MINI-SYMPOSIUM: PATHOLOGY OF THE JAWS

Odontogenic cysts than tooth forming tissues are classified as ‘non-odontogenic’

and are thought to be ‘fissural’ in origin. Non-epithelialised
cavities, such as the solitary bone cyst or aneurysmal bone
Lisette Martin
cyst, are also regarded as cysts.3
Paul M Speight The current World Health Organisation (WHO) classification
of head and neck tumours was published in 2005,4 but in
contrast to all previous classifications, the odontogenic cysts
Abstract were not included, although a number of changes of terminology
A variety of cysts frequently present in the jaws. Cysts that derive their
of ‘cystic’ lesions did occur.5 Reclassification of some odonto-
epithelium from tissues involved in tooth formation are classed ‘odonto-
genic cysts as odontogenic tumours, including the odontogenic
genic’ and can be inflammatory or developmental in origin. These cysts
keratocyst (termed ‘keratocystic odontogenic tumour’) and
show variable features and some lie on a cyst-tumour interface, making
calcifying odontogenic cyst (‘calcifying cystic odontogenic
classification and diagnosis difficult. In this review we discuss the perti-
tumour’) remains a controversial decision, and has not been fully
nent histological features, as well as highlighting the importance of radio-
accepted.6
graphic analysis to achieve a definitive diagnosis. The current
In this review we present the common features of the odon-
controversies regarding cyst classification are also covered and we
togenic cysts and discuss our position on the current
state our position on this highly debated topic.
classification.
Keywords cyst-tumour interface; collateral cysts; dentigerous cyst;
gingival cysts; glandular odontogenic cyst; keratocystic odontogenic Pathogenesis of odontogenic cysts
tumour; odontogenic cysts; odontogenic keratocyst; radicular cyst
Cyst formation in the jaws requires three elements: a source of
epithelium, a stimulus for epithelial proliferation and the ca-
Introduction pacity for bone resorption and cyst growth. For the inflammatory
cysts these processes are quite well understood and have been
Odontogenic cysts are among the most common lesions to affect reviewed extensively elsewhere.3 In the case of the radicular cyst
the oral and maxillofacial regions.1 Kramer2 defined a cyst as ‘a for example, residual epithelial rests are stimulated to proliferate
pathological cavity having fluid, semi-fluid or gaseous contents by the presence of chronic inflammation at the apex of the tooth
and which is not created by the accumulation of pus’, but he did root as a result of a necrotic pulp following death of the tooth,
not insist on the presence of an epithelial lining as essential for a usually due to dental caries. For developmental cysts, however,
diagnosis, recognising that a number of lesions are cystic, but not the mechanisms are not so clear and many theories of prolifer-
of epithelial origin. In the jaws all the odontogenic cysts are ation have been suggested, including aberrant developmental
epithelium lined, but a number of cystic lesions, which may be processes and underlying genetic abnormalities.3
included in the differential diagnosis, are not e these include, for In most cases, the source of the epithelium has been quite well
example, solitary bone cyst and aneurysmal bone cyst. Many oral established and is based on a thorough understanding of tooth
and maxillofacial cysts are asymptomatic and may be found as development, which involves complex interactions between
incidental radiographic findings. However, others are capable of epithelium and mesenchyme. Early in human development, an
causing significant bony disfigurement, tooth displacement and epithelial process, known as the dental lamina, extends as a band
pathological fracture. into the jaws and represents future sites of tooth bud formation
for both primary and secondary dentitions. The epithelial
Classification component of the tooth bud is termed the enamel organ and is
involved in enamel formation as well as initiation of dentine
There is no single accepted classification for these lesions, as
formation. At the cervical loop region of a developing tooth,
many exist as part of a cyst-tumour spectrum and their catego-
there is a down growth of components of the enamel organ into
risation has come under much debate. Overall, cysts of the oral
what is known as ‘Hertwig’s epithelial root sheath’, which is
and maxillofacial regions have been classified based first on the
crucial to root development. The dental lamina, enamel organ
origin of the epithelial lining and then according to their putative
and Hertwig’s epithelial root sheath all break down following
pathogenesis.3 Those that derive their lining from remnants of
tooth development. Their epithelial remnants: the glands of
the tooth forming tissues are termed ‘odontogenic’ and are then
Serres, reduced enamel epithelium and rests of Malassez, are all
further subdivided into inflammatory or developmental (Table
implicated in the origin of odontogenic cyst epithelial linings
1). Cysts whose epithelial lining is derived from sources other
(Table 2).

Incidence
Lisette Martin BSc BDS MFDS RCSEd is a Specialty Registrar in Oral and
Numerous worldwide retrospective studies have investigated the
Maxillofacial Pathology, Department of Oral Pathology, Charles Clifford
incidence of oral and maxillofacial pathologies. Over 90% of
Dental Hospital, Sheffield, UK. Conflicts of interest: none declared.
cysts of the oral and maxillofacial region are odontogenic in
Paul M Speight BDS PhD FDSRCPS FDSRCS (Eng) FDSRCS (Edin) FRCPath is origin,1 and odontogenic cysts are the second most common oral
Professor in Oral Pathology and Honorary Consultant Histopathologist, and maxillofacial lesions in adults, after mucosal pathologies,
Academic Unit of Oral and Maxillofacial Pathology, School of Clinical accounting for 14e15% of specimens.1,7 In terms of bone pa-
Dentistry, Sheffield, UK. Conflicts of interest: none declared. thology, odontogenic cysts are by far the most common cause of

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 MINI-SYMPOSIUM: PATHOLOGY OF THE JAWS

important diagnostic criterion for radiolucent lesions at the apex

A proposed working classification of the odontogenic of the teeth.
cysts
Radicular and residual cyst
Inflammatory Radicular cyst Radicular cysts are the most common jaw cyst comprising more
Residual cyst than 60% of all odontogenic cysts.7 They most commonly
Inflammatory collateral (paradental) cysts present in the fourth and fifth decades but affect a wide age
Developmental Dentigerous cyst range with little gender difference. The majority of radicular
Odontogenic keratocyst cysts go unnoticed and are asymptomatic, with pain usually
Gingival cyst of infants only a feature if infected and secondarily inflamed. In some
Gingival cyst of adults instances these cysts can grow large in size and cause expan-
Lateral periodontal cyst sion of the cortical plate. It is difficult to differentiate a radicular
Botryoid odontogenic cyst cyst from a periapical granuloma based on radiological analysis
Glandular odontogenic cyst as both present as a well-defined round or oval radiolucency
Calcifying odontogenic cyst associated with the root apex of a non-vital tooth and contin-
Orthokeratinised odontogenic cyst uous with the lamina dura. However, findings by Mortensen
et al. (1970), which have been confirmed in more recent
Table 1
studies, found that the larger the lesion, the greater the asso-
ciation with cyst formation, as two thirds of periapical radio-
lucencies measuring over 15 mm in diameter were found to be
bony swellings of the jaws, and should be excluded first in most
radicular cysts.9
differential diagnoses. In paediatric populations dental pathology
Histological examination shows an inflamed fibrous connec-
(extracted teeth and odontomes) is the most recorded diagnostic
tive tissue wall lined by non-keratinised stratified squamous
group, however, odontogenic cysts are still documented as being
epithelium (Figure 1a). The epithelium is often of variable
highly prevalent in this group of patients, comprising about 12
thickness with a hyperplastic, arcaded rete peg architecture
e17% of specimens received.8 Odontogenic cysts appear to show
(Figure 1b). A variety of features may be seen in the cyst lining or
little sex predilection, with the male: female ratio ranging from
wall. Cholesterol clefts, which are a common feature of chronic
1:1.03e1:1.26.
inflammatory lesions, are seen in about 50% of all radicular
cysts, as focal accumulations in the wall or as nodules protruding
Inflammatory odontogenic cysts
into the lumen (Figure 1c). Macroscopically the cyst contents
This group of lesions result from the proliferation of odontogenic may be golden coloured and shimmer due to the cholesterol.
epithelium due to inflammation. The source of inflammation is Hyaline bodies are typical of radicular cysts and are rarely seen
apical periodontitis following the death of a tooth and necrosis of in any other type of odontogenic lesion. They are found in about
the pulp. Chronic inflammation in the periradicular tissues re- 10% of cysts and are seen as bright eosinophilic bodies within
sults in a periapical granuloma and stimulates proliferation of the epithelial lining, often forming small nodules (Figure 1d).
the epithelial rests of Malassez. This is followed by central They may be small and rounded like psammoma-bodies, but are
degeneration and necrosis to produce a cavity which becomes more often curvilinear and folded. Other notable features, which
lined by epithelium. Cyst expansion then occurs due to hydro- may be encountered include mucous metaplasia (w40%), cili-
static pressure as debris accumulates centrally. Radicular cysts ated epithelium (11%) and focal keratinisation (2%). The cyst
are always associated with a non-vital tooth, and this is an wall often contains focal accumulations of plump foamy histio-
cytes or Russell bodies.
Treatment of radicular cysts is successfully achieved by tooth
extraction or apicectomy with curettage of the cystic lining.
The epithelial lining origins of odontogenic cysts There is still debate as to whether root canal treatment (RCT) is
always an effective treatment modality. The theory is that RCT
Epithelial residue Origin of Cyst removes the inflammatory stimulants, thereby allowing the
epithelium lesion to heal. It is reported that an estimated 85e90% of
radicular cysts heal successfully following RCT, but without
Rests of Malassez Epithelial root Radicular/residual cyst
certainty as to whether periapical lesions are radicular cysts or
sheath of Hertwig Paradental cyst
periapical granulomas prior to treatment, it is difficulty to accu-
Glands of Serres Dental lamina Odontogenic keratocyst
rately determine the validity of these claims.3
Glandular odontogenic cyst
Gingival cyst of infants
Residual cysts
Gingival cyst of adults
Residual cysts are radicular cysts that remain after tooth
Reduced enamel Enamel organ Dentigerous cyst
extraction or root canal treatment has been carried out. The
epithelium Eruption cyst
histopathological features are the same, although, as the source
Lateral periodontal cyst
of inflammation has been removed, the cyst wall may mature
Botryoid odontogenic cyst
and become relatively uninflamed and the epithelial lining be-
Table 2
comes thin and regular (Figure 2). In these cases they may be

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 MINI-SYMPOSIUM: PATHOLOGY OF THE JAWS

Figure 1 (a) Radicular cyst at the apex of a dead tooth with necrotic pulp. The cyst is attached to the apex and is composed of an inflamed wall lined by
epithelium. The lumen is filled with necrotic cell debris. (b) The epithelial lining is hyperplastic with branching arcading rete pegs. Chronic inflammatory
cells including numerous histocytes are seen in the wall. (c) Cholesterol clefts and necrotic debris fill the cyst lumen. In this field, occasional mucous cells
can be seen in the epithelial lining. (d) Eosinophilic hyaline (Rushton) bodies within radicular cyst epithelial lining.

mistaken for developmental odontogenic cysts, but radiological (Figure 3a). The lesions are of inflammatory origin and histology
examination and the clinical history can determine that they are is non-specific, with features very similar to the radicular cyst.
located at a site of previous tooth extraction or RCT. Treatment is There is a lining of variably hyperplastic and atrophic non-
by enucleation. keratinised stratified squamous epithelium and dense chronic
inflammatory infiltrates within the connective tissue wall
Inflammatory collateral cysts (Inflammatory paradental (Figure 3b). This histological appearance would be indistin-
cyst, Mandibular infected buccal cyst) guishable from a radicular cyst or from an inflamed periodontal
Collateral cysts occur on the lateral, usually buccal, aspect of a pocket lining. The cyst forms as a ‘pocket’ and the lumen is
partially erupted vital tooth and comprise between 2% and 7% of
all odontogenic cysts.1,3,7 They affect a wide age range, but
usually occur below the age of 50. There is little gender differ-
ence, with a M:F ratio of 1:0.7. Collateral cysts were first fully
described by Craig in 197610 who coined the term ‘paradental
cyst’, but three variants have now been described.3,11 They most
frequently occur in the posterior mandible (60%) associated with
partially erupted mandibular third molars (wisdom teeth) with a
history of pericoronitits. Inflammation stimulates the reduced
enamel epithelium to proliferate and form the cyst lining. About
35% of collateral cysts occur in children, usually at the buccal
aspect of an erupting first molar, and have been called mandib-
ular infected buccal cyst, or juvenile paradental cyst.3 Rarely,
collateral cysts may arise in association with partially erupted
teeth at other sites, including the upper canines and lower
premolars.
Radiology of collateral cysts shows a ‘cupping out’ of the Figure 2 Low power image of a residual cyst with uninflamed wall and thin
alveolar bone adjacent to the partially erupted tooth crown epithelial lining.

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 MINI-SYMPOSIUM: PATHOLOGY OF THE JAWS

Figure 3 Collateral cysts. (a) Cropped panoramic radiograph showing corticated radiolucency distal to a partially erupted left mandibular third permanent
molar tooth. (b) Histology shows a hyperplastic arcaded epithelial lining and inflammatory infiltrate, similar in appearance to a radicular cyst.

usually in continuity with the oral cavity through an opening in circumferentially around the crown of an impacted tooth
the periodontal tissues. Treatment is by enucleation usually (Figure 4a). The lesion is well demarcated and corticated. It is not
coupled with extraction of the adjacent tooth. Recurrence is uncommon for other lesions to simulate a dentigerous cyst
unlikely, unless the source of inflammation continues. radiographically, and full radiographic assessment is essential.
Odontogenic keratocysts and ameloblastomas are also common
Developmental odontogenic cysts in the mandibular third molar region and both may envelope the
crown of an impacted wisdom tooth and resemble a dentigerous
Odontogenic cysts with a developmental aetiology occur with no
cyst. Other mimics include radicular cysts from overlying de-
obvious clinical cause. Many of the developmental cysts show
ciduous teeth, and collateral cysts. In younger patients, amelo-
overlapping histopathological features, and a diagnosis may only
blastic fibroma must be considered. Dilated or hyperplastic
be reached after careful consideration of clinical and radio-
follicles are also frequently taken to be dentigerous cysts. As a
graphic evidence, particularly in the presence of secondary
rule, if the follicular space is >4 mm it is more likely to represent
inflammation.
a cyst than an enlarged follicle.13
Dentigerous cysts The histopathology is that of a typical developmental cyst,
Dentigerous cysts embrace the crown of an unerupted tooth and with a thin regular non-keratinised stratified squamous epithe-
arise from the remnants of the dental follicle. They are lined by lium overlying an uninflamed fibrous connective tissue wall
epithelium that derives from the reduced enamel epithelium. The (Figure 4b). If possible, it is important to note, macroscopically,
most common type of dentigerous cyst develops around the any association between the soft tissue cyst wall and its attach-
crown of an unerupted, impacted tooth and attaches to it at the ment to the amelocemental junction (the interface between the
amelocemental junction. The second type overlies an erupting tooth crown and root) of the tooth. Common pitfalls arise if the
tooth and is called an eruption cyst. There have been many cyst is secondarily inflamed, or long standing. Mucous meta-
theories regarding the pathogenesis of dentigerous cysts. The plasia (24%) and even cilia formation (11%) have been noted in
most accepted theory is that fluid accumulates between the
reduced enamel epithelium and the crown of the unerupted or
erupting tooth. The hydrostatic pressure caused by the fluid
The frequency of the most common impacted permanent
accumulation results in expansion of the dental follicle and cyst
teeth and frequency of dentigerous cyst site (Adapted
formation.3
from Brown et al. 198212)
Dentigerous cysts are the most common developmental
odontogenic cyst. In a 30-year study by Jones et al. in which they Tooth Impacted (%) Dentigerous cyst
reviewed 7171 odontogenic cysts, they comprised 18% of all involvement (%)
odontogenic cysts and 58% of developmental odontogenic
cysts.7 In paediatric populations they account for 30% of the total Mandibular third molar 48.1 45.7
number.8 Overall, dentigerous cysts are most frequently Maxillary third molar 29.6 5.4
encountered in association with impacted third molar (wisdom) Maxillary canine 11.9 19.6
teeth, but their distribution is, not surprisingly, directly compa- Mandibular canine 3.5 3.8
rable to the frequency of impacted teeth (Table 3).12 Mandibular second premolar 3.3 7.6
Radiographically, a dentigerous cyst presents as a unilocular Maxillary second premolar 2.2 3.8
radiolucency which may lie centrally, laterally or
Table 3

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 MINI-SYMPOSIUM: PATHOLOGY OF THE JAWS

similar to that of the dentigerous cyst, however, trauma from

masticatory forces may contribute to a chronic inflammatory
infiltrate within the surrounding connective tissue.
Enucleation of the cyst and extraction of the involved tooth is
usually advocated, although marsupialisation may be indicated
for eruption cysts where tooth eruption is desired.

Gingival cyst of infants (Gingival cyst of newborns)

Babies are often born with small yellow or cream nodules on
their gingival or palatal mucosa, which are often referred to as
Epstein’s pearls or Bohn’s nodules. Those that occur on the crest
of the alveolar ridge are known as gingival cysts of infants and
are odontogenic in origin, developing from remnants of the
dental lamina (the “glands of Serres”). Nodules that develop
elsewhere, such as the midline of the palate, are not odontogenic
in origin and are not discussed here. Gingival cysts are usually
small and oval, less than 2e3 mm in diameter. They usually
comprise a thin parakeratinised stratified squamous lining with
desquamative keratin filling the lumen. No treatment is required
as these cysts naturally degenerate or fuse with the overlying
surface epithelium and expel their contents. They are very
common and may be found in 13% or more of newborns.15

Gingival cyst of adults

Gingival cysts of adults are uncommon and are frequently
confused with the lateral periodontal cyst. They are thought to
arise from the epithelial remnants of the dental lamina which
become entrapped in the soft tissues overlying the alveolar bone.
They are found on the attached gingivae as small (<1 cm) pink or
bluish sessile swellings. The frequency is reported to range from
0.2 to 3%.3,7 They present in a wide age range from 23 to 70
years, with a predilection for females (F:M, 2:1) and are most
common in the premolar-canine area of the mandible, or in the
anterior maxilla. Radiographic imaging is usually unhelpful,
although occasional erosion of the superficial bone results in a
Figure 4 Dentigerous cyst. (a) Cropped panoramic radiograph showing
well defined, corticated radiolucency enveloping the crown of an faint ‘saucer-like’ oval or round defect. Histological examination
impacted left mandibular third permanent molar tooth (arrowed). (b) High shows a thin 1e4 cell thick stratified squamous epithelial lining
power image of uninflamed cyst wall with thin, regular, non-keratinised supported by an uninflamed fibrous connective tissue wall
epithelium. In places the lining is only two cell layers thick, similar to (Figure 5). Multilocular lesions have been reported and epithelial
reduced enamel epithelium. plaque-like thickenings may also be seen. Treatment is by local
excision.
dentigerous cysts14 so it can be confused with other odontogenic
cysts, especially the glandular odontogenic cyst (GOC). Charac- Lateral periodontal cyst
teristic diagnostic differentiating features are discussed later in Lateral periodontal cysts arise in association with the lateral
the GOC section. surface of a tooth root. They are usually asymptomatic and found
Eruption cysts are essentially dentigerous cysts associated as incidental radiographic findings, where they appear as a well
with an unerupted tooth in a normal orientation and which may demarcated corticated radiolucency usually about 5 mm in
otherwise erupt. They are found almost exclusively in children diameter. They account for just 0.4% of odontogenic cysts,7 and
and occur twice as often in males than females (M:F, 2:1)8 and are found predominantly in the mandibular premolar area, fol-
are most frequently associated with mandibular deciduous cen- lowed by the anterior maxilla. Studies show they occur within a
tral incisors and first permanent molars. Bilateral symmetrical wide age range (21e82 years) with an overall equal gender
lesions are not uncommon. When impeded by the cyst, the distribution.3,7
unerupted tooth lies superficially within the alveolar bone and The lateral periodontal cyst has a similar histological
the cyst presents in the overlying soft tissues as a bluish soft appearance to the gingival cyst of adults. The cyst is lined by a
fluctuant swelling on the alveolus at the site of the missing tooth. thin layer of non-keratinised squamous epithelium overlying an
They can often be diagnosed on clinical appearance alone but a uninflamed fibrous wall. However a characteristic feature of
radiograph will confirm the presence of the underlying tooth and these lesions is the presence of epithelial plaques or thickenings
confirm its orientation. Often, they rupture due to normal with whorling of the epithelial cells, often with clear cell change
masticatory forces and no treatment may be needed. Histology is (Figure 6).

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 MINI-SYMPOSIUM: PATHOLOGY OF THE JAWS

variant of the lateral periodontal cyst, it is not surprising that it

commonly presents in similar sites, favouring the premolar
mandibular region and anterior maxilla. The BOC differs some-
what from the lateral periodontal cyst due to its larger size and
multicystic nature. Radiographically they present similarly, at the
lateral aspect of a tooth root, but they are usually much larger and
have a multilocular appearance. They typically have a corticated
well-defined margin, and significant tooth displacement may be
present. This multilocular appearance can make the BOC a diag-
nostic dilemma. The differential diagnosis for such a multilocular
radiolucency would include the odontogenic keratocyst, amelo-
blastoma and odontogenic myxoma, therefore correct histological
analysis is important for correct patient management.17
Histological and radiographic features are often enough to
provide a diagnosis. BOC are usually small (<3 cm) and histo-
logically show multiple cystic spaces lined by thin non-
Figure 5 Low power view of a gingival cyst of adults. The cyst lies within keratinised stratified squamous epithelium, with occasional
the lamina propria just below the oral epithelium. The thin epithelial plaque-like thickenings, however, immunohistological tech-
lining is surrounded by uninflamed connective tissue. At the lower right niques may sometimes be helpful to differentiate it from other
there is small plaque-like thickening and a papillary projection. lesions. Absence of CD56 and calretinin expression help to rule
out ameloblastoma.17,18
Many aetiological theories have been proposed, one of which The BOCs multicystic nature results in a tendency to recur,
is that the cyst obtains its epithelial lining from reduced enamel with a reported recurrence rate of 40%, likely due to incomplete
epithelium. Initially there is expansion of the tooth follicle, but as removal, therefore long term follow-up is recommended after
eruption occurs, the follicle remains within the bone and is dis- surgical excision.16 It is therefore important to differentiate it
placed to the lateral aspect of the tooth in continuity with the from the lateral periodontal cyst.
periodontal ligament. They may also arise from rest cells of
Malassez in the periodontal ligament. Glandular odontogenic cyst (Sialo-odontogenic cyst)
Lateral periodontal cysts are treated by simple enucleation, The glandular odontogenic cyst (GOC) is a rare lesion, account-
which usually allows complete bony healing. ing for just 0.2% of all odontogenic cysts. It presents in middle
age (range: 31e81 years, mean 51 years) with a male predomi-
Botryoid odontogenic cyst nance (M:F ¼ 4:1).7 It was first described as a distinct entity in
The botryoid odontogenic cyst (BOC) is a multilocular variant of 1987 by Padayachee and Van Wyk who recognised that, although
the lateral periodontal cyst and as such it is usually grouped it shared features with lateral periodontal, botryoid odontogenic
together with the lateral periodontal cyst. Like many odontogenic and central mucoepidermoid cysts, it warranted its own recog-
cysts, it presents in a wide age range. Santos et al. (2011) reviewed nition.19 Eighty percent occur in the mandible, particularly in the
a series of 10 cases of botryoid odontogenic cyst and found the age anterior region, accounting for 60% of lesions. Its usual pre-
range to be 34e83 years with a mean age of 60 years.16 There was a sentation is that of a bony swelling, however, asymptomatic
male predominance, with 70% of cases observed in males. As a cases have been reported. Radiographically, the GOC presents as
a well-defined multilocular radiolucency which may have a
sclerotic or scalloped margin. The lesion may reach a large size
and CT imaging can be particularly useful to show the extent of
the lesion, which may cause erosion of the cortical plates
(Figure 7). Tooth displacement and root resorption have been
reported in up to a quarter of cases.
The GOC shows a variety of histological features, many of
which are shared with other lesions, including the dentigerous,
botryoid, and surgical ciliated cysts, and with intraosseous
mucoepidermoid carcinoma. For this reason Kaplan et al.
compared a series of GOC to similar lesions and suggested major
and minor criteria which can be used to differentiate GOC from
other, similar, cystic lesions.20 A similar multicentre retrospec-
tive review by Fowler et al. (2011) analysed 46 cases with the
aim of identifying the histological features necessary for diag-
nosis.21 Histology shows a multilocular cyst with an uninflamed
fibrous wall lined by epithelium with variable appearances
Figure 6 Lining of a lateral periodontal cyst showing the typical histology
(Figure 8a). Typically there is evidence of small microcysts or
of a developmental odontogenic cyst: thin, regular, epithelium sur-
rounded by an uninflamed connective tissue wall. In this example there is duct-like structures (Figure 8b), which often contain mucus, as
formation of clear cells and a small plaque-like thickening. well as goblet cells (Figure 8c). Most lesions also show plaque-

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 MINI-SYMPOSIUM: PATHOLOGY OF THE JAWS

(Figure 8d arrows). These are not specific to GOC, but are seen in
all lesions and are considered necessary for the diagnosis.21
Other features which Fowler et al.21 identified as important in
the diagnosis included papillary projections in 85% (Figure 8d),
clear cells (89%), apocrine secretion (91%) and cilia (22%). Of
these, microcysts, epithelial thickenings, clear cells and variable
thickness of the lining were found to be most specific for GOC
(Table 4). Kaplan et al.20 showed that these features were major
criteria, which should be present for diagnosis.
Studies have shown that the GOC has a high recurrence rate of
around 50% if conservative management is carried out, with the
first recurrence averaging at 8 years post-treatment.21 Multiple
recurrences are not unusual.
The behaviour of the GOC and the histological features of a
cystic lesion with squamous and mucous elements may lead to
confusion with intraosseous mucoepidermoid carcinoma
(CMEC). Some have suggested that GOC and CMEC may be part
Figure 7 CT image of a glandular odontogenic cyst in the anterior
of the same spectrum or that CMEC may arise from GOC. The
mandible. The cyst extends from the left molar region to the right pre-
molar region and has a multiloculated, scalloped outline. The lesion has
specific criteria identified by Fowler et al.21 are not present in
eroded the buccal/labial cortical plate of the mandible. CMEC and are useful in the differential diagnosis. In addition,
CMEC may be infiltrative and show solid areas with the typical
admixture of epidermoid or intermediate cells and mucous cells.
like thickenings or spheres, with whorling of the epithelial cells, More recently, Bishop et al.22 showed that GOC do not show
similar to the lining of lateral periodontal or botryoid cysts MAML2 rearrangements that are characteristic of CMEC.
(Figure 8d). A characteristic feature is the presence of superficial Although it is possible that CMEC may arise from GOC, the
eosinophilic columnar cells, sometimes called “hob-nail’ cells current evidence suggests that they are separate entities.

Figure 8 Glandular odontogenic cyst. (a) A low power image shows a multilocular, botryoid cystic morphology. Even at this low power, the variable
thickness of the epithelial lining can be seen. (b) Typical features show a lining of variable thickness with many microcystic or duct-like structures.
Throughout the lining superficial cuboidal cells can be seen and cilia are evident at centre left. (c) Medium power image showing thickenings and
prominent mucous or goblet cells. (d) Medium power image showing short papillary projections and epithelial thickenings with a spherical whorling
pattern. The arrows highlight the superficial eosinophilic cuboidal or “hob-nail” cells.

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 MINI-SYMPOSIUM: PATHOLOGY OF THE JAWS

ameloblastomatous proliferations and may recur and should be

The most helpful distinguishing histological features for regarded as neoplasms. A new classification should revert back
GOC (Adapted from Fowler et al. 201121). Those marked to the original terminology and classify the cyst as calcifying
* were the most specific for GOC odontogenic cyst and the neoplasm as dentinogenic ghost cell
Histological feature Number (%) of cases tumour.
COC is most commonly seen in the maxilla, usually anterior to
Eosinophilic cuboidal (“hob-nail”) cells 46 (100%) the first molar tooth, presenting as a slowly enlarging swelling.
Apocrine secretion 42 (91.3%) Its characteristic microscopic feature is the presence of a simple
Presence of microcysts 44 (95.7%)* lining resembling ameloblastoma with ghost cells, which may
Clear cells 41 (89.1%)* calcify (Figure 9).
Variable thickness of cyst lining 41 (89.1%)*
Papillary projections 39 (84.8%) Odontogenic keratocyst (OKC) vs. keratocystic odontogenic
Mucous cells 33 (71.7%) tumour (KCOT)
Plaque-like thickening/epithelial spheres 31 (67.4%)* The term ‘odontogenic keratocyst’ was first used in the 1950s to
Multiple compartments/multilocular 29 (21.7%) describe any odontogenic cyst in which keratin had formed (for a
Cilia 10 (21.7%) full review see3). Subsequently, however, it became apparent
that keratinisation was quite often seen in a range of jaw cysts
Table 4 and the term keratocyst became reserved for a specific cyst type
with a range of features which distinguish it as a distinctive en-
tity. The odontogenic keratocyst (OKC ) thus appeared in both the
The cyst-tumour interface 1971 and 1992 WHO classifications.
The 2005 WHO classification of head and neck tumours4 did not The OKC is the third most common odontogenic cyst (after
include a classification of cysts and also reclassified a number of radicular and dentigerous cysts) and comprises about 12% of all
lesions, previously regarded as cysts, as neoplasms. Despite the cysts occurring in the maxillofacial region.3,7 This lesion affects a
publication being a decade old, these new classifications still fail wide age range, with a peak incidence in the second and third
to gain full acceptance, with many texts still retaining the old decades. Most studies report a male predilection.
terminology.3,6 Moreover, there has been no definitive revision Radiographically, the OKC presents as a well demarcated
of cyst classifications since 1992. Resolution of the cyst-tumour corticated radiolucency. They often have scalloped margins and
interface would allow a much needed definitive classification about 25% are multilocular. Most cause tooth displacement. As
for head and neck cysts to be formulated. these cysts typically expand in an antero-posterior direction, they
often present very late and therefore are frequently identified
Calcifying odontogenic cyst (COC) vs. calcifying cystic during routine radiographic examination and may reach large
odontogenic tumour (CCOT) sizes (Figure 10). The majority of OKC (75%) occur in the
CCOT is part of a group of lesions characterised by the presence mandible and overall about half are located at the angle and
of ghost cells, the key features of which have been reviewed by ascending ramus. Many of these may be associated with an
Brierley & Hunter (vide infra). The epithelial lining of CCOT re- unerupted third molar (wisdom) tooth and occasionally envelop
sembles ameloblastoma, but most lesions have a simple cystic the crown of the tooth in a dentigerous relationship.
morphology. The 1992 WHO classification23 regarded these The histology of the OKC is quite distinctive and histological
cystic lesions as non-neoplastic, but also described a solid variant diagnosis is rarely a problem. The connective tissue wall is
with ameloblastomatous proliferations which they regarded as a uninflamed and is lined by thin parakeratinised stratified
true neoplasm and called dentinogenic ghost cell tumour. In the
2005 WHO classification the cystic and solid variants were
described as separate entities, and the term calcifying odonto-
genic cyst was replaced by CCOT, which the authors regarded as
a neoplasm. However, its true nature remains uncertain. In a
detailed multicentre review of ghost cell lesions and their ter-
minology Ledesma-Montes et al.24 showed that over 85% of
CCOTs are simple cysts either alone (65%) or associated with
odontomes (20%). Very few showed ameloblastomatous pro-
liferations and only 5% of lesions were solid and described as
true neoplastic dentinogenic ghost cell tumours. These findings
agree with a previous study by Hong et al.25 and both authors
show that simple cystic lesions rarely recur and have a
completely benign course. Hong et al. describe these lesions as
simple cysts and only regard the solid lesions as true neoplasms.
There seems, therefore, to be good evidence that simple cystic
lesions should be regarded as developmental cysts, which arise
Figure 9 Medium power image of a calcifying odontogenic cyst showing
alone or in association with other developmental lesions, espe- an area of thickening with accumulations of ghost cells in the epithelial
cially odontomes. Solid lesions, however, show solid lining.

DIAGNOSTIC HISTOPATHOLOGY 21:9 366 Ó 2015 Elsevier Ltd. All rights reserved.
 MINI-SYMPOSIUM: PATHOLOGY OF THE JAWS

(Figure 10), an autosomal dominant condition resulting in mul-

tiple odontogenic keratocysts in combination with multiple
naevoid basal cell carcinomas and skeletal abnormalities.
In the latest WHO classification4 the OKC was renamed ker-
atocystic odontogenic tumour and was reclassified as a
neoplasm. The authors argued that the high recurrence rate,
permeative growth pattern and the presence of satellite cysts and
budding, all indicate “aggressive” behaviour and are consistent
with a neoplasm (reviewed in3,28). In addition, OKC are associ-
ated with mutations in the PTCH tumour suppressor gene which
is also responsible for basal cell carcinomas.29 This genetic
Figure 10 Odontogenic keratocysts. A panoramic tomography of the jaws change has been taken as indicative of neoplasia, but although
showing two large cysts in the left and right mandible. The patient suffers
PTCH gene alterations may be found in up to 85% of OKC
from the naevoid basal cell carcinoma syndrome (NBCCS) and has mul-
associated with NBCCS they are only found in 30% of sporadic
tiple cysts. Both are well defined and corticated. The lesion on the (pa-
tient’s) left is multilocular and scalloped and has displaced the second cysts.29 In addition, changes in PTCH have been found in a range
and third molar teeth. It embraces the crown of the second molar in a of non-neoplastic lesions, including dentigerous cysts,30 indi-
dentigerous relationship. cating that neoplasia cannot be simply defined on the basis of
single genetic events. The name change and evidence for
neoplasia therefore remains controversial and a study in 2012
squamous epithelium with a characteristic corrugated surface.
showed that 81% of papers from an online PubMed search still
The basal epithelial layer is well defined, with palisaded basal
used the term ‘odontogenic keratocyst’,27 showing that this new
cells with reversal of nuclear polarity (Figure 11). The cyst
classification has not been accepted. Furthermore, resolution of
lumen, if intact, may contain desquamated keratin. Often OKCs
cysts after marsupialisation is not consistent with a neoplastic
become traumatised, and when inflamed the epithelial lining can
origin.27 It is recommended therefore that we revert back to the
lose these characteristic features and resemble an inflammatory
original and well accepted terminology of OKC.6
cyst. Careful examination of the whole lining becomes essential
to identify the typical features, but if inflammation is extensive, Orthokeratinised odontogenic cyst as a distinct clinical entity
diagnosis may be difficult. The orthokeratinised odontogenic cyst (OOC) is an uncommon
Treatment is most often by enucleation or surgical resection, developmental cyst characterised by a lining of orthokeratinised
however, the recurrence rate is high. A systematic review found stratified squamous epithelium. Although first described in 198131
an overall recurrence rate of about 25%, but this was reduced to it is still regarded as a variant of OKC. OOC predominantly occurs
8% using enucleation with Carnoy’s solution.26 Recurrence after in the third and fourth decades with a mean age of 33.5 years and
resection is very rare (<2%). The level of recurrence may be due has a male predilection.32 The clinical presentation is similar to
to incomplete removal as well as the presence of ‘daughter cysts’, that of OKC, often showing cortical expansion and swelling in the
which may persist following treatment. Large lesions may be posterior mandibular region. Radiographic features are also
marsupialised followed by enucleation. It has been shown that in similar, with the cyst appearing as a well-circumscribed uni- or
some cases marsupialisation alone may be effective and that the multi-locular radiolucency.33 Tooth displacement is not uncom-
cyst lining may revert to normal mucosal epithelium.27 mon. As its name suggests, histological examination reveals an
These cysts usually occur as solitary lesions but multiple cysts orthokeratinised stratified squamous cell lining with a prominent
do occur and are usually associated with naevoid basal cell granular cell layer (Figure 12). There is no recorded case of OOC
carcinoma syndrome (NBCCS, GorlineGoltz syndrome)

Figure 11 A high power view of the epithelial lining of an odontogenic

keratocyst exhibiting parakeratinisation with a corrugated surface pattern Figure 12 High power view of the lining of an orthokeratinised odonto-
with prominent palisading of basal cells. Reverse nuclear polarity of the genic cyst. A prominent granular cell layer is noted within the orthoker-
basal cells can also be seen. atinised stratified squamous epithelium. The basal layer is not prominent.

DIAGNOSTIC HISTOPATHOLOGY 21:9 367 Ó 2015 Elsevier Ltd. All rights reserved.
 MINI-SYMPOSIUM: PATHOLOGY OF THE JAWS

occurring with the naevoid basal cell carcinoma syndrome and, classification we have proposed that the next WHO classification
unlike OKC, the lesions very rarely recur even following simple should include the odontogenic cysts and that we should revert
enucleation. There is good evidence therefore that OOC should be back to the original terminology shown in the working classifi-
regarded as an entity and should stand alone in the classification of cation in Table 1.6 A
developmental odontogenic cysts.

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DIAGNOSTIC HISTOPATHOLOGY 21:9 369 Ó 2015 Elsevier Ltd. All rights reserved.