Hybrid ameloblastoma and adenomatoid odontogenic tumor: report of a case and review of hybrid variations in the literature Manabu Yamazaki, DDS, PhD,a Satoshi Maruyama, DDS, PhD,b Tatsuya Abé, DDS,c Hamzah Babkair, DDS,d Hajime Fujita, DDS, PhD,e Ritsuo Takagi, DDS, PhD,f Jun-ichi Koyama, DDS, PhD,g Takafumi Hayashi, DDS, PhD,h Jun Cheng, MD, PhD,i and Takashi Saku, DDS, PhDj Niigata University and Niigata University Hospital, Niigata, Japan
Hybrid odontogenic tumors including 2 or more different histologic types have been documented, but their occurrences are not very common. We present a case of hybrid odontogenic tumor composed of ameloblastoma and adenomatoid odontogenic tumor (AOT) arising in the mandibular molar region of a 31-year-old Japanese woman who had a history of familial adenomatous polyposis. The tumor, measuring 10 mm in diameter, was surgically removed from the alveolar bone. Histopathologically, the tumor consisted of both follicular and plexiform types of ameloblastoma in which multiple and smaller foci of AOT were intermingled. There have been 3 reported cases of hybrid ameloblastoma and AOT, all of which presented unicystic types as ameloblastoma components. This, however, is the first report of a hybrid tumor containing an authentic solid-type ameloblastoma compartment and an AOT compartment in a patient with a background of familial adenomatous polyposis. (Oral Surg Oral Med Oral Pathol Oral Radiol 2013;-:e1-e7)
Odontogenic tumors are characterized by their diverse histopathologic spectra, because the tooth germs themselves develop through complicated interactions between epithelial and mesenchymal elements,1 which are critically regulated in time-dependent manners.2-4 Based on their combination of predominant histologic a Assistant Professor, Division of Oral Pathology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. b Lecturer, Oral Pathology Section, Department of Surgical Pathology, Niigata University Hospital, Niigata, Japan. c Resident, Oral Pathology Section, Department of Surgical Pathology, Niigata University Hospital; Graduate Student, Division of Oral Pathology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. d Graduate Student, Division of Oral Pathology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. e Assistant Professor, Division of Oral and Maxillofacial Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. f Professor, Division of Oral and Maxillofacial Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. g Assistant Professor, Division of Oral and Maxillofacial Radiology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. h Professor, Division of Oral and Maxillofacial Radiology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. i Associate Professor, Division of Oral Pathology, Niigata University Graduate School of Medical and Dental Sciences; Oral Pathology Section, Department of Surgical Pathology, Niigata University Hospital, Niigata, Japan. j Professor, Division of Oral Pathology, Niigata University Graduate School of Medical and Dental Sciences; Oral Pathology Section, Department of Surgical Pathology, Niigata University Hospital, Niigata, Japan. Received for publication Jul 3, 2013; returned for revision Aug 23, 2013; accepted for publication Aug 29, 2013. Ó 2013 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2013.08.032
elements, benign odontogenic tumors have roughly been classiﬁed into 3 categories: (1) odontogenic epithelial tumors without odontogenic ectomesenchyme; (2) odontogenic epithelial tumors with odontogenic ectomesenchyme; and (3) odontogenic ectomesenchymal tumors with or without included odontogenic epithelium.5 The histopathologic diagnosis of odontogenic tumors can be challenging, owing to complicated clinicopathologic features and nomenclatural confusion. Furthermore, unusual combinations of neoplastic components, namely hybrid odontogenic tumors, are occasionally observed. In fact, the presence of hybrid odontogenic tumors which contain 2 or more different histologic types is well recognized, and various cases of hybrid odontogenic tumors have been documented in the literature. However, their frequencies and component combinations are not well understood due to ambiguous histologic classiﬁcations.6 In this article, we report a rare case of hybrid ameloblastoma and adenomatoid odontogenic tumor (AOT) arising in the mandible of a 31-year-old woman with familial adenomatous polyposis (FAP). We show the characteristic histopathologic features with immunohistochemical proﬁles, and we discuss the possible association with FAP. In addition, we review the varieties of hybrid odontogenic tumors documented in the literature to analyze their frequencies.
CASE REPORT A 31-year-old Japanese woman, who had undergone total colectomy and ileoanal anastomosis for FAP and colon adenocarcinoma 3 months earlier, was referred to the Division of Oral and Maxillofacial Surgery, Niigata University Hospital, for detailed examination of FAP-related jaw lesions, although she had no obvious symptoms. She had a history of extraction of supernumerary teeth in her childhood. On intraoral
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Fig. 1. Clinical ﬁndings of hybrid ameloblastoma and adenomatoid odontogenic tumor arising in the molar region of the mandible of a 31-year-old Japanese woman. A, Intraoral view. B, Dental radiograph. C, Computed tomography (CT) image, bone window, axial section. D, T1-weighted magnetic resonance image (MRI), axial scan. E, Fat-suppressed contrast-enhanced T1-weighted MRI, axial scan. The patient had a 2-mm space between the right ﬁrst and third molars of the mandible with the second molar unerupted (A). Radiographically, her second molar was shown to be impacted horizontally in the alveolar bone, and above the impacted tooth there was a round radiolucent lesion. The distal root of the ﬁrst molar was sharply resorbed (B). CT revealed a spherical unilocular mass between the 2 molars in the mandible (C). T1-weighted MRI showed muscle signal intensity in the lesion (D, arrow), but it was signiﬁcantly enhanced after contrast medium administration (E, arrow).
Fig. 2. Macroscopic ﬁndings of hybrid ameloblastoma and adenomatoid odontogenic tumor of the mandible. A, Gross view of the cut surface of the surgical specimen. B, Loupe view of the histologic section at the same cut surface (hematoxylin-eosin). On the cut surface, there was a tumorous mass with cystic spaces circumscribed with a thick ﬁbrous capsule beneath the gingival mucosa (A). Histologically, the tumor was mainly composed of ameloblastoma with cystic changes of stromal space, and there were multiple small adenomatoid odontogenic tumor foci within the ameloblastoma (B, arrows). inspection, her mandibular right second molar was unerupted, resulting in a 2-mm-long interdental space between the ﬁrst and third molars (Figure 1, A). Plain radiographic examinations
revealed an oval radiolucent lesion circumscribed with an irregular-shaped radiopaque rim in the alveolar bone between the ﬁrst and third molars (see Figure 1, B), below which
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Fig. 3. Histopathologic ﬁndings of hybrid ameloblastoma and adenomatoid odontogenic tumor (AOT). A to E, hematoxylin-eosin; F, Congo red; A, 100; B, 250; C, 80; D, 300; E and F, 400. In ameloblastoma compartments, both follicular and plexiform patterns were observed (A). Each ameloblastoma focus consisted of peripheral columnar cells and central satellite cells (B). AOT foci were located in the central area and circumscribed with ameloblastoma foci (C). In the AOT compartment, shortspindle cells were arranged in small nodules, and gland-like structures were formed by cuboidal cells with eosinophilic contents in the lumina inside the nodules (D). Eosinophilic materials in various shapes were scattered in AOT foci (E), and were Congo redpositive (F), indicating their calcifying epithelial odontogenic tumor-like differentiation. a second molar tooth was horizontally impacted. The distal root of the ﬁrst molar was resorbed with a knife-edge interface against the lesion and the impacted tooth. Computed tomography (CT) showed that the lesion was a spherical and
unilocular mass, measuring 10 mm in diameter, with a smooth margin and sclerotic area in the distal area (see Figure 1, C). T1-weighted magnetic resonance (MR) images showed that the mandibular mass had low signal intensity (see Figure 1, D,
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Fig. 4. Immunohistochemical proﬁles of hybrid ameloblastoma and adenomatoid odontogenic tumor (AOT). Immunoperoxidase stain for keratin 19 (A), keratin 17 (B), calretinin (C), and Ki-67 (D), hematoxylin counterstain; A, B, and D, 80; C, 40. Keratin 19 was demonstrated in both ameloblastoma and AOT cells (A). Ameloblastoma cells were strongly positive for keratin 17, while AOT cells were not (B). Only ameloblastoma cells were positive for calretinin (C). Ki-67 labeling indices were higher in ameloblastoma than in AOT (D).
arrow), but it was heterogeneously enhanced after contrast medium administration (see Figure 1, E, arrow). In addition, CT of the cranial and mandibular bones disclosed multiple osteomas, which were considered to be FAP-related lesions (not shown). With a tentative diagnosis of a benign tumor of the mandible, the lesion was surgically removed. The surgically removed specimen was a spheroid nodular mass, measuring 10 mm in diameter, which was covered by gingival mucosa. On the cut surface, the nodule consisted of tan multicystic spaces on the periphery and a whitish solid mass in the center (Figure 2, A). Histopathologically, the lesion was well circumscribed by a thick ﬁbrous capsule located under the submucosal layer, which was thickened by ﬁbrosis (see Figure 2, B). Most of the lesion was composed of follicular and plexiform proliferations of ameloblastoma with ﬁbrous and hyaline stroma, some of which showed edematous degeneration resulting in cystic change (Figure 3, A). Each tumor cell nest was bordered by palisaded columnar cells with nuclei that were hyperchromatic and polarized toward the distal end. Some of the foci showed characteristic stellate-reticulum-like
arrangements (see Figure 3, B). Within the ameloblastomatous components, there were multiple foci of AOT (see Figure 2, B, arrows; see Figure 3, C). AOT foci were composed of a nodular and dense proliferation of short-spindled cells, in which variously shaped eosinophilic or calciﬁed materials were deposited (see Figure 3, C). At higher magniﬁcation, cuboidal cells formed gland-like structures with eosinophilic contents in the lumina, and short-spindle cells with clear or granular cytoplasm and oval and vesicular nuclei were arranged in whorled fashions (see Figure 3, D). In the background of sheet-like foci composed of eosinophilic polyhedral AOT cells, Congo red-positive eosinophilic amyloid-like materials were fused with each other and turned into larger and irregular shapes (see Figure 3, E and F). These were regarded as foci with a calcifying epithelial odontogenic tumor (CEOT)-like differentiation. Ameloblastoma and AOT components were intermingled, but each type tumor was clearly separated by ﬁbrous stroma. Immunohistochemically, both ameloblastoma and AOT components were positive for keratin 19 (Figure 4, A). Ameloblastoma cells were strongly positive for keratin 17,
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Table I. Varieties of combinations of hybrid odontogenic tumors Combination CCOT þ
AM þ AOT þ CEOT þ
OD AM AOT AF AFO AFO þ AOT AM þ AOT OA OFM AOT CEOT OD AFO
65 6 4 4 3 1 1 1 1 3 2 2 1
8-22 15, 23-26 19, 42-44 19, 45, 46 19, 47, 48 27 28 19 24 31, 32 49, 50 51, 52 17
5 2 1
CCOT, calcifying cystic odontogenic tumor; OD, odontoma; AM, ameloblastoma; AOT, adenomatoid odontogenic tumor; AF, ameloblastic ﬁbroma; AFO, ameloblastic ﬁbro-odontoma; OA, odontoameloblastoma; OFM, odontogenic ﬁbromyxoma; CEOT, calcifying epithelial odontogenic tumor.
while AOT cells were not (see Figure 4, B). Calretinin was focally but solely positive in ameloblastoma cells (see Figure 4, C). Ki-67 labeling indices were approximately 5% and 1% in ameloblastoma and AOT, respectively (see Figure 4, D). Thus, immunohistochemical proﬁles were apparently distinguishable between these 2 components. From these pathologic ﬁndings, the lesion was diagnosed as hybrid ameloblastoma and AOT. The patient has been followed for 3 years with no signs of recurrence.
DISCUSSION Hybrid neoplasms composed of 2 or more different histologic types occur rarely, but their occurrences have been relatively well recognized among odontogenic tumors. Table I summarizes documented cases of hybrid odontogenic tumors in the English-language literature.42-52 Hybrid odontogenic tumors with a combination of calcifying cystic odontogenic tumor (CCOT) þ odontoma are the most frequently documented,7-22 followed by CCOT þ ameloblastoma.15,23-26 Interestingly, CCOT tends to be combined with various types of odontogenic tumors, and 2 of the case reports of CCOT contained 3 distinct histologic types.27,28 On the contrary, there seems to be no deﬁnite hybrid variation of keratocystic odontogenic tumors. A tumor with combined foci of ameloblastoma and keratocystic odontogenic tumor was ﬁrst described by Siar and Ng,29 who used the term keratoameloblastoma. Later, however, histologically heterogeneous components of a keratinizing variant of ameloblastoma and a solid variant of keratocystic odontogenic tumor were included in the disease entity of keratoameloblastoma.30 As a result, whether these cases with combined histology are hybrids or simply lie within a range of histologic variation is a matter of controversy.
The combination of ameloblastoma and AOT seems to be extremely rare. There have been only 3 previously reported cases of hybrid ameloblastoma and AOT.31,32 In those cases, AOT components existed as mural nodules within cyst walls of unicystic ameloblastoma, and they did not contain any solid ameloblastoma foci with follicular or plexiform patterns. In the present case, however, ameloblastoma and AOT foci were intermingled with each other, indicating that it is a true hybrid neoplasm, not a collision lesion in which 2 distinct components coincided at the same location. Based on our review of the literature, we believe that the present report presents the ﬁrst hybrid example of solid-type ameloblastoma and AOT. Hybrid odontogenic neoplasms may result from diverse differentiation potentials in odontogenic epithelial cells, while their multipotentiality has been represented by the histopathologic varieties of odontogenic tumors themselves.1 AOT often contains foci resembling CEOT with amyloid materials,33,34 which were also observed in the present case. As Damm et al.35 pointed out, these features were ﬁrst considered to be hybrid, and cases were reported as “combined epithelial odontogenic tumor.” Recently, however, these have come to be regarded as CEOT-like features within the histomorphologic spectrum of AOT, because these phenomena are identiﬁed in most AOT cases (92.3%-100%).33,34 In addition, clinical behavior of CEOT, with local invasive tendencies are different from those of AOT.1 The history of FAP in the present patient was also considered in the pathogenesis of this particular hybrid lesion. Oral manifestations of FAP include odontomas, supernumerary teeth, unerupted teeth, and osteomas,36 and the present patient had osteomas, as well as supernumerary and unerupted teeth. Although it remains uncertain whether odontogenic neoplasms other than odontoma, which is regarded as a hamartoma rather than a true neoplasm, are associated with FAP,1,37 there has been only one case report of unicystic ameloblastoma arising in a patient with Gardner syndrome.38 FAP has been associated with high risks of benign and malignant neoplasms, including colorectal adenoma/adenocarcinoma.39 The present paper provides the second case report of an odontogenic neoplasm arising in a patient with FAP. It is uncertain whether mutational events in the adenomatous polyposis coli (APC) gene contribute to the occurrence of odontogenic neoplasms. Although we could not analyze the APC gene in the present case, Siriwardena et al.40 reported that 3 of the 6 ameloblastomas of their series, which were not related with FAP, shared the same point mutation at codon 1339 in the mutational cluster region of exon 15 of the APC gene as well as nuclear translocation of b-catenin.
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Meanwhile, Tanahashi et al.41 did not ﬁnd any point mutations in Wnt signaling molecules including the APC and b-catenin genes in their 18 cases of ameloblastoma. There has been no report of AOT accompanied with FAP. Thus, further documented cases, including hybrid ones, are needed before the relationship between odontogenic neoplasms and FAP is elucidated.
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Reprint requests: Takashi Saku, DDS, PhD Division of Oral Pathology Department of Tissue Regeneration and Reconstruction Niigata University Graduate School of Medical and Dental Sciences 2-5274, Gakkocho-dori Chuo-ku, Niigata 951-8514 Japan [email protected]