—  SYMPOSIUM #24  —

Oral Pathology
Moderators: Dr. Antonio Cardesa and Dr. Bruce Wenig

Section 6 - Selected Odontogenic Tumors

Eugenio Mairano


Clear Cell Odontogenic Carcinoma
Clear cell odontogenic carcinoma (CCOC) is a very uncommon tumor, less than 30 cases having been reported so far. [2, 3, 11, 15, 16, 20, 24] The peak incidence is in the 5th-7th decades, with a female predominance and a prevalent localization in the anterior segments of the jaws, the mandible being much more commonly affected than the maxilla. Radiologically, these tumors appear as radiolucent lesions with irregular margins, associated with root resorption in most cases.

Histologically, two main patterns have emerged: most commonly these tumors show a biphasic pattern characterized by nests of clear cells intermixed with smaller islands of polygonal cells with eosinophilic cytoplasm. The second variant consists of epithelial islands exclusively composed of clear cells. [12] Usually, the detection of a subpopulation of small eosinophilic cells, arranged in a double layer and centrally located within the clear cell clusters, resembling duct structures, may suggest the odontogenic origin of the tumor.

Intra-cytoplasmic glycogen storage is quite common in these tumors [15, 16]a nd possibly is responsible for cytoplasmic clearing. In addition, immunoreactivity for cytokeratins (cytokeratins 8, 13 and 19) has been reported, [15, 16, 20] together with occasional EMA, S-100 protein and anti-ameloblastoma antigen immunoreactivity. [2, 15, 20] In a previous study, we have also shown prominent vimentin and collagen type IV immunoreactivity around the tumor cell clusters, whereas actin, CD 34, melanoma antigen HMB 45, myosin and S-100 protein were not detected. [18]

Clues for an appropriate differential diagnosis with other clear cell tumors are: [17, 18]
  • absence of amyloid deposition and calcifications in the stroma to rule out the clear cell variant of the calcifying epithelial odontogenic tumor (Pindborg tumour);

  • lack of intermediate cells, squamous differentiation and mucin (Alcian blue positive) production to exclude mucoepidermoid carcinoma;

  • absence of intracytoplasmic, PAS-positive, diastase-resistant secretory granules and S100 protein, muscle actin/smooth muscle myosin-positive non-luminal cells to rule out acinic cell carcinoma, myoepithelial carcinoma and epithelial-myoepithelial carcinoma;

  • primary intra-osseous localization and absence of salivary glands or mucosal swellings for differentiation with the hyalinising clear cell carcinoma (HCCC) of salivary glands; [4]

  • lack of the prominent intra-tumoral hemorrhage and the typical vascularity of metastatic renal cell carcinoma;

  • immunohistochemical negativity for hepatocyte antigen, prostate specific antigen, TTF-1 and thyroglobulin to exclude metastatic liver, prostate and thyroid carcinomas;

  • absence of S-100 protein and melanoma antigens (HMB 45 and MART-1) immunoreactivities to rule out malignant melanomas and PEComas (so called sugar tumors).
Based on previously published and our own experience, [18] the diagnosis of CCOC usually is made by exclusion of other tumors, and we still lack histological, immunohistochemical and ultrastructural features to specifically identify this entity.

The aggressive potential of clear cell odontogenic carcinoma is well documented by the extensive invasion of adjacent tissues, multiple recurrences [15] and regional [2] or distant metastases. [2] Therefore, clear cell odontogenic carcinomas surely are capable of aggressive growth towards adjacent tissues and distant sites that may eventually kill the patient. In this view, the use of equivocal terminology, such as clear cell odontogenic tumor [11, 15, 16]i s discouraged.

Adenomatoid Odontogenic Tumor
Adenomatoid odontogenic tumor (AOT) is a rare, benign odontogenic neoplasm that most commonly affects the anterior maxilla of young (adolescent) individuals, especially females, and may be associated with impacted teeth. [3, 5, 22] It may share some morphologic similarities with ameloblastoma, particularly the occurrence of a prominent basaloid pattern. Nevertheless, the presence of distinct duct-like structures and rosette-like (whorling) structures are very helpful to discriminate among these two entities. AOT also is characterized by the presence of calcified material resembling enamel matrix or abortive dentine, which is lacking in ameloblastoma. [10, 19]

At scanning magnification, AOT usually demonstrates cystic areas, randomly distributed duct-like structures and solid aggregates of epithelial cells. [23] Residual bone may be occasionally present at the borders of the lesion and scattered tumor cell nests can be evident within the bone. Most of the tumor consists in epithelial cells arranged in solid sheets, whorls-like structures, thin cords or even in single cells, without apparent orientation. Frequently, lumens of different diameter are evident within the solid sheets of tumor cells, somehow recapitulating abortive duct-like structures but without definite palizading around the lumens or at the periphery of solid cell nests.

Most epithelial tumor cells are medium to small-sized and possess moderate amounts of weakly eosinophilic cytoplasm and centrally placed, rounded nuclei. The latter contain open chromatin and inconspicuous chromocenters. The intercellular stroma is scarse, irregularly distibuted and composed by loose connective tissue with interspersed fibroblast-like cells.

The tumor cells show consistent cytokeratin immunoreactivity and calretinin negativity, the latter feature being helpful to rule out ameloblastoma. [1, 8] Intra-tumoral calcifications are not evident after von Kossa stain and extensive search for amyloid, both with Congo Red and observation under polarized light usually fails to reveal amyloid deposits. The lack of both intra-tumoral calcifications and stromal/intercellular amyloid deposits rules out the diagnosis of calcifying epithelial odontogenic tumor (CEOT or Pindborg tumor). Nevertheless, AOT exhibiting CEOT-like features, such as large clusters of flat epithelial cells with distinct intercellular bridges and pleomorphic nuclei with prominent nucleoli, have been repeatedly reported [5, 10, 21] and previously named combined odontogenic tumor. More recent analyses on this issue [3, 23] have highlighted that the biological behavior of AOT with CEOT-like features does not differ from that of conventional AOT and, therefore, combined odontogenic tumor should not be considered a separate entity any longer.

Ameloblastic Carcinoma
Ameloblastomas usually are benign tumors, with tendency to recur locally, and which rarely manifest an aggressive clinical course. [13] Two aggressive variants of ameloblastoma have been recognized: ameloblastomas with cytological evidence of malignancy (ameloblastic carcinoma - AC) or histologically benign ameloblastomas that subsequently develop distant metastases (malignant ameloblastoma). [12, 14] According to relevant papers on this issue, amalignant ameloblastoma can be diagnosed only after the tumor has metastasized and both the primary and the metastatic tumors should reproduce the typical histopathological features of conventional ameloblastoma. [6, 7] AC may arise de novo, from remnants of the dental lamina or from odontogenic cysts, and may be located centrally in the jaws or peripherally in the surrounding mucosa. [6, 19] The diagnosis is facilitated by appropriate imaging studies documenting ill-defined, destructive radiolucencies, associated with root resorption and perforation of the buccal and lingual plates. [7, 9] Focal radiopacities, possibly due to dystrophic calcifications, may occasionally occur, at variance with conventional ameloblastoma that does not manifest such features. [9]

Morphologically, AC consists of large sheets or clusters of neoplastic epithelial cells, with distinct peripheral palizading and both follicular and plexiform growth patterns. The neoplastic cells show evident cytological abnormalities, suggestive of malignant behavior, such as nuclear pleomorphism, high mitotic rate and evident nucleoli and may additionally show intra-cytoplasmic clearing, granularity or keratinization. A destructive growth pattern with invasion of adjacent soft tissues and oral mucosa is usually evident. [6] This tumor type is able to metastasize, after variable time intervals, and the metastatic deposits may not completely ricapitulate the primary tumor. [6, 7]

AC may be easily diagnosed when marked cellular anaplasia and high mitotic rate are present and the tumor shows typical ameloblastic features (peripheral palizading, plexiform/follicular growth patterns and evidence of stellate reticulum). When the latter are less evident, the detection of calretinin immunoreactivity may help to support the ameloblastic nature of the tumor. Nevertheless, in our experience on a limited number of cases, calretinin positivity in AC usually is restricted to a few neoplastic cells, if any. Therefore, the lack of calretinin immunostaining does not preclude the diagnosis of AC. In addition, as mentioned for CCOC, the correct diagnosis of cases lacking of typical ameloblastic differentiation frequently is achieved after exclusion of squamous cell carcinoma of mucosal derivation (especially in cases showing extensive keratinization), salivary gland or metastatic neoplasms and is facilitated by the use of the above mentioned (see CCOC) histo-immunoistochemical procedures.

A word of caution is worth on the use of incisional biopsies for diagnosing AC. Infact, while completely intra-osseous odontogenic neoplasms usually are treated by curettage or resection, thus yielding adequate amounts of tissue for histopathology, surgeons are more prone at taking small biopsies form the periphery of the lesion when large tumors extending beyond the jawbones and infiltrating the adjacent tissues are present. In such instances, while the ameloblastomatous nature of the neoplasm may be usually ascertained, the typical aggressive features of AC may be scarce or absent and the pathologist should carefully compare the histological features with imaging studies or ask for additional neoplastic tissue, possibly taken from the mid protions of the neoplasm.

References
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  2. Bang G, Koppang HS, Hansen LS, et al. Clear cell odontogenic carcinoma: report of three cases with pulmonary and lymph node metastases. J Oral Pathol Med 1989;18:113-8

  3. Barnes L, Eveson JW, Reichart P, Sidransky D. (Eds) WHO classification of tumours. Pathology and genetics of head and neck tumours. IARC Press, Lyon, France. 2005:287-305

  4. Berho M, Huvos AG: Central hyalinizing clear cell carcinoma of the mandible and maxilla. A clinicopathologic study of two cases with an analysis of the literature. Hum Pathol 1999;30:101-5.

  5. Bingham RA, Adrian JC. Combined epithelial odontogenic tumor – adenomatoid odontogenic tumor and calcifying epithelial odontogenic tumor. J Oral Maxillofac Surg 1986; 44: 574-7

  6. Bruce RA, Jackson IT. Ameloblastic carcinoma. Report of an aggressive case and review of the literature. J Craniomaxillofac Surg 1991;19:267-71

  7. Cawson RA, Binnie WH, Speight P, et al. Lucas' pathology of tumors of the oral tissues. Churchill-Livingstone, London, 1998:32-5

  8. Coleman H, Altini M, Ali H, et al. Use of calretinin in the differential diagnosis of unicystic ameloblastomas . Histopathology 2001;38:312-7

  9. Corio RC, Goldblatt LI, Edwards PA, et al. Ameloblastic carcinoma: a clinicopathologic study and assessment of eight cases. Oral Surg Oral Med Oral Pathol 1987;64:570-6

  10. Damm D, White DK, Crummond JF, et al. Combined epithelial odontogenic tumor: adenomatoid odontogenic tumor and calcifying epithelial odontogenic tumor. Oral Surg Oral Med Oral Pathol 1983;55:487-96

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  19. McClatchey KD, Sullivan MJ, Paugh DR. Peripheral ameloblastic carcinoma: a case report of a rare neoplasm. J Otolaryngol 1989;18:109-11

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  21. Okada Y, Mochizuki K, Sugimura M, et al. Odontogenic tumor with combined characteristics of adenomatoid odontogenic and calcifying odontogenic tumors. Pathol Res Pract 1987;182:647-57

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