Oral Maxillofacial Surg Clin N Am 16 (2004) 333–354

Adenomatoid odontogenic tumor

Gordon M. Rick, DDS, MSa,b,*

aLoma Linda University, School of Dentistry, Loma Linda, CA, USAbScripps Oral Pathology Service, 5190 Governor Drive, Suite 106, San Diego, CA 92122-2848, USA

The adenomatoid odontogenic tumor (AOT) is lial odontome’’ is almost certainly an AOT. The first

included in classifications of odontogenic tumors

because it occurs only in the tooth-bearing area of

the jaws and because of its histomorphologic resem-

blance to components of the dental organ (tooth

germ). Although numerous cases have been reported,

AOT generally is considered to be an uncommon

tumor. Its distinctive, although not pathognomonic,

clinicopathologic profile is unique among odonto-

genic tumors because most lesions occur in associa-

tion with an unerupted maxillary cuspid in teenage

girls. Although the so-called ‘‘duct-like structures’’

are a unique (although not always present) micro-

scopic feature of AOT, a diagnostic pitfall has been

delineated. No unequivocal recurrences have been

reported despite known incomplete removal of

some tumors.

History and terminology

The AOT, like many odontogenic tumors, has an

interesting history. The search for the first identifiable

case is challenging because many names have been

used for it, some early cases were grouped with other

superficially similar tumors, and especially because

photomicrographic documentation was not available

in that era. The earliest irrefutable case that I found

was reported from Norway by Harbitz [1] in 1915 as

‘‘adamantoma’’; however, the case reported by James

and Forbes [2] from England in 1909 as an ‘‘epithe-

1042-3699/04/$ – see front matter D 2004 Elsevier Inc. All right

doi:10.1016/j.coms.2004.04.001

This work was supported partially by Fellowship No.

1FO6 TW00820-01 from the National Institutes of Health.

* Scripps Oral Pathology Service, 5190 Governor

Drive, Suite 106, San Diego, CA 92122-2848.

E-mail address: grick@scrippsoralpathology.com

acceptable American case that I found was reported

in 1916 as ‘‘tooth germ (or chorioblastomatous) cyst

of the jaw’’ by Wohl [3] of Omaha, Nebraska.

Although he did not propose a specific name for

it, Stafne [4] reported the first series of AOT in 1948

under the title ‘‘epithelial tumors associated with

developmental cysts of the maxilla’’. Presumably,

he chose not to use ‘‘adenoadamantoblastoma’’ or

‘‘adamantoblastoma, adenoma type’’ because none of

his three cases resembled the case that was illustrated

under those terms in the first several editions of

Thoma’s [5] Oral Pathology textbook. Thoma’s con-

cept of this tumor obviously was influenced by his

earlier work in salivary gland embryology as seen in

his explanation of the derivation of this lengthy term

[6]. He believed that in this variant of the adamanto-

blastoma ‘‘the epithelium in its differentiation may

tend toward glandular structure and arrangement.

This is due to the fact that the oral epithelium has

the potential ability to form glandular as well as

dental structures.’’ In a later case report he goes to

even greater lengths to defend this belief [7].

Bernier and Tiecke [8] were the first to publish a

case using the name ‘‘adeno-ameloblastoma.’’ The

superb photomicrographs in their later series of nine

cases from the Armed Forces Institute of Pathology

undoubtedly made a profound contribution to the

eventual recognition that AOT is not merely a type

of ameloblastoma [9]. Although they emphasized the

younger average age of affected patients, the fre-

quent association with impacted teeth, and the lack

of recurrence (with follow-up ranging up to nearly

15 years), they did not divest this innocent lesion of

its taxonomic link to the ameloblastoma.

A classification of odontogenic tumors that listed

‘‘simple ameloblastoma’’ and ‘‘adenoameloblastoma’’

as separate entities ‘‘was presented for further consid-

s reserved.

G.M. Rick / Oral Maxillofacial Surg Clin N Am 16 (2004) 333–354334

eration but was not adopted’’ at the fifth annual

American Academy of Oral Pathology meeting in

1951 [10]. This failed to prevent the subsequent path

to a more universally accepted term that reflected the

lesion’s true nature from being strewn with numerous

rejected terms with varying degrees of nosologic

merit. An abbreviated list of the discarded terms

includes ‘‘cystic complex composite odontome’’ from

England [11], ‘‘an unusual pleomorphic adenoma-like

tumor in the wall of a dentigerous cyst’’ from Singa-

pore [12], ‘‘tumor of enamel organ epithelium’’ from

London [13], ‘‘adenomatoid ameloblastoma’’ from

Japan [14], and ‘‘adenomatoid odontoma’’ from the

United States [15].

In an attempt to ‘‘remove unjust stigma from this

lesion’’ and to eliminate the risk of unnecessarily

mutilating surgery for patients who had the tumor that

seemed to be occurring because of use of the term

‘‘adenoameloblastoma,’’ in 1961, Gorlin et al [16]

introduced the term ‘‘ameloblastic adenomatoid tu-

mor.’’ Shafer et al [17] provided additional support

for this moniker by adopting it in the second edition

of their widely used Textbook of Oral Pathology in

1963. Admitting that this term was an improvement,

and yet, concerned about the remaining ‘‘spector of

ameloblastoma,’’ in 1968, Abrams et al [18] sug-

gested consideration of the term ‘‘odontogenic adeno-

matoid tumor.’’ This paper was in press and was not

available to Philipsen and Birn [19] when they

proposed the name ‘‘adenomatoid odontogenic tu-

mor’’ in 1969. Shortly thereafter, the latter term was

adopted in the initial edition of the World Health

Organization’s (WHO) Histological Typing of Odon-

togenic Tumors, Jaw Cysts and Allied Lesions in

1971 [20] and was retained in the second edition in

1992 [21]. It subsequently became the generally

accepted nomenclature and apparently has facilitated

effective management of patients who have the lesion

ever since.

Therefore, although their concern about keeping

‘‘disease name’’ terminology current is laudable, I

disagree with the following statements by the re-

spected American surgeon-pathologist team, Marx

and Stern [22], in their recent 10-pound tome. They

state that ‘‘the catchy abbreviation AOT prevailed,

which unfortunately is also incorrect’’ and an ‘‘out-

dated term’’ and ‘‘therefore, the more appropriate term

is adenomatoid odontogenic cyst or AOC.’’ For a

lesion that generally is not a fluid-filled pathologic

cavity and often has a predominantly solid compo-

nent, it is difficult to understand how this change can

be considered an improvement or how it will contrib-

ute to better clinical management of patients who have

this bland tumor.

In the nearly 90 years since Harbitz clearly de-

scribed and illustrated his case, more than 800 cases

have been reported—most as individual case reports

because only 10 series with seven or more previously

unreported cases were found in the English-language

literature [9,18,23–30]. In 1991, Philipsen et al [31]

thoroughly reviewed the extensive world literature

and, on the basis of the 499 cases that they considered

acceptable, provided a clinical, radiographic, and

microscopic profile of the tumor that leaves few

remaining questions as to its diagnosis, biologic

behavior, and management. A subsequent update that

was based on more than 600 cases was published in

1998 [32] and AOT warrants an entire chapter in

Reichart and Philipsen’s [33] recent reference work

Odontogenic Tumors and Allied Lesions. It will be

interesting to compare this book with the chapter on

odontogenic tumors in the latest WHO ‘‘Blue Book’’

series, Pathology and Genetics of Tumours of the

Head and Neck that is expected later this year.

Classification

The classification of odontogenic tumors has been

the source of endless fascination and frustration for

microscopists for more than a century. Gabell et al

seem to be the first investigators to divide this group

of complex tumors into categories based on the

embryonal tissue of origin—epithelial, composite

(epithelial and mesoblastic), and connective tissue

(mesoblastic) [34]. The refinement of their scheme,

suggested by Thoma and Goldman [35], forms the

basis of most classifications to the present. Although

it is not known how closely odontogenic tumors

mimic the complicated process of odontogenesis, a

classification of odontogenic tumors that is based on

the inductive influences between epithelial and mes-

enchymal tissues during odontogenesis was proposed

by Pindborg and Clausen [36] and was modified

slightly by Gorlin et al [37,38]. Although the position

of AOT has varied in subsequent versions of the

classification [20,21,33], it always has been included

in the epithelial category rather than the mixed group,

despite the presence of abnormal hard tissue elements

within the tumor. Its subclassification by some inves-

tigators as a tumor of ‘‘odontogenic epithelium with-

out odontogenic ectomesenchyme’’ may need to be

reconsidered in view of the cases that are discussed

later that contain significant amounts of dentin, and

rarely, enamel matrix. The classification of AOT

simply as an epithelial tumor, however, also was sup-

ported in a recent immunohistochemical study that

used bone morphogenetic protein (BMP) to divide

G.M. Rick / Oral Maxillofacial Surg Clin N Am 16 (2004) 333–354 335

odontogenic tumors into those that were purely

epithelial (ie, negative for BMP) and those that

formed enamel, dentin, cementum, or bone (ie, posi-

tive for BMP) [39]. As new tumor-related proteins are

discovered [40] and gene-expression profiles are

developed for odontogenic tumors, more meaningful

classifications of these neoplasms may become avail-

able. However, it is likely to be some time before

the results of these studies will lead to more specific

diagnoses, more rational therapy, or more reliable

prognostication for patients that suffer from these

uncommon tumors.

Hamartoma versus neoplasm

The long-term debate as to whether AOT is an

anomalous developmental hamartomatous growth or

a true benign neoplasm has not been settled and it

likely never will be. This is due, in part, to difficulties

with precise definitions of what seem to be, at least

superficially, simple terms and concepts. Lucas and

Pindborg [41] eloquently discussed this problem as it

pertains to odontogenic tumors.

Meanwhile, investigators who prefer to consider

AOT to be a hamartoma [18,20,24,32,42–44] point

to the limited size of most cases (attributed to its

minimal growth potential) and to the lack of recur-

rence (even following definitely incomplete removal)

to support their belief. Those who prefer to consider

AOT to be a nonaggressive noninvasive benign

neoplasm [9,13,45–48] presumably believe that the

limited size of most cases stems from the fact that

most are detected early (often on a routine dental

radiograph) and removed before the slow-growing

tumor reaches a clinically noticeable size. They also

point to the considerable size of some reported cases

that had gone undetected or untreated for many years

and resulted in facial asymmetry and distortion that

rival many ameloblastomas [48–51]. Additional sup-

port comes from the microscopic features of the

lesional tissue that show greater departure from the

arrangement of the normal odontogenic apparatus

than should be expected in a developmental anomaly.

Based on currently available evidence, I agree with

Gardner [52] that AOT is ‘‘most appropriately con-

sidered a benign embryonal neoplasm.’’

Histogenesis

Like all other odontogenic tumors, the specific

stimulus that triggers proliferation of the progenitor

cells of AOT is unknown. Because of its exclusive

occurrence within the tooth-bearing areas of the jaws

(most often associated closely with an unerupted or

impacted tooth) and its cytologic resemblance to the

dental lamina and components of the enamel organ,

there is no disagreement that the AOT is of odonto-

genic origin. Since its earliest recognition as an entity,

however, many investigators have debated the histo-

genesis of AOT and the nature of the acellular

materials within the tumor. Even though their argu-

ments were based solely on routine light microscopy

and nonspecific histochemistry, their speculations

are interesting, and in some cases, farsighted. Be-

cause these theories have been discussed exhaustively

in the literature, they will not be reiterated here.

Although the precise progenitor cell or tissue of

AOT has not been settled, the development of the

transmission electron microscope (TEM) and the

availability of an ever-increasing variety of specific

antibodies for immunohistochemical (IHC) studies

have engendered considerable progress during the

past 30 to 40 years. Studies that used these tools

have confirmed that some AOT tumor cells are

equipped metabolically similar to ameloblasts during

particular stages of amelogenesis and are capable of,

and responsible for, generating the variety of extra-

cellular materials that commonly are observed in

these microscopically-fascinating tumors.

Thirteen ultrastructural studies [53–65] and 10 im-

munohistochemical studies [39,66–75] of AOT exist

in the English-language literature. Because formalin

fixation is prone to cause tissue artifacts at the TEM

level of observation, it should be mentioned that only

9 of the 17 tumors that were examined had been fixed

optimally for TEM. Also, because of the histomor-

phologic variation that exists between and within

examples of this tumor, it is possible that some of

the various tumor constituents may not have been

scrutinized fully (tissue samples for TEM study are

1-mm cubes). I have attempted to compare and har-

monize the results of these two branches of investi-

gation (TEM and IHC) but this proved challenging,

partially because of the different terminology that is

used. Some interesting observations have emerged,

however, and for the sake of brevity, the following

update concentrates on decisive findings although

equivocal observations also may be important.

Generally, TEM studies have confirmed the

resemblance of the various AOT tumor cells to

counterparts in the enamel organ. The presence of

hemidesmosomes and basal lamina at the luminal

pole of the cells that form the ductlike structures

conclusively rules out Thoma’s notion of a dual

salivary and odontogenic origin for AOT [57]. This

G.M. Rick / Oral Maxillofacial Surg Clin N Am 16 (2004) 333–354336

was corroborated by the negative reactivity of these

cells to lactoferrin and a1-antichymotrypsin anti-

bodies [74]. The duct-forming cells also exhibit

secretory granules and coated vesicles near the lumi-

nal pole which renders them highly reminiscent of

preameloblasts; these structures also were reported in

the nonduct-forming columnar cells in various pat-

terns [57–59,61]. IHC studies revealed differences

between the duct- and nonduct-forming cells; the

nonduct-forming columnar cells expressed ameloge-

nin reactivity, whereas the duct-forming cells showed

no reactivity to amelogenin [71] or the other enamel

matrix protein (enamelin and sheathlin) antibodies

[68,69,72]. Additionally, the eosinophilic material

that lines the periluminal surface (the so-called ‘‘hya-

line ring’’) resembled basal lamina by way of TEM

[53,56,57,60] and coexpressed basement membrane

extracellular matrix proteins (laminin, type IV colla-

gen, heparan sulfate proteoglycan, fibronectin) and

enamel matrix proteins (amelogenin, enamelin) [66,

68,71,75]. The same pattern of reactivity was seen

in the occasionally more abundant intraluminal ma-

terial. The droplets of eosinophilic material (the so-

called ‘‘hyaline’’ or ‘‘tumor droplets’’) between the

cuboidal, low columnar, and polygonal cells that

form the cell-rich tumor nodules exhibit TEM fea-

tures that are consistent with enamel matrix-like ma-

terial [59,60,65]. They also colocalized enamel matrix

and basement membrane antibodies and enamely-

sin (a tooth specific protease) antibodies [66,68,69,

71–73,75]. The tumor cells immediately adjacent to

the droplets also demonstrate cytoplasmic positivity to

the enamel protein, sheathlin [72]. These findings

provide additional support for the odontogenic origin

of AOT and indicate that some of the epithelial tumor

cells display features that are consistent with neoplas-

tic (pre)ameloblasts in a state of arrested development,

yet they apparently are metabolically active enough to

produce basement membrane and enamel matrix pro-

teins. It was suggested that the accumulation and

eventual (enamelysin) degradation of these secretory

products are responsible for the development of the

ductlike structures [71] that some investigators prefer

to think of as enclosed spherical microcysts, whether

they are considered as completely intraepithelial or

stromal in nature.

The spindle cells that are between the cell-rich

nodules resemble ultrastructurally the stellate reticu-

lum and those that are immediately adjacent to the

nodules resemble the stratum intermedium of the

enamel organ. The juxtanodular spindle cells are

amelogenin positive [68], whereas the internodular

spindle cells are nonreactive to amelogenin, ename-

lin, and sheathlin [69,72] which confirms the lesser

degree of differentiation of the latter cells that some

investigators suggested may be the progenitor cells of

the duct-forming cells [59].

The ultrastructural suggestion that the small, irreg-

ular calcifications may be partially composed of atypi-

cal enamel [60] is supported by positive reactivity of

this material to amelogenin, enamelin, and enamelysin

although it is sheathlin negative [69,71–73]. A TEM

study reported that the concentrically-laminated calci-

fied bodies were indistinguishable from calcified amy-

loid [64]. The ultrastructural morphologic variability

that is seen in this class of proteinaceous materials and

the similarity of the b-pleated sheet conformation of

amyloid and enamel must be kept in mind when

amyloid is being discussed. The fine structure of the

large, irregular, globular masses was reported in only

one study where it was conjectured to be atubular

dentin [60]. This must be evaluated further, especially

in view of reported positivity (especially at the pe-

riphery of the masses) to amelogenin and enamelin,

although they were enamelysin negative [69,73].

The gubernaculum dentis

Philipsen et al [76] argued that the AOT arises

from remnants of the successional dental lamina or

the accessional dental lamina (a distal extension of

the dental lamina in the permanent molar region).

Disintegration of the dental lamina complex leads to

numerous epithelial remnants that persist (presum-

ably indefinitely) in the jaws and gingiva following

completion of odontogenesis. According to Hodgson

[77] and expanded and explained by Philipsen et al

[76] and Reichart and Philipsen [33], these epithelial

rests are not distributed haphazardly but are confined

to the gubernaculum dentis—the fibrous connective

tissue that runs in intrabony gubernacular canals from

the bony crypts of all developing permanent tooth

buds to the overlying gingival lamina propria and

which is believed to guide or direct the course of

erupting succedaneous teeth and permanent molars.

Theoretically, eruption of a permanent tooth/teeth

adjacent to an odontogenic tumor may be halted when

the tumor envelopes the crown of the tooth and

disrupts the gubernaculum dentis or the developing

tooth erupts into a hamartomatous or neoplastic mass

and loses the guiding influence of the gubernaculum

dentis—hence a pericoronal lesion associated with an

unerupted tooth. Similarly, if the odontogenic tumor

were to arise from epithelial rests outside the eruptive

path, eruption of the adjacent tooth/teeth would not be

impaired and, following normal eruption, the tumor

would be located lateral, or possibly even apical, to

the erupted tooth/teeth.

G.M. Rick / Oral Maxillofacial Surg Clin N Am 16 (2004) 333–354 337

Epidemiology

The incidence and prevalence of odontogenic

tumors is unknown, largely because most of them

are benign and are not reported to local, regional, or

national tumor registries that compile and track

malignant tumors. AOT accounts for approximately

3% to 7% of odontogenic tumors that are accessioned

by a variety of institutions around the world which

makes it the fourth most frequent odontogenic tumor

[31,32].

Demographic features

Age

Although AOT has been reported in patients from

3 to 82 years of age, its predilection for young

patients is well-established. It is unique among odon-

togenic tumors and unexplainable that more than two

thirds (69%) are diagnosed between the ages of

10 and 19 years; more than half (53%) are diagnosed

in teenagers; 21% are diagnosed between ages 20 and

29; and altogether, 88% are diagnosed in the second

and third decades. Pericoronal (dentigerous, follicu-

lar) AOTs are diagnosed at an earlier age than lesions

that are not in a pericoronal relationship to a tooth,

probably because affected patients seek consultation

concerning failure of the associated tooth to erupt.

The early detection of gingival (peripheral, extraos-

seous) AOTs is likely due to the discovery of a

variably obvious anterior maxillary gingival mass.

Although the average age at the time of excision

of gingival lesions is 13 years (and ranges from 3 to

19 years), the fact that some lesions had already been

present for 3 to 5 years suggests that gingival AOTs

develop at an early age [31,32].

Gender

Overall, the tumor is diagnosed approximately

twice as frequently in women. Although in the third

decade AOT is nearly four times more frequent in

women, in patients who are older than age 30 it is

diagnosed nearly twice as commonly in men. It also

is interesting and unexplainable that the female:male

ratio for gingival lesions is 14:1 [31,32].

Race

Like ameloblastoma, the AOT may be more

common in blacks, but this may be just a ‘‘harvest-

ing’’ phenomenon rather than a true racial difference.

The significant female:male predominance of about

3:1 for reported cases from Sri Lanka and Japan

remains unexplained [31,32].

Clinical features

Anatomic site

Like most odontogenic tumors, AOT may occur

within the jawbones or the gingiva. Radiographic

findings are of more value than clinical findings for

the more than 95% of AOTs that develop within the

maxilla or mandible. Before age 30, nearly twice as

many maxillary lesions are diagnosed, whereas after

age 30, almost twice as many lesions are diagnosed

in the mandible [31].

Clinical signs

Most central lesions are discovered on routine

dental radiographic examination; however, delayed

eruption of (especially an anterior maxillary) perma-

nent tooth or slow-growing bony expansion (with or

without displacement of adjacent teeth) that overlies

the lesion commonly lead to the discovery of the

intragnathic AOTs. Mobility of teeth [42,78–80],

swelling of the cheek [51], and asymmetrical facial

swelling have been reported less frequently. Periph-

eral lesions present as a gingival-colored mass that

ranges from 1 to 1.5 mm in diameter (the size was

listed in only 4 of 18 reported cases). They are

10 times more prevalent in the maxillary gingiva

than in the mandibular gingiva; all but 3 of the 18 re-

ported cases were located adjacent to an incisor—

usually the maxillary central incisor [32].

Clinical symptoms

Usually, AOTs are asymptomatic; however pa-

tients may be aware of a gingival swelling or an

area of jaw enlargement. Rarely, infection of the

tumor or fracture of the mandible [11] has led to

discovery of the condition. Nasal obstruction was

reported in conjunction with rarely encountered

large maxillary lesions [50,51]. Gingival lesions most

often are painless.

Clinical differential diagnosis

Because the diffuse swelling that can accompany

central lesions is clinically indistinguishable from the

maxillary or mandibular enlargement that may occur

with central odontogenic cysts and tumors as well as

G.M. Rick / Oral Maxillofacial Surg Clin N Am 16 (2004) 333–354338

benign fibro-osseous lesions and benign mesenchy-

mal neoplasms; radiographic evaluation is indicated

to narrow the differential diagnostic considerations.

Gingival lesions cannot be differentiated clinically

from gingival fibromas, peripheral cemento-ossifying

fibromas, peripheral giant cell lesions, or from other

peripheral odontogenic tumors, such as odontogenic

fibroma, ameloblastoma, calcifying odontogenic cyst,

and calcifying epithelial odontogenic tumor.

Fig. 2. A 13-year-old girl presented because of delayed

eruption a maxillary lateral incisor and the surgeon de-

scribed an overlying ‘‘fluctuant bulge.’’ This corticated

unilocular radiolucent lesion was superimposed partially

on the unerupted tooth. (Courtesy of R.E. Barsan, DDS,

El Centro, CA.)

Radiographic features

Anatomic site

A significant number of AOTs are discovered

radiographically because more than 95% occur intra-

osseously (centrally), usually as small asymptomatic

lesions [32].

Pericoronal

About 71% of AOTs are associated with the

crown of an unerupted permanent tooth (Fig. 1),

including about 6% that are associated with two or

more unerupted teeth. Nearly 60% of AOTs are

associated with cuspids—40% with the maxillary

cuspids. Only rarely (f3% or 7/220) is AOT asso-

ciated with permanent molars and reported cases

have been almost exclusively related to third molars

but at a mean age of 9 years greater than those

associated with cuspids (i.e. 25.6 vs. 16.5) presum-

ably due to the later biologic development of molars

than anterior teeth. This age difference also is related

to the fact that unerupted/impacted posterior teeth

are diagnosed later than unerupted/impacted anterior

teeth, at least partially because of their lesser cosmetic

Fig. 1. Distribution of pericoronal (dentigerous, follicular)

AOT associated with unerupted permanent teeth (n = 341).

(Data from Philipsen HP, Reichart PA. Adenomatoid

odontogenic tumor: facts and figures. Oral Oncol 1998;35:

125–31.)

impact [76]. Only two reported cases involved pri-

mary teeth [31,81].

Extracoronal

Nearly 30% of the central AOTs are not pericoro-

nal and demonstrate a relationship to the roots of

adjacent or nearby teeth that ranges from lateral or

interproximal to periapical to no relationship at all.

Among the extracoronal cases where the exact loca-

tion was reported, 89% of AOTs occurred adjacent to

a permanent cuspid. Four of 86 lesions appeared in a

periapical position but some likely were superim-

posed on the apex radiographically [31,82].

Radiographic signs

Central AOTs almost invariably display the radio-

graphic features of a benign intrabony odontogenic

lesion by presenting as a well-demarcated, almost

always unilocular radiolucency that generally exhibits

a smooth corticated (and sometimes sclerotic) border.

Most lesions are pericoronal or juxtacoronal (Fig. 2)

but the radiolucency may extend apically beyond the

cemento-enamel junction on at least one side of the

root (Fig. 3) [18,47]. Rare, multilocular cases have

been reported [48,83,84] and a scalloped border is

observed occasionally [9,45]. Most cases are between

1 and 3 cm in greatest diameter and are associated

with only one impacted tooth; however, several much

larger cases were reported, including one that was

12 cm in diameter and was associated with seven

Fig. 3. A 16-year-old girl presented with a 3-cm hard bony

expansion of unknown duration. The corticated unilocular

pericoronal radiolucency does not ‘‘respect’’ the cemento-

enamel junction and there is displacement of the adjacent

teeth and apical resorption of the second bicuspid. (Courtesy

of J.J. Moses, DDS, MD, Encinitas, CA.)

Fig. 4. This 2-cm soft mass from the maxillary lateral incisor

area of a 12-year-old girl had a capsule of varying thickness

and was composed of soft granular tan material without

evidence of a cyst cavity or lining. (Courtesy of R.S.

Mowry, DDS, Chula Vista, CA.)

G.M. Rick / Oral Maxillofacial Surg

impacted teeth (including some deciduous teeth) [48].

About 65% of reported cases also demonstrate faintly

detectable radiopaque foci within the radiolucent

lesion. Because this feature often is not visible on

panoramic films, obtaining good quality periapical

views of the lesional area of suspected cases is

advisable [85]. Occasionally, a more obvious intrale-

sional radiopacity may be identified, usually eccentri-

cally positioned within the lesion. Although not

mentioned often in case reports, divergence of roots

and displacement of teeth [47,48,50,51] occurs more

frequently than root resorption [47,86–90]. Several

reported cases have encroached on [12] or filled or

expanded the maxillary sinus [4,9,51,80,91–95], in-

cluding one case that contained a calcified, craterlike

mass of dentinoid material [96]. Orbital encroachment

also has been mentioned occasionally [12,80,95].

Gingival lesions rarely are detectable radiograph-

ically but there may be slight erosion of the underly-

ing alveolar bone cortex. One reported case [97]

demonstrated central and peripheral involvement; it

could not be determined whether the bilobed lesion

was primarily a gingival lesion that had eroded into

the underlying alveolar bone or if a superficial,

primarily intraosseous lesion had expanded out into

the overlying gingiva. I saw a case in a 9-year-old girl

who had been aware of an asymptomatic firm gingi-

val swelling adjacent to a maxillary central incisor for

a year. A periapical radiograph revealed slight peri-

radicular widening of the periodontal ligament space

as the only radiographic finding.

Radiographic differential diagnosis

Pericoronal

The differential diagnosis of dentigerous (follicu-

lar) AOTs includes the following radiolucent lesions

that range from frequently to rarely identified in a

pericoronal relationship to a tooth: dentigerous (fol-

licular) cyst, odontogenic keratocyst, calcifying

odontogenic cyst, unicystic ameloblastoma, amelo-

blastic fibroma, early ameloblastic fibro-odontoma,

odontogenic fibroma, and calcifying epithelial odon-

togenic tumor.

Extracoronal

The differential diagnosis of extracoronal AOTs

includes most of the aforementioned odontogenic

cysts and tumors because they also may occur in a

nonpericoronal relationship to an unerupted or erup-

ted tooth (some dentigerous cysts are lateral rather

than pericoronal). Additional considerations include

central giant cell lesion (granuloma, tumor), benign

fibro-osseous lesions (eg, early cemento-ossifying

fibroma), lateral periodontal cyst, lateral radicular

cyst, apical radicular cyst and much rarer central

benign mesenchymal neoplasms (eg, neurilemoma).

Clin N Am 16 (2004) 333–354 339

Macroscopic features

Unmagnified gross examination of most excision-

al surgical specimens of central AOTs reveal a soft,

roughly spherical mass with a discernible fibrous

capsule. Upon gross sectioning, the tumor may ex-

hibit white to tan solid to crumbly tissue or one or

G.M. Rick / Oral Maxillofacial Surg Clin N Am 16 (2004) 333–354340

more cystic spaces of varying size; minimal yellow-

brown fluid to semisolid material; fine, hard ‘‘gritty’’

granular material; and one to several larger calcified

masses. Additionally, intact dentigerous specimens

demonstrate the crown of a tooth embedded in the

solid tumor mass or projecting into a cystic cavity

(Fig. 4).

Routine light microscopic features

The AOT exhibits diverse histomorphologic fea-

tures but the light microscopic findings are remark-

Fig. 5. (A) The characteristic clusters of cell-rich nodules are identi

magnification �40). (B) Droplets of eosinophilic material are seen

layering of the juxtanodular spindle cells is discernible (hematoxyl

of some of the ‘‘peridroplet’’ tumor cells (hematoxylin-eosin, orig

ably consistent from tumor to tumor. Although present

in varying proportions, the tumor is made up of a

cellular multinodular proliferation of spindle, cuboi-

dal, and columnar cells in a variety of patterns; usually

scattered ductlike structures, eosinophilic material,

and calcifications in several forms; and a fibrous

capsule of variable thickness. Although the literature

contains multiple histochemical, ultrastructural, and

immunohistochemical analyses, these special tests are

not needed to establish a reliable diagnosis of this

distinctive neoplasm. They have been used almost

exclusively in research attempts to determine the cell

of origin or the nature of the lesional products.

fied easily in this scanning view (hematoxylin-eosin, original

between the spindle to polygonal cells and vague concentric

in-eosin, original magnification �100). (C) Vague clustering

inal magnification �250).

Fig. 6. (A) Microcysts (‘‘ducts’’ or ‘‘tubules’’) lined by cuboidal to low-columnar cells with some pale basophilic fibrillar and

floccular material (consistent with basement membrane and enamel matrix proteins) in the lumen in addition to a residual

droplet of eosinophilic material (enameloid?) (arrow) (hematoxylin-eosin, original magnification �400). (B) An eosinophilic

rim of varying thickness lines several ducts one of which shows more prominent nuclear polarization (hematoxylin-eosin,

original magnification �250).

Fig. 7. Tall eosinophilic columnar cells resembling func-

tional ameloblasts abutting a partially calcified mass of

eosinophilic material and an adjacent focus of CEOT-

like polygonal cells with intercellular bridges (hematoxylin-

eosin, original magnification �250).

G.M. Rick / Oral Maxillofacial Surg Clin N Am 16 (2004) 333–354 341

Cell-rich epithelial nodules

Examination at scanning or low magnification

usually is dominated by variably sized, cell-rich nests

or nodules that are composed of spindle to cuboidal

to polygonal epithelial cells. At higher magnification,

it is apparent that some of the cells are arranged in

clusters, frequently around small foci of eosinophilic

material (so-called ‘‘hyaline droplets’’ or ‘‘tumor

droplets’’) (Fig. 5).

Microcysts

Although not present in all tumors, the most

distinctive microscopic feature of AOT is varying

numbers of ductlike structures with lumina of varying

size that are lined by a single layer of cuboidal to

columnar epithelial cells that have nuclei that fre-

quently are polarized away from the lumen. Follow-

ing examination of several tumors, it is not difficult to

develop the impression that there is a continuous

spectrum from the cells of the peridroplet clusters to

the cuboidal to progressively more columnar cells

that line lumina of gradually increasing diameter

(Fig. 6). One study of serial sections supports an

earlier contention that these structures are closed

spherical microcysts rather than ducts or tubules

[98], whereas another study purported a direct con-

nection from the tumor stoma into the duct lumina

[14]. These ductlike or microcyst lumina frequently

are lined by an eosinophilic rim of varying thickness

(the so-called ‘‘hyaline ring’’) and they may be empty

or contain finely fibrillar or flocculent material of

variable staining quality. Extremely tall columnar

cells with intensely eosinophilic cytoplasm and mark-

edly polarized nuclei are seen occasionally (espe-

cially near calcifying epithelial odontogenic tumor

[CEOT]-like areas) abutting a solid mass of usually

partially calcified eosinophilic material (Fig. 7). Usu-

ally, the columnar cells demonstrate clear cytoplasm

and form rosettes as well as linear, curved, convo-

luted, invaginated, and occasionally branching rows

of opposing cells. A strip or band of noncalcified

Fig. 8. Rosette (hematoxylin-eosin, original magnification �250) (A) and convoluted double row (B) of columnar cells

(hematoxylin-eosin, original magnification �400).

G.M. Rick / Oral Maxillofacial Surg Clin N Am 16 (2004) 333–354342

eosinophilic material (that resembles the hyaline ring)

usually is present between the opposing rows of

columnar cells that also may demonstrate separations

of varying width at irregular intervals (Figs. 8–10).

Internodular epithelial cells

Swirling streams of variably stellate reticulum-

like spindle cells to occasionally round or polygonal

epithelial cells that can demonstrate zones of intense

basophilia dominate the tissue between the cell-rich

nodules. Small amounts of eosinophilic material or

calcifications also may be present between these cells

(Fig. 11). The spindle cells that are immediately

adjacent to the cell-rich nodules are sometimes ar-

ranged with their long axis parallel to the periphery of

the nodule which results in a vague layered appear-

ance (Fig. 5B).

Fig. 9. Curved rows of columnar cells with a tubular ap-

pearance (hematoxylin-eosin, original magnification �100).

Basaloid epithelial cells

Variably-sized areas that are composed of one-

to two-cell wide anastomosing strands of basaloid

epithelial cells that are arranged in a plexiform,

trabecular, cribriform, or latticework configuration

occasionally extend between the cell-rich nodules

and usually are present in the peripheral subcapsular

area of most tumors (Fig. 12). These small, round to

cuboidal cells with small round dark nuclei, and often

clear cytoplasm, resemble cells or rests of the den-

tal lamina.

Calcifying epithelial odontogenic tumor-like foci

Many AOTs contain up to a few clusters of well-

defined eosinophilic polyhedral squamous epithelial

Fig. 10. Branching rows of tall columnar cells with a band

of eosinophilic material between the rows that periodi-

cally separate to varying degrees (hematoxylin-eosin, origi-

nal magnification �100).

Fig. 11. (A) The stellate reticulum-like spindle cells between the cell-rich nodules and microcysts/duct-like structures may

demonstrate areas of intense hyperchromasia (hematoxylin-eosin, original magnification �100). (B) Small droplets of

eosinophilic material and more basophilic calcifications may be present between these internodular cells (hematoxylin-eosin,

original magnification �400).

G.M. Rick / Oral Maxillofacial Surg Clin N Am 16 (2004) 333–354 343

cells with prominent intercellular bridges and, occa-

sionally, mild nuclear pleomorphism. Usually, pools

of amorphous, amyloid-like material and globular

masses of calcified substances also are present in or

near these squamous islands that bear considerable

histopathologic resemblance to the CEOT (Pindborg

tumor) (Fig. 13). Although some investigators refer to

these foci as areas of squamous metaplasia, ultra-

structural evidence confirms their metabolic capabil-

ity and similarity to CEOT tumor cells [99].

Cystic space

Although a considerable number of AOTs dem-

onstrate an identifiable cystic component, it is not

clear whether this represents pooling of the mucoid

stroma due to rupture of the thin lattice-work pattern

Fig. 12. Thin anastomosing strands of basaloid epithelial

cells in a plexiform, cribriform, or lattice-work pattern

(hematoxylin-eosin, original magnification �40).

or if the tumor developed within or adjacent to a pre-

existing cyst—presumably either could occur. Al-

though the cyst lining occasionally may resemble

that seen in dentigerous cysts, it more often is similar

to the basaloid cells that form the plexiform pattern

that was described above and may demonstrate bud-

like extensions into the adjacent stroma (Fig. 14).

Reduplicated basement membrane

Some tumors exhibit pools of finely fibrillar

eosinophilic material at the epithelial–connective

tissue interface; this was immunoreactive for the

basement membrane component laminin in the first

IHC study of AOT (Fig. 15) [66].

Dysplastic dentin/dentinoid

In addition to the droplets, bands, and globules of

amorphous eosinophilic material, some AOTs contain

varying amounts of usually paler and nonmineralized

fibrillar eosinophilic material that also may contain a

few entrapped cells. It has been labeled dysplastic

dentin, dentinoid, and osteodentin (Fig. 16) and

identification of dentinal tubules was reported occa-

sionally. A few cases with significant amounts of

dentinoid also were reported (see later discussion).

Calcified bodies

Varying amounts of calcified material in differing

forms is present in most AOTs. Most common are

irregular to round calcified bodies that may be seen

in parenchymal or stromal zones (Fig. 17) and may

exhibit areas with a concentric layered pattern

Fig. 13. (A) One to several small foci of eosinophilic polygonal cells with intercellular bridges resembling the CEOT are not

present infrequently in the cell-rich nodules or less frequently in the internodular areas of many AOT (hematoxylin-eosin,

original magnification �100). (B) The squamoid cells also may demonstrate intracellular amyloid-like material and admixed

or adjacent calcifications with or without concentric laminations generally are present (hematoxylin-eosin, original magnifica-

tion �250).

G.M. Rick / Oral Maxillofacial Surg Clin N Am 16 (2004) 333–354344

(so-called ‘‘Liesegang rings’’). Larger, globular

masses often appear to be a fused conglomeration

of smaller masses that also may display Liesegang

rings (Fig. 18).

Stroma

Generally, the supporting stroma of AOTs is

loose, parvicellular, fibrovascular connective tissue

that may show considerable dilatation and congestion

of a prominent vascular component (Fig. 14).

Fibrous capsule

Invariably, the tumor has a fibrous capsule of

varying thickness and demonstrates no evidence of

local infiltration or invasion of the surrounding tissues.

Fig. 14. (A) Cell-rich nodules in loose fibrous stroma adjacent to cy

original magnification �100). (B) Basaloid cells lining cystic

(hematoxylin-eosin, original magnification �400).

Cytologic atypia

Although occasional foci of epithelial mitotic

activity have been reported, it never is a prominent

feature. Neither epithelial nor stromal cytologic

atypia has ever been reported, apart from the slight

nuclear pleomorphism that is observed in some

CEOT-like foci.

Microscopic differential diagnosis and diagnostic

pitfall

Typically, most AOTs are distinctive enough that

no other tumor or lesion needs to enter the patholo-

gist’s microscopic differential diagnostic considera-

tion. The problem of misdiagnosing an AOT with

a highly vascular stroma as a vascular ameloblas-

stic cavity along top of photomicrograph (hematoxylin-eosin,

cavity demonstrate an area of budding into the stroma

Fig. 15. (A) Thick aggregates of fibrillar eosinophilic material occasionally accumulate at the periphery of the tumor epithelial

cell masses (periodic acid-Schiff, original magnification �250). (B) This fibrillar material has been shown by electron micros-

copy and in this photomicrograph by immunohistochemistry to represent reduplicated basement membrane material. (antilaminin

immunoperoxidase stain, original magnification �250).

G.M. Rick / Oral Maxillofacial Surg Clin N Am 16 (2004) 333–354 345

toma (‘‘adamantohemangioma’’ [100], ‘‘ameloblasto-

hemangioma’’ [101], ‘‘hemangioameloblastoma’’

[102], ‘‘vascular ameloblastoma’’ [103]) that oc-

curred around the time that the AOT was being

recognized as an entity was identified early and dealt

with promptly [45,104,105].

In the past several years we have become aware

of a new diagnostic pitfall. Rarely, ameloblastomas

with a plexiform pattern may exhibit a highly mucoid

stroma that can result in an adenoid appearance. The

similarity to AOT can be striking when the cells

that border the pale-staining to apparently empty,

round to ovoid stromal spaces demonstrate amelo-

blastic differentiation with nuclei that are polarized

away from the pseudolumen. This situation is well-

illustrated by the Armed Forces Institute of Pathol-

Fig. 16. Irregular islands of pale fibrillar eosinophilic material that

few entrapped cells and varying numbers of adjacent tumor epith

(hematoxylin-eosin, original magnification �250).

ogy (AFIP) Registry of Oral Pathology Case of

the Month for January 1994. The respondents to

the monthly, diagnostically-challenging cases are

almost exclusively oral and maxillofacial patholo-

gists; 42% returned a diagnosis of AOT (many

mentioned that it was atypical), 40% favored a

diagnosis of ameloblastoma, and 12% diagnosed it

as one of several other odontogenic tumors. The

AFIP interpretation was ‘‘adenoid ameloblastoma

with dentinoid’’ on the basis that: (1) the intraepithe-

lial ductlike spaces were lined by cuboidal to low-

columnar cells with some nuclei polarized away

from the (pseudoluminal) basement membrane and

occasionally contained blood vessels indicating that

the adenoid spaces likely contain connective tissue

mucoid matrix and (2) the presence of dentinoid

is consistent with dysplastic dentin or ‘‘dentinoid’’ contains a

elial cells (hematoxylin-eosin, original magnification �40)

Fig. 17. (A) Small round and larger irregular conglomerates of basophilic calcifications within the stroma (hematoxylin-eosin,

original magnification �100). (B) Multiple rounded and irregular globules with varying calcification within the tumor pa-

renchyma (hematoxylin-eosin, original magnification �400).

G.M. Rick / Oral Maxillofacial Surg Clin N Am 16 (2004) 333–354346

material with focal dentin tubules [106] (Fig. 19).

Waldron [107] reported ‘‘an identical case’’ that had

recurred twice in less than nine years, one of the

reportedly recurrent AOTs (see prognosis section)

likely was an adenoid ameloblastoma [108], two

similar cases were reported from Japan [96,109], we

recently reviewed a case in consultation from another

institution, and we have several similar cases in our

archives. Altogether, these cases demonstrate a po-

tential diagnostic pitfall that can be avoided by

careful evaluation of the epithelium at the tumor–

stroma interface. In the adenoid ameloblastoma, the

ameloblast-like epithelial cells at the subcapsular

interface exhibit varying degrees of nuclear polariza-

Fig. 18. (A) Irregular stromal calcified body containing aggregate

magnification �125). (B) Calcified stromal globules of varying siz

(hematoxylin-eosin, original magnification �250).

tion away from the basement membrane (a feature

that is not present in AOT) and the other distinctive

features of AOT are not present (ie, rosettes, variably

convoluted opposing rows of columnar cells, and a

distinct capsule).

Treatment

Surgical findings

Although there may be expansion of the alveolar

bone overlying central lesions, the cortex is almost

invariably intact; however, on rare occasions, pene-

s of smaller rounded globules (hematoxylin-eosin, original

e with focal areas of concentric laminations (liesgang rings)

Fig. 19. (A) Plexiform ameloblastoma with cuboidal to columnar cells that exhibit varying nuclear polarization at the stromal

interface, including around ovoid ‘‘adenoid’’ spaces that contain abundant mucoid stroma (hematoxylin-eosin, original

magnification �100). (B) High power view of same features as well as a few small blood vessels in the adenoid stromal spaces

(hematoxylin-eosin, original magnification �400).

G.M. Rick / Oral Maxillofacial Surg Clin N Am 16 (2004) 333–354 347

tration of the cortical plate has been reported. Essen-

tially all cases have a smooth, well-defined capsule of

varying thickness [31].

Enucleation and curettage

Because of the uniformly benign biologic behav-

ior of nearly all typical AOTs and the consistent

presence of a well-developed fibrous capsule, con-

servative complete surgical excision—usually ac-

complished by enucleation and curettage—is the

treatment of choice.

Incisional biopsy only

Although not considered to be the preferred treat-

ment, several reported cases resolved or failed to

progress following incomplete removal of varying

extent [98]. In one case, following complete removal

of a solid mass that had destroyed about one half of

the distal bone adjacent to an unerupted maxillary

cuspid, the ‘‘slightly loose’’ tooth was allowed to

erupt some before it was orthodontically-guided into

position; there was no evidence of recurrence during

6 years of observation [110]. Another similar case

that was managed by subtotal excision (presumably

following confirmatory incisional biopsy) showed no

evidence of persistence or recurrence during several

years of follow-up [111]. Finally, a 22-year-old Japa-

nese man who had swelling of the cheek, unilateral

nasal obstruction, a ‘‘large’’ unilocular radiolucency

that contained a displaced maxillary third molar, and

expansion of the maxillary sinus was presumed to

have a dentigerous cyst following aspiration of

40 mL of brown fluid that contained cholesterol

crystals. Although the lesion decreased in size during

the first 6 months of marsupialization, it showed

no change in the next 7 months and cystectomy

was performed. A mural AOT was diagnosed upon

microscopic examination of the 6-cm postmarsupial-

ization specimen, the sinus returned to normal ap-

pearance, and there were no signs of recurrence

7 months postoperatively [51].

Prognosis

Growth rate

AOT almost is always referred to as ‘‘slow’’ or

‘‘very-slowly growing’’ but no report of measure-

ments of growth rate over a course of time could be

located. The large size of a few of the reported cases

in young children from underdeveloped countries

indicate that some cases have shown at least a

moderate rate of growth [48,50]. Rarely, a period of

rapid growth is reported in a lesion of considerable

duration [112].

Recurrence rate

I was not able to find a single unequivocal case of

recurrence of an AOT. The five reportedly recurrent

cases that I located are summarized below in the

chronologic order in which they were published.

Case 1. Case report of adenoadamantoblastoma

This case [113,114] was rejected as a recurrent

AOT because no photomicrographs are available

G.M. Rick / Oral Maxillofacial Surg Clin N Am 16 (2004) 333–354348

for diagnostic confirmation, clinicoradiographic evi-

dence is more consistent with a unicystic ameloblas-

toma or an ameloblastoma that arose in a dentigerous

cyst, and the described microscopic features of the

1944 biopsy and excisional specimens are more

consistent with a plexiform or adenoid ameloblas-

toma. However, the enamel deposition that was

mentioned in the 1944 biopsy specimen is not

consistent with an ameloblastoma.

Case 2. Ameloblastic adenomatoid tumors: a report

of four new cases

Case 1 in this series of 4 cases was rejected as a

recurrent AOT because the age and gender of the

patient and the site of the tumor are not typical of

AOT, but it cannot be ruled out on that data alone.

The initial partial excision resulted in a microscopic

diagnosis of ‘‘adamantinoma’’ in 1916 and the

single published photomicrograph portrays a few

ductlike structures that are lined by cuboidal cells.

The lack of nuclear polarization in the ductal cells

and the cellularity and possible cytologic atypia of

the interductal epithelial cells preclude ruling out a

primarily solid ameloblastoma with mucoid stroma,

however [42]. If the tumor was not atypical or

malignant before treatment, the extensive radiation

treatments likely promoted the malignant transforma-

tion to which the patient eventually succumbed in

1925 [115].

Case 3. A case report of adenoameloblastoma of the

maxilla

This case in a 10-year-old Japanese girl [116] is

the most likely bona fide recurrent case; however, it is

not completely unequivocal. The published photo-

micrographs of the reportedly recurrent lesion are

typical for AOT as are the patient’s age at the time of

original treatment and the location of the lesion;

therefore, the original diagnosis likely is correct.

The possibility that the original ‘‘cyst’’ was some-

thing other than an AOT cannot be excluded on the

basis of the material that is available for analysis,

however. The nature and completeness of the original

cystectomy also is unknown. Because this may be the

only bona fide case of AOT recurrence, it would be

interesting to review the radiographs of the original

lesion and at the time of the apparent recurrence at

age 13 to 15. It also would be especially helpful to

review the microslides of the original surgical speci-

men. It is my understanding that this material prob-

ably is not available and it may never be known for

certain whether the microscopic features of the origi-

nal surgical specimen are similar enough to the final

specimen to qualify it as a genuine recurrence.

Case 4. Odontogenic adenomatoid tumor of the

mandible (adenoameloblastoma)

This case [108] cannot be accepted as an unequiv-

ocal recurrent AOT for several reasons. Although the

age of the patient and the site of the tumor are not

typical of AOT (like case 2, above) it cannot be

excluded on that basis alone. There is no photo-

micrograph of the original surgical specimen and no

histopathology report is available. Additionally, the

description of the radiographic features of the recur-

rent lesion that was noted 5 years following the initial

curettage fits the clinician’s published radiographic

impression of ameloblastoma. Finally, the three pub-

lished photomicrographic images of the recurrent

tumor are similar to the adenoid ameloblastoma that

was described above. Other investigators who

reviewed this case favor a diagnosis of adenoid cystic

carcinoma [31].

Case 5. A case of adenomatoid odontogenic tumor

with intracranial extension

The paper is written in Japanese [117] with a brief

English abstract and it cannot be accepted as an

unequivocal recurrent AOT for several reasons. Al-

though AOT cannot be ruled out on the basis of the

patient’s age, the plain radiographic, tomographic, and

CT scan descriptions of the large lesion with involve-

ment of several paranasal sinuses, extensive destruc-

tion of the base of the skull, and intracranial extension

do not conform to any previously reported AOT. The

fact that it ‘‘recurred several times’’ before intracranial

extension does not coincide with the behavior of any

other reported AOT. Most importantly, however, be-

cause the single published photomicrograph does not

demonstrate the classic microscopic features of AOT,

this recurring aggressive case cannot be accepted as

such unless more evidence is provided. I believe that

the features that are seen in the only available photo-

micrograph are more suggestive of an ameloblastoma.

Association of adenomatoid odontogenic tumor

with other odontogenic cysts and tumors

Over the years, several odontogenic tumors of

various types were reported to occur in association

with odontogenic cysts, or, more rarely, in association

with other odontogenic tumors. In addition to its

frequently reported association with a dentigerous

G.M. Rick / Oral Maxillofacial Surg Clin N Am 16 (2004) 333–354 349

(follicular) cyst, the AOT occasionally was reported

in conjunction with other odontogenic tumors.

Dentigerous cyst

The AOT may demonstrate, grossly and micro-

scopically, one or more associated cystic cavities.

Some of these cysts may be lined by nonkeratinized,

stratified, squamous epithelium that is similar to the

lining of dentigerous cysts, whereas others may be

lined by a less structured membrane that may dem-

onstrate budlike extensions into the supporting stroma.

Although most central AOTs occur in a pericoronal

relationship with an associated tooth, there is noway to

be certain whether the lining of an associated cyst

represents a true dentigerous cyst or cystic change

within the AOT.

Combined epithelial odontogenic tumor

Several investigators mentioned foci of squamous

metaplasia among the tumor cells in some of the

AOTs that they reported [18,24,58]. Following a

report of scattered ‘‘CEOT-like foci’’ within other-

wise typical AOTs and the introduction of the term

‘‘combined epithelial odontogenic tumor’’ [118], at

least 24 cases with this combination of features have

been reported [32]. In the largest series reported to

date, all AOTs (with paraffin blocks available for

additional sections) that were accessioned (within an

unspecified period of time) by three dental school

diagnostic oral pathology services in Mexico were

reviewed; CEOT-like foci were found in all 12 cases

[119]. All of the patients fell within the usual profile

of AOT and the conclusion that this feature forms part

of the usual histomorphologic spectrum of AOT

apparently is shared by most oral and maxillofa-

cial pathologists.

Odontoma (and similar tumors)

In 1951, Miles [11] reported an AOT from the left

posterior mandible as ‘‘a cystic complex composite

odontome’’ because hard tissue that he interpreted as

dentin and enamel matrix was identified within the

tumor. His descriptions of these materials and the

single photomicrograph raise the possibility that he

observed calcified bodies that now are recognized as

commonly present in AOT. Similar cases were

reported later by other investigators who used the

term ‘‘adenoameloblastic odontoma’’ [120,121] or

descriptive terminology [122]. The most recent simi-

lar cases were published as ‘‘adenomatoid odontoma’’

[123–125]. Additionally, at least seven similar cases

have been reported that include, in addition to areas of

typical AOT, varying amounts of dentin, apparently

without any associated formation of atypical ename-

loid or prismatic enamel matrix [83,90,126,127]. Five

of the seven cases were described as having a pe-

ripheral rim of dentin [90,127], six of them occurred

in the mandibular bicuspid-molar area of 29- to

82-year-old adults [83,90,127], and no recurrences

were reported. Although Allen et al [127] suggested

that ‘‘the term adenomatoid dentinoma should be

applied’’ to this tumor, until there is evidence that

these histomorphologic features are accompanied by

altered biologic behavior, it seems advisable to in-

clude them tentatively under the ‘‘AOT umbrella.’’ It

also is prudent to obtain long-term follow-up before

permanently accepting them into the ‘‘AOT fold.’’

A similar situation was reported in conjunc-

tion with other odontogenic tumors, including the

ameloblastoma, as evidenced by such terms as ‘‘ame-

loblastoma with dentinoid induction (dentinoamelo-

blastoma)’’ [128] and unicystic ameloblastoma with

dentinogenesis [129]. This brings to mind another

recently reported case that may illustrate the point

more easily to an audience of oral and maxillofacial

surgeons—an ‘‘odontogenic keratocyst with dentinoid

formation’’ [130]. Although the temptation to intro-

duce a new name (such as ‘‘dentinogenic odontogenic

keratocyst’’ or ‘‘odontogenic dentinokeratocyst’’) for

such a unique lesion can be almost overwhelming, it

always is wise to refrain from creating new entities

until distinctive clinicopathologic parameters are es-

tablished and have been confirmed.

Ameloblastoma

Raubenheimer et al [131] cited two cases of

unicystic ameloblastoma that showed focal mural

‘‘microscopic changes resembling an AOT.’’ No fol-

low-up information was provided; however, it proba-

bly can be assumed safely that these AOT foci had no

effect on the clinical course of the ameloblastomas.

Calcifying odontogenic cyst

Although a variety of odontogenic tumors have

been reported in association with calcifying odonto-

genic cysts (COC), the first reported association with

AOT was from Saudi Arabia in 1996. A ‘‘prominent

area’’ of AOT-like tissue was noted in the luminal

lining of a typical COC from the anterior mandible of

a 35-year-old man; there was no evidence of recur-

rence 18 months later [132]. Just as foci of CEOT do

not seem to alter the biologic behavior of AOT, a

focus of AOT should not be expected to alter the

G.M. Rick / Oral Maxillofacial Surg Clin N Am 16 (2004) 333–354350

clinical behavior of COC. A reportedly similar case in

the Japanese literature has not been obtained and

translated [133].

A mini-plea

Although it is a potentially valuable endeavor to

continue to collect, document, and report the demo-

graphic, clinical, radiographic, microscopic, and fol-

low-up information on these potential variants of

AOT, it seems unlikely that minor foci resembling

one odontogenic tumor or another will have any

significant effect on the clinical behavior of a dif-

ferent associated odontogenic tumor that makes up

the majority of a given lesion. Until proven other-

wise, it seems to be safe to manage an affected

patient in accordance with the majority lesion or the

worst-acting lesion if lesions of disparate behavior

are present.

Unusual cases

Melanotic adenomatoid odontogenic tumor

Three reported cases of otherwise typical AOTs (all

in nonwhites) showed varying numbers of melanin-

containing epithelial and stromal cells and admixed

melanocytes; so far, this has had no reported effect on

the innocent behavior of the tumor [134–136]. This

finding also was reported in several other odonto-

genic tumors (eg, ameloblastoma, COC, ameloblastic

fibroma, ameloblastic fibro-odontoma).

Multifocal adenomatoid odontogenic tumor

A most unusual case was reported recently from

Sweden in which a 12-year-old girl, over the course of

5 years, developed about a dozen separate radiolucent

lesions that were removed surgically on seven differ-

ent occasions along with about 20 associated tooth

germs and multiple erupted and unerupted malformed

teeth. The excised encapsulated soft tissue lesions

resembled AOT microscopically and invariably were

associated with the roots of the developing teeth

rather than their crowns as are most AOTs [137].

Future research and reporting of cases

Modern research methods have facilitated the

advancement of our understanding of the histogenesis

of this intriguing tumor but unanswered questions

remain. We eagerly await the results of in situ

hybridization, DNA microarray analysis, gene re-

arrangement studies, and other developing molecular

biology techniques to solve the remaining mysteries.

For these research efforts to move forward there is a

continuing need for tissue from these rare tumors.

Because this in the one exclusive area of oncology

that our two dental specialties can claim, I suggest

that the American Academy of Oral and Maxillo-

facial Pathology and the American Association of

Oral and Maxillofacial Surgeons appoint a joint

committee on Odontogenic Tumor Research to work

with the National Institutes of Health or academic

institutions. In addition to prioritizing a list of impor-

tant remaining questions concerning odontogenic

tumors, the group could set up protocols for obtain-

ing, transporting, and storing fresh tumor tissue from

these rare tumors to establish a research tissue bank

that could help to advance our understanding of these

fascinating lesions.

On a more practical level, I agree with following

recommendations of Philipsen et al [31] to discon-

tinue reporting ‘‘classic’’ pericoronal cases of AOT

but to continue to report well-documented cases that

are associated with primary teeth, extracoronal intra-

osseous cases, gingival cases, and, especially, all fully

documented recurrences.

Summary

The AOT is one of the most unique and thor-

oughly profiled odontogenic tumors; however, oral

and maxillofacial surgeons also must be familiar with

its unusual variants to provide optimal patient care.

They also should be aware of a rarely encountered

potential diagnostic pitfall at the light microscopic

level that was delineated herein. The association of

AOT with other established and recently proposed

odontogenic tumors was reviewed and analyzed and

reportedly recurrent AOTs were evaluated case by

case. Because of its consistently benign behavior, in

selected cases it may be possible to preserve the tooth

or teeth associated with the tumor provided on-going

follow-up is assured. Clinicians are encouraged to

publish only case reports of completely documented

nonclassic cases.

Acknowledgments

The author gratefully acknowledges the kind

assistance of the following individuals: the late

Professor Jens Pindborg for most enthusiastic en-

couragement to undertake odontogenic tumor re-

G.M. Rick / Oral Maxillofacial Surg Clin N Am 16 (2004) 333–354 351

search; Professor Jesper Reibel for incredibly patient

support during tedious research procedures; Dr. Lee

Slater for superb collegial discussions, manuscript

review, advice, and extended practice coverage;

Drs. Lane Thomsen and Phil Sapp for library research

assistance; and Dr. Mamiko Kuriya for translation of

the Japanese case report. My special thanks to my

wife, Judy, for her understanding and patience.

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