are summarised in Table 11.3.
Frequency
Calcifying odontogenic cysts are rare and constitute less
than 1% of odontogenic cysts. Over a 46-­year period
1958–2004, only 28 examples were recorded in the archives
of the University of the Witwatersrand, representing 0.8%
of 3498  jaw cysts (Table  1.1). In the large series from
Sheffield, Jones et al. (2006) found 21 cases over a 30-­year
period, representing 0.3% of odontogenic cysts (Table 1.2).

Table 11.3  Age, sex, and site distribution and association with odontomas from selected series of calcifying odontogenic cyst, and
from the reviews of Based on Buchner (1991) and de Arruda et al. (2018a).

References Country n Mean age Peak decade Male (%) Mandible (%) Associated with odontoma (%)

Hong et al. (1991) USA 79 33.0 2nd 60.3 55.2 20.3

Yoshida et al. (2001) Japan 16 23.0 2nd 56.3 31.3 75.0
Li and Yu (2003) China 16 31.0 2nd 56.3 31.3 31.3
Ledesma-­Montes et al. (2008) Multicentre 113 26.0 2nd 55.5 44.8 23.9
Gomes da Silva et al. (2014) Brazil 21 27.1 NR 52.5 38.1 19.0
Irani and Foroughi (2017) Iran 43 26.2 2nd 55.8 62.8 37.2
Rosa et al. (2019) Brazil 30 37.1 2nd 50.0 50.0 26.7
Nel et al. (2021) S Africa 27 29.0 2nd 55.5 59.3 22.2
Buchner (1991) Review 215a 30.3 2nd 48.8 48.4 26.5
de Arruda et al. (2018a) SR 367a 30.7 2nd 51.8 51.7 23.4

NR, not reported; SR, systematic review.

a
 Total cases in review, but n for each parameter varies depending on number of reports.
186 Calcifying Odontogenic Cyst

Five of the reports summarised in Table 1.3 included calci-
fying odontogenic cyst and reported frequencies of 1.0%
(Grossmann et al. 2007), 0.7% (Soluk Tekkeşin et al. 2012b),
0.4% (Tamiolakis et al. 2019), 0.8% (Bhat et al. 2019), and
1.48% (Kammer et al. 2020).
With regard to the subtypes of calcifying odontogenic
cyst, simple cystic lesions and cysts associated with odon-
tomas represent about 90% of all cases (Ledesma-­Montes
et al. 2008). Of these, simple cystic calcifying odontogenic
cysts were the most common, constituting 65% of the total,
while lesions associated with odontoma represented 22%.
Overall, about 25% of cysts are associated with odontomas
(Buchner 1991; de Arruda et al. 2018a; Table 11.3).
Age
The two largest reviews of calcifying odontogenic cyst have
shown an average age of 30 years (Buchner 1991; de Arruda
et al. 2018a), with a peak in the second decade (Table 11.3).
Figure 11.1 shows the age distribution of 708 cases. These
comprise 141 cases reported in the previous edition of this
book (Prætorius et al. 1981; Shamaskin et al. 1989; Yoshida
et  al.  2001; Moleri et  al.  2002; Fregnani et  al.  2003; Li
and  Yu  2003) and a further 567 cases accumulated from
Buchner (1991), Ledesma-­Montes et  al. (2008), and de
Arruda et  al. (2018b). The lesion occurs over a wide age
range, with the youngest recorded patient at 1 year old and
the oldest 82 years. There is however a significant peak in
the second decade, and 60% of all cases were encountered
before the age of 30 years.
Buchner (1991) showed that lesions associated with
odontomas occurred in a younger age group than cystic
lesions alone. The mean age of patients with calcifying
odontogenic cyst was 34 years, but patients with odontoma-­
associated lesions had a mean age of 17 years. Of 52
odontoma-­associated lesions, 92.3% were below the age of
30 years, compared to only 53.5% of conventional cystic
lesions. Hong et al. (1991) found a similar age difference.
In their series the average age of all calcifying odontogenic
cyst patients was 33 years, but patients with odontoma-­
associated lesions had an average of 14.7 years.
Sex
All studies show an almost equal sex distribution of calcify-
ing odontogenic cyst, with only a small male predilection
in some series (Table 11.3). In the two largest reviews, there
was no significance difference between males and females
(Buchner  1991; de Arruda et  al.  2018a). Nel et  al. (2021)
found an equal sex distribution for simple cystic calcifying
odontogenic cysts (n  =  20), but a male predilection for
other types, with 71.4% males (n = 7). Furthermore, 4 of
the 6 cases associated with odontomas were found in males.
Site
Most studies have shown a slight predilection for the max-
illa (Table 11.3), with as few as 31% arising in the mandi-
ble (Yoshida et  al.  2001; Li and Yu  2003). The larger
reviews however show an almost equal distribution
between mandible and maxilla (Buchner 1991; de Arruda

300 Figure 11.1  Age distribution of 708

patients with calcifying odontogenic
263 cysts (see text for details).
250

200
No. of cases

150

119

100
85

57 57
52
50 37
33

5 0
0
0-9 10-19 20-29 30-39 40-49 50-59 60-69 70-79 80-89 90-99
Age
 ­Clinical Feature 187

Figure 11.2  Site distribution of calcifying

odontogenic cyst. Data are the percentage of Maxilla
lesions in each sextant of the jaws. Source: Data
from Buchner (1991) and Ledesma-­Montes et al.
(2008) (n = 255). Mandible

Percent of cases
37.6

13.3
3.1

10.2 13.7
22.0

Incisor/Canine Premolar Molar

et al. 2018a). Figure 11.2 illustrates the site distribution of

255 cases where the site has been recorded by sextant: 179
cases from Buchner (1991) and 76 from Ledesma-­Montes
et al. (2008). Of these, 54% were located in the maxilla, and
the majority of lesions (60%) were located in the anterior
regions of the jaws, with the single most common site the
maxillary incisor/canine region (96 cases: 37.6%). The pos-
terior mandible is the second most frequent site, but
lesions in the posterior maxilla are rare. In the series of
Nel et al. (2021), simple cystic lesions showed an equal dis-
tribution between mandible and maxilla, but 5 of 6 lesions
(83.3%) associated with odontomas were found in the
mandible.
Multiple or bilateral calcifying odontogenic cysts appear
to be very rare and none of the series summarised in
Table  11.3 recorded multiple lesions. There is only one
fully documented report of bilateral calcifying odontogenic
cysts. Gadipelly et al. (2015) reported bilateral lesions in an
8-­year-­old child, arising in the posterior mandible. Both
lesions occurred in association with unerupted second
molars, and extended from the canine region to the ante-
rior ramus.
Clinical Presentation
The majority of lesions present as a painless swelling. In
their systematic review, de Arruda et al. (2018a) identified
249 cases in which the clinical signs and symptoms had
been reported, and found that 76.7% (191) presented with
swelling alone and a further 20 (8.0%) had swelling and
pain. Only 7 (2.9%) reported pain alone, and 20 cases (8.0%)
were symptomless incidental findings. Occasional cases
presented with unerupted teeth (3.2%) or with tooth dis-
placement (1 case; 0.4%), and up to 20% may be associated
with tooth mobility (Nel et al. 2021).
Box 11.1  Calcifying Odontogenic Cyst: Clinical
and Radiological Features
●● They are rare – less than 1% of odontogenic cysts
●● Average age 30 years. Peak in the second decade
●● Occur equally in males and females
●● Slightly more common in the maxilla
●● Single most common site (37%) is the maxillary inci-
sor/canine region
●● Usually symptomless, but 80% show swelling/bony
expansion
●● Well-­defined radiolucency with corticated margin
●● Most are unilocular. Up to 18% may be multilocular
●● 60% contain areas of calcification
●● 25% are associated with an odontoma
●● Average size is 30 mm. Only about 25% are greater
than 40 mm
●● Recurrence is rare. Overall recurrence rate is less than 4%
Over 80% of lesions cause bony expansion (de Arruda
et al. 2018a), so the swelling is often bony hard and is usu-
ally on the buccal or labial aspect of the jaws. Occasional
lesions may perforate the cortical plate and extend into the
soft tissues.
The calcifying odontogenic cyst rarely recurs. Buchner
(1991) reviewed 215 cases and found only 8 cases that had
recurred (3.7%). Of their 113 cases, Ledesma-­Montes et al.
(2008) recorded only 5 recurrences of intraosseous lesions
(4.6%), Hong et  al. (1991) found only 1 recurrence in 79
cases (1.3%), and de Arruda et  al. (2018b) found only 10
(3.7%) recurrent cases out of 268. In their systematic review
they identified 202 cases where follow-­up had been
recorded and found that only 8 (4.0%) had recurred (de
Arruda et al. 2018a).
188 Calcifying Odontogenic Cyst
Peripheral (Extraosseous) Calcifying
Odontogenic Cyst
Peripheral lesions of calcifying odontogenic cyst are well
documented, but only represent a small proportion of the
total reported cases. In their large series Ledesma-­Montes
et al. (2008) reported that 5 of their 113 cases (4.4%) were
peripheral, and de Arruda et al. (2018b) recorded 7 out of
268 cases (2.6%). Hong et  al. (1991), in their series of 92
‘calcifying odontogenic cysts’, found 8 cases that were
peripheral, but all were of the ‘solid’ variety. Buchner et al.
(1991) reviewed 45 cases of peripheral calcifying odonto-
genic cyst, but 36% were described as ‘solid’ and repre-
sented dentinogenic ghost cell tumours. Chrcanovic and
Gomez (2016) undertook a systematic review of peripheral
ghost cell lesions and found reports of 55 calcifying odon-
togenic cysts and 50 dentinogenic ghost cell tumours.
The age data in Figure 11.1 include a small number of
peripheral lesions – for example, Ledesma-­Montes et al.
(2008) and de Arruda et  al. (2018b) included 5 and 7
cases, respectively – but these are unlikely to affect the
overall distribution. There is however some evidence
that peripheral lesions may arise in an older age group
than intraosseous calcifying odontogenic cysts. Kaugars
et al. (1989a) reviewed 29 extraosseous cases, and found
that 16 patients were in their sixth decade or older. In
their study of 45 peripheral lesions, Buchner et al. (1991)
observed a bimodal age distribution with a peak in the
second decade, but a larger peak (24.4% of cases) in the
sixth decade. In a more recent systematic review,
Chrcanovic and Gomez (2016) identified 55 peripheral
calcifying odontogenic cysts and found an average age of
41.8 years.
The series of extraosseous cases reported by Kaugars
et al. (1989a) and Buchner et al. (1991), and the systematic
review of Chrcanovic and Gomez (2016), all showed an
equal sex distribution.
When they do arise in an extraosseous location, calcify-
ing odontogenic cysts appear to arise slightly more often in
the mandible (59.6%; Chrcanovic and Gomez  2016), but
have a predilection for the incisor/canine region of both
jaws (Buchner et  al.  1991; Chrcanovic and Gomez 2016).
They tend to be pink to red, smooth, circumscribed ele-
vated masses on the gingivae or alveolar mucosa. They
measure an average diameter of 11 mm (range: 5–30 mm;
Chrcanovic and Gomez 2016), and there is only one report
of a lesion exceeding 30 mm (Buchner et al. 1991).
­Radiological Features
The calcifying odontogenic cyst most often presents as
a  unilocular radiolucency with a well-­defined corticated
margin (Figure 11.3). Up to 60% of cases contain variable
amounts of radiopaque material (Buchner 1991; de Arruda
et al. 2018a; Nel et al. 2021), which vary from occasional
small flecks to dense radiopaque masses. These calcifica-
tions may represent foci of dystrophic calcification in the
ghost cells, accumulations of dentinoid, or may have the
density of enamel and dentine if the cyst is associated with
an odontoma (Figures  11.4 and  11.5). Occasional cases
may be multilocular. Buchner (1991) found that 12  cases
(7.1%) were multilocular, but in their systematic review de
Arruda et  al. (2018a) found that 21 of 116 cases (18.1%)
where locularity had been described were multilocular. Nel
et al. (2021) reviewed the radiological features of 27 cases
and found that 19 (70.4%) were unilocular and 6 (22.2%)
were multilocular; 2 cases (7.4%) were unilocular, but with
a scalloped margin.
Buchner (1991) reported 68 cases (32.2%) as being associ-
ated with unerupted teeth, but did not describe the rela-
tionship in detail, so how many may be seen in a radiological
dentigerous relationship is uncertain. The most commonly
involved tooth in both jaws was a canine, but in the mandi-
ble second and third molars were also involved. Review of
case reports suggests that lesions do arise in a dentigerous
relationship, but displacement of unerupted teeth is also a
frequent feature (Figure  11.5). De Arruda et  al. (2018a)
reported that 57% of lesions were associated with unerupted
teeth and 39.5% caused tooth displacement or divergence
of the roots (e.g. see Figures 11.4 and 11.5).
Iida et al. (2006a) gave a detailed description of the radio-
logical features of 11 cases and showed that 5 enveloped
the crowns of unerupted teeth and that all 5 arose in the
Figure 11.3  Calcifying odontogenic cyst. The lesion is well
demarcated and corticated, with a slightly loculated outline.
Note resorption of the roots of the second pre molar first molar.
Source: Prof Paul Speight (Previously published: El-Naggar AK
2017 / Courtesy of IARC).

Figure 11.4  Calcifying odontogenic cyst of the maxilla.
Radiograph shows a well-­demarcated margin and calcifications
suggestive of an odontoma. The adjacent teeth are displaced.
Source: Courtesy of Prof. J.E. Seeliger.
posterior regions, most often (3 cases) associated with
mandibular second or third molars. They also found that 5
cases (45.5%) caused tooth displacement, and 4 (36.4%)
showed evidence of root resorption. Resorption of the roots
of adjacent teeth is a frequent finding, and may be seen in
Figure 11.5  Radiograph of a large
calcifying odontogenic cyst with
well-­demarcated margins extending from
the right canine to the left premolar
region of the mandible. Numerous
calcifications are present, some
suggestive of small denticles or a
compound odontoma. Note displacement
of the developing canine to the lower
border of the mandible.
­Radiological Feature 189
about 40% of cases (de Arruda et al. 2018a; Figure 11.3). In
the series of Nel et al. (2021), 23 cases were found in den-
tate areas of the jaws and of these, 19 (82.6%) showed root
resorption, 14 (60.9%) were associated with tooth displace-
ment, and 8 (34.8%) caused tooth impaction.
Many lesions are spherical or rounded in shape and
cause expansion of the cortical plates, usually towards the
buccal or labial aspect. De Arruda et al. (2018a) found that
81.9% of cases showed bone expansion and 61.6% had per-
forated the cortical plate. Computed tomography (CT) is
particularly useful for demonstrating bucco-­lingual corti-
cal expansion and radiopacities (Figure  11.6). Uchiyama
et  al. (2012) analysed nine cases by conventional radio-
graphs and by CT, and found that CT showed two cases
with radiopacities and three cases with odontomas that
were not apparent on plane radiographs. They also noted
that when present (in eight cases), radiopaque calcifica-
tions tended to be orientated around the margins of the
lesions, confirming a feature described previously as a
‘peripheral band of intracystic calcification’ that was
regarded as a characteristic finding of calcifying odonto-
genic cyst on CT (Rushton and Horner 1997).
With regard to the size of calcifying odontogenic cysts,
Buchner (1991) found data for 58 cases and showed a range
from 5 to 120 mm. However, the average size was 33 mm
and 76% of cases were less than 40 mm. De Arruda et al.
(2018a) found data for 109 cases and showed an average
size of 29.5 mm (range 2–90 mm).
Radiology does not have a role in the diagnosis of
peripheral calcifying odontogenic cysts, except to exclude
peripheral extension of an intraosseous lesion. However,
peripheral lesions may show superficial bony erosion and
saucerisation of the cortical plate in about 17% of cases
(Chrcanovic and Gomez 2016).
190 Calcifying Odontogenic Cyst

Figure 11.6  Computed tomography (CT) and a three-­dimensional CT reconstruction of a calcifying odontogenic cyst in the mandible.
The extent of the lesion is well demonstrated by CT, which shows the prominent buccal expansion and evidence of perforation. This
case is in a 4-­year-­old child.

Radiological Differential Diagnosis reduced enamel epithelium. Gorlin et  al. (1962) and
Prætorius et  al. (1981) in their early descriptions showed
The radiological features of calcifying odontogenic cyst are
lesions that enveloped the crown of unerupted teeth and
not diagnostic and overall the lesion is so rare that an initial
where the lining was in continuity with the ‘epithelium of
diagnosis of calcifying odontogenic cyst is unlikely to be
a developing or unerupted tooth’. They speculated that the
made on clinical and radiological features alone. The charac-
lesion thus arose from reduced enamel epithelium or from
teristic feature of a unilocular radiolucency containing calci-
rest cells of dental lamina in the dental follicle, bone, or
fications may be seen in a number of odontogenic tumours,
gingival tissues. This issue has never been resolved, but ori-
including adenomatoid odontogenic tumour, calcifying epi-
gins from different sources of epithelium are not mutually
thelial odontogenic tumour, and dentinogenic ghost cell
exclusive. What remains unknown are the factors that ini-
tumour. Rushton and Horner (1997), however, showed that a
tiate cyst formation and growth.
peripheral band of calcification at the margins of the radiolu-
Previously we have discussed the long-­standing debate
cency was characteristic of calcifying odontogenic cyst on CT
regarding the terminology and classification of the calcify-
examination, and this was confirmed by Uchiyama et  al.
ing odontogenic cyst. This reflects the uncertainty regard-
(2012). For lesions that are heavily calcified, the differential
ing the nature of the lesion, and although the calcifying
diagnosis will include a conventional odontoma.
odontogenic cyst has found a place in the classification
When calcifying odontogenic cyst presents as a simple
under the developmental cysts (WHO  2022a), this does
radiolucency without calcifications, the differential diag-
not  exclude the possibility that it is a neoplasm or that a
nosis may include any of the cystic jaw lesions, and a final
neoplastic variant (e.g. the ‘calcifying cystic odontogenic
diagnosis may only be possible on histological examina-
tumour’) exists (see discussion below on β-­catenin).
tion. However, lesions do have characteristic clinical and
Elucidation of the pathogenesis is further complicated
radiological features in terms of age, sex, and site that can
by the fact that the epithelial lining of a calcifying odonto-
assist in making a differential diagnosis (Box 11.1). Buchner
genic cyst appears to have the ability to induce the forma-
(1991) reported that the most frequent pre-­biopsy diag-
tion of dental hard tissues in the adjacent connective tissue
nosis was dentigerous cyst, followed by radicular cyst,
wall; and that other odontogenic tumours  – especially
ameloblastoma, and residual cyst. Occasionally lesions are
odontomas, but also ameloblastoma, ameloblastic fibroma,
suspected to be odontogenic keratocysts or myxomas, espe-
and adenomatoid odontogenic tumour – may be associ-
cially if they are lobulated or multilocular.
ated with it (Prætorius et  al.  1981; Hirshberg et  al.  1994;
Lin et  al.  2004; Ledesma-­Montes et  al.  2008; de Arruda
­Pathogenesis et al. 2018a).
The apparent ability of the cyst lining to induce dentine
The literature is unanimous that the calcifying odonto- formation and the association with odontomas have led to
genic cyst is of odontogenic origin and probably arises suggestions that the calcifying odontogenic cyst is itself a
from the rest cells of the dental lamina, or possibly from hamartoma and that lesions will progressively undergo

formation of dental hard tissues to develop into an odon-
toma. This concept has been generally discounted on the
basis that calcifying odontogenic cysts associated with
odontoma arise in a younger age group than calcifying
odontogenic cyst alone, and there is no evidence of pro-
gression over time, since hard tissue is less likely to be seen
in older patients. Hirshberg et  al. (1994) discussed this
issue at length and suggested that the cyst associated with
an odontoma is so distinctive that it should be regarded as
a separate entity. They proposed the name odontocalcifying
odontogenic cyst and suggested that it should be classified
as a benign mixed odontogenic tumour, although they
were undecided as to whether it is a neoplasm or a hamar-
toma. Alternatively, Hong et al. (1991) felt that the calci-
fying odontogenic cyst may develop secondary to the
odontoma, similar to development of a dentigerous cyst.
This would explain the association, and the younger age
group affected by this lesion.
Others have proposed that odontoma and ameloblasto-
matous proliferations in the wall of the cyst – correspond-
ing to Types 1B and 1C, Table 11.1; or CCOT types 2 and 3
described by Ledesma-­Montes et  al. (2008)  – are integral
components of the lesion that may arise in a small number
of cases and are due to inductive change or to excessive
proliferation of the lining. Odontoma formation is seen in
about 25% of cases and may be regarded as a clinicopatho-
logical variant, but luminal or mural ameloblastomatous
proliferation of the cyst lining, although well described, is
seen in less than 3.0% of cases (Ledesma-­Montes et al. 2008;
Nel et  al.  2021). Hong et  al. (1991) suggested that those
with mural proliferations should be diagnosed as a sepa-
rate ‘ameloblastomatous’ variant, but Ledesma-­Montes
et  al. (2008) pointed out that these lesions behave as a
benign cyst and do not show any of the features of amelo-
blastoma, and should be regarded as histological variants
with proliferation of the lining.
Occasionally, calcifying odontogenic cysts have been
described in association with other odontogenic tumours.
Ledesma-­Montes et al. (2008) found 4 cases (3.3%) in their
series, associated with ameloblastic fibroma, ameloblastic
fibro-­odontoma, adenomatoid odontogenic tumour, and
odontoameloblastoma, and de Arruda et al. (2018a), in an
analysis of 367 cases, found 14 (3.85%) associated with
ameloblastic fibroma (5), ameloblastic fibro-­odontoma (2),
adenomatoid odontogenic tumour (3), ameloblastoma (2),
odontogenic keratocyst (1), and orthokeratinised odonto-
genic cyst (1). Many of these probably represent hybrid
lesions or unusual oddities. However, it should be noted
that ameloblastic fibroma and ameloblastic fibro-­odontoma
are indistinguishable from early developing odontomas,
and these may represent the early stages of formation of an
odontoma associated with a calcifying odontogenic cyst,
rather than a separate tumour arising in the wall. Lin et al.
­Pathogenesi 191
(2004) reported three cases of ameloblastic fibroma with
calcifying odontogenic cyst and presented details of three
previous cases. Five of these six presented at a site and an
age that would be consistent with the lesion being an early
stage of odontoma formation within the wall of the cyst.
A further area of confusion is the association of
­ameloblastoma and calcifying odontogenic cyst.
Ameloblastomatous proliferations of the cyst lining should
not be confused with, or misinterpreted as, an ameloblas-
toma forming in the cyst wall. Although this is possible, it
does seem to be an extremely rare event, if it has occurred at
all (Hong et al. 1991; Ledesma-­Montes et al. 2008). Nel et al.
(2021), however, in their series of 27 cases, had one with
ameloblastomatous proliferations and found that this case
showed aggressive behaviour, being highly expansive and
featuring destruction of cortical bone. This does suggest that
such lesions are possible, but should be regarded as a hybrid
of ­calcifying odontogenic cyst and ameloblastoma, and that
management should be for the most aggressive component.
Ghost Cells and the β-­Catenin Gene (CTNNB1)
A characteristic feature of the calcifying odontogenic cyst
is the presence of ghost cells (sometimes referred to as
shadow cells). These are not specific to calcifying odonto-
genic cyst and are seen in a number lesions that recent evi-
dence suggests may be related by a unifying mechanism
involving  mutations in the β-­catenin gene, CTNNB1
(Gomes et al. 2019). The lesions are odontogenic ghost cell
lesions, the cutaneous pilomatrixoma (calcifying epitheli-
oma of Malherbe), and craniopharyngioma (specifically
the adamantinomatous variant), all of which are character-
ised by accumulations of ghost cells.
In 2003, two concurrent publications reported β-­catenin
expression or mutations in calcifying odontogenic cysts.
First, Hassanein et  al. (2003) showed strong cytoplasmic
and nuclear expression of β-­catenin in the basaloid cells of
calcifying odontogenic cyst, pilomatrixoma, and crani-
opharyngioma. This was unusual, because normally
β- catenin is expressed at the cell membrane. In all cases,
the ghost cells were negative. In the second study, Sekine
et  al. (2003) showed that 9 out of 10 cases of calcifying
odontogenic cyst harboured a somatic mutation in the β-­
catenin gene (CTNNB1). All lesions also showed cytoplas-
mic and nuclear expression of β-­catenin by
immunohistochemistry. A further 20 ameloblastomas (10
follicular and 10 plexiform) were also studied and only
one case showed a CTNNB1 mutation. All 10 follicular
ameloblastomas showed cytoplasmic and nuclear stain-
ing, but the plexiform lesions were negative. The authors
interpreted the results to show that calcifying odontogenic
cyst and ameloblastoma may show similar histology, but
are genetically distinct, and that CTNNB1 mutations and
192 Calcifying Odontogenic Cyst
intracellular accumulation of β-­catenin are important for
the histogenesis of calcifying odontogenic cyst.
These results were confirmed by others (Ahn et al. 2008)
and suggest a role for β-­catenin and the WNT signalling
pathway in the pathogenesis of calcifying odontogenic
cyst. β-­catenin and LEF-­1 act as transcriptional co-­factors
that regulate the WNT signalling pathway, which is essen-
tial for normal tooth development. CTNNB1 mutations
cause intracellular accumulation of β-­catenin that disrupts
the pathway and interferes with cellular differentiation.
Similar ectomesenchymal interactions occur in tooth, hair,
and pituitary development, and it is suggested that acti-
vating mutations in the β-­catenin gene and disruption
of the WNT signalling pathway explain a common patho-
genic mechanism for development of calcifying odonto-
genic cyst, pilomatrixoma, and craniopharyngioma (Sekine
et al. 2003; Gomes et al. 2019).
More recently, de Sousa et al. (2016) and Yukimori et al.
(2017) interrogated calcifying odontogenic cysts for muta-
tional hotspots in 50 cancer genes and both groups found
mutations only in CTNNB1, at a similar site to mutations
found in pilomatrixoma and craniopharyngioma. This sug-
gests that CTNNB1 mutations are a specific driver in the
pathogenesis of calcifying odontogenic cyst and other
ghost cell lesions. Yukimori et  al. (2017) also showed
nuclear staining for β-­catenin in cells surrounding ghost
cells, but not in the ghost cells. However, ghost cells were
positive for hair keratins. To test the association between
CTNNB1 mutations and ghost cells, the authors transfected
embryonic kidney 293 cells with normal and mutant
CTNNB1, and showed that the mutant cells were associ-
ated with ectopic expression of hair keratins that initiate
the formation of ghost cells.
This hypothesis is also supported by studies that have
shown that ghost cells express cytokeratins (CKs) that are
associated with hair formation, including hard α-­keratins
(Kusama et al. 2005; Kikuchi et al. 2012), CK6 (Kaminagakura
et  al.  2013), AE1/AE3 (Rumayor et  al.  2015), and AE13
(CK40; Yukimori et al. 2017). It is interesting that Yukimori
et al. (2017) found CTNNB1 mutations in two ameloblasto-
mas, but both were subsequently shown to contain ghost
cells, which also expressed hair keratins. Although ghost
cells express these ‘hard’ hair-­type keratins, they may not
express many of the more common keratins such as CK8,
CK13, CK18, or CK19 (Fregnani et al. 2003; Kaminagakura
et al. 2013; Rumayor et al. 2015).
These changes, however, are not specific for the ghost
cell lesions, since they have been identified in odontomas,
which is of particular interest given the association
between calcifying odontogenic cysts and odontomas.
Tanaka et al. (2007) examined 69 cases of odontomas using
antibodies against human hair hard α-­keratins (Kusama
et al. 2005) and found positively stained ghost cells in 66.7%
of cases (78.8% of compound odontomas and 29.4% of
complex odontomas). Ghost cells were mostly observed in
odontogenic epithelium adjacent to immature enamel in
developing lesions. In more mature lesions the ghost cells
became calcified, but still expressed the keratin proteins.
Of particular interest, however, is that they also found that
the odontogenic epithelium adjacent to the ghost cells
showed cytoplasmic and nuclear positivity for β-­catenin,
and for LEF-­1, a downstream transcriptional factor that
interacts with β-­catenin in the WNT signalling pathway.
Bilodeau et al. (2015) investigated LEF-­1 expression in sali-
vary and odontogenic tumours and found that calcifying
odontogenic cysts (CCOT in their study) showed high
expression in 64% (7 of 11) of cases. Furthermore, LEF-­1
was always co-­expressed with nuclear β-­catenin, which
was seen in 82% (9 of 11) of cases.
These data suggest that ghost cells in odontoma, a
hamartoma, may arise as a result of intracellular accumu-
lation of β-­catenin, in a similar mechanism as that seen
in the ghost cell lesions. To date, however, CTNNB1 muta-
tions have not been identified in human odontomas,
although studies have shown that activation of WNT sig-
nalling by expression of mutated β-­catenin can generate
odontoma formation in mice (Xavier et al. 2015).
A number of studies have also shown accumulation
of the enamel protein amelogenin in the ghost cells in cal-
cifying odontogenic cysts (Abiko et  al.  2001; Yoshida
et  al.  2001). Takata et  al. (2000) found that ghost cells
expressed amelogenin as well as enamelin, enamelysin
(MMP-­20), and sheathlin (prism sheath protein). They also
showed that the ghost cells of pilomatrixomas were nega-
tive. The significance of these findings is not clear, but they
suggest that the aberrant differentiation, thought to be a
factor in the formation of ghost cells, may cause accumula-
tion of enamel proteins as well as hair-­type keratins.
Taken together, these data have been interpreted to sug-
gest that most calcifying odontogenic cysts are neoplasms
caused by mutations in CTNNB1 (Yukimori et  al.  2017).
The mutations are associated with intracellular accumula-
tion of β-­catenin and disruption of the WNT signalling
pathway, causing aberrant epithelial differentiation and
formation of ghost cells. These mechanisms provide a uni-
fying hypothesis for the pathogenesis of ghost cell lesions,
including calcifying odontogenic cyst, pilomatrixoma, and
craniopharyngioma (Gomes et al. 2019).
It should be noted, however, that β-­catenin gene muta-
tions are not specific to ghost cell lesions and have been
detected in a wide range of human tumours (reviewed by
Kim and Jeong  2019). Also, only a single mutation has
been recorded in calcifying odontogenic cyst and this
may not be sufficient for the development of a neoplasm.

This single β-­catenin gene (CTNNB1) mutation may act as
a common driver mutation or gatekeeper that initiates
altered cell differentiation at different anatomical sites, but
further genetic events may be necessary for progression to
neoplasia. This lack of association with neoplasia is sup-
ported by the fact that odontomas may be formed as a
result of aberrant WNT signalling induced by mutated
β- catenin (Xavier et al. 2015), and that ghost cells in odon-
tomas express hair keratins and are associated with nuclear
accumulation of β-­catenin in the adjacent epithelium, in a
pattern similar to that seen in calcifying odontogenic cyst
(Tanaka et al. 2007).
­Histopathology
The majority of calcifying odontogenic cysts are enucleated
with or without curettage, so the pathologist may receive a
collapsed cyst, or the specimen may be fragmented or sepa-
rated into many parts. This is especially the case if the lesion
is associated with an odontoma (Figure 11.7). Gross exami-
nation of the specimen and review of radiographs are espe-
cially important in helping to diagnose this lesion. In a
fragmented specimen it may be particularly difficult to
appreciate the relationships between the components of the
lesion and to determine its cystic nature. On gross examina-
tion it should be possible to identify a cyst wall, although
the lumen may be filled, giving the impression of a solid
tumour. It is helpful to open the cyst and search the wall
and lining for thickenings, which should be sampled. Many
lesions will contain hard tissue and it is important to
(a)
Figure 11.7  A low-­power view of a specimen of a calcifying odontogenic cyst associated with an odontoma. The cyst (a) is collapsed
and fragmented and the hard tissue component (b) has been presented separately (see also Figure 11.13).
­Histopatholog 193
establish where this is located and its nature. The calcified
tissue may be calcified ghost cells, dentinoid material, or
tooth substance associated with an odontoma. In calcifying
odontogenic cyst, calcified ghost cells are usually located in
the epithelial lining or the lumen, and dentinoid or odon-
toma is located in the wall. If the lesion appears solid or the
lumen appears to be filled with dentinoid, then a dentino-
genic ghost cell tumour should be considered. It follows
from this that it is important to decalcify the hard tissue for
microscopic examination to establish its true nature.
The histological features of a classic calcifying odonto-
genic cyst are characteristic and present few diagnostic
problems (Buchner 1991; Wright and Soluk ­Tekkeşin 2022;
Figures 11.8–11.10; Box 11.2). The typical cyst is lined by
epithelium, with a well-­defined basal layer of columnar
cells and an overlying layer of varying thickness that may
resemble stellate reticulum. The characteristic feature is
the presence of focal accumulations of ghost cells, which
may be in the epithelial lining or may form masses protrud-
ing into the lumen, or occasionally pushing into the fibrous
capsule. The ghost cells often become calcified. Calcifying
odontogenic cyst is almost always unicystic, but occasional
multicystic examples have been reported (Buchner 1991).
These features are seen in all types of calcifying odonto-
genic cyst, but there may be considerable variation in the
proportions of each component and a variety of features
may be seen in the lining or the connective tissue wall. For
the most part, the epithelial lining is thin and regular, as
can be seen in Figures  11.7–11.9, but with focal areas of
thickening, usually associated with accumulations of ghost
cells (Figures  11.8 and  11.10). The typical, and often
(b)
194 Calcifying Odontogenic Cyst
(a)
(b)
Figure 11.8  Calcifying odontogenic cyst. (a) A typical simple cystic lesion. (b) The lining is thin and regular and, in this section, is
mostly ameloblastomatous. (c) Careful examination will show focal accumulations of ghost cells. Note a small island of odontogenic
epithelium in the wall (c, arrowhead).
diagnostic, lining resembles a unicystic ameloblastoma
and shows a columnar basal layer of ameloblast-­like cells,
with reversal of nuclear polarity and a superficial layer
resembling stellate reticulum (Figures  11.8b and  11.10c).
Often however, areas of the lining are flattened and show a
simple stratified squamous epithelium (seen in
Figure 11.10b, e).
The main diagnostic feature of the calcifying odonto-
genic cyst is the presence of ghost cells. The ghost cells are
large ballooned or elliptoid cells with amorphous and
eosinophilic cytoplasm, and with a pale clear space where
the nucleus has been lost (Figure 11.10). Ghost cells may
arise as scattered single cells in the epithelial lining, but
most often they form focal accumulates that produce epi-
thelial thickenings or protrusions into the lumen
(c)
(Figures 11.9 and 11.10). Occasionally masses of ghost cells
may form and may fill the lumen to form what appears to
be a solid tumourous lesion. Prætorius et  al. (1981) and
Ledesma-­Montes et  al. (2008) classified a small number
of  calcifying odontogenic cysts as a proliferative type,
with  ameloblastomatous proliferations that may extend
into the lumen (Figure  11.9) or be seen in the cyst wall
(Figure 11.11d). When this occurs the proliferation into the
lumen usually resembles a plexiform ameloblastoma, but
is associated with accumulations of coalesced ghost cells
(Figure  11.9), which often show areas of calcification.
Similarly, when ameloblastoma-­like islands are seen in
the  wall, they are usually associated with ghost cells
(Figure 11.11d). The ghost cells often calcify and individual
or small numbers of calcified ghost cells can be seen in

(a)
(b)
Figure 11.9  (a) Calcifying odontogenic cyst, showing luminal proliferations. These resemble plexiform ameloblastoma (b), but
contain sheets of ghost cells (c).
almost all lesions. Occasionally accumulations of coa-
lesced ghost cells may calcify to form calcified masses, but
this is most prominent in calcifying odontogenic cyst asso-
ciated with odontoma (Figures 11.7b and 11.10f).
Often, the ghost cells extrude from the epithelial lining
through the basement membrane into the fibrous cyst wall
(Figure  11.10d, e), where they may elicit a foreign-­body
giant cell reaction or be associated with dystrophic calcifi-
cation (Figure 11.11). Other features that may be seen in
the wall include islands of odontogenic epithelium that
usually resemble quiescent rest cells of dental lamina
(Figure 11.11a), but may occasionally show ameloblast-­like
differentiation with juxta-­epithelial formation of a dentine-­
like material (Figure  11.11c). Takeda et  al. (1990) found
islands of odontogenic epithelium or small satellite cysts in
9 out of 13 cysts examined.
­Histopatholog 195
(c)
Dentinoid formation is also seen adjacent to the epithe-
lial lining, and is seen in calcifying odontogenic cysts asso-
ciated with odontoma and in about 50% of simple cystic
lesions. It should be noted that dentinoid is not seen as fre-
quently in calcifying odontogenic cyst as it is in dentino-
genic ghost cell tumour, where it is a consistent finding.
When present, it forms small masses or strips just below
the epithelial lining (Figure 11.12a, b). Large sheets of den-
tinoid are unusual except in those lesions associated with
odontomas, where an admixture of dental hard tissues may
be seen (Figure 11.7b and 11.13). Occasionally masses of
dentinoid and ghost cells may fuse to form large amor-
phous sheets (Figures  11.12c and  11.13), but a simple
van  Gieson stain will differentiate the two structures
(Figure  11.12d). The ghost cells may also express some
cytokeratins, as discussed in pathogenesis.
196 Calcifying Odontogenic Cyst

(a) (b)

(c) (d)

(e) (f)

Figure 11.10  Ghost cells are eosinophilic cells with a pale central area where the nucleus has been lost. They may form masses
replacing the epithelium (a, b) or may appear as small intraepithelial focal accumulations or even single cells (c). Often the ghost cells
protrude through the basement membrane (d) and form masses within the cyst wall (e). Calcification of ghost cells is common, either
as single cells (c, top left) or as coalesced masses (f). (b, e) Note that the adjacent cyst lining is thin stratified squamous epithelium.
 ­Histopatholog 197

Box 11.2  Calcifying Odontogenic Cyst: Diagnostic Criteria and Differential Diagnosis

●● Simple unicystic lesion
●● Lined predominantly by ameloblastomatous epithe-
lium, with columnar basal layer and superficial stel-
Caution: features that suggest an alternative diagnosis:
late reticulum-­like cells
●● All lesions contain ghost cells, which often show
dystrophic calcification
●● Ghost cells may be scattered single cells, but usually
form focal accumulations protruding into the lumen
●● Epithelium may proliferate into the lumen or into the
wall, occasionally resembling plexiform ameloblastoma
●● About 50% contain dentinoid in the cyst wall adja-
cent to the epithelium
●● About 25% are associated with an odontoma
●● Immunohistochemistry shows characteristic nuclear
and cytoplasmic staining for β-­catenin, but this is not
specific, and may be seen in follicular ameloblastoma
●● Lesions harbour a mutation in the β-­catenin gene
(CTNNB1)
●● Solid or multicystic lesion with prominent dentinoid
that is admixed with the epithelium: consider denti-
nogenic ghost cell tumour
●● Prominent calcified tissue with enamel and dentine,
but very little epithelium and no cystic areas: con-
sider odontoma
●● Cyst lined by ameloblastomatous epithelium with or
without luminal proliferations, but with absence of
ghost cells: consider unicystic ameloblastoma
●● Prominent epithelial proliferation with evidence of
cytological atypia, mitoses, or an infiltrative pattern:
consider ghost cell odontogenic carcinoma

(a) (b)

(c) (d)

Figure 11.11  Features seen in the wall of calcifying odontogenic cyst. (a) Dystrophic calcifications associated with ghost cells
(arrow) and islands of odontogenic epithelium (arrowheads). (b) Ghost cells (arrow) elicit a foreign-­body giant cell response. (c) An
island of odontogenic epithelium that has induced a ring of dentinoid formation. (d) Islands resembling follicles of ameloblastoma,
but ghost cells are also present (arrow).
198 Calcifying Odontogenic Cyst

(a) (b)

(c) (d)

Figure 11.12  Features of dentinoid in calcifying odontogenic cyst. (a, b) Typically, small sheets of dentinoid can be seen in the
fibrous connective tissue in close proximity to the epithelial lining. (c) Occasionally amorphous masses of dentinoid and ghost cells
coalesce, but a simple van Gieson stain (d) can distinguish the red staining dentinoid (arrow) from yellow ghost cells. (b) Note that
cholesterol clefts can be seen (top right).

Figure 11.13  A high-­power view of part

of the lesion shown in Figure 11.7b. This
GC shows odontoma formation with
well-­formed enamel matrix (e), tubular
dentine (d) and dentinoid (de).
Accumulations of ghost cells are also
seen (gc), many of which are calcifying
(see also Figure 11.10f).

d
e
de

A rare feature, but one that is often remarked upon, is the
presence of melanin pigmentation in a small number of
cases (Buchner 1991). Han et al. (2007) reported a case and
reviewed 20 previous cases. Melanin pigment was found in
variable amounts in the epithelial lining, including within
ghost cells.
A small number of calcifying odontogenic cysts may be
associated with other odontogenic lesions apart from
odontomas (Ledesma-­Montes et  al.  2008). These have
been discussed in the section on pathogenesis.
Buchner et  al. (1991) reviewed 45 cases of peripheral
ghost cell lesions. At the time, all were classified as calcify-
ing odontogenic cysts, but they found that 15 cases were
solid and would now be classified as peripheral dentino-
genic ghost cell tumours. Of the cystic lesions, they found
that the histological features were very similar to those
described here for the intraosseous lesions.
Immunohistochemistry does not have an important role
in diagnosis. Expression of β-­catenin, cytokeratins, and
enamel proteins has been discussed in the section on
pathogenesis. Although these have provided some insight
into the histogenesis of the lesion, they have little role
in differential diagnosis. For example, although β-­catenin
shows unusual nuclear expression in calcifying odonto-
genic cyst, this may also be seen in ameloblastomas, which
are the main lesions that may cause diagnostic confusion.
A number of studies have also investigated proliferation
and apoptotic markers in calcifying odontogenic cyst and
have shown evidence of greater expression of Bcl-­2, Ki-­67,
and proliferating cell nuclear antigen (PCNA) in prolifera-
tive or ameloblastomatous lesions (Yoshida et  al.  2001;
Fregnani et al. 2003; Gomes da Silva et al. 2014), but these
findings are of little diagnostic value when examining a
single case.
Histological Differential Diagnosis
In most cases the histological diagnosis is straightforward
(Box 11.2), since the finding of a cyst lined by ameloblasto-
matous epithelium with ghost cells is diagnostic. However,
in small or fragmented biopsies not all the features may be
apparent, and it is important to properly sample the speci-
men and examine multiple blocks. As Figure 11.8 shows, in
any given section ghost cells may not be numerous and the
lining must be examined carefully. In this circumstance, if
the ghost cells are missed, the main diagnostic error is to
misdiagnose the lesion as a unicystic ameloblastoma.
Ghost cells are characteristic of calcifying odontogenic
cyst, but they are not specific and the presence of ghost
cells in an odontogenic lesion should not automatically
lead to a diagnosis of a ghost cell lesion. In particular, ghost
cells have been reported in odontomas with a frequency
­Histopatholog 199
varying between about 10% (Sedano and Pindborg  1975;
Soluk Tekkeşin et al. 2012b) and 67% (Tanaka et al. 2007).
Odontomas are the most common of the odontogenic
tumours, and although they are see in about 25% of calcify-
ing odontogenic cysts, the converse is not true – less than
1% of odontomas may contain a calcifying odontogenic
cyst. Care must be taken not to overdiagnose ghost cell
lesions when ghost cells are seen in association with an
odontoma. A calcifying odontogenic cyst should only be
diagnosed if there is clear evidence of an associated
cystic lesion with the histological features described above
(Figure 11.7 and Box 11.2).
A further diagnostic problem is to differentiate between
a calcifying odontogenic cyst and a dentinogenic ghost cell
tumour. As discussed at the beginning of this chapter, these
two lesions have been regarded as variants of the same
entity, originally as a ‘cystic’ and a ‘solid’ calcifying odonto-
genic cyst, with overlapping features and no clear diagnos-
tic criteria. If the criteria for calcifying odontogenic cyst are
followed, then the distinction should be clear. The calcify-
ing odontogenic cyst is primarily a unicystic lesion, and
although occasional satellite cysts may arise in the wall,
these are rare, few in number, and probably represent
microcystic degeneration in islands of odontogenic epithe-
lium. Dentinogenic ghost cell tumour, on the other hand, is
a solid lesion that shows an admixture of ameloblastoma-­
like epithelium, ghost cells, and prominent dentinoid. Like
ameloblastoma, however, it may be multicystic and a
biopsy of a cystic area may resemble calcifying odonto-
genic cyst. Errors can be avoided by properly considering
the clinical and radiological features and by careful exami-
nation and sampling of the gross specimen. In particular,
solid areas of apparently hard tissue should be decalcified
and examined.
Ghost Cell Odontogenic Carcinoma
and Malignant Progression of Calcifying
Odontogenic Cyst
Ghost cell odontogenic carcinomas are very rare, but many
appear to arise in a precursor benign ghost cell lesion,
either a calcifying odontogenic cyst or a dentinogenic ghost
cell tumour (van Heerden and Gomes  2022). De Arruda
et al. (2018a), in their systematic review, only identified 44
cases reported up to 2018, but found that 12 (27.3%) had
been preceded by a calcifying odontogenic cyst. In their
series of 122 ghost cell lesions, Ledesma-­Montes et  al.
(2008) found only 3 carcinomas and showed that 2 arose
de novo and 1 had progressed from a simple type of calcify-
ing odontogenic cyst. Lu et al. (1999) reported 4 cases and
showed that 1  had arisen after recurrence of a typical
benign calcifying odontogenic cyst, and the other 3 showed
200 Calcifying Odontogenic Cyst
areas of typical calcifying odontogenic cyst associated with
more solid areas showing cytological evidence of malig-
nancy. They also reviewed 12 previously reported cases and
found 1 that had occurred after recurrence of a calcifying
odontogenic cyst, and 2 associated with recurrence of
ameloblastomas. Of the total of 16  lesions, therefore,
12 appeared to arise de novo, although most also showed
areas of typical calcifying odontogenic cyst on histology.
Arashiyama et al. (2012) reported a single case that arose
18 years after removal of a typical calcifying odontogenic
cyst. In their literature review they identified 30 previously
reported cases of ghost cell odontogenic carcinoma, and
found that 11 (36.7%) had arisen secondary to a calcifying
odontogenic cyst, and only 1 was secondary to a dentino-
genic ghost cell tumour. More recently, Nel et  al. (2020)
reported a calcifying odontogenic cyst in a 12-­year-­old
male that presented as a large, well-­demarcated radiolu-
cency filling the ramus of the mandible, with considera-
ble  bucco-­lingual expansion. Within three years the cyst
expanded to also fill the body of the mandible, and histol-
ogy showed progression to a ghost cell odontogenic carci-
noma. Mokhtari et  al. (2013) also reported a case and
reviewed factors that may predict onset of malignancy
in  calcifying odontogenic cysts. They concluded that
malignant transformation should be considered in all
recurrent calcifying odontogenic cysts. Histological fea-
tures that should arouse suspicion of malignant progres-
sion include proliferation of the lining with a cribriform
pattern, cytological atypia with increased mitoses, high
expression of Ki-­67, and loss of ghost cells (Mokhtari
et al. 2013). Ghost cell odontogenic carcinoma is also twice
as common in males as in females and in the maxilla as in
the mandible.
­Treatment
Calcifying odontogenic cyst is treated by surgical enu-
cleation unless it is associated with another odontogenic
tumour, in which case wider excision may be required. In
the presence of an odontoma, conservative removal will
still be adequate. Although classic uncomplicated cases
of  calcifying odontogenic cyst may grow to a large size,
reported recurrences are rare and are seen in less than 5%
of cases (de Arruda et al. 2018a). Marsupialisation followed
by enucleation has occasionally been used for large lesions.
Care must be taken with lesions showing unusual features
or ameloblastomatous proliferations. It has been shown
that these may be more aggressive and should probably be
regarded as hybrid lesions (Nel et al. 2021).
 201

12

Orthokeratinised Odontogenic Cyst

CHAPTER MENU
Clinical Features, 202
•• Frequency, 202
•• Age, 202
•• Sex, 202
•• Site, 202
•• Clinical Presentation,  203
Radiological Features, 204
Pathogenesis, 205
•• Relationship to the Dentigerous Cyst,  206
Histopathology, 207
•• Histological Differential Diagnosis,  211
•• Relationship to the Odontogenic Keratocyst,  211
•• Verrucous Odontogenic Cyst,  212
Treatment, 213

The orthokeratinised odontogenic cyst is a developmental
odontogenic cyst lined by orthokeratinised stratified squa-
mous epithelium (Speight and Neville  2022). Previously,
most authors, including early World Health Organization
(WHO) classifications and previous editions of this book,
have referred to this cyst as a variant of odontogenic kerato-
cyst. It was Philipsen (1956) who first used the term odonto-
genic keratocyst, but in his original series of seven cases one
was lined by orthokeratinised epithelium, and because of
this subsequent authors and classifications stated that
odontogenic keratocysts are normally lined by  parakerati-
nised epithelium, but may on occasions be orthokeratinised
(Pindborg and Kramer 1971; Brannon 1976, 1977; Kramer
et al. 1992). Wright (1981) was the first to properly record
the distinctive features of the orthokeratinised variant of
the odontogenic keratocyst and suggest that it should be
recognised as a distinct entity. After Wright’s paper, Li et al.
(1998) proposed the term orthokeratinised odontogenic cyst
and a number of authors subsequently recognised the
orthokeratinised odontogenic cyst as a distinct entity (Li
et al. 1998; Dong et al. 2010; MacDonald-­Jankowski 2010;
Selvamani et  al.  2014). However, it still took almost four
decades for the lesion to be properly categorised as a dis-
tinct entity in the fourth (2017) edition of the WHO classifi-
cation (Speight et al. 2017b). The key distinguishing features
of  the orthokeratinised odontogenic cyst are that it is
orthokeratinised and, in distinction to the odontogenic
keratocyst, it rarely recurs.
Although we credit Philipsen (1956) and then Wright
(1981) as the originators of our contemporary understand-
ing of keratinising jaw cysts, Ide et al. (2020) have pointed
out that they have been described since the mid-­nineteenth
century. In this fascinating historical review, Ide and col-
leagues trace the origin of keratocysts to 1855, when they
were first referred to as ‘buttery cysts’ by Maisonneuve,
the term ‘buttery’ referring to the thick, keratinaceous con-
tents that resemble butter. The authors record many exam-
ples of references to keratinising cysts up to 1933, and
attribute the first record of an orthokeratinised jaw cyst to
Jeannel in 1886. In the early twentieth century Schultz
(1927) described an orthokeratinised jaw cyst as a dermoid
cyst, but other authors often referred to them as

Shear’s Cysts of the Oral and Maxillofacial Regions, Fifth Edition. Paul M. Speight.
© 2022 John Wiley & Sons Ltd. Published 2022 by John Wiley & Sons Ltd.
202   Orthokeratinised Odontogenic Cyst

cholesteatoma. It was Philipsen (1956) who then described
‘cholesteatoma’ of the jaws as odontogenic keratocyst.
­Clinical Features
Most descriptions of the orthokeratinised odontogenic cyst
have been included in large series of odontogenic kerato-
cysts. In his systematic review, MacDonald-­Jankowski
(2010) found 36 papers up to 2009 that, between them,
described 408 cases of orthokeratinised odontogenic cyst.
Since 2009, Dong et  al. (2010) and Oh et al. (2022) have
reported series of 60 lesions, and a literature search shows
a further 23 papers reporting findings in about 140 cysts,
including three smaller series recording clinical features
(Aragaki et  al.  2010; Selvamani et  al.  2014; Uddin
et al. 2019). Table 12.1 summarises the clinical features of
orthokeratinised odontogenic cyst in selected series that
have included 10 or more cases and from the systematic
review of MacDonald-­Jankowski (2010).
Frequency
The orthokeratinised odontogenic cyst is rare, with a fre-
quency of less than 2% of all odontogenic cysts. Most
studies recording the relative frequency of odontogenic
cysts (see Table  1.3) have included orthokeratinised
odontogenic cyst in with odontogenic keratocysts, so
the frequency is uncertain. Only six of the reports in
Table 1.3 included specific reference to orthokeratinised
odontogenic cyst, and showed frequencies of 0.3%
(Grossmann et  al.  2007; Brazil), 0.3% (Tamiolakis
et al. 2019; Greece), 1.5% (Ali 2011; Kuwait), 1.6% (Bhat
et al. 2019; India), 1.2% (Aquilanti et al. 2021; Italy), and
1.7% (Kammer et al. 2020; Brazil). This accords well with
early papers that suggest that about 10% of odontogenic
keratocysts are orthokeratinised: 13% (Wright  1981);
9.7% (Brannon  1977); 12.2% (Crowley et  al.  1992); 8.0%
(Li et al. 1998); and 9.9% (MacDonald-­Jankowski 2011).
Age
Orthokeratinised odontogenic cyst presents in the third or
fourth decades, with an average age of about 35 years
(Table  12.1). In his systematic review, MacDonald-­
Jankowski (2010) found 10 reports that recorded the age at
presentation (n  =  181), with an average age of 34.8 years
and a peak in the third decade. Only 19 cases were under
age 20 years and only 1 case was found in the first decade.
Sex
There is a predilection for males, with studies showing that
up to 75% of lesions have been encountered in males
(Table  12.1). MacDonald-­Jankowski (2010) found that 12
reports recorded sex (n = 192 cysts) and that 66.1% were
encountered in males (M : F 2 : 1).
Site
All studies show that orthokeratinised odontogenic cyst is
found most often in the mandible, with an overall fre-
quency of about 70% (Table 12.1), and with the single most
common site being the mandibular molar/ramus region.
The two largest series shown in Table 12.1 (Wright 1981;
Dong et  al.  2010) analysed the site distribution of their
cases and their combined data (n = 121) are illustrated in
Figure 12.1. Of these, 78.5% were located in the mandible
and 62.8% of all cases were found in the posterior mandi-
ble. Crowley et al. (1992) found that 73.4% of their lesions

Table 12.1  Age, gender and site distribution from selected reports of orthokeratinised odontogenic cyst (where n ≥10), and from the
review of MacDonald-Jankowski (2010).

References Country n Mean age Peak decade Male (%) Mandible (%) Associated with impacted tooth (%)

Wright (1981) USA 60 35.4 3rd 75.0 63.3 72.9

Li et al. (1998) Japan/China 15 31.5 4th 66.6 93.3 46.7
Crowley et al. (1992) USA 55 33.8 NR 56.6 NR 75.7
Dong et al. (2010) China 61 38.9 4th 72.1 90.2 50.0
Aragaki et al. (2010) Japan 20 31.5 3rd 65.0 75.0 NR
Selvamani et al. (2014) India 11 29.1 3rd 72.7 81.8 NR
Uddin et al. (2019) Afghanistan 10 38.9 4th 70.0 70.0 30.0
Oh et al. (2022) S Korea 65 32.9 NR 72.3 80.0 70.8
MacDonald-­Jankowski (2010) SR 408a 34.8 3rd 66.1 70.8 69.4

NR, not reported; SR, systematic review.

a
 Total cases in review, but n for each parameter varies depending on number of reports.

Figure 12.1  Site distribution of 121
orthokeratinised odontogenic cysts. Source:
Data from Wright (1981) and Dong et al. (2010).
Percent of cases
were located in the posterior jaws, and that 20.8% were in
the anterior regions. They also compared their 55 cases to
387 odontogenic keratocysts and specifically noted that
16.3% (9 cases) of orthokeratinised odontogenic cyst were
found in the midline, compared to only 22 (5.7%) odonto-
genic keratocysts. One case has been reported in the condy-
lar head (Managutti et al. 2016), but this is very rare and
may represent an unusual intraosseous epidermoid cyst.
There have been a number of reports of patients with
multiple orthokeratinised odontogenic cysts. Most often,
these have been two cysts located bilaterally in the mandi-
ble and usually associated with unerupted third molars
(Pereira et  al.  2012; Premalatha et  al.  2012; Pimpalkar
Figure 12.2  Orthokeratinised odontogenic cyst shows a
well-­demarcated unilocular radiolucency. Note that although the
lesion is associated with an impacted tooth, it is not in a
dentigerous relationship.
­Clinical Feature  203
8.3% 10.7%
2.5%
4.1%
11.6%
Mandible
Maxilla
62.8%
Molar Premolar Anterior
et al. 2014; Oh et al. 2022). Joseph et al. (2021) reported a
patient with two cysts located on the upper and lower right
third molars. Others have reported more than two lesions
in the same patient. Cheng et al. (2015) described a patient
with four cysts, associated with unerupted third molars in
all four quadrants. Crane et al. (2020) reported two patients
with multiple cysts. The first had two cysts bilaterally in
the mandible and a third cyst associated with an unerupted
maxillary third molar. The mandibular cases were found
overlying the apices of the right first and second molars,
and a larger lesion on the left side, in a dentigerous rela-
tionship with an unerupted second molar and displacing
the third molar (Figure  12.3). The second patient (Crane
et  al.  2020) had bilateral cysts associated with unerupted
maxillary third molars, one of which completely filled and
expanded the maxillary sinus.
Although these cases are striking, multiple orthokerati-
nised odontogenic cysts appear to be rare, with only seven
patients reported. In the series shown in Table 12.1, none
recorded multiple cysts. None of the patients with multiple
cysts showed any features of the naevoid basal cell carci-
noma syndrome (NBCCS).
Clinical Presentation
The majority of lesions present as painless swellings, and
often as an incidental finding. In MacDonald-­Jankowski’s
(2010) review, 47.6% were incidental findings, in 41.1% there
was evidence of swelling, and only 24.1% had a history of
pain. Wright (1981) found that 25 of his 60 cases (41.7%) were
completely asymptomatic, 13 (21.7%) presented with pain, 8
(13.3%) had swelling, and 5 (8.3%) had evidence of infection.
In the other large series of 61 cases (Dong et  al. 2010), 46
(75.4%) showed swelling of the jaw and 13 (21.3%) also had
pain. Two patients had evidence of infection (3.3%).
204   Orthokeratinised Odontogenic Cyst
Recurrence of the orthokeratinised odontogenic cyst is rare.
Indeed, it was the benign behaviour and lack of recurrence of
the orthokeratinised variant of the odontogenic keratocyst
that led to its recognition as a distinct entity (Wright 1981). In
the series shown in Table  12.1 only two reported recurrent
lesions (Wright  1981; Crowley et  al.  1992). These authors
reported one recurrence each, a total of 2 out of 115 cysts
(1.7%). In his systematic review, MacDonald-­Jankowski
(2010), found only nine papers (n  =  165 cysts) that had
reported recurrences, with an overall frequency of 4.2% (7 out
of 165 cases), compared to 28.1% of odontogenic keratocysts.
There is some evidence that orthokeratinised odonto-
genic cyst may rarely be associated with NBCCS, but fur-
ther research is needed. Although none of the series in
Table 12.1 reported a case associated with the syndrome,
MacDonald-­Jankowski (2010) found one paper that
recorded a syndrome-­associated case (Bolbaran
et al. 2000). Woolgar et al. (1987a) compared the histologi-
cal features of solitary keratocysts with keratocysts associ-
ated with NBCCS, and found that a similar number of
cysts in each group contained orthokeratin (23% and 32%,
respectively), but the text of the paper suggests that this
includes cysts with small focal areas of orthokeratin that
would not meet the current definition of orthokeratinised
odontogenic cyst (see Box  12.2). In a similar study,
Dominguez and Keszler (1988) compared 33 cases each of
syndromic and solitary keratocysts and found orthokerati-
nisation in 9% (3 cases) and 24% (8 cases), respectively,
suggesting that they had identified 3 cases of orthokerati-
nised odontogenic cyst associated with NBCCS. Of the 7
patients reported in the literature with multiple
orthokeratinised odontogenic cyst, there were no cases
associated with NBCCS (Pereira et  al.  2012; Premalatha
et al. 2012; Pimpalkar et al. 2014; Cheng et al. 2015; Crane
et al. 2020; Joseph et al. 2021).
Figure 12.3  A case of multiple orthokeratinised odontogenic cysts. Two cysts are noted in the mandible, both well demarcated and
corticated. On the left side the cyst is in a dentigerous relationship with the impacted second molar. A third cyst is associated with the
displaced and rotated left maxillary third molar. Source: Crane et al. (2020) / Springer Nature / CC BY 4.0.
­Radiological Features
The typical orthokeratinised odontogenic cyst presents as a
unilocular radiolucency with a well-­demarcated and often
corticated outline (Figures  12.2 and  12.3). Lesions are fre-
quently spherical and over 90% are unilocular (MacDonald-­
Jankowski 2010). Wright (1981) found only one case that was
multilocular (1.6%), although Dong et al. (2010) found seven
cases in their series (13.0%). Overall, however, this is far fewer
than are found in odontogenic keratocyst, where about 30%
of lesions are multilocular (Table 12.2).
In most reports, between about 50% and 75% of lesions
(Table 12.1) have been associated with an impacted tooth.
This implies that they may be in a dentigerous relationship,
and that the lesion envelops the crown of an unerupted
tooth. However, this may not always be the case, and most
reports do not provide sufficient information to determine
exactly how many lesions may be truly dentigerous. Li et al.
(1998) did make this distinction and noted that while seven
cases were associated with an impacted tooth, only four of
them were radiographically in a dentigerous relationship.
As shown in Figure 12.2, a cyst may be associated with an
impacted tooth but not dentigerous. In Figure  12.3, how-
ever, the lesion on the left side of the mandible does appear
to truly envelop the crown of the impacted second molar.
A review of the many case reports of orthokeratinised
odontogenic cysts suggests that the majority of lesions
have a well-­defined spherical outline (see Figures  12.2
and  12.3), suggesting a ballooning or centripetal growth
pattern with expansion of the cortical plates. MacDonald-­
Jankowski (2010) showed that 100% of the orthokerati-
nised odontogenic cysts were well defined, corticated, and
had bucco-­lingual expansion, but that these features were
less common in odontogenic keratocysts, where they were
seen in 64.5%, 60.0%, and 61.7% of cases, respectively.
 ­Pathogenesi  205

Table 12.2  A summary of the differences and similarities

between the orthokeratinised odontogenic cyst and odontogenic Box 12.1  Orthokeratinised Odontogenic Cyst: Clinical
keratocyst (see text for details). and Radiological Features
●● They are rare – less than 2% of odontogenic cysts
Orthokeratinised Odontogenic
●● Almost always in adults, mean age 35 years. Peak in
odontogenic cyst keratocyst
third and fourth decades
Clinical and radiological ●● About 70% are found in males (M : F 2 : 1)
features ●● About 75% arise in the mandible, and 63% in the
Age (Mean) 35 yr 38 yr mandibular molar/ramus region
Males 66.1% 60.0% ●● Well-­defined corticated radiolucency. Usually spheri-
Mandiblea 90.2% 74.6% cal and unilocular
a ●● Only about 10% may be multilocular
Posterior mandible 75.4% 59.9%
●● About 70% are associated with an impacted tooth
Swellingb 41.1% 58.3%
and may appear dentigerous
Incidental findingb 47.6% 21.0% ●● Recurrence is rare – less than 5%
Pain 24.1% 32.4%
Unilocular 93.0% 72.2%
Well defined/corticatedb 100% 60%
Associated with unerupted 69.4% 35.5% aetiology. The lesions share a similar site distribution and
toothb both are most commonly encountered in the posterior
Recurrencesb 4.2% 28.1% mandible, where residual dental lamina is abundant. Most
Histology authors therefore agree that the source of epithelium for
the orthokeratinised odontogenic cyst is the rest cells of the
Orthokeratinised 100% N
dental lamina.
Parakeratinised N 100%
Early studies have shown that dental lamina rests can
Corrugated surface N 100%
undergo cystic change and form microcysts lined by
Palisaded basal layer N Y orthokeratinised epithelium (Hodson  1962; Moskow and
Budding/rete pegs N Y Bloom 1983). These have been described as ‘microkerato-
Islands/satellite cysts 5% 20% cysts’ (Moreillon and Schroeder  1982) and have been
Ki-­67a 8%; basal 20%; described in Chapter  9 (see Figure  9.4). Most agree that
suprabasal this cystic degeneration in rest cells of dental lamina is the
Cytokeratins K1/K10 K4/3, K19 initiating event in the pathogenesis of a number of jaw
cysts, including lateral periodontal and botryoid odonto-
100%, present in all lesions; N, not present, rare, or focal;
Y, characteristic, often present. genic cysts, gingival cysts, and orthokeratinised odonto-
Bold: parameters that are significantly different (see text for details). genic cyst. There is however no explanation as to why each
a
 Dong et al. (2010). type of cyst has a histologically different type of epithe-
b
 MacDonald-­Jankowski (2010).
lial lining.
The mechanisms of cyst growth and enlargement have
not been described for orthokeratinised odontogenic cyst
Reports of the size of the cyst show the smallest to be
and are poorly understood. The cyst is not inflammatory in
10 mm in diameter (Wright  1981) and the largest to be
origin, so inflammatory mechanisms may not play a sig-
155 mm (Dong et al. 2010). However, this large size is unu-
nificant role. However, cyst formation may be promoted by
sual and both Wright (1981) and Li et al. (1998) found that
accumulation of cell debris within the microcysts, result-
their largest lesions were 70 mm, with an average of about
ing in an increased osmotic pressure that promotes cyst
25 mm. In their comparison, Dong et al. (2010) found that the
expansion and growth. The role of osmosis in cyst growth
average diameter of odontogenic keratocysts was 51 mm.
has been described in detail in Chapter 3. Cyst growth in
the odontogenic keratocyst is thought to be primarily by
­Pathogenesis cell proliferation in the epithelial lining, resulting in lateral
expansion of the cyst, but this does not seem to apply to the
Little has been written about the pathogenesis of the orthokeratinised odontogenic cyst. A number of studies
orthokeratinised odontogenic cyst, since it has been have shown that the cell proliferation rate and apoptotic
regarded as a variant of odontogenic keratocyst and most index in orthokeratinised odontogenic cyst are similar to
authors have assumed that the lesions have a similar dentigerous cyst, and lower than seen in the odontogenic
206   Orthokeratinised Odontogenic Cyst
keratocyst (Li et al. 1998; Thosaporn et al. 2004; Rangiani
and Motahhary 2009; Dong et al. 2010). Dong et al. (2010)
compared expression of Ki-­67 and p63  in 15 orthokerati-
nised odontogenic cysts and 15 odontogenic keratocysts,
and found significantly greater expression in the kerato-
cysts. In particular, Ki-­67  was found mainly in the basal
layers of orthokeratinised odontogenic cyst and in only 8%
of cells, compared to suprabasal expression in 20% of cells
in keratocysts. Rangiani and Motahhary (2009) examined
expression of bcl-­2 and bax in 28  keratocysts and 9
orthokeratinised odontogenic cysts, and found that all
cysts showed strong expression of bax, but bcl-­2 was only
expressed in keratocysts, and all orthokeratinised odonto-
genic cysts were negative. Since bcl-­2 is anti-­apoptotic, the
authors interpreted its expression in keratocysts as promot-
ing cyst growth. In a similar study, Vered et al. (2009) also
showed that orthokeratinised odontogenic cysts, as well as
dentigerous and radicular cysts, were negative for bcl-­2,
while positive expression was found in odontogenic kerato-
cysts and ameloblastomas.
These studies suggest that increased cell proliferation
does not play an important role in driving growth of the
orthokeratinised odontogenic cyst, and that expansion may
be driven by increased intracystic osmotic pressure. This is
further supported by the observation that orthokeratinised
odontogenic cysts are often spherical with cortical expan-
sion, suggesting a centripetal growth pattern.
The role of the PTCH gene in the pathogenesis and neo-
plastic potential of the odontogenic keratocyst has been
discussed in Chapter 7. With regard to the orthokeratinised
odontogenic cyst, there has been no suggestion that it is
neoplastic. Indeed, when the odontogenic keratocyst was
renamed and designated as a neoplasm in the 2005 WHO
classification (Philipsen 2005), it was explicitly stated that
the orthokeratinised odontogenic cyst did not form ‘part of
the spectrum of keratocystic odontogenic tumour’. We
have discussed the role of PTCH and the sonic hedgehog
signalling pathway in the dentigerous cyst (Chapter 5) and
the point was made that, although PTCH alterations are
important in keratocysts, they do not seem to be specific
and that there is evidence that PTCH may be involved in
other odontogenic lesions (Gomes and Gomez  2011),
including dentigerous cyst, radicular cyst, and orthokerati-
nised odontogenic cyst (Levanat et  al.  2000; Pavelić
et al. 2001; Vered et al. 2009).
Diniz et  al. (2011) investigated loss of heterozygosity
(LOH) of the PTCH gene in seven each of odontogenic
keratocyst and orthokeratinised odontogenic cyst, and
found a similar pattern of LOH in both, with 5 of 7 and 4 of
7, respectively, showing LOH in at least one locus of the
PTCH region of chromosome 9q. The authors concluded
that PTCH gene alterations may not be specific to kerato-
cysts, but may be shared by a number of odontogenic
lesions. Gomes and Gomez (2011) proposed that PTCH1
may act as a gatekeeper gene for many types of odonto-
genic lesions, and that further genetic events drive the for-
mation of different cysts or tumours.
These studies suggest that aberrations in the PTCH gene
may be an early initiating event in a number of odontogenic
lesions, but that further genetic changes are needed to deter-
mine the lesion type. Such a scenario could explain a role for
PTCH in orthokeratinised odontogenic cyst, but does not
exclude a further role for specific PTCH mutations in kerato-
cysts. A key event in keratocysts that supports a neoplastic
origin is biallelic alterations in the PTCH gene, but there is
no evidence for this in orthokeratinised odontogenic cyst or
other cyst types. This is discussed in detail in Chapter 7.
Relationship to the Dentigerous Cyst
It has been noted above that the orthokeratinised odonto-
genic cyst is often described as being in a dentigerous rela-
tionship with an unerupted tooth (Table  12.1). However,
few papers accurately describe the relationship of the cyst
to the tooth, and it is not known how many are actually in a
true dentigerous relationship. While Wright (1981) used the
term ‘dentigerous’, most other authors have described the
cyst as associated with an ‘impacted’ or ‘unerupted’ tooth,
without defining or clarifying the relationship with the
crown (Crowley et  al.  1992; MacDonald-­Jankowski  2010;
Dong et al. 2010; Uddin et al. 2019). It is important to note
that these terms are not synonymous, and that a cyst may be
associated with an impacted tooth, but not be in a dentiger-
ous relationship (see Figure 12.2). In their series of 15 cases,
Li et al. (1998) did make this distinction and found that 7
cases were associated with an impacted tooth, but only 4 of
them were radiographically in a dentigerous relationship.
Almost always, however, this description has been based on
clinical and radiological findings and there are few reports
that have properly documented a case of an orthokerati-
nised cyst in a true dentigerous relationship, where the cyst
lining is attached to the tooth at the cementoenamel junc-
tion (Shetty et al. 2016).
Nevertheless, the frequency of a dentigerous relationship
has led to speculation that some orthokeratinised odonto-
genic cysts may arise from reduced enamel epithelium, and
form a truly keratinised dentigerous cyst. Vuhahula et  al.
(1993) were the first to suggest this. They identified 12
orthokeratinised jaw cysts and found that 9 (75%) were in a
dentigerous relationship with an unerupted tooth on radio-
logical examination, but did not demonstrate attachment at
the cementoenamel junction. In the discussion they also
noted that odontogenic keratocysts may envelop a tooth and
be in a ‘pseudo-­dentigerous’ relationship. Despite this they
still proposed that orthokeratinised cysts in this relationship
represent true dentigerous cysts with orthokeratinisation.

In his series of 312 odontogenic keratocysts, Brannon
(1976, 1977) showed that 83 (26.6%) were found, on radio-
graphs, to be associated with an impacted tooth, but he only
reported 2 cases with histological evidence that the cyst was
attached at the cementoenamel junction. In other cases, the
cyst was separated from the tooth by a zone of fibrous con-
nective tissue. This latter relationship has been described as
extrafollicular, and suggests that the cyst is ‘pseudo-­
dentigerous’ and has arisen from dental lamina rests in the
tooth follicle, and has then grown and enveloped an
unerupted tooth. It is also possible that a tooth may actually
erupt into an overlying cyst with fusion of the reduced
enamel epithelium and the cyst lining to produce a true den-
tigerous relationship. In this case Browne (1971a,  1991b)
suggested that the epithelial lining immediately adjacent to
the tooth is simple and non-­keratinised, resembling reduced
enamel epithelium, while the remainder is keratinising.
A further possibility is that a typical dentigerous cyst
may undergo progressive keratinisation to produce a histo-
logical appearance of a keratocyst or orthokeratinised
odontogenic cyst. Yeo et al. (2007) examined 119 cysts that,
on radiological examination, were dentigerous. Almost all
(108: 90.8%) were lined by non-­keratinised stratified squa-
mous epithelium, and only 2 (1.7%) showed focal areas of
keratin formation (both parakeratin). These data support
an early study by Browne (1972) that showed focal keratin
formation in only 2 of 81 dentigerous cysts (2.5%). Mucous
metaplasia or ciliated cells were much more common and
were seen in 14 (11.8%) cases. Yeo et al. (2007) also found
that 6 cases were fully parakeratinised and diagnosed as
Figure 12.4  Orthokeratinised odontogenic
cyst. The pathologist will typically receive
multiple fragments. The cyst is lined by thin
regular epithelium. Areas of folding can be seen
as well as accumulations of exfoliated keratin. A
microcyst and islands of epithelium are seen in
this cyst (square) and are shown in Figure 12.8.
­Histopatholog  207
odontogenic keratocyst, and 1 case was an orthokeratinised
odontogenic cyst.
These data suggest that focal keratinisation in dentigerous
cysts is rare, but that complete keratinisation, resulting in a
diagnosis of keratocyst or orthokeratinised odontogenic cyst,
is more common (7 of 119 cases: 5.9%). This was also noted
by Brannon (1977), who found that about 8.5% of cysts in a
dentigerous relationship were keratinised and that about 30%
of these were orthokeratinised. There is no evidence that
dentigerous (or other) cysts may progressively keratinise and,
if they did, then the frequency of focal keratinisation should
be much higher than complete keratinisation.
Taken together, these observations cannot exclude the
possibility that an orthokeratinised odontogenic cyst (or an
odontogenic keratocyst) may arise by keratinisation of a
dentigerous cyst, but overall it seems to be very unlikely.
We suggest therefore that the source of epithelium is rest
cells of the dental lamina, and that those cysts that occur in
a dentigerous relationship result from an adjacent
unerupted tooth becoming enveloped by a cyst that has
arisen in the overlying dental follicle. In rare cases, a tooth
may erupt into the cyst, with fusion of the lining with the
reduced enamel epithelium.
­Histopathology
Orthokeratinised odontogenic cysts are most often removed
conservatively by enucleation, so the pathologist may
receive multiple fragments of cyst wall (Figure 12.4). The
208   Orthokeratinised Odontogenic Cyst

Box 12.2  Orthokeratinised Odontogenic Cyst: Histopathology and Diagnostic Criteria

●● Lined by a thin, regular stratified squamous epithelium
●● Orthokeratinised with a granular cell layer
●● Prominent keratin that forms lamellae filling the lumen (‘onion-­skin’ appearance)
●● Basal layer of flattened or cuboidal cells
●● Surface is not corrugated and basal layer is not palisaded
●● Only occasional epithelial islands or microcysts (less than 5% of cases)
Caution: features that suggest an alternative diagnosis:
●● If the lining shows areas of parakeratin, typical of a parakeratinised odontogenic keratocyst, it should be diag-
nosed as odontogenic keratocyst
●● If orthokeratin is only focal and the lining is mostly non-­keratinised, consider an odontogenic cyst with metaplasia,
especially a dentigerous cyst
●● If the lesion is outside of the tooth-­bearing areas or is peripheral, consider a non-­odontogenic cyst, especially an
epidermoid cyst
●● Focal or small areas of sebaceous cells are acceptable, but if these are extensive, or if other dermal appendages
are present, consider a diagnosis of intraosseous dermoid cyst

specimen may also include the cyst contents, which are
composed of keratinaceous material that is cream or yel-
low coloured, with a cheesy, fatty, or ‘buttery’ texture and a
characteristically unpleasant odour. Similar contents may
be found in odontogenic keratocysts, but will also be famil-
iar to many pathologists as a characteristic feature of cuta-
neous epidermal cysts.
In the context of intraosseous jaw lesions, the histological
features are virtually diagnostic (Box 12.2). The cyst lining is
composed of thin, regular stratified squamous
epithelium, five to eight cells layers thick, lying on a flat
basement membrane (Figures  12.4–12.6). The surface is
orthokeratinised with a prominent granular cell layer and it
is not corrugated. Keratinisation is prominent and the kera-
tin forms thick lamellated sheets, sometimes described as an
‘onion-­skin’ pattern (Figures  12.5–12.7a). Keratin sloughs
off from the surface and may fill the cyst lumen (Figure 12.6).
The basal layer is composed of flattened or cuboidal epithe-
lial cells, but the palisading and reversal of nuclear polarity
seen in keratocysts are not seen in orthokeratinised odonto-
genic cyst. Separation of the epithelium from the fibrous
cyst wall is commonly seen (Figure 12.7a). Often the cyst lin-
ing is folded and may resemble the typical folds seen in
keratocysts (Figures 12.4 and 12.7b).

Figure 12.5  Typical lining of the orthokeratinised odontogenic cyst. There is prominent keratinisation with a well-­formed granular
cell layer. The basal layer is composed of flattened or cuboidal cells (inset). Lamellated sheets of keratin slough off into the lumen.
 ­Histopatholog  209

Figure 12.6  Orthokeratinised odontogenic cyst. The lining is thin and regular. Keratin sloughs off from the surface of the lining
and may fill the lumen.

(a) (b)

(c) (d)

Figure 12.7  Variable appearances of the lining of the orthokeratinised odontogenic cyst. (a) Typical lining, but with evidence of
separation from the underlying fibrous cyst wall. (b) The lining may appear folded. (c) The cyst wall is inflamed and here the lining
may be thickened and non-­keratinised. (d) In this area the lining is thin and non-­keratinised and overlies an area of inflammation and
loose granulation tissue.
210   Orthokeratinised Odontogenic Cyst
Focal areas of the cyst may be parakeratinised or non-­
keratinised, but this is usually in areas where the cyst wall
has become inflamed (Figure  12.7c, d). Wright (1981)
found focal areas of parakeratin in only 4 of 60 cases
(6.6%), but non-­keratinised areas in 51 (85.0%) cases, often
associated with areas of inflammation. He also found that
27 cases had areas with rete pegs, but these were most
prominent in areas of inflammation (14 cases) and only
rarely seen where the cyst was orthokeratinised.
The cyst wall is composed of fibrous connective tissue
that is usually uninflamed, although focal areas of inflam-
mation may be seen in about half of cases (Wright 1981)
and focal accumulation of cholesterol clefts may also be
seen. Occasional small microcysts or islands of epithelium
may be seen in the cyst wall (Figure 12.8). The islands may
resemble rests of dental lamina (Figure 12.8b) or may be
islands of squamous epithelium with evidence of central
keratinisation (Figure  12.8a). Islands or microcysts are
only seen in about 5% of cases (Wright 1981; Li et al. 1998)
and are not as common as in keratocysts, about 20% of
which show solid islands or satellite cysts (Woolgar
et al. 1987a; Cottom et al. 2012).
Immunohistochemistry does not play a role in diagno-
sis, since the immunophenotype reflects the degree of
keratinisation of the lining epithelium, which is clearly
visible on a routine haematoxylin and eosin (H&E)-­
stained section. Aragaki et al. (2010) undertook a compre-
hensive study of the keratin profiles of orthokeratinised
odontogenic cyst and odontogenic keratocyst, and found
Figure 12.8  A portion of the lining of the cyst illustrated in Figure 12.4. The wall contains a small microcyst filled with keratin
and islands of epithelium. The epithelial islands may show focal keratinisation (inset a, arrows) or may resemble rest cells of
dental lamina (inset b).
that the keratin profiles appear to reflect the histological
differentiation of the lesions. Simple keratins (especially
K4/13, K17, and K19) characterised keratocysts that are
parakeratinised, while high molecular weight keratins
(K1/10) and loricrin were seen in the orthokeratinised
odontogenic cyst. A number of studies have shown simi-
lar keratin profiles (Li et al. 1998; da Silva et al. 2002; Tsuji
et  al.  2014), but all have also shown wide variations
between individual lesions, suggesting that, although the
results confirm differences between the cyst types, the use
of keratin immunocytochemistry may not help in the
diagnosis of individual lesions. Other studies have inves-
tigated expression of proliferation and apoptotic markers
(Thosaporn et  al.  2004; Rangiani and Motahhary  2009;
Dong et  al.  2010) and have been discussed earlier.
Although there is a difference between orthokeratinised
odontogenic cysts and keratocysts in the number and dis-
tribution of cells expressing bcl-­2 and p63 (Dong
et al. 2010), these have been shown in lesions with typical
histological features, so their value in diagnosing lesions
from small biopsies, or where the lining is altered by
inflammation, is not known.
Occasional unusual orthokeratinised odontogenic cysts
have been reported where the histological features suggest
divergent differentiation or hybrid lesions. De Fátima
Bernardes et al. (2008) described an orthokeratinised odon-
togenic cyst associated with a calcifying odontogenic cyst.
Most of the cyst was lined by ameloblastomatous epithe-
lium with focal accumulation of ghost cells, but areas of
b

orthokeratin were noted. The authors felt that the lesion
represented an example of diverse differentiation of the lin-
ing, rather than a true hybrid lesion. Argyris and Koutlas
(2017) described a similar lesion in a patient with Gardner
syndrome. In this case, the cyst was lined by epithelium
showing areas of parakeratosis and orthokeratosis, as well
as areas resembling ameloblastoma with ghost cells and
areas of calcification. They interpreted the lesion to be an
orthokeratinised odontogenic cyst in association with an
odontogenic keratocyst with ghost cells. This lesion could
be dismissed as an unusual oddity, although Ide et al. (2019)
have described another lesion with multiple features,
including areas of calcifying odontogenic cyst, orthokerati-
nised odontogenic cyst, and odontogenic keratocyst, but
also with areas of mucous cells and duct-­like structures. It
was a unilocular cyst in a true dentigerous relationship with
an impacted maxillary canine, and contained luminal nod-
ules typical of calcifying odontogenic cyst as well as the
other features. The authors regarded it as an example of the
diverse histomorphological features that may be seen in
odontogenic cysts as a result of the pluripotentiality of
odontogenic epithelium. These cases are difficult to inter-
pret, but overall they probably represent examples of mor-
phologically diverse cysts with areas of orthokeratin, rather
than lesions that can be regarded as orthokeratinised odon-
togenic cysts with unusual features.
Chi et  al. (2007) reported 5 cases of orthokeratinised
odontogenic cyst with focal areas of sebaceous glands. This
is interesting, because usually a keratinising cyst with evi-
dence of dermal appendages (including sebaceous glands)
would be regarded as a dermoid cyst (see Chapter  18).
However, the 5 cases reported by Chi et  al. (2007) all
showed clinical and radiological features typical of an
odontogenic cyst, and the authors strongly argued that
they should be regarded as orthokeratinised odontogenic
cysts with sebaceous differentiation. Vuhahula et al. (1993)
examined 12 orthokeratinised jaw cysts and found 2 that
contained sebaceous cells. In one the sebaceous cells were
focal and few in number and the authors interpreted the
case as an odontogenic cyst with sebaceous metaplasia.
The second cyst was unusually large and had prominent
sebaceous glands, as well as other dermal appendages
including hair follicles and sweat glands. This was diag-
nosed as an intraosseous dermoid cyst. More recently, Oh et
al. (2022) examined 65 orthokeratinised odontogenic cysts
and found focal areas of sebaceous differentiation in 2 cases.
Histological Differential Diagnosis
The clinical and radiological features of the orthokerati-
nised odontogenic cyst (Box 12.1) are not specific, since
they are shared with many other odontogenic and
­Histopatholog  211
non-­odontogenic cystic lesions, especially dentigerous
cyst, odontogenic keratocyst, and ameloblastoma. Faced
with these appearances, it is very unlikely that a clinician
would consider an orthokeratinised odontogenic cyst as a
likely diagnosis. In their series of 55 cases, Crowley et al.
(1992) found that the most common preliminary diagno-
sis was dentigerous cyst (22 cases; 40%), followed by
odontogenic keratocyst (12 cases; 21.8%). Other diagno-
ses included ameloblastoma (1) and lateral periodontal
cyst (1) and 19 diagnoses of ‘cyst of undetermined origin’.
Li et al. (1998) found that the clinical diagnoses of their
15 cases included dentigerous cyst (4 times), odontogenic
keratocyst (7), ameloblastoma (4), radicular cyst (2), and
undetermined cyst (2). These diagnoses reflect the rela-
tive frequency of the lesions. Since about 70% of lesions
are associated with an impacted tooth, it seems inevita-
ble that the most common presurgical diagnosis is denti-
gerous cyst, and the site predilection in the posterior
mandible will always arouse suspicion of keratocyst or
ameloblastoma. Most times, therefore, a diagnosis of
orthokeratinised odontogenic cyst will be first encoun-
tered on pathological examination and will be unex-
pected by the surgeon.
It should be noted that the histology of the orthokerati-
nised odontogenic cyst is almost identical to the epidermal
(‘sebaceous’) cyst of the skin. Occasional epidermoid cysts
have been reported in the jaws, but these are unusual (see
Chapter 18). If an orthokeratinising cyst arises within the
tooth-­bearing areas, then a diagnosis of orthokeratinised
odontogenic cyst can be given, but if it is outside the tooth-­
bearing areas, or within the soft tissues, then an epider-
moid cyst should be considered. Similarly, if dermal
appendages are found, even if the lesion is within the
tooth-­bearing areas, then a diagnosis of dermoid cyst
should be considered (Vuhahula et al. 1993; Box 12.2).
Relationship to the Odontogenic Keratocyst
As discussed above, faced with an individual lesion it is
almost impossible to differentiate an orthokeratinised
odontogenic cyst from an odontogenic keratocyst based
on the clinical and radiological features. Some of the
differences have been discussed previously and the differ-
ences and similarities between the two lesions are sum-
marised in Table 12.2. The orthokeratinised odontogenic
cyst is slightly more common in the posterior mandible, is
more often in a dentigerous relationship, and is more
likely to be spherical, unilocular, and corticated. It is also
less likely to present as a swelling and more likely to be an
incidental finding than an odontogenic keratocyst
(MacDonald-­Jankowski 2010). This is in keeping with the
observation that orthokeratinised odontogenic cysts are
212   Orthokeratinised Odontogenic Cyst
usually smaller at presentation (Dong et al. 2010). These
differences, however, are unlikely to be helpful in making
a distinction between the two lesions when faced with a
single patient.
Once a biopsy specimen has been examined, a diagnosis
of orthokeratinised odontogenic cyst is usually straightfor-
ward, since a finding of an orthokeratinised lining is virtu-
ally diagnostic. However, orthokeratinised odontogenic
cysts may occasionally show focal areas of parakeratin and
odontogenic keratocysts may show focal areas of orthoker-
atin. In Brannon’s (1977) early series of 312 odontogenic
keratocysts, he found that 9.7% would meet the criteria for
an orthokeratinised odontogenic cyst, but that 22 cases
(7.1%) showed both parakeratin and orthokeratin. Because
the orthokeratin was focal, he regarded these lesions as
odontogenic keratocysts. Crowley et al. (1992) also found a
small number of lesions with both para-­ and orthokeratin
(7 of 449 cases: 1.6%) and also considered these to be
keratocysts. In his series of 60 orthokeratinised odonto-
genic cysts, Wright (1981) found 4 (6.6%) with focal areas
of parakeratin.
It appears therefore that there is no clear cut-­off for
how much orthokeratin must be present to determine a
diagnosis of orthokeratinised odontogenic cyst. The WHO
definition states that the lesion is lined by orthokerati-
nised odontogenic epithelium, but may show small areas
of para-­or non-­keratinised epithelium, usually associated
with inflammation (Speight and Neville 2022). We would
interpret this to mean that most of the cyst lining is com-
posed of orthokeratin. If the lining shows prominent
areas of a typical parakeratinised odontogenic keratocyst
(see Chapter 7), then a diagnosis of odontogenic kerato-
cyst should be given. As discussed above, immunocyto-
chemistry is of little help, because the cytokeratin profiles
only reflect the pattern of keratinisation, which can be
clearly seen on a routine H&E-­stained section. Doubt
may arise in a small biopsy or if the lining is inflamed,
when only non-­keratinised or proliferative epithelium
Table 12.3  Cases reported as keratinising odontogenic cysts with verrucous features.
References Age/Sex Site
Aldred et al. (2002) 13/F Maxilla
Canine/premolar area
Ueeck et al. (2007) 46/M Mandible
Molar/ramus
Argyris et al. (2015a) 32/M Mandible
Molar/ramus
Crane et al. (2020) 23/M Mandible
Third molar region
may be seen (e.g. see Figure 12.7c, d), but in these cases
immunocytochemistry does not help and further sections
or blocks must be examined.
Verrucous Odontogenic Cyst
There are a small number of case reports of a keratinising
odontogenic cyst with a verrucous or verruciform prolifer-
ation of the cyst lining. These are summarised in Table 12.3.
Few have been specifically diagnosed as orthokeratinised
odontogenic cyst, but in most cases the lining has been at
least partially composed of orthokeratin.
Aldred et al. (2002) reported the first case in a 13-­year-­old
girl, in which the lining comprised a thin stratified squa-
mous epithelium with an area of markedly hyperplastic
stratified squamous epithelium thrown up into a series of
verrucous projections shedding keratin into the lumen
(Figure 12.9). The cases of Ueeck et al. (2007) and Argyris
et  al. (2015a) were similar, with linings of ortho-­ or par-
akeratinised epithelium and focal areas of verrucous
hyperplasia. The verrucous areas were exophytic and pro-
truded into the lumen, with no evidence of pushing or
invasion into the cyst wall that may suggest verrucous car-
cinoma. All the lesions have been negative for human pap-
illomavirus (HPV), although the case of Argyris et  al.
(2015a) stained for p16. The case of Crane et  al. (2020)
showed only small focal areas of verrucous hyperplasia in
one cyst of a patient with three orthokeratinised odonto-
genic cysts. The case is illustrated in Figure  12.3 and the
verrucous lesion was associated with the left mandibular
second molar.
Lalla et al. (2016) examined the histology of 29 keratinis-
ing jaw cysts and found 13 that met the criteria of orthokerati-
nised odontogenic cyst, while the remainder showed a
mixed keratin pattern. They also identified 5  in which at
least one-­third of the lining showed verruciform hyperpla-
sia. This verruciform architecture was found in 3 of the 13
(23.1%) orthokeratinised odontogenic cysts, while the other
Histology Radiology
Mostly non-­keratinised Unilocular
Partially verrucous with parakeratin
Ortho-­and parakeratin Multilocular, corticated
Mostly verrucous
Orthokeratin Multilocular, corticated
Partially verrucoid
Orthokeratin Unilocular, corticated
Small focal verrucous area

Figure 12.9  An odontogenic cyst showing transition of
the epithelial lining to a verrucous hyperplasia. Source:
From the case reported by Aldred et al. (2002).
2 were in cysts with a mixed keratin pattern. All the cysts
were negative for HPV. This study suggests that verrucous
hyperplasia may be more common than previously reported,
but may have been overlooked as unimportant by reporting
pathologists. In the paper by Lalla et al. (2016) only a portion
of one case is illustrated, and this shows a small area with
columns of parakeratin, described as a ‘verrucous-­like pat-
tern’. Such a feature may be regarded as focal hyperplasia
rather than true verrucous change by some pathologists.
A further case was reported by Manaktala et al. (2017) in
a 13-­year-­old male. This appeared to be similar to the previ-
ously reported lesions, but as well as an unusual verrucous
­Treatmen  213
surface, it also showed bulbous ‘pushing’ rete pegs and the
lesion subsequently recurred and metastasised, suggesting
that it represented an unusual malignancy, possibly a ver-
rucous carcinoma arising in an odontogenic cyst.
­Treatment
In reports where the treatment of the orthokeratinised
odontogenic cyst has been described, lesions have been
removed conservatively by enucleation. Recurrences are
rare and have been reported in less than 5% of cases.
214

13

Nasopalatine Duct Cyst

CHAPTER MENU
Terminology and the Anatomy of the Incisive Canal, 214
Clinical Features, 218
●● Frequency, 218

●● Age, 219

●● Sex, 219

●● Site, 219

●● Clinical Presentation,  220

Radiological Features, 221
●● Radiological Differential Diagnosis,  223

●● Median Palatal Cyst,  223

Pathogenesis, 225
Histopathology, 226
Treatment, 229

The nasopalatine duct cyst is a non-­odontogenic cyst that
arises in the midline of the anterior maxilla, just posterior
to the central incisors. The cyst is thought to arise from epi-
thelial remnants of the nasopalatine duct that are found in
the incisive canal (Rich and Neville 2022). The first descrip-
tion of the nasopalatine duct cyst is attributed to Meyer,
who described it as a supernumerary midline paranasal
sinus (Meyer 1914) and subsequently as a median anterior
maxillary cyst (Meyer 1931). This latter term remained in
the literature for many years and is still used in some text-
books as a synonym. However, the association with the
nasopalatine duct led the World Health Organization
(WHO) classifications to adopt the term nasopalatine duct
cyst (Pindborg and Kramer  1971; Kramer et  al.  1992;
­El-­Naggar et  al.  2017; WHO  2022a). The cyst is found in
association with the incisive canal and the alternative term
of incisive canal cyst is sometimes used. To fully understand
the pathogenesis and clinical features of the nasopalatine
duct cyst, it is helpful to have an appreciation of the termi-
nology, embryology, and anatomy of the incisive canal and
related structures.
­ erminology and the Anatomy of the
T
Incisive Canal
The terms incisive canal and nasopalatine canal are used
interchangeably to describe the bony channel that links the
anterior oral cavity with the floor of the nose. Either term
can be used, but here we will refer to the canal as the
­incisive canal, since this term is more commonly used in
the dental literature. For a more detailed account of the
anatomy and embryology of the incisive canal and related
structures, readers should consult current textbooks of oral
anatomy and embryology. Early studies of the anatomy of
the region involved examination of dried skulls (Roper-­
Hall  1938; Chamda and Shear  1980) or fetal material
(Abrams et al. 1963), but these studies yielded little detailed
information on the structure. More recently, the advent of
cone beam computed tomography (CBCT) and interest in
the microanatomy of alveolar bone in the context of
implant placement has resulted in more detailed studies of
the anterior maxillary region (Jacob et  al.  2000; Song
et al. 2009; Bornstein et al. 2011; Falci et al. 2013; Al-­Amery

Shear’s Cysts of the Oral and Maxillofacial Regions, Fifth Edition. Paul M. Speight.
© 2022 John Wiley & Sons Ltd. Published 2022 by John Wiley & Sons Ltd.
 ­Terminology and the Anatomy of the Incisive Cana 215

Nasal septum

Nasopalatine foramen

Incisive canal

Incisive foramen Incisive foramen

(a) (b)

Figure 13.1  The anatomy of the incisive canal. The canal passes from the incisive foramen in the oral cavity to the nasopalatine
foramen in the floor of the nose. (a) Coronal view. The canal forms a Y shape with two foramina in the nasal floor separated by the
nasal septum. (b) Sagittal view. The canal may be vertical (solid lines) entering the nose perpendicular to the nasal floor, or may be
slanted (dotted lines) and enter the nasal floor more posteriorly.

et al. 2015; Friedrich et al. 2015; Lake et al. 2018). The ter-
minology and key features of the region are summarised in
Box  13.1, and Figure  13.1 presents a simple diagram to
illustrate the main anatomical features.
The incisive canal runs from the oral cavity to the floor of
the nose (Figure  13.1). In the oral cavity, the foramen or
opening is in the midline of the anterior palate, posterior to
the incisor teeth and just deep to the incisive papilla. The
foramen is found in a shallow funnel-­shaped indentation
of bone called the incisive fossae. The shape and size of the
fossae and the foramen show considerable variations
(reviewed by Abrams et  al.  1963), but in general it is the
incisive foramen that is seen on anterior occlusal radio-
graphs as a radiolucency in the anterior palate. The incisive
canal passes superiorly and opens into a fossa in the floor
of the nose that is divided by the nasal septum into two
foramina, each referred to as a nasopalatine foramen or
foramen of Stensen.1 The foramina in the floor of the nose
lie either side of the nasal septum and are found approxi-
mately 20 mm inside the nasal cavity, at the junction of the
septum and the nasal floor (Jacob et  al.  2000). Thus the
1
A historical note: Niels Stensen (also known as Nicolas Steno) was a
Danish anatomist and geologist (1638–1686) who described a
number of anatomical and geological features. He is also known for
describing the duct of the parotid gland – called Stensen’s duct.
Occasionally both the duct and the foramen are incorrectly attributed
to ‘Stenson’.
incisive canal is a Y-­shaped structure with a single opening
on the oral side (the incisive foramen) and two openings on
the nasal side (the nasopalatine foramina; Song et al. 2009;
Figures 13.1a and 13.2). However, between the single infe-
rior opening and the branching of the Y, the canal is often
divided into two or more smaller channels or ‘canaliculi’
(Bornstein et  al. 2011). Bornstein et  al. (2011) and
­Al-­Amery et  al. (2015) studied 100 and 96 subjects,
respectively, by CBCT and found a single channel in 45%
and 65% and two channels in 15% and 34%, respectively.
In  Bornstein’s study 40% of cases had multiple channels,
but Al-­Amery et al. (2015) found only one case with three
channels. In a more a detailed micro-­computed tomogra-
phy (CT) analysis of dissected cadavers, Song et al. (2009)
found that 43% of incisive canals had one channel, 23% had
two, 25% had three, and 9% had four. Occasionally, multi-
ple channels may be a serendipitous finding on CT exami-
nation of the anterior maxilla (Figure 13.2). This complex
anatomy, and the presence of more than one channel
within the bony canal, may explain why, on occasion, a
nasopalatine duct cyst is located off-­centre or lateral to the
midline.
A number of workers have determined the length and
direction of the incisive canal. On average, the distance
between the oral and nasal foramina is about 10 mm (Lake
et  al.  2018), but there is wide variation, with maximum
lengths of 15.8 mm (Song et  al.  2009; South Korea),
17.8 mm (Bornstein et  al.  2011; Switzerland), 19.8 mm
216 Nasopalatine Duct Cyst

(a) (Friedrich et  al.  2015; Germany), 21.3 mm (Etoz and

(b)
(c)
Figure 13.2  The anatomy of the incisive canal is illustrated in
this series of axial computed tomography (CT) images from the
same individual. (a) In the oral cavity, at the level of the incisive
foramen, there is a single channel. (b) In the midline of the canal
three small channels can be seen, each with a corticated outline.
(c) In the floor of the nose there are two openings, the
nasopalatine foramina, one on each side of the nasal septum.
Sisman 2014; Turkey), and 30.2 mm (Al-­Amery et al. 2015;
Malaysia) (Table  13.1). Sekerci et  al. (2014) recorded a
mean length of 10.83 mm in a paediatric population
(<16 years), with a range of 2.4–16.1 mm. There is evi-
dence that the size and shape of the canal may vary
between different ethnicities (Table  13.1). The smallest
dimensions have been recorded in South Korea (Song
et al. 2009) and Switzerland (Bornstein et al. 2011) and the
largest in Malaysia (Al-­Amery et al. 2015). However, the
length of the canal is not a simple measure of the thick-
ness of the anterior maxillary bone, because the canal also
varies in direction and shape. Song et al. (2009) classified
the canals as vertical or slanted and each as curved or
straight. Vertical canals are the shortest and run vertically
upwards and perpendicular to the floor of the nose, while
slanted canals mostly run in an anterior to posterior direc-
tion, with an angle of up to 35° (Figure 13.1b). Song et al.
(2009) found that 60.7% of canals were vertical, of which
about one-­third were curved. The remainder (39.3%) were
slanted and about one-­quarter of these were also curved.
Al-­Amery et  al. (2015), however, found that 96.6% of
canals were slanted and half of these were curved. The
slanted morphology means that many canals are longer
and may be orientated posteriorly towards the centre of
the palate. This explains why some nasopalatine duct cysts
may appear posterior to the incisive papilla and be diag-
nosed as ‘median palatal cyst’.
The incisive canal contains fibrous tissue and neurovas-
cular bundles that provide nerve (the nasopalatine nerve)
and blood supply (palatine arteries) to the anterior palate. It
may also contain mucous glands, especially in the region of
the incisive papilla and nasopalatine fossae in the nose. In
animals (in particular cats, cattle, horses, and some rodents),

Table 13.1  Dimensions of the incisive canal and related foramina.

Diameter of the incisive canal

Centre of Nasopalatine Incisive

Reference Country n Incisive foramen the canal foramen canal length

Bornstein et al. (2011) Switzerland 100 4.45 (1.5–9.7) NR 3.49 (0.9–8.8) 10.99 (5.9–17.8)
Etoz and Sisman (2014) Turkey 500 5.26 (1.8–13.7) NR 3.25 (0.4–6.7) 13.50 (3.8–21.3)
a
Sekerci et al. (2014) Turkey 368 4.13 (1.5–9.0) NR 2.53 (0.3–5.4) 10.83 (2.4–16.1)
Al-­Amery et al. (2015) Malaysia 90 3.49 (1.5–6.6) 3.85 (1.5–7.2) 6.06 (1.3–16.0) 16.33 (4.5–30.2)
Friedrich et al. (2015) Germany 200 4.49 (0.7–11.4) 2.48 (0.3–9.1) 3.43 (0.7–7.7) 11.15 (2.1–19.8)
Suter et al. (2016) Belgium 100 3.27 [1.20] 2.26 [1.08] 2.86 [1.10] 8.81 [1.89]

Data are maximum diameters or length: mean (range) or standard deviation [SD].
NR, not recorded.
a
 Sekerci et al. reported a paediatric population only (<16 years).
 ­Terminology and the Anatomy of the Incisive Cana 217

Box 13.1  The Incisive Canal: Key Features, Definitions, and Synonyms

Incisive canal: a bony channel in the anterior maxilla, passing from the oral cavity to the floor of the nose. May be
referred to as the nasopalatine canal. The canal is Y shaped – divided into two parts superiorly by the nasal septum.
About 50% of people may have two canals and rarely an individual may have three or four.
Incisive foramen: also called the incisive fossae. The opening of the canal in the oral cavity.
Incisive papilla: a soft-­tissue papilla, in the midline of the anterior hard palate just posterior to the central incisors. The
papilla overlies the incisive foramen.
Nasopalatine foramen: also called the nasopalatine fossae. The opening of the incisive canal in the floor of the nose.
There are actually two nasopalatine foramina, one on each side of the nasal septum. The foramina are also called the
foramen of Stensen.
Nasopalatine duct: an epithelial-­lined duct that lies in the incisive canal and joins the oral cavity to the nose. It is pat-
ent in many mammals, but in humans it usually disintegrates at about 10 weeks of fetal life and remains as epithelial
remnants. Very rarely an individual may have a patent duct.
Vomeronasal organ or Jacobson’s organ: an accessory olfactory organ found in mammals in the floor of the nose just
anterior to the nasopalatine foramen. It is vestigial in humans, but may be seen as a blind pouch in the floor of the nose.

the canal also contains an epithelial-­lined ­nasopalatine
duct, which provides a patent conduit between the oral and
nasal cavities. On the nasal side the duct opens close to an
accessory olfactory organ called the vomeronasal organ
(also called Jacobson’s organ) that is found bilaterally on
either side of the nasal septum. Together the nasopalatine
duct and vomeronasal organ provide an enhanced sense of
smell for identifying prey or predators and for detecting
pheromones for sex recognition and courtship.
In humans the nasopalatine duct and vomeronasal organ
are usually lost during development, but vestigial structures,
including evidence of a nasal aperture and a blind pouch
representing the vomeronasal organ, may be found in the
nasal mucosa in over 90% of individuals (Jacob et al. 2000).
In addition, a small number of individuals have a patent
nasopalatine duct that traverses the canal and results in a
direct communication between the oral cavity and nasal
floor. The prevalence of this occurrence is not known, but
von Arx et al. (2018) documented 4 cases and reviewed 37
publications reporting 57 cases between 1881 and 2016.
Patent ducts have been found in all age groups and are often
symptomless, although patients may be aware of the passage
of air or secretions, or may be able to elicit a squeaky or
whistling noise. In 60% of the reports there were two bilat-
eral openings of the duct in the oral mucosa on either side of
the incisive papilla. Treatment was rarely needed.
In most humans, however, the nasopalatine duct is only
found during fetal life and is lined by simple stratified
squamous (oral-­type) epithelium or by pseudostratified
columnar ciliated (respiratory-­type) epithelium. After
about nine weeks of intrauterine life the duct disappears,
but epithelial remnants and mucous glands remain
(Abrams et  al.  1963; Falci et  al.  2013; Lake et  al.  2018).
These epithelial remnants may persist into adult life and
give rise to the nasopalatine duct cyst (see ‘Pathogenesis’).
Bodin et  al. (1986) examined histologically tissue extir-
pated from clinically and radiologically normal incisive
foramina from 20 patients who had had a palatal flap raised
for other reasons. Of the 20 cases, 10 (50%) contained epi-
thelial remnants, including oral and respiratory types.
These authors also found that 6 (30%) of the normal speci-
mens contained a small nasopalatine duct cyst. In 1 case
they also found a small mucous extravasation cyst.
Many studies have been undertaken to determine the
dimensions of the bony incisive canal. This is particularly
relevant to radiological examination and the criteria for
diagnosis of a cyst. Early studies measured the dimensions
on dried skulls (Roper-­Hall 1938; Chamda and Shear 1980)
and showed that the incisive foramen is oval shaped, ori-
entated with the greatest dimension in the antero-­posterior
plane. The average dimensions were approximately 10 mm
antero-­posteriorly and 5 mm wide, although the greatest
dimension was 17.5 mm (Chamda and Shear 1980).
More recent studies have been highly detailed and have
been undertaken using CBCT (Song et  al.  2009; Bornstein
et al. 2011; Al-­Amery et al. 2015; Friedrich et al. 2015; Suter
et al. 2016). These studies have measured the dimensions of
the canal and also of the associated foramina. The dimen-
sions on imaging have been shown to be lower than actual
measurements on dried specimens (Chamda and
Shear 1980) and therefore the imaging data is of more value
to the diagnostic radiologist. The dimensions are summa-
rised in Table 13.1. The incisive foramen has a mean diame-
ter of between 3.5 and 5.3 mm and a maximum dimension of
218 Nasopalatine Duct Cyst

about 13.5 mm (Etoz and Sisman 2014). All the studies have
shown that the dimensions of the canal, including diameter
and length, are greater in males than in females, but the dif-
ference rarely exceeds 1 mm. The diagnostic ­relevance of the
dimensions of the incisive foramen is discussed later in this
chapter (see ‘Radiological Features’).
­Clinical Features
Most descriptions of the nasopalatine duct cyst are to be
found in short case reports that often record unusual or
interesting findings that may not be typical. There have
also been a number of case series that record the overall
features of this lesion. Descriptions of the clinical features
have been taken from a number of selected larger case
series that are summarised in Tables 13.2 and 13.3.
Frequency
The nasopalatine duct cyst represents about 4% of cysts of
the jaws, but is by far the most common of the non-­
odontogenic cysts. Shear’s series from the University of the
Witwatersrand shows the highest frequency, where it con-
stituted 404 (11.6%) of the 3498 jaw cysts registered over a
46-­year period and was slightly more common than the
odontogenic keratocyst (see Table  1.1). In other series,
however, the frequency has ranged from about 1% to 5.5%.
In two large studies from Sheffield, Jones and Franklin
(2006a,b) reviewed almost 50 000 oral and maxillofacial

Table 13.2  Nasopalatine duct cyst. Age, sex, and diameter, from selected case series.

Age Diametera

Reference Country n Mean Range Males (%) Mean (mm) Range

Allard et al. (1981a) Netherlands 22 44.1 11–71 59.1 12.8 5–22

Bodin et al. (1986) Sweden 70 45.0 8–77 67.1 NR 4–40
Anneroth et al. (1986) Sweden 32 54.0 23–88 65.6 15.0 8–25
Nortjé and Wood (1988) S Africa 46 31.0 7–61 75.0 32.0 9–52
Swanson et al. (1991) USA 334 42.5 9–84 54.2 17.1 6–60
Vasconcelos et al. (1999a) Brazil 31 37.4 20–69 77.4 NR NR
Escoda Francolí et al. (2008) Italy 22 46.0 16–73 54.5 14.0 NR
Suter et al. (2015) Switzerland 40 51.3 7–80 62.5 15.0 7–47
Barros et al. (2018) Brazil 30 42.7 17–90 50.0 23.7 NR
a
 In all studies the size is recorded as the maximum diameter of the lesion.

Table 13.3  The frequency of clinical signs and symptoms (%) reported in selected case series of nasopalatine duct cysts.

Clinical signs or symptoms

References n No symptomsa Swelling Pain Infectionb

Allard et al. (1981a) 22 32 55 23 NR

Bodin et al. (1986) 70 20 49 51 37
Anneroth et al. (1986) 32 69 38 31 22
Swanson et al. (1991) 334 29 52 20 25
Vasconcelos et al. (1999a) 31 87 3 1 10
Escoda Francolí et al. (2008) 22 64 18 18 18
Suter et al. (2015) 40 35 25 20 10
Average 52 34 23 20
a
 Usually reported as an incidental finding on clinical examination or radiology.
b
 Signs of infection include fistula, discharge, or foul taste. Totals are over 100% because more than one symptom may be present.

biopsy specimens and found a total of 254  nasopalatine
duct cysts. These represented 3.5% of all jaw cysts. The fre-
quency in children (2.9% of all jaw cysts; n  =  586; Jones
and Franklin 2006b) was slightly less than in adults (3.6%
of all jaw cysts; n  =  6634; Jones and Franklin  2006a).
In  other series, nasopalatine duct cysts have constituted
from 0.74% (Italy; Aquilanti et  al.  2021) to 5.6% (Kuwait;
Ali 2011) of total jaw cysts. Other frequencies include 1.3%
(Soluk Tekkeşin et  al.  2012b; Turkey), 2.2% (Grossmann
et al. 2007; Brazil), 2.9% (Tamiolakis et al. 2019; Greece),
and 4.0% (Daley et al. 1994; Canada).
As a proportion of non-­odontogenic cysts, the nasopala-
tine duct cyst represents between about 30% and 70%.
Daley et  al. (1994) found 403  non-­odontogenic cysts in a
review of 40 000 oral biopsies, of which the nasopalatine
duct cyst was the most frequently diagnosed, comprising
295 (73.4%). In other studies, nasopalatine duct cyst has
constituted 39.1% (Jones and Franklin 2006a,b) and 32.8%
(Nonaka et al. 2011) of non-­odontogenic cysts.
The reason for the variability in reports of frequency is
probably due to the inclusion criteria for the total number
of cysts used in the denominator. Some studies only include
cysts in the bone of the jaws, while others have incorpo-
rated a wider range of maxillofacial cysts (e.g. lymphoepi-
thelial cysts or epidermoid cysts).
Age
Nasopalatine duct cysts are found in adults, but the age
range is wide (Table 13.2). The age of presentation ranges
70
61
60
19
50
43
No. of cases
40
12
30
42
20
16
31
5 29
10
11
1 1
0
0-9 10-19 20-29 30-39
Figure 13.3  Age and sex distribution of 227 patients with nasopalatine duct cysts.
­Clinical Feature 219
from 7 to 90 years, with a mean age of 30–55 years. The age
distribution of 227 of the University of the Witwatersrand
cases is given in Figure 13.3 and shows a peak in the fourth
decade. Cases in children and adolescents are rare.
Sex
Almost without exception, studies have shown a predilec-
tion for males, with overall about 65% of lesions being
found in males (Table 13.2). In our material (Figure 13.3)
there were 156  males (68.5%), and other studies have
shown from 54% to 77% in males (Table 13.2).
Site
The nasopalatine duct cyst is always located in the mid-
line of the anterior palate. Clinically the cyst presents as a
swelling on, or just posterior to, the incisive papilla.
Almost without exception, radiology shows that the cyst
is located within the incisive canal. In rare cases, how-
ever, the cyst may arise in the superior/posterior aspect of
the canal, close to the nasal floor and towards the centre
of the palate (see Figure  13.1b). In this case a plane
occlusal radiograph may show the cyst located posterior
to the shadow of the normal incisive foramen. A sagittal
CT, however, will show that the cyst is continuous with or
located within the superior aspect of the canal. The cyst is
almost always located in the midline of the palate, but
occasionally it may be located laterally if it has arisen in a
secondary canal.
43
40
Females
14
13 Males
19
6
27
13
3
40-49 50-59 60-69 70-79 80-89
Age
220 Nasopalatine Duct Cyst
Clinical Presentation
Clinical signs and symptoms vary, but in a significant pro-
portion of patients the lesion is symptomless and may be
found as an incidental finding during a clinical or radio-
logical examination for another purpose (Table 13.3). The
most common sign or symptom is swelling in the anterior
region of the midline of the palate (Figures 13.4 and 13.5).
Occasionally the swelling may extend to the midline on the
labial aspect of the alveolar ridge (Figure  13.6). In some
cases, ‘through and through’ fluctuation may be elicited
between the labial and palatal swellings. The cyst may also
produce bulging of the floor of the nose. Pain or tenderness
is less often encountered, but when present is usually
accompanied by swelling and evidence of infection.
Various combinations of swelling, pain, and discharge may
occur. The discharge may be mucoid, in which case patients
Figure 13.4  Nasopalatine duct cyst. A typical lesion presenting
as a soft ovoid swelling in the midline of the anterior maxilla,
posterior to the central incisor teeth. Source: Courtesy of the late
Prof. J.J. Pindborg.
Figure 13.5  Large nasopalatine duct cyst extending posteriorly
to involve much of the anterior third of the hard palate.
sometimes describe a salty taste, or it may be purulent and
patients complain of a foul taste. Although swelling or ten-
derness is often found on clinical examination, it may not
be appreciated by the patient. Anneroth et al. (1986) found
that although clinical signs were found in 75% of cases (24
of 32), 22 (69%) cysts were symptomless and were an inci-
dental finding on clinical or radiological examination.
Displacement or splaying of the incisor teeth is observed
fairly often.
Occasionally cysts are superficial and appear to affect
only the palatine papilla (incisive papilla cyst). In these
cases, there may be a history of recurrent swellings that
periodically discharge and then ‘go down’ and recur. Some
of these superficial lesions may not be true nasopalatine
duct cysts, but may represent a superficial mucocele (see
‘Pathogenesis’).
The swellings are usually located in the anterior maxilla,
just behind the incisor teeth, and rarely exceed 20 mm in
diameter (Figure 13.4), although radiological diameters of
up to 60 mm have been recorded (Swanson et  al.  1991;
Table 13.2). Occasionally the lesion may be large and may
extend towards the middle of the palate (Figure  13.5).
Midline swellings of the palate that occur further posteri-
orly have sometimes been diagnosed as ‘median palatal
cysts’ and have been thought to be a specific type of mid-
line fissural cyst. However, they are probably posteriorly
located nasopalatine duct cysts that have arisen towards
the postero-­superior aspect of a slanting incisive canal (see
Figure 13.1b). The median palatal cyst is discussed later in
this chapter.
In general, symptoms are not severe and patients often
disregard them for many years. The cyst may also be com-
pletely symptomless and be discovered fortuitously by the
dentist during routine radiological examination, and occa-
sionally the presence of a cyst may become apparent only
Figure 13.6  Nasopalatine duct cyst producing a midline
swelling of the labial aspect of the alveolar ridge.
 ­Radiological Feature 221

after dentures are placed. Sometimes the cyst may become
apparent due to trauma from the lower anterior teeth, and
this has also been thought to be an aetiological factor.
However, a history of trauma is not often reported and
when it has been seen, it is only in up to 16% of patients
(Bodin et al. 1986; Anneroth et al. 1986).
­Radiological Features
The nasopalatine duct cyst is always located in the midline
of the anterior palate and presents most often as a well-­
demarcated, round or oval radiolucency (Figure  13.7).
Between 75% and 85% of lesions are round or oval
(Anneroth et al. 1986; Bodin et al. 1986), with a slight pre-
dilection for an oval or slight ‘pear shape’ (Figure 13.7a). Of
the remainder, up to 20% (Bodin et  al.  1986) may appear
heart shaped, either because they become notched by the
nasal septum during their expansion or because the ante-
rior nasal spine is superimposed on the radiolucent area
(Figure 13.7c).
Most cysts arise within the inferior (oral) aspect of the
incisive canal, palatal to the central incisors, and on a plain
radiograph the radiolucency may be superimposed over
the tooth roots. A key feature of the nasopalatine duct cyst,
however, is that the periodontal ligament of the involved
roots and the lamina dura are intact (Figure  13.7a, b).
Larger cysts cause the incisor tooth roots to diverge and
become splayed (Figures  13.7a and  13.8; Anneroth et  al.
1986; Bodin et al. 1986; Escoda Francolí et al. 2008).
Cysts that arise higher in the incisive canal may appear
above the apices of the incisor teeth and be located towards
the floor of the nose (Figure 13.7b). Escoda Francolí et al.
(2008) reported the features of 22 cysts and found that 15
(68.2%) were palatal to the incisors and that 7 (31.8%) were
located above the apices towards the nasal regions. Very
large cysts may extend posteriorly and superiorly and may
be associated with labial swelling (Figures 13.6 and 13.8),
or even swelling in the floor of the nose.
The margins of nasopalatine duct cysts are well demar-
cated, but exhibit varying degrees of cortication (Bodin
et al. 1986; Nortjé and Wood 1988). Bodin et al. (1986) found
that 80% of their 70 cysts had a well-­demarcated border that
was corticated to varying degrees. Most cases (60%) were
completely surrounded by a clearly perceptible corticated
margin (Figures 13.7b and 13.8b), whereas in others the infe-
rior border may be less distinct or not visible (Figures 13.7a
and  13.8a). In 2 of their 70 cases, the cysts were located
entirely within the soft tissues of the palatine papillae and
were not visible on radiographs (Bodin et al. 1986).
The nasopalatine duct cyst occurs in the incisive canal
and on radiological examination it may be difficult to

(a) (b) (c)

Figure 13.7  Variable radiological features of the nasopalatine duct cyst. (a) The cyst is oval or slightly pear shaped. Note that the
inferior border is less corticated than the superior margin. The roots of the maxillary incisor teeth are displaced laterally. (b) A rounded
radiolucency located above the apices of the teeth. (c) The cyst is heart shaped. A key feature is that the periodontal space and lamina
dura remain intact (arrows) even when the tooth apex appears to be in the cyst (a).
222 Nasopalatine Duct Cyst
(a)
Figure 13.8  Radiographs of large nasopalatine duct cysts. (a) Large cysts may cause splaying or separation of the incisor roots. This
cyst is corticated at the superior margin, but is indistinct inferiorly. (b) A rare, very large cyst almost filling the hard palate and abutting
the nasolacrimal canals.
decide whether a radiolucency in the anterior maxilla is a
small cyst or a normal incisive foramen. As shown in
Table 13.1, many studies have recorded the dimensions of
the incisive canal, but it is the incisive foramen that is seen
on occlusal radiographs. Overall, the studies summarised
in Table 13.1 show a mean diameter of the incisive foramen
of between 3.5 and 5.3 mm and a maximum diameter of
13.7 mm. Most studies, however, suggest that a normal
foramen over 6 mm in diameter is unusual. Roper-­Hall
(1938) examined 2162 dried skulls and found that only 7
(0.3%) were larger than 6 mm. All 7 were oval, with maxi-
mum antero-­posterior dimensions between 8 and 15 mm.
He concluded that any radiograph that showed a width of
6 mm or less may be considered to be within normal limits,
provided the patients have no other symptoms. Chamda
and Shear (1980) agreed with this finding and showed that
incisive foramen widths of greater than 6 mm were only
found in 148 (15.3%) of 970 specimens, but that antero-­
posterior dimensions of greater than 7 mm were found in
799 (82.4%).
These data show that the normal incisive foramen is usu-
ally oval in shape and may have a width up to 6 mm, but
antero-­posterior dimensions of as much as 10 mm or more
are also found. Bodin et  al. (1986) proposed that if the
width of the foramen was less than 6 mm, then a cyst was
very unlikely. If a radiolucency was between 6 and 8 mm,
then further observation may be indicated, and if greater
than 8 mm and with a thin corticated border, exploratory
surgery should be considered. Radiolucencies exceeding
14 mm in diameter (width) were always cysts.
A number of studies have measured the size of nasopala-
tine duct cysts, and these are summarised in Table  13.2.
(b)
The mean maximum diameter is recorded as between
about 13 mm (Allard et al. 1981a) and 32 mm (Nortjé and
Wood 1988), with a range from 4 to 60 mm. Most studies,
however, agree that the majority of lesions are small and
rarely exceed 20 mm.
Anneroth et  al. (1986) found that 24 of their 32 cysts
(75%) were 15 mm or less in diameter, and only 7 (21.9%)
were greater then 15 mm. Only one cyst was found to be
less that 10 mm. Swanson et al. (1991) recorded the size dis-
tribution of 116 of their cysts and found that 75% (87 cases)
were 20 mm or less and 50% were between 11 and 20 mm.
Only 8 cysts were 6 mm or less in diameter. Of these, 7 were
diagnosed because the patient had symptoms. Bodin et al.
(1986) studied 70  nasopalatine duct cysts and found that
the maximum dimension was 40 mm, but that 79% (55)
were 12 mm or less. Only 2 lesions (3%) were found to be
less than 6 mm in diameter and both were found within the
incisive papillae.
The use of CT or CBCT may be valuable in the investiga-
tion of nasopalatine duct cysts, especially to appreciate the
relationship of larger lesions to the teeth and to the floor of
the nose and other vital structures. Suter et al. (2011, 2015)
have undertaken detailed CBCT analyses of nasopalatine
duct cysts. They found that CBCT was particularly useful
to determine the relationship of the cyst to the apices of the
teeth, and enabled informed decisions regarding the need
for preoperative endodontic treatment (Suter et al. 2015).
They found that 15% of patients required endodontic treat-
ment because of the involvement of tooth apices in the
lumen of larger cysts. Overall, however, they found no cor-
relations between the diameters or volume of cysts and
clinical symptoms, although larger cysts were more likely

to have postoperative complications (Suter et  al.  2011).
These data suggest that although CBCT is able to provide
more information, it has few advantages over conventional
radiology for treatment planning for the majority of lesions.
CBCT may, however, be of value for careful analysis of
large lesions, where knowledge of the relationships to adja-
cent structures is helpful for surgical planning.
Radiological Differential Diagnosis
The nasopalatine duct cyst shows characteristic clinical,
radiological, and histological features (Box 13.2) that, when
considered together, enable an accurate diagnosis in almost
all cases. Although the radiological features are typical, a
number of other lesions may arise in, or close to, the mid-
line of the anterior palate and be mistaken for a nasopala-
tine duct cyst.
The most common alternative diagnosis that must be
considered is radicular cyst. In establishing a diagnosis of
nasopalatine duct cyst, it is important to attempt to exclude
the possibility of a periapical lesion. Clinically and radio-
logically, nasopalatine duct cysts may occasionally be
found lateral to the midline, or may extend over the apical
regions of the incisor teeth and be indistinguishable from a
radicular cyst. The key diagnostic features are that in a
nasopalatine duct cyst the incisor teeth should be vital on
pulp vitality tests and the lamina dura and periodontal
space should be intact on radiographic examination.
However, the lamina dura is not always clearly visible (e.g.
see Figures 13.7c and 13.8b), and a review of the images in
case reports will show that it is not uncommon to see that
one or more of the associated teeth have been root filled.
In their series of 22 cases, Escoda Francolí et al. (2008)
showed that in 8 (36.4%) cases an associated tooth had a
necrotic pulp or had been root canal treated. In a similar
study, Suter et al. (2015) investigated 40 cases by CBCT and
found that 15 (37.5%) patients had a root filling in an asso-
ciated tooth. In a study of 41 lesions, Tsuneki et al. (2013)
showed that a tooth root was close to the lesion in 18
(43.9%) cases and that in 9 of these the tooth was non-­vital
by electric pulp tests, although some of these cases (num-
ber not given) had been root canal treated.
It is difficult to know how to interpret these data. Clearly,
in most cases the cyst had not been removed and a tooth in
close proximity to the cyst lumen had been root treated. This
suggests that a (mis)diagnosis of radicular cyst had been
made on finding a radiolucency close to the tooth apex. It is
also possible that a tooth may be rendered non-­vital by the
presence of a cyst that impinges onto the apex, especially if
the cyst itself were to be secondarily infected. Others, how-
ever, have proposed that the close association of the cyst to
non-­vital teeth suggests that some nasopalatine duct cysts
­Radiological Feature 223
are of inflammatory origin and are actually radicular cysts in
the median maxilla (Tsuneki et al. 2013; see ‘Pathogenesis’
for further discussion). Nevertheless, if the diagnostic crite-
ria are followed (Box 13.2), a correct diagnosis of nasopala-
tine duct cyst should be possible in the vast majority of cases.
Occasionally, however, it may not be possible to distinguish
between a nasopalatine duct cyst and a radicular cyst. This
difficulty is most likely to arise if a nasopalatine duct cyst is
laterally placed, since a midline radicular cyst is rarely
encountered.
Although it is possible that other jaw lesions may arise in
the anterior palate, it is very unusual. Of the odontogenic
cysts, the keratocyst appears to be the most likely to arise at
this location. Woo et al. (1987) reported a single case of a
keratocyst that occurred in the anterior midline of the
maxilla, and Neville et al. (1997) reported 18 cases at this
site. Many of these lesions had been diagnosed clinically or
radiologically as nasopalatine duct cyst and images show
radiological features indistinguishable from those illus-
trated in Figures 13.7 and 13.8. Faced with these features, it
would not be possible to distinguish these keratocysts from
a nasopalatine duct cyst. The only distinguishing feature
was that 90% of Neville et al.’s cases occurred over the age
of 60 years, with a mean age of 69.9 years, which is one or
two decades older than seen in nasopalatine duct cyst
(Table  13.2). Of relevance to the above discussion, it is
interesting to note that Neville et al. (1997) included repre-
sentative radiographs from four cases and all four showed
that an associated tooth had been root treated.
Median Palatal Cyst
A further consideration in the differential diagnosis is the
median palatal cyst (often also call the median palatine
cyst). The very existence of this cyst is controversial. It is
thought to be a fissural cyst, arising from epithelial rem-
nants entrapped in the midline of the developing palate.
The hard palate forms in the seventh to eighth week of
intrauterine life by the fusion of the palatal shelves or pro-
cesses. The shelves come into contact above the tongue
along the midline, and to fuse fully the epithelial covering
of the shelves must disintegrate to allow merging of the
mesenchyme to form the secondary palate. At first the epi-
thelium merges, but then breaks up and fragments into
multiple small epithelial remnants. It is the existence and
location of these remnants that are controversial and fuel
the debate on the existence of cysts in the palatal midline.
It is thought that the remnants ‘dissolve’ or disintegrate
and disappear at or shortly after birth. The actual process
involves an epithelial–mesenchymal transformation,
whereby the epithelial cells change into mesenchymal cells
and disappear. However, there is good evidence that
224 Nasopalatine Duct Cyst
epithelial rests may persist in soft tissues of the midpalate
in the first year of life, and these remnants give rise to the
midpalatal raphe cyst or Epstein pearls. The formation of
the palate and these cysts are discussed in detail in
Chapter 9. Although it is accepted that Epstein pearls arise
from epithelial remnants following palate formation, these
cysts are found only in neonates and there is very little evi-
dence that remnants remain or can give rise to cysts in
adults. Because of doubts about the fissural pathogenesis,
the concept of the median palatal cyst fell out of favour and
there have been few reports after 1985. In the 1992 WHO
classification it was clearly stated that the existence of the
cyst was in doubt and the ‘fissural cysts’ were not included
(Kramer et al. 1992).
Gingell et al. (1985) reviewed 17 cases of median palatal
cyst reported between 1930 and 1985. The cysts were
described as fissural cysts that presented in the midline of
the palate posterior to the incisive papilla. These authors
suggested five criteria that must be met for a diagnosis of a
true median palatal cyst:
1) The cyst must arise in the midline of the palate.
2) It should be located posterior to the palatine (incisive)
papilla.
3) It is an ovoid or circular radiolucency.
4) It is not associated with a non-­vital tooth or with the
incisive canal.
5) There should be no histological evidence of nerve
trunks, large vessels, cartilage, or mucous glands in the
cyst wall.
It can be seen that these criteria are not specific and all
except number four would be consistent with a nasopala-
tine duct cyst. If the median palatal cyst truly exists, it must
be posterior to the incisive papilla, and on radiology it must
be shown to not be associated with the incisive canal. Most
case reports of median palatal cyst illustrate a clinical
swelling posterior to the incisive papilla, but almost all
show radiographs of a lesion that impinges on, or is super-
imposed over, the incisive canal and is indistinguishable
from a nasopalatine duct cyst. Although most nasopalatine
duct cysts arise towards the inferior (oral) aspect of the
incisive canal, close to the incisive papilla, some may arise
towards the posterior/superior aspect of the canal (Escoda
Francolí et al. 2008; Figure 13.1b) and in these cases, the
clinical findings may suggest a cyst posterior to the papillae
and a plain occlusal radiograph may show a cyst posterior
to the incisive foramen.
Many authors also cited an absence of large nerves
and other structures (criterion 5) as evidence that a
median palatal cyst has not arisen in the incisive canal
and must be a separate entity to nasopalatine duct cyst.
However, these structures may be absent in up to
one-­third or more of nasopalatine duct cysts (see
‘Histopathology’ and Table 13.4).
Most authors therefore do not accept the concept of
intraosseous midpalatal fissural cysts and regard all
‘median palatal cysts’ as variants of nasopalatine duct cyst.
Nevertheless, a number of standard textbooks on oral and
maxillofacial pathology still include the median palatal
cyst as a rare, but controversial, entity (Neville et al. 2016;
Woo 2016), while others either do not mention it, or regard
it as a posterior extension of the nasopalatine duct cyst
(Regezi et al. 2017).
Some authors, however, have shown a renewed enthusi-
asm for this cyst (Hadi et  al.  2001; Manzon et  al.  2009;
Allmendinger et  al.  2009; Bacci et  al.  2011; Rangaswamy
et al. 2018). In part, this is because CT or CBCT imaging in
the sagittal plane can more accurately determine the
antero-­posterior relationship of the cyst and the incisive
canal. Sadly, although many of these authors cite Gingell’s
five criteria, they do not meet them, and imaging often
shows a large lesion in the anterior maxilla obliterating the
incisive foramen. Bacci et al. (2011) report a case with CT
imaging that they describe as separate from the incisive
canal, but their illustrations suggest a direct communica-
tion with the superior/posterior aspect of the canal and
also with the nasopalatine foramen in the floor of the nose.
Hadi et al. (2001) show a case that fills the anterior maxilla
and histologically resembles an orthokeratinised odonto-
genic cyst. Both these authors and others (Rangaswamy
et al. 2018) have cited a lack of large nerves or vessels as
supportive of their diagnosis of median palatal cyst, but
this finding does not exclude a nasopalatine duct cyst
(Table 13.4).
Allmendinger et  al. (2009) have reported a well-­
demarcated intrabony cyst in the centre of the hard palate.
They illustrated a sagittal CT that shows the cyst located in
the hard palate with no communication with the incisive
canal, which is clearly visible approximately 10 mm ante-
rior to the lesion. This report does suggest that a true
median palatal cyst may exist, and that the defining crite-
rion to distinguish it from a nasopalatine duct cyst should
be a CT to show that it does not involve the incisive canal.
Note, however, that the lesion was not removed and the
authors did not illustrate any histology.
Taken together, the literature rarely offers strong evi-
dence for the existence of a median palatal cyst as a sepa-
rate and independent entity. We would support the views
of Rapidis and Langdon (1982) four decades ago that most
of these cysts represent large or posteriorly placed naso-
palatine duct cysts, while others represent the random
localisation of other cyst types. However, there are few
immutable rules in biology and it remains possible that
such a cyst may exist. The case of Allmendinger et  al.

(2009) is one of the most convincing, and further reports,
with high-­resolution imaging and histology, may shed fur-
ther light on this conundrum.
­Pathogenesis
Nasopalatine duct cysts arise from epithelial remnants of
the nasopalatine duct in the incisive canal. The anatomy of
the incisive canal and nasopalatine duct have been dis-
cussed earlier in this chapter (Figures 13.1 and 13.2) and it
was shown that there is good evidence that epithelial rem-
nants may persist into adult life. Bodin et al. (1986) demon-
strated that 50% of normal canals contained epithelial
remnants, and we and others (Abrams et  al.  1963) have
noted epithelial cell rests in the wall of up to about one-­
third of nasopalatine duct cysts.
Although it is widely accepted that the nasopalatine duct
cyst arises from epithelial remnants in the incisive canal, the
factors associated with cyst formation are poorly understood
and the pathogenesis is largely speculative. It has been sug-
gested that trauma or bacterial infection could stimulate the
nasopalatine duct remnants to proliferate. There is, how-
ever, very little evidence to support such hypotheses, and a
number of observations tend to preclude these mechanisms.
Very few reports record trauma as a significant clinical find-
ing and when it has been noted it has only been reported in
up to 16% of cases (Bodin et al. 1986; Anneroth et al. 1986).
If trauma to the area during mastication were the cause, it
would not explain why the cysts are found so infrequently
when such trauma is common, and it cannot explain the
male predilection. It is also noted that although many cysts
show inflammation in the wall, it is not consistent and when
present is often focal and mild. Occasionally this can be
shown to be associated with secondary infection and may
also be a result of trauma to the developed cyst, but it would
not appear to be an aetiological factor.
These observations do not of course definitely exclude
the possibility of an inflammatory origin, as the inflamma-
tory process could have subsided before the cyst was
removed. As discussed previously (see ‘Radiological
Differential Diagnosis’), on occasion it may not be possible
to distinguish between a nasopalatine duct cyst and a
radicular cyst, and a number of studies have demonstrated
an association with non-­vital teeth. In particular, Tsuneki
et al. (2013) showed that a tooth root was close to the cyst
in about 45% of cases and that in half of these the tooth was
found to be non-­vital. They suggested that the close asso-
ciation to non-­vital teeth was evidence that some nasopala-
tine duct cysts are of inflammatory origin and are actually
radicular cysts in the midline of the maxilla. There are
three possible explanations for the association with
­Pathogenesi 225
non-­vital teeth: first, that a nasopalatine duct cyst may
expand to resorb the lamina dura and involve the apices of
the tooth, which is then rendered non-­vital; secondly, that
a radicular cyst associated with a central incisor expands
into the incisive canal and is indistinguishable from a naso-
palatine duct cyst; and thirdly, that chronic periapical
infection at the apices of an incisor involves the incisive
canal and initiates cyst formation by inflammatory stimu-
lation of the epithelial remnants of the nasopalatine duct.
These possibilities are speculative, but cannot be dismissed,
and it has to be accepted that occasionally it may not be
possible to distinguish between a nasopalatine duct cyst
and a radicular cyst.
The fact that mucous glands develop in association with
nasopalatine ducts and are sometimes seen in the walls of
the cysts has led to the suggestion that some nasopalatine
duct cysts are in fact a retention or extravasation type of
mucocele. A number of authors have considered this
mechanism, but have dismissed it on the basis that mucus
is rarely found in the lesion, there is rarely an association
between the cyst lumen and glandular ducts, and histology
does not show mucous extravasation nor a lining of duct
epithelium (Abrams et  al.  1963; Allard et  al.  1981a;
Anneroth et al. 1986; Bodin et al. 1986). These authors also
felt that the secretory pressure that would exist in a
mucocele is unlikely to be sufficient to produce bone
resorption and form an intraosseous cyst. As discussed pre-
viously, it has also been noted that mucoceles in the ante-
rior palate must be extremely rare, since large series have
not recorded a single case (Hayashida et  al.  2010; Chi
et al. 2011).
More recently, Tsuneki et al. (2013) found small mucous
glands in about half of their cysts and showed that the
immunohistochemical profiles of the glandular ducts and
the cyst lining were similar. They also found ‘daughter cysts’
with similar features, but on review of the text and images,
these appear to be dilated ducts or cross-­cut ­sections of the
cyst walls. Nevertheless, Tsuneki et al. (2013) suggested that
the similar immunohistochemical profiles were evidence
that up to 50% of nasopalatine duct cysts are in fact a type of
mucous retention cyst. Based on these findings and on their
finding of associations with non-­vital teeth, these authors
have dismissed the concept of the nasopalatine duct cyst
and propose that cysts in the midline of the anterior palate
are all either radicular cysts (with evidence of metaplastic
change) or mucous retention cysts. The evidence to support
their proposal is very circumstantial and does not appear to
be well supported in the literature. Further studies may
shed light on their suggestion.
In the absence of evidence to the contrary, most authors
accept that the nasopalatine duct cyst is a developmental
cyst that arises from cystic degeneration of epithelial
226 Nasopalatine Duct Cyst

Box 13.2  Nasopalatine Duct Cyst: Key Features and Diagnostic Criteria

Clinical Features
●● Comprise only about 4% of all jaw cysts, but are the most common non-­ odontogenic cyst
●● Found in adults with a mean age of about 45 years and peak in the fourth decade

●● There is a wide age range (7–90 years), but lesions in children are rare

●● About 65% arise in males

●● Always located in the midline of the anterior hard palate

●● Most lesions are 10–15 mm in diameter

●● Most common presentation is a swelling, but 50% or more may be symptomless and an incidental finding

Radiological Features
●● Well-­
demarcated and corticated radiolucency
●● Always in the midline of the anterior palate. Arise in the incisive canal

●● Most are round or oval, but a ‘heart shape’ may be seen

●● 15 mm to 20 mm in diameter. Rare lesions may be up to 60 mm and fill the palate

●● Often involve the apices of the incisors

●● The lamina dura and periodontal space are intact

Histological Features
●● Lined by stratified squamous and/or pseudostratified columnar epithelium

●● Most lesions show both types of epithelium

●● Rarely have three or more types, with areas of columnar or cuboidal epithelium

●● Large nerves and blood vessels are typically seen in the wall

●● Often inflamed, but usually focal and mild

●● Mucous glands are seen in up to one-­ third of cases

remnants of the nasopalatine duct. Although there is no
proof for this, the concept is supported by a number of
observations. First, there is the observation that small
cystic dilatations of portions of the nasopalatine ducts are
occasionally seen in fetal material (Abrams et  al.  1963),
and secondly, remnants of the duct and small cysts may be
found in normal incisive canals and in the wall of cysts
(Abrams et  al.  1963; Bodin et  al.  1986; Falci et  al.  2013;
Lake et  al.  2018). It would also explain the absence of
inflammatory cell infiltrates in so many cases, as well as
the relative infrequency of an association with trauma in
the nasopalatine area.
Like other developmental cysts, although the stimulus
for proliferation is not known, the mechanism for growth
and enlargement appears to be through a process of
osmotic pressure, since the cysts are almost always sym-
metrically round or oval, suggesting even centripetal
expansion.
­Histopathology
The nasopalatine duct cyst does not have any distinctive
features on gross or macroscopic examination. The cysts
are usually enucleated, and because most are between 10
and 20 mm in diameter, the pathologist may often receive
the lesion in one piece, although it may be ruptured
(Figure 13.9a). Otherwise multiple fragments of cyst wall
are received. The wall may be thick and fibrous, but is usu-
ally of even thickness. If present, the luminal contents are
usually brown and watery. Occasional cysts may contain
mucus or, if infected, pus.
On histological examination, the nasopalatine duct cyst
is characterised by having a variable microscopic appear-
ance, so the finding of more than one type of epithelium,
and of nerves, vessels, and mucous glands in the wall, are
in themselves almost diagnostic. Table  13.4 summarises
the variable histological features reported in a number of
larger cases series and in 86 of our own cases.
Although most cyst linings include a typical stratified
squamous epithelium, only up to 50% are lined in their
entirety by one type of epithelium. Most of the remainder
have two types of epithelium, but up to four types have
been reported in a single cyst. The four types of epithelium
that may be seen are stratified squamous, pseudostratified
columnar, cuboidal, and columnar. These are seen individ-
ually or in combination, and often there is a transition
between them.
 ­Histopatholog 227

Table 13.4  Histological features of nasopalatine duct cysts (proportion of cysts showing each feature (%). Totals may be greater than
100% because multiple features are seen).

Abrams et al. Allard Anneroth et al. Bodin et al. Vasconcelos et al. Barros et al.
Shear (1963) (1981a) (1986) (1986) (1999a) (2018)

n = 86 n = 61 n = 22 n = 32 n = 50 n = 31 n = 30

Epithelial lining
Stratified squamous 77.9 82.0 72.7 50.0 42.0 93.5 73.3
Pseudostratified columnar 45.3 44.3 27.3 23.3 42.0 77.4 53.3
Simple columnar 4.7 14.8 31.8 73.3 34.0 3.2 30.0
Simple cuboidal 21.0 31.1 27.3 29.0 40.0
One type of epithelium 46.5 36.1 54.5 53.3 46.0 35.5 40.0
Two types of epithelium 51.2 54.1 31.8 40.0 24.0 38.7 30.0
Three or more types 2.3 9.8 13.6 6.7 30.0 25.8 30.0
Mucous (goblet) cells NR 8.2 NR 6.7 14.0 16.1 50.0
Fibrous cyst wall
Neurovascular bundle 45.3 88.5 77.3 78.1 72.0 48.4 50.0
Mucous glands 7.0 31.1 36.7 25.0 18.0 12.9 23.3
Inflammatory infiltrate 75.6 92.8 77.3 71.9 62.0 80.6 83.3

(a) (b)

(c)

(c)

(b)

Figure 13.9  Nasopalatine duct cyst. (a) Low power shows a typical cyst with a fibrous wall of regular thickness lined by a number of
types of epithelium. There are focal accumulations of inflammatory cells (arrows). (b) Inset shows a pseudostratified ciliated columnar
(respiratory) epithelium. (c) Inset shows a proliferative stratified squamous epithelium, associated with inflammation.
228 Nasopalatine Duct Cyst

Stratified squamous epithelium is always non-­keratinised
and may be thin and regular, but is often thickened and
acanthotic or hyperplastic, especially when the cyst is
inflamed (Figures  13.9c and  13.10). Overall, stratified
­squamous epithelium is the most frequently encountered
type of epithelium and is found in between 50% and about
94% of lesions (Table  13.4), but is most often seen in
­combination with pseudostratified columnar epithelium
(Figure 13.9). In our series of 86 cases, 67 (77.9%) showed
stratified squamous epithelium, but only 33 (38.4%) were
entirely lined by this epithelium. Furthermore, 39 cysts
(45.3%) contained pseudostratified ciliated columnar epi-
thelium in part of their linings, but only 7 (8.1%) were lined
entirely in this way. Only 4 cysts showed areas of simple
columnar epithelium, although 18 (20.9%) had areas of
cuboidal epithelium. One cyst was lined entirely by cuboi-
dal epithelium.
These frequencies are very similar to those reported by
others (Table 13.4). For example, Abrams et al. (1963) found
that 82% of their cysts had stratified squamous epithelium
in the lining, but only 26.2% (16 of 61) were entirely lined by
epithelium of this type and only 6.6% of cysts were lined
entirely by pseudostratified columnar epithelium. Bodin
et al. (1986) found 16.0% and 14.0% lined entirely by strati-
fied squamous epithelium or pseudostratified columnar
epithelium, respectively, while the equivalent numbers
reported by Barros et al. (2018) were 30% and 10%.
Pseudostratified columnar epithelium is usually ciliated
and is of typical respiratory type. It often contains mucous
or goblet cells (Figure  13.9b). Overall, up to 50% of cysts
may show prominent goblet cells. These may be found in
the respiratory-­type epithelium, or at the surface of strati-
fied squamous epithelium, or occasionally in association
with columnar or cuboidal epithelium (Figure 13.10c).
A simple cuboidal or columnar epithelium is frequently
seen and has been reported in up to 73% of cysts, but almost
always in combination with stratified squamous or pseu-
dostratified epithelium (Anneroth et al. 1986; Table 13.4).
This epithelium is difficult to define, but usually appears as
a simple epithelium two to five cell layers thick
(Figures 13.10b and 13.11). Most often, however, a transi-
tion is seen between epithelial types, with cuboidal or low

(a) (b)

(c) (d)

Figure 13.10  Nasopalatine duct cysts, showing different patterns of epithelium. (a) Stratified squamous epithelium of variable
thickness. (b) A thin, regular epithelium composed predominantly of cuboidal cells. (c) Stratified squamous epithelium, with prominent
mucous (goblet) cells in the superficial layer. (d) This cyst wall contains mucous glands. A duct enters the cyst lumen in the lower left
corner of the field.

Figure 13.11  Large nerves in the wall of a nasopalatine duct
cyst. In this field the cyst is lined by simple cuboidal epithelium.
Courtesy of Dr Daniel Brierley.
columnar cells admixed with squamous cells. Often, a pre-
dominantly stratified squamous epithelium may be seen
but with superficial columnar, goblet or ciliated cells
(Figure 13.10c, d).
It has frequently been suggested that cysts lined by res-
piratory epithelium probably originate within the superior
aspect of the incisive canal adjacent to the nasal cavity,
whereas those lined by stratified squamous epithelium
develop in the lower portion of the canal. However, this is
not a consistent finding and no studies have been able to
establish a relationship between the nature of the lining
and the site of the cyst. Abrams et al. (1963), for example,
found two cysts in the incisive papilla lined by pseudostrat-
ified ciliated columnar epithelium. The fact that the major-
ity of cyst linings have a combination of types of epithelium
is suggestive of an origin from pluripotential epithelium,
but the possibility that metaplasia occurs must also be
considered.
The cyst wall is composed of collagenous fibrous connec-
tive tissue, which contains a number of characteristic struc-
tures. A valuable diagnostic feature of nasopalatine duct
cyst is the presence of prominent neurovascular bundles
with obvious moderate to large nerves in the fibrous cap-
sule (Figure 13.11). These have been reported in up to about
90% of cases (Table 13.4). Abrams et al. (1963) noted nerves
in all their cases, but found they were moderate to large in
88.5%. In 87% of their cases, muscular arteries and numer-
ous small veins were also present. Our own observations
support the frequency with which these features are found.
In our series of 86 cases, prominent neurovascular bundles
were found in 45% and large muscular arteries in 72%. The
explanation for this is that the long sphenopalatine (naso-
palatine) nerve and vessels that pass through the incisive
canal are either included in the cyst wall or are removed
with the cyst in the course of surgical enucleation.
­Treatmen 229
Small foci of mucous glands (Figure 13.10d) have been
found in the fibrous capsules of up to one-­third of cases
(Abrams et al. 1963; Allard et al. 1981a; Table 13.4). As the
foci are small, it is probable that their frequency would be
higher if biopsy material were more extensively sampled.
Abrams et al. (1963) found evidence of fibrosed glands in
association with areas of inflammation and suggested that
glands may have degenerated in some lesions. Mucous
glands are a consistent finding within the incisive canal,
but in fetal tissues they were found only towards the nasal
aspect. Since nasopalatine duct cysts most often arise in the
inferior portions of the canal, this may explain the paucity
of glandular tissue.
Nasopalatine duct cysts are often inflamed, but this is not a
consistent finding. In our series of 86 cases, 65 (75.6%) showed
evidence of inflammation, but this was only prominent or
severe in 9 (10.5%). Bodin et al. (1986) and Barros et al. (2018)
also found that prominent inflammation was unusual (12%
and 10% of cysts, respectively), but others found a heavy
inflammatory infiltrate in about half of cases (Abrams
et al. 1963; Allard et al. 1981a). When present, the inflamma-
tion is usually focal and is associated with a hyperplastic or
proliferative squamous epithelial lining (Figure 13.9c).
Occasionally, epithelial cell rests may be seen in the cyst
wall. Some of these may be cross-­sectioned fragments of
mucous glands or small ducts, but others appear to be
squamous and probably represent remnants of the naso-
palatine duct. These were found in 19 (22.1%) of our 86
cases and Abrams et al. (1963) found epithelial cell rests in
22 (36.1%) cysts, of which 19 were squamous and 3 showed
small proliferations of cuboidal cells.
Other features include small islands of hyaline cartilage
that may very rarely be seen in the cyst walls. They were
present in 6 of our cases (7%) and Abrams et  al. (1963)
found cartilage in 5 (8.2%) of their 61 cysts. However, 4 of
these were cysts in the palatine papilla (‘incisive papilla
cysts’) and cartilage was only seen in 1 of 57 cysts that they
felt had actually arisen within the canal. It is not unusual to
find small amounts of cartilage in the region of the normal
palatine papilla, so its presence in the cyst wall should not
be regarded as a pathological process.
­Treatment
Nasopalatine duct cysts are treated by surgical enucleation.
Most cysts are less than 20 mm in diameter and do not
involve the teeth, which can be preserved. Occasionally,
however, the apices of the incisor teeth may be involved in
the cyst lumen and some authors advocate presurgical
endodontic treatment (Suter et al. 2015). Nasopalatine duct
cysts rarely recur. In their series of 334 cases, Swanson
et al. (1991) found recurrences in only 2% of cases.
230

14

Nasolabial Cyst

CHAPTER MENU
Clinical Features, 230
●● Frequency, 230
●● Age, 230
●● Sex, 231
●● Clinical Presentation,  231
Radiological Features, 233
Pathogenesis, 234
●● Nasolacrimal Cyst,  234
Histopathology, 234
Treatment, 236

The nasolabial cyst occurs outside the bone in the soft
­tissues of the upper lip below the alae of the nose. Because
it arises in the maxillofacial region, in close proximity
to  the maxillary alveolus, it is often classified among
the jaw cysts. The nasolabial cyst has also been called the
­nasoalveolar cyst, but as the alveolus is not involved,
the term nasolabial is preferred. Occasionally the literature
still includes the term Klestadt cyst after Klestadt, who
described the cyst in a number of papers in the early 1900s
(reviewed by Klestadt 1953; Roed-­Petersen 1969).
­Clinical Features
Nasolabial cysts are rare and most reports in the literature
are single case reports or small case series. Roed-­Petersen
(1969) undertook a review of the literature between 1882
and 1969 and found 155 patients reported with nasolabial
cysts. He was able to carry out an analysis of the combined
data of 111 of these patients plus 5 of his own cases. Van
Bruggen et  al. (1985) identified a further 45 cases up to
1985 and added 10 cases of their own. Subsequently there
have been many case reports and small series, but overall
fewer than 350 cases have been reported. Sheikh et  al.
(2016) undertook a systematic review and identified
79 publications reporting 311 cases up to 2016. Tables 14.1
and  14.2 summarise data from selected case series and
from the reviews of Roed-­Petersen (1969) and Sheikh
et al. (2016).
Frequency
Nasolabial cysts are rare lesions and probably represent
only about 0.5% of all cysts of the maxillofacial region.
Shear found only 21 examples in the archives of the
University of the Witwatersrand over a period of 46 years,
representing 0.6% of jaw cysts (see Table  1.1). Jones and
Franklin (2006a), in a review of almost 45 000 biopsy speci-
mens in Sheffield, found only 20  nasolabial cysts, repre-
senting 3.4% of non-­odontogenic cysts and only 0.3% of all
jaw cysts. Data from other large series have shown a fre-
quency among jaw cysts of 0.04% (Soluk Tekkeşin
et al. 2012b; Turkey), 0.1% (Daley et al. 1994; Canada) and
1.0% (Grossmann et al. 2007; Brazil).
Age
The nasolabial cyst occurs in adults, with a mean age of
about 42 years (Table  14.1). The age distribution of 167
patients is shown in Figure 14.1. These data are taken from

Shear’s Cysts of the Oral and Maxillofacial Regions, Fifth Edition. Paul M. Speight.
© 2022 John Wiley & Sons Ltd. Published 2022 by John Wiley & Sons Ltd.
 ­Clinical Feature 231

Table 14.1  Age, sex, and clinical findings from selected case series of nasolabial cysts and from the large reviews of Roed-­Petersen
(1969) and Sheikh et al. (2016).

Age Sizea

Reference Country n Mean Range Female (%) Mean Range Bilateral (%)

Chinellato and Damante (1984) Brazil 8 26.6 24–35 87.5 NR 10–30 0

van Bruggen et al. (1985) S Africa 10 43.3 30–72 100 23.3 20–25 0
Vasconcelos et al. (1999b) Brazil 15 42.0 20–69 86.7 NR NR 6.6
Choi et al. (2002) S Korea 18 42.8 17–67 72.2 NR 10–50 0
Yuen et al. (2007) Singapore 17 41.0 31–75 64.7 NR NR 5.8
Tiago et al. (2008) Brazil 8 47.6 20–67 100 21.8 13–20 12.5
Lopes-­Rocha et al. (2011) Brazil 7 40.3 27–62 100 14.7 10–30 0
Roed-­Petersen (1969) Review 116 42.4 12–75 77.6 NR NR 11.2
Sheikh et al. (2016) SR 311 41.8 4 m-­78 78.2 NR NR 9.6

NR, not reported; SR, systematic review.

a
 Size (mm): in all studies the size appears to be recorded as an estimate of the diameter of the lesion on clinical examination.

Table 14.2  Clinical signs and symptoms (%) reported in selected case series of nasolabial cysts and in the large reviews of Roed-­
Petersen (1969) and Sheikh et al. (2016).

Clinical findings (%)

Reference n Swelling Nasal obstruction Paina Infectionb

Chinellato and Damante (1984) 8 100 NR 25.0 12.5

Vasconcelos et al. (1999b) 15 100 13.3 0 0
Choi et al. (2002) 18 55.6 27.8 16.7 NR
Yuen et al. (2007) 17 41.2 23.5 11.8 29.4
Tiago et al. (2008) 8 50.0 62.5 25.0 0
Roed-­Petersen (1969) 116 83.6 31.0 31.9 NR
Sheikh et al. (2016) 311 70.9 17.3 41.9 3.8

NR, not reported.

a
 Includes complaints of pain and tenderness on clinical examination.
b
 Signs of infection include fistula, discharge, foul taste. Totals are over 100% because more than one symptom may be present.

10 cases of Shear’s from the University of the Witwatersrand Sex

and from a number of reviews or case series where the age
Of all the cysts of the maxillofacial region, the nasolabial
distribution was known: Roed-­Petersen (1969; n  =  106);
cyst is the only one that shows a predilection for females.
van Bruggen et al. (1985; n = 25); Choi et al. (2002; n = 18);
Table 14.1 shows that in some series 100% of patients have
Chinellato and Damante (1984; n = 8). There is a wide age
been female, but the largest review found that 78.2% of
range, with a peak frequency in the fourth and fifth dec-
cases occurred in females (Sheikh et al. 2016). Of the 167
ades. Very few series have reported cases in children,
cases shown in Figure  14.1, 78.4% (131 cases) arose in
although a few were found in the second decade
females.
(Figure 14.1). In a review of over 4400 maxillofacial biop-
sies from children, Jones and Franklin (2006b) found only
one case of nasolabial cyst, in a 12-­year-­old female. In their
Clinical Presentation
systematic review, Sheikh et  al. (2016) found a wide age
range and recorded one case in a 4-­month-­old child, but The nasolabial cyst presents as a swelling of the upper lip,
details were not provided. which is often visible on extraoral examination. The cyst
232 Nasolabial Cyst

50
46
45
40
40

35

30
No. of cases

26 36
Females
25 31 23
Males
20
16
15 21
20
10 8 12 8

5
5 6 10 9
0 5 4 0
2 3 3
0
0-9 10-19 20-29 30-39 40-49 50-59 60-69 70-79 80-89
Age

Figure 14.1  Age and sex distribution of 167 patients with nasolabial cysts.

found swelling as a symptom in only about 50% of cases

Figure 14.2  Nasolabial cyst producing a swelling of the right
upper lip, forming a bulge high in the labial sulcus (arrows).
fills out the nasolabial fold, often lifts the ala, and may dis-
tort the nostril. It may produce a swelling of the floor of the
nose and can displace the inferior turbinate. Intraorally it
forms a sessile bulge high in the labial sulcus (Figure 14.2).
Signs and symptoms are summarised in Tables  14.1
and  14.2. The most frequent finding is of a swelling and
very often this was the only complaint. However, some-
times if the swelling is small the cyst may be an incidental
finding, diagnosed fortuitously during routine examina-
tion. Roed-­Petersen (1969) found that only 97 (83.6%) of
116 patients complained of swelling, while others have
(Choi et  al.  2002; Tiago et  al.  2008). In their systematic
review, Sheikh et  al. (2016) found that 70.9% of patients
complained of swelling, the majority of which involved the
nasolabial fold and the alar region. Only 16 cases (6.8%)
showed lip swelling only. They recorded only 2 cases that
were found incidentally. Physical examination of the
lesions was recorded in 93 cases: 40 (43.0%) were described
as fluctuant, 14 (15.0%) as mobile, and 39 (41.9%) were ten-
der. Fluctuance may be elicited between the swellings in
the floor of the nose and in the labial sulcus.
Patients may complain of nasal obstruction or difficulty
in nasal breathing, but the frequency of this is variable
(Table  14.2). This may depend on where the cyst was
managed. For example, Tiago et  al. (2008) reported that
62.5% of their patients had nasal obstruction, but these
patients were seen in a department of otorhinolaryngology
(Ear, Nose, and Throat), whereas lower frequencies were
seen in a dental clinic environment (13.3%; Vasconcelos
et al. 1999b). Pain, or tenderness on palpation, is seen in up
to about 40% of patients and occasionally there may be
clear signs of infection (Table 14.2). Infected cysts may dis-
charge into the labial sulcus, or into the nose. In some
cases, difficulty with an upper denture has drawn attention
to the problem.
A number of series have recorded the size of the cyst and
have shown mean diameters up to 23.3 mm (van Bruggen
et al. 1985; Table 14.1). The cysts ranged in size from less
than 10 mm to as large as 50 mm (Choi et  al.  2002).

Occasional ‘giant’ or massive nasolabial cysts have been
recorded. Cohen and Hertzanu (1985) reported a case that
reached 70 mm in diameter, causing severe facial deformity.
In most cases the cysts are unilateral, but about 10% of
patients have been found to have bilateral lesions. In the
two large reviews, the frequency of bilateral cases was
11.2% and 9.6% (Table 14.1).
­Radiological Features
Radiological examination can assist in the diagnosis of
nasolabial cyst, in the first instance by excluding a lesion of
intraosseous origin, but the cyst also has some characteristic
radiological features. The lesion overlies the maxilla and may
cause pressure resorption of the cortical plate that appears as
a slight radiolucency of the alveolar process above the apices
of the incisor teeth (Figure  14.3). A more characteristic
feature, however, is seen on an anterior occlusal plane
radiograph. In this view, the normal nasal septum and lateral
and anterior margins of the nasal aperture form an ‘anchor’
shape that is symmetrical about the midline. The nasolabial
cyst may distort or displace the radiopaque line of the inferior
margins of the nose to form a convexity towards the posterior
aspect (Figure 14.3, arrows). This “distorted anchor” feature
was first described by Seward (1962) and was seen in 6 of the
8 cases reported by Chinellato and Damante (1984).
Figure 14.3  Anterior occlusal radiograph of a patient with a
nasolabial cyst. There is a posterior convexity of the left half of
the radiopaque line that forms the bony border of the nasal
aperture (arrows). ⃝ is located within the cyst and shows an
area of very slight radiolucency. Source: Courtesy of
Drs L.E.M. Chinellato and J.H. Damante.
­Radiological Feature 233
If a radiopaque contrast medium is introduced, the cyst
appears as a spherical or bean-­shaped lesion lying against the
inferior and lateral borders of the anterior bony aperture of
the nose, extending from the midline to the canine fossa
(Figure 14.4; Chinellato and Damante 1984). Computed tomog-
raphy (CT) and magnetic resonance imaging (MRI) show these
features with more clarity. Choi et al. (2002) reported CT find-
ings on 11 patients, and found that the cysts presented as well-­
demarcated, low-­density lesions lying just lateral and inferior to
the nasal opening (the pyriform aperture). They observed no
invasion of bone in any of their patients.
MRI shows a well-­demarcated, hypointense cystic lesion,
but T2  weighting highlights the lesions as hyperintense
(white). In axial views, the cyst lies just below the alae of
the nose and displaces the nasal cavity and nasolabial fold
(Iida et al. 2006b; Sumer et al. 2010). In coronal and sagittal
views, the cyst often has a characteristic bean shape with
the concave margin orientated towards the medial or pos-
terior aspect, where the cyst impinges on the lateral or
anterior nasal margins of the maxilla. Occasionally, a fluid
level may be seen that shows as slight hyperintensity on T1
and hypointensity on T2  weighting (Iida et  al.  2006b).
Although there may be displacement of bone or slight sau-
cerisation of the cortical plates, there is no evidence of
bone destruction or perforation.
A number of workers have used ultrasound to examine
the nasolabial cyst. This shows a well-­defined anechoic
cystic lesion (Ocak et al. 2017). An advantage of ultrasound
is that it does not involve ionising radiation and it is quick
and cheap. It is also valuable in easily distinguishing
between a cystic lesion and a solid lesion that may present
Figure 14.4  Nasolabial cyst. The extraosseous position of the
cyst is demonstrated by injection of a radiopaque fluid. Source:
Courtesy of Drs L.E.M. Chinellato and J.H. Damante.
234 Nasolabial Cyst
at this site. In particular, benign salivary gland tumours are
not uncommon in the upper lip.
­Pathogenesis
There is general agreement that nasolabial cysts are of devel-
opmental origin. Early workers regarded the lesion as a fis-
sural cyst that arose from epithelial remnants entrapped after
fusion of the lateral nasal and maxillary processes. A fissural
origin is now regarded as not tenable, since the embryologi-
cal basis for this has been disputed and discredited.
It is now thought that the cyst arises from the lower
­anterior part of the nasolacrimal duct, a proposal that was
first suggested in 1920 by Brüggemann (reviewed by
Allard  1982). The nasolacrimal duct (also called the tear
duct) runs from the lacrimal sac in the medial aspect of the
orbit and drains tears into the nose. It runs in a bony canal
or groove (the nasolacrimal canal) that lies between the
maxilla and the lacrimal bone superiorly and through the
inferior turbinate bone inferiorly to open in the lateral wall
of the nose into the inferior meatus below the inferior tur-
binate. The nasolacrimal canal can sometimes be seen on
occlusal radiographs, superimposed over the posterior part
of the hard palate (for example, see Figure 13.8).
The nasolacrimal duct begins to form at about six weeks
of intrauterine life, at the junction of the maxillary process
and the lateral nasal process. As the processes fuse, a deep
groove is formed and the epithelium at the base of the
groove thickens to form a solid cord, the nasolacrimal
ridge, which eventually canalises and separates from the
surface to form a duct within the mesenchyme. The supe-
rior (cranial) end of the duct connects with the developing
lacrimal sac, while the inferior (caudal) end proliferates to
connect with the lower part of the lateral nasal wall. The
location of the nasolabial cyst is such that it most likely
arises from epithelial remnants at the inferior end of the
embryonic nasolacrimal rod or duct, or possibly from the
lower anterior portion of the mature duct. The mature
nasolacrimal duct is lined by pseudostratified columnar
epithelium and this is the type of epithelium most often
found lining nasolabial cysts.
A developmental origin for the nasolabial cyst is further
reinforced by the finding that about 10.0% are bilateral.
Another remarkable feature is the high frequency in
females, the only cyst of the oral regions that shows a
female preponderance. The reason for this is unknown.
Nasolacrimal Cyst
Another cyst that may arise in this region, and must not be
confused with the nasolabial cyst, is the nasolacrimal cyst.
The nasolacrimal cyst is an acquired retention cyst arising
due to fluid retention within the nasolacrimal duct. The
developing nasolacrimal canal opens into the lateral wall
of the nose in the inferior meatus, but is covered by a mem-
brane (the membrane of Hasner) and does not become pat-
ent until birth or shortly thereafter. In a small number of
neonates, the duct does not become patent and the block-
age results in retention of tears and cyst formation in the
duct or lacrimal sac, called a dacryocystocele. These may be
congenital or arise in neonates, but are very rare after a few
months of age. However, occasionally a dacryocystocele
may arise in adults if the nasolacrimal duct is blocked due
to another reason, such as infection or trauma. Nevertheless,
these lesions arise in the lateral wall of the nose adjacent to
the inferior turbinate, and differentiation from nasolabial
cysts should be straightforward (Eloy et al. 2012; Box 14.1).
­Histopathology
Nasolabial cysts are soft-­tissue lesions and may be removed
by a conservative excision, so that the pathologist receives
an intact cyst with a fibrous wall. On dissection, the lesion
may reveal watery or mucous fluid. Larger cysts may be
enucleated and in some cases may be marsupialised, often
by a transnasal route. In these cases, the specimen may be
composed of cystic fragments.
The nasolabial cyst is usually lined by a non-­ciliated
pseudostratified columnar epithelium (Figure  14.5),
although other epithelial types may be seen, including
stratified squamous, cuboidal, or respiratory epithelium. In
Roed-­Petersen’s (1969) review, 64 cases that had been eval-
uated histologically were summarised. Pseudostratified
columnar epithelium was seen in 53 (82.8%) cysts and in 26
(40.6%) was the only type of lining present. In 9 cases,
pseudostratified columnar epithelium was present in asso-
ciation with stratified squamous epithelium, and in 15 with
cuboidal epithelium. Only 4 cases (6.3%) were lined solely
by stratified squamous epithelium and 4 solely by cuboidal
epithelium. Overall, 53.1% (n = 34) were lined by one epi-
thelial type, 42.2% (n  =  27) by two epithelia, and 4.7%
(n = 3) by all three types. The most frequent combinations
of epithelial types were pseudostratified columnar with
cuboidal epithelium (15 cases: 23.4%) or with stratified
squamous epithelium (9 cases: 14.1%). Mucous or goblet
cells were present in only 51.5% (n = 33) of cysts and only
34.3% (n = 22) contained ciliated cells.
Most workers have found a similar type of epithelial lin-
ing. Chinellato and Damante (1984) found that all 8 of
their cysts were lined by pseudostratified columnar epithe-
lium and that 4 also had areas of stratified squamous epi-
thelium; 7 cases also contained goblet cells. Yuen et  al.
 ­Histopatholog 235

Box 14.1  Nasolabial Cyst: Key Features

Clinical Features
●● Rare cyst, comprising about 0.5% of jaw cysts

●● Affects adults with a mean age of 42 years and peak in the fourth and fifth decades

●● About 80% arise in females

●● Presents as a swelling in the upper lip

●● May displace the nasolabial fold and the floor of the nose

●● Most are about 20 mm in diameter

●● 10% may be bilateral

Radiological Features
●● They are extraosseous, but often resorb the alveolar bone

●● May see a slight radiolucency above the incisor roots

●● On an occlusal radiograph, they may displace the inferior margins of the nasal aperture to form a characteristic

­convexity towards the inside of the nose

●● Magnetic resonance imaging (MRI) shows a hyperintense T2-­ weighted image, well demarcated and ‘bean’ shaped
on coronal and sagittal views
Histological Features
●● Lined predominantly by pseudostratified columnar epithelium

●● About 40% lined by two types of epithelium, usually pseudostratified with stratified squamous or columnar

●● Often show subepithelial hyalinisation of the collagen

●● May see goblet cells, or mucous glands in the wall

Figure 14.5  Nasolabial cyst lined predominantly by a pseudostratified columnar epithelium containing many goblet cells. A small
area of lining is composed of simple cuboidal epithelium (arrow). The cyst wall shows prominent eosinophilic hyalinisation below the
epithelium. Source: Courtesy of Dr Daniel Brierley.

(2007) reviewed 17 cases and found that 9 (52.9%) were
lined by pseudostratified columnar epithelium, 4 (23.5%)
by stratified squamous epithelium, and 3 (17.6%) by both
types. One case was lined by cuboidal epithelium alone.
In their systematic review of 311 cysts, Sheikh et  al.
(2016) found that 71.1% (n = 221) were lined by a mixed
epithelium and that 47.9% contained goblet cells or mucous
glands. Only 33 (10.6%) were reported to be inflamed.
The cyst wall is composed of relatively acellular fibrous
connective tissue, which may contain small numbers of
mucous glands. Focal areas of inflammation may also be
seen. Roed-­Petersen (1969) noted that in 4 of their own 5
236 Nasolabial Cyst
cases there was a prominent subepithelial zone of eosino-
philic hyalinised connective tissue. Although this feature is
rarely mentioned in publications, we have noted it in our
own cases (Figure 14.5).
­Treatment
Although nasolabial cysts are extraosseous, careful surgi-
cal excision or enucleation via a transoral sublabial
approach is the most common treatment. Cysts lying close
to the floor of the nose can be treated by a transnasal endo-
scopic marsupialisation technique. This was developed by
Su et al. (1999), who treated 16 patients and found that the
cyst became replaced by an air-­containing sinus with a per-
sistent opening at the anterior or anterolateral nasal floor.
More recently, Chao et al. (2009) compared the costs and
outcomes of transnasal marsupialisation (n = 34) with sub-
labial excision (n = 23) and found that both were equally
effective, but that transnasal marsupialisation was cheaper
and involved fewer days of hospitalisation. Marsupialisation
was used for larger lesions with a mean diameter of
21.2 mm. In their systematic review, Sheik et  al. (2016)
found information about treatment in 263 cases. Most
(70.0%; n = 184) were treated by sublabial excision or enu-
cleation and 79 (30.0%) were treated by transnasal marsu-
pialisation. They found that complications following
surgery were seen in 27.2% of the patients treated by the
sublabial approach, compared with only 13.9% in the trans-
nasal group. The most common complication was facial
swelling, seen in 19 sublabial patients, but only 5 treated by
marsupialisation. Other complications of the sublabial
approach included perforation of the nasal mucosa, pain or
paraesthesia, and toothache.
 237

15

Cysts of the Salivary and Minor Mucous Glands

CHAPTER MENU
­Mucoceles, 237 ­Retention Cyst and Pseudocyst of the Maxillary Sinus,  253
•• Classification and Terminology,  238 •• Clinical Features,  253
•• Clinical Features,  238 –– Frequency,  254
–– Frequency,  238 –– Age,  254
–– Age,  239 –– Sex,  254
–– Sex,  240 –– Site,  254
–– Site,  240 –– Clinical Presentation,  254
–– Clinical Presentation,  241 •• Radiological Features,  254
–– Superficial Mucoceles,  241 •• Pathogenesis,  254
–– Mucocele of the Glands of Blandin–Nuhn,  242 •• Histopathology,  255
•• Ranula,  242 •• Treatment,  255
•• Pathogenesis,  244
­Lymphoepithelial Cysts,  255
•• Histopathology,  244
–– Mucous Extravasation Cysts,  244 ­Intraoral Lymphoepithelial Cysts,  256
–– Superficial Mucoceles,  247 •• Clinical Features,  256
–– Mucous Retention Cysts,  248 •• Frequency,  256
–– Histological Differential Diagnosis,  249 •• Age,  256
•• Treatment,  250 •• Sex,  256
­Salivary Duct Cysts,  251 •• Site,  256
­Cysts of the Maxillary Sinus,  252 –– Clinical Presentation,  256
­Mucocele of the Maxillary Sinus,  252 •• Pathogenesis,  256
•• Histopathology,  257
•• Clinical Features,  252
–– Frequency,  252 •• Treatment,  258
–– Age and Sex,  252 ­Lymphoepithelial Cysts of the Parotid Gland,  258
–– Clinical Presentation,  253 –– HIV-­Associated Salivary Gland Disease,  259
•• Radiological Features,  253
•• Pathogenesis,  253 ­Polycystic (Dysgenetic) Disease of the Parotid Glands,  259
•• Histopathology,  253 ­Sclerosing Polycystic Adenoma,  260
­Keratocystoma,  260

Cysts of the salivary and minor mucous glands of the
head and neck are common and fall into three broad cat-
egories: developmental, reactive, and neoplastic. Cysts
may arise in the major salivary glands or in the minor
glands that are found in the submucosa of the oral cavity.
Similar lesions arise in the minor mucous and seromu-
cous glands that are dispersed throughout the upper aer-
odigestive tract and the paranasal sinuses. This chapter
will discuss the more common cystic lesions that affect
the oral cavity, the major salivary glands, and the maxil-
lary sinus.
­Mucoceles
Mucoceles are the most common of all lesions of the sali-
vary glands and are mucus-­filled cystic cavities that arise in
the mucosa of the upper aerodigestive tract. Although

Shear’s Cysts of the Oral and Maxillofacial Regions, Fifth Edition. Paul M. Speight.
© 2022 John Wiley & Sons Ltd. Published 2022 by John Wiley & Sons Ltd.
238 Cysts of the Salivary and Minor Mucous Glands
mucocele is a well-­recognised and widely used term, there
is still much debate and disagreement about how it should
be defined and its precise usage.
Classification and Terminology
The term mucocele is used in different ways by different
authors and in different countries, leading to confusion
and lack of consistency when considering case series and
case reports. We have been unable to find a consensus on
the correct terminology or even spelling of what consti-
tutes a mucocele.1 Most clinicians and especially paediat-
ric dentists recognise the mucocele as a cystic lesion
arising on the oral mucosa, and use the term regardless of
the histological findings. It is recognised, however, that
there are two types of mucocele. One arises as a result of
mucus extravasation and the other as a result of mucus
retention within a dilated duct. Many pathologists never-
theless choose to make a clear distinction between these
two types and some decline to use the term ‘cyst’ for the
extravasation type because it does not have an epithelial
lining. Thus, many authors in the USA prefer to use the
term ‘extravasation phenomenon’ or ‘mucus escape reac-
tion’ for the extravasation type, and often use ‘mucocele’
as synonymous with this type of lesion. It is ironic that
these authors still use the terms ‘solitary bone cyst’ and
‘aneurysmal bone cyst’ for other cystic lesions that are also
not lined by epithelium.
The retention type is usually called a ‘mucous retention
cyst’, but others use the term ‘salivary duct cyst’ and do not
regard this as a type of mucocele. The term sialocyst is also
commonly used, but it is ill defined and is used by different
authors as a name for a variety of lesions.
Clinicians will appreciate that extravasation and reten-
tion mucoceles are indistinguishable on clinical examina-
tion and that both present as a cystic lesion. They are often
therefore referred to as mucous extravasation cyst and
mucous retention cyst. This terminology is clear and pre-
cise, is in common usage, and recognises that the lesions
are clinically cystic.
With regard to a definition for mucocele, this is hard to
come by, but the best we have found is that of Richardson
(2019) used in a contemporary pathology textbook:
1  The alternative spelling is mucocoele. Both –cele and –coele are
suffixes derived from Greek, but have similar meanings. Cele is
derived from kēlē, meaning tumour, swelling, or hernia, while coele is
derived from koîlos, meaning a cavity or hollow. The two are used
interchangeably and synonymously in medicine as a suffix to refer to
swellings, cystic or not, involving a particular organ or tissue. In the
literature, mucocele is used far more commonly (by a factor of more
than 10) than mucocoele. For these reasons, we have chosen to use
the term mucocele.
The pooling of salivary mucus within a cystic cavity
resulting from blockage or rupture of a salivary duct.
This definition describes the lesion as a cystic cavity regard-
less of lining and includes both the retention type (caused by
blockage) and the extravasation type (caused by rupture).
In this chapter we use this definition and will refer to the
extravasation type of mucocele as mucous extravasation cyst
and the retention type as mucous retention cyst. Furthermore,
we regard salivary mucoceles as intraoral lesions and use
the term salivary duct cyst for retention cysts of the major
salivary glands. Although the clinical appearance of mucous
extravasation cysts and mucous retention cysts may be
indistinguishable, they do have some distinctive clinico-
pathological features (Table 15.1; Box 15.1).
Clinical Features
Frequency
Mucoceles of the mouth are very common. Their true inci-
dence is difficult to determine as many lesions may rupture
and resolve, patients do not always seek treatment, and of
those diagnosed a large number are not surgically excised
and do not reach a pathology department. In series of oral
biopsies, however, mucoceles are one of the most com-
monly encountered diagnoses. Jones and Franklin
(2006a,b) reviewed more than 48 000 biopsies received
from adults and children over a 30-­year period and found a
total of 2472 mucoceles, representing 5.1% of all biopsies
and 13.8% of biopsies of the oral mucosa. As a comparison,
radicular cysts and dentigerous cysts represented 7.1% and
2.5%, respectively, of all biopsies. Other studies have shown
a similar proportion of all biopsies, with reported frequen-
cies of 4.6% (Re Cecconi et al. 2010), 5.3% (Chi et al. 2011),
5.8% (de Brito Monteiro et  al.  2016), and 5.8% (Bezerra
et  al.  2016). Note that some of these studies reported
extravasation cysts only.
Mucoceles are more common in children than in adults,
with the single most common occurrence being lesions on
the lip in children. In their reviews, Jones and Franklin
found that the frequency in children was 17.1% of all biop-
sies (n = 4406; 752 mucoceles; Jones and Franklin 2006b),
compared with 3.9% in adults (n = 44 007; 1720 mucoceles;
Jones and Franklin 2006a).
With regard to the different types of mucocele, the
mucous extravasation cyst is the most common. Jones and
Franklin (2006a,b) found that of all mucoceles (n = 2427),
90.3% were extravasation cysts and only 9.7% (n = 235) were
mucous retention cysts, but they also found a difference
between children and adults. Mucous retention cysts were
relatively more common in adults, constituting 12.7% of all
mucoceles, while in children they only represented 2.3%.
 ­Mucocele 239

Table 15.1  Mucoceles: age, sex, and site distribution from selected reports that have distinguished extravasation and retention cysts.

Type of mucocele

Extravasation Retention

References N Male (%) n Age mean (range)a Lower lip (%) n Age mean (range)a Lower lip (%)

Harrison (1975)b 400 58.4 360 2nd 71.7 40 7th 2.5

Southam (1974) 236 NR 224 2nd 68.3 12 7th 0
Eversole (1987) 121 43.0 – – – 121 51.7 (10–80) 14.8
Stojanov et al. (2017) 177 41.8 – – – 177 56.0 (2–95) 15.8
Chi et al. (2011) 1715 50.7 1715 24.9 (1–87) 81.9 – – –
Conceição et al. (2014) 100 60.0 100 23.2 (1–57) 92.0 – – –
Bezerra et al. (2016) 719 45.3 719 20.8 (1–82) 67.3 – – –
c c
Mínguez-­Martinez 89 42.7 89 6.1 (0–14) 79.8 – – –
et al. (2010)
c c
Bodner et al. (2015) 56 43.0 56 11.2 (1–16) 67.9 – – –

N = total number of patients; n = number of patients with each type; NR, not reported.
a
 In some studies no means are given. Peak decades are quoted.
b
 Harrison reported 45 cases, but reviewed 400.
c
 Paediatric cases only.

Box 15.1  Key Distinctive Features of the Two Types of Mucocele

Mucous extravasation cyst Mucous retention cyst

Most common site Lower lip Buccal mucosa, floor of mouth

% of all mucoceles 90% 10%
Frequencya 5.0% (17% in children) <0.5%
Proportion in males 50%. Equal sex distribution 45%. Slightly more common in females
Age 80% below age 40. Mean age 80% above age 40. Mean age about 55. Peak in
about 22. Peak in second seventh decade
decade
Clinical features Sessile swelling, usually on Sessile swelling, buccal mucosa, floor of
the lower lip. Pale blue/grey mouth, occasionally palate. Pale blue/grey or
or normal colour. Contains normal colour. Contains fluid/fluctuant.
fluid/fluctuant. May be 10 mm diameter
superficial and resemble a
blister. 10 mm diameter
Histology Pools of mucus surrounded Cystic cavity filled with mucus. Lined by
by inflamed fibrous or simple cuboidal or columnar bilayered
granulation tissue, with duct-­like epithelium. Minimal inflammation
prominent mucus-­filled
histiocytes
a
 Frequency as a proportion of all oral biopsies.

These proportions of retention cysts are similar to those Age

reported in other series: 4.0% (Cataldo and Mosadomi, 1970; The age distribution of mucoceles is illustrated in
n = 594), 5.1% (Southam 1974; n = 236), 8.8% (Eversole 1987; Table 15.1. In many clinical studies a bimodal distribution
n  =  1380), 7.5% (Oliveira et  al.  1993; n  =  112), and 7.8% has been noted and, as can be seen in Table  15.1, this is
(Stojanov et al., 2017; n = 2275). due  to different ages of occurrence of extravasation and
240 Cysts of the Salivary and Minor Mucous Glands

retention cysts. However, because extravasation cysts are Site

more common, the vast majority of mucoceles are encoun- Overall the great majority of mucoceles, up to about 80%,
tered in children and young adults, below the age of are found in the lower lip and they are rare in the upper lip.
30 years. They are located on the mucosal side of the lower lip
Mucous extravasation cysts occur at an average age of towards the commissure (Figure  15.1). This predilection
about 20–25 years and all studies show a peak incidence in for the lower lip can be explained by the susceptibility of
the second decade. In the largest series (Chi et  al.  2011), this site to trauma from biting, lip chewing, or acciden-
507 (29.6%) of the 1715 cases arose in the second decade tal trauma.
and 65.9% of all cases were found below the age of 30 years. There is a difference, however, in the site distribution of
In his review, Harrison (1975) showed the age distribu- mucous extravasation cysts and mucous retention cysts
tion  of 356 extravasation cysts and found that 34.6% (Tables 15.1 and 15.2). Table 15.2 summarises the locations
occurred in the second decade, and 70.8% were below the of extravasation and retention cysts. These data are esti-
age of 30 years. Only 11.2% arose in patients over the age mated from a number of publications that have recorded
of  40 years. More recently, Bezerra et  al. (2016) reported the site distribution (Southam  1974; Harrison  1975;
719  mucous extravasation cysts and found that 36.7% Eversole 1987; Chi et al. 2011; Bezerra et al. 2016; Stojanov
occurred in the second decade and 78.7% below the age of et al. 2017). The proportions are rounded to the nearest 1%
30 years. or 5% for illustrative purposes and to aid recall.
In contrast, mucous retention cysts are found in older age In the largest study, Chi et al. (2011) found that 81.9% of
groups, with an average age of about 55 years and a peak extravasation cysts were located in the lower lip, and about
incidence in the sixth and seventh decades (Table  15.1). 5% each in the floor of the mouth and buccal mucosa.
Harrison (1975) reported that 42.5% of cases occurred in
the seventh decade and that 85% were found in patients
over 40 years of age. Only one case was found in the sec-
ond decade.
Mucoceles are frequently found in the first decade, and
are often diagnosed in neonates and even newborns. All
mucoceles in children are of the extravasation type. In a
large series of 594 cases reported by Cataldo and Mosadomi
(1970), 16 (2.7%) were in infants less than 1 year old.
Mínguez-­Martinez et al. (2010) described 89 cases in chil-
dren ( 14 years) and found 11 cases in children under
1 year and 4 cases that were congenital; 3 occurred on the
lower lip and 1 was found on the uvula. Shapira and Akrish
(2014) reviewed the literature up to 2014 and found 60
cases of mucoceles in infants ( 1 year), of which 30 were
Figure 15.1  Mucocele of the lower lip. This is the most
found in neonates ( 1 month). Of these 30 cases, 19 (63.3%) common site and clinical presentation of this lesion.
arose in the floor of the mouth and were designated
as ranulas. Table 15.2  Site distribution of mucoceles (%).

Sex Type of mucocele

Most studies show that the frequency of mucoceles in
males and females is almost equal, but with an overall Site Extravasation Retention
slight predilection for females (Table 15.1). This predilec-
tion may arise because mucous retention cysts may be Lower lip 75 10
found somewhat more frequently in females than in males. Floor of mouth 10 25
Chi et al. (2011) reported only extravasation cysts (n = 1715) Buccal mucosa 5 30
and found an equal sex distribution (50.7% males), whereas Ventral tongue 10 5
Stojanov et al. (2017) reported only retention cysts (n = 177)
Palate 1 20
and found that 58.2% arose in females. In Harrison’s (1975)
Upper lip <1 5
review, he found that 54.8% of extravasation cysts (n = 356)
arose in males, but that 27 of 40 retention cysts (67.5%) Data are estimates from a number of publications that have recorded
were found in females. site (see text for details).

Conceição et  al. (2014) also found a very high frequency
(92%) in the lower lip, but others have found lower propor-
tions, ranging from 67.3% (Bezerra et  al.  2016) to 79.8%
(Mínguez-­Martinez et  al.  2010), and most studies record
about 10% each in the floor of the mouth and buccal
mucosa (Table  15.2). Extravasation cysts in the upper lip
are very rare. Chi et al. (2011) and Conceição et al. (2014)
reported nearly 2000 cases between them and did not find
a single cyst in the upper lip. Bezerra et  al. (2016) found
only 2 cases (0.3%) in the upper lip.
In contrast, retention cysts are most commonly found in
the floor of the mouth and buccal mucosa, accounting for
about 55% of the total, but are relatively uncommon in the
lower lip. About 5% are found on the upper lip. The palate is
rarely affected by mucoceles, but when they do occur they
are almost always retention cysts, and are usually found in
the soft palate or at the junction of hard and soft palate.
A distinctive type of extravasation mucocele has been
reported in the anterior aspect of the ventral surface of the
tongue associated with the glands of Blandin and Nuhn
(Sugerman et al. 2000). A number of series have been pub-
lished that suggest that these cysts may represent up to 15%
of extravasation mucoceles (Jinbu et al. 2003; de Camargo
Moraes et al. 2009). The clinical variants are discussed in
more detail in the next section.
Clinical Presentation
Mucoceles present as painless swellings that are round or
oval with a smooth surface (Figure 15.1). The swelling is
often firm and the colour of normal mucosa, but about 30%
of lesions are quite superficial and may be blue or grey in
colour and fluctuant (Chi et al. 2011). Occasional lesions
are clear or blister-­like or may be red due to intralesional
haemorrhage. The colour and texture of the lesion depend
on its size and depth, with more superficial lesions being
blueish or clear and fluctuant. Mucoceles are almost always
sessile, but occasionally a superficial pedunculated and
‘ballooning’ lesion may be seen.
Sometimes the swelling may develop suddenly at meal-
times and then resolve. Patients often report that the cyst
has recurred or that it periodically bursts and drains. They
may have been present for only a few days, but some
patients tolerate them for months or even years before
seeking treatment. The mucocele may be only 1–2 mm in
diameter, but are usually larger: the majority are between 5
and 10 mm, but they may reach up to 40 mm (Chi
et al. 2011).
Mucoceles are usually symptomless and complaints of
pain or discomfort are rare. Although they are caused by
trauma and patients are often aware of biting them, only
about one-­quarter of patients are able to relate the develop-
ment of the cyst to trauma and a similar proportion report
­Mucocele 241
a history of repeated rupture (Chi et  al.  2011; Bezerra
et al. 2016).
Most mucoceles arise in the lower lip and give few
­diagnostic problems, with most studies showing that 85%
are correctly diagnosed on clinical examination (Chi
et al. 2011; Bezerra et al. 2016). Deeper, firmer lesions may
be confused with a fibroepithelial polyp or a small salivary
gland tumour. However, when considering the differential
diagnosis, it should be noted that mucoceles affect the
lower lip while salivary gland tumours almost always affect
the upper lip. Some mucoceles have been diagnosed as
lipomas or, if they become blood filled, may resemble
haemangioma.
At some sites, oral mucoceles have a characteristic clini-
cal presentation and may pose particular management or
diagnostic problems. These clinical variants include super-
ficial mucoceles, mucoceles of the anterior ventral tongue
affecting the glands of Blandin–Nuhn, and the ranula.
Superficial Mucoceles
Occasionally, mucoceles may be very superficial and lie
just below the epithelium and resemble a subepithelial
blister or vesicle (Figure 15.2). These were first described
by Eveson (1988), who reported eight cases. All presented
as  small superficial lesions that resembled blisters, and
all  had been given a preliminary clinical diagnosis of a
vesiculo-­bullous disorder, either bullous lichen planus or
mucous membrane pemphigoid. All the lesions occurred
in females and six were associated with lichen planus and
one with pemphigoid. The soft palate (six cases) was the
most common site. Superficial mucoceles often rupture
and may present as small ulcers.
Figure 15.2  A superficial mucocele in the retromolar region.
The lesion is raised and slightly polypoid, and resembles a
blister or vesicle. Source: Courtesy of Prof. John Eveson.
242 Cysts of the Salivary and Minor Mucous Glands
Subsequently there have been a number of reports that
have confirmed a predilection for females and an associa-
tion with lichen planus (Bermejo et al. 1999; Lv et al. 2019).
Lv et  al. (2019) reported nine patients with oral lichen
planus who presented with multiple small superficial
mucoceles. All cases involved the soft palate and some also
had lesions on the buccal mucosa and lower lip. The
authors speculated that the lesions may be caused by
­damage or blockage of small salivary ducts secondary to
lymphocytic infiltration and fibrosis associated with the
lichenoid reaction.
Superficial mucoceles have also been associated with
graft-­versus-­host disease (Campana et al. 2006) and, more
recently, 10 cases have been reported associated with
mucositis following radiotherapy for head and neck cancer
(Prado-­Ribeiro et al. 2018). These cases were seen in 1.2%
of patients who had received radiotherapy, and affected
mostly the floor of the mouth or buccal mucosa.
Overall, superficial mucoceles are uncommon. In their
analysis of 1715  mucous extravasation cysts, Chi et  al.
(2011) found only 3 (0.2%) that met the clinical and histo-
logical criteria for a superficial mucocele, although a fur-
ther 4.1% showed either clinical or histological features.
Similarly, in a histological review of 667  mucoceles, de
Brito Monteiro et al. (2016) found only 20 (2.9%) cases.
Mucocele of the Glands of Blandin–Nuhn
Mucoceles are relatively rare on the tongue and when
they  do arise, a distinctive clinical presentation is of a
mucocele arising towards the anterior aspect of the ventral
tongue, affecting the seromucous glands of Blandin–Nuhn
(Figure  15.3). They were first described in detail by
Sugerman et al. (2000), who reported five cases. Subsequently
Figure 15.3  A mucocele on the ventral aspect of the tongue,
associated with the glands of Blandin–Nuhn. Source: Courtesy of
Prof. John Eveson.
there have been many case reports and two series (Jinbu
et  al.  2003; de Camargo Moraes et  al.  2009) that are
­summarised in Table 15.3.
These mucoceles occur in a wide age range, but with a
mean of about 15–17 years and a peak in the second dec-
ade. The cysts are usually less than 10 mm in diameter, and
appear as polypoid or pedunculated swellings. Most lesions
(65–70%; Table 15.3) arise in the midline towards the tip of
the ventral surface of the tongue. The remainder are found
in the midline towards the root of the tongue, although
very occasional lesions may be lateral to the midline. They
are always extravasation in type, and are characterised by a
blueish colour and fluctuance. Cysts at this site are proba-
bly associated with biting or tongue thrusting and there is
often a history of trauma. Occasionally, cysts of Blandin–
Nuhn may reach a large size and cases of 30 mm or greater
have been reported (Andiran et al. 2001). One case that was
21 mm in diameter has been reported in a neonate (Ochiai
and Nakayama  2015). At this site, and in infants, large
lesions may be alarming and may interfere with normal
feeding or may compromise the airway.
Ranula
The term ranula2 is used to describe a characteristic type of
mucocele that occurs in the floor of the mouth. It is worthy
of special consideration because on occasion, and espe-
cially in children, a ranula may be so extensive as to cause
gross swelling in the neck and may compromise the airway.
The clinical presentation, treatment, and pathogenesis of
ranula have been well reviewed by Baurmash (2003) and
Harrison (2010).
Ranulas appear as soft, fluctuant swellings in the floor of
the mouth and are always to one side of the midline
(Figure 15.4), although rare examples have been reported
that are bilateral. The majority arise from the sublingual
glands, although some may arise from other small glands
in the anterior floor of the mouth. The sublingual gland is
actually a collection of multiple, small unencapsulated
mucous glands that lie between the floor of the mouth and
the mylohyoid muscle. There is often a large duct (Bartholin
duct) that opens into the submandibular duct or directly
into the mouth at the sublingual papillae (carunculae sub-
lingualis), but there are also between 10 and 30 small ducts
(the ducts of Rivinus) that open along the sublingual folds,
each one from a small gland. The posterior part of the
2  Ranula is a slightly unfortunate term, since it is derived from the
Latin word for frog and refers to the similarity of the lesion to the
underbelly or to the air sac of a small frog. The derivation is from the
Latin rāna (frog) and the suffix -­ula (small). Harrison (2010)
attributes its first usage to John Bannister in A Compendious
Chyrurgerie, 1585.

Table 15.3  Mucocele of the glands of Blandin–Nuhn.
 
References n Male (%) Age mean (range)
Jinbu et al. (2003) 26 19.2 17.0 (5–36)
De Camargo Moraes et al. (2009) 48 58.3 15.3 (5–49)
Summary of the key features from two large series.
n, number of patients.
a 
Refers to lesions towards the tip of the tongue in the midline. Other lesions arose towards the root of the tongue.
b 
Frequency as a proportion of all mucous extravasation cysts.
Figure 15.4  Ranula. The cyst arises to one side of the midline
in the floor of the mouth. The lesion is superficial and appears
as a blueish fluctuant swelling.
sublingual gland often merges with a superior extension of
the submandibular gland (the uncinate process) that
curves upwards and extends over the posterior aspect of
the mylohyoid muscle. Occasionally a small oral ranula
may be of the retention type, arising from a blocked duct of
Rivinus, but the vast majority are extravasation cysts
caused by spillage of mucus from a ruptured duct or acini
(Harrison 2010; McGurk et al. 2008)
Ranulas may present in three different ways. Most com-
monly they are a simple oral or superficial ranula and pre-
sent as an intraoral swelling only. They may however extend
into the submandibular space as a plunging ranula. Plunging
ranulas may present as a submandibular or submental swell-
ing only, or as a mixed intraoral and extraoral swelling.
Plunging ranula are mucous extravasation cysts of sublin-
gual gland origin that ramify diffusely into the subman-
dibular space and may extend into the neck. The extravasated
mucus enters the submandibular space by either ‘spilling’
over the posterior aspect of the mylohyoid muscle, or
through a perforation in the mylohyoid muscle. A deficiency
or hiatus between the deep and superficial aspects of the
mylohyoid muscle has been reported to be fairly common
and herniated projections of the sublingual gland through
these perforations may permit mucus extravasation into the
­Mucocele 243
Size (mm)
Mean (range) polypoid (%) Tip, midlinea (%) Frequencyb (%)
6 (3–12) 73.1 65.4 9.9
NR 85.7 70.8 15.4
submandibular space and tissues of the neck. Examination
of human cadavers has shown that mylohyoid perforations
and herniation of the sublingual gland may be found in up
to 43% of individuals (Nathan and Luchanski 1985; Harrison
et al. 2013). Lee et al. (2016) reviewed computed tomogra-
phy (CT) scans of 41 patients with plunging ranulas and
found that in 36 (87.8%) cases the mucus passed directly
through a defect in the mylohyoid muscle, and only 5 (12.2%)
showed spillage of mucus over the posterior margin of the
muscle. They also demonstrated that in 31 (75.6%) patients
there was herniation of the sublingual gland through the
mylohyoid defect into the submandibular space.
In the largest series of ranulas, Zhao et al. (2004) reviewed
580 cases and found that the majority (67.9%; n  =  394)
were simple oral mucoceles presenting as a swelling in the
floor of the mouth. The remainder (32.1%; n = 186) were
plunging ranulas.
Of the plunging ranulas, the majority (64.0%; 119 cases)
presented in the submandibular or submental region only
without an oral swelling, and 36.0% (67 cases) presented as
a mixed intraoral and extraoral swelling. The peak age of
presentation was in the second decade (range 3 months to
80 years) and there was a slight predilection for females
(54.5%). Most lesions, whether plunging or not, were 2–3 cm
in diameter. Zhao et al. found 9 cases (1.6%) that were bilat-
eral. All 580 lesions were mucous extravasation cysts.
Occasionally a ranula may be associated with a swelling
of the submandibular gland that increases and decreases in
size with gustatory stimulation. This was found in 13 (2.3%)
cases in Zhao’s series. Although mucoceles may arise from
the submandibular gland (Anastassov et  al.  2000), this is
thought to be extremely rare (Harrison 2010) and the sub-
mandibular swelling associated with eating is thought to
be due to partial blockage of the submandibular duct by
fibrosis or by pressure (Zhao et al. 2004; Harrison 2010).
In most cases of plunging ranula the swelling is limited
to the submandibular or submental region, but occasional
lesions may be extensive, with evidence of mucus extrava-
sation into the parapharyngeal space, or extending deep
into the cervical tissues and occasionally into the thorax
(Zhao et al. 2004; Pang et al. 2005). Extensive ranulas in the
244 Cysts of the Salivary and Minor Mucous Glands
neck, especially in children, may be mistaken for a cystic
hygroma (Jain et al. 2012).
Pathogenesis
Most mucoceles, whether of the extravasation or retention
type, are thought to arise as a result of trauma that causes
rupture or blockage of a salivary duct or damage to acini.
The evidence for a traumatic aetiology is most convincing
for mucous extravasation cysts, the vast majority of which
arise in young people and at sites that are most likely to be
exposed to trauma, including the lower lip and ventral
tongue. Acute trauma causes rupture of the salivary ducts so
that the continually secreted saliva spills into the adjacent
tissues, resulting in a mucus-­filled cavity. Overall, only about
25% of patients are able to associate their lesions with trauma
(Chi et  al.  2011), but a number of early animal studies,
which are unlikely to be repeated, have convincingly shown
that damage or rupture of salivary ducts causes pooling of
mucus in the connective tissues and formation of mucous
extravasation cysts (Bhaskar et  al.  1956; Standish and
Shafer  1957,  1959; Chaudhry et  al.  1960). In other experi-
ments on cats, it has been shown that ligation of the sublin-
gual ducts, without impairment of the parasympathetic
nerve supply, resulted in rupture of acini and extravasation
of mucus, without dilatation or rupture of ducts (Harrison
and Garrett  1972,  1975). The authors suggested that the
minor salivary glands of humans, like the cat sublingual
gland, secreted spontaneously, and that duct blockage with
subsequent rupture of the acini may also be a factor in the
pathogenesis of mucoceles of the oral mucosa. Ranulas are
mucous extravasation cysts and have a similar pathogenesis,
although the distinctive anatomy of the floor of the mouth
determines the clinicopathological features of the plunging
ranula. This has been discussed in the previous section.
The pathogenesis of the mucous retention cyst is less
clearly established, although it is thought that complete or
partial obstruction may lead to ductal dilatation and forma-
tion of an epithelial-­lined cystic space. In most cases, it is
likely that chronic persistent trauma may lead to hyper-
keratosis or periductal fibrosis that constricts the ducts,
resulting in complete blockage or slowing of salivary flow
and formation of mucous plugs.
Stojanov et  al. (2017) examined 177  mucous retention
cysts (they used the term ‘intraoral salivary duct cyst’) and
found that 41.8% showed histological evidence of ductal
obstruction in the form of mucus stasis, which varied from
intraluminal accumulations of mucus to well-­formed
mucous plugs that obstructed the lumen. Occasional cysts
(4.5%) contained calcifications, suggesting that sialoliths
may sometimes be a factor. Stojanov et al. also found that
90% of the cysts were associated with chronic sialadenitis
with ductal dilatation, which they interpreted as indicative
of an obstructive aetiology. Eversole (1987) had also noted
sialadenitis and ductal ectasia and suggested an obstruc-
tive aetiology associated with mucous plugs, or with duct
constriction secondary to trauma and fibrosis.
Lesions similar to mucoceles are occasionally associated
with persistent sialadenitis of the minor glands of the lips or
buccal mucosa. Such lesions have been termed cheilitis
glandularis and stomatitis glandularis, respectively (Tal
et al. 1984; Williams and Williams 1989; Cannell et al. 1997;
Musa et  al.  2005). Affected patients present with multiple
cysts, often with suppuration, that histologically showed
mucous extravasation, as well as cystic spaces lined by ductal
epithelium that had often undergone oncocytic metaplasia.
Histopathology
The optimal treatment for oral mucoceles is excision of the
lesion along with the underlying glands. On gross examina-
tion the specimen is often a thin-­walled cyst with associated
salivary gland, and frequently a portion of oral mucosa is pre-
sent on the superficial surface (Figure 15.5). When the speci-
men is cut, the cyst may be discrete, bound by a thin lining,
and filled with gelatinous mucoid material. For extravasation
mucoceles the lumen may not always be obvious and the
specimen may resemble loose connective tissue with a mucoid
texture. If the lesion has been marsupialised or removed
piecemeal, then only fragments of t­ issue may be received.
Microscopically, mucous extravasation and retention
cysts show distinctive features. The mucous extravasation
cyst is not lined by epithelium and should properly be
regarded as a pseudocyst, whereas the retention cyst is a
true cyst lined by epithelium that is derived from the duct
of the involved gland.
Mucous Extravasation Cyst
Extravasation cysts most often show a well-­defined cystic
space lined by a wall of inflamed fibrous or granulation tis-
sue (Figures 15.5a and 15.6a). The granulation tissue may
be of variable thickness and is often surrounded by a zone
of denser, collagenous fibrous tissue with variable degrees
of inflammation. Macrophages are almost always promi-
nent and are seen within the granulation tissue wall as well
as within the lumen of the cyst (Figures  15.6a and 15.8),
where they may be few in number and scattered, or occa-
sionally may fill the lumen. The macrophages are often
mucus filled and foamy and will stain positive with mucin
stains, for example periodic acid–Schiff (PAS) or mucicar-
mine. Often macrophages are prominent on the luminal
surface of the granulation tissue and occasionally they may
be epithelioid in morphology and form a palisade that
shows a close resemblance to a simple epithelial lining
 ­Mucocele 245

(a) (b)

*
Figure 15.5  A mucous extravasation cyst (a) and a mucous retention cyst (b). The cysts have been received intact and show oral
mucosa on one aspect (top of both images) and lobules of salivary tissue at the base (*). Both cysts contain mucus, and in b there are
focal accumulations of inflammatory cells. (Insets a and b: see Figure 15.6.)

(a) (b)

Figure 15.6  The typical linings of a mucous extravasation cyst (a) and a mucous retention cyst (b). (a) The lumen of the
extravasation cyst is filled with mucus containing scattered macrophages. (b) The retention cyst is lined by cuboidal or columnar
epithelium showing oncocytic change. Images are taken from the cysts shown in Figure 15.5, insets a and b.
246 Cysts of the Salivary and Minor Mucous Glands
(Figure 15.7). Adjacent mucous glands are usually inflamed
and show dilatation of the ducts. Sometimes a ruptured
duct may be seen feeding into the cyst lumen.
Chi et  al. (2010) described two mucous extravasation
cysts where the granulation tissue wall was folded into pap-
illary projections, with an amorphous eosinophilic surface
layer resembling a membrane. Below this was a layer of
rounded to spindled cells with occasional palisading. These
cells were shown to be macrophages. The authors were
struck by the resemblance of these features to synovial
membrane, and in particular to examples of papillary
Figure 15.8  Mucous extravasation cyst. The lumen is filled with
macrophages, most of which are foamy and filled with mucus. In
the centre is an eosinophilic, slightly laminated or fibrillar
globular structure.
Figure 15.7  A mucous extravasation cyst. The
wall is folded into papillary projections and is lined
by an amorphous eosinophilic ‘membrane’
overlying a layer of prominent macrophages with
evidence of palisading.
synovial metaplasia that have been described in association
with implants and prostheses in other tissues including
breast and hips. They have called this feature ‘papillary
synovial-­like change’ and suggest it is a variant of mucocele
that must be distinguished from other salivary lesions that
may exhibit a papillary growth pattern. In their large series
of lesions, the same authors found only two extravasation
cysts (0.1%) with these features (Chi et al. 2011).
We have seen similar changes (Figure 15.7) and feel that
they are rather more common than Chi et al. (2010, 2011)
suggested, since on occasion they may only involve a por-
tion of the cyst wall. A number of authors have drawn
attention to, or have illustrated, similar appearances
(Harrison  1975; Conceição et  al.  2014; de Brito Monteiro
et al. 2016). Conceição et al. (2014) found palisaded mac-
rophages in 4% of cases and papillary projections in 3%,
while de Brito Monteiro et  al. (2016) found synovial-­like
changes in 54 (8.1%) of their 667 cysts, and papillary pro-
jections in a total of 86 (12.9%) cases. Often, however, illus-
trations of the papillary processes show folding of the
lining rather than true papillary outgrowths.
Li et al. (1997) reported a single case of a mucous extrava-
sation cyst that was lined by typical granulation tissue, but
the lumen was filled with round or polygonal, slightly lam-
inated eosinophilic globules. Many of the globules were
surrounded by spindled fibroblast-­like cells and in places
similar globular protrusions were in continuity with the
granulation tissue of the wall. The authors noted that the
globules were similar to those reported in mucoceles of
the  appendix, which have been called ‘myxoglobulosis’
of the appendix. Li et al. (1997) therefore were the first to
introduce this term in relation to oral extravasation cysts.
Subsequently there have been a number of reports of simi-
lar globular structures and authors have continued to use

the term myxoglobulosis (Ide and Kusama  2002a; Shah
2003; Paremala et  al.  2011; Schulman and Jordan  2014).
Most reports have shown a striking accumulation of glob-
ules that fill the cyst lumen and have noted that this is a
rare occurrence. In Li et al.’s original report, they only saw
this feature in 1 of 657 cysts examined (0.15%). Chi et al.
(2011) defined oral myxoglobulosis as globules occupying
30% or more of the lesion and found a frequency of only
6 cases in 1715 cysts examined (0.4%). Others have found
them to be more common and similar globules have been
reported in 2.9% (de Brito Monteiro et  al.  2016), 9%
(Conceição et al. 2014), and 31% (Shah 2003) of cases.
We have also found eosinophilic, slightly laminated, or
fibrillar globules to be quite common (Figure 15.8), and it is
apparent that the reported frequencies may depend on how
much importance each author places on the findings and on
different definitions of ‘myxoglobulosis’. Shah (2003) found
globular structures in 31% of 71 mucous extravasation cysts
examined. He described a spectrum of change, from mucous
extravasation without cyst formation, to fully formed cystic
lesions lined by granulation tissue. In lesions with early
mucous extravasation, he noted separation of collagen bun-
dles that in places rounded up to form globular structures
that continued capillaries and were associated with mac-
rophages. Similar globular structures were found in 11 of 38
(28.9%) fully formed cysts, but only between 1 and 5 glob-
ules were seen in most lesions (e.g. Figure 15.8). He found
that the globules had the staining characteristics of collagen
and proposed that they arose as a result of walling-­off of
separated fragments of collagen that then become incorpo-
rated into the cyst lumen. Shah (2003) did not support the
use of the term ‘myxoglobulosis’ for oral lesions. He and
others (Henry et al. 2008) have pointed out that the similar
structures seen in appendix lesions are composed primarily
of mucins, whereas those in oral mucoceles appear to be
collagenous, and are probably associated with fragmenta-
tion of collagen during the evolution of the lesion.
Figure 15.9  A superficial mucocele. The
base of the lesion is composed of
inflamed granulation tissue and the roof
of atrophic oral epithelium. Note the
inflamed salivary tissue and dilated
ducts beneath the lesion.
­Mucocele 247
Shah’s views were supported by Ide et  al. (2010), who
also illustrated an extravasation cyst that showed transi-
tions between papillary processes and collagenous globules
in the lumen. They suggested that the intraluminal globu-
lar structures could be isolated spherules, or be a result of
cross-­cutting of papillary structures protruding into the
lumen (e.g. Figure 15.7). Furthermore, Ide et al. (2010) also
showed that the papillary processes that gave rise to the
globules had a hyalinised or eosinophilic surface similar to
that described by Chi et al. (2010) as synovial-­like (Figure
15.8). They suggest that the two features are associated and
represent an evolving continuum in the formation of the
cyst, associated with the ongoing repair process and
walling-­off of mucus by granulation tissue.
We would support this concept and would not regard
the globules or synovial-­like changes as representing vari-
ants of mucoceles, but rather regard them as random inci-
dental findings that have probably been noted but ignored
by pathologists when making a straightforward diagnosis of
common lesions. The term myxoglobulosis should be used
only as a descriptive term for those cases where the lumen
is filled with globules, but even then it is not associated with
any distinctive clinical features or management problems.
In the majority of cases mucous extravasation cysts will
show obvious cystic cavities filled with mucus, but over time
the lesion may become more solid as the tissue organises to fill
the lumen and the cyst is replaced by loose, inflamed granula-
tion tissue containing pools of mucus. Mucin stains may be
helpful to demonstrate residual pools of mucus and mucus-­
filled macrophages. Many cysts are also ruptured or collapsed
and the lumen may appear only as ramifying slit-­like spaces.
Superficial Mucoceles
Superficial mucoceles are extravasation cysts where the
spilled mucus accumulates at the epithelial–connective
­tissue interface and raises the epithelium to form a blister
or vesicle (Figure  15.9). At the base the cyst is lined by
248 Cysts of the Salivary and Minor Mucous Glands

inflamed granulation tissue and the roof is composed of a
thin atrophic epithelium. Often, as part of the healing pro-
cess, the adjacent epithelium may migrate across the floor
of the mucocele, and in a certain plane of section the lesion
may appear as wholly intraepithelial. Care must be taken
not to misdiagnose these lesions as a vesiculobullous disor-
der. Mucin stains are helpful, but the presence of foamy
macrophages and inflamed salivary tissue at the base help
to make the correct diagnosis (Figure 15.9).
Mucous Retention Cysts
Retention cysts are true cystic lesions lined by epithelium.
Most are lined by a simple cuboidal or columnar epithe-
lium, which may resemble a normal salivary duct
(Figures 15.5b, 15.6b, 15.10). Most retention cysts are uni-
cystic, but multicystic lesions have been described in up to
18% of cases (Eversole 1987; Stojanov et al. 2017).
The epithelial lining often shows additional features due to
reactive or metaplastic changes. The histopathology of mucous
retention cysts and the variable pattern of the epithelium have
been well described by a number of authors (Southam 1974;
Harrison  1975; Eversole  1987), but more recently Stojanov
et al. (2017) have undertaken a detailed quantitative analysis
of the histopathological features of 177 cysts. Their findings
are representative of the findings of the previous papers.
Stojanov et al. (2017) found that 85.3% of cysts were lined
by a layer of flattened cuboidal or columnar epithelium,
one to two cell layers thick (Figure 15.10a), but that 68.4%
of cases showed additional reactive or metaplastic changes
that involved all or part of the lining. The most common
feature was oncocytic metaplasia, which was seen in 50.8%
of cysts. Oncocytes were seen as deeply eosinophilic and
sometimes granular cells that often occupied the whole of
the cyst lining (Figures 15.6a and 15.10d).

(a) (b)

(c) (d)

Figure 15.10  Mucous retention cysts. Variable features of the epithelial lining. (a) The typical lining is of flattened cuboidal or
columnar cells. (b) Pseudostratified ciliated epithelium. (c) A dilated duct is continuous with the cyst lumen. (d) Folding of the cyst wall
produces infoldings or undulations that resemble intraluminal papillae. This lining also shows oncocytic change.

Other features that were seen in the lining epithelium
included mucous (goblet) cells (36.2%), squamous cells
(23.7%), pseudostratified ciliated epithelium (16.4%;
Figure  15.10b), and apocrine changes (14.1%; Stojanov
et al. 2017). These authors also found that 40.1% of cases
showed more than one type of metaplasia and that 7.3% of
lesions were multicystic (Figure 15.11).
Many cysts also show undulation or folding of the cyst
wall to form variably sized papillary-­like processes that pro-
trude into the lumen (Figures 15.5b and 15.10d). Stojanov
et al. (2017) found an undulating architecture in 41.2% of
cases, and interpreted this as folding due to collapse of the
cyst wall, rather than true papillary processes with a fibro-
vascular core. Nevertheless, their photomicrographs show
papillary-­like structures and 39 (22.0%) of their cases were
lined by oncocytic epithelium with infoldings, closely
resembling oncocytic papillary cystadenomas.
Eversole (1987) described similar features. He examined
121 epithelial-­lined mucoceles (which he preferred to call
sialocysts) and found that 41 (33.8%) were lined by onco-
cytic epithelium and that 27% of these had small papillary
projections. A further 10 (8.3%) cases were described as
‘mucopapillary cysts’, which were lined by a cuboidal and
columnar epithelium with prominent mucous cells, and
papillary projections that protruded into the lumen. There
is no doubt that some of these lesions resemble papillary
cystadenoma and Eversole (1987) suggested that in some
cases this may be the correct diagnosis.
Most cysts contain mucus in the lumen, which in places
may form amorphous eosinophilic ‘plugs’, and about 5%
may show focal areas of calcification resembling a salivary
sialolith (Figure  15.11). However, this is probably associ-
ated with stasis within the cyst and there is no evidence
Figure 15.11  Mucous retention cyst. This lesion is
multicystic, but also shows a number of other
features. There is folding of the wall with a
papillary pattern and the lumina contain mucus
with amorphous eosinophilic ‘plugs’. Associated
glands show features consistent with obstructive
sialadenitis, with prominent dilated ducts. One of
these (arrow) contains a sialolith.
­Mucocele 249
that sialoliths are an important factor in the pathogenesis
of retention cysts. In their examinations of more than
300 lesions, none of the authors has been able to identify
any obvious cause of ductal obstruction that may be associ-
ated with mucous retention (Southam 1974; Harrison 1975;
Eversole 1987; Stojanov et al. 2017).
More than 70% of cysts are inflamed and in over 90%
of cases the associated salivary glands show inflammation
and ductal ectasia consistent with chronic obstructive
sialadenitis (Stojanov et al. 2017). Occasionally a fortuitous
plane of section may show a dilated duct entering the
lumen of the cyst (Figure 15.10c).
Histological Differential Diagnosis
A diagnosis of mucous extravasation cyst is usually
straightforward and should not present a problem. The
main area of confusion arises in the diagnosis of a superfi-
cial mucocele, which may clinically and histologically
resemble a vesiculobullous lesion. In Eveson’s (1988) origi-
nal report, all eight cases were misdiagnosed clinically as
vesiculobullous disorders, and three were misdiagnosed
histologically as mucous membrane pemphigoid. On a sin-
gle haematoxylin and eosin (H&E)-­stained section, distinc-
tion between a mucocele and pemphigoid may be difficult.
Direct immunofluorescence can be used to confirm a diag-
nosis of pemphigoid, but false negative staining is com-
mon. More useful is a mucin stain that will confirm mucus
in a mucocele. Other helpful features include the presence
of foamy macrophages and of inflamed salivary tissue with
dilated and sometimes ruptured ducts at the deep aspect.
A histological diagnosis of retention cysts may be more
problematic, because a number of salivary neoplasms may
present as cystic lesions. The two most commonly
250 Cysts of the Salivary and Minor Mucous Glands
misdiagnosed lesions are cystadenomas and low-­grade
mucoepidermoid carcinoma.
Mucous retention cysts are lined by a simple cuboidal
to columnar epithelium, which often shows oncocytic change.
These features are also seen in cystadenomas of both the
minor and major glands. On occasion it may be difficult to
make a distinction and a definitive diagnosis may not always
be possible. A particular problem may arise when faced with
a retention cyst that shows infoldings of the lining and onco-
cytic change. Cystadenomas, however, are more often multi-
cystic with variably sized cystic spaces, and more often contain
intraluminal papillary projections. These are true epithelial
papillae that may proliferate and occupy much of the lumen.
Retention cysts are more likely to be associated with inflamed
salivary tissue that shows features typical of chronic obstruc-
tive sialadenitis (Stojanov et al. 2017). Occasionally retention
cysts are associated with dense lymphocytic infiltrates and
may resemble a Warthin tumour. Stojanov et al. (2017) found
7 (4.0%) cases with a prominent lymphoplasmacytic infiltrate
that resembled Warthin tumour. However, the cysts did not
have the typical prominent papillae seen in Warthin tumour,
and their photomicrographs show diffuse lymphocytic infil-
trates without the germinal centres or follicles that are typi-
cally seen in the lymphoid infiltrate of Warthin tumour. Some
of these cysts resemble intraoral lymphoepithelial cysts, some
of which probably arise from salivary ducts and may be
regarded as a mucous retention cyst.
A more important diagnostic trap is to miss a diagnosis
of low-­grade mucoepidermoid carcinoma when faced with
a small incisional biopsy of an epithelial-­lined cyst. On
examination of a whole specimen, the distinction should
be easy since a mucoepidermoid carcinoma is usually mul-
ticystic, but also shows evidence of infiltration and areas
with an admixture of squamous, intermediate, and mucous
cell. However, in places a cystic space may be lined by sim-
ple ducal epithelium and the fact is that on a small inci-
sional biopsy, it may be impossible to differentiate between
a simple retention cyst and a mucoepidermoid carcinoma.
It must be noted that mucoepidermoid carcinomas are one
of the most common malignant salivary gland tumours in
children, while retention cysts are uncommon in children.
The best advice is that a pathologist must always be cau-
tious when faced with a small biopsy of a simple cystic
lesion lined by ductal or oncocytic epithelium. Such lesions
in children, especially at unusual sites such as the palate or
retromolar area, should always be treated with caution.
Never hesitate to defer a diagnosis and to seek imaging or a
second, larger or excisional biopsy.
Treatment
Small mucoceles may require no surgical treatment provided
that the patient finds them no hindrance. In a review of 89
children with mucous extravasation cysts, Mínguez-­Martinez
et al. (2010) found that 39 (43.8%) cysts resolved spontane-
ously after an average time of three months. Most lesions,
however, are removed surgically and the basic principle is
that the offending gland should be removed with the cyst, to
avoid recurrence. Marsupialisation of extravasation cysts is
sometimes carried out and can be successful if the underly-
ing gland is also removed (Baurmash 2003). Marsupialisation
alone has a recurrence rate of up to 50% or more.
Treatment of ranulas is particularly problematic because
lesions may be large and surgery in the floor of the mouth
may be extremely difficult and hazardous. Management of
ranulas is the subject of an extensive literature that is well
covered in more appropriate surgical texts. Overall, most
agree that surgical removal of the sublingual gland through
the mouth without any cervical approach is the favoured
form of treatment. This removes the secreting source,
thereby preventing recurrence, and also avoids the problem
of a difficult neck dissection. In the large series of Zhao
et al. (2004), only 1.2% of lesions recurred if the ­sublingual
gland was removed, compared with 57.7% if the ranula was
excised alone and 66.7% following marsupialisation only. A
more recent meta-­analysis of 39 reports supported this and
showed that intraoral removal of the sublingual gland had a
cure rate of 98.8% (Chung et al. 2019).
Harrison (2010) undertook a detailed review of the litera-
ture and found reports of 13 different treatments for oral
ranula, and 12 for plunging ranula. Treatments that
included removal of the sublingual gland were always the
most successful, with recurrence rates as low as 0%.
Marsupialisation alone had recurrence rates of 50% or
more, but if marsupialisation was followed by packing the
success rate rose to close to 100%. Harrison (2010) suggested
that packing encouraged fibrosis that may seal the source of
mucus extravasation. Since the lumen of the ranula itself is
lined by granulation tissue, the cyst wall does not have to be
removed, as it will eventually resolve. These observations
have led to a more conservative approach for the manage-
ment of the ranula, which reduces surgical intervention in
an anatomically compromised area. McGurk and colleagues
(McGurk et al. 2008; Harrison 2010; Hills et al. 2016) have
described conservative treatments that involved decom-
pression of the cyst followed by local removal of only the
attached part of the sublingual gland, or by ligation of the
leaking part of the gland with a mattress suture.
Ranulas have also been treated by injection of the scle-
rosing agent OK-­432 (Rho et al. 2006). This substance only
appears to have been used in South Korea and Japan and is
a sclerosing and immune system–stimulating agent derived
from lyophilised Streptococcus pyogenes. Rho et al. (2006)
treated 21 patients with plunging ranulas and found total
resolution in 7 (33.3%) cases and near-­total or marked
shrinkage in most of the remainder. They propose that

sclerotherapy using OK-­432 is a safe and potentially cura-
tive substitute for surgery. Overall, however, success rates
are variable and sclerotherapy does not appear to be as
effective as surgery. In their meta-­analysis, Chung et  al.
(2019) found 6 studies that had used OK-­432 and reported
overall cure rates of only 76.4% for oral ranulas, and 65.6%
for plunging ranulas.
­Salivary Duct Cysts
The term salivary duct cyst is often used to refer to a cystic
lesion of the salivary glands caused by dilatation of the
ducts secondary to ductal obstruction. In this context it
would include mucous retention cysts, as described in the
previous sections. Thus, in some current textbooks and in
the literature, intraoral retention mucoceles are sometimes
called salivary duct cyst (Stojanov et al. 2017). However, it
is more common that authors make a distinction between
intraoral and major gland lesions by using the term sali-
vary duct cyst to describe mucous retention cysts arising in
the major salivary glands, most often the parotid (Batsakis
and Raymond 1989).
Major gland salivary duct cysts appear to be rare and
there are few reports in the literature and no large case
series. In a review of 586  non-­neoplastic salivary gland
cysts, Takeda and Yamamoto (2001) found that 580 (99.0%)
were extravasation cysts, of which 113 (19.3% of the total)
were ranulas. There were only 3  intraoral mucous reten-
tion cysts and 3 (0.5%) salivary duct cysts. More than 90%
arise in the parotid gland, and about 8.0% are seen in the
submandibular gland (Ellis and Auclair 2008).
Most lesions are slowly enlarging, painless swellings up
to 20 mm in diameter. They are usually mobile and may be
fluctuant. Salivary duct cysts are found in adults, most
often in the sixth and seventh decades (Takeda and
Figure 15.12  A salivary duct cyst of the parotid
gland. An irregular cyst wall lined by ductal
epithelium.
­Salivary Duct Cyst 251
Yamamoto  2001; Vinayachandran and Sankarapandian
2013; Belli et al. 2004), although occasional cases have been
reported in children (Munteanu et al. 2019). Most lesions
have affected only one gland, but occasional cases of bilat-
eral parotid cysts have been reported (Belli et al. 2004).
Salivary duct cysts are thought to be retention cysts,
with a similar pathogenesis and histopathological features
to retention cysts of minor salivary glands. However, some
authors suggest that at least some salivary duct cysts may
be developmental in origin, although it is difficult, if not
impossible, to establish the true cause of these lesions. A
review of the few reports and published images of cases
often shows inflamed salivary tissue and dilated ducts
consistent with obstructive sialadenitis. Obstructive
lesions in the parotid gland are frequently assumed to be
caused by mucus plugs, but such plugs or other causes are
rarely documented. Trauma, and stenosis to the parotid
duct, has been reported as a possible cause (Belli
et al. 2004). It is ironic that so few cases are reported in the
submandibular gland, which is commonly obstructed by a
sialolith. In the recent past, it was commonplace for sub-
mandibular glands to be removed if there was evidence of
ductal obstruction due to a sialolith, and in histological
examination of such glands we have noted that cystic dila-
tation of ducts was common. However, this was often
regarded as part of the spectrum of changes associated
with obstructive sialadenitis and a diagnosis of duct cyst
was not made. In contrast, such lesions are unusual in the
parotid gland and obstruction is not evident clinically,
making it more likely that cystic change would be noted. It
is possible therefore that salivary duct cysts are equally
common in the submandibular gland as in the parotid
gland, but are not reported.
Histologically, salivary duct cysts are usually unilocular
cysts lined by a simple cuboidal or columnar ductal epithe-
lium (Figure 15.12). Mucous cells and oncocytic metaplasia
252 Cysts of the Salivary and Minor Mucous Glands
similar to that seen in mucous retention cysts may be
found. Occasional lesions may be multilocular or papillary
and must be distinguished from cystic neoplasms. The
cysts are usually simple with a uniform lining, whereas
neoplasms show a more complex morphology, with a range
of cell types. Cysts with an associated lymphocytic infil-
trate are discussed later in this chapter (‘Lymphoepithelial
Cysts’), but it is quite possible that some of these are sim-
ple retention cysts that have arisen from ducts associated
with an intraglandular lymph node or duct-­associated
­lymphoid tissue.
­Cysts of the Maxillary Sinus
Although not of salivary gland origin, these lesions are
associated with mucosal seromucous glands and are suffi-
ciently similar to salivary mucous cysts that they can be
included in this chapter.
When applied to the paranasal sinuses, the term
mucocele has often been used loosely to refer to any type
of cystic lesion associated with extravasation or accumula-
tion of mucus. However, there are a number of distinctive
entities that may affect the sinuses, including what is
regarded as a true sinus mucocele, retention cysts, and
mucosal pseudocysts. The distinction is important, because
these lesions have different clinicopathological features
and behaviours. The distinctive features and criteria for
diagnosis of this group of lesions were reviewed by Meer
and Altini (2006) and a simple classification with key fea-
tures is shown in Box 15.2. A further cyst that may arise in
the maxilla is the surgical ciliated cyst, which is discussed
in Chapter 16.
­Mucocele of the Maxillary Sinus
A true sinus mucocele completely fills the sinus and is
caused by blockage of the outlet or ostium, usually second-
ary to inflammatory changes associated with chronic rhi-
nosinusitis. It most often affects the frontal and ethmoidal
sinuses, but about 10% occur in the maxillary sinus. The
lesion is a true cyst filled with mucus and lined by the
mucoperiosteum of the involved sinus. Sinus mucoceles
are characterised by ballooning expansion, with destruc-
tion and perforation of the surrounding bone and dis-
placement of adjacent structures. This may result in nasal
blockage, proptosis, and a range of other clinical symptoms
that are often mistaken for more aggressive neoplastic
lesions. The lesion has characteristic clinicopathological
features that serve to differentiate it from other cystic
lesions of the sinus. This, along with its locally destructive
Box 15.2  Key Features of Mucoceles and Cysts of the
Maxillary Sinus
Mucocele
●● Occupies the entire sinus
●● Caused by blockage of the ostium, often secondary
to chronic sinusitis
●● Cystic structure filled with mucus and lined by
sinus epithelium
●● Expands the sinus and may destroy and perforate
adjacent bone
Retention Cyst
●● Epithelial-­
lined cyst
●● Caused by mucus retention as a result of blockage
of a duct of a minor gland
●● Often small and clinically silent and found associ-
ated with sinusitis or polyps
●● Dome-­ shaped radiopacity of antral wall. No expan-
sion and not destructive
Pseudocyst
●● Accumulation of mucus and inflammatory exudates
that raise the mucosa from the bone of the sinus floor
●● Inflammatory in origin
●● Often secondary to odontogenic infection or sinusitis
●● Dome-­ shaped radiopacity on the floor of the sinus
behaviour and the importance of early diagnosis and man-
agement, warrants its separate consideration
Clinical Features
Frequency
Mucoceles are uncommon cystic lesions affecting the para-
nasal sinuses, but the frontal and ethmoid sinuses are most
often affected, with only about 10% arising in the maxillary
sinus (Natvig and Larsen  1978). Overall, therefore, true
maxillary sinus mucoceles appear to be rare. In a study of
symptomless young men, Savolainen et  al. (1997) exam-
ined radiographs of 404 subjects and recorded ‘cysts or pol-
yps’ in 7.2%. However, only 3.3% had a completely opaque
sinus, suggesting that this would be the highest possible
prevalence of true mucoceles. Pérez-­Sayáns et  al. (2020)
reviewed the features of 214 patients with maxillary sinus
pathologies and found 8 (3.7%) retention cysts, but only 5
(2.3%) mucoceles. The most common lesions were sinusitis
(54.2%) and polyps (18.2%).
Age and Sex
Mucoceles affect all age groups, with one of the largest
series reporting a range from 13 to 71 years with a mean age

of 49.9 years (Busaba and Salman 1999). There appears to
be no sex predilection for this lesion.
Clinical Presentation
The characteristic clinical presentation is of a gradually
enlarging swelling of the cheek and lateral nasal region,
with obliteration of the nasolabial fold or of the buccal sul-
cus intraorally (Meer and Altini 2006). The lesion is expan-
sile and in over 75% of cases there is bulging of the medial
wall of the sinus, causing partial obliteration of the nasal
cavity (Busaba and Salman  1999). Other features include
pain or tenderness of the cheek or teeth, nasal drainage,
headache, and occasionally the orbit is involved, causing
proptosis. Patients may report a long history of symptoms
of nasal congestion and sinusitis.
Radiological Features
Radiology is important and usually the diagnosis is made
on imaging and then confirmed by histology. The lesions
are better visualised using CT or magnetic resonance imag-
ing (MRI; Han et al. 1995; Busaba and Salman 1999). The
defining criteria are complete opacification of the maxil-
lary sinus on CT associated with evidence of bony expan-
sion (Figure 15.13). Early lesions may show only an opacity
and the overall morphology and bony margins of the sinus
may be normal, but over time, first the medial wall of the
sinus expands into the nasal passages, followed by progres-
sive expansion anteriorly and superiorly to raise the floor
of the orbit. As the lesion enlarges, there is often perfora-
tion of bone with extension into the soft tissues. With CT it
may be possible to demonstrate obstruction of the ostium.
Figure 15.13  Mucocele of the right maxillary sinus. There is
complete opacification of the sinus, with medial bulging into
the nose.
­Retention Cyst and Pseudocyst of the Maxillary Sinu 253
Pathogenesis
Sinus mucoceles are caused by obstruction of the ostium
with accumulation of mucus within the sinus that causes
increased pressure and ballooning expansion. Often the
cause of obstruction is not apparent, but most patients
record a history or show symptoms of chronic sinusitis.
Occasionally blockage may follow nasal surgery, or may be
due to a neoplasm or other pathology.
Histopathology
The histological features are not specific, but will con-
firm the diagnosis and, more importantly, exclude another
cause of expansion and bone destruction. Pathologists
should note that occasionally the blockage is caused by a
neoplastic process or other pathology and one should be
alert to this possibility. Histologically, the appearance is
of a cyst filled with mucus or mucoid material, and lined
by  essentially normal sinus mucosa, covered by ciliated
respiratory-­type epithelium or flattened simple cuboidal or
squamous epithelium. It is unusual to receive an intact
cyst, so most often the pathologist will examine multiple
fragments of mucoid material lined in places by epithe-
lium. Portions of reactive bone may be seen at the margins.
There may be chronic inflammation in the wall and if there
is an associated allergic sinusitis, then acute inflamma-
tory cells and eosinophils may also be present (Meer and
Altini 2006).
­ etention Cyst and Pseudocyst of the
R
Maxillary Sinus
Retention cysts and pseudocysts are considered together
because they have similar behaviour and may be indistin-
guishable on radiological or clinical examination.
Together they are often referred to as a sinus cyst or
mucosal antral cyst, and many studies have not distin-
guished between them.
Clinical Features
Most studies use similar criteria for the definition of antral
cysts and illustrate ‘dome-­shaped’ soft-­tissue opacities
or  shadows arising from the sinus wall (MacDonald-­
Jankowski  1994; Myall et  al.  1974), and none used com-
plete opacification or ballooning expansion as a definition
of these cysts. It appears therefore that these studies did
not include true mucoceles, but investigated either reten-
tion cysts or pseudocysts as distinctive lesions as defined by
Meer and Altini (2006) (Box 15.2).
254 Cysts of the Salivary and Minor Mucous Glands
Frequency
Antral cysts and pseudocysts are probably quite common.
Myall et al. (1974) surveyed 1469 orthopantomographs and
made a radiological diagnosis of mucosal antral cyst in 75
cases (5.1%). Allard et al. (1981b) found 94 examples in a
series of 1080 radiographs (8.7%), and in their literature
review quoted the frequency in 11 other publications,
which ranged from 1.4% to 9.6%. In a review of 5021
sequential radiographs, Vallo et  al. (2010) found a fre-
quency of 7.0%. A similar study by Casamassimo and Lilly
(1980) on 4546 panoramic radiographs showed a lower
­frequency of 1.6%, while MacDonald-­Jankowski (1994)
found a prevalence of 14% in a survey of 1000 consecutive
panoramic radiographs in a South London dental casualty
department.
Age
Antral cysts are found in young adults, with a peak in
the  third decade and a reported mean age of 35.0 years
(Myall et  al.  1974; Casamassimo and Lilly  1980;
MacDonald-­Jankowski 1994).
Sex
There is a slight predilection for males. Of the total of
382  cases reported by Myall et  al. (1974), Casamassimo
and  Lilly (1980), Allard et  al. (1981b), and MacDonald-­
Jankowski (1994), 225 (58.9%) occurred in males. The pro-
portion of males in each of these studies was roughly
the same.
Site
Most lesions are found on the floor of the sinus, with
between 50% (Bhattacharyya  2000) and 100% at this site
(Casamassimo and Lilly 1980; Berg et al. 1989; MacDonald-­
Jankowski  1994). Pseudocysts are always located on the
floor of the sinus, but retention cysts may be found attached
to the walls (Yeung et  al.  2018). In the majority of cases
only single cysts occur, but up to 20% of patients have bilat-
eral lesions (Casamassimo and Lilly  1980; MacDonald-­
Jankowski 1994; Bhattacharyya 2000).
Clinical Presentation
Retention cysts and pseudocysts are characterised by the
absence of symptoms, with the majority of lesions discov-
ered in the course of routine radiological examination.
Although many patients have a history of chronic sinusitis
or symptoms associated with dental pathology, these are
not specific and are no more common than in patients
without cysts (MacDonald-­Jankowski  1994; Vallo
et  al.  2010; Yeung et  al.  2018). MacDonald-­Jankowski
(1994) reviewed 140 patients with mucosal cysts and found
that 48 (34.3%) had pain or swelling that might be of dental
origin. However, similar symptoms were seen 23.5% of
patients who did not have a mucosal antral cyst.
Radiological Features
It is on the basis of the radiological or CT features that
these lesions are most clearly distinguished from sinus
mucoceles. The cysts appear as spherical, ovoid, or dome-­
shaped radiopacities that have a smooth and uniform out-
line (Figure 15.14). They may have a narrow or broad base
but, unlike mucoceles, the lesions are not destructive and
the bony walls of the sinus maintain the normal contours.
They vary in size from very small to large, but are distinct
from sinus mucoceles because they never completely fill
the sinus (MacDonald-­Jankowski 1994). Yeung et al. (2018)
measured 40 antral cysts and found an average size of
6.28 mm (range 3–16.2 mm).
Pseudocysts, which are often associated with odonto-
genic infections, are located on the floor of the sinus, but
retention cysts may be located elsewhere, with up to 40%
located on the lateral walls or roof (Yeung et  al.  2018).
They are otherwise indistinguishable. Follow-­up radiologi-
cal examination has shown that the cyst may persist with-
out a change in size for a long time, and may eventually
disappear spontaneously.
Pathogenesis
The pathogenesis of mucosal cysts of the sinus has not
been definitely determined, but a previous infection is fre-
quently implicated. Studies have shown that there is a sig-
nificant association between dental infections and changes
to the mucosal lining of the maxillary sinus. However,
Figure 15.14  Radiograph of a mucosal cyst of the maxillary
sinus. The lesion appears as a dome-­shaped radiopacity rising
from the floor of the sinus.

there is no distinction between nonspecific mucosal thick-
ening and localised dome-­shaped cystic change, both of
which are equally associated with sinusitis or dental or
periodontal pathology (MacDonald-­Jankowski 1994; Vallo
et al. 2010; Yeung et al. 2018; Pérez-­Sayáns et al. 2020).
Few studies distinguish between pseudocysts due to
accumulation of fluid and retention cysts associated with
mucus retention. Meer and Altini (2006) agreed with
Gardner and Gullane (1986) that pseudocysts arise as a
result of accumulation of inflammatory and mucus exu-
dates below the sinus mucosa, which is lifted from the
underlying bone to form the characteristic dome-­shaped
swelling on the floor of the sinus. Thus, the lesion is formed
by pools of ‘mucoid’ material surrounded by inflamed
fibrous and granulation tissue, with periosteum on the
deep aspect. Meer and Altini (2006) reviewed the findings
of earlier studies and suggested that odontogenic infection
of the maxillary teeth is the most common cause.
Pseudocysts are to be distinguished from antral polyps,
which may be multiple, affect any part of the antral lining,
and are a result of inflammation and accumulation of exu-
dates in the hyperplastic and oedematous fibrous tissue of
the mucosa.
With regard to retention cysts, it is generally agreed that
these are caused by blockage of the ducts of the small
mucous glands in the sinus mucosa, resulting in a mucus-­
filled cyst lined by epithelium. Most of these lesions are
small and clinically silent and are found as incidental find-
ings in thickened and inflamed sinus mucosa removed for
chronic sinusitis, or within antral polyps. The cause of the
duct blockage may be an inspissated mucus plug or a small
calculus.
Histopathology
When explored surgically, it is possible to demonstrate the
intact and undisturbed cyst. It has a smooth blue surface, is
thin-­walled, and contains mucinous material. Allard et al.
(1981b) stated that pseudocysts are almost always found
in an otherwise healthy-­looking sinus, whereas antral pol-
yps will usually be seen in groups on inflamed oedema-
tous mucosa.
Microscopically, a pseudocyst shows inflamed fibrous or
granulation tissue containing pools of mucoid material.
Sinus mucosa may be seen on one aspect and periosteum
on the other. Ducts or glands are not seen and the mucoid
material appears to be primarily an inflammatory infil-
trate, because mucin stains are usually negative (Meer and
Altini 2006).
Retention cysts are usually small and are found within
an inflamed sinus mucosa or an inflammatory polyp. They
­Lymphoepithelial Cyst 255
are similar to mucous retention cysts of the oral mucosa
(see Figures  15.5, 15.10, and  15.11) and are lined by flat-
tened, duct-­like cuboidal or columnar epithelium, or by
pesudostratified columnar epithelium. There may be little
inflammation other than related to the associated sinusitis
and the cyst is filled with mucus. A calculus or mucus plug
may be evident.
Treatment
Retention cysts and pseudocysts are not destructive and
usually remain static, although many appear to regress
spontaneously. Because they usually cause little discom-
fort, surgical intervention is often unnecessary. Removal is
only needed if there are persistent and pertinent clinical
symptoms. Hadar et al. (2000) limited treatment to lesions
that occupied at least 50% of the sinus and used an endo-
scopic approach, which is now accepted as an effective
treatment. In their series of 60 patients there were only two
cases that recurred and there were no complications.
Pseudocysts associated with a dental infection usually
resolve when the cause has been removed.
By contrast, sinus mucoceles grow to a large size and can
be destructive. The basis of management is to decompress
the cyst, either by complete removal by curettage through
a  Caldwell–Luc approach or by an endoscopic approach
through the middle meatus with marsupialisation of
the cyst.
­Lymphoepithelial Cysts
The term lymphoepithelial cyst is often used as a generic
term for an epithelial-­lined cyst embedded in, or sur-
rounded by, lymphoid tissue. This description would
include branchial cleft cysts, intraoral lymphoepithelial
cysts, and lymphoepithelial cysts of the parotid gland. It
has also been used to include cystic lymphoepithelial
lesions of the sort associated with Sjögren syndrome or
with HIV. Lymphoepithelial cysts of the parotid gland are
probably developmental in origin, although some may be
salivary duct cysts that arise as a result of cystic change in
intranodal salivary gland inclusions. Most intraoral lym-
phoepithelial cysts arise in association with oral tonsils,
although an origin from the epithelium of minor salivary
gland ducts, especially in the floor of the mouth where ton-
sillar tissue is scarce, is a possibility. Intraoral lymphoepi-
thelial cysts and lymphoepithelial cysts of the parotid gland
are considered in this chapter. They are regarded as distinct
from branchial cleft cysts, which are true developmental
cysts and are discussed in Chapter 18.
256 Cysts of the Salivary and Minor Mucous Glands
­Intraoral Lymphoepithelial Cysts
Clinical Features
Reports of oral lymphoepithelial cysts have mostly been
single case reports, although there have been a number
of case series. Sykara et al. (2017) reported 25 cases and
reviewed the literature up to 2017. They found a total of
45 papers that had documented 316 cases, including a
series of 120 cases by Yang et al. (2012). Subsequently, da
Silva et  al. (2020) have reported a further 77 cases.
Table  15.4 summarises data from four of the larg-
est series.
Frequency
Oral lymphoepithelial cysts are rare. In their review of
more than 48 000 biopsies received from adults and chil-
dren over a 30-­year period, Jones and Franklin (2006a,b)
found 49 lymphoepithelial cysts representing only 0.10% of
all biopsies. As a comparison, mucous extravasation and
retention cysts represented 4.6% and 0.49%, respectively, of
all biopsies.
These proportions are similar to those reported in other
series: 0.16% (Daley et al. 1994), 0.10% (Nonaka et al. 2011),
0.08% (Sykara et al. 2017), and 0.05% (da Silva et al. 2020).
Age
Lymphoepithelial cysts occur across a wide age range from
2 to 85 years with an average age of about 40 years and a
peak in the fourth to sixth decades (Table  15.4). At least
70% of lesions occur in adults over the age of 40 years (Yang
et al. 2012; da Silva et al. 2020).
Sex
Studies have shown variable frequencies in males and
females, but suggest a slight predilection for females
(Table  15.4). The largest review, of 316 cases, found that
169 (53.5%) arose in females (Sykara et al. 2017).
Table 15.4  Intraoral lymphoepithelial cysts: age, sex, and site distribution.
References n Male (%)
Buchner and Hansen (1980) 38 60.5
Yang et al. (2012) 120 30.8
Sykara et al. (2017) 25 44.0
a
da Silva et al. (2020) 77 29.9
FOM, floor of mouth; n, number of patients.
a
 da Silva et al. included oropharynx (22% of lesions).
Site
The most common sites are the floor of the mouth and the
ventral surface of the tongue, with about 70% of all lesions
at these two sites (Table 15.4). In the largest series (Yang
et al., 2012), 50% of lesions were located on the tongue and
38.3% in the floor of the mouth. Most tongue lesions were
found on the ventral surface (34.2% of the total), with 9.2%
at the base and 5.8% on the lateral border. The next most
common site was the palate (5.0%), with rare lesions on the
buccal mucosa. In their review, da Silva et al. (2020) found
that 50.6% of cases were reported to be in the floor of the
mouth, but we have noted that a number of papers do not
make a clear distinction between floor of the mouth and
ventral tongue. Cases have been reported on the anterior
pillar of the fauces (Buchner and Hansen 1980) and in the
oropharynx (da Silva et al. 2020).
Clinical Presentation
Lymphoepithelial cysts are usually symptomless and are
detected on routine examination, but a few patients com-
plain of swelling or discharge. Their size ranges from 1 to
20 mm, but 80–90% of lesions are less than 10 mm in diam-
eter (Yang et al. 2012; Sykara et al. 2017). The usual find-
ing is of a round or oval swelling of the oral mucosa, with
most lesions (50–60%) being yellow/white in colour (Yang
et al. 2012; da Silva et al. 2020). The swellings are submu-
cosal and freely mobile. Some were described as firm, but
most lesions are soft and painless. The clinical diagnosis is
rarely correct, with most being diagnosed as mucoceles,
‘tumours’, lipomas, or ‘irritation fibromas’.
Pathogenesis
Most authors suggest that the intraoral lymphoepithelial
cyst arises from oral tonsillar tissue. Oral tonsils were first
described in detail by Knapp (1970a,b), and are small accu-
mulations of normal lymphoid tissue that resemble the
tonsils in Waldeyer’s ring. They are 1–3 mm in diameter
and are found in varying numbers on the soft palate, ven-
tral surface of the tongue, and floor of the mouth. Knapp
Age, mean (range) FOM (%) Vent tongue (%)
39.8 (14–81) 50.0 18.4
44.1 (2–75) 38.3 34.2
33.0 (15–51) 30.8 36.0
46.5 (13–85) 19.5 10.4

first suggested that lymphoepithelial cysts develop in oral
tonsils in which the crypt opening becomes plugged, caus-
ing dilation of the crypt and a cystic structure. Buchner and
Hansen (1980) agreed that most lymphoepithelial cysts
probably arise from tonsillar crypts, but they noted that
very few lesions showed any continuity between the lining
epithelium of the cyst and the surface epithelium. They
postulated that some cysts may arise from epithelial inclu-
sions or salivary gland tissue that may be located in close
proximity to tonsillar tissue.
The studies of Toto et  al. (1982) found that cyst-­lining
epithelium could be of tonsillar crypt or of salivary duct
origin. An origin from salivary duct epithelium, especially
in the floor of the mouth where tonsillar tissue is scarce, is
likely. Nair and Schroeder (1986, 1987) undertook a num-
ber of studies of the anatomy of the minor salivary glands
in monkeys and described aggregates of normal lymphoid
tissue embracing the ducts of minor glands close to the
orifice. Such tissue is termed duct-­associated lymphoid tis-
sue (DALT) and was thought to be analogous to similar
tissues in the lungs or gastrointestinal tract. DALT may be
found associated with minor salivary gland ducts through-
out the oral mucosa, and Nair and Schroeder (1986) con-
tend that some of the oral tonsils illustrated by Knapp
(1970a) are in fact ducts with accumulations of lym-
phoid tissue.
These studies suggest that intraoral lymphoepithelial
cysts may arise through a number of mechanisms. Some
may arise as a result of cystic dilatation of tonsillar crypts,
while others may be retention cysts arising from the super-
ficial ducts of minor salivary glands. Histological exami-
nation of lesions suggests that the majority probably arise
from tonsillar tissue, since most lesions are lined by par-
akeratinised stratified squamous epithelium and the
lumen is filled with desquamated epithelial cells without
Figure 15.15  Lymphoepithelial cyst of the floor
of the mouth. The cyst lies just below the oral
epithelium and is surrounded by lymphoid tissue
with normal germinal centres (arrows).
­Intraoral Lymphoepithelial Cyst 257
evidence of mucus. On the other hand, a small number of
lymphoepithelial cysts are lined by duct-­like or pseu-
dostratified epithelium, with mucus in the lumen and sali-
vary tissue in the wall (Buchner and Hansen 1980; Yang
et al. 2012; Sykara et al. 2017; da Silva et al. 2020). In their
report of 177 cases of oral mucous retention cysts, Stojanov
et  al. (2017) described and illustrated a number of cases
that were surrounded by a dense lymphocytic infiltrate
and resembled lymphoepithelial cysts.
Histopathology
Lymphoepithelial cysts in the oral cavity show similar
­histological features to the lymphoepithelial cysts of the
parotid gland and to branchial cleft cysts. They show an
epithelial-­lined cystic cavity surrounded by lymphoid tis-
sue, usually with well-­formed and normal germinal cen-
tres (lymphoid follicles; Figure 15.15). Overall about 95%
are lined by stratified squamous epithelium that is usu-
ally parakeratinised, and about half of these may show
hyperplasia (Buchner and Hansen  1980; Sykara
et  al.  2017; da Silva et  al. 2020). Occasional cases have
been orthokeratinised (Buchner and Hansen,  1980).
Pseudostratified ciliated (respiratory-­type) epithelium or
simple cuboidal duct-­like epithelium has been reported in
less than 5% of cases and mucous or goblet cells are occa-
sionally seen. In almost all cases the lumen contains des-
quamated parakeratotic cells and debris (Figure 15.15),
and some contain inflammatory cell or amorphous eosin-
ophilic material resembling mucus.
In some cases, the lumen of the cyst communicates with
the oral cavity through an epithelial-­lined tract. In their
series of 77 cases, da Silva et  al. (2020) found 23 (29.9%)
that communicated with the oral epithelium and 3 (3.9%)
that communicated with an adjacent salivary duct.
258 Cysts of the Salivary and Minor Mucous Glands
The cyst is closely enveloped by lymphoid tissue, which
in most cases surrounds the entire cyst, but in a few it is
present in only part of the wall. In most cysts the lymphoid
tissue shows normal germinal centres (Figure 15.15), but
in up to half of cases there may be only a diffuse infiltrate
of lymphocytes.
Treatment
The treatment of choice for oral lymphoepithelial cysts is
complete surgical excision. The precise technique and sur-
gical approach depend on the location of the cyst and the
proximity of adjacent vital structures.
­ ymphoepithelial Cysts of the
L Figure 15.16  A parotid lymphoepithelial cyst is lined by thin
Parotid Gland
Lymphoepithelial cysts of the parotid gland are essentially
salivary duct cysts associated with a dense lymphoid stroma.
Some regard parotid lymphoepithelial cysts to be branchial
cleft cysts that have arisen from branchial cleft remnants
sequestered in the parotid gland. Although this may be pos-
sible, we would regard the two as distinct and separate enti-
ties. Branchial cleft cysts are discussed in Chapter  18.
Parotid cysts with associated dense lymphoid tissue are also
seen in association with HIV disease and may be a feature
of benign lymphoepithelial lesions (lymphoepithelial
sialadenitis) associated with Sjögren syndrome. We would
also regard these as separate and distinctive lesions and
would use the terms HIV-­associated salivary gland disease
and cystic lymphoepithelial lesion, respectively.
Parotid gland lymphoepithelial cysts are uncommon and
there are very few reported cases. Camilleri and Lloyd
(1990) found about 70 cases in the literature up to 1990, but
since then there have been very few cases reported that
have not been associated with HIV. The largest case series,
which forms the basis for this discussion, comprises 64
cases reported in 2009 (Wu et al. 2009).
The lesions are found over a wide age range (3–76 years),
but the majority are encountered in adults, with a mean
age of 52 years. There is a slight predilection for females
(56.3%; 36 of 64 cases). The cysts are unilateral and present
as slow-­growing, soft painless swellings with an average
size of 30 mm (range 5–65 mm).
Histologically, the cysts show similar features to oral
lymphoepithelial cysts and are composed of an epithelial-­
lined cystic space surrounded by, or embedded in, dense
lymphoid tissue (Figures 15.15 and 15.16). Most lesions are
unilocular, but about 25% were found to be multilocular.
Wu et al. (2009) described three distinctive histomorpho-
logical patterns that they called Types I, II, and III.
epithelium overlying dense lymphoid tissue.
Type I cysts (14.1%; 9 cases) were simple cysts formed
from dilated ducts surrounded by diffuse infiltrates of
inflammatory cells, but without germinal centres. The epi-
thelial lining was most often simple columnar and duct-­
like. Epimyoepithelial islands were seen in 8 of the 9 cases,
and 7 cysts in this category were multilocular.
Type II cysts (42.2%; 27 cases) were partially encapsu-
lated and separated from the surrounding parotid tissue.
These cysts were lined by squamous epithelium and half
showed lymphoid follicles in the walls. Epimyoepithelial
islands were seen in only 5 cases.
Type III (43.8%; 28 cases) cysts were well encapsulated,
lined by squamous epithelium, and showed prominent
­germinal centres. Epimyoepithelial islands were seen in
5  cases. These cysts had a fibrous capsule resembling a
lymph node, but although lymphatic vessels were seen, no
subcapsular sinus structures could be identified.
Weidner et  al. (1986) described 5 cases and had found
similar features, although in 3 cases he found stratified or a
single layer of cuboidal cells with occasional mucous cells.
With regard to pathogenesis, Bernier and Bhaskar (1958)
were the first to introduce the term lymphoepithelial cyst,
and made a clear distinction between these and branchial
cleft cysts. They felt that parotid lesions were not derived
from embryonic epithelial remnants, but probably arose
from glandular inclusions in intraparotid lymph nodes.
An origin in lymph nodes is suggested by the finding that
many lesions are encapsulated (e.g. Types II and III) and
contain well-­formed germinal centres typical of normal
lymphoid tissue. On the other hand, germinal centres
are not seen in all cases, and some show diffuse lympho-
cytic infiltrates and epimyoepithelial islands similar to
the  ­features of benign lymphoepithelial lesions or lym-
phoepithelial sialadenitis. Wu et al. (2009) interpreted their

findings to propose that the lesions start as ductal dila-
tion in association with sialadenitis (Type I histology).
Subsequently a cyst develops and is accompanied by reac-
tive lymphoid hyperplasia and gradual encapsulation as
peripheral granulation tissue matures (progression to Type
II and III histology). It is not possible to definitively state
which mechanism is correct and it is probable that a num-
ber of different pathogenic processes may be responsible
for a common end result – an epithelial-­lined cyst embed-
ded in lymphoid tissue.
HIV-­Associated Salivary Gland Disease
Disorders of the salivary glands are a common manifesta-
tion of HIV infection and may be increasing as HIV infec-
tion persists following the advent of effective therapies
such as highly active antiretroviral therapy (HAART;
reviewed by Meer 2019). A particular disorder that affects
the parotid glands and is associated with cystic change has
been called HIV-­associated lymphoepithelial cysts, but is
now usually referred to simply as HIV-­associated salivary
gland disease or more precisely as cystic lymphoid hyperpla-
sia. This was first fully characterised in the early 1990s and
is the subject of a large literature. The lesions are character-
ised by lymphoepithelial cysts and a brief description is
relevant to allow distinction from non-­HIV-­related cysts of
the parotid gland.
Cystic lymphoid hyperplasia affects up to about 20% of
patients with HIV, occurs primarily in adult males, and
may be seen before the onset of AIDS. It almost always
affects the parotid glands and is bilateral in over 60% of
cases. It presents as diffuse enlargement of the glands and
may be accompanied by Sjögren-­like symptoms, including
dry mouth and eyes, and arthralgia.
Histologically, the glands show changes similar to the
lymphoepithelial lesions of Sjögren syndrome. However,
lesions in HIV patients are associated with diffuse lym-
phoid infiltrates with prominent follicular hyperplasia and
lysis of germinal centres. Another distinguishing feature is
the presence of multinucleated giant cells (Figure 15.17),
which have been shown to contain p24 (HIV-­1) protein in
immunocytochemical studies (Vicandi et  al.  1999). The
most characteristic feature is the finding of large and mul-
tiple cystic spaces lined by duct-­like epithelium.
Although these lesions are superficially similar to parotid
lymphoepithelial cysts, they can be differentiated on the
basis of the distinctive clinical presentation and by the
­histology that shows that the cysts are almost always mul-
tiple and often bilateral, and are embedded in diffuse lym-
phoid infiltrates with prominent follicles. In contrast,
lymphoepithelial cysts tend to be single, unilocular, and
surrounded by a zone of lymphoid tissue, often with few
or no follicles.
­Polycystic (Dysgenetic) Disease of the Parotid Gland 259
Figure 15.17  A multinucleated giant cell (arrow) is seen within
the dense lymphoid infiltrate of HIV-­associated cystic lymphoid
hyperplasia.
­ olycystic (Dysgenetic) Disease
P
of the Parotid Glands
This is a rare developmental disorder that arises in the
parotid glands and is not related to similar polycystic disor-
ders affecting other organs. Seifert et al. (1981) and Batsakis
et al. (1988) first drew attention to this condition, but up to
2017 fewer than 20 cases had been reported (Srikant
et  al.  2017). Although the lesion is associated with the
parotid glands, 3 cases have been reported in the subman-
dibular and minor glands (Koudounarakis et  al.  2016;
Srikant et al. 2017).
Clinically, the disorder occurs almost always in females,
with only 6 reported cases in males, and with a wide age
range at presentation of between 6 and 85 years. It presents
as bilateral parotid involvement, with a history of fluctuat-
ing, non-­tender parotid gland swelling, often with a long
history before diagnosis. A number of cases have been
reported with a familial background in which parents and
their offspring have been affected (Seifert et al. 1981; Smyth
et al. 1993; Srikant et al. 2017).
Histology shows that the normal acinar parenchyma of
the glands is almost completely replaced by a honeycombed,
net-­like pattern of thin-­walled interlinked cysts that appear
to arise from the intercalated ducts (Figure 15.18). The lob-
ular architecture of the gland is maintained, however.
Small clusters of serous acini and occasional ducts may be
retained in the intercystic fibrous septa. In places, the lin-
ing cells may be cuboidal and show apocrine change. The
cyst lumina contain amorphous eosinophilic mucus-­like
material and may occasionally contain mucus plugs or
sialoliths The lesions are not inflamed.
260 Cysts of the Salivary and Minor Mucous Glands
Figure 15.18  Polycystic disease of the parotid gland. The gland
is largely replaced by a network of thin-­walled cysts of variable
size and shape. Source: Courtesy of Dr K. Donath.
Familiarity with this disease should prevent a histologi-
cal misdiagnosis of a cystic neoplasm. No surgery is nec-
essary except for diagnosis and for cosmetic reasons if
required.
­Sclerosing Polycystic Adenoma
This lesion was first reported as a reactive fibrosing pseu-
doneoplastic lesion in the major salivary glands and was
called sclerosing polycystic adenosis (Smith et al. 1996). It is
now known that the lesion is a neoplasm and it has been
classified as sclerosing polycystic adenoma in the latest
World Health Organization (WHO) classification of head
and neck tumours (Bishop et  al.  2022) The lesion is not
primarily a cystic lesion, but it is multicystic and has been
included in this chapter for completion and to ensure that
it is properly distinguished from polycystic disease of the
parotid glands.
Sclerosing polycystic adenoma is a rare neoplasm, with
fewer than 100 cases reported. Almost all cases have arisen
in the parotid gland, but occasional lesions have been
found in the submandibular gland and about 15 have been
reported in the minor glands (Das et al. 2020). Lesions have
a slight predilection for females and are found over a wide
age range (7–84 years), but with a peak in the fifth decade
(Bishop et  al.  2020; Bishop et  al.  2022). Clinically, the
lesions present as a solitary swelling.
Histologically the tumour shows an unencapsulated
mass of sclerotic and fibrosed collagenous connective
­tissue containing accumulations of ductal and acinar epi-
thelial elements, with cystic spaces (Figure  15.19) form-
ing  a cribriform pattern. Areas of apocrine or squamous
metaplasia and mucous cell may be seen. About half of
cases have shown features of epithelial dysplasia or even
Figure 15.19  Sclerosing polycystic adenoma. Cystically dilated
ducts, with a cribriform pattern, are embedded in a fibrosed and
sclerosing collagenous stroma. Source: Courtesy of Prof.
John Eveson.
carcinoma in situ in the ductal epithelium (Gnepp  2003;
Gnepp et al. 2006).
Immunohistochemical and molecular studies have
shown good evidence that the lesion is a true neoplasm.
Skálová et  al. (2006) examined polymorphisms of the
human androgen receptor (HUMARA) and showed that
lesions were monoclonal, which was the first evidence of a
neoplastic nature. More recently, studies have shown con-
sistent mutations in PTEN and alterations in the PI3 kinase
pathway, as well as loss of PTEN protein expression in
ductal and acinar cells (Bishop et  al.  2020; Skálová
et  al.  2021). This profile is similar to salivary duct carci-
noma and confirms that sclerosing polycystic adenoma is a
neoplasm (Bishop et al. 2022; Bishop and Thompson 2021).
The histological features are characteristic and should
not cause confusion with polycystic disease or with other
salivary cysts. The main area of diagnostic difficulty is dif-
ferentiation from other benign or malignant salivary gland
tumours (Bishop and Thompson 2021).
­Keratocystoma
Another multicystic lesion that may be encountered in the
parotid gland is the keratocystoma. The true nature of
the  lesion is unknown and the literature has variously
described it as a benign cyst, a choristoma, or more fre-
quently as a benign neoplasm. It was first reported in the
parotid gland of an 8-­year-­old girl and was thought to be a
choristoma with adnexal features resembling a trichoade-
noma (Seifert et  al.  1999). Subsequently, only 10 further
cases have been reported, arising in adults from 18 to
51 years (Nagao et  al.  2002; Zhang et  al.  2010; Huang
et  al.  2012; Hirata et  al.  2014; Wang et  al.  2015; Ahuja
et al. 2016; Aresta et al. 2019; Komatsu et al. 2020). Most

authors consider the lesion to be a benign neoplasm, with
evidence that it arises from intercalated ducts that have
undergone squamous metaplasia (Nagao et al. 2002; Wang
et al. 2015).
Keratocystoma arises as a tumour-­like mass in the
parotid gland and is composed of multiple cystic spaces
lined by stratified squamous epithelium showing ortho-­
and parakeratinisation, but without a prominent granular
cell layer. The cystic spaces may be filled with lamellated
keratin to form solid masses. Solid islands of squamous
epithelium are also seen. The cysts are often irregular and
multilocular.
Many more cases need to be reported before this lesion
is  fully understood. It appears to be completely benign,
with no evidence of recurrence after adequate surgical
removal (Wang et  al.  2015; Aresta et  al.  2019; Komatsu
et al. 2020). The lesion is unlikely to be confused with other
cysts that may arise in the salivary glands. The prominent
keratinisation distinguishes it from lymphoepithelial cysts
­Keratocystom 261
and from polycystic disease or sclerosing polycystic ade-
noma, and the multicystic nature distinguishes it from rare
epidermoid cysts that might arise at this site. The main
area of diagnostic difficulty is differentiation from kerati-
nising squamous cell carcinoma and from salivary gland
tumours that may have a similar cystic morphology. This
might include mucoepidermoid carcinoma and pleomor-
phic adenoma, which may on occasion show prominent
squamous metaplasia with prominent cyst formation
(Goulart et al. 2011).
Keratocystoma also shows remarkably similar histologi-
cal features to the solid or multicystic odontogenic kerato-
cyst (see Chapter 7). However, it has only been reported in
the parotid gland and cannot be confused with intraosse-
ous keratocysts, but may cause diagnostic difficulties when
faced with a multicystic soft-­tissue lesion lined by kerati-
nised stratified squamous epithelium. Such lesions located
in the parotid gland should be diagnosed as keratocystoma,
not as soft-­tissue keratocyst.
262

16

Surgical Ciliated Cyst

CHAPTER MENU
­Clinical Features, 263
•• Frequency, 263
•• Age, 264
•• Sex, 264
•• Site, 264
•• Clinical Presentation,  264
­Radiological Features, 265
•• Radiological Differential Diagnosis,  266
­Pathogenesis, 267
­Histopathology, 268
­Treatment, 268

The surgical ciliated cyst is an implantation cyst that arises
as a result of entrapment of fragments of respiratory epi-
thelium into a wound following maxillary sinus surgery or
facial trauma (Nelson and Speight 2022). It can be regarded
as a type of mucous retention cyst of iatrogenic origin.
It  was first reported in Japan in 1927 (Kubo  1927) as
a  ­maxillary cyst occurring after radical sinus surgery.
Subsequently, Gregory and Shafer (1958) drew attention to
the development of these cysts in the maxilla of patients
whose sinuses had been opened surgically and first pro-
posed the term ‘surgical ciliated cyst of the maxilla’.
This was followed by a small number of reports in the
German literature, but it was not until the 1980s that many
reports began to record a high incidence in Japan. These
cases followed treatment of chronic sinusitis by a maxillary
antrostomy procedure that entered the sinus through
the  antero-­lateral wall (Caldwell-­Luc surgery; Kaneshiro
et al. 1981; Maeda et al. 1987; Yamamoto and Takagi 1986;
Nishioka et al. 2005).
The Caldwell-­Luc procedure has become less common
as sinusitis is now treated more conservatively.
Increasingly, therefore, cases are reported following max-
illary osteotomy procedures, although they may occasion-
ally arise after midfacial (le Fort) fractures or traumatic
tooth extractions.
A similar ciliated cyst has also been reported in the man-
dible (reviewed by Theofilou et al. 2021), but all cases have
resulted from implantation of sinus epithelium into a man-
dibular wound during simultaneous surgery on the maxilla.
With regard to terminology, the cyst has been called
­surgical ciliated cyst of the maxilla, but in Japan the favoured
name is postoperative maxillary cyst. However, these terms do
not account for lesions that arise in the mandible. The lesions
have also been included as a type of antral mucocele or have
been called respiratory implantation cyst or surgical implan-
tation cyst, but these names have not been widely adopted.
The name surgical ciliated cyst remains the most widely
used, and we will use this term here, specifying as appro-
priate mandible or maxilla as the site of occurrence.
Because the surgical ciliated cyst is a simple implanta-
tion cyst, similar to lesions that may arise randomly at
other anatomical sites, it has usually been regarded as an
oddity and has rarely been included in studies of jaw cysts
or in published classifications. However, it has a distinctive
aetiology and clinicopathological features and has been
considered as a distinct entity in Japan for many years. For
the first time, it has now been included as an entity in the
latest (fifth) edition of the World Health Organization (WHO)
classification of head and neck tumours (WHO  2022a;
Nelson and Speight 2022).

Shear’s Cysts of the Oral and Maxillofacial Regions, Fifth Edition. Paul M. Speight.
© 2022 John Wiley & Sons Ltd. Published 2022 by John Wiley & Sons Ltd.

­Clinical Features
Most descriptions of the surgical ciliated cyst are case reports
recording a single or a few cases. Niederquell et al. (2016)
reviewed the literature and found 23 articles recording
details of 284 patients between 1978 and 2014. In addition,
however, there are many papers, especially from Japan,
recording a high prevalence of this cyst and experience with
many hundreds of cases (Kaneshiro et  al.  1981; Maeda
et  al.  1987; Yamamoto and Takagi  1986; Nakamura
et al. 1995; Maruyama et al. 2002). One paper from Japan
recorded 1141 cases from one department alone (Nishioka
et al. 2005). There is only one case series from Europe or the
USA, and this reports only 21 patients (Basu et  al.  1988;
England). Table  16.1 summarises data from representative
selected series and reviews where details have been provided.
Frequency
Globally the surgical ciliated cyst appears to be rare, but
a  very high prevalence has been recorded in Japan.
Yamamoto and Takagi (1986) found that surgical ciliated
cysts constituted 19.5% of all oral cysts in their department.
Nakamura et al. (1995) reviewed 1234 jaw cysts and found
that 21.6% (n  =  267) were surgical ciliated cysts. More
recently, Nishioka et al. (2005) reported 1141 surgical cili-
ated cysts, representing 16.1% of all jaw cysts.
Outside of Japan, the cyst shows a much lower frequency.
In Shear’s department at the University of the Witwatersrand,
only 5 cases were diagnosed over a 32-­year period (see
Table  1.1), representing 0.1% of 3498  jaw cysts, and in
Sheffield we have seen only 7 cases since 1996. Nonaka
et  al. (2011) diagnosed only 3 cases among over 10 300
Table 16.1  Age, sex, and causation from selected case series or reviews of surgical ciliated cysts.
References n Age mean (range)
Case series
Yamamoto and Takagi (1986) 60 39.1 (21–72)
Basu et al. (1988) 21 43.7 (25–74)
Pe et al. (1990) 22 49.0 (33–68)
Nishioka et al. (2005) 1141 48.5 (21–80)
Reviews
Niederquell et al. (2016) 284 47.0 (19–85)
Kahn et al. (2021) 9 59.4 (41–76)
Theofilou et al. (2021) 15 32.4 (15–53)
n, number of patients.
a
 Delay is years between surgery and diagnosis.
b
 Surgery for sinusitis was almost always a Caldwell-­Luc procedure.
c
 Six cases were after osteotomy. The remainder followed sinus surgery.
­Clinical Features 263
biopsies (0.03%), while others have recorded no cases at all.
In the series recorded in Table 1.3, only two papers reported
surgical ciliated cysts, with frequencies of 0.08% (Daley
et  al.  1994; Canada) and 0.5% (Ali  2011; Kuwait) of all
jaw cysts.
Nishioka et  al. (2005) reviewed the worldwide preva-
lence over a 20-­year period and found only 56 cases from
outside of Japan compared to 1141 from just their own
department. They also asked colleagues from 31 university
departments in 16 countries to report on the number of
cysts encountered between 1976 and 1996. The largest
number (80 cases) were reported in South Korea, followed
by one department in Germany with 42 cases, 23 cases in
Birmingham (England), and 16  in Sao Paulo (Brazil). No
cases at all were reported in 20 departments, and the
remainder reported only 2 or 3.
Outside Japan, the only case series suggesting the lesion
may not be rare is from Birmingham (England; Basu et al.
1988), where 21 patients were diagnosed over a period of
three years (Table 16.1).
The variability in frequency is intriguing, but is clearly
associated with the number of surgical procedures carried
out in different settings. The high number of cases in Japan
were mostly reported between about 1970 and 1995, and is
thought to be due to a high prevalence of chronic sinusitis
among young people and the very common use of the
Caldwell-­Luc procedure in the immediate postwar period.
Outside of Japan radical sinus surgery has been less com-
mon, and more recent cases have been associated with
osteotomies. The Caldwell-­Luc procedure is used less fre-
quently now and a reduction in cases from Japan is to be
expected. The different causes of the cyst are discussed
later in this chapter (see ‘Pathogenesis’).
Male (%) Type of surgery Delaya mean (range)
50.0 Sinusitisb 18.3 (4–49)
42.9 Sinusitis 20.0 (7–39)
72.7 Sinusitis 26.5 (10–48)
58.7 Sinusitis 31.0 (3–61)
57.0 Mixedc 22.0 (0.5–60)
44.4 Sinus lift (implants) 3.9 (0.5–10)
53.3 Osteotomy 9.1 (3–21)
264 Surgical Ciliated Cyst

Age Sex
The age of presentation is, to some extent, determined The sex distribution varies between studies, with no clear
by the type of surgery that precedes the lesion. The evidence of a predilection for males or females (Table 16.1).
majority of reported cases follow a Caldwell-­Luc proce-
dure and diagnosis is made about 20–30 years after the Site
surgery (Table 16.1). The surgical ciliated cyst is there-
The surgical ciliated cyst has always been reported as an
fore seen in adults, with very few cases reported below
implantation cyst that arises in the maxilla, following sinus
the age of 20 years. The average age of presentation is
surgery. In 1994, however, the first case of a ciliated cyst
about 45–50 years (Table  16.1). Figure  16.1 shows the
was reported in the mandible following implantation of
age distribution of 1141 patients in the study of Nishioka
sinus epithelium from a nasal osteocartilagenous graft
et al. (2005). The majority of their patients were in the
used for chin augmentation (Nastri and Hookey  1994).
fourth to sixth decades, with a clear peak (34.7% of
Subsequently 14 cases have been reported in the mandible
cases) in the fifth decade and an age range of 21–80 years.
as a result of chin augmentation surgery or bimaxillary
The vast majority of the cases in this study (98.7%) arose
osteotomies (reviewed by Theofilou et al. 2021).
following surgery for sinusitis and there were no
Maxillary lesions are located in the posterior, molar/pre-
osteotomies.
molar region of the maxilla. The cysts are always found
More recent studies suggest that cysts following osteoto-
towards the floor of the sinus. Occasional bilateral cysts
mies occur in a younger age group. Theofilou et al. (2021)
have been reported in patients who have had sinus surgery
reviewed the literature and found 15 cases that followed
on both sides.
maxillary osteotomies, with an average age of 32.4 years
The site of mandibular cases depends on the type of sur-
(range 15–53) and a delay between surgery and diagnosis
gery. Those associated with chin augmentation are found in
of between 3 and 21 years.
the anterior mandible, while those that follow a mandibular
Conversely, cases that have followed sinus lift surgery
osteotomy may be located in the premolar/molar region.
(sinus floor augmentation) appear to arise in older age
groups, reflecting the fact that the purpose of this surgery
Clinical Presentation
is to facilitate the insertion of implants. In a systematic
review, Kahn et al. (2021) found 9 cases, with an average Surgical ciliated cysts are postoperative implantation cysts
age at presentation of 59.4 years and a delay following sur- and patients must always have a previous history of sur-
gery of only 3.9 years (Table 16.1) gery involving the maxillary sinus. The period between

400 Figure 16.1  Age distribution of 1141

patients with surgical ciliated cyst.
Males Source: Data from Nishioka et al. (2005).
350
Females

300
222

250
No of cases

180
200
139

150

100
174 80
125
50 102
32
43 14
16 11 3
0
0-9 10-19 20-29 30-39 40-49 50-59 60-69 70-79 80-89 90+
Age

surgery and onset of symptoms varies from 6 months to
60 years, with an average of about 20 years (Table 16.1). The
majority of patients (about 90%) present between 10 and
30 years after surgery (Kaneshiro et  al.  1981; Yamamoto
and Takagi  1986). Cysts associated with osteotomies may
present at a younger age and with a shorter delay since sur-
gery (Theofilou et al. 2021; Table 16.1).
Occasionally a cyst may be silent and symptomless and
found incidentally on radiographs taken for other reasons.
In most cases, however, patients complain of swelling with
pain or tenderness.
Basu et al. (1988) found that 20 of their 21 patients pre-
sented with pain and intraoral swelling and 13 (61.9%) also
showed extraoral swelling. In their systematic review,
Niederquell et al. (2016) found that clinical symptoms were
recorded for 219 patients. Of these, 142 (64.8%) complained
of pain, 54 (24.6%) of pain and swelling, and 14 (6.5%) of
swelling alone. Thus almost all patients (95.6%) presented
with a combination of pain and/or swelling. Nishioka et al.
(2005) found that only 2 of their 1141 patients were
symptomless.
Cases reported in the mandible have usually presented
as a swelling with pain or tenderness. Theofilou et  al.
(2021) found that only 2 of the 14 reported cases were
­incidental findings. Moreover, 11 cases presented with
swelling, of which 4 also showed pain or tenderness. One
case presented with mental nerve paraesthesia. One man-
dibular case was found to be extraosseous and presented
as a fluctuant subcutaneous swelling on the chin (Kelly
et al. 2000).
Box 16.1  Surgical Ciliated Cyst: Key Features
●● It is an implantation cyst caused by entrapment of
sinus epithelium into a wound
●● Patients always have previous history of surgery or
trauma involving the maxillary sinus
●● Arise in the alveolar bone of the posterior maxilla
●● Rare cases in the mandible follow implantation of
sinus epithelium during bimaxillary surgery
●● Globally, they are rare – less than 0.5% of jaw cysts
●● Common in Japan, representing up to 20% of jaw cysts
●● Mean age is about 45 years, with a peak in the
fifth decade
●● No sex predilection
●● Most patients complain of swelling and pain or
tenderness
●● Radiology shows a well-­demarcated unilocular
lesion that is at least partially corticated
●● Histology shows a cyst lined by pseudostratified cili-
ated columnar (respiratory) epithelium
­Radiological Features 265
­Radiological Features
Radiographs show a well-­defined radiolucent lesion in the
alveolar bone, closely related to the floor of the maxillary
sinus. The cyst is usually rounded and unilocular and may
be at least partially corticated (Figures 16.2–16.4).
In the series of 60 cases reported by Yamamoto and
Takagi (1986), 56 (93.3%) were unilocular lesions, with
only 4 reported as multilocular. In 42 of their 60 cases buc-
cal cortical bone was present and 58% (35 cases) had a cor-
ticated margin in at least part of the cyst. Most cases (43:
71.6%) were located below the antral floor, although 24
(40%) raised the floor and occupied half of the sinus, and
17 cases (28.3%) filled the entire sinus. Kaneshiro et  al.
(1981) found that 68% of their 71 cases had evidence of cor-
tication. Most (61.7%) were between 21 and 30 mm in
diameter, with only 7 (9.9%) cases greater then 31 mm.
The cystic area appears to encroach on the sinus itself,
but lack of communication between the two has been dem-
onstrated by injecting the sinus with a radiopaque material
(Kaneshiro et al. 1981; Basu et al. 1988).
As the cysts enlarge, ballooning expansion of the buccal
and palatal cortical plates may become apparent and the
sinus wall may become thinned and eventually perforated
(Basu et al. 1988; Leung et al. 2012). Gradually, a cyst may
expand beyond the original boundaries of the sinus
(Figure  16.3). Expansion is best seen on examination by
computed tomography (CT) or magnetic resonance imag-
ing (MRI). The cysts show a ballooning pattern of expan-
sion with corticated margins, and T2-­weighted MRI shows
hypointense contents suggesting low water and high
Figure 16.2  Surgical ciliated cyst. Radiograph shows a
well-­defined radiolucency at the site of a previously extracted
tooth. The cyst is clearly corticated along the inferior and
anterior margin. Note that the lamina dura and periodontal
space of the adjacent teeth are intact (arrows).
266 Surgical Ciliated Cyst
protein content, consistent with mucus (Leung et al. 2012;
Theofilou et al. 2021).
Pe et  al. (1990) evaluated 34 cysts using CT and found
that they were round and expansile and many showed evi-
dence of fluid contents. All but 1 of their 34 cases showed
some evidence of perforation of the sinus wall: 28 of the
antero-­lateral wall, 27 of the medial or nasal wall, and 14 of
the posterior wall. Furthermore, 13 cases (38.2%) filled the
sinus and 21 (61.8%) partially filled the sinus. The largest
case in their series also perforated the orbital floor.
Surgical ciliated cysts in the mandible usually present as
a well-­defined unilocular radiolucency with a corticated
margin (Nastri and Hookey  1994; Bourgeois and Nelson
2005; Lazar et al. 2006; Li et al. 2014; Cai et al. 2015). Most
lesions are solitary, but multiple cysts have been described,
adjacent to inserted plates and to the wound margins
(Bourgeois and Nelson 2005; Cai et al. 2015). Mandibular
lesions have also been described that are multilocular
(Koutlas et al. 2002) or have an irregular scalloped outline
(Ragsdale et al. 2009). One mandibular case was found to
be extraosseous and presented entirely in the soft tissue of
the chin (Kelly et al. 2000).
Radiological Differential Diagnosis
Although the radiological features are characteristic, a
diagnosis cannot be made on radiology alone. The key
diagnostic criteria are a history of previous surgical inter-
vention, and an epithelial lining of respiratory-­type epithe-
lium (Box  16.1). On radiology alone the surgical ciliated
cyst may be indistinguishable from other cysts that arise in
the maxillary antrum (discussed in Chapter  15). A com-
parison of Figures 16.2 and 15.14 illustrates the similarity
Figure 16.3  Surgical ciliated cyst
located in the posterior maxilla
associated with a Le Fort I osteotomy
(metal plates can be seen towards the
top right of the figure). The cyst is well
demarcated and corticated (arrows).
of the surgical ciliated cyst to a mucosal cyst of the sinus.
In both cases a tooth has been extracted and if a respiratory
epithelial lining is present the lesions may be indistin-
guishable. A history of sinus surgery or a difficult trau-
matic extraction may suggest a diagnosis of surgical ciliated
cyst. Note, however, that retention cysts arise in the floor of
the sinus and are not intraosseous, whereas the surgical
ciliated cyst is within the alveolar bone and has a well-­
defined bone margin that is at least partially corticated
(Figure 16.2). Mucosal retention cysts can never be corti-
cated on the superior surface. On occasion it may not in
fact be possible to distinguish between a surgical ciliated
cyst and a retention cyst of the maxillary sinus.
Surgical ciliated cysts may also fill the sinus and may
cause bony expansion or perforation of the sinus walls
(Basu et al. 1988; Pe et al. 1990). Such features are an omi-
nous sign and may be indistinguishable from a sinus
mucocele, but must also be differentiated from destructive
neoplasms. The surgical ciliated cyst is ballooning and
expansile, and even when filling the sinus, a corticated mar-
gin may be visible and the cyst can be shown to be separate
from the sinus by CT or using contrast medium. Many sur-
gical ciliated cysts also show a fluid level. A final diagnosis,
however, may depend on histological examination.
A further consideration is differentiation from radicular or
residual cysts. The surgical ciliated cyst arises in the alveolar
bone of the maxilla and may be in close proximity to the
roots of the maxillary teeth. On radiology the lamina dura
and periodontal space of the associated teeth will be intact
(Figure 16.2), and this excludes a diagnosis of radicular cyst.
A radicular cyst can also be excluded if the teeth are vital.
Figure 16.4 shows a well-­demarcated corticated cyst in an
edentulous region of the maxilla. This radiological

Figure 16.4  A surgical ciliated cyst located in the
edentulous maxilla. Such a lesion is
indistinguishable from a residual cyst and
diagnosis must depend on the histological
findings.
appearance is almost diagnostic of a residual cyst, but in this
case the cyst was lined entirely by respiratory epithelium
and a diagnosis of surgical ciliated cyst was made, with an
assumption that it had followed a previous difficult
extraction.
Another maxillary cyst that can cause diagnostic confu-
sion is the nasopalatine duct cyst, since this may also be
lined by respiratory epithelium (see Chapter 13). However,
nasopalatine duct cysts are found in the midline of the ante-
rior maxilla and surgical ciliated cysts are almost always
located in the posterior maxilla. A diagnosis of surgical cili-
ated cyst in the midline anterior maxilla could only be made
if there was clear evidence of previous surgery at this site.
­Pathogenesis
The surgical ciliated cyst is caused by implantation of sinus
mucosal epithelium into a wound following surgery involv-
ing the maxillary sinus. The vast majority of cases have
been reported in Japan and have followed surgery for
chronic sinusitis using the Caldwell-­Luc procedure, which
involves perforation of the antero-­lateral wall of the sinus
by an intraoral approach. The high frequency of cysts in
Japan has been attributed to the large number of cases of
maxillary sinusitis that occurred in Japan during and just
after the Second World War, which were treated by the
Caldwell-­Luc procedure because antibiotics were not avail-
able. Most large series in Japan were reported between
about 1970 and 1990 and there have been few since, sug-
gesting that the frequency of this postoperative cyst is now
declining. This is probably caused in part by conservative
management of sinusitis with antibiotics, and to the
increasing use of endoscopy to treat sinus disease as an
alternative to the Caldwell-­Luc procedure.
­Pathogenesis 267
In 1990, Sugar et al. (1990) reported the first cases of sur-
gical ciliated cyst arising in the maxilla at the site of maxil-
lary (Le Fort) osteotomies. Subsequently there have been
10 reports of postosteotomy cysts, with a total of 15 cases
(reviewed by Theofilou et al. 2021). All have followed max-
illary osteotomies, mostly advancement procedures of the
Le Fort I type.
Nishioka et  al. (2005) reported 1141 of their own cases
from Japan and reviewed 54 cases from other parts of the
world. Of their own cases, 98.7% were caused by surgery for
chronic sinusitis, while the rest were associated with removal
of polyps or dental extraction, or 1 case that followed a facial
fracture. Of the cases from other countries, only 67.3% were
caused by sinus surgery, 9.1% by trauma or fracture, and
5.5% followed osteotomies. In their systematic review of 23
published papers, Niederquell et al. (2016) found 210 cases
where the cause was documented: 190 (90.1%) had had
Caldwell-­Luc surgery, 14 (6.7%) had had other types of sinus
surgery, and 6 cases followed a Le Fort osteotomy.
More recently, cases have been reported after sinus floor
augmentation surgery for insertion of implants. Kahn et al.
(2021) reported 4 cases and in a systematic review found a
further 5 cases. The cysts arose from 6 months to 10 years
after surgery (Table  16.1) and were located in the aug-
mented bone adjacent to implants.
Cases reported in the mandible have all been associated
with implantation of sinus epithelium during surgery that
has involved simultaneous interventions in the maxilla and
mandible. There have been 12 reports of mandibular cili-
ated cysts, with a total of 14 cases (Nastri and Hookey 1994;
Anastassov and Lee  1999; Kelly et  al.  2000; Imholte and
Schwartz 2001; Koutlas et al. 2002; Bourgeois and Nelson
2005; Lazar et al. 2006; Ragsdale et al. 2009; Li et al. 2014;
Cai et al. 2015; Seifi et al. 2016; Syyed et al. 2019; reviewed
by Theofilou et al. 2021). Of the 14 cases, 8 were caused by
implantation of sinus or nasal epithelium into the anterior
268 Surgical Ciliated Cyst
mandible during chin augmentation using an autologous
graft from the maxilla or an osteocartilaginous graft from
the anterior nose. The remaining 6 cases followed bimaxil-
lary osteotomies and were probably caused by transfer of
epithelial fragments on contaminated instruments.
The pathogenesis of the cyst must be due to proliferation
of the implanted epithelium with subsequent cyst forma-
tion. This may follow a similar process to that seen in radic-
ular cysts, where chronic inflammation causes epithelial
proliferation followed by formation of a cyst cavity and
growth by hydrostatic pressure. However, this does not
explain why implanted cysts of the jaws only follow sinus
surgery and are always lined by respiratory epithelium.
During all the surgical procedures in and around the jaws,
implantation of epithelial fragments must be quite com-
mon and must involve stratified squamous as well as sinus
epithelium. Although it is known that implanted stratified
squamous epithelium can result in epidermal implant
cysts in the skin, this does not appear to occur in the mouth.
We must assume therefore that implanted oral epithe-
lium may not survive, but that respiratory epithelium can
retain the ability to persist and to form cysts. This is likely
to be due to secretion of mucus. Surgical ciliated cysts are
lined by respiratory-­type epithelium with frequent mucous
or goblet cells. Cyst formation is probably due to persistent
secretion of mucus by the epithelial remnants, with accu-
mulation of the mucus creating a cyst lumen. Continuous
secretion causes intraluminal pressure and gradual
expansion. The delay between surgery and diagnosis of
10–30 years or more suggests that growth is slow. In  this
respect, the surgical ciliated cyst can be regarded as a type
of mucous retention cyst of iatrogenic origin. Although
this process is rarely cited, the Japanese literature has long
regarded the surgical ciliated cyst to be a form of retention
cyst (Yamamoto and Takagi 1986).
None of these mechanisms wholly explains the higher
prevalence in Japanese patients. As mentioned previously,
the frequent use of Caldwell-­Luc surgery to treat chronic
sinusitis in the postwar period has been cited as the reason
for the high prevalence of cysts in Japan. Nishioka et  al.
(2005), however, reported 1141 cases in their single depart-
ment and noted that the annual rate had remained almost
constant, at 50 cases per year, right up until 2001. They sug-
gested therefore that the Caldwell-­Luc operation could not
be the only explanation for the high prevalence since, even
in Japan, the operation had become less common. They
suggested that age may be a factor, because antral surgery
in Japan is often at a younger age and the high incidence of
cysts may be related to the fact that the facial skeleton is
still growing. Although this is possible, there is no research
evidence to support it.
­Histopathology
The cysts may be removed intact and will be seen as a sac-­
like cystic lesion with a thick fibrous wall. On dissection
the lumen contains a brown, watery or mucoid liquid.
Many lesions are removed piecemeal or will be ruptured,
and the pathologist will receive fragments of cyst wall. The
luminal surface is covered with epithelium. Thickenings or
papillary process are not seen.
Histologically, the surgical ciliated cyst is lined in whole
or in part by typical respiratory-­type, pseudostratified cili-
ated columnar epithelium (Figure  16.5; Yamamoto and
Takagi 1986; Maeda et al. 1987; Basu et al. 1988; Maruyama
et al. 2002; Nishioka et al. 2005). About 30% of cysts may
also show focal areas of stratified squamous epithelium
that is often thin and flattened, or of cuboidal cells only two
to five cell layers thick (Figure 16.6).
Maruyama et  al. (2002) examined 360 cysts and found
that all cases showed pseudostratified ciliated columnar
epithelium that occupied 66% or more of the lining, with
frequent goblet cells. Up to 28% of the lining was simple
cuboidal epithelium with goblet cells, and up to 6% may
be a flattened stratified squamous epithelium. In another
study (Maeda et  al.  1987), 12.9% of cysts were lined
­predominantly by squamous epithelium, 2.9% by simple
cuboidal epithelium, and the remainder (84.2%) by
­pseudostratified ciliated columnar epithelium, either alone
(67.1%) or with focal areas of squamous epithelium.
Mucous (goblet) cells were always a prominent feature.
The cyst wall is composed of loose, fibrous connective
tissue, often with focal areas of inflammation. A character-
istic feature that has been noted by a number of workers
(Yamamoto and Takagi 1986; Basu et al. 1988; Maruyama
et al. 2002; Nishioka et al. 2005) is that the fibrous tissue
beneath the flattened or squamous epithelium is often
acellular and hyalinised (Figure  16.6). This is not seen
associated with the respiratory-­type epithelium.
The cyst wall does not usually contain any mucous
glands or ducts. This feature helps to distinguish the cyst
from normal sinus mucosa, where subepithelial mucous
glands are often seen.
­Treatment
Surgical ciliated cysts are usually treated by enucleation or
by marsupialisation into the sinus (Kaneshiro et al. 1981;
Yoshikawa et al. 1982). In both methods access to the sinus
is required and this can be by an antrostomy through the
antero-­lateral wall of the sinus via an intraoral approach
(Caldwell-­Luc procedure), or by a meatal antrostomy via
 ­Treatment 269

Figure 16.5  Surgical ciliated cyst. The lining is

composed of pseudostratified ciliated columnar
epithelium.

Figure 16.6  Surgical ciliated cyst. In this field the

cyst is lined in part by pseudostratified ciliated
columnar epithelium (right side), but elsewhere the
lining is thin, flattened simple squamous or
cuboidal epithelium. In these areas the fibrous wall
shows a subepithelial band of acellular hyalinised
fibrous tissue (arrows).

nasal endoscopy. The exact approach may depend on the
site of the cyst. If the cyst is located close to the anterior or
lateral wall, then a Caldwell-­Luc approach may be neces-
sary (Cho et al. 2019). Sometimes the cyst may be marsupi-
alised via a Caldwell-­Luc procedure, followed by insertion
of a drain through a meatal antrostomy. Cho et al. (2019)
treated 67 patients by transnasal endoscopic marsupialisa-
tion and found an overall recurrence rate of 9.0% (6 cases),
but noted that 5 of the recurrences were associated with
cysts located at the antero-­lateral aspect of the sinus. They
concluded that over 90% of all cases could be treated
with  meatal antrostomy alone, but that a concomitant
Caldwell-­Luc procedure may be needed for larger lesions,
multilocular lesions, or cysts located in the antero-­lateral
region of the sinus.
A number of authors have emphasised the need to pre-
vent the onset of surgical ciliated cysts. Theofilou et  al.
(2021) noted that postosteotomy cases most often arose in
the gap created by a maxillary advancement procedure,
either with or without a concomitant graft. They suggested
that the gap or the graft could be protected by placement of
a protective membrane that would prevent the ingress of
epithelial cells. Niederquell et  al. (2016) proposed that
chronic sinusitis should be treated whenever possible by
conservative methods, with avoidance of invasive surgery
of the maxillary sinus.
270

17

Pseudocysts of the Jaws: Simple Bone Cyst and Stafne Bone Cavity

CHAPTER MENU
Simple Bone Cyst, 271
●● Classification and Terminology,  271
●● Clinical Features,  272
–– Frequency, 272
–– Age, 273
–– Sex, 273
–– Site, 273
–– Clinical Presentation,  274
●● Radiological Features,  275
–– Multiple Simple Bone Cysts,  276
●● Simple Bone Cysts Associated with Cemento-­osseous Dysplasia,  276
–– Summary and Conclusions,  278
●● Pathogenesis, 278
–– Summary and Conclusions,  280
●● Histopathology, 280
●● Treatment, 281
Stafne Bone Cavity, 281
●● Clinical Features,  281
–– Frequency, 281
–– Age, 281
–– Sex, 282
–– Site, 282
–– Clinical Presentation,  282
●● Radiological Features,  282
–– Radiological Differential Diagnosis,  284
●● Pathogenesis, 284
●● Histopathology, 285
●● Treatment, 285
Focal Osteoporotic Bone Marrow Defect, 285
●● Clinical Features,  285
●● Radiological Features,  286
–– Radiological Differential Diagnosis,  286
●● Pathogenesis, 286
●● Histopathology, 286
●● Cavitational Osteonecrosis,  286
Aneurysmal Bone Cyst, 287

Shear’s Cysts of the Oral and Maxillofacial Regions, Fifth Edition. Paul M. Speight.
© 2022 John Wiley & Sons Ltd. Published 2022 by John Wiley & Sons Ltd.
 ­Simple Bone Cys  271

This chapter considers a number of lesions of the jaws that Classification and Terminology
present clinically or radiologically as cystic lesions, but are
A notable feature of all the publications is uncertainty
empty or fluid-­filled bony cavities without an epithelial
about the nature of this lesion and this is reflected in the
­lining. These pseudocysts are rare in the jaws, but are
large number of different names that have been used. This
important in the differential diagnosis of cystic lesions. The
has led to inconsistency and confusion in the literature,
most commonly encountered are the simple bone cyst and
meaning that readers cannot always be certain that the
the Stafne bone cavity, and these will be considered in
same lesion is being discussed. The earliest reports used
some detail. Other lesions  –  focal osteoporotic bone
the term traumatic bone cyst (Blum  1932; Hansen
­marrow defect and aneurysmal bone cyst – will be briefly
et  al.  1974), while at the same time others used haemor-
reviewed.
rhagic bone cyst (Howe  1965) or solitary bone cyst
(Rushton  1946). In the long bones, the lesion is often
referred to as unicameral bone cyst. Although this term is
­Simple Bone Cyst an accurate description,1 it is not widely used and is very
rarely applied to jaw lesions.
Simple bone cysts are fluid-­filled or empty intraosseous
Other terms that appear in the literature include idiopathic
cavities found most commonly in the proximal metaphy-
bone cavity, extravasation bone cyst, solitary bone cyst, and
seal region of the long bones in children and adolescents.
simple bone cyst. Most of these terms imply a causation or a
Similar lesions are found in the mandible and very sel-
clinical feature and are thus inaccurate or potentially mis-
dom in the maxilla. The first report of a jaw lesion is
leading. Traumatic bone cyst is often used, but should prob-
attributed to C.D. Lucas, who mentioned it during a dis-
ably be avoided because it assumes a traumatic aetiology that
cussion following a presentation to the American Dental
has not been fully substantiated. Similarly, the terms extrava-
Association by Theodor Blum, who reported his realisa-
sation cyst and haemorrhagic cyst emphasise the possible
tion that not all jaw cysts were of dental origin
role of haemorrhage, but this also is not fully substantiated
(Blum 1929). Later, Blum described three cases in detail
and these terms should not be used. ‘Idiopathic’ is a good
and called them traumatic bone cysts (Blum  1932).
term and is accurate in that it means ‘of unknown cause’.
Subsequently, Rushton (1946) described more cases in
Unfortunately, this name is also applied to the Stafne bone
detail and suggested diagnostic ­criteria that are similar to
cavity (discussed later in this chapter) and therefore this term
those used today (Hansen et al. 1974; Harnet et al. 2008;
should also be avoided. The most widely used names are soli-
Raubenheimer et al. 2017; Chrcanovic and Gomez 2019c;
tary bone cyst and simple bone cyst and these can be regarded
Box 17.1).
as synonymous. However, ‘solitary bone cyst’ implies that
lesions are solitary or single, but multiple or bilateral lesions
have been reported, so this term also lacks accuracy.
In the World Health Organization (WHO) classifications
Box 17.1  Simple Bone Cyst: Definition and
of jaw lesions, this cyst has been included under the cate-
Diagnostic Criteria
gory of ‘bone cysts’. In the first edition it was called simple
Simple bone cyst is a cystic radiolucency that on gross bone cyst (Pindborg and Kramer 1971), but in the second
or histological examination does not have an epithelial edition it was solitary bone cyst (Kramer et  al.  1992).
lining, but shows a cavity that is empty or contains Subsequent editions (Barnes et  al.  2005; El-­Naggar
small amounts of fluid. et al. 2017), including the latest (fifth) edition (WHO 2022a),
have consistently called this lesion simple bone cyst with
Diagnostic Criteria
‘solitary’, ‘traumatic’, and ‘haemorrhagic’ as synonyms.
●● A well-­demarcated cystic radiolucency, usually
Furthermore, the latest WHO classification of soft-­tissue
(>98%) in the mandible
and bone tumours also ­prefers the term simple bone cyst
●● The cavity is empty or contains small amounts of fluid
and only recommends ­‘solitary’ as an acceptable alternative
●● There is no epithelial lining
term (WHO 2022b).
●● Diagnosis is by exclusion  –  examination during

surgical intervention or histology excludes any

­
other known diagnosis
Cystic lesions that meet these criteria may be found
in association with fibro-­ osseous lesions, especially
florid cemento-­osseous dysplasia.
1
Unicameral derives from ‘uni-­’, meaning one, and the Latin ‘camera’,
meaning chamber. It is therefore accurate as a term for a unilocular
or unicystic lesion. Interestingly, the term unicameral is more often
used to describe a system of government that uses only a single
legislative or parliamentary chamber.
272 Pseudocysts of the Jaws: Simple Bone Cyst and Stafne Bone Cavity

For these reasons we suggest that simple bone cyst should
always be used. This reflects the simple nature of the lesion
and makes no presumptions regarding pathogenesis or
clinical findings. Although it is not a true cyst, it presents
clinically and radiologically as a cystic lesion and the term
‘cyst’ remains acceptable and widely used. Simple bone
cyst is also the preferred term for all lesions, no matter
where in the skeleton they are encountered.
There is some evidence, discussed in detail in the follow-
ing sections, that the simple bone cyst is not a single clin-
icopathological entity, but may be a common end result of
a number of causative factors (see ‘Pathogenesis’). The vast
majority of lesions are single or solitary, affecting the man-
dible, but about 5.0% of patients may have multiple cysts
(Chrcanovic and Gomez  2019c). In addition, there are a
number of reports of lesions similar to simple bone cysts
arising in association with cemento-­osseous dysplasia (e.g.
Chadwick et al. 2011; Yeom and Yoon 2020). Shimoyama
et al. (1999) suggested that the simple bone cyst may take
three distinctive clinicopathological forms: simple solitary
lesions, multiple lesions that may progress or recur, and
cysts associated with other lesions, primarily cemento-­
osseous dysplasia. In the following sections solitary and
multiple lesions will be considered together as variants of
the same entity, but lesions associated with cemento-­
osseous dysplasia will be discussed separately (see later
Box 17.3 and ‘Simple Bone Cysts Associated with Cemento-­
osseous Dysplasia’).
Clinical Features
Most reports of simple bone cyst in the jaws are single case
reports or small series. Lima et  al. (2020) found 29 pub-
lished case series (5 cases or more) between 1951 and 2019,
reporting almost 800  lesions. In a detailed systematic
review, including single case reports, Chrcanovic and
Gomez (2019c) identified 284 papers that reported 1253
cysts. Table  17.1 summarises a number of selected larger
case series (>20 cases) with a broad geographical distribu-
tion, as well as the findings of the review by Chrcanovic
and Gomez (2019c). The simple bone cyst shows a number
of characteristic features (Box 17.2) that assist in making a
diagnosis, but ultimately a final diagnosis is made by exclu-
sion of any known cause of a cystic cavity in the jaws
(Box 17.1).
Frequency
Simple bone cysts account for about 3% of bone lesions and
are most common in children and adolescents. Most
lesions (about 80%) are found in the proximal metaphyseal
regions of the humerus (50%) or femur (30%), with most of
the remainder found in the proximal tibia or other long
bones. Jaw lesions are rare and represent less than 5% of all
skeletal lesions and about 1% of all jaw cysts.
In his review of cases from the University of the
Witwatersrand, Shear found only 35 specimens during the
46-­year period under review, constituting 1% of all jaw
cysts, and 7.2% of non-­odontogenic cysts (see Table 1.1). In
a review of Sheffield specimens there were only 36 cases
reported over a 30-­year period, representing 0.5% of 6862
cysts of the jaws (Jones and Franklin  2006a,b) and only
0.07% of all oral biopsies. Other studies have shown similar
low frequencies, with only 4 cases reported among 2030 jaw
cysts (0.2%) in a study from Italy (Lo Muzio et al. 2017) and
9 cases among 5295 cysts in Greece (0.2%; Tamiolakis
et al. 2019).
Most simple bone cysts are found below the age of
20 years and so they are relatively more common in chil-
dren. Jones and Franklin found an overall frequency of
0.5% of jaw cysts, but the frequency in their paediatric pop-
ulation was 3.4% (19 cases among 556 jaw cysts; Jones and
Franklin  2006b), which was more than 10 times greater

Table 17.1  Age, sex, and site distribution, and frequency of scalloping, of simple bone cysts from selected case series and the
systematic review of Chrcanovic and Gomez (2019c).

References Country n Age mean (range) Male (%) Mandible (%) Scalloped (%)

Suei et al. (1998) Japan 52 23.0 (10–56) 48.1 98.1 NR

Cortell-­Ballester et al. (2009) Spain 21 26.5 (4–45) 33.3 100 NR
Chadwick et al. (2011) Canada 68 18.5 (11–58) 50.0 98.5 54.4
You et al. (2017) S Korea 27 29.5 (10–63) 29.6 96.6 56.7
Flores et al. (2017) Brazil 42 19.6 (7–66) 47.6 100 30.8
Lima et al. (2020) Brazil 60 16.9 (7–74) 50.0 98.4 72.4
Roma et al. (2021) Brazil 30 22.2 (11–52) 50.0 100 NR
Chrcanovic and Gomez (2019c) SR 1253 20.4 (2–79) 48.3 96.4 41.7

NR, not reported; SR, systematic review.

 ­Simple Bone Cys  273

Box 17.2  Simple Bone Cyst: Key Features

Clinical
●● 60–70% arise in the second decade

●● Average age is 20 years

●● Equal sex distribution

●● Over 98% are found in the mandible, often premolar/molar region

●● About 5% of patients may have multiple lesions – usually two and often bilateral

●● Usually symptomless

●● Cysts are occasionally seen in older females (fifth decade), associated with cemento-­
osseous dysplasia
Radiology
●● A well-­
demarcated radiolucency
●● 50% show areas of cortication

●● Up to 70% are scalloped around the tooth roots, which ‘hang’ into the cavity

●● A cone shape is characteristic, but only seen in about 10%

Histopathology
●● Gross examination at surgery shows an empty cavity

●● About 50% contain blood or a serosanguinous fluid

●● Do not have an epithelial lining

●● About 10% have a thin membranous lining of loose fibrovascular tissue

●● May be scattered osteoclasts and inflammatory cells

than the frequency of 0.3% in adults (Jones and
Franklin 2006a). They also found that in children the simple
bone cyst represented 51.4% of non-­odontogenic cysts (19
cases among 37), compared with only 6.7% in adults. Other
but smaller studies have found higher frequencies in children.
In a study from Israel, Manor et al. (2012) encountered 95 jaw
cysts in children over a 20-­year period and found 17 (17.9%)
simple bone cysts. Over the same period, they recorded no
cases in adults (≥17 years). Resnick et al. (2016) reported 45
cases of simple bone cyst diagnosed over a 15-­year period at
the Boston Children’s Hospital (Boston, MA, USA).
Age
The simple bone cyst occurs in young individuals, with the
vast majority of cases occurring below the age of 20 years.
There is a wide age range, with cases reported in patents up
to 74 years and with an overall average of between about 20
and 25 years (Table 17.1). In all studies, however, the peak
age is always in the second decade, with reported frequen-
cies in this decade of 78% (Howe 1965), 66% (Chrcanovic
and Gomez 2019c), 60% (Roma et al. 2021), 58% (Hansen
et al. 1974), and 56% (You et al. 2017).
Sex
Studies have shown a variable sex distribution (Table 17.1).
A small number of studies show a predilection for females
(Cortell-­Ballester et al. 2009; You et al. 2017), but overall
the sex distribution appears to be about equal or with only
a slight female predilection. In their large systematic
review, Chrcanovic and Gomez (2019c) found that 51.7% of
cases arose in females and 48.3% in males. However, it has
been shown that multiple lesions and lesions associated
with cemento-­osseous dysplasia arise more commonly in
females and in older age groups. This is discussed later in
this chapter.
Site
Simple bone cysts involving the jaws are almost always
found in the mandible, with each case series only reporting
one or two cases in the maxilla (Table 17.1). Studies have
consistently shown that almost all the maxillary cases have
involved the anterior regions and the majority of the man-
dibular cases have been reported in the body (about 65%)
or symphyseal areas (about 25%) (Copete et  al.  1998;
Cortell-­Ballester et  al.  2009; Resnick et  al.  2016; Flores
et al. 2017; You et al. 2017; Lima et al. 2020).
In their detailed analysis, Chrcanovic and Gomez (2019c)
identified 1237 cases where the site was recorded and only
45 (3.6%) were found in the maxilla. Of the mandibular
lesions, 26% were found anterior to the canines, and 42.8%
were located in the premolar/molar area. A further 10.3%
extended from the molar region into the angle or ramus,
and 8.4% occupied most of the body of the mandible, from
the canine region to the molars. Overall, therefore, more
than 60% of lesions occupied the posterior body (molar/
premolar area) of the mandible, with a small number
274 Pseudocysts of the Jaws: Simple Bone Cyst and Stafne Bone Cavity
extending further posteriorly or anteriorly. They also found
that 129 lesions (16.5%) crossed the midline of the mandi-
ble and 6 (0.8%) involved the coronoid process.
Occasional cases have been reported in the mandibular
condyle (Persson  1985; Rubin and Murphy  1989; Telfer
et al. 1990; Magliocca et al. 2007).
Clinical Presentation
Most simple bone cysts are found incidentally when a
patient undergoes radiological examination for another
purpose. In the case series shown in Table 17.1, three of the
studies reported that all their cases were incidental find-
ings with no clinical signs or symptoms (Cortell-­Ballester
et al. 2009: You et al. 2017; Roma et al. 2021). In the studies
that recorded clinical findings, the frequency of symptoms
was 18.3% (Lima et al. 2020) and 9.5% (Flores et al. 2017).
In their review of the literature, Lima et al. (2020) identi-
fied 25 case series that had recorded clinical findings and
found that in 9, all the cases were incidental findings on
radiology, with no clinical signs or symptoms. Of the
remaining 16 reports, signs and symptoms were found in
between 2.2% and 30.4% of patients, with an overall aver-
age of 15.2% (range 0.0–30.4%). Chrcanovic and Gomez
(2019c) found that clinical findings were recorded for 836
patients and that only 88 (10.5%) reported symptoms.
In almost all reports, the only clinical symptoms are
complaints of swelling associated with pain or tenderness.
Flores et al. (2017) found that 4 of their 42 patients were
aware of swelling, but none had pain, whereas Lima et al.
(2020) stated that 11 of their patients complained of pain or
swelling. Hansen (1974) detailed clinical findings in 61
patients and found that 44 (72.1%) were incidental findings
and only 8 (13.1%) complained of pain or tenderness. In
the remaining 9 patients the symptoms were vague and
non-­specific. No patients complained of swelling, although
on clinical or radiological examination 14 (23.0%) cases
showed some evidence of bone expansion. Howe (1965)
reviewed 60 early cases and found that 20 (33.3%) patients
reported symptoms. Of these, 16 (26.7%) had noted swell-
ing and in 2 cases this was accompanied by pain. The
remaining 4 cases reported pain alone (2 cases) or pain
with paraesthesia (2 cases).
The simple bone cyst has been thought to be caused by
trauma (see ‘Pathogenesis’), but overall only about 25% of
patients report an episode of trauma (Chrcanovic and
Gomez  2019c). In the series in Table  17.1, trauma was
recorded in 4 of the reports. The proportion of patients
reporting an episode of trauma was 28.6% (Flores
et  al.  2017), 23.8% (Cortell-­Ballester et  al.  2009), 11.7%
(Lima et al. 2020), and 7.4% (You et al. 2017). In their series
of 45 paediatric patients, Resnick et al. (2016) found that
only 6 (13.3) patients had a history of trauma.
Lima et al. (2020) identified 23 published case series that
had recorded any history of trauma and found that 5
reported that no patients could recollect a traumatic event.
The remaining 18 reports recorded trauma in between 5.0%
and 87.5% of patients, with an overall average of 22.2%
(range 0.0–87.5%).
It seems that early case reports may have been more fas-
tidious in recording possible traumatic events. In his review
of 60 cases reported between 1929 and 1963, Howe (1965)
found details of trauma in 33 (55%) cases. Of these, 11 were
sporting injuries, 5 were road accidents (including 1 hit by
a trolley car), 4 were due to falls (1 after an explosion), and
4 followed dental extraction. A further 10 cases were
recorded as miscellaneous, including a gunshot to the face,
a blow with an axe, and being trapped in swing doors.
A number of authors have noted an association with
orthodontic treatment (Copete et al. 1998; Velez et al. 2010;
Resnick et  al.  2016). Velez et  al. (2010) found that 10
(22.7%) of their patients had undergone orthodontic treat-
ment and considered this to be an important factor in the
pathogenesis of the lesion. They suggested that the ‘micro-
trauma’ associated with tooth movement may increase vas-
cular activity and osteoclast stimulation, or that a
piezoelectric affect may promote bone cavity formation
(Velez et al. 2010). In support of this hypothesis, they did
provide some evidence of a true association with orthodon-
tic treatment. They compared the incidence of orthodontic
treatment in their group of patients with simple bone cysts
to the incidence in an age-­and sex-­matched control group
without cysts. Of the cyst patients 23% had undergone
orthodontic treatment, compared with only 13% of the
matched controls.
Others suggest, however, that the association with ortho-
dontic treatment is entirely coincidental, since the peak
age of presentation of the simple bone cyst (the second dec-
ade) is the same as the age at which most adolescents have
orthodontic treatment and have radiographs taken (Copete
et al. 1998). Resnick et al. (2016) noted that all the cases in
their series were found incidentally on radiographs taken
during orthodontic treatment or routine dental care.
Routine radiology of the jaws at a young age may also be
the reason why the peak age of presentation is in the sec-
ond decade. It is possible that many lesions may remain
symptomless and undiscovered until later in life when
radiographs are taken to investigate other disorders. This
would explain the much lower prevalence in older age
groups, when routine panoramic radiographs are much
less common. This same premise may also account for the
association with trauma. Young people are more likely to
sustain a traumatic injury and undergo radiological exami-
nation, whereupon an asymptomatic lesion may be
discovered.

Although simple bone cysts often embrace the teeth, the
teeth are found to be vital in about 95% of cases (Chrcanovic
and Gomez 2019c; Lima et al. 2020).
Simple bone cysts of the long bones are one of the most
common causes of pathological fracture in children and
adolescents, and about 80% of cases present with a fracture
of the humerus or femur. In the jaws, however, pathologi-
cal fractures are very rare, and have only been encountered
in 0.6% of cases (Chrcanovic and Gomez 2019c).
Radiological Features
Most simple bone cysts are symptomless and a final diag-
nosis is made on the basis of radiological examination and
a lack of specific pathological features. This means that the
diagnosis is always made on the basis of radiology followed
by exclusion of other causes of a radiolucent cystic cavity
(Box 17.1).
The cyst appears as a radiolucent area that is well demar-
cated, with an irregular but definite margin and slight cor-
tication (Figure 17.1). The majority of lesions (85–90%) are
unilocular (Velez et al. 2010; Chrcanovic and Gomez 2019c;
Roma et al. 2021), but a scalloped margin is common and is
regarded as a characteristic feature.
The scalloped margin is at the superior aspect of the
lesion, where extensions of the cyst rise up between the
tooth roots (Figure 17.1). This feature is so characteristic as
to be regarded as almost diagnostic of the simple bone cyst.
However, it is not seen in all cases (Table 17.1). The reported
frequencies of a scalloped margin have been 72.4% (Lima
et al. 2020), 71.7% (Howe 1965), 68.2% (Copete et al. 1998),
56.7% (You et al. 2017), 31.6% (MacDonald-­Jankowski 1995),
Figure 17.1  Simple bone cyst. Radiograph shows a cystic cavity
involving an extensive area in the right body of the mandible.
This example has a well-­defined margin with cortication.
Inter-­radicular scalloping is a prominent feature, and the tooth
roots appear to ‘hang’ into the cystic cavity. The anterior margin
of the cyst is cone shaped (arrows). Source: Courtesy of Prof.
Christoffel Nortjé.
­Simple Bone Cys  275
30.8% (Flores et al. 2017), and 25.0% (Velez et al. 2010). In
their systematic review, Chrcanovic and Gomez (2019c)
found that 41.7% of 561 cases where the feature was
recorded showed scalloping. MacDonald-­Jankowski (1995)
regarded this feature as typical of the simple bone cyst and
used the wonderfully descriptive term of the tooth roots or
apices ‘hanging’ within the cavity of the cyst (Figure 17.1).
In most cases the lamina dura and periodontal space are
intact and normal, but scalloped lesions may closely
embrace the teeth, and the lamina dura may be lost
(Figure  17.1). Suei et  al. (2010) reviewed the radiological
findings of 30 cases and found that 9 (30%) had a scalloped
margin, and that in all 9 there was some loss of the lamina
dura. Conversely, 21 cases had a smooth margin and only 4
of these (19.0%) showed any loss of lamina dura. Cases
with loss of lamina dura were also larger, may show root
resorption, and were more likely to have recurred. Overall,
however, root resorption or displacement of the teeth is
very rare and has been noted in only about 1.0% of cases
(Chrcanovic and Gomez 2019c).
Another characteristic radiological feature that is almost
diagnostic of the simple bone cyst is the presence of a cone-­
shaped margin. Copete et al. (1998) described this charac-
teristic cone-­shaped morphology in 28 (63.6%) of their 44
cases. The typical shape was of a lesion that was oval or
rounded towards the posterior aspect of the mandible, but
with a cone shape at the anterior margin, with two planes
converging at a 45° angle (Figure 17.1, arrows). This mor-
phology was present in 23 (52.3%) of their cases. Two cases
showed a double cone shape, with cones projected at the
anterior and posterior margins, and three cases had ‘half-­
cones’, with a single straight edge interfacing with the
curved margin. Their remaining cases were oval (7 cases:
15.9%), irregular (7 cases: 15.9%), or round (2 cases: 4.5%).
Copete et al. (1998) also found that 22 (50%) of their cases
had a corticated margin, but of these only 6 were corticated
around the whole periphery. Lima et  al. (2020) recorded
the shape of 49 of their cases and found that 40 (81.6%)
were oval and 9 (18.4%) were cone shaped. In their system-
atic review, Chrcanovic and Gomez (2019c) found that
only 8.2% (28 of 340) of cases where the shape was recorded
were cone shaped. These data suggest that although the
cone shape may be specific to the simple bone cyst, it is
only seen in up to 10% of cases.
A number of studies have recorded the size of the lesions
and have found that it ranges from 5 to 140 mm, with an
average of 31 mm (Copete et al. 1998; Resnick et al. 2016;
Flores et  al.  2017; You et  al.  2017; Roma et  al.  2021;
Chrcanovic and Gomez 2019c). Although they may grow to
a large size, most lesions appear to expand through the
cancellous bone, often with minimal buccal or lingual
expansion. In the larger reviews or case series, the
276 Pseudocysts of the Jaws: Simple Bone Cyst and Stafne Bone Cavity
proportion that have shown expansion has been between
12% and 25% (Velez et  al.  2010; Flores et  al.  2017;
Chrcanovic and Gomez  2019c; Lima et  al.  2020), but the
images and descriptions suggest that expansion is minimal
and tends to be smooth and fusiform (Suei et  al.  2010).
Thinning of the cortical plates is commonly seen (73.6% of
cases), but perforation of the cortical plates is rare and has
been reported in less than 4% of cases (Chrcanovic and
Gomez 2019c).
Multiple Simple Bone Cysts
It has been reported that in about 5.0% of patients, sim-
ple bone cysts may be multiple or bilateral. In the case
series shown in Table  17.1, bilateral lesions were
reported in 2 cases (3.4%) by Lima et al. (2020) and in 2
cases (7.4%) by You et al. (2017). Howe (1965) reviewed
60 patients and found 1 (1.7%) who had two lesions. A
number of studies have reported multiple lesions that
have arisen in association with cemento-­osseous dyspla-
sia, but these may be a separate entity and are discussed
in the next section.
It is important to note that Chrcanovic and Gomez
(2019c), in their systematic review, excluded cases that
were associated with cemento-­osseous or fibrous dysplasia
on the basis that they behave differently. They found a total
of 1253 cysts in 1187 patients. There were 58 patients (4.9%)
with multiple cysts, of which 45 patients had two cysts,
11 had three cysts, and 2 had many cysts. They also found
that patients with multiple cysts were more often female
(71.3% vs 49.5% for solitary cysts) and older (26.6 years vs
19.7 years) and that multiple cysts were more often scal-
loped (67.1% vs 37.4%), were more likely to cause bone
expansion (36.2% vs 24.6%) and to recur or persist (12.0%
vs 3.3%).
These data support the views of Shimoyama et al. (1999)
that multiple or bilateral lesions could be regarded as a
separate type of simple bone cyst that is distinctive from
solitary lesions (Box 17.3).
Table 17.2  Age and sex distribution of simple bone cysts that have been reported to be associated
with cemento-­osseous dysplasia, from selected case series and the review of Yeom and Yoon (2020).
References Country
Horner and Forman (1988) UK
Higuchi et al. (1988) Japan
Mahomed et al. (2005) S Africa
Tong et al. (2003) China
Zillo Martini et al. (2010) Brazil
Yeom and Yoon (2020) Review
Note: The review by Yeom and Yoon (2020) incorporates some of the included case series.
Simple Bone Cyst Associated
with Cemento-­osseous Dysplasia
In 1976, Melrose et  al. described a series of cases of
cemento-­osseous dysplasia that were extensive, with mul-
tiple lesions affecting more than one quadrant, mostly in
the mandible. They introduced the term ‘florid osseous
dysplasia’ for these lesions. They presented 34 patients and
in 14 noted cystic radiolucencies that they regarded as sim-
ple bone cysts. This was the first report of a possible asso-
ciation of simple bone cysts with florid cemento-­osseous
dysplasia. Subsequently there have been a number of small
case series and single case reports (Table 17.2; Horner and
Forman  1988; Higuchi et  al.  1988; Tong et  al.  2003;
Mahomed et  al.  2005; Velez et  al.  2010; Zillo Martini
et al. 2010; Peacock et al. 2015; Yeom and Yoon 2020).
It is uncertain whether these lesions should be regarded
as simple bone cysts or as cystic change that may occur as
part of the natural history and development of cemento-­
osseous dysplasia. In this respect, it is well documented
that a number of fibro-­osseous lesions, including cemento-­
osseous dysplasia, show cystic change both on radiology
and on histological examination. Su et al. (1997a,b) under-
took a detailed analysis of 241 cemento-­osseous dysplasias
and found that about 30% showed radiolucent lesions with
well-­demarcated margins that may resemble simple bone
cysts. On histological examination, they noted that large
blood-­filled spaces are common. In a more recent review of
fibro-­osseous lesions, Eversole et  al. (2008) noted that
empty bone cavities and circumscribed radiolucent areas
are a characteristic feature of fibro-­osseous lesions, includ-
ing ossifying fibroma and cemento-­osseous dysplasia. They
noted that in florid cemento-­osseous dysplasia, these cavi-
ties may be empty, without a lining, and resemble simple
bone cyst. In large case series of cemento-­osseous lesions,
however, cystic change has not been prominent or has not
been noted as a specific feature. Cavalcanti et  al. (2018)
reviewed the cone beam computed tomography (CBCT)
n Age mean (range) Female (%)
4 36.0 (28–43) 100
4 40.5 (31–49) 100
7 42.3 (26–54) 85.7
3 57.3 (31–49) 100
3 49.7 (11–66) 100
45 43.5 (11–66) 93.3

features of 82 cemento-­osseous dysplasias, and although
their images show a number of well-­demarcated cystic
radiolucencies, they did not regard any cases as being asso-
ciated with simple bone cyst. Many of the hypodense
(lucent) lesions that they illustrated contained areas of
opacity typical of cemento-­osseous dysplasia.
Kato et al. (2020) undertook a detailed CBCT analysis of
60 cases of cemento-­osseous dysplasia involving 244 areas
of the jaws. They identified five areas that they described as
simple bone cyst, characterised as hypodense (lucent) cor-
ticated lesions that caused expansion and perforation of
the cortical bone. However, the case that they illustrated
showed a corticated hypodense area containing the roots of
a molar tooth with hypercementosis and irregular deposits
of mineralisation typical of cemento-­osseous dysplasia.
In a similar review, also of 82 cases, Pereira et al. (2016)
did not find any cases that they described as being associ-
ated with simple bone cysts. They did find, however, that
florid cemento-­osseous dysplasia typically shows multiple
radiolucent and mixed radiolucent/radiopaque areas.
Their illustrations show radiolucencies that resemble sim-
ple bone cysts, with scalloping of the margins and the
‘hanging’ roots feature. Furthermore, they showed that
early and intermediate lesions showed multiple well-­
demarcated radiolucencies and suggested that cemento-­
osseous dysplasia is a progressive disease that becomes
increasingly mineralised over time.
This progression was also shown in the original series
described by Melrose (1976). He found that 14 of his
patients had cystic radiolucencies that proved to be empty
on surgical exploration or histological examination.
Although he called these simple bone cysts, he also sug-
gested that they were a stage in the progression of the
cemento-­osseous dysplasia. He described and illustrated
progressive mineralisation of the radiolucencies over a
period of 1–29 years. On histological examination, he also
found that cases often showed ‘aneurysmally’ dilated ves-
sels and blood-­filled spaces that he thought might repre-
sent early cyst development. Other cystic spaces were lined
by a thin layer of fibrous tissue with scattered osteoclasts.
These features are in keeping with the concept that fibro-­
osseous lesions show cystic degeneration of the stroma,
either in early lesions before mineralisation (Pereira
et al. 2016) or in the stroma of later mineralised lesions (Su
et al. 1997a,b; Eversole et al. 2008). Such degeneration may
result in empty or blood-­filled spaces, often resembling sim-
ple bone cyst or aneurysmal bone cyst (van Heerden
et al. 1989; Raubenheimer et al. 2016). Raubenheimer et al.
(2016) described 18 cases (in 14 patients) of large expansile
osseous dysplasia. Of these cases, 5 were described as con-
taining simple bone cysts, but these were illustrated as
hypodense areas on computed tomography (CT) within the
­Simple Bone Cys  277
stroma of heavily mineralised lesions. Histological examina-
tion showed a variable pattern of mineralisation, but the
authors noted areas of cellular osteoid associated with resorp-
tion that created fluid-­or blood-­filled spaces that coalesced to
form empty, smooth-­surfaced cystic spaces. The authors pro-
posed that this process represented the formation of simple
bone cysts and may explain the association of bone cysts and
cemento-­osseous dysplasia. However, their illustrations sug-
gest cystic spaces within the stroma of the lesions surrounded
or lined by lesional tissue, rather than a cavity within the
bone, which is a feature of the simple bone cyst.
We would suggest that this process represents a form of
cystic degeneration that might be a common feature of
fibro-­osseous lesions generally, rather than a specific exam-
ple of an association of two different lesions. A similar pro-
cess also explains the often-­cited association between
fibro-­osseous lesions and blood-­filled cystic spaces that
have been called secondary aneurysmal bone cyst. These
almost certainly represent degenerative change and are not
true aneurysmal bone cysts, which are now known to be a
neoplasm. The term aneurysmal bone cyst should no
longer be used in the context of these secondary, reactive
changes (WHO 2022b). Aneurysmal bone cyst is discussed
in more detail later in this chapter.
Table  17.2 summarises demographic data from five
reports of simple bone cysts associated with cemento-­
osseous dysplasia, and from a review of 45 cases by Yeom
and Yoon (2020). In addition, there are reports of cysts aris-
ing within cemento-­osseous dysplasia in some of the larger
series of simple bone cysts, including 6 cases included in a
series of 44 cysts by Velez et al. (2010), 6 cases among 20
cysts by Peacock et  al. (2015), and 1 case in each of the
series of 60 and 44 cysts reported by Lima et al. (2020) and
Copete et  al. (1998), respectively. In total about 50 cases
have been reported.
The data in Table 17.2 show a different demographic of
patients to those summarised in Table  17.1. Patients
reported as having cysts associated with cemento-­osseous
dysplasia were almost all female and had an average age of
about 45 years, with a peak in the fifth and sixth decades,
compared with patients with simple bone cysts alone who
show an equal sex distribution and an average age of about
20 years, with a peak in the second decade. In reports where
the ethnicity is recorded, cases associated with cemento-­
osseous dysplasia have, almost without exception, been
reported in black females. This demographic is the same as
for cemento-­osseous dysplasia generally (Su et  al.  1997b;
Eversole et  al.  2008; Pereira et  al.  2016). A review of the
papers and of the illustrations shows that most cases have
presented as typical florid cemento-­osseous dysplasia with
multiple radiolucencies, many of which are mixed with
focal areas of mineralisation.
278 Pseudocysts of the Jaws: Simple Bone Cyst and Stafne Bone Cavity
A diagnosis of simple bone cyst is by exclusion (Box 17.1)
and most reports have recorded surgical intervention with
or without histological examination, which has demon-
strated an empty bone cavity (Horner and Forman  1988;
Higuchi et al. 1988; Tong et al. 2003; Mahomed et al. 2005;
Velez et  al.  2010; Zillo Martini et  al.  2010; Peacock
et al. 2015). Taken together, the findings of multiple radio-
lucencies and an empty cavity have been taken to confirm
a diagnosis of simple bone cyst. However, in many of the
reports, the radiolucent cystic spaces often contained foci
of mineralisation and the associated teeth showed hyperce-
mentosis. These features have been reported in most cases
of cemento-­osseous dysplasia and radiolucent, empty
cystic spaces are a consistent feature, especially in early
and developing lesions (Su et al. 1997b; Pereira et al. 2016;
Kato et al. 2020).
The largest case series of simple bone cysts associated
with cemento-­osseous dysplasia is of 23 cases reported by
Chadwick et al. (2011). This series is widely cited and often
used to confirm the association between the two lesions
and to suggest that up to one-­third of simple bone cysts
may be associated with florid cemento-­osseous dysplasia
(e.g. Raubenheimer et  al.  2017). However, care must be
taken in interpreting this report. First, it is not clear
whether Chadwick et al. (2011) reported a sequential series
of cases, or rather reported and compared selected cohorts
of 68 solitary and 23 cemento-­osseous dysplasia-­associated
cysts. Secondly, the 23 cases recorded as simple bone cysts
in cemento-­osseous dysplasia did not meet the criteria for
diagnosis (Box 17.1), but were diagnosed only on the radio-
logical findings, with no exclusion of other pathologies by
surgical intervention or histological analysis. It is possible,
therefore, that many of the multiple radiolucent lesions
reported as simple bone cysts were in fact early lesions of
cemento-­osseous dysplasia. The authors stated that histo-
logical examination was not necessary for the diagnosis of
cemento-­osseous dysplasia, but overlooked the fact that
surgical or histological examination is necessary to con-
firm a diagnosis of simple bone cyst.
Chadwick et al. (2011) suggested that simple bone cysts
associated with cemento-­osseous dysplasia are larger and
more extensive than solitary lesions because they present
later in older individuals, but they conclude that they are
similar lesions that arise in different biological circum-
stances. In both cases, however, they propose that the
underlying pathogenesis is related to a disturbance of
the normal balance of osteoblast–osteoclast function. In
the young this may be associated with remodelling of the
alveolar bone during growth and development, while in
adults with cemento-­osseous dysplasia there may be a
pathological imbalance with a common end result (see
‘Pathogenesis’).
Summary and Conclusions
These studies present a rather complex account of the
relationship between cystic radiolucencies in cemento-­
osseous dysplasia and simple bone cysts. On the one hand,
cystic areas and well-­demarcated radiolucencies are a
well-­established feature of fibro-­osseous lesions, includ-
ing cemento-­osseous dysplasia (van Heerden et  al.  1989;
Su et al. 1997a,b; Eversole et al. 2008; Pereira et al. 2016;
Raubenheimer et  al.  2016; Cavalcanti et  al.  2018; Kato
et al. 2020). These may be seen in early lesions that have
not yet mineralised or in later or large lesions that may
undergo cystic degeneration. In this respect, therefore,
these cystic spaces may not be simple bone cysts, but
merely part of the spectrum of radiological and histologi-
cal features that are seen in a variety of fibro-­osseous
lesions.
An alternative explanation is that they represent a variant
of simple bone cyst that may be seen in older individuals in
association with cemento-­osseous dysplasia as a result of a
similar pathogenic mechanism (see ‘Pathogenesis’) with a
common end result. This explanation is supported by the
observation that most of the cysts described in cemento-­
osseous dysplasia have been empty cavities with character-
istic radiological features similar to simple bone cysts in
young people (Horner and Forman  1988; Higuchi
et  al.  1988; Tong et  al.  2003; Mahomed et  al.  2005; Velez
et  al.  2010; Zillo Martini et  al.  2010; Peacock et  al.  2015).
This concept supports the proposal of Shimoyama et  al.
(1999) that the simple bone cyst takes three clinicopatho-
logical forms: simple solitary lesions, multiple lesions that
may progress or recur, and cysts in older patients associated
with cemento-­osseous dysplasia (Box 17.3).
A number of authors regard simple bone cysts associated
with cemento-­osseous dysplasia as distinctive and separate
lesions that have different clinicopathological presentation
and behaviour and should not be included in the spectrum
of ‘classic’ simple bone cyst (Chrcanovic and Gomez 2019c).
Pathogenesis
Neither the aetiology nor the pathogenesis of the simple
bone cyst is known, but there are a number of theories that
have been examined. As discussed previously (see ‘Clinical
Presentation’), it has often been stated that the lesion is
caused by trauma or may be associated with orthodontic
treatment. Although about 25% of patients report an asso-
ciated traumatic episode (Chrcanovic and Gomez 2019c) or
are undergoing orthodontic treatment (Velez et al. 2010),
these are a minority and the associations cannot be inter-
preted as causation. In particular, no studies have com-
pared the incidence of trauma among patients with simple
bone cysts with the incidence of trauma in a matched
 ­Simple Bone Cys  279

cohort of young people without cysts. It is quite possible
that the association is entirely coincidental due to the
­frequent radiological examination of young people follow-
ing trauma to the face.
With regard to orthodontic treatment, Velez et al. (2010)
did provide some evidence of a true association by showing
that 23% of their cyst patients had undergone orthodontic
treatment compared to only 13% of matched controls.
Olech et  al. (1951) first suggested that trauma was the
cause and proposed that trauma to a bone results in
intramedullary haemorrhage, which on occasion may fail
to organise and can resorb to leave an empty cystic cavity.
They suggested that cysts seem to develop only after injury
to those areas of the skeleton where cancellous bone is
enclosed in a heavy compact cortical layer. This would
explain the most frequent sites in the metaphyses of long
bones and in the mandible. It would also explain the fact
that most simple bone cysts develop in young individuals.
This proposal by Olech et  al. (1951) has never been
substantiated nor refuted and most authors still regard
some form of trauma as the most likely cause. The
breakdown of haematomas and their failure to organ-
ise, particularly if they are large, is a well-­known prob-
lem in surgery and it is perfectly conceivable that this
could occur following intramedullary haemorrhage.
Although the majority of simple bone cysts are found
at operation to be empty, the fact that some contain
blood or serosanguineous fluid tends to support the
concept of a ­h aematoma breaking down. As noted pre-
viously, cystic degeneration is a common finding in
fibro-­o sseous lesions and is often associated with
haemorrhage to produce empty or blood-­f illed cavities
resembling simple bone cyst or aneurysmal bone cyst
(van Heerden et  al.  1989; Raubenheimer et  al.  2016).
Raubenheimer et al. (2016) in particular noted areas of
cellular osteoid that were associated with resorption
that created fluid-­ or blood-­f illed spaces that coalesced
to form empty, smooth-­s urfaced cystic spaces. They
proposed that this process represented the formation of
simple bone cysts, and it is possible that a similar
mechanism may occur within an organising haema-
toma following trauma.
Shimoyama et  al. (1999) reviewed the literature and
found that there had been eight different theories about the
pathogenesis of the simple bone cyst, but these can be con-
solidated into three potential mechanisms (Harnet
et al. 2008): trauma, a disorder or imbalance in bone growth
or turnover, and degeneration of a bone lesion or tumour.
Harnet et al. (2008) regarded trauma as the most likely
and the most widely accepted cause of the simple bone
cyst. They suggested that the process first proposed by
Olech et  al. (1951), of intramedullary haemorrhage

Box 17.3  Simple Bone Cyst: Clinicopathological Variants

Solitary Cysts
●● Represent more than 90% of all simple bone cysts

●● Average age about 20 years

●● Males and females affected equally

●● More than 98% are found in the mandible

Multiple Cysts
●● Represent 5% or less of all simple bone cysts

●● Usually only two lesions and may be bilateral

●● Average age about 27 years

●● 70% are found in females

●● More than 90% found in the mandible

Cysts Associated with Florid Cement-­osseous Dysplasia

●● Frequency uncertain, but probably less than 5% of total

●● May be multiple lesions

●● Average age about 45 years

●● More than 90% are found in females

●● The vast majority reported in black females

●● Usually in the mandible, but involve more than one quadrant

●● The cysts are empty or contain fluid, but often contain focal mineralisation

●● The cysts may represent secondary degenerative changes

280 Pseudocysts of the Jaws: Simple Bone Cyst and Stafne Bone Cavity

followed by breakdown of the haematoma, is the primary Histopathology

pathogenic mechanism. They further proposed that this is
Pathological examination cannot be used to diagnose a sim-
facilitated by venous stasis that causes aseptic necrosis and
ple bone cyst, but is essential to confirm the radiological
activation of osteoclasts. Although trauma is less likely to
diagnosis and to exclude any other cause for the cystic lesion.
be involved in lesions of the long bones, Abdel-­Wanis and
When the cyst cavities are opened at operation, they are
Tsuchiya (2002) suggested that the primary event in lesions
usually found to be empty or to contain small amounts of
of the humerus and femur was obstruction of venous
blood or serosanguineous fluid. Howe (1965) reviewed 60
drainage, resulting in accumulation of interstitial fluid and
cysts and found that where the contents were recorded,
cavity formation. In the metaphyseal regions of long bones
37.5% were completely empty and 78% showed no evidence
they proposed that venous obstruction may be secondary to
of a lining. In a similar study, Hansen et al. (1974) found
a developmental error, but at other sites the aetiological
that 50% of their cysts were completely empty, 38.3% con-
factors were unknown.
tained fluid, and the remainder (11.7%) contained frag-
A developmental error, or disorder of bone growth, is the
ments of connective tissue.
second of the three possible mechanisms. This would cer-
In their systematic review, Chrcanovic and Gomez
tainly explain the common location of long-­bone lesions
(2019c) found that of 706 cases where the contents were
adjacent to the growth plates. In the mandible, Harnet et al.
recorded, 54.0% were completely empty cavities and 46.0%
(2008) suggested that this is related to development of the
contained some fluid.
mandible, but it is more likely that the alveolar bone, which
Most surgeons, when they encounter the empty cavity,
has a high rate of bone turnover and remodelling, is highly
undertake curettage of the underlying bone, which often
susceptible to an imbalance in osteoblast/osteoclast func-
appears firm and normal. If a specimen is taken for histo-
tion. Velez et al. (2010) proposed that the tooth movement
logical examination, the pathologist may receive only frag-
associated with orthodontic treatment may increase vascu-
ments of soft tissue and bone.
lar activity and osteoclast stimulation. Raubenheimer et al.
When a lining is present, histological examination shows
(2016) noted increased osteoclast activity as a factor in the
a loose, vascular fibrous tissue of variable thickness
initiation of cystic cavities in fibro-­osseous lesions, and
(Figure  17.2). There is no epithelial lining. Haemorrhage
Chadwick et  al. (2011) supported the suggestion that an
is usually present and haemosiderin pigment, foamy histi-
imbalance in osteoblast/osteoclast function initiated cyst
ocytes, and scattered small multinucleate cells may be
formation, and would explain the occurrence of simple bone
seen. The adjacent bone, when included in the specimen, is
cysts in older individuals associated with cemento-­osseous
usually normal, but may show areas of osteoid, or of
lesions. Furthermore, they and others (Mahomed et al. 2005;
resorption with osteoclasts.
Velez et  al.  2010; Peacock et  al.  2015) suggested that the
A common finding is accumulation of amorphous, often
association with older females may be due to impaired oste-
fibrillar eosinophilic material that is usually described as
oblastic activity associated with hormonal changes.
fibrin (Figure  17.3). Although it resembles fibrin,
The third proposed mechanism is degeneration of a bone
Baumhoer et  al. (2011) have shown that this material is
lesion or tumour. The idea that simple bone cysts arise as a
actually composed of collagen or the bone matrix protein
result of necrosis of an intraosseous neoplasm is no longer
considered tenable, since residual tumour or epithelial ele-
ments are never seen histologically. However, as already
discussed, cystic degeneration in fibro-­osseous lesions may
result in an empty cystic cavity that shows features of sim-
ple bone cyst.

Summary and Conclusions
As can be seen from this discussion, these three pathogenic
mechanisms have similar elements and are not mutually
exclusive. Overall, it seems that the simple bone cyst is not
a single clinicopathological entity, but can be regarded as a
spectrum with different causes although with a similar
pathogenesis and a common end result – an intraosseous
cystic cavity. This is in keeping with the concept that there
Figure 17.2  A simple bone cyst is lined by loose vascular
are three clinicopathological variants of the simple bone fibrous tissue. The underlying bone is normal, but areas of
cyst (Box 17.3). cellular bone and osteoid can be seen.

Figure 17.3  Simple bone cyst. Here the lining is thickened and
inflamed, with accumulations of macrophages and eosinophilic
fibrin-­like material. Studies have shown that this is not fibrin, but
is composed of collagens and matrix proteins (see text for details).
decorin. These authors undertook a histological and immu-
nohistochemical analysis of 51 simple bone cysts, includ-
ing 20 from the mandible. They found that 12 (23.5%)
contained deposits of hypocellular eosinophilic fibrin-­like
material. Immunohistochemistry demonstrated that in all
cases this material was negative for fibrin, but showed
expression of collagens I or III and decorin.
Treatment
Simple bone cysts are usually treated as part of the diagnos-
tic process. To determine the nature of the radiolucency, the
lesion is opened to reveal an empty cavity, as described
above. The cyst wall is then curetted causing haemorrhage
into the cavity, and in the vast majority of cases this results
in uneventful healing. It is presumed that granulation tis-
sue and eventually new bone proliferate and replace the
haemorrhage caused as a result of the surgery. In their sys-
tematic review, Chrcanovic and Gomez (2019c) found that
99.2% of all cases had been treated by surgical access only
(32.7%) or by surgical access and curettage (66.5%).
Recurrence is unusual, but many papers have reported
lesions that persist, and often do not differentiate between
recurrence and persistence. Overall, however, Chrcanovic
and Gomez (2019c) found that of 691 lesions that had been
followed up, only 32 (4.6%) persisted during a follow-­up
period of between 1 and 216 months.
­Stafne Bone Cavity
The Stafne bone cavity is not a cyst, but it appears as an
intraosseous cystic lesion on a plain radiograph. Nor can it
­Stafne Bone Cavit  281
really be called a pseudocyst, because the cystic appearance
is essentially an illusion caused by an anatomical anomaly
that produces an indentation of the lingual aspect of the
mandible. Although not strictly pathological in nature, it is
important because the cystic appearance on radiology must
be correctly interpreted and considered in the differential
diagnosis of radiolucent lesions in the mandible.
The condition was first described in 1942 by Stafne, who
reported 35 bone cavities at the angle of the mandible.
Since then the features have become well documented and
many hundreds of cases have been reported. Philipsen
et al. (2002) undertook a comprehensive review of the lit-
erature and identified 103 publications reporting 316 clini-
cal cases (including 69 of their own), and an additional 16
papers reporting 267 cases found on archaeological or
museum specimens of dried skulls. Subsequently there
have been many further single case reports and a number
of series that have examined the radiological or imaging
features (Quesada-­Gómez et al. 2006; Schneider et al. 2014;
Hisatomi et al. 2019; Morita et al. 2021).
With regard to terminology, a number of names have
been used for this lesion, including static bone cavity, static
bone cyst, static bone defect, idiopathic bone cavity or cyst,
latent bone cavity or cyst, lingual mandibular bone defect
or depression, and mandibular concavity. However, the
most widely used term pays homage to Stafne, and most
authors call it the Stafne bone cavity.
Clinical Features
Frequency
Stafne bone cavity is almost always encountered inciden-
tally during radiological examination for another purpose.
It is rarely classified as a jaw cyst and is not usually included
in reports of jaw lesions from pathology departments.
Overall the condition is not uncommon and has been
found as an incidental finding in about one in every 1000
radiographs.
Philipsen et al. (2002) reported 69 new cases from Japan that
had been found on examination of 42 600 consecutive radio-
graphs, giving a frequency of 0.16%. Others have reported
similar frequencies. Oikarinen and Julku (1974) examined
10 000 orthopantomograms and found 10 examples, a fre-
quency of 0.1%. MacDonald and Yu (2020) reviewed 6252 con-
secutive radiographs and found 3 cases (0.05%) and Assaf et al.
(2014) found 11 (0.08%) cases on review of 14 005 radiographs.
Age
The cavities are found in adults with an average age of
between 50 and 60 years (Stafne  1942; Schneider
et  al.  2014; Hisatomi et  al.  2019; Aps et  al.  2020; Morita
et al. 2021). About 65% of all cases are encountered in the
282 Pseudocysts of the Jaws: Simple Bone Cyst and Stafne Bone Cavity

fifth and sixth decades. The age range has been shown to
be 11–87 years. No cases have ever been reported in an
individual less than 11 years of age, and only about 2%
have been found in persons under 20 years (Philipsen
et al. 2002).

Sex
About 85% of cases occur in males (male : female ratio of
about 6 : 1). Philipsen et  al. (2002) reviewed 316 clinical
cases and found that 268 (84.8%) arose in males. A similar
sex distribution has been reported in other large series. In
the original report, Stafne (1942) found 28 of 34 (82.4%)
cases in men and Schneider et  al. (2014), Hisatomi et  al.
(2019), Aps et al. (2020), and Morita et al. (2021) found that
Figure 17.4  Stafne bone cavity. A dried bone specimen shows a
males were affected in 66.6%, 79.0%, 87.2%, and 70.0% of
well-­demarcated indentation in the lingual aspect of the
cases, respectively. posterior mandible. Source: Courtesy of Prof. Philip V. Tobias.

Site
Stafne bone cavities are only found in the mandible and the
vast majority are located on the lingual aspect, at the angle
of the mandible below the inferior dental (ID) canal
(Figures  17.4 and  17.5). However, cases are occasionally
seen in the anterior mandible, and very rarely in the ramus.
Philipsen et al. (2002) found that of 316 clinical cases, 270
(85.4%) were located on the lingual aspect of the posterior
mandible, 40 (12.7%) on the lingual aspect of the anterior
mandible, and 6 (1.9%) on the lingual aspect of the ramus.
Among the 267 archaeological or museum specimens that
they reviewed, they found a similar distribution (85.0%,
12.0%, and 1.5%, respectively), but also found a report of a
single case on the buccal aspect of the ascending ramus
(Shields 2000). Figure 17.5  Stafne bone cavity. A plain radiograph shows a
Posterior cases are always located below the ID canal and well-­demarcated and corticated oval radiolucency. The cavity is
below the inferior dental canal and impinges onto the lower
are associated with the submandibular gland below the
border of the mandible. Source: Courtesy of Dr Hilton Mirels.
mylohyoid muscle in the submandibular space. Anterior
cases, however, are associated with the sublingual gland
Radiological Features
and are located above the mylohyoid muscle. A more
detailed analysis of the location of the cavities and the rela- On plain radiographs the cavities appear as a round or oval
tionship to the teeth and ID canal is discussed later (see cystic radiolucency that is well demarcated, often with a
‘Radiological Features’). characteristic ‘punched-­out’ appearance (Figure  17.5).
Most cases have a smooth outline and in about 90% the
Clinical Presentation margin is partially or totally corticated (Hisatomi
Stafne bone cavities are symptomless and do not cause et  al.  2019). The appearance of an intraosseous lesion
swellings, and patients never present with clinical com- (Figure 17.5) is an illusion and on three-­dimensional anal-
plaints. However, a small number of cases in the posterior yses by CT or direct observation it can be seen that the cav-
mandible may disrupt the continuity of the lower border ity is an indentation in the lingual aspect of the mandible
and an indentation may be felt if the region is palpated (Figures  17.4 and  17.6). Mann (1992) studied 10 cases in
extraorally (Stafne  1942). Hisatomi et  al. (2019) showed dried bone archaeological specimens and prepared moulds
that 17% of cases caused a discontinuity of the lower using silicone impression material. He found that the max-
­border of the mandible, but they did not report on clinical imum dimensions ranged from 7 to 14 mm and that 7 of the
findings or whether these cases were detectable on 10 cases had a ‘mushroom’ shape, in that the internal
palpation. dimensions were greater than the opening. This feature is

clearly visible when the cavities are examined by CT or
magnetic resonance imaging (MRI) (Figure 17.6), but may
also be appreciated on plain radiographs when, apart from
the outer distinct cortication, a second inner ring can
sometimes be seen that encircles an area of more marked
radiolucency (Figure 17.5).
Examination by plain radiographs may lead to an errone-
ous diagnosis of an intraosseous lesion, resulting in unnec-
essary surgical intervention. The true nature of the cavity is
therefore best appreciated by examination using CT or
MRI, which will show that the margins are continuous
with the lingual cortical plate and the lumen opens into the
soft tissues at the lingual aspect of the mandible (Ariji
et al. 1993; MacDonald 2016; Friedrich et al. 2020; Morita
et al. 2021). MRI also enables soft tissues to be visualised
and shows that in most cases the defects contain exten-
sions of the adjacent submandibular (posterior cases) or
sublingual gland (anterior cases) (Probst et  al.  2014;
Friedrich et al. 2020). Earlier studies have used sialography
to confirm the presence of salivary tissue and in this way it
has been shown that a Stafne bone cavity located in the
posterior aspect of the ascending ramus contained lobes of
the parotid gland (Barker 1988).
CT analysis has also shown that the cavities may extend
across the full width of the mandible and may impinge on,
or even expand, the buccal cortical plate. Ariji et al. (1993)
examined 15 cases by CT and classified them into three
types. In Type I the bottom of the concavity was located in
cancellous bone and did not contact the buccal cortical
Figure 17.6  Stafne bone cavity. Computed tomography (CT)
shows the cavity to be a well-­demarcated indentation into the
lingual aspect of the mandible. Note that the internal superior–
inferior dimension is greater than than the opening.
­Stafne Bone Cavit  283
plate. Type II showed the bottom of the cavity touching the
buccal cortical plate, and in Type III the buccal cortical
plate was expanded. Six cases were Type I, 7 were Type II,
and 3 were Type III. In a similar study, Morita et al. (2021)
examined 40 cases and found that 60% were Type I and 40%
were Type II. They did not find any cases with buccal
expansion (Type III).
Aps et  al. (2020) have undertaken a detailed review of
the radiology of the Stafne bone cavity in order to accu-
rately map the location and relationships to adjacent struc-
tures (Figure 17.7). They identified 64 papers reporting 109
cases where there was sufficient detailed information to
accurately locate the defects. They found 8 patients who
had multiple cavities and in 6 cases these were bilateral. Of
the remaining 101 solitary cases, they found that 76 (75.2%)
were located in the posterior mandible, 11 (10.9%) in the
premolar region, 9 (8.9%) in the canine/incisor region, and
5 (5.0%) in the ramus. Three cases in the anterior region
crossed the midline.
Of the 76 cases that affected the posterior mandible, 29
(28.7% of the total) involved only the angle and 37 (36.6%)
only the molar region; 10 (9.9%) extended from the molar
region to the angle. All the posterior cases were located
below the ID canal, but about half of cases (50.5%)
encroached on or were contiguous with the canal. Only 3
(3.0%) cases, all in the anterior region, were seen to be asso-
ciated with a root apex and might mimic a periapical lesion.
The authors concluded that the bone cavities can arise at
any site in the mandible and drew attention to fact that on
a plain radiograph many can mimic other types of radiolu-
cent lesions. Figure  17.7 summarises the distribution of
Stafne bone cavities based on the data of Aps et al. (2020).
5%
30%
10%
35% 10%
10%
Figure 17.7  Stafne bone cavity. Site distribution of cavities
within the mandible. Source: Data from Aps et al. (2020), rounded
to the nearest 5% for clarity and to aid recall.
284 Pseudocysts of the Jaws: Simple Bone Cyst and Stafne Bone Cavity
Radiological Differential Diagnosis
Stafne bone cavities are found incidentally on radiological
investigation, but because they are simple radiolucencies, a
definitive diagnosis cannot be made on plain radiographs
alone. In early studies, the finding of a radiolucency,
­presumed to represent an intraosseous cystic lesion, led to
surgical intervention, whereupon the surgeon would find
an empty cavity that was continuous with the soft tissues at
the lingual aspect of the mandible. This would confirm the
diagnosis, but had involved an unnecessary surgical
procedure.
The majority of lesions are well-­demarcated radiolucen-
cies in the molar/angle region of the mandible and are
located below the ID canal. This appearance is typical of
the Stafne bone cavity and excludes a lesion of odontogenic
origin, since these are located in the tooth-­bearing alveolar
bone above the ID canal. When such a radiolucency is seen
incidentally on a routine radiograph, the diagnosis should
be confirmed by CT or MRI. Schneider et  al. (2014) pre-
sented an algorithm for diagnosis of the Stafne bone cavity,
in which they suggest that a unilocular radiolucency in the
posterior mandible with corticated margins and below the
ID canal is diagnostic. If these four criterion are not met,
then CBCT or MRI can be used to confirm the diagnosis by
demonstrating a lingual opening or presence of soft tissue
in the cavity. Schneider et al. state that surgical exploration
can be avoided in almost all cases by careful consideration
of the radiological findings.
If the radiolucency does prove to be intraosseous, then a
bone lesion is the likely diagnosis. A central giant cell
lesion is one of the most commonly encountered non-­
odontogenic radiolucent lesions of the jaws, but even these
are rare at this site (Chrcanovic et al. 2018). Other possibili-
ties include tumour metastases, ossifying fibroma, osteoma,
or osteoblastoma, but all are uncommon and some will
show a mixed radiolucent/radiopaque lesion. Note that the
simple bone cyst arises above the ID canal and should not
be confused with a posteriorly located Stafne bone cavity.
Anterior bone cavities are more problematic because they
arise in the tooth-­bearing areas (above the mylohyoid mus-
cle) and occasionally may be located at the apex of a tooth.
For anterior radiolucencies, therefore, a provisional diagno-
sis of an odontogenic cyst is most likely to be the first
­consideration and a final diagnosis will depend on further
imaging, but will often necessitate surgical intervention.
Pathogenesis
Early papers suggested that the bone defect was congenital
and of developmental origin, caused by entrapment or pro-
trusion of salivary tissue into the lingual aspect of the man-
dible during ossification (Fordyce  1956). However, this
Box 17.4  Stafne Bone Cavity: Key Features
●● The cavity is an indentation on the lingual aspect of
the mandible
●● Not uncommon: frequency is about 1 in every 1000
radiographs (0.1%)
●● Predominantly found in males (85%)
●● Average age about 55  years. Peak in fifth and
sixth decades
●● Symptomless and found as an incidental finding on
radiographs
●● Well-­demarcated, usually corticated radiolucency
●● More than 80% are found in the posterior mandible
●● Always below the ID canal
●● About 12% are found in the anterior mandible, above
the mylohyoid muscle
●● Rarely found (<5.0%) in the ramus
●● They contain lobules of normal salivary gland
proposal seems extremely unlikely given that the cavities
are never seen in children and have a peak age of presenta-
tion in the fifth and sixth decades. It is now generally
accepted that the defect is acquired as a result of resorption
of the bone due to pressure from a lobe of the submandibu-
lar or sublingual glands. This is supported by the observa-
tion that the cavities almost always contain salivary tissue.
If such a mechanism were to apply, then it would be
expected that the cavities might grow over time. This has
been shown by Friedrich et  al. (2020), who reported and
illustrated four cases that gradually increased in size over
periods ranging from 1 to 12 years. These authors also pro-
posed that very early lesions might manifest only as depres-
sions of the lingual cortex that would not be visible on
radiological examination. This is supported by direct exam-
ination of dried mandibles from museum or archaeological
collections that show a higher incidence of bone defects
than seen in clinical cases detected on radiology (Harvey
and Noble  1968; Philipsen et  al.  2002). It has also been
shown that larger lesions are seen in older individuals
(Oikarinen and Julku 1974).
Although pressure resorption is regarded as the most
likely cause, there have been no explanations as to how this
might happen. Some have proposed that it may be associ-
ated with vascular changes resulting in increased pressure
from the facial artery that results in cavitation into which
salivary tissue might proliferate (Lello and Makek  1985).
There is very little evidence for this, however, and it does
not explain cavities at sites away from vascular areas.
The ‘glandular hypothesis’ is therefore the most widely
accepted. Philipsen et al. (2002) suggested that inflamma-
tion and fibrosis in a salivary gland might increase the

pressure on the mandibular cortex. This theory also seems
unlikely. If it were the case that an altered texture of the
gland was necessary, then it might be expected that bone
cavities would be associated with salivary gland tumours,
and might be more commonly encountered in the ramus
adjacent to the parotid gland, where tumours are most
common. Nevertheless, local resorption over time is still
the most accepted theory and is given credence by the
observation that the surface of the bone in the depth of the
defects is irregular and shows pitting consistent with osteo-
clastic activity (Harvey and Noble 1968; Mann 1992).
Histopathology
On gross examination during surgical exploration, the
cavities contain soft tissue or may appear empty if the con-
tents are displaced by instrumentation. In either case, the
cavities are usually approached from a buccal aspect and
the surgeon will find that there is no lingual cortex and
they may have inadvertently entered the submandibu-
lar space.
Histological examination of the contents does not
­provide any diagnostic information, but may be helpful to
exclude another cause for the cystic cavity if radiological
examination has not been diagnostic.
Many early reports have reported on the contents of the
cavities and have shown that the vast majority contain lob-
ules of normal salivary gland tissue, although occasionally
only fibrous tissue or fat has been found (Philipsen
et al. 2002). Buchner et al. (1991) reviewed 24 anterior lin-
gual cases and found salivary tissue in 21 (87.5%), fat or
fibrous tissue in 2, and 1 case that was empty. The salivary
tissue is submandibular gland in posterior cavities and sub-
lingual gland in anterior cavities. Parotid gland has been
reported in the ramus (Barker 1988).
Treatment
The most appropriate management of the Stafne bone cav-
ity is to establish a correct diagnosis, after which no further
treatment is needed. In most cases the diagnosis can be
Table 17.3  Age, sex, and site distribution of focal osteoporotic bone marrow defect from the two largest case series and the review
of Reichart and Philipsen (2004).
Reference n Age mean (range)
Barker et al. (1974) 197
Shankland and Bouquot (2004) 100
Reichart and Philipsen (2004) 277
NR, not recorded.
­Focal Osteoporotic Bone Marrow Defec  285
made by careful radiological examination alone (Schneider
et al. 2014; see ‘Radiological Features’) and surgical inter-
vention is rarely needed. Although most cavities remain
static, progression has been reported, especially in younger
individuals (Friedrich et  al.  2020). Periodic radiological
follow-­up may be advisable until it can be confirmed that
the defect is static.
­Focal Osteoporotic Bone
Marrow Defect
The focal osteoporotic bone marrow defect is a cystic radi-
olucency associated with a focal proliferation or hyper-
plasia of normal haematopoietic or fatty marrow. It is
usually regarded as an anatomical anomaly that is an
incidental finding and does not require treatment.
However, it is important in the differential diagnosis of
cystic radiolucencies of the jaws, and a final diagnosis can
only be made on histological examination of the contents.
The defect was first reported by Cahn in 1954 and has
become well recognised. Most reports are single case
reports, but there have been a number of early case series
of about 20 cases (Lipani et al. 1982; Makek and Lello 1986;
Schneider et  al.  1988). The largest series, however, was
reported by Barker et al. (1974), who recorded 197 cases.
Reichart and Philipsen (2004) reviewed 277 cases and
Shankland and Bouquot (2004) added a further 100 new
cases. Table 17.3 summarises data from these three larger
studies.
Clinical Features
About 90% of the defects are found in the mandible, with
most (80%) in the molar region. Between about 70%
(Shankland and Bouquot 2004) and 85% (Lipani et al. 1982;
Schneider et  al.  1988) have been located in edentulous
areas at the site of a previous tooth extraction. They are
more frequent in females (Table  17.3) and are found in
adults with an average age of 40–50 years. Over 70% are
encountered in the fourth to sixth decades.
Female (%) Mandible (%)
41.8 (7-73) 72.9 90.9
50.1 (NR) 77.0 65.0
40.2 (25–71) 76.9 90.5
286 Pseudocysts of the Jaws: Simple Bone Cyst and Stafne Bone Cavity
The vast majority of cases have been reported as symp-
tomless and have been diagnosed after a chance finding
during radiological examination for other reasons.
However, Shankland and Bouquot (2004) noted that 57% of
their 100 patients reported tenderness on palpation, and
Makek and Lello (1986) found that 25% of their patients
had experienced pain.
Radiological Features
The focal osteoporotic bone marrow defect is a round or
oval cystic radiolucency that may be well demarcated,
but only infrequently shows evidence of cortication. The
degree of radiolucency is variable and some cases may
be difficult to visualise on a standard plain radiograph.
Cases in the mandible are always located in the alveolar
bone above the ID canal. Schneider et al. (1988) exam-
ined 20 cases and found corticated margins in only 2
(10.0%). They also found that in all cases, the normal
bony trabeculae were still visible and in 55% there were
areas of radiopacity. Barker et  al. (1974) reported that
most cases had ill-­defined borders and occasionally had
a ‘moth-­eaten’ appearance. They illustrated a number of
cases with variable shapes and borders, but most also
showed evidence of normal ­trabeculae. Most cases are
between 10 and 20 mm in maximum diameter, but
defects up to 60 mm have been reported (Schneider
et  al.  1988). Shankland and Bouquot (2004) measured
100 cases and found an average diameter of 16.2 mm
(range 5–35 mm).
Radiological Differential Diagnosis
The radiological features are so variable that the bone mar-
row defect may resemble any other type of radiolucency of
the jaws. The only reported characteristic features are the
association with a previous tooth extraction, and that the
normal trabecular structure of the cancellous bone might
still be visible within the radiolucency. Nevertheless, in
most cases surgical exploration with histological examina-
tion of the contents of the cavity is necessary to exclude
known pathological entities and to confirm the diagnosis.
Pathogenesis
The cause of these defects is not known, but the most com-
pelling explanation is of an accumulation of hyperplastic
marrow in an area of bone healing. This would account for
the fact that the defects are often found at a site of a previ-
ous tooth extraction. Other theories have suggested an
association with anaemias, where there is an increased
demand for haematopoiesis, or persistence of haematopoi-
etic marrow into adulthood.
Shankland and Bouquot (2004) discussed the possible
pathogenic mechanisms and proposed that the defect may
represent an early manifestation of osteoporosis and bone
marrow oedema, associated with ischaemia and a local
malfunction of blood flow. They suggest that local trauma
may be one factor that could initiate these changes.
Histopathology
When explored surgically, the cavities contain soft tissue
with small amounts of residual bone. In most cases histo-
logical examination shows normal haematopoietic marrow
with varying amounts of fat. Barker et al. (1974) examined
the histology of 181 defects and found that normal marrow
occupied more than half the contents in 61.3% of cases. In
38 (21.0%) cases the contents were almost entirely fat.
Shankland and Bouquot (2004) found that all cases con-
tained viable trabeculae of bone, with marrow that was
essentially normal, although 79% was fatty and only 21%
contained red (haematopoietic) elements. They also
showed that 55% of cases showed evidence of inflamma-
tion and 51% had small focal areas of ischaemia or necrosis.
Cavitational Osteonecrosis
Two research groups have reported bone cavities of the
jaws, similar to osteoporotic bone marrow defects, that are
associated with a type of aseptic osteonecrosis. Bouquot
et al. (1992) described bone cavities associated with neural-
gia and used the term neuralgia inducing cavitational oste-
onecrosis (NICO), and Lechner et  al. (2017) described
similar lesions that they called fatty degenerative osteone-
crosis in the jawbone (FDOJ).
Bouquot et  al. (1992) reported 135 patients who pre-
sented with bone cavities (224  in total) associated with
facial neuralgia. In their detailed analysis they found that
the lesions were composed of fibrosed bone marrow, with
evidence of bone or marrow necrosis and inflammation.
The average age of the patients was 49.1 years (range
24–84 years) and 66.6% were female. Cases were distrib-
uted equally between the mandible and maxilla, but the
most common sites were the mandibular molar region
(32.3% of cases) or the maxillary canine region (18.5%). The
authors regarded NICO as a localised form of chronic
osteomyelitis of the jaws, and believed that it is a form of
ischaemic osteonecrosis similar to that associated with
bone pain in other parts of the skeleton, especially the
femur or humerus (Bouquot and McMahon  2003).
Although Bouquot et al. (1992) introduced the term NICO,
they were not the first to note an association between facial
neuralgia and bone cavities. In their paper, they recorded
almost 2000 cases that had been reported between 1976

and 1991, and credited Ratner et  al. (1979) with the first
definitive description.
More recently, members of a German research group
have described similar lesions that they have called FDOJ
(Lechner et  al.  2017,  2019,  2020). They first described 24
patients with bone cavities associated with systemic immu-
nological disorders or facial pain (Lechner et al. 2017). In
this and a later study, they demonstrated that the bone
cavities showed chronic inflammation and fatty necrosis
and were almost always aseptic and associated with
increased expression of the pro-­inflammatory chemokine
CCL5 (RANTES; Lechner et  al.  2019). The lesions were
similar to the cavities described by Bouquot et  al. (1992)
and the authors suggested that NICO and FDOJ are the
same lesion. In a later paper, Lechner et al. (2020) stated
that FDOJ is also synonymous with osteoporotic bone mar-
row defect. Since the authors have provided few details
about the clinical context of this lesion, further research is
needed to establish the relationship between osteoporotic
bone marrow defects and these reported osteonecrotic
cavities.
In the absence of further research, these lesions have
never been widely accepted and, shamefully, the original
authors who described NICO have been the subject of ridi-
cule, personal abuse, and litigation (Bouquot and
McMahon 2003). A number of authors have reviewed the
controversy around NICO (Zuniga  2000; Sciubba  2009)
and have suggested that further research and clinical trials
are needed.
­Aneurysmal Bone Cyst
In previous editions of this book and in many textbooks of
oral and maxillofacial pathology, the aneurysmal bone cyst
has been included in the classification of jaw cysts, usually
categorised as a non-­odontogenic cyst or pseudocyst. It has
been described as a multicystic lesion composed of variably
sized blood-­filled spaces surrounded by vascular fibrous tis-
sue, rich in osteoclast-­type giant cells. Aneurysmal bone cysts
can arise at any site, but have a predilection for the metaphysis
­Aneurysmal Bone Cys  287
of long bones, especially the femur, tibia, humerus, and verte-
brae. Only about 1.5% arise in the jaw bones.
Aneurysmal bone cysts, including jaw lesions, have been
divided into primary and secondary types, where the sec-
ondary type arises in association with other lesions, most
often fibro-­osseous or giant cell lesions (Arora et al. 2014).
In the previous edition of this book and in the 2005 WHO
classification of head and neck tumours (Barnes
et al. 2005), the aneurysmal bone cyst was defined as pri-
mary or secondary and it was thought that most lesions
were reactive in nature. It is now known that this concept
is wrong and outdated.
Aneurysmal bone cyst has been shown to be a neoplasm
associated with rearrangements of the USP6 gene with a
wide range of fusion partners (Oliveira et  al.  2004,  2005;
Oliveira and Chou  2014; Warren et  al.  2017; Šekoranja
et  al.  2020). Specifically, primary aneurysmal bone cysts
are neoplasms that show USP6 gene rearrangements, but
so-­called secondary aneurysmal bone cysts do not show
USP6 rearrangements and should be regarded as secondary
changes in pre-­existing lesions (Oliveira et al. 2004; Arora
et  al.  2014; Flanagan and Speight  2014). True neoplastic
aneurysmal bone cyst does occur in the jaw bones, but very
few cases have yet been reported (Oliveira et  al.  2004;
Brooks et al. 2019; McMullen et al. 2019; Cleven et al. 2020).
In the fourth (2017) and fifth (2022) editions of the WHO
classification of head and neck tumours, the aneurysmal
bone cyst is defined as a cystic or multicystic, osteolytic
neoplasm associated with blood-­filled spaces lined by
fibrous septae that contain osteoclast-­type giant cells (El-­
Naggar et al. 2017; WHO 2022a; Jordan and Koutlas 2022).
Furthermore, the classification does not encompass sec-
ondary changes in other lesions and the term ‘secondary
aneurysmal bone cyst’ is no longer acceptable and should
not be used (WHO 2022a,b). Changes resembling aneurys-
mal bone cyst, seen in a variety of jaw lesions, represent
haemorrhagic cystic change and should be described sim-
ply as cystic degeneration or cystic change within the
lesion. Any reference to these features as ‘aneurysmal bone
cyst-­like’ is probably best avoided, since it may cause
­confusion with rare but truly neoplastic lesions.
288

18

Developmental Cysts

CHAPTER MENU
Classification and Terminology, 289
Dermoid and Epidermoid Cysts, 291
●● Clinical Features,  291
–– Frequency, 292
–– Age, 292
–– Sex, 292
–– Site, 292
–– Clinical Presentation,  293
●● Radiological Features,  293
●● Pathogenesis, 294
●● Histopathology, 294
●● Treatment, 295
Developmental Cysts of Foregut Origin, 295
●● Classification and Terminology,  295
Heterotopic Gastrointestinal Cyst, 296
●● Clinical Features,  296
–– Frequency, 296
–– Age, 297
–– Sex, 297
–– Site, 297
–– Clinical Presentation,  298
●● Histopathology, 298
●● Treatment, 298
Bronchogenic Cyst, 298
●●Clinical Features,  299
●●Histopathology, 299
●● Treatment, 300
Branchial Cleft Anomalies, 300
Branchial Cleft Cysts, 300
●● Clinical Features,  300
–– Frequency, 300
–– Age and Sex,  300
–– Site, 300
–– Clinical Presentation,  301
●● Histopathology, 301

●● Differential Diagnosis,  303

–– Differentiation of Branchial Cleft Cyst from Cystic Metastatic Carcinoma,  305
●● Treatment, 305

Thyroglossal Duct Cyst, 305

Shear’s Cysts of the Oral and Maxillofacial Regions, Fifth Edition. Paul M. Speight.
© 2022 John Wiley & Sons Ltd. Published 2022 by John Wiley & Sons Ltd.

●● Clinical Features,  305
–– Frequency, 305
–– Age, 305
–– Sex, 306
–– Site, 306
–– Clinical Presentation,  306
●● Histopathology, 307
–– Differential Diagnosis,  307
●● Treatment, 308
Nasopharyngeal Cysts, 308
Thymic Cyst, 308
The development of the head and neck commences at
about the third week of intrauterine life, when the three
germ cell layers form the trilaminar embryonic disk that
subsequently undergoes a complex process of three-­
dimensional folding to form the developed embryo
(Nanci 2017). In this way, the three germ cell layers become
orientated to form the internal and external structures of
the fully developed human. A crucial process in the head
and neck region is the formation of the branchial or phar-
yngeal arches, which give rise to the facial processes that
eventually migrate and fuse to form the eyes, ears, jaws and
mouth, and associated structures. Aberrations in these pro-
cesses give rise to many facial developmental anomalies.
Developmental cysts of the head and neck are mostly
congenital and are present at birth, although some grow
slowly and remain occult for many years, with clinical
presentation in childhood or adolescence, and occasionally
in later adulthood. The majority of these cysts are formed
due to entrapment of ectoderm or endoderm during fusion
of the facial processes, or incomplete obliteration of the
branchial clefts or pouches. All developmental cysts are
rare, but the most commonly encountered cyst, constitut-
ing about 50%, is the thyroglossal duct cyst, followed by
branchial cleft cysts (about 20%). Other lesions are very
rarely encountered.
The classification of developmental cysts of the head and
neck is difficult and complex (see next section), but in the
maxillofacial regions they cause clinical problems in two
main areas related to their site of origin. Many arise in the
midline and often present clinically as swellings in the
upper neck, in the sublingual space, or in the tongue. In
neonates these cysts may be associated with obstruction of
the airway and require urgent attention, while in children
and adolescents they must be considered in the differential
diagnosis of swellings affecting the floor of the mouth
and tongue.
The second area of difficulty is cysts presenting in the
lateral neck (branchial cleft cysts), which are usually
benign but can cause considerable diagnostic problems,
­Classification and Terminolog  289
especially in adult patients when they must be distin-
guished clinically and histologically from metastatic carci-
noma. In adults, most neck swellings are caused by lymph
node enlargement of one sort or another, with neoplastic
disease being more likely with increasing age. Of cystic
neck lesions metastatic carcinoma is, overall, probably the
most common lesion encountered in adults. The relative
frequency and differential diagnosis of cysts of the neck
have been reviewed by Luna and Pfaltz (2009).
­Classification and Terminology
The literature and terminology relating to the develop-
mental cysts of the oral and maxillofacial regions are com-
plex and reflect their rarity and our lack of understanding
about their pathogenesis. A particular area of confusion is
the terminology relating to dermoid cysts, epidermoid
cysts, and teratomas. Much of the head and neck literature
uses ‘dermoid’ as a generic term to refer to developmental
cysts in the floor of the mouth that are lined by stratified
squamous epithelium. The ‘sublingual dermoid’ is often
divided into three variants, as originally suggested by
Meyer (1955), who had recognised the confusion around
these lesions and noted that many different names and
classifications had been used. He suggested that, as a
group, the developmental cysts in the floor of the mouth
should be called ‘dysontogenic cysts’, which literally
means cysts formed by a disorder of development. He
divided them into three types based on the histological
features: epidermoid cyst, lined by stratified squamous epi-
thelium with no evidence of appendages; dermoid cyst,
lined by epithelium with skin appendages including hair
follicles and sebaceous or sweat glands; and teratoid cyst,
lined by stratified squamous epithelium with appendages,
but also with connective tissue elements and respiratory-­
or gastrointestinal-­type epithelium.
Although this terminology is still widely used, many
papers still refer to the sublingual dermoid cyst as
290 Developmental Cysts
encompassing cystic lesions with any of these features.
However, the teratoid cyst is often also interpreted to mean
teratoma. Although Meyer (1955) defined the teratoid cyst
as having elements from all three germ cell layers, the case
he illustrated was lined by skin-­type and respiratory-­type
epithelium, but the connective tissue element was normal
for the site and not heterotopic. A true teratoma is defined
as a germ cell neoplasm (Smirniotopoulos and
Chiechi 1995), and the vast majority (about 90%) arise in
the gonads or sacral regions and show lines of differentia-
tion representing all three germ cell layers (ectoderm, mes-
oderm, and endoderm). They are often multicystic and are
lined by epithelium of ectodermal (skin-­type) and endo-
dermal (respiratory-­ or gastrointestinal-­type) origin, but
also show mesodermal structures, including cartilage,
bone, neural elements, and sometimes fully formed teeth.
Although they are often well formed, the connective tissue
elements are heterotopic in that they are located away
from their normal anatomical site. Teratomas can be
divided into mature types that are usually benign, and
immature malignant types (Smirniotopoulos and
Chiechi 1995).
True teratomas do arise in the head and neck
(Smirniotopoulos and Chiechi  1995; Lopes et  al.  2005;
Shah et al. 2009; Tonni et al. 2010; Morlino et al. 2015) and
are found within the cranium, oropharynx, nasopharynx,
or in the midline of the neck. Most are diagnosed in utero
or at birth and the cervical region is most commonly
affected. Oropharyngeal and jaw lesions are the second
most common and are often referred to as ‘epignathus’.
Morlino et al. (2015) recorded reports of only 48 oropharyn-
geal (including the nasopharynx) cases between 1931 and
2013; 32 (66.6%) of the cases were diagnosed in utero or at
birth. Lopes et  al. (2005) reported a mass in the buccal
mucosa in a 9-­year-­old girl, which comprised stratified
squamous epithelium with appendages, respiratory epithe-
lium, and heterotopic mesodermal elements, including
bone and neuroglial tissue. In a review of the literature the
authors found only 21 previously recorded cases within the
oral cavity; 13 (61.9%) arose in the tongue and the remain-
der (38.1%) were found in the palate, although two showed
pharyngeal extension. All cases were diagnosed in utero or
at birth and all were located in the tongue or palate and in
the midline. Their own case was the only case reported
arising in childhood and was the first in the buccal mucosa.
Subsequently a second case arising in the cheek of a neo-
nate has been reported (Singh et al. 2012).
From this brief discussion it can be seen that true terato-
mas of the maxillofacial regions do occur, but they are rare
and are very unlikely to be encountered after birth. Teratoid
cysts, on the other hand, have often been reported as part
of the spectrum of ‘dermoid’ cysts, but these should not be
regarded as teratomas. Most reports of teratoid cysts illus-
trate cysts lined by a mixture of stratified squamous epithe-
lium and respiratory or gastrointestinal epithelium.
Because these are of ectodermal and endodermal origin,
respectively, it has often been stated that these cysts show
tissue derived from two germ cell layers and thus represent
a type of mature teratoma. For this reason, the terms tera-
toid and teratoma have on occasion been used synony-
mously. Similarly, the dermoid cyst, which shows skin-­type
epithelium with appendages at a heterotopic site (e.g. the
tongue), has been called a type of mature teratoma. A num-
ber of reports have also shown that a dermoid cyst may be
lined by more than one type of epithelium. Furthermore,
foregut cysts, which take their origin from foregut epithe-
lium of endodermal origin, may also show a mixed epithe-
lial lining. For these reasons, some regard all these cyst
types as variants of mature teratoma and use ‘dermoid’ as a
generic term to encompass all cysts in the sublingual region.
A further cause of confusion is the epidermoid cyst.
This cyst is lined by stratified squamous epithelium with-
out appendages and in the context of the oral cavity it is
clinically indistinguishable from a dermoid cyst. Both are
regarded as developmental cysts, but the epidermoid cyst
is histologically similar to the common type of cutaneous
cyst that is often called the ‘sebaceous cyst’. Clinicians fre-
quently use ‘sebaceous’ as a descriptive name for any type
of simple skin cyst, but the term should not be used by
pathologists or as a diagnosis. There are many types of
cutaneous (adnexal) cyst, the most common of which is
an inclusion cyst that arises in the superficial or infun-
dibular part of the hair follicle and should be called the
epidermal cyst, epidermal inclusion cyst, or infundibular
cyst (Kaya and Saurat  2018). Other common types of
adnexal cyst are the tricholemmal cyst (arising from the
outer root sheaf of the hair follicle) and the true seba-
ceous cyst, which is properly called the steatocystoma.
Confusion arises because the common epidermal cyst is
often called epidermoid cyst, and a number of early pub-
lications have included the ­common cutaneous acquired
epidermal cyst as a developmental cyst of the oral regions
and have occasionally ­categorised it alongside der-
moid cysts.
Branchial cleft cysts are more clearly defined, since they
take their origin from the branchial clefts and are always in
the lateral neck. Although histologically they may be simi-
lar to other developmental cysts, their distinctive clinical
features mean that they are unlikely to be confused with
other cyst types.
In this chapter we make a clear distinction between the
developmental cysts that arise most commonly in the
tongue or floor of the mouth and the common epidermal
inclusion cysts of the skin. Although these commonly arise
 ­Dermoid and Epidermoid Cyst  291

on the skin of the face, they are acquired and are not con-
sidered here. Readers are referred to reviews (e.g. Kaya and
Saurat  2018) or to standard dermatopathology texts for
details of these common skin lesions.
We also make a distinction between dermoid and epider-
moid cysts, and teratomas. We regard teratomas as germ
cell neoplasms that occasionally may arise in the head and
neck or oral cavity, but are distinct from the developmental
cysts discussed here. Teratoid cysts are poorly defined, but
most reports describe a cyst lined by two types of epithe-
lium, and we would regard these as histological variants of
dermoid cysts or foregut cysts. Although occasionally these
may be histologically similar to a mature teratoma, they are
distinctive in their clinical presentation, and teratoma
should only be diagnosed if there is clear evidence of tis-
sues derived from all three germ cell layers, including het-
erotopic connective tissue elements. True teratomas in the
head and neck usually include well-­formed cartilage, bone,
and neuroectodermal or neuroglial tissues (Smirniotopoulos
and Chiechi 1995; Lopes et al. 2005; Shah et al. 2009; Tonni
et al. 2010).
From the forgoing discussion it is clear that there is great
overlap in the clinical and histological features of the
developmental cysts and a simple classification is not pos-
sible. Here we distinguish the cysts primarily by their clini-
cal characteristics and histological features. Boxes 18.1–18.4
summarise the key features of the most commonly encoun-
tered lesions.
­Dermoid and Epidermoid Cysts
Dermoid and epidermoid cysts are developmental cysts
that can occur at any site in the body. The majority are con-
genital and are found in the gonads or the sacral region. In
one of the largest studies, Taylor et al. (1966) reviewed 514
cases from the Mayo Clinic and found 184 (35.8%) in the
head and neck region, of which only 35 (6.8% of the total)
were located in the floor of the mouth. Most head and neck
lesions are found at the lateral aspect of the eyebrow at the
site of fusion of the zygomatofrontal suture (Taylor
et  al.  1966; Pollard et  al.  1976; Smirniotopoulos and
Chiechi 1995). Dermoid and epidermoid cysts are develop-
mental cysts arising from entrapped ectodermal tissue and
are lined by stratified squamous epithelium with (dermoid
cyst) or without (epidermoid cyst) skin appendages. Apart
from these histological differences, the cysts are indistin-
guishable and are usually considered together (Box 18.1).
Because they represent a developmental disorder they are
sometimes referred to as dysontogenic cysts.
Clinical Features
Most reports of these cysts are single case reports or small
case series. King et  al. (1994) reviewed the literature and
found 195 fully documented floor-­of-­mouth cases. More
recently, MacNeil and Moxham (2010) found 198 floor-­of-­
mouth cysts, but only included cases where there was

Box 18.1  Dermoid and Epidermoid Cysts: Key Features

Significance and
Pathogenesis Clinical features Histopathology differential diagnosis

Epidermoid cyst Entrapment of Third most common (12%) Lined by stratified Sublingual swellings
ectoderm during developmental cyst in the squamous epithelium may cause airway
fusion of the man- head and neck without appendages obstruction and
Dermoid cyst dibular processes Only 0.2% of oral lesions Lined by stratified difficulties with
arising from the first
Mean age about 35 years, squamous epithelium feeding and speech
branchial arch with peak in second to with appendages, Must be differenti-
fourth decades including sebaceous ated from other
Equal sex distribution glands, sweat glands, or lesions that may
Located in the floor of hair follicles arise in the sublin-
the mouth gual/tongue region,
Teratoid cyst A variant of dermoid Lined by stratified
Cause sublingual (50%) or including ranula,
and epidermoid cyst, squamous and
submental (45%) swelling, foregut cysts,
but with concurrent respiratory or gastroin-
occasionally in anterior thyroglossal duct
entrapment of testinal epithelium
tongue or submandibu- cyst, and salivary
endodermal elements.
lar region gland tumours
Some may be fore-
gut cysts
292 Developmental Cysts
information about treatment. Santos et  al. (2020) and
Misch et al. (2020) added 27 and 12 new cases, respectively,
to the literature. Lesions have also been reported in the
tongue. Campbell and Walker (2010) found 12 reports of
dermoid cyst in the tongue, and Ueno et al. (2018) reviewed
13 cases of epidermoid cyst.
Frequency
Dermoid and epidermoid cysts are the third most common
congenital cyst affecting the head and neck region, consti-
tuting about 12% of the total (Al-­Khateeb and Al Zoubi
2007; Brucoli et  al.  2020). Thyroglossal duct cyst and
branchial cleft cyst are the first and second most common,
respectively.
Nevertheless, they are still relatively rare and represent
less than 0.2% of maxillofacial lesions. Santos et al. (2020)
found 27 (0.17%) cases among a total of 15 387 maxillofa-
cial biopsies. Of these, 14 (0.09%) were dermoid cysts and
13 (0.08%) were epidermoid. In the Sheffield series, Jones
and Franklin (2006a,b) found only 27 (0.06%) dermoid
cysts reported from a total of more than 48 000 head and
neck specimens over a 30-­year period. The lesion was
more common in children, with 8 (0.2%) cases identified
among 4406 specimens (Jones and Franklin 2006b) com-
pared with only 19 (0.04%) cases in adults (n  =  44 007;
Jones and Franklin 2006a). In a review of 10 311 oral biop-
sies, Nonaka et  al. (2011) found 12 (0.1%) epidermoid
cysts and 6 (0.05%) dermoid cysts. For comparison, these
frequencies are similar to nasolabial cyst and simple
bone cyst.
Age
Although these cysts are congenital, they grow slowly and
may enlarge over years or decades and not become clini-
cally apparent until late adolescence or adulthood
(Smirniotopoulos and Chiechi  1995). Most dermoid and
epidermoid cysts occur in the second to fourth decades.
Santos et al. (2020) found that dermoid cysts presented at
an average age of 37.2 years (n = 14; range 1–81 years) and
epidermoid cysts at 38.2 years (n  =  13; range
11 months–82 years). Longo et al. (2003) reported 16 cases
with an average age of 27.8 years (range 5–51 years). In
their review of 198 cases, MacNeil and Moxham (2010)
found that 66.0% arose in adults over the age of 16, 20%
were in children, and 14% were in neonates (<1 year).
There is some evidence that lesions in the body of the
tongue may present at an earlier age than floor-­of-­mouth
lesions. Campbell and Walker (2010) reviewed 12  lingual
dermoid cysts and found an average age of 8.8 years (range
2 months–17 years), and Ueno et al. (2018) reported 13 lin-
gual epidermoid cysts with an average age of 18.0 years
(range 4 months-­45 years).
Sex
Overall, dermoid and epidermoid cysts seem to have a
slight predilection for males, but there are varied reports.
King et al. (1994) recorded 61% of lesions in males and 39%
in females (n  =  124), and MacNeil and Moxham (2010)
found 58.0% in males (n = 188). Longo et al. (2003) reported
that 12 (75.0%) of their 16 cases were in males. In their
series of 27 cases, however, Santos et  al. (2020) found 18
(66.6%) in females. They also noted a higher female predi-
lection for dermoid cysts, where 10 of 14 (71.4%) cases
arose in females. Among paediatric cases, Misch et  al.
(2020) also showed a female predilection of 66.6% (8 of 12
cases). For cases in the tongue, Campbell and Walker
(2010) found that 58.3% were female, while Ueno et  al.
(2018) reported that 61.5% were male.
Site
For oral lesions, the midline of the floor of the mouth is the
most common location (Figure 18.1). At this site they may
cause an intraoral sublingual swelling or an extraoral sub-
mental swelling or both. Meyer (1955) noted that floor-­of-­
mouth lesions are always located above (deep or lingual to)
the mylohyoid muscle, but may be found above or below
the geniohyoid muscle. If above the geniohyoid, the cyst is
located between the genioglossus and geniohyoid muscles
and presents primarily as a sublingual swelling in the floor
of the mouth. Conversely, if the cyst is below the geniohy-
oid, it is located between the geniohyoid and mylohyoid
muscles and presents primarily as an extraoral swelling in
the submental region.
King et  al. (1994) reviewed 195 case reports and noted
that some cases might penetrate the mylohyoid muscle and
occupy the sublingual and submandibular spaces concur-
rently. They found that 52% of cases were recorded as
­sublingual, 26% as submental, and 6% as submandibular.
The remaining cases (16%) occupied more than one space.
In their similar review of 198 case reports, MacNeil and
Moxham (2010) showed that 52.5% were reported as sub-
lingual, 40.5% as submental, 18.2% as submandibular, and
11.6% as mixed.
Almost all cases have been reported in the midline of the
floor of the mouth or submental region, but occasionally a
cyst may have a lateral location. Teszler et  al. (2007)
reported two cases that presented as submandibular swell-
ings in the lateral aspect of the upper neck. One case was
located in the lateral floor of the mouth deep to the mylo-
hyoid muscle in the sublingual space, but close to the deep
lobe of the submandibular gland. The second case was
located superficial to the mylohyoid muscle in the subman-
dibular space. Lateral cysts appear to be rare and probably
represent less than 5% of the total reported. Teszler et al.
(2007) noted only 12 reported cases, but MacNeil and

Moxham (2010) suggest that there have been about 36
cases reported. However, most authors consider that later-
ally located cysts are midline cysts that have become dis-
placed and bulge over the posterior aspect of the mylohyoid
muscle to enter the submandibular space. It is also possible
that some lesions reported in the upper neck are
branchial cysts.
As suggested above, the vast majority of these develop-
mental (dysontogenic) cysts arise in the sublingual region,
but cases have been reported at other sites in the oral cavity.
Most of these have been reported in the body of the tongue
(Campbell and Walker  2010; Ueno et  al.  2018). They are
found in the mobile anterior two-­thirds of the tongue and
present as firm swellings about 15 mm in diameter,
although cases up to 70 mm have been reported (Campbell
and Walker 2010). Ueno et al. (2018) reviewed 13 cases of
epidermoid cyst in the body of the tongue, but noted that
some cases might be acquired as a result of trauma and
implantation of surface epithelium into deeper tissues.
This might apply especially to cysts on the ventral tongue
in older individuals.
Santos et al. (2020) presented 27 new cases and showed
that only 10 (37.0%) were located in the floor of the mouth.
These were 6 dermoid cysts and 4 epidermoid cysts. They
also found 6 dermoid cysts in the lip and 2 on the gingiva or
alveolus. Of the 9 epidermoid cysts, 2 were found on the
gingivae, 3 on the plate, 2 in the tongue, and 2 in the buc-
cal mucosa.
There have been a number of reports of intraosseous der-
moid cysts in the mandible. Issa and Davies (1971) recorded
an exceptionally rare example of a dermoid cyst that
occurred in the coronoid region of the mandible in a
26-­year-­old woman, and Craig et  al. (1980) reported an
intraosseous dermoid cyst in the midline of the mandible
in a 28-­year-­old man. However, the diagnosis was made on
the basis of finding sebaceous glands associated with a lin-
ing of ortho-­ and parakeratinised stratified squamous epi-
thelium. It is possible that these cysts actually represented
sebaceous metaplasia in an odontogenic cyst. Sebaceous
glands have been found in occasional odontogenic kerato-
cysts (Brannon, 1977; discussed in Chapter 7) and Chi et al.
(2007) reported 5 cases of orthokeratinised odontogenic
cyst with focal areas of sebaceous glands (discussed in
Chapter 12). Although these might be regarded as dermoid
cysts, Chi et al. (2007) found that all 5 showed clinical and
radiological features typical for an odontogenic cyst, and
they strongly argued that they should be regarded as
orthokeratinised odontogenic cysts with focal sebaceous
differentiation. Vuhahula et al. (1993), however, suggested
that a true dermoid cyst can be found within the bone.
They examined 12 orthokeratinised jaw cysts and found 2
that contained sebaceous cells. In the first the sebaceous
­Dermoid and Epidermoid Cyst  293
cells were focal and few in number and the authors inter-
preted it as an odontogenic cyst with sebaceous metaplasia.
The second cyst was unusually large and had prominent
sebaceous glands, as well as other dermal appendages
including hair follicles and sweat glands. This cyst was
diagnosed as an intraosseous dermoid cyst.
Clinical Presentation
The most common presentation is of an intraoral sublingual
swelling that lifts the tongue (Figure 18.1) and may lead to
difficulty in speaking, eating, breathing, or closing the
mouth. Deeper lesions between the geniohyoid and mylohy-
oid muscles produce a submental swelling in the neck, giv-
ing the patient a ‘double-­chin’ appearance. The swelling
may feel doughy or fluctuant. Lesions presenting at birth can
obstruct the airway and be life threatening. However, this is
rare, and most cysts grow slowly and present in childhood or
adolescence. Santos et  al. (2020) found that patients had
been aware of a lesion for up to 25 years, but with an average
duration of 53.3 months (range 1–300) for dermoid cysts and
45.7 months (range 2–120) for epidermoid cysts.
As noted previously (see ‘Site’), the cyst may occasionally
present as a swelling in the anterior, mobile part of the
tongue or in the submandibular region. Lesions at other
sites, including the buccal mucosa, palate, and gingiva,
have been reported but are rare.
Radiological Features
Radiology plays little role in diagnosis, but imaging is
important for surgical planning and to confirm the cystic
nature of the lesion. Ultrasound can be used to identify the
lesions as cystic, but they are best visualised using mag-
netic resonance imaging (MRI), which shows the extent of
the lesion and the relationships to mylohyoid and
Figure 18.1  Dermoid cyst. The cyst fills the floor of the mouth
and has raised the tongue.
294 Developmental Cysts

geniohyoid muscles and adjacent structures. The cyst Histopathology

appears as a well-­demarcated, round or oval, hypointense
When removed intact, the cysts appear as firm, rounded
(lucent) lesion. T2-­weighted images show a markedly
masses. On dissection they often have a thick wall and con-
hyperintense (white) lesion, suggesting fluid contents. The
tain keratinaceous material similar to epidermal cysts of
cysts range in size from 5 to 70 mm, but the overall average
the skin. Dermoid cysts contain appendages and may show
is about 30 mm (Santos et al. 2020).
areas of thickening.
Both dermoid and epidermoid cysts are lined by kerati-
nised stratified squamous epithelium resembling epider-
Pathogenesis mis, but are distinguished by the fact that dermoid cysts
The origin of dermoid and epidermoid cysts, like other have skin appendages.
developmental cysts, is controversial. They are lined by Dermoid cysts are lined by stratified squamous epithe-
epithelium of ectodermal origin, suggesting that they arise lium, usually without rete pegs, but with prominent
due to abnormal sequestration of epithelium during fusion orthokeratinisation. By definition, the dermoid cyst con-
of the facial processes (Smirniotopoulos and Chiechi 1995). tains skin appendages and sebaceous glands, sweat glands,
With regard to oral lesions, these are found in the anterior or hair follicles may be seen (Figures 18.2 and 18.3). Santos
aspect of the oral cavity in the floor of the mouth or ante- et al. (2020) described the histopathological features of 14
rior tongue, consistent with entrapment of epithelium of dermoid cysts and found that 12 (85.7%) contained hair fol-
ectodermal origin during fusion of the mandibular pro- licles, 12 (85.7%) had sebaceous glands, and 4 (28.6%) had
cesses, which take their origin from the first branchial sweat glands.
arches (Adams et al. 2016; Nanci 2017). Epidermoid cysts are lined by flattened stratified squa-
A number of cysts have been described that are lined by mous epithelium without adnexal structures. Oral lesions
epithelium of ectodermal (skin-­type) and endodermal (res- are similar to epidermal cysts of the skin and may be filled
piratory-­ or gastrointestinal-­type) origin. These are often with lamellae of desquamated keratin.
referred to as teratoid cysts. As the primitive mouth (sto- Occasionally, cysts may be encountered that are lined by
modeum) develops, it is separated from the developing two types of epithelium. These are termed teratoid cysts
foregut by a bilaminar membrane (the buccopharyngeal and are the rarest of the developmental cysts of the oral
membrane) formed by apposed ectoderm and endoderm. cavity. These were originally described by Meyer (1955)
At about 32 days of intrauterine life, the membrane breaks and were defined as showing two types of epithelium and
down so that the oral cavity communicates directly with connective tissue elements. King et  al. (1994), in their
the foregut and there is probably a considerable amount of review of 195 case reports of ‘dermoid’ cysts of the floor of
intermingling of ectoderm and endoderm. It is possible
therefore that occasional dermoid or epidermoid cysts may
include heterotopic elements of endoderm derived from
the foregut, and this may explain why some cysts are lined
in part by respiratory, gastric, or intestinal epithelium. It is
these cysts that have been referred to as ‘teratoid’. Foregut
cysts, discussed later in this chapter, also take their origin
from heterotopic endodermal elements within the tongue.
Cysts similar to the developmental epidermoid cysts
under discussion may also be acquired and arise as a result
of inclusion or implantation of epithelium as a result of
trauma. Common cutaneous epidermal cysts arise as a
result of inclusion of epithelium following trauma, infec-
tion, or blocked hair follicles. It is possible that some epi-
dermoid cysts in the oral cavity may also be acquired as a
result of implantation of epithelium following trauma
(Smirniotopoulos and Chiechi 1995). Epidermal inclusion
cysts may arise on the lips, but Ueno et al. (2018) also sug-
gested that tongue lesions may be caused by trauma. They
presented a small epidermoid cyst on the ventral aspect of Figure 18.2  Low-­power view of a dermoid cyst. The cyst lies
just below the mucosa of the floor of the mouth (arrow) and is
the tongue, lateral to the midline, that they felt may have lined mostly by flattened stratified squamous epithelium. Skin
been acquired following trauma. appendages are noted at the deep aspect (see Figure 18.3).

Figure 18.3  High-­power of part of the cyst seen in Figure 18.2. The lining is orthokeratinised and well-­formed hair follicles and
sebaceous glands can be seen.
the mouth, found that 72.9% were diagnosed as dermoid
cysts, 22.2% as epidermoid cysts, and only 4.9% as teratoid.
This suggests that cysts with multiple phenotypes are
rare. However, most cases reported as teratoid in the litera-
ture have shown stratified squamous epithelium and
another epithelium, but no evidence of heterotopic con-
nective tissue elements. Many cases show muscle or sali-
vary tissue in the wall, but these are normal for the site of
occurrence of the lesion. Crivelini et al. (2001) reported a
cyst lined by gastrointestinal epithelium and typical der-
moid cyst epithelium, and in their report of 14 cases of der-
moid cysts, Santos et al. (2020) found 2 (14.3%) cases with
areas of respiratory epithelium and 1 (7.1%) with gut epi-
thelium. Alsharif and Zhao (2009) reviewed 101 cysts in
the floor of the mouth and found that 33  were dermoid
cysts, 48 were epidermoid cysts, and 20 were described as
teratoid. Histological details were not given for all lesions,
but they were described as being lined partly by stratified
squamous epithelium and partly by gastric or intestinal
epithelium. The authors also reviewed the literature and
found 15 cases reported between 1959 and 2007. The major-
ity were described as simple cysts and only 3 of the total of
35 cases recurred.
We would regard these cysts as simple variants of dermoid
or epidermoid cysts. As discussed previously (see
‘Classification and Terminology’), care must be taken not to
overdiagnose these as true teratomas. Nevertheless, true tera-
tomas do on occasion arise within the oral cavity (Lopes
et  al.  2005; Shah et  al.  2009; Tonni et  al.  2010; Morlino
et al. 2015). There are also cases reported as teratoid cysts that
do include connective tissue elements and thus may be true
mature teratomas (Harada et  al.  1995; Bonilla et  al.  1996).
From these reports, it can be seen that occasionally, it may
­Developmental Cysts of Foregut Origi  295
not be possible to make a clear distinction between a dermoid
cyst with focal areas of another epithelial type and a benign
mature teratoma. It should be noted, however, that true tera-
tomas contain obvious heterotopic connective tissue ele-
ments and are diagnosed in utero or at birth.
There are a number of reports of simultaneous occur-
rence of dermoid cysts in association with another type of
developmental cyst. These appear to arise in the floor of
the mouth as well as at other sites, including the pancreas,
spleen, and mediastinum. The entrapment during develop-
ment of pluripotential cells may allow for different path-
ways of differentiation at the same site, or multiple cysts
may arise concurrently from entrapped epithelium from
different sources. In the floor of the mouth, dermoid cysts
have been described in association with gastrointestinal
cysts (Eppley et  al.  1985; Arcand et  al.  1988; Crivelini
et al. 2001; Ho and Crean 2003; Şimşek-­Kaya et al. 2018;
Robinson et  al.  2021), bronchogenic cysts (Obiechina
et al. 1999; Gleizal et al. 2006), and lymphoepithelial cysts
(Ahn et al. 1996; Epivatianos et al. 2005).
Treatment
Treatment of epidermoid and dermoid cysts of the soft tis-
sues is by surgical excision.
­Developmental Cysts of Foregut Origin
Classification and Terminology
Developmental cysts of the alimentary tract are relatively
common, with an overall incidence of about 1  in 4500
births and a prevalence in children of 0.2% (reviewed by
296 Developmental Cysts
Sangüesa Nebot et  al.  2018). Mostly they are formed by
errors in the development of the notochord, when strands
or islands of endoderm are sequestered during folding of
the notochordal plate and become separated from the
developing gastrointestinal tract. These isolated cells then
give rise to alimentary tract or enteric duplication cysts,
which are found in the midline along the axis of the noto-
chord at any site along the gastrointestinal tract from the
mouth to the rectum (Sangüesa Nebot et al. 2018). Although
usually referred to as cysts, about 20% are tubular struc-
tures and rarely they may present as diverticulae. Enteric
duplication cysts are characterised by three elements: a lin-
ing of epithelium of endodermal origin (gastrointestinal or
respiratory), an envelope of smooth muscle, and a close
attachment to the associated gastrointestinal tract. In most
cases, the lining of the cyst is the same as the associated
adjacent normal gastrointestinal structure. Most duplica-
tion cysts (about 35%) affect the small intestines, but over-
all about one-­third are associated with the foregut.
The developing foregut is separated from the stomodeum
by the buccopharyngeal membrane, which breaks down at
about 32 days of intrauterine life so that the oral cavity
communicates directly with the alimentary canal. The
foregut gives rise to the pharynx, oesophagus, lower res-
piratory tract (trachea and lungs), stomach, liver, gallblad-
der, pancreas, and duodenum. Foregut duplication cysts
may be found associated with any of these structures, but
most often arise in the oesophagus (20%), followed by the
bronchial apparatus (15%), stomach (7%), and duodenum
(5%) (Sangüesa Nebot et  al.  2018; Liu and Adler  2014).
Cysts in the head and neck are rare and account for less
than 0.5% of foregut lesions and less than 0.3% of all enteric
duplication cysts. When they do arise, the vast majority are
found in the tongue or floor of the mouth (Morgan
et al. 1996; Kieran et al. 2010; Luo et al. 2015). Occasional
cases are found in the palate, tonsils, epiglottis, orophar-
ynx, or anterior neck (Kieran et al. 2010).
The anatomical level of origin may determine the precise
nature of the lesion. Cysts in the oral cavity are almost
exclusively found in the tongue and the varied nature of the
epithelial lining suggests that they do not meet the three
defining characteristics of enteric duplication cysts that
arise in the hindgut. Rather, it seems that the entrapped
endoderm in tongue lesions may be pluripotent, with the
ability to differentiate into any of the epithelial types of
endodermal origin: respiratory, gastric, or intestinal, as well
as stratified squamous. It is also probable that endoderm of
the foregut and ectoderm of the stomodeum can become
entrapped in the developing tongue at the sites of fusion of
the tuberculum impar (of first branchial arch origin, lined
by ectoderm) with the hyperbranchial eminence that forms
the posterior one-­third of the tongue and is derived from
the second, third and fourth arches lined by endoderm. This
would explain the varied epithelial linings that are found in
lingual cysts of foregut origin, as well as the occasional find-
ing of endodermal elements in dermoid cysts.
Intraoral cysts of foregut origin may show a variety of
histological features, but the clinical features and mode of
presentation are similar. For this reason, they have been
described under a number of names, including heterotopic
gastrointestinal cyst, oral alimentary tract cyst, anterior
median lingual cyst, bronchogenic cyst, foregut duplication
cyst, and lingual foregut cyst. They can, however, be divided
into two groups based on the histological features: those
lined primarily by mixed types of gastrointestinal epithe-
lium and those lined primarily by respiratory epithelium
without gastric or intestinal epithelium. For this reason,
case reports and series often define more accurately the
type of cyst being referred to, so terms such as lingual cyst
with respiratory epithelium and lingual cyst with gastrointes-
tinal epithelium may be seen in the literature.
Despite the many terms used to describe these lesions,
we will use those most commonly used in the literature.
The first group are called heterotopic gastrointestinal cyst,
while those lined by respiratory epithelium are broncho-
genic cyst. The key features of the two types are summa-
rised in Box 18.2.
­Heterotopic Gastrointestinal Cyst
Clinical Features
Heterotopic gastrointestinal cysts are rare and most cases
in the literature have been single case reports. Morgan
et al. (1996) reviewed the literature from 1895 and found
only 32 cases, and in a similar review Said-­Al-­Naief et al.
(1999) found only 40 cases. In addition, there have been 9
cases reported by Wiersma et  al. (1992) and 6 by Eaton
et al. (2001). Subsequently there have been about 30 single
case reports and a large series of 22 cases reported by
Kieran et  al. (2010). Luo et  al. (2015) reviewed 23 cases
reported between 1971 and 2014.
Frequency
Oral cysts are very rare and most maxillofacial clinicians
are unlikely ever to encounter a case. Overall, enteric
duplication cysts have an incidence of about 1  in every
4500 births and a prevalence in children of about 0.2%, but
only about 0.3% of these might be encountered in the oral
cavity (Eaton et al. 2001; Okur et al. 2014; Sangüesa Nebot
et al. 2018). They are very rarely included in series of oral
biopsies. In their reviews of almost 50 000 oral lesions,
Jones and Franklin (2006a,b) did not record a single case.
In similar reports, covering over 70 000 maxillofacial biop-
sies, no cases were recorded (Daley et al. 1994; Grossmann
et al. 2007; Nonaka et al. 2011).
 ­Heterotopic Gastrointestinal Cys  297

Box 18.2  Developmental Cysts of Foregut Origin: Key Features

Significance and differential

Pathogenesis Clinical features Histopathology diagnosis

Gastrointestinal Arise from the Very rare in the oral Lined by gastric and/ Cysts in neonates may
cyst endoderm of the cavity. Less than 0.3% of or intestinal obstruct the airway and be
develop- enteric duplication cysts epithelium life threatening
ing foregut 85% before 2 years Occasional cases also Must be differentiated from
65% in males contain squamous or other lesions that may arise in
70% in the tongue, respiratory the sublingual/tongue region,
usually anterior epithelium including ranula, dermoid and
30% in floor of epidermoid cysts, thyroglossal
the mouth duct cyst, and salivary gland
Asymptomatic tumours Histology allows
swellings differentiation from
other cysts
Bronchogenic Arise from the Very rare in the Lined by respiratory Must be differentiated from
cyst endoderm of the oral cavity epithelium without thyroglossal duct cyst. Both
develop- 70% occur in the midline evidence of gastro- are lined by respiratory
ing foregut neck, usually in the intestinal epithelium epithelium, but bronchogenic
suprasternal notch Stratified squamous cyst may contain cartilage
More common in epithelium is and smooth muscle in
males (75%) occasionally seen the wall
Only about 30 oral The wall may Thyroglossal cyst may have
cases reported contain cartilage or thyroid gland in the wall
75% located in smooth muscle
the tongue

Age
Most cases are diagnosed in neonates and infants, with
about 70% of cases diagnosed in the first year and 85%
before two years. Morgan et  al. (1996) reviewed 32 cases
and found that although the majority were diagnosed
before 2 years of age, cases had been reported up to 35 years.
Manor et  al. (1999) reported an age range of 0–42 years,
with a mean age of 5.5 years and median age of 6 months.
Kieran et al. (2010) reported 22 cases with an average age
of 2.5 years and a median of 1.5 years. The age range was
from 5 days to 7 years; 9 cases were diagnosed in the first
year and 3 were in neonates. Luo et al. (2015) reviewed 22
cases and found an age range from birth to 41 years, but the
majority (16 cases: 73%) were diagnosed in the first year,
including 9  in neonates. Of the 16 cases of foregut cysts
reported by Wiersma et al. (1992), 14 presented in neonates
and the other two at 3 and 6 years.
Sex
There is a male predilection, with about 65% of cases in
males. In the largest reviews or series, the proportion of
males has been reported as 70% (n = 32; Morgan et al. 1996),
62% (n  =  42; Manor et  al.  1999), 64% (n  =  22; Kieran
et al. 2010), and 62% (n = 21; Luo et al. 2015).
Site
Almost all oral gastrointestinal cysts have been found in
the tongue or the floor of the mouth. In the most detailed
analysis, Morgan et  al. (1996) found that 97% (31 of 32
cases) arose at these sites, with 58% in the tongue and 39%
in the floor of the mouth. One case was reported in the
submandibular region. Of the 18 tongue lesions, 12 (66.6%)
were located in the anterior dorsum, and 2 (11%) were at
the posterior junction; 1 case was at the lateral border and
3 (16.6%) were found on the ventral surface. Luo et  al.
(2015) reviewed 23 oral cases and found that 7 (30.4%)
were in the dorsum of the tongue, 9 (39.1%) on the ventral
surface, and 7 (30.4%) were located in the floor of
the mouth.
Manor et  al. (1999) reviewed a total of 54 cases, all of
which were in the tongue. Of these, 45 (83.3%) affected the
dorsum, of which 5 extended into the posterior tongue.
There were 6 cases (11.0%) found on the ventral surface,
of which 3 extended into the floor of the mouth. Three
298 Developmental Cysts
cases were so large as to present with both dorsal and
­ventral swelling.
Clinical Presentation
The most frequent clinical presentation is an asympto-
matic lingual swelling covered by clinically normal
mucosa. Larger cysts, especially in neonates and infants,
may cause obstruction of the airway or problems with
feeding. Of the 54 cases reviewed by Manor et al. (1999),
only 5 recorded any disturbance in tongue function, eat-
ing, or speaking. Similarly, Morgan et  al. (1996) found
that 69% of cases presented as symptomless swellings,
while the remainder caused functional problems associ-
ated with feeding, swallowing, or breathing. Of the 23
cases reviewed by Luo et  al. (2015), 13 (56.5%) were
symptomless. The remainder caused problems with
speech or feeding, and 2 cases in neonates also obstructed
the airway.
Histopathology
Gastrointestinal cysts are lined by epithelium derived from
the endoderm of the foregut, but, by definition, must con-
tain either gastric or intestinal epithelium or both. Cysts
may also show areas of squamous epithelium or respira-
tory epithelium. The most commonly encountered epithe-
lium is gastric (Figure  18.4). Note, however, that lingual
cysts lined only by squamous epithelium are dermoid or
epidermoid cysts and those lined predominantly by respir-
atory epithelium without gastrointestinal epithelium are
bronchogenic cysts.
Figure 18.4  Gastrointestinal cyst, lined by gastric-­type
epithelium with surface mucous cells (foveolar cells) and glands.
Source: Courtesy of Dr Jos Hille.
In the 32 cases reviewed by Morgan et al. (1996), 26 (81%)
contained gastric epithelium and 6 (19%) contained intesti-
nal epithelium. However, only 13 (41%) were lined entirely
by gastric epithelium and 5 (16%) entirely by intestinal epi-
thelium. The remainder showed a mixed lining, with combi-
nations of gastric and intestinal with squamous or respiratory
epithelium. There were areas of squamous epithelium in 10
cases, but only 2 had respiratory epithelium. However, this is
a small series and the true frequency of different epithelial
combinations is not known. Cysts with a mix of gastrointes-
tinal and respiratory epithelium do appear to be very rare.
Luo et  al. (2015) reviewed case reports of gastrointestinal
cysts that contained respiratory epithelium and found only
21 reports between 1971 and 2014.
When lined by gastric mucosa, the epithelium is of the
type seen in the body and fundus of the stomach
(Figure 18.4). Both parietal and chief cells may be found,
and typical gastric glands may be present. Some cysts have
a muscularis mucosa (Lipsett et al. 1993; Eaton et al. 2001).
Cysts lined with intestinal mucosa may show Paneth cells,
goblet cells, and argentaffin cells (Gorlin and Jirasek 1970;
Lipsett et al. 1993).
As mentioned previously in this chapter, gastrointestinal
cysts are occasionally multiple or found in combination
with dermoid or epidermoid cysts (Eppley et  al.  1985;
Arcand et al. 1988; Wiersma et al. 1992; Crivelini et al. 2001;
Ho and Crean  2003; Şimşek-­Kaya et  al.  2018; Robinson
et al. 2021).
Treatment
Treatment consists of surgical excision. Recurrences are
rare, but have been reported.
­Bronchogenic Cyst
Bronchogenic cyst is the second type of developmental
cysts that may arise from the developing foregut. They are
distinguished from other types of duplication cyst because
they arise from the primitive foregut during the formation
of the tracheobronchial tree, and are lined predominantly
by respiratory epithelium without evidence of gastrointesti-
nal epithelium. They are also known as bronchial cysts or
descriptively as cysts with respiratory epithelium.
They are found most frequently within the mediastinum
or thorax, but may rarely be encountered in the neck
(McAdams et  al.  2000; Ustundag et  al.  2005; Luna and
Pfaltz  2009) and less often in the tongue or floor of the
mouth (Wiersma et  al.  1992; Obiechina et  al.  1999;
Benhammou et  al.  2006; Gleizal et  al.  2006; Aldawood
et al. 2021).
 ­Bronchogenic Cys  299

Clinical Features (8 of 14 cases) were males. Of the 5 cases reviewed by

Aldawood et  al. (2021), 2  were located in the ventral
Bronchogenic cysts in the neck are most often encountered
tongue, 1 in the base of the tongue and 1 in the floor of
in the suprasternal notch region and over 70% are in the
the mouth. There was 1  lesion in the mandibular vesti-
midline (Ustundag et al. 2005). In a review of 70 cases in
bule extending into the lower lip. Of the 5 cases, 4 were in
the head and neck region reported up to 2005, Ustundag
males and the age of presentation ranged from 1  day to
et al. (2005) found only 5 lesions above the hyoid bone, 3 of
6 years.
which were submental and 2 in the tongue. The subman-
dibular region was the site of 2 cases, while others were
found in the upper neck close to the thyroid gland, or just Histopathology
lateral to the larynx or epiglottis. Most lesions are located
Bronchogenic cysts are lined by pseudostratified ciliated
in the skin or immediate subcutaneous tissues.
columnar (respiratory-­type) epithelium (Figure  18.5),
When present at a lateral site, they may be found overly-
although focal areas of simple cuboidal or stratified squa-
ing the clavicles or at the anterior border of the sternomas-
mous epithelium may be present. They do not contain gas-
toid muscle. At this site they must be considered in the
tric or intestinal epithelium. The cyst wall may contain
differential diagnosis of branchial cleft cysts and metastatic
cartilage, smooth muscle, and seromucous glands. Focal
head and neck carcinoma (Luna and Pfaltz 2009).
areas of inflammation are occasionally seen. Of the 21
Cervical bronchogenic cysts are found in males with a
cases reviewed by Peters et al. (2018), all were lined by typi-
M : F ratio of about 3 : 1 (Ustundag et al. 2005) and become
cal respiratory epithelium, but in addition 10 (47.6%)
clinically apparent just after birth. In the series of Ustundag
showed focal areas of squamous epithelium and 6 (28.6%)
et  al. the age range was from 0 to 54 years, but only 12
had areas of simple cuboidal epithelium. Wiersma et  al.
(17.1%) cases were found in adults. They usually present as
(1992) found 7 bronchogenic cysts in their series of 16 fore-
symptomless masses that slowly increase in size. Lesions
gut cysts and showed that 3 were lined by respiratory epi-
may communicate with the skin through a sinus tract.
thelium alone, 3 also had focal areas of squamous
Oral lesions are very rare, but the frequency may depend
epithelium, and 1 case showed foci of both squamous and
on the criteria for diagnosis. Peters et al. (2018) reviewed
simple columnar epithelium.
the literature from 1963 and found only 21 cases affecting
Aldawood et al. (2021) presented a case that was lined by
the tongue (including 2 of their own). They called the cysts
respiratory epithelium and had foci of cartilage and smooth
‘lingual cysts with respiratory epithelium’ and defined
muscle in the wall. They also found 4 similar cases in the
them as being lined by respiratory epithelium without evi-
literature. All had focal areas of stratified squamous epi-
dence of gastrointestinal epithelium. More recently,
thelium and cartilage in the wall; 1 case also showed areas
Aldawood et al. (2021) applied more stringent criteria and
of smooth muscle.
only included cases that also showed evidence of cartilage
in the wall. They reported 1  new case, but only found 4
previous cases in the literature since 1982.
Although cartilage and other mesodermal elements
(including smooth muscle) may be present in the wall, we
suggest that a diagnosis of bronchogenic cyst is appropri-
ate for a cyst lined predominantly by respiratory epithe-
lium without evidence of gastrointestinal epithelium.
Areas of stratified squamous epithelium may be found
and some cases will show cartilage or smooth muscle in
the wall.
Using these broader criteria, there are still only about 30
cases of oral lesions in the literature (Obiechina et al. 1999;
Ustundag et  al.  2005; Benhammou et  al.  2006; Gleizal
et al. 2006; Peters et al. 2018; Aldawood et al. 2021).
In the cases reviewed by Peters et al. (2018), 13 (61.9%)
were in the anterior dorsum of the tongue, 4 in the ventral
tongue, and 4 were located in the floor of the mouth. The
Figure 18.5  Bronchogenic cyst, lined by pseudostratified
average age of presentation was 9.4 years (range 6 months ciliated columnar epithelium with occasional mucous (goblet)
to 42 years) and in those where the sex was reported 57% cells. Source: Courtesy of Dr Colin Ades.
300 Developmental Cysts
Treatment
Treatment consists of complete surgical excision, after
which recurrence is rare.
­Branchial Cleft Anomalies
The branchial arches form between the fourth and seventh
weeks of gestation, and give rise to most of the structures
of the face, oral cavity, neck, and pharynx. The branchial
apparatus comprises six paired arches, but the fifth arch is
rudimentary in humans and the sixth arch is small and is
often considered as part of the fourth arch. For practical
purposes, therefore, the developing face and oral cavity are
derived from four branchial arches (Adams et  al.  2016;
Nanci 2017). These are composed of expansions of meso-
derm forming bulges that are separated externally by
branchial clefts and internally by pharyngeal pouches. The
first arch develops in front of the buccopharyngeal mem-
brane and is lined externally and internally by ectoderm.
The second to fourth arches develop behind the membrane
and are lined externally by ectoderm and internally by
endoderm.
Branchial cleft anomalies occur due to incomplete oblit-
eration of the branchial clefts or pharyngeal pouches caus-
ing persistence or entrapment of the epithelial linings. In
this way, the anomalies may present as cysts, sinuses or
fistulas, or combinations of these defects. Detailed and
excellent reviews of branchial anomalies have been pro-
vided by Luna and Pfaltz (2009), Adams et al. (2016), and
Wenig (2017a).
The vast majority of anomalies (about 95%) derive from
the second branchial arch and up to 4% from the first arch.
Anomalies of the third and fourth arches are very rare and
usually present as sinuses or abscesses in the lower neck
that open either onto the skin at the lower third of the ster-
nocleidomastoid muscle, or internally into the piriform
sinus. Anomalies of the first and second arches are most
often cysts, although up to one-­third may present as a sinus
or fistula. All the anomalies are congenital, but in general
sinuses and fistulas are diagnosed in neonates or infants,
while cysts grow slowly over a long period of time and most
present in adults in the third to fifth decades.
­Branchial Cleft Cysts
Branchial cleft cysts arise in the lateral aspect of the neck.
When used without qualification, the term branchial cleft
cyst is taken to refer to cysts found in the upper lateral neck
and derived from the second branchial arch. Because of
their similar histopathological features, they are often
referred to as lymphoepithelial cysts. Lymphoepithelial
cysts arise in the oral cavity or the parotid glands and arise
from tonsil or salivary gland. They should be regarded as
distinct from developmental cysts of branchial arch origin.
Lymphoepithelial cysts are considered in Chapter 15. Note,
however, that true branchial cysts of first-­arch origin may
arise in association with the parotid gland and present as a
pre-­auricular swelling. The key features of branchial cleft
cysts are summarised in Box 18.3.
Clinical Features
Frequency
Branchial cleft cysts are rare, but are still the second most
common cause of swellings in the neck in neonates and
children, after thyroglossal duct cyst. In their review of
more than 44 000  maxillofacial biopsies in adults, Jones
and Franklin (2006a) found 24 branchial cysts (0.05%).
Balikci et al. (2013) reviewed 630 sequential neck masses in
all age groups and found that 119 (18.9%) were congenital
and of these only 26 (21.9% of congenital lesions and 4.1%
of the total) were branchial cysts. The most common con-
genital lesion was thyroglossal duct cyst (39 cases). The
overall most common cause of neck masses was neoplastic
(300 cases: 47.6%), followed by inflammatory (211 cases:
33.9%). They found, however, that congenital cysts were
significantly more likely to be diagnosed in people less
than 20 years of age, where 45.1% of cases were congenital.
Conversely, masses in patients over 40 years were more
likely to be malignant, accounting for 47.5% of cases. Of all
congenital neck masses, Al-­Khateeb and Al Zoubi (2007)
found that 22% (55 of 252 cases) were branchial cysts and
in a review of 226 congenital developmental cysts, Brucoli
et al. (2020) found that 44% were thyroglossal duct cysts,
43% branchial cysts, and 13% dermoid cysts.
Age and Sex
Branchial cleft cysts affect males and females equally and
most present in the third and fourth decades, with reported
average ages of 18.6 years (Al-­Khateeb and Al Zoubi 2007),
34.0 years (Brucoli et  al.  2020), and 31.7 years (Pupić-­
Bakrač et  al.  2021). In the largest series ever published
(n  =  468; Bhaskar and Bernier  1959), 61% of cases were
diagnosed in the third decade and 92.5% were diagnosed
under the age of 40 years. Only 35 cases (7.5%) were
encountered over the age of 40 years.
Site
Because most branchial cysts arise from the second arch,
the most common location is in the upper lateral aspect of
the neck, just anterior to the sternocleidomastoid muscle
close to the angle of the mandible. Pupić-­Bakrač et  al.
 ­Branchial Cleft Cyst  301

Box 18.3  Branchial Cleft Cyst: Key Features

Pathogenesis
●● Entrapment of epithelium due to incomplete obliteration of the branchial clefts
●● 95% arise from the 2nd branchial arch
Clinical features
●● Second most common (22%) developmental cyst in the head and neck
●● Found in the lateral aspect of the neck
●● Most are in the submandibular region just anterior to the sternocleidomastoid muscle
●● Rare 1st arch cysts are pre- or post-auricular
●● Mean age about 30 years with peak in 3rd & 4th decades
●● Equal gender distribution
●● Wide age range but 90% diagnosed under 40 years.
●● Usually present as symptomless neck masses
Histopathology
●● Simple unilocular cysts lined by stratified squamous epithelium
●● Respiratory epithelium is occasionally (<5%) seen
●● The wall contains lymphoid tissue
Significance and differential diagnosis
●● Must be differentiated from cystic metastatic carcinoma.
●● Over age 35 years assume a metastatic carcinoma until proved otherwise.
●● Carcinomas show cytological evidence of malignancy and usually have solid areas or invasion of the wall.
●● HPV-associated carcinomas are strongly p16 positive

(2021) reported 46 patients with 48 branchial anomalies
and found that 77% were cysts of second-­arch origin and
were located in the upper lateral neck.
Anomalies arising from the first arch are found in the
region of the parotid gland and present as pre-­auricular or
post-­auricular swellings. In the series presented by Pupić-­
Bakrač et al. (2021), 8 (16.7%) cases were of first-­arch origin
presenting in the parotid region, of which 4 (50%) pre-
sented as sinuses opening onto the skin.
Anomalies associated with the third or fourth branchial
arches are most often sinuses and are found in the lower
neck, adjacent to the lower third of the sternocleidomas-
toid muscle and the suprasternal notch.
Clinical Presentation
Branchial cysts have an average size of about 40 mm, but
can range from 10 to 140 mm (Wenig 2017a; Pupić-­Bakrač
et  al.  2021). The most frequent symptoms are swelling,
which may be progressive or intermittent, with occasional
pain. Sometimes lesions have been found to enlarge in
response to an upper respiratory tract infection. The swell-
ings are soft and compressible and often fluctuant.
Occasionally, there may be a sinus or fistula that opens
onto the skin at the anterior aspect of the
sternocleidomastoid muscle (Luna and Pfaltz 2009). There
may be a mucoid or, if infected, a purulent discharge.
Anomalies of the third or fourth arches that open into the
piriform sinus may compromise the airway and present as
stridor.
Histopathology
Most cysts are carefully excised and the pathologist will
receive an intact round or spherical cystic mass. On dissec-
tion there is a thin fibrous wall, but thickenings are often
noted, representing areas where there is an accumulation
of lymphoid tissue (Figure 18.6). The lumen may contain a
semi-­solid cheesy material (sometimes referred to as ‘gru-
mous’) or a mucoid or pale brown fluid. If the lumen con-
tains thickened or solid areas, then a diagnosis of branchial
cyst is unlikely and solid areas should be carefully sampled.
Histological examination shows that most branchial cysts
are simple unilocular cysts lined by thin, regular stratified
squamous epithelium that may be para-­or orthokeratinised
(Figure 18.6). About 95% of cases are lined wholly by strati-
fied squamous epithelium (Bhaskar and Bernier  1959;
Wenig 2017a; Pupić-­Bakrač et al. 2021), while the remainder
also show areas of simple columnar, respiratory, or ciliated
302 Developmental Cysts

(a)

(b) (c)

Figure 18.6  Branchial cyst. Images from three different cysts. The cysts are lined by thin regular stratified squamous epithelium.
(a) Focal accumulations of lymphoid tissue can be seen (right and top). (b) Well-­formed normal germinal centres are seen. (c) In this
example a focal area shows respiratory-­type epithelium with surface cilia (arrows).

epithelium (Figure  18.6c). Occasional cases (<2%) may be
lined wholly by respiratory epithelium. Most cases arise
superficially from the branchial clefts and the lining is
derived from ectoderm, but it is possible that cysts showing
respiratory epithelium arise at least in part from the endo-
derm of a pharyngeal pouch. The lumen of the cyst is
usually empty or contains only sparse amounts of cellular
debris and occasional inflammatory cells.
In virtually all cases, the cyst wall contains lymphoid tis-
sue with well-­formed germinal centres (Figure  18.6a, b).
The lymphoid tissue may embrace the whole of the cyst or
may be focal. Focal areas of inflammation are seen in up to

50% of cases and may be accompanied by granulation tis-
sue and fibrosis. If the lining is ruptured, foreign-­body
giant cells may be seen in the wall. The epithelial lining is
cytologically bland, but in inflamed cases there may be
some evidence of reactive atypia.
There have been occasional reports of carcinomas aris-
ing in branchial cysts (often referred to as bronchogenic
carcinoma). These have shown an otherwise quite typical
cyst, but with cytologically malignant epithelium. In the
absence of clinical evidence of a primary carcinoma else-
where, authors have assumed that these lesions represent
primary carcinomas arising in a developmental cyst.
However, this is regarded as extremely rare or unlikely, and
it is generally accepted that a diagnosis of carcinoma aris-
ing in branchial cyst is not appropriate (Luna and
Pfaltz 2009; Wenig 2017a). All cases should be regarded as
metastatic carcinoma, even in those rare cases where a pri-
mary lesion cannot be found.
Differential Diagnosis
Branchial cysts present as neck masses and any cause of
neck swelling must be considered in the clinical differential
diagnosis. In infants and children, the majority of neck
swellings are congenital developmental lesions and the
most likely cause is either thyroglossal duct cyst or branchial
cleft cyst. The distinction is usually clear: thyroglossal duct
cysts arise in the midline of the upper neck, while branchial
cleft cysts are always lateral. Haemangioma or lymphangi-
oma (cystic hygroma) may also arise in the lateral neck
(Balikci et al. 2013), but has distinctive diagnostic features
that should not cause confusion with branchial cysts.
The cystic hygroma is a developmental abnormality that is
often present at birth and most cases are diagnosed before
the age of 2 years. The lesion is more correctly designated as
a cavernous type of lymphangioma, but cystic hygroma is a
commonly used clinical term. It most frequently involves
the face and lateral neck, where it presents as a large diffuse,
soft, and compressible swelling. The lesion is usually unilat-
eral, but the entire side of the neck and lower face may be
involved. The dilated vessels are often superficial, the overly-
ing skin may be blue, and the swelling transilluminates.
There may be a history of gradual or sudden enlargement.
Histologically, the cystic hygroma consists of multiple
dilated cystic spaces lined by endothelial cells, and often
filled with pale eosinophilic lymph.
In older children and adolescents (<20 years), inflamma-
tory masses may also be encountered (Balikci et al. 2013).
These are not cystic, are usually firm or tender on palpa-
tion, and represent enlarged lymph nodes.
Neck masses in adults are more likely to be neoplastic,
but the majority of these are not cystic and most are associ-
ated with lymph nodes (lymphomas or metastatic
­Branchial Cleft Cyst  303
carcinoma) or are salivary gland tumours associated with
the submandibular gland. Occasionally, however, a meta-
static carcinoma may be cystic in nature both on clinical exami-
nation and histologically.
Differentiation of Branchial Cleft Cyst from Cystic
Metastatic Carcinoma
One of the greatest challenges for clinicians and patholo-
gists, when faced with a cystic mass in the neck, is to differ-
entiate between a branchial cleft cyst and a cystic metastasis
from a carcinoma in the nasopharynx or oropharynx.
In a study of 135 patients from all age groups, with cysts
in the lateral neck (Grønlund et al. 2016), 19 (14.5%) were
found to be metastatic carcinoma. Of these, 16 were meta-
static squamous cell carcinomas and 3 were papillary carci-
noma of the thyroid. The diagnosis for 89 cysts (65.9%) was
benign lateral neck cyst (branchial cleft cyst). However, it
was found that all the malignant cases arose over the age of
35 years and that 33.3% (14 of 42) of cysts in the fourth and
fifth decades were metastases. Conversely, 87.0% of cysts in
patients under 31 years were branchial cysts. The authors
concluded that in patients over the age of 35 years, any
neck cyst should be regarded as malignant until proved
otherwise. In an analysis of 630  neck swellings, Balikci
et al. (2013) found that in patients under the age of 20 years,
85% of swellings are congenital or inflammatory, while
over the age of 40 years, 85% are neoplastic or inflamma-
tory and about 15% are malignant.
Up to about 50% of head and neck carcinomas may show
cervical lymph node metastases at first presentation and in
lesions of the nasopharynx and oropharynx a neck mass is
often the first clinical sign of disease. Furthermore, these
metastases, especially from human papillomavirus (HPV)–
associated oropharyngeal squamous cell carcinoma, are
often cystic and must be differentiated from benign cystic
lesions. Cystic metastases usually show cytological evi-
dence of malignancy and have solid areas that resemble a
typical conventional keratinising squamous carcinoma.
Non-­keratinising, HPV-­associated metastases, however,
may be more difficult to diagnose. Often the cyst lining will
show areas of thickening, with ribbon-­like proliferations of
carcinoma (Figure 18.7a), and tumour may invade into the
wall. Malignant cysts are also more likely to contain
necrotic material, show inflammation, and have thicken-
ing or fibrosis of the wall. Metastases are also within a
lymph node, so the periphery of the lesion may show obvi-
ous lymphatic vessels and normal subcapsular sinuses. In
the majority of cases, therefore, histological examination
should confirm the diagnosis.
Occasionally a cystic metastasis may show histological
features of a simple cyst and a precise diagnosis may not be
possible (Figure  18.7b). Furthermore, occasional cystic
metastases from HPV-­associated oropharyngeal carcinomas
304 Developmental Cysts

(a) (b)

(c) (d)

Figure 18.7  Cystic metastasis of a human papillomavirus (HPV)–associated oropharyngeal carcinoma. (a) In places the lining is
thickened with obvious cytological atypia. (b) Elsewhere the lining is thin and bland, with no evidence of malignancy (compare to
Figure 18.6b). (c, d) p16 is strongly expressed throughout the epithelium.

show focal areas with ciliated epithelium, leading to a misdi-
agnosis of branchial cyst (Bishop and Westra  2015). The
presence of cilia cannot therefore be taken as a sign of benig-
nity nor considered as a diagnostic feature of a developmen-
tal cyst.
These data show that great care must be taken when try-
ing to interpret the histology of cystic neck masses, espe-
cially in adults over the age of 35. Special care is needed
when presented with small incisional biopsies that may not
be representative (e.g. compare Figures 18.6b and 18.7b). If
there is any doubt, a diagnosis should not be given and in
patients over 35 years of age a malignancy should be
assumed until proved otherwise. Although a primary
lesion may be occult, in 80–90% of cases a primary tumour
can be found on careful imaging or by blind biopsies in the
oropharynx or upper aerodigestive tract.
Fine needle aspiration (FNA) cytology is often used in
the differential diagnosis of neck masses. An FNA from
a branchial cyst usually shows a hypocellular smear or
cell block, with nucleated squamous cells and variable
numbers of inflammatory cells. Fragments of keratin or
parakeratotic cells with smooth hyperchromatic nuclei
may be seen, but are not prominent. An FNA from an
inflamed case may show cells with some nuclear atypia,
but this is usually accompanied by evidence of inflam-
mation and the nuclear changes appear reactive or
degenerative. An FNA from a metastatic carcinoma will
usually show obvious malignant cells, but cytology of a
cystic lesion may be less helpful and FNA cytology is
notoriously difficult, with sensitivities and specificities
of about 90% and 60%, respectively (Grønlund et al. 2016;
Layfield et  al.  2016). In general, an FNA from a cystic
metastasis will show a greater degree of cellularity, cell
clusters, more necrotic debris, and clear evidence of
cytological atypia and mitoses (Layfield et  al.  2016;
Wenig 2017a).

The majority of cystic metastases may come from HPV-­
associated squamous cell carcinomas in the oropharynx.
Immunocytochemistry for p16 is an acceptable surrogate
marker for high-­risk HPV and can be used as a test for both
primary or metastatic HPV-­associated carcinomas
(Lewis 2020). Metastatic carcinomas show positive expres-
sion of p16 that is diagnostic if greater than 70% of the cells
show strong nuclear and cytoplasmic staining (Figure 18.7c,
d). However, up to 50% of branchial cysts may show expres-
sion of p16 (Pai et al. 2009; Cao et al. 2010), although it is
usually weak, focal, and limited to the basal and parabasal
layers (Cao et  al.  2010; Müller et  al.  2015). With careful
interpretation, p16 can be useful in tissue sections to dif-
ferentiate between a branchial cyst and a metastatic HPV-­
associated carcinoma. Again, care is needed in small
biopsies and if there is any doubt, then HPV testing using
polymerase chain reaction (PCR) or in situ hybridisation
should be carried out.
p16 staining is not recommended in the assessment of
FNA cytology specimens, since it is unreliable and is diffi-
cult to interpret because few cases reach the 70% positive
threshold (El-­Salem et al. 2019; Lewis 2020). If an FNA is
equivocal, then it must be repeated or a biopsy is required.
However, direct HPV testing by PCR on FNA specimens
may be useful, and a number of centres now use liquid-­
based HPV testing, similar to that used for cervical screen-
ing (Lewis 2020).
Metastatic lesions from papillary thyroid carcinoma may
occasionally be cystic, but usually show areas with a papil-
lary architecture, follicles with colloid, and typical nuclear
features that are diagnostic. Immunohistochemistry is also
helpful, since papillary thyroid carcinomas may express
thyroglobulin, TTF1, and PAX8, none of which is seen in
branchial cysts.
Treatment
Branchial cysts are removed by careful surgical excision.
Recurrence is very rare (Papadogeorgakis et  al.  2009;
Brucoli et al. 2020; Pupić-­Bakrač et al. 2021).
­Thyroglossal Duct Cyst
The thyroid gland develops at about the fourth week of
intrauterine life from the foramen caecum on the dorsal
surface of the tongue, just posterior to the circumvallate
papillae. The developing gland descends in a caudal direc-
tion, forming a hollow epithelial stalk, known as the thy-
roglossal duct. The thyroglossal duct crosses the anterior
surface of the hyoid bone, loops onto the posterior surface,
and then descends to the site of the normal thyroid gland
­Thyroglossal Duct Cys  305
in the anterior neck, just below the thyroid and cricoid car-
tilages. The thyroglossal duct disintegrates by about the
eighth week, but remnants of the duct may remain at any
site along its line of descent. In an autopsy study, Sprinzl
et al. (2000) found that 41% of children had retained rem-
nants of the thyroglossal duct, or ectopic thyroid tissue.
These residual islands of epithelium give rise to the thy-
roglossal duct cyst. Furthermore, up to 40% of the adult
population may have an accessory, median lobe of the thy-
roid, the pyramidal lobe, which represents a vestigial rem-
nant of the thyroglossal duct.
Clinical Features
Frequency
The thyroglossal duct cyst is the most common of the
developmental cysts of the neck, accounting for about 45%
of congenital abnormalities in the neck in children. In
their analysis of 630 neck masses in all age groups, Balikci
et al. (2013) found 119 congenital cysts, of which 39 were
thyroglossal duct cysts, representing 32.7% of congenital
cysts and 6.2% of all neck masses. Al-­Khateeb and Al Zoubi
(2007) found that thyroglossal duct cysts constituted 55.6%
of all congenital cysts in the neck and about 63% of cysts
diagnosed in the first two decades. In a similar study,
Brucoli et al. (2020) reviewed 226 patients with congenital
neck cysts and found that 100 (44%) were thyroglossal duct
cysts. Thompson et al. (2016) estimated a population inci-
dence of 2.23 cases per 100 000 persons per year in their
catchment area of Southern California.
Age
Although the lesion is congenital, most cysts grow slowly
and many are not diagnosed until adulthood, with an aver-
age age of presentation of about 30 years.
Thompson et al. (2016) reported a series of 685 thyroglos-
sal duct cysts and found an average age at diagnosis of
31.3 years (range 10 months–87 years). Only 38% of cases
were diagnosed in the first two decades, while 39.3% were
diagnosed over the age of 40 years. Thus, there is a bimodal
age distribution, with peaks in the first decade (26.1% of
cases) and in the fifth decade (15.0% of cases). De Tristan
et al. (2015) also showed a bimodal distribution with peaks
in the first and fourth decades, but with an overall average
age of 29 years (n = 282; range 1–78 years).
Cysts affecting the tongue may present in a younger
age group, probably because they are more likely to
cause symptoms. Burkart et  al. (2009) reviewed 16  lin-
gual cysts and found an average age at presentation of
3.01 years (range 1 month–16 years), but with 50% of
cases presenting in the first year and only one case in the
second decade.
306 Developmental Cysts

Box 18.4  Thyroglossal Duct Cyst: Key Features

Pathogenesis
●● Arises from remnants of the thyroglossal duct
Clinical features
●● The most common (45%) developmental cyst in the head and neck
●● Mean age about 30 years with bimodal peaks in the 1st and 5th decades
●● Equal gender distribution in adults
●● More common in males (60%) in children
●● Located in the midline of the upper neck close to the hyoid bone.
●● Rare in the tongue – about 3% of cases
●● Usually a symptomless swelling, but 25% may have pain or tenderness
●● May lift on swallowing
Histopathology
●● Most are lined by respiratory epithelium but squamous epithelium may be seen
●● Most (70%) contain ectopic thyroid gland in the wall
Significance and differential diagnosis
●● Tongue lesions may obstruct the airway, especially in neonates.
●● Very high recurrence rate (40% - 50%) if thyroglossal duct remnants are not removed with the cyst (Sistrunk
procedure)
●● Rare cases (3%) contain papillary thyroid carcinoma.
●● Must be differentiated from bronchogenic cyst. Both are lined by respiratory epithelium but thyroglossal duct
cyst has thyroid gland in the wall.
●● Bronchogenic cyst may contain cartilage and smooth muscle..

Sex connected to the bone at operation. Cysts are never located

Across all age groups, thyroglossal duct cyst shows an
equal sex distribution, but there is some evidence that in
children males are more likely to be affected. Thompson
et  al. (2016) found that overall, 50.2% of their 685 cases
presented in males and 49.8% in females, but in the first
two decades 57.5% arose in males and over the age of
20 years 54.2% arose in females. This distribution is sup-
ported by the study of Geller et  al. (2014), who reported
128 paediatric patients ( 14 years) and found that 60.9%
were males, and also by Burkart et al. (2009), who found
that 13 of their 16 (81.2%) paediatric patients with tongue
cysts were male.
Site
Thyroglossal duct cysts are always located in the upper
neck and the vast majority (98%) are located in the midline
and below the hyoid bone (de Tristan et al. 2015; Thompson
et al. 2016). In their review of 685 cases, Thompson et al.
(2016) found that the majority (75.9%) were located below
the hyoid bone and 24.1% were suprahyoid. Whether above
or below the hyoid bone, most lesions are found to be
in the lateral neck and those few not in the midline are just
to one side in a paramedial location. A number of studies
have shown a slight predilection for the left side (Ren
et al. 2011; de Tristan et al. 2015; Thompson et al. 2016).
Cysts may be located in the oral cavity, either in the poste-
rior floor of the mouth just above the hyoid bone or very rarely
in the tongue. Burkart et al. (2009) reviewed 189 patients with
thyroglossal duct cysts and found 16 (8.5%) with cysts located
in the tongue. In a systematic review, however, Gioacchini
et al. (2015) found 24 studies reporting a total of 1371 cysts
and noted that only 39 (2.8%) were located in the tongue.
Clinical Presentation
Thyroglossal duct cysts present as a mobile swelling or
cystic mass with or without associated pain or tenderness.
Thompson et al. (2016) found that 99.7% of their cases pre-
sented with a mobile mass, while the remaining 5 cases
(2.3%) were fixed. In addition, 164 cases (23.9%) also
showed pain or tenderness, and 123 (18.0%) showed signs
of infection. There were 67 cases (9.8%) with a draining
sinus or fistula.
 ­Thyroglossal Duct Cys  307

In their systematic review, Gioacchini et al. (2015) found

that 75% of cases presented as a painless swelling, while C
34% showed evidence of infection or an abscess and 18%
had a fistula or sinus. In their series of 282 cases, de Tristan C
et al. (2015) showed that 280 (99.3%) presented as a swell-
ing, of which about 25% were growing and 25% were inter-
mittent. Only 30.0% of patients complained of pain and
20.6% had signs of infection. They also found that 23.4%
were associated with difficulty swallowing and a small
number caused problems with speech (1.4%) or breath-
ing (0.4%).
A classic sign of the thyroglossal duct cyst is that it lifts
when the patient swallows or protrudes the tongue, but
this is only seen in about 20% of cases (de Tristan
et al. 2015).
Cysts arising in the tongue are more likely to present
with symptoms associated with difficulty in eating or
breathing and large cysts in neonates may be life threaten-
ing. In Burkart et al.’s (2009) series of 16 tongue lesions, 7
cases (43.8%) presented with signs of airway obstruction.

Histopathology
Thyroglossal duct cysts are surgically excised, usually with
a portion of the hyoid bone and associated tissue contain-
ing residual duct (the ‘Sistrunk’ procedure). The cyst itself
has a fibrous wall and on dissection may be multilocular.
Cysts have an average size of about 25 mm (range 2–85 mm;
Thompson et al. 2016). Lingual cysts may be removed by
excision alone and the cysts are usually smaller, with a
range from 5 to 20 mm (Burkart et al. 2009).
Thyroglossal duct cysts are lined by pseudostratified
columnar (respiratory) epithelium, stratified squamous
epithelium, or both. Most often a lining of both respiratory
and stratified squamous epithelium is seen (Figure 18.8).
Thompson et al. (2016) undertook a detailed analysis of the
histology of their 685 cases. They found that 51% were
lined by both respiratory and stratified squamous epithe-
lium, 38% by respiratory epithelium alone, and 10% by
stratified squamous epithelium alone.
The cyst wall is fibrous, but most cases (87%) showed evi-
dence of inflammation and 65% showed small areas of cyst
rupture with associated foamy histiocytes. Most lesions
(71%) had ectopic thyroid gland in the wall (Figure  18.8)
and 15.2% showed seromucous glands. Occasional cases
may show well-­formed lymphoid tissue in the wall.
There is a well-­recognised association between thyroglos-
sal duct cyst and papillary thyroid carcinoma (Thompson
et  al.  2016,  2017). In their series of 685 cases, Thompson
et  al. (2016) found 22 (3.2%) cysts that contained classic
papillary thyroid carcinomas. The carcinomas are found in
the cyst wall and are usually associated with ectopic thyroid
gland. Occasional examples of follicular thyroid carcinoma
Figure 18.8  Thyroglossal duct cyst (C) lined by
pseudostratified columnar epithelium. Thyroid tissue (arrows) is
present in the wall; haematoxylin and eosin (H&E) stain.
and squamous cell carcinoma have also been reported
(Lustmann et al. 1989; Thompson et al. 2017).
Differential Diagnosis
The major source of potential confusion is with other cystic
neck masses, but the thyroglossal duct cyst is always in the
midline (or paramedial) and arises high in the neck close to
the hyoid bone. When upward displacement of the cyst
occurs on swallowing, it is diagnostic. Most other neck
masses arise in the lateral neck.
Bronchogenic cysts are the main possible source of misdi-
agnosis. These may arise in the midline, but are more often
located in the lower neck close to the sternal notch.
Histologically, bronchogenic cysts may also be lined by res-
piratory epithelium and stratified squamous epithelium,
but they usually show cartilage in the wall and may have
smooth muscle. Conversely, thyroglossal duct cysts do not
show smooth muscle and usually have focal nodules of
thyroid gland in the wall. A small number (<1.0%) of thy-
roglossal duct cysts, however, may have cartilage in the
wall (Thompson et al. 2016).
The differential diagnosis of lingual cysts includes thy-
roglossal duct cyst, bronchogenic cyst, gastrointestinal
cyst, and dermoid and epidermoid cysts. Thyroglossal duct
cyst is always located deep in the posterior tongue, whereas
the others are more often located in the anterior tongue or
308 Developmental Cysts
in the ventral tongue and anterior floor of the mouth.
Histologically each cyst has distinguishing features, except
for bronchogenic cyst, which as discussed can resemble
thyroglossal duct cyst.
Treatment
Surgical excision is usually advised for the treatment of
thyroglossal duct cysts. The recommended approach is
called the Sistrunk operation (first described in detail by
Walter Sistrunk in 1920; Geller et  al.  2014; Gioacchini
et al. 2015; Thompson et al. 2016). The procedure involves
removal of the cyst along with the central part of the hyoid
bone and a 1 cm block of tissue surrounding the duct. The
thyroglossal duct should be traced down to the pyramidal
lobe of the thyroid gland and up to the foramen caecum at
the base of the tongue.
This method ensures that any residual remnants of the
duct are removed and reduces recurrence. In their system-
atic review, Gioacchini et al. (2015) reported that 90.4% of
cases had been treated according to this procedure, with a
recurrence rate of 5.3%. Of the few cases that had been
treated by cystectomy alone, 47.6% recurred. In Thompson
et al.’s (2016) series, 94.4% of the patients had the Sistrunk
procedure, with a recurrence rate of about 1.0%; 31 patients
had a cystectomy alone, of which 14 (45.2%) recurred.
Burkart et al. (2009) treated 16 lingual cases by a tran-
soral route using endoscopy. The cysts were excised alone
without a Sistrunk procedure. None of their cases recurred.
­Nasopharyngeal Cysts
Nasopharyngeal cysts are cystic entities that arise high in
the nasopharynx and can be classified as congenital or
acquired. All are rare and do not present problems in the
differential diagnosis of the developmental cysts of the
neck and maxillofacial regions discussed in this chapter.
Nasopharyngeal cysts have been well reviewed by Marom
et  al. (2009) and Wenig (2017b). Acquired cysts are most
common and are retention cysts associated with seromu-
cous glands or tonsillar tissue. They may be located in the
midline or laterally. They are lined by ciliated or non-­
ciliated columnar epithelium, with areas of squamous
metaplasia in response to inflammatory stimuli. Lymphoid
follicles are often present in the wall. The cyst lumen con-
tains mucoid material and epithelial debris.
Congenital cysts in the nasopharynx are found in the
midline and may arise either from the pharyngeal bursa
(Tornwaldt’s bursa) or from Rathke’s pouch. These cysts
are very rare, rarely cause any symptoms, and are usually
incidental findings at autopsy or on imaging.
Tornwaldt cyst derives from entrapped ectoderm if
the notochord fails to detach from the pharyngeal wall.
The cyst forms a smooth, submucosal mass covered by
normal mucosa, and is usually less than 20 mm in
diameter. It is usually symptomless unless infected,
when patients may experience headaches, dizziness,
earache, halitosis, and sore throat. It is lined by respira-
tory epithelium, unless infected when there may be
squamous metaplasia.
Rathke cleft cysts are found anterior or cranial to the
usual site of origin of retention or Tornwaldt cysts, and
arise at the same site as craniopharyngiomas from part of
the craniopharyngeal canal. The cyst is formed by a failure
to obliterate Rathke’s pouch during formation of the pitui-
tary gland. Most cysts are intracranial, but occasional
lesions may occur in the nasopharynx. They are usually
symptomless and are found incidentally on imaging for
other reasons. When symptoms do arise, patients may
complain of sudden-­onset headaches, visual disturbances,
nausea, and pituitary symptoms. The cysts are lined by res-
piratory or squamous epithelium.
Other cysts that can arise in the pharynx or nasopharynx
include branchial cleft cysts, dermoid or epidermoid cysts,
and teratoid cysts.
­Thymic Cyst
Thymic cysts are rare clinical entities that arise in persis-
tent thymic tissue. The thymus develops from the pharyn-
geal pouches of the third branchial arches and descends
caudally into the upper chest. Thymic cysts arise from rem-
nants of thymic tissue, can be found in any location
between the angle of the mandible and the sternal notch,
and can be midline or lateral. About 70% present in the first
decade and the remainder are usually diagnosed before the
age of 30 years.
Thymic cysts are rarely diagnosed clinically, but are a
chance finding on histological examination of a cystic mass
that has provisionally been diagnosed as another type of
developmental cyst, usually a branchial or thyroglossal
duct cyst (Luna and Pfaltz 2009). On histological examina-
tion the cyst is lined by squamous or simple cuboidal epi-
thelium, but by definition, and to make the diagnosis, the
cyst wall contains thymic tissue including lymphoid tissue
and Hassall corpuscles.

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Index
a pseudocyst of maxillary sinus  254
abscess theory, radicular cyst  31–33
adjunctive therapy, keratocyst
surgery  137
adult gingival cyst  155–160
clinical features  156–157
clinical presentation  157
diagnosis  158–160
differential diagnosis  159–160
histopathology  159
microkeratocyst  160
pathogenesis  158–159
radiological features  158
treatment  160
AE1/AE3 see pan‐cytokeratin
age distribution
botryoid odontogenic cyst  150–151
branchial cleft cyst  300
calcifying odontogenic cyst  186
dentigerous cyst  63–65
dermoid cyst  292
epidermoid cyst  292
eruption cyst  83–84
gingival cysts  156, 161, 163
glandular odontogenic cyst  165–166
heterotopic gastrointestinal cyst  297
inflammatory collateral cysts  50, 52
intraoral lymphoepithelial cyst  256
keratocyst  92–93
lateral periodontal cyst  141
mandibular buccal bifurcation
cyst  51, 52
mucoceles  239–240, 252–253
nasolabial cyst  230–231
nasopalatine duct cyst  219
orthokeratinised odontogenic cyst  cyst  50, 52–53
202
paradental cyst  51, 52
Shear’s Cysts of the Oral and Maxillofacial Regions, Fifth Edition. Paul M. Speight.
© 2022 John Wiley & Sons Ltd. Published 2022 by John Wiley & Sons Ltd.
radicular cyst  21–22, 24
retention cyst of maxillary
sinus  254
simple bone cyst  272–273, 276
Stafne bone cavity  281–282
surgical ciliated cyst  263–264
thyroglossal duct cyst  308
ameloblastoma
calcifying odontogenic cyst
differentiation  191, 197, 199
dentigerous cyst relationship  76–77
glandular odontogenic cyst
differentiation  172–173
keratocyst  128–129, 132
anatomical distribution
botryoid odontogenic cyst  151
branchial cleft cyst  300
calcifying odontogenic
cyst  186–187
dentigerous cyst  66–67
dermoid cyst  292–293
epidermoid cyst  292–293
eruption cyst  84
gingival cysts  156–157, 161, 162
glandular odontogenic cyst  165–166
heterotopic gastrointestinal cyst  bay cyst see pocket cyst
297
inflammatory collateral cysts  50,
52–53
intraoral lymphoepithelial cyst  glandular odontogenic cyst
256
keratocyst  94–95
lateral periodontal cyst  142
mandibular buccal bifurcation
mucoceles  239–241
nasopalatine duct cyst  219
357
orthokeratinised odontogenic
cyst  202–203
paradental cyst  51–53
pseudocyst of maxillary sinus  254
radicular cyst  22–23
retention cyst of maxillary sinus  254
simple bone cyst  272–274
Stafne bone cavity  282
surgical ciliated cyst  264
thyroglossal duct cyst  306
anatomy, incisive canal  214–218
aneurysmal bone cyst  287
antral cyst of the maxillary
sinus  253–255
apical cyst see radicular cyst
apical granuloma see periapical
granuloma
aspiration biopsy, keratocyst  129–130
b
B lymphocytes, periapical
periodontitis  28
bacterial factors, radicular cyst  26,
27, 29, 30
basal cell nevus syndrome see naevoid
basal cell carcinoma syndrome
Bcl‐2  115
biomarkers
dentigerous cyst  80–81
 
178–180
keratocyst  130–132
biopsy, keratocyst  129–130
Blandin–Nuhn glands, mucoceles  242
Bohn’s nodules  160
bone marrow, focal osteoporotic
defects  285–287
358 Index
bone resorption
dentigerous cyst  74
radicular cyst  23, 35–36
Stafne bone cavity  284
botryoid odontogenic cyst  147,
150–154
clinical features  150–151
clinical presentation  151
diagnosis  152–154
differential diagnosis  154
pathogenesis  152
radiological features  151–152
recurrence  152
treatment  154
branchial cleft anomalies  300
branchial cleft cyst  290, 300–305
bronchogenic cyst  298–300
c cell rests of Malassez
calcifying cystic odontogenic tumour
(CCOT) see calcifying
odontogenic cyst
calcifying ghost cell tumours  cellular changes, radicular cyst  38–40
199–200
calcifying odontogenic cyst  182–200
β‐catenin  191–193
classification  182–185
clinical features  185–188
clinical presentation  187–188
CTNNB1 gene  191–193
dentinoid formation  195, 199–200
differential diagnosis  190, 199–200
ghost cells  183–184, 191–200
histopathology  193–199
malignant transformation  199–200
pathogenesis  190–193
peripheral/extraosseous
lesions  188, 199
radiological features  188–190
recurrence  200
terminology  182–185
treatment  200
Caldwell‐Luc operation  255, 262, 263,
267–269, 281
Calretinin  18
carcinoma
central mucoepidermoid  176–178
cystic metastatic  303–305
dentigerous cyst transitions  81–82
ghost cells  195, 199–200
keratocyst transformation  132–133
mucoepidermoid  170, 172, 176–178
naevoid basal cell  98–100, 109–113,
115, 124–125, 204
radicular cyst transitions  45–46
Carnoy’s solution  137
cartilage
keratocyst  122–123
nasopalatine duct cyst  229
β‐catenin  18, 191–193
cavitational osteonecrosis  286–287
cell proliferation
hedgehog signalling  115
keratocyst  107–109, 114–115
radicular cyst  31–33, 35
cell rests of the dental lamina
gingival cysts  28–29
glandular odontogenic cyst  170
keratocyst  107
lateral periodontal cyst  145–146
lateral periodontal cyst  144–145
periapical periodontitis  27
radicular cyst  28–30
cemento‐osseous dysplasia  276–279
central mucoepidermoid
carcinoma  176–178
central necrosis theory, radicular
cyst  31–33
chemokines  27–30
cholesterol deposition
dentigerous cyst  78
radicular cyst  42–44
ciliated cells, radicular cyst  38–40
CK see cytokeratins
classification  2–5
calcifying odontogenic cyst  epidermoid cyst  293
182–185
developmental cyst  289–291
developmental cyst of foregut
origin  295–296
inflammatory collateral cysts  47–49
keratocyst  88–89
mucoceles  238
simple bone cyst  271–272
clinical features
adult gingival cyst  156–157
botryoid odontogenic cyst  150–151
branchial cleft cyst  300–301
bronchogenic cyst  299
calcifying odontogenic cyst  185–188
dentigerous cyst  63–67
dermoid cyst  291–293
epidermoid cyst  291–293
Epstein Pearls  163
eruption cyst  83–84
focal osteoporotic bone marrow
defects  285–286
gingival cysts  156–157, 161, 163
glandular odontogenic cyst  165–166
heterotopic gastrointestinal cyst 
296–298
inflammatory collateral cysts  49–53
intraoral lymphoepithelial cyst  256
keratocyst  89–95
lateral periodontal cyst  141–142
mucoceles  238–241, 252–253
nasolabial cyst  230–233
nasopalatine duct cyst  218–221
orthokeratinised odontogenic
cyst  202–204
pseudocyst of maxillary
sinus  253–254
radicular cyst  23–25
retention cyst of maxillary
sinus  253–254
simple bone cyst  272–275
Stafne bone cavity  281–282
surgical ciliated cyst  263–265
thyroglossal duct cyst  305–307
clinical presentation
adult gingival cyst  157
botryoid odontogenic cyst  151
branchial cleft cyst  301
calcifying odontogenic
cyst  187–188
dentigerous cyst  67
dermoid cyst  293
Epstein Pearls  163
eruption cyst  83–84
gingival cysts  157, 161, 163
glandular odontogenic cyst  166
heterotopic gastrointestinal
cyst  298
inflammatory collateral cysts 
53–54
intraoral lymphoepithelial cyst  256
keratocyst  95–98
lateral periodontal cyst  142
mucoceles  241–244, 253
nasolabial cyst  231–233
nasopalatine duct cyst  220–221
orthokeratinised odontogenic
cyst  203–204

pseudocyst of maxillary sinus  254
radicular cyst  23–25
retention cyst of maxillary
sinus  253–254
simple bone cyst  274–275
Stafne bone cavity  282
surgical ciliated cyst  264–265
thyroglossal duct cyst  306–307
collateral cyst see inflammatory
collateral cyst
compression, dentigerous cyst  82
computed tomography (CT)
calcifying odontogenic
cyst  189, 190
dentigerous cyst  67–69
glandular odontogenic cyst  169
incisive canal  214–216
inflammatory collateral cysts  56
keratocyst  103–104
nasolabial cyst  233
nasopalatine duct cyst  222–223
radicular cyst  26
simple bone cyst  276–278
Stafne bone cavity  283
surgical ciliated cyst  265–266
cone beam computerised
tomography (CBCT)
dentigerous cyst  69
incisive canal  214–216
inflammatory collateral cysts  56
keratocyst  103–104
nasopalatine duct cyst  222–223
radicular cyst  26
simple bone cyst  276–277
congenital cyst see developmental cyst
connective tissue degradation
dentigerous cyst  74
radicular cyst  35–36
cryotherapy, keratocyst  137
CT see computed tomography
CTNNB1 gene  14, 19, 191–193
curettage
botryoid odontogenic cyst  154
glandular odontogenic cyst  181
keratocyst  136
lateral periodontal cyst  150
radicular cyst  46
simple bone cyst  281
cyclosporine, eruption cyst  85
cystic hygroma  244, 304
cystic metastatic carcinoma  303–305
cyst of the jaw
classification  3–4
diagnosis  14–19
histopathology  8–9, 16–17
immunohistochemistry  17–18
molecular pathology  17, 19
radiology  7–8, 15–16
cyst–tumour interface  13–14
cytokeratins (CK)
dentigerous cyst  80–81
diagnostic applications, general  18
glandular odontogenic cyst  178
inflammatory collateral cysts  59
keratocyst  131
radicular cyst  40
cytokine‐mediated remodelling  11–12
cytokines  11–12, 27–30, 35–36
cytology, keratocyst  129
cytotoxic/suppressor cells  27–28
d clinical features  291–293
DALT see duct‐associated
lymphoid tissue
deciduous teeth
dentigerous cyst  65, 75, 76, 84, 86
eruption cyst  84, 86
gingival cysts  156
radicular cyst  22–24
decompression, keratocyst  137
dental lamina
gingival cysts  28–29
glandular odontogenic cyst  170
keratocyst  107, 109
lateral periodontal cyst  145–146
dentigerous cyst  62–82
age distribution  63–65
ameloblastoma relationship  76–77
biomarkers  80–81
bone resorption  74
clinical features  63–67
clinical presentation  67
diagnosis  67–72, 78–81
differential diagnosis  70–72
vs. dilated follicles  71–72
enamel hypoplasia  72
epithelial sources  72–73
eruption cyst  62, 83–86
extrafollicular  76
formation  73
frequency  63
growth and enlargement  73–74
histopathology  78–80
hydrostatic pressure  73
Index 359
immunohistochemistry  80–81
inflammatory  75–76, 78
initiation  72–73
keratinisation  207
malignant changes  81–82
metaplastic changes  80
orthokeratinised odontogenic cyst
relationship  206–207
paradental cyst relationship  60–61
pathogenesis  11, 72–77, 207
PTCH gene  74–75, 111
radiological features  67–72
sex distribution  65–66
site distributions  66–67
treatment  82
dentinogenic ghost cell tumours  195,
199–200
dentinoid formation  195, 199–200
dermoid cyst  291–295
clinical presentation  293
definition  289, 291
histopathology  294–295
pathogenesis  294
radiological features  293–294
treatment  295
developmental cysts  288–308
branchial cleft  300–305
bronchogenic  298–300
classification  4–5, 289–291
dermoid  291–295
epidermoid  291–295
of foregut origin  295–300
heterotopic gastrointestinal  296–298
neonates, gingival  160–163
sources of epithelial lining  11
terminology  289–291
thyroglossal duct cyst  305–308
see also specific forms of cyst
diagnosis
adult gingival cyst  158–160
botryoid odontogenic cyst  151–154
dentigerous cyst  67–72, 78–81
Epstein pearls  163
eruption cyst  84
glandular odontogenic cyst  166–168,
170–180
histopathology  8–9, 16–17
infant gingival cyst  161–163
inflammatory collateral cysts  54–58
jaw cyst  14–19
keratocyst  100–106
360 Index
diagnosis (cont’d)
lateral periodontal cyst  142–150
median palatal cyst  223–225
naevoid basal cell carcinoma
syndrome  98–100
nasolabial cyst  231–236
nasopalatine duct cyst  221–223,
226–229
orthokeratinised odontogenic
cyst  204–205, 207–211
radicular cyst  23–26, 36–45
radiological principles  7–8, 15–16
surgical ciliated cyst  264–268
thyroglossal duct cyst  306–307
differential diagnosis
adult gingival cyst  159–160
botryoid odontogenic cyst  154
branchial cleft cyst  303–305
calcifying odontogenic cyst  190,
199–200
dentigerous cyst  70–72
focal osteoporotic bone marrow
defects  286
glandular odontogenic cyst  168,
175–178
immunohistochemistry  17–18
inflammatory collateral cysts  56–58
keratocyst  104–106, 125–126
lateral periodontal cyst  143–144,
149
mandibular buccal bifurcation
cyst  57–58
median palatal cyst  223–225
molecular pathology  17, 19
mucoceles  249–250
nasopalatine duct cyst  223–225
orthokeratinised odontogenic
cyst  205, 211–212
paradental cyst  56–58
Stafne bone cavity  284
surgical ciliated cyst  266–267
thyroglossal duct cyst  307–308
duct‐associated lymphoid tissue
(DALT)  257
dysgenetic disease of the parotid
glands  259–260
dysplasia, epithelial  120
e clinical features  83–84
enamel
hypoplasia  72–73, 144, 207
projections  60
endotoxins  27, 29, 30
enlargement
dentigerous cyst  73–74
keratocyst  114–117
lateral periodontal cyst  146
radicular cyst  26, 33–36
enteric duplication cyst  296–298
enucleation
botryoid odontogenic cyst  154
calcifying odontogenic cyst  200
glandular odontogenic cyst  181
keratocyst  136
lateral periodontal cyst  150
nasolabial cyst  236
nasopalatine duct cyst  229
orthokeratinised odontogenic
cyst  213
surgical ciliated cyst  268–269
epidemiology
radicular cyst  22
see also age distribution; frequency;
sex distribution
epidermal cyst  290
epidermoid cyst  290–295
clinical features  291–293
clinical presentation  293
definition  289–291
histopathology  294–295
pathogenesis  294
radiological features  293–294
treatment  295
epithelia
bronchogenic cyst  298–300
dentigerous cyst  72
glandular odontogenic
cyst  170–172
heterotopic gastrointestinal
cyst  296–297
hyaline bodies  40–42
inflammatory collateral cysts  58
keratocyst  107–109, 114–115
lateral periodontal cyst  144–146
mucoceles  240–241
radicular cyst  31–33, 35
sources of  10–11
epithelial dysplasia  120
Epstein Pearls  162–163
eruption cyst  62, 83–86
clinical presentation  83–84
diagnosis  84
histopathology  85
pathogenesis  85
radiological features  84
treatment  85
excision
mucosa, keratocyst  137
nasolabial cyst  236
experimental studies, hyaline
bodies  41–42
extrafollicular dentigerous cyst  76
extraosseous odontogenic keratocyst 
96–97
f
fatty degenerative osteonecrosis in the
jawbone (FDOJ)  286–287
FDOJ see fatty degenerative
osteonecrosis in the jawbone
fine needle aspiration
cystic metastatic carcinoma 
304–305
keratocyst  129–130
floor of mouth see mouth floor
florid osseous dysplasia  276–279
focal osteoporotic bone marrow
defects  285–287
follicular cyst see dentigerous cyst
foramen caecum  305
foregut
developmental cyst originating
from  295–300
bronchogenic  298–300
heterotopic gastrointestinal  296–298
formation
dentigerous cyst  73
lateral periodontal cyst  146
radicular cyst  26, 31–33
frequency  4, 5
botryoid odontogenic cyst  150
branchial cleft cyst  300
calcifying odontogenic cyst 
185–186
dentigerous cyst  63
dermoid cyst  292
epidermoid cyst  292
eruption cyst  84
gingival cysts  156, 161, 163
glandular odontogenic cyst  165
heterotopic gastrointestinal
cyst  296
inflammatory collateral cysts  49–52
intraoral lymphoepithelial cyst  256
keratocyst  89–91

lateral periodontal cyst  141
mandibular buccal bifurcation
cyst  49–52
mucoceles  238–239, 252
nasolabial cyst  230
nasopalatine duct cyst  218–219
neonatal cyst  160–163
orthokeratinised odontogenic
cyst  202
paradental cyst  49–52
pseudocyst of maxillary sinus  254
radicular cyst  20–24
retention cyst of maxillary sinus  254
simple bone cyst  272–273
Stafne bone cavity  281
surgical ciliated cyst  263–264
thyroglossal duct cyst  308
g dentigerous cyst  73–74
gastric epithelium in oral cyst  296–298
ghost cells
calcifying odontogenic cyst  radicular cyst  26, 33–36
183–184, 191–200
carcinoma  195, 199–200
β‐catenin CTNNB1 gene  191–193
histopathology  193–199
gingival cysts  155–163
clinical features  156–157, 161, 163
clinical presentation  157, 161, 163
histopathology  159, 162, 163
pathogenesis  158–159, 161–163
treatment  160, 162, 163
gingival cyst of adults  155–160
clinical features  156–157
clinical presentation  157
diagnosis  158–160
differential diagnosis  159–160
histopathology  159
microkeratocyst  160
pathogenesis  158–159
radiological features  158
treatment  160
gingival cyst of infants  160–163
clinical features  161, 163
clinical presentation  161, 163
Epstein Pearls  162–163
histopathology  162, 163
pathogenesis  161–163
treatment  162, 163
glands of Blandin–Nuhn  242
glandular odontogenic cyst  164–181
clinical features  165–166
clinical presentation  166
diagnosis  166–168, 170–180
differential diagnosis  168, 175–178
histopathology  170–180
immunohistochemistry  178–180
molecular studies  178–180
mucoepidermoid carcinoma
similarity  170, 172, 176–178
pathogenesis  169–170
radiological features  167–168
recurrence  169, 181
treatment  181
Gli1 gene  110, 170
glycogen, lateral periodontal cyst  147
goblet cells see mucous cells
Gorlin–Golz syndrome see naevoid
basal cell carcinoma syndrome
growth
keratocyst  114–117
lateral periodontal cyst  146
growth factors  27–28, 30, 35
gubernacular canal  107
h thyroglossal duct cyst  307
haematogenous mechanisms, hyaline
bodies  41–42
haemorrhagic bone cyst see simple
bone cyst
haemosiderin  42–43, 280
hedgehog (HH) signalling
pathway  12
cell proliferation  115
dentigerous cyst  74
glandular odontogenic cyst  170
keratocyst  99–100, 112–113, 115
naevoid basal cell carcinoma
syndrome  115
signalling pathway  99–100
heterotopic gastrointestinal cyst  dentigerous cyst  73
296–298
histopathology
branchial cleft cyst  301–305
bronchogenic cyst  299
calcifying odontogenic cyst  immune mechanisms, radicular
193–199
dentigerous cyst  78–80
dermoid cyst  294–295
epidermoid cyst  294–295
Epstein Pearls  163
eruption cyst  85
Index 361
focal osteoporotic bone marrow
defects  286
gingival cysts  159, 162, 163
glandular odontogenic cyst 
170–180
inflammatory collateral cysts  61
intraoral lymphoepithelial cyst 
257–258
jaw cyst  8–9, 16–17
keratocyst  117–133
lateral periodontal cyst  146–150
mucoceles  244–250, 253
mucous extravasation cyst  244–248
mucous retention cyst  248–249
nasolabial cyst  234–236
nasopalatine duct cyst  226–229
orthokeratinised odontogenic
cyst  207–213
pseudocyst of maxillary sinus  255
radicular cyst  36–45
retention cyst of maxillary sinus  255
simple bone cyst  273, 280–289
Stafne bone cavity  285
superficial mucoceles  247–248
surgical ciliated cyst  268
HIV‐associated salivary gland
disease  259
hobnail cells, glandular odontogenic
cyst  171, 173
HPV see human papilloma virus
human papilloma virus (HPV) 
303–305
hyaline (Rushton) bodies
dentigerous cyst  80
keratocyst  122
lateral periodontal cyst  147
nasopalatine duct cyst  229
radicular cyst  40–42
hydrostatic pressure  12–13
keratocyst  115–116
radicular cyst  33–35
i
cyst  27–33, 35
immunohistochemistry
dentigerous cyst  80–81
glandular odontogenic cyst  178–180
jaw cyst  17–18
keratocyst  110–111, 130–132
362 Index
immunosuppression, eruption cyst  85
impacted teeth, orthokeratinised
odontogenic cyst  207
incisive canal  214–218
incisive canal cyst see nasopalatine
duct cyst
incisive foramen  217–218, 222
incisive papilla  217, 220
incisive papilla cyst  220
infants
Epstein pearls  162–163
gingival cyst  160–162
inflammation
hyaline bodies  41
keratocyst  120
nasopalatine duct cyst  229
paradental cyst  58–59
periapical periodontitis  26–28
Stafne bone cavity  284–285
inflammatory collateral cysts  47–61
age distribution  50, 52
classification  47–49
clinical features  49–53
diagnosis  54–58
differential diagnosis  56–58
frequency  49–52
histopathology  61
initiation  59
radiological features  54–58
site distribution  50, 52–53
treatment  61
inflammatory dental cyst see
radicular cyst
inflammatory dentigerous
cyst  75–76, 78
inflammatory paradental cyst see
paradental cyst
initiation
dentigerous cyst  72–73
inflammatory collateral cysts  59
lateral periodontal cyst  144–146
radicular cyst  26, 28–31
interleukins  29, 31
intraoral lymphoepithelial
cyst  256–258
j 115, 124–125
Jacobson’s (vomeronasal) organ  217
jaw cyst
diagnosis  14–19
histopathology  8–9, 16–17
immunohistochemistry  17–18
molecular pathology  17, 19
radiology  7–8, 15–16
jaws
classifications  3–4
pseudocyst  3–4, 270–287
aneurysmal bone cyst  287
focal osteoporotic bone marrow
defects  285–287
simple bone cyst  271–281
Stafne bone cavity  281–285
k
KCOT (keratocystic odontogenic
tumour) see keratocyst
keratin expression patterns  17
keratocyst  122–124
keratinisation
dentigerous cyst  207
orthokeratinised odontogenic
cyst  207–210
radicular cyst  38
keratoameloblastoma  128–129, 132
keratocystoma  129, 260–261
keratocyst (odontogenic
keratocyst)  87–139
age distribution  92–93
aspiration biopsy  129–130
as a benign neoplasm  111–114
biomarkers  130–132
biopsy  129–130
classification  88–89
clinical features  89–95
clinical presentation  95–98
cytology  129–130
diagnosis  100–106
differential diagnosis  104–106,
125–126
epithelial sources  107–109
frequency  89–91
growth and enlargement  114–117
histopathology  117–133
immunohistochemistry  110–111,
130–132
malignant transformation  132–133
naevoid basal cell carcinoma
syndrome  98–100, 109–113,
orthokeratinised  123–124, 211–212
pathogenesis  107–117, 207
peripheral  96–97
PTCH gene  99–100, 108–113, 115
radiological features  100–106
recurrence  133–138
sex distribution  93–94
site distribution  94–95
soft tissue  97–98
solid  126–129
terminology, history of  88–89
treatment  136–138
see also orthokeratinised
odontogenic cyst
Ki‐67  114–115, 179, 206
Klestadt cyst see nasolabial cyst
l
lateral periodontal cyst  141–154
clinical features  141–142
clinical presentation  142
differential diagnosis  143–144, 149
histopathology  146–150
multicystic variant see botryoid
odontogenic cyst
pathogenesis  144–146
radiological features  142–144
treatment  150
lichen planus  241–242
lingual cyst
foregut originating  297, 299
glands of Blandin–Nuhn  242
lymphoepithelial  256–258
thyroglossal duct  305
lingual mandibular bone defect see
Stafne bone cavity
lipofuscin, radicular cyst  43–44
lipopolysaccharide (LPS)  29,
30, 35–36
loss of heterozygosity (LOH)  12–14
dentigerous cyst  74, 75, 111
glandular odontogenic cyst  170
keratocyst  109–114
orthokeratinised odontogenic cyst  206
lymphoepithelial cyst  255–259
branchial cleft  300–305
intraoral  256–258
parotid gland  258–259
m
magnetic resonance imaging (MRI)
dermoid cyst  293–294
epidermoid cyst  293–294
keratocyst  104
nasolabial cyst  233
Stafne bone cavity  283
surgical ciliated cyst  265–266
 Index 363

Malassez (rest cells of) see rest cells of classifications  4 multicystic lateral periodontal
Malassez sources of epithelial lining  11 cyst  145, 149–154
malignant transformation see also salivary duct cyst; salivary multiple simple bone cyst  276, 279
calcifying odontogenic cyst  gland cyst myofibroblasts, keratocyst  116–117
199–200 mitotic figures, keratocyst  118–119 myxoglobulosis  246, 247
dentigerous cyst  81–82 MMPs see matrix metalloproteinases
keratocyst  132–133 molecular pathology n
radicular cyst  45–46 glandular odontogenic cyst  naevoid basal cell carcinoma syndrome
MAML2 gene  14, 17, 19, 179–180 178–180 (NBCCS)  98–100, 109–113,
mandibular buccal bifurcation cyst jaw cyst  17, 19 115, 124–125, 204
clinical features  49–53 bronchogenic cyst  299 nasoalveolar cyst see nasolabial cyst
clinical presentation  53–54 dermoid/epidermoid cyst  292–293 nasolabial cyst  230–236
diagnosis  54 heterotopic gastrointestinal clinical features  230–233
differential diagnosis  56–58 cyst  297 clinical presentation  231–233
histopathology  61 lymphoepithelial cyst  256–258 histopathology  234–236
pathogenesis  60 mucoceles  242–244 pathogenesis  234
treatment  61 thyroglossal duct cyst  306 radiological features  233–234
mandibular infected buccal cyst see MRI see magnetic resonance imaging treatment  236
mandibular buccal mucoceles  237–253 nasolacrimal cyst  234
bifurcation cyst classification  238 nasopalatine duct cyst  214–229
marginal wisdom tooth cyst  48 clinical features  238–241, 252–253 clinical features  218–221
marsupialization clinical presentation  241–244, 253 clinical presentation  220–221
calcifying odontogenic cyst  200 differential diagnosis  249–250 diagnosis  221–223, 226–229
dentigerous cyst  82 extravasation cyst  238–241, differential diagnosis  223–225
keratocyst  136 243–248 histopathology  226–229
mandibular buccal glands of Blandin–Nuhn  242 incisive canal anatomy  214–218
bifurcation cyst  61 histopathology  244–250 median palatal cyst  223–225
nasolabial cyst  236 maxillary sinus  252–253 pathogenesis  225–226
surgical ciliated cyst  268–269 pathogenesis  244 radiological features  221–225
Maspin  18 plunging ranula  243–244 recurrence  229
matrix metalloproteinases (MMPs)  ranula  242–244, 250 treatment  229
35–36, 116, 192 retention cyst  238–241, 248–249 nasopharyngeal cyst  290, 308
maxillary sinus cyst  4, 252–255 superficial  241–242, 247–248 NBCCS see naevoid basal cell
mucoceles  252–253 terminology  238 carcinoma syndrome
pseudocyst  252–255 treatment  250–251 neck
retention cyst  252–255 mucoepidermoid carcinoma  170, developmental cyst  4–5
surgical ciliated cyst see surgical 172, 176–178 sources of epithelial lining  10–11
ciliated cyst mucosal excision, keratocyst  137 neonates
median palatal cyst  223–225 mucous cells Epstein pearls  162–163
melanin, calcifying odontogenic bronchogenic cyst  299 gingival cyst  160–162
cyst  199 dentigerous cyst  80 neoplastic changes
merging epithelial strands theory, glandular odontogenic cyst  definition  111–112
radicular cyst  31–33 171–172, 174 dentigerous cyst  76–77
metaplastic changes nasolabial cyst  235 keratocyst as  111–114
dentigerous cyst  80 nasopalatine duct cyst  225 neuralgia‐inducing cavitational
radicular cyst  38–40 radicular cyst  38–40 osteonecrosis (NICO) 
microcyst, glandular odontogenic thyroglossal duct cyst  306–307 286–287
cyst  171–174 mucous extravasation cyst  238–241, neurovascular bundles  229
microkeratocyst  107, 160 243–248 non‐odontogenic cyst
Midpalatal raphe cyst (Epstein mucous retention cyst  238–241, classification  3–4
Pearls)  162–163 248–249 sources of epithelial lining  10
minor mucous glands multicystic keratocyst  129 see also individual types. . .
364 Index

non‐surgical treatment pan‐cytokeratin (AE1/AE3)  130 Stafne bone cavity  284–285

eruption cyst  85 paradental cyst surgical ciliated cyst  267–268
inflammatory collateral cyst  61 clinical features  49–53 PCNA see proliferating cell
radicular cyst  46 clinical presentation  53–54 nuclear antigen
nutritional deficiency theory, radicular dentigerous cyst relationship  60–61 pemphigoid  241–242
cyst  31–33 diagnosis  54 periapical cyst see radicular cyst
differential diagnosis  56–58 periapical granuloma
o
histopathology  61 periapical periodontitis  26–27
OAF see osteoclast activating factor
pathogenesis  58–60 radicular cyst  28–30
odontogenic cyst
treatment  61 periapical periodontitis,
classification  2–4
parotid gland pathogenesis  27–28
frequency  4, 5
HIV‐associated salivary gland pericoronitis  7, 47–53, 57–59
immunohistochemistry  17–18
disease  259 periodic acid–Schiff (PAS) staining 
pathogenesis  10–13
keratocystoma  129, 260–261 39, 43–44, 147
PTCH gene  17, 19
lymphoepithelial cyst  258–259, peripheral (extraosseous)
sources of epithelial lining  10
300–305 odontogenic cyst
see also individual types. . .
polycystic disease  259–260 calcifying  187, 199
odontogenic keratocyst see keratocyst
sclerosing polycystic adenoma  260 keratocyst  96–97
oncogenes  12, 17, 19
PAS see periodic acid–Schiff (PAS) see also gingival cyst
’onion‐skin’ pattern  208–209
staining peripheral ostectomy  137
OPG see osteoprotogerin
pathogenesis  6–13 phases of cyst formation  10
oral epithelia, islands, keratocyst  107
botryoid odontogenic cyst  152 plunging ranula  243–244, 250
oral tonsils  255–257
calcifying odontogenic cyst  pocket cyst  24, 44–45, 59
orthokeratinised odontogenic
190–193 podoplanin  117
cyst  123–124, 201–213
dentigerous cyst  72–77, 207 polymorphonuclear leukocytes
clinical features  202–204
dermoid cyst  294 (PMNs)  27, 31–33
clinical presentation  203–204
epidermoid cyst  294 postoperative maxillary cyst see
dentigerous cyst
Epstein Pearls  163 surgical ciliated cyst
relationship  206–207
eruption cyst  85 prevalence
diagnosis  204–205, 207–212
focal osteoporotic bone marrow inflammatory collateral cysts  49–52
differential diagnosis  205, 211–212
defects  286 radicular cyst  20–23
histopathology  207–213
gingival cysts  158–159, 161–163 see also clinical features
odontogenic keratocyst relationship 
glandular odontogenic cyst  169–170 proliferating cell nuclear antigen
211–212
inflammatory collateral cysts  58–60 (PCNA)  114–115, 179
pathogenesis  205–207
intraoral lymphoepithelial cyst  prostaglandins  28, 30, 36
radiological features  204–205
256–257 pseudocyst
recurrence  213
keratocyst  107–117, 207 of the jaw  3–4, 270–287
treatment  213
lateral periodontal cyst  144–146 aneurysmal bone cyst  287
with verrucous proliferation  212–213
mandibular buccal bifurcation focal osteoporotic bone marrow
osmolality
cyst  60 defects  285–287
dentigerous cyst  73
mucoceles  244, 253 simple bone cyst  271–281
keratocyst  116
nasolabial cyst  234 Stafne bone cavity  281–285
radicular cyst  33–34
nasopalatine duct cyst  225–226 maxillary sinus  252–255
osteoclast activating factor (OAF)  29
orthokeratinised odontogenic PTCH gene  12–14, 17, 19
osteonecrosis  286–287
cyst  205–207 dentigerous cyst  74–75, 111
osteoporotic focal bone marrow
paradental cyst  58–60 glandular odontogenic cyst  170
defects  285–287
periapical periodontitis  27–28 keratocyst  99–100, 108–113, 115
osteoprotogerin (OPG)  35–36
pseudocyst of maxillary sinus  naevoid basal cell carcinoma
p 254–255 syndrome  99–100, 109–113,
p16  18 radicular cyst  26–36 115
p53  115, 179 retention cyst of maxillary sinus  orthokeratinised odontogenic
palatine papilla see incisive papilla 254–255 cyst  206

r orthokeratinised odontogenic
radicular cyst  20–46
age distribution  21–22, 24
bacterial factors  26, 27, 29, 30
biological factors  29–30
chemokines  27–30
cholesterol deposition  42–44
clinical features  23–25
clinical presentation  23–25
cytokines  27–30, 35–36
diagnosis  23–26, 36–45
epithelial proliferation  31–33, 35
formation  26, 31–33
frequency  20–24
growth and enlargement  26, 33–36
histopathology  36–45
hyaline bodies  40–42
hydrostatic pressure  33–35
immune mechanisms  27–33, 35
initiation  26, 28–31
malignant changes  45–46
metaplastic changes  38–40
pathogenesis  11, 16, 26–36
periapical granuloma  28–30
periapical periodontitis  27–28
pocket cyst  44–45
prostaglandins  28, 30, 36
radiological features  25–26
residual  24–25, 44
resorption of bone  23, 35–36
sites  22–23
treatment  46
radiological features
botryoid odontogenic cyst  151–152
calcifying odontogenic
cyst  188–190
dentigerous cyst  67–72
dermoid cyst  293–294
epidermoid cyst  293–294
eruption cyst  84
focal osteoporotic bone marrow
defects  286
glandular odontogenic
cyst  167–168
inflammatory collateral cysts  maxillary sinus  252–255
54–58
jaw cyst  7–8, 15–16
keratocyst  100–106
lateral periodontal cyst  142–144
mucocele of maxillary sinus  253
nasolabial cyst  233–234
nasopalatine duct cyst  221–225
cyst  204–205
pseudocyst of maxillary sinus  254
radicular cyst  25–26
retention cyst of maxillary sinus  254
simple bone cyst  273, 275–278
Stafne bone cavity  282–284
surgical ciliated cyst  265–267
RANKL see receptor activator of
nuclear factor kappa B ligand
ranula  242–244, 250
Rathke’s cleft cyst  308
receptor activator of nuclear factor
kappa B ligand (RANKL),
radicular cyst  35–36
recurrence
botryoid odontogenic cyst  152
calcifying odontogenic cyst  sex distribution
199–200
glandular odontogenic cyst  169, 181
keratocyst  133–138
nasopalatine duct cyst  229
orthokeratinised odontogenic
cyst  213
simple bone cyst  281
resection, keratocyst  137
residual radicular cyst  24–25, 44
resorption of bone
dentigerous cyst  74
radicular cyst  23, 35–36
resorption of roots, dentigerous
cyst  69
respiratory epithelia, bronchogenic
cyst  298–300
rest cells of the dental lamina
gingival cysts  28–29
glandular odontogenic cyst  170
keratocyst  107
lateral periodontal cyst  145–146
rest cells of Malassez
lateral periodontal cyst  144–145
periapical periodontitis  27
radicular cyst  28–30
retention cyst
mucoceles  238–241, 248–249
root resorption, dentigerous cyst  69
Rushton bodies see hyaline bodies
s thyroglossal duct cyst  306
salivary duct cyst  251–252
HIV‐associated  259
Index 365
keratocystoma  260–261
lymphoepithelial cyst  255–259
intraoral  256–258
of the parotids  258–259
maxillary sinus  252–255
polycystic disease of the
parotids  259–260
sclerosing polycystic adenoma  260
salivary gland cyst
classifications  4
mucoceles  237–251
sources of epithelial lining  11
satellite cyst, keratocyst  120
sclerosing polycystic adenoma  260
sebaceous cyst, definition  290
sebaceous glands, orthokeratinised
odontogenic cyst  211
branchial cleft cyst  300
calcifying odontogenic cyst  186
dentigerous cyst  64–66
dermoid cyst  292
epidermoid cyst  292
eruption cyst  84
gingival cysts  156, 161, 163
glandular odontogenic
cyst  165–166
heterotopic gastrointestinal
cyst  297
inflammatory collateral cysts  50, 52
intraoral lymphoepithelial cyst 
256
keratocyst  93–94
lateral periodontal cyst  141–142
mandibular buccal bifurcation
cyst  50, 52
mucoceles  239–240, 252–253
nasolabial cyst  231
nasopalatine duct cyst  219
orthokeratinised odontogenic
cyst  202
paradental cyst  50, 52
pseudocyst of maxillary sinus  254
radicular cyst  22, 24
retention cyst of maxillary sinus 
254
simple bone cyst  272–273, 276
Stafne bone cavity  282
surgical ciliated cyst  263–264
sialo‐odontogenic cyst see glandular
odontogenic cyst
366 Index
simple bone cyst  271–281
cemento‐osseous dysplasia  276–279
classification  271–272
clinical features  272–275
clinical presentation  274–275
histopathology  273, 280–289
multiple  276, 279
pathogenesis  278–280
radiological features  273, 275–278
recurrence  281
solitary  279
terminology  271–272
site distribution
botryoid odontogenic cyst  151
branchial cleft cyst  300–301
calcifying odontogenic
cyst  186–187
dentigerous cyst  66–67
dermoid cyst  292–293
epidermoid cyst  292–293
eruption cyst  84
gingival cysts  156–157, 161, 162
glandular odontogenic cyst  clinical presentation  264–265
165–166
heterotopic gastrointestinal cyst  297
inflammatory collateral cysts  50, 52–53
intraoral lymphoepithelial cyst  256
keratocyst  94–95
lateral periodontal cyst  142
mandibular buccal bifurcation cyst  adult gingival cyst  160
50, 52–53
mucoceles  239–241
nasopalatine duct cyst  219
orthokeratinised odontogenic
cyst  202–203
paradental cyst  50, 52–53
pseudocyst of maxillary sinus  254
radicular cyst  22–23
retention cyst of maxillary
sinus  254
simple bone cyst  272–274
Stafne bone cavity  282
surgical ciliated cyst  264
thyroglossal duct cyst  306
Sjögren syndrome  255, 258–259
SMO see smoothened protein
smoothened protein (SMO)  75,
99–100, 110, 170
soft tissue keratocyst  97–98
solid odontogenic keratocyst  126–129
solitary bone cyst see simple bone cyst
sonic hedgehog (SHH) protein  12
cell proliferation  115
dentigerous cyst  74–75
glandular odontogenic cyst  170
keratocyst  99–100, 112–113, 115
naevoid basal cell carcinoma
syndrome  115
signalling pathway  99–100
spherules  171–172
Stafne bone cavity  281–285
clinical features  281–282
clinical presentation  282
differential diagnosis  284
histopathology  285
pathogenesis  284–285
radiological features  282–284
treatment  285
steatocystoma  290
SUFU gene  99, 109–110
superficial mucoceles  241–242,
247–248
surgical ciliated cyst  262–269
clinical features  263–265
differential diagnosis  266–267
histopathology  268
pathogenesis  267–268
radiological features  265–267
treatment  268–269
surgical treatment
botryoid odontogenic cyst  154
branchial cleft cyst  305
calcifying odontogenic cyst  200
dentigerous cyst  82
dermoid cyst  295
epidermoid cyst  295
eruption cyst  85
glandular odontogenic cyst  181
heterotopic gastrointestinal cyst  298
inflammatory collateral cysts  61
keratocyst  136–138
lateral periodontal cyst  150
mucoceles  250–251
nasolabial cyst  236
nasopalatine duct cyst  229
orthokeratinised odontogenic
cyst  213
pseudocyst of maxillary sinus  255
radicular cyst  46
ranula  250
retention cyst of maxillary
sinus  255
simple bone cyst  281
thyroglossal duct cyst  308
t
T lymphocytes, periapical
periodontitis  27–28
teeth
displacement
aneurysmal bone cyst  287
calcifying odontogenic cyst 
188–189
dentigerous cyst  68
keratocyst  91, 95–96, 100–103,
107
nasopalatine duct cyst  220
simple bone cyst  273–278
enamel hypoplasia  72, 144, 207
enamel projections  59–60
impacted  207
normal eruption  11
see also deciduous teeth; wisdom
teeth
teratoid cyst, definition  289–291
teratomas, definition  290–291
thymic cyst  308
thyroglossal duct cyst  305–308
TNF see tumour necrosis factor
tongue
bronchogenic cyst  299
glands of Blandin–Nuhn  242
heterotopic gastrointestinal
cyst  297
lymphoepithelial cyst  256–258
thyroglossal duct cyst  306
tonsils  255–257, 296
Tornwaldt cyst  308
transnasal marsupialization  236
trauma
mucoceles  240
simple bone cyst  271–272, 274–279
treatment
botryoid odontogenic cyst  154
branchial cleft cyst  305
bronchogenic cyst  300
calcifying odontogenic cyst  200
dentigerous cyst  82
dermoid cyst  295
epidermoid cyst  295
Epstein Pearls  163
eruption cyst  85
gingival cysts  160, 162, 163
glandular odontogenic cyst  181

heterotopic gastrointestinal cyst  298
inflammatory collateral cysts  61
intraoral lymphoepithelial cyst  258
keratocyst  136–138
lateral periodontal cyst  150
mucoceles  250–251
nasolabial cyst  236
nasopalatine duct cyst  229
orthokeratinised odontogenic
cyst  213
pseudocyst of maxillary sinus  255
radicular cyst  46
ranula  250
retention cyst of maxillary sinus  255
Index 367
simple bone cyst  281 verrucous odontogenic cyst 
Stafne bone cavity  285 212–213
surgical ciliated cyst  268–269 vomeronasal (Jacobson’s) organ  217
thyroglossal duct cyst  308
tricholemmal cyst  290 w
tumour necrosis factor (TNF)  30, 31 whorling  171–172
wisdom teeth
u dentigerous cyst  65–72, 82
ultrasound, nasolabial cyst  233 glandular odontogenic cyst  168
unicameral bone cyst see simple inflammatory collateral cysts  48–53,
bone cyst 56, 58, 60
keratocyst  102, 105, 107–108
v orthokeratinised odontogenic
vacuolated cells  39–40 cyst  203, 204
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