Rick 2004 Omscna

Oral Maxillofacial Surg Clin N Am 16 (2004) 333 354
Adenomatoid odontogenic tumor

Gordon M. Rick, DDS, MSa,b,*
b a Loma Linda University, School of Dentistry, Loma Linda, CA, USA Scripps Oral Pathology Service, 5190 Governor Drive, Suite 106, San Diego, CA 92122-2848, USA
The adenomatoid odontogenic tumor (AOT) is included in classifications of odontogenic tumors because it occurs only in the tooth-bearing area of the jaws and because of its histomorphologic resemblance 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 odontogenic tumors because most lesions occur in association with an unerupted maxillary cuspid in teenage girls. Although the so-called duct-like structures are a unique (although not always present) microscopic 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-
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
lial odontome is almost certainly an AOT. The first 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 Thomas [5] Oral Pathology textbook. Thomas concept 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 adamantoblastoma 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 frequent 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-
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G.M. Rick / Oral Maxillofacial Surg Clin N Am 16 (2004) 333354
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 lesions 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 Singapore [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 tumor. 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] suggested consideration of the term odontogenic adenomatoid tumor. This paper was in press and was not available to Philipsen and Birn [19] when they proposed the name adenomatoid odontogenic tumor in 1969. Shortly thereafter, the latter term was adopted in the initial edition of the World Health Organizations (WHO) Histological Typing of Odontogenic 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 respected 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 outdated 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 component, it is difficult to understand how this change can be considered an improvement or how it will contribute to better clinical management of patients who have this bland tumor.
In the nearly 90 years since Harbitz clearly described and illustrated his case, more than 800 cases have been reportedmost 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 Philipsens [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 originepithelial, 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 mesenchymal 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 investigators as a tumor of odontogenic epithelium without 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 supported in a recent immunohistochemical study that used bone morphogenetic protein (BMP) to divide
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odontogenic tumors into those that were purely epithelial (ie, negative for BMP) and those that formed enamel, dentin, cementum, or bone (ie, positive 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 available. 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 recurrence (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 support 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 considered 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 odontogenic origin. Since its earliest recognition as an entity, however, many investigators have debated the histogenesis of AOT and the nature of the acellular materials within the tumor. Even though their arguments were based solely on routine light microscopy and nonspecific histochemistry, their speculations are interesting, and in some cases, farsighted. Because 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 extracellular materials that commonly are observed in these microscopically-fascinating tumors. Thirteen ultrastructural studies [53 65] and 10 immunohistochemical 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 histomorphologic 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 harmonize the results of these two branches of investigation (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 Thomas notion of a dual salivary and odontogenic origin for AOT [57]. This
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was corroborated by the negative reactivity of these cells to lactoferrin and a1-antichymotrypsin antibodies [74]. The duct-forming cells also exhibit secretory granules and coated vesicles near the luminal pole which renders them highly reminiscent of preameloblasts; these structures also were reported in the nonduct-forming columnar cells in various patterns [57 59,61]. IHC studies revealed differences between the duct- and nonduct-forming cells; the nonduct-forming columnar cells expressed amelogenin 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 hyaline ring) resembled basal lamina by way of TEM [53,56,57,60] and coexpressed basement membrane extracellular matrix proteins (laminin, type IV collagen, 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 material. The droplets of eosinophilic material (the socalled hyaline or tumor droplets) between the cuboidal, low columnar, and polygonal cells that form the cell-rich tumor nodules exhibit TEM features that are consistent with enamel matrix-like material [59,60,65]. They also colocalized enamel matrix and basement membrane antibodies and enamelysin (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 neoplastic (pre)ameloblasts in a state of arrested development, yet they apparently are metabolically active enough to produce basement membrane and enamel matrix proteins. 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 reticulum 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, enamelin, 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, irregular calcifications may be partially composed of atypical 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 calcified bodies were indistinguishable from calcified amyloid [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 periphery 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 (presumably 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 dentisthe 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 dentishence 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.
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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].
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) permanent 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. Peripheral 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 reported cases were located adjacent to an incisor usually the maxillary central incisor [32]. Clinical symptoms Usually, AOTs are asymptomatic; however patients 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
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 odontogenic 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, follicular) 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, extraosseous) 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 harvesting phenomenon rather than a true racial difference.
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
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benign fibro-osseous lesions and benign mesenchymal 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.
Radiographic features Anatomic site A significant number of AOTs are discovered radiographically because more than 95% occur intraosseously (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 cuspids40% with the maxillary cuspids. Only rarely (f3% or 7/220) is AOT associated 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) presumably 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. 2. A 13-year-old girl presented because of delayed eruption a maxillary lateral incisor and the surgeon described 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.)
impact [76]. Only two reported cases involved primary teeth [31,81]. Extracoronal Nearly 30% of the central AOTs are not pericoronal 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 location was reported, 89% of AOTs occurred adjacent to a permanent cuspid. Four of 86 lesions appeared in a periapical position but some likely were superimposed on the apex radiographically [31,82]. Radiographic signs Central AOTs almost invariably display the radiographic 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. 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.)
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Radiographic differential diagnosis Pericoronal The differential diagnosis of dentigerous (follicular) AOTs includes the following radiolucent lesions that range from frequently to rarely identified in a pericoronal relationship to a tooth: dentigerous (follicular) cyst, odontogenic keratocyst, calcifying odontogenic cyst, unicystic ameloblastoma, ameloblastic fibroma, early ameloblastic fibro-odontoma, odontogenic fibroma, and calcifying epithelial odontogenic 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 erupted 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).
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 cementoenamel 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.)
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 intralesional radiopacity may be identified, usually eccentrically 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], including 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 radiographically but there may be slight erosion of the underlying 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 gingival swelling adjacent to a maxillary central incisor for a year. A periapical radiograph revealed slight periradicular widening of the periodontal ligament space as the only radiographic finding.
Macroscopic features Unmagnified gross examination of most excisional surgical specimens of central AOTs reveal a soft, roughly spherical mass with a discernible fibrous capsule. Upon gross sectioning, the tumor may exhibit white to tan solid to crumbly tissue or one or
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.)
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more cystic spaces of varying size; minimal yellowbrown 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 features but the light microscopic findings are remark-
ably consistent from tumor to tumor. Although present in varying proportions, the tumor is made up of a cellular multinodular proliferation of spindle, cuboidal, 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.
Fig. 5. (A) The characteristic clusters of cell-rich nodules are identified easily in this scanning view (hematoxylin-eosin, original magnification 40). (B) Droplets of eosinophilic material are seen between the spindle to polygonal cells and vague concentric layering of the juxtanodular spindle cells is discernible (hematoxylin-eosin, original magnification 100). (C) Vague clustering of some of the peridroplet tumor cells (hematoxylin-eosin, original magnification 250).
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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).
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 frequently are polarized away from the lumen. Following 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 connection 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 markedly polarized nuclei are seen occasionally (especially near calcifying epithelial odontogenic tumor [CEOT]-like areas) abutting a solid mass of usually partially calcified eosinophilic material (Fig. 7). Usually, the columnar cells demonstrate clear cytoplasm and form rosettes as well as linear, curved, convoluted, invaginated, and occasionally branching rows of opposing cells. A strip or band of noncalcified
Fig. 7. Tall eosinophilic columnar cells resembling functional ameloblasts abutting a partially calcified mass of eosinophilic material and an adjacent focus of CEOTlike polygonal cells with intercellular bridges (hematoxylineosin, original magnification 250).
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Fig. 8. Rosette (hematoxylin-eosin, original magnification 250) (A) and convoluted double row (B) of columnar cells (hematoxylin-eosin, original magnification 400).
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).
Basaloid epithelial cells Variably-sized areas that are composed of oneto 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 dental lamina. Calcifying epithelial odontogenic tumor-like foci Many AOTs contain up to a few clusters of welldefined eosinophilic polyhedral squamous epithelial
Internodular epithelial cells Swirling streams of variably stellate reticulumlike 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 arranged with their long axis parallel to the periphery of the nodule which results in a vague layered appearance (Fig. 5B).
Fig. 9. Curved rows of columnar cells with a tubular appearance (hematoxylin-eosin, original magnification 100).
Fig. 10. Branching rows of tall columnar cells with a band of eosinophilic material between the rows that periodically separate to varying degrees (hematoxylin-eosin, original magnification 100).
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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).
cells with prominent intercellular bridges and, occasionally, 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, ultrastructural evidence confirms their metabolic capability and similarity to CEOT tumor cells [99]. Cystic space Although a considerable number of AOTs demonstrate 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
or if the tumor developed within or adjacent to a preexisting cystpresumably either could occur. Although 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 budlike 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 occasionally. 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. 12. Thin anastomosing strands of basaloid epithelial cells in a plexiform, cribriform, or lattice-work pattern (hematoxylin-eosin, original magnification 40).
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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 magnification 250).
(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.
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 pathologists microscopic differential diagnostic consideration. The problem of misdiagnosing an AOT with a highly vascular stroma as a vascular ameloblas-
Fig. 14. (A) Cell-rich nodules in loose fibrous stroma adjacent to cystic cavity along top of photomicrograph (hematoxylin-eosin, original magnification 100). (B) Basaloid cells lining cystic cavity demonstrate an area of budding into the stroma (hematoxylin-eosin, original magnification 400).
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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 microscopy and in this photomicrograph by immunohistochemistry to represent reduplicated basement membrane material. (antilaminin immunoperoxidase stain, original magnification 250).
toma (adamantohemangioma [100], ameloblastohemangioma [101], hemangioameloblastoma [102], vascular ameloblastoma [103]) that occurred 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 ameloblastic differentiation with nuclei that are polarized away from the pseudolumen. This situation is wellillustrated by the Armed Forces Institute of Pathol-
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 pathologists; 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 intraepithelial ductlike spaces were lined by cuboidal to lowcolumnar 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
Fig. 16. Irregular islands of pale fibrillar eosinophilic material that is consistent with dysplastic dentin or dentinoid contains a few entrapped cells and varying numbers of adjacent tumor epithelial cells (hematoxylin-eosin, original magnification 40) (hematoxylin-eosin, original magnification 250).
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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 parenchyma (hematoxylin-eosin, original magnification 400).
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 potential 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-
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-
Fig. 18. (A) Irregular stromal calcified body containing aggregates of smaller rounded globules (hematoxylin-eosin, original magnification 125). (B) Calcified stromal globules of varying size with focal areas of concentric laminations (liesgang rings) (hematoxylin-eosin, original magnification 250).
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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).
tration of the cortical plate has been reported. Essentially all cases have a smooth, well-defined capsule of varying thickness [31]. Enucleation and curettage Because of the uniformly benign biologic behavior of nearly all typical AOTs and the consistent presence of a well-developed fibrous capsule, conservative complete surgical excisionusually accomplished by enucleation and curettageis the treatment of choice. Incisional biopsy only Although not considered to be the preferred treatment, 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 Japanese 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 postmarsupialization specimen, the sinus returned to normal appearance, 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 measurements 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
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for diagnostic confirmation, clinicoradiographic evidence is more consistent with a unicystic ameloblastoma 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 ameloblastoma. 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 transformation 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 photomicrographs of the reportedly recurrent lesion are typical for AOT as are the patients 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 something 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 specimen. It is my understanding that this material probably 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 unequivocal 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 photomicrograph of the original surgical specimen and no histopathology report is available. Additionally, the description of the radiographic features of the recurrent lesion that was noted 5 years following the initial curettage fits the clinicians published radiographic impression of ameloblastoma. Finally, the three published 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. Although AOT cannot be ruled out on the basis of the patients age, the plain radiographic, tomographic, and CT scan descriptions of the large lesion with involvement of several paranasal sinuses, extensive destruction 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, because 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 photomicrograph 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
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(follicular) cyst, the AOT occasionally was reported in conjunction with other odontogenic tumors. Dentigerous cyst The AOT may demonstrate, grossly and microscopically, 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 demonstrate budlike extensions into the supporting stroma. Although most central AOTs occur in a pericoronal relationship with an associated tooth, there is no way 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 otherwise 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 maxillofacial 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 similar 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 enameloid or prismatic enamel matrix [83,90,126,127]. Five of the seven cases were described as having a peripheral 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 include 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 conjunction with other odontogenic tumors, including the ameloblastoma, as evidenced by such terms as ameloblastoma with dentinoid induction (dentinoameloblastoma) [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 surgeonsan odontogenic keratocyst with dentinoid formation [130]. Although the temptation to introduce 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 established 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 follow-up information was provided; however, it probably 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 odontogenic 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 recurrence 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
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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 demographic, clinical, radiographic, microscopic, and follow-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 different associated odontogenic tumor that makes up the majority of a given lesion. Until proven otherwise, 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 melanincontaining 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 odontogenic 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 different 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].
hybridization, DNA microarray analysis, gene rearrangement 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 Maxillofacial 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 important remaining questions concerning odontogenic tumors, the group could set up protocols for obtaining, 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 discontinue reporting classic pericoronal cases of AOT but to continue to report well-documented cases that are associated with primary teeth, extracoronal intraosseous cases, gingival cases, and, especially, all fully documented recurrences.
Summary The AOT is one of the most unique and thoroughly 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.
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
Acknowledgments The author gratefully acknowledges the kind assistance of the following individuals: the late Professor Jens Pindborg for most enthusiastic encouragement to undertake odontogenic tumor re-
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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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Oral Maxillofacial Surg Clin N Am 16 (2004) 333 354

Adenomatoid odontogenic tumor

G.M. Rick / Oral Maxillofacial Surg Clin N Am 16 (2004) 333354

G.M. Rick / Oral Maxillofacial Surg Clin N Am 16 (2004) 333354

G.M. Rick / Oral Maxillofacial Surg Clin N Am 16 (2004) 333354

G.M. Rick / Oral Maxillofacial Surg Clin N Am 16 (2004) 333354

G.M. Rick / Oral Maxillofacial Surg Clin N Am 16 (2004) 333354

G.M. Rick / Oral Maxillofacial Surg Clin N Am 16 (2004) 333354

G.M. Rick / Oral Maxillofacial Surg Clin N Am 16 (2004) 333354

G.M. Rick / Oral Maxillofacial Surg Clin N Am 16 (2004) 333354

G.M. Rick / Oral Maxillofacial Surg Clin N Am 16 (2004) 333354

G.M. Rick / Oral Maxillofacial Surg Clin N Am 16 (2004) 333354

G.M. Rick / Oral Maxillofacial Surg Clin N Am 16 (2004) 333354

G.M. Rick / Oral Maxillofacial Surg Clin N Am 16 (2004) 333354

G.M. Rick / Oral Maxillofacial Surg Clin N Am 16 (2004) 333354

G.M. Rick / Oral Maxillofacial Surg Clin N Am 16 (2004) 333354

G.M. Rick / Oral Maxillofacial Surg Clin N Am 16 (2004) 333354

G.M. Rick / Oral Maxillofacial Surg Clin N Am 16 (2004) 333354

G.M. Rick / Oral Maxillofacial Surg Clin N Am 16 (2004) 333354

G.M. Rick / Oral Maxillofacial Surg Clin N Am 16 (2004) 333354

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