Clear Cell Odontogenic Carcinoma. A Clinicopathologic and Immunocytochemical Study of 5 Cases

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1 Clear Cell Odontogenic Carcinoma A Clinicopathologic and Immunocytochemical Study of 5 Cases Tie-Jun Li, PhD; Shi-Feng Yu, MD; Yan Gao, PhD; En-Bo Wang, PhD The clear cell odontogenic tumor is classified as a benign but locally invasive odontogenic tumor in the current World Health Organization classification for odontogenic tumors. 1 However, published descriptions of this variant have all indicated aggressive behavior characterized by an infiltrative growth pattern with a high rate of recurrence and local or distant metastasis Several deaths have also been related to tumor progression. 2,4,11 Consequently, the name clear cell odontogenic carcinoma was thought to be more appropriate in view of the malignant potential manifested by this neoplastic lesion. The objectives of this article were to present 5 additional cases and to describe the clinical course, histologic spectrum, and immunocytochemical characteristics of these lesions. MATERIALS AND METHODS After reviewing patient data, clinical information, and histologic studies, 5 cases fulfilling the criteria of clear cell odontogenic carcinomas were identified from the files of the Department of Oral Pathology, School of Stomatology, Peking Univer- Context. Odontogenic tumor composed predominantly of clear cells is a rare neoplasm of the jaws that was initially designated as clear cell odontogenic tumor. Subsequent reports in the literature, however, all have indicated that this tumor exhibits an aggressive behavior characterized by infiltrative local growth, recurrence, or metastases. Objective. To ascertain the clinicomorphologic features and biologic behavior of this tumor group, we present 5 additional cases using the term clear cell odontogenic carcinoma. Design. Histologic and immunohistochemical examinations were performed on clear cell odontogenic carcinomas from 5 patients. Clinical and follow-up data were recorded, and the literature was reviewed. Results. The patients were 1 man and 4 women with an average age of 42.4 years at diagnosis. Three tumors occurred in the mandible and the other 2 in the maxilla. Four of the 5 cases occurred in the anterior or premolar areas of the jaws, appearing as poorly marginated radiolucencies. All cases consisted of islands and sheets of large clear cells and small basaloid cells with scanty eosinophilic cytoplasm, which were separated by thin, mature, fibrous septae. The tumors were unencapsulated and showed aggressive infiltration of the surrounding muscle and perineural tissues. Most of the clear cells contained cytoplasmic glycogen. Immunocytochemically, the tumor cells were positive for pan-keratin, cytokeratin 19, and epithelial membrane antigen, but were negative for vimentin, S100 protein, desmin, smooth muscle actin, human melanoma antigen (HMB-45), and 1 -antichymotrypsin. Follow-up data showed 4 of 5 patients to have multiple local recurrences, and 1 of these 4 had submandibular lymph node metastasis and a fatal outcome due to uncontrollable tumor growth. Conclusion. These results suggest that odontogenic clear cell neoplasms are at least low-grade malignancies and should be classified as carcinomas. (Arch Pathol Lab Med. 2001;125: ) sity (Beijing, People s Republic of China) during the years 1985 through For inclusion in this series, all cases were primary intraosseous tumors of the jaws. The tumors had a conspicuous clear cell epithelial component, with or without separate areas of tumor elements exhibiting some morphologic featuressimilar to ameloblastoma. Typical ameloblastomas containing small foci of clear cells but not showing general features of aggressiveness were not included in the series. Clinical outcome and follow-up data were evaluated by consulting individual clinical reports and pathology files. In addition, the patient or close relatives were contacted and were asked to complete a questionnaire regarding the current condition of the patient. The surgical specimens had been fixed routinely in 10% neutral formalin (18 48 hours), processed, and embedded in paraffin. In some cases, decalcification of the specimen was performed in 10% formic acid for 5 to 72 hours. Four-micrometer-thick serial sections were cut and used for hematoxylin-eosin, periodic acid Schiff (PAS, with or without diastase digestion), Alcian blue (ph 2.5), Congo red, and immunocytochemical stainings. Immunocytochemical staining was performed using a standard streptavidin-biotin-peroxidase complex method (LAB-SA kits, Zymed Laboratories, South San Francisco, Calif). Details of primary antibodies used are listed in Table 1. Accepted for publication July 2, From the Departments of Oral Pathology (Drs Li, Yu, and Gao) and Oral and Maxillofacial Surgery (Dr Wang), School of Stomatology, Peking University, Beijing, People s Republic of China. Reprints: Tie-Jun Li, PhD, Department of Oral Pathology, School of Stomatology, Peking University, 22 S Zhongguancun Ave, Haidian District, Beijing , People s Republic of China ( tiejunli3@ yahoo.com). RESULTS Clinical Features The clinical features of our patients are summarized in Table 2. Patients included 1 man and 4 women, whose ages ranged from 31 to 58 years (mean 42.4 years). Three tumors were found in the mandible; 2 occurred in the 1566 Arch Pathol Lab Med Vol 125, December 2001 Clear Cell Odontogenic Carcinoma Li et al

2 Table 1. Technical Data and Results of Immunocytochemical Staining* Antibodies Pretreatment Dilution Pan-keratin (AE1/AE3) Keratin 19 (CK-19) Epithelial membrane antigen S100 Vimentin Desmin Smooth muscle actin (1A4) HMB antichymotrypsin Citrate HIER Trypsin (20) Trypsin (20) 1:200 Tumor Cells Case 1 Case 2 Case 3 Case 4 Case 5 * HIER indicates heat-induced epitope retrieval;, positive staining;, negative staining; and, patchy positive staining. All antibodies were purchased from Zymed Laboratories, South San Francisco, Calif. Case No. Sex Table 2. Clinical Details of Patients With Clear Cell Odontogenic Carcinomas Age at Diagnosis, y Location Clinical Presentation 1 F 31 Mandible: right premolar to left premolar 2 F 42 Mandible: right molar and ramus region 3 F 58 Mandible: symphyseal region 4 M 32 Maxilla: right incisor to first molar 5 F 49 Maxilla: right premolar area Unhealing wound after extraction of the lower incisors, swelling, pain Unhealing wound after extraction of the lower third molar, swelling, pain Swelling Labial expansion of the alveolar bone Gingival swelling, bleeding, loosening of the premolars Initial Surgery and Postoperative Course* Tumor Spread Present Follow-up Block resection REC (1 y), neck dissection REC (2 y), no surgery due to uncontrollable tumor growth Enucleation REC (1 y), enucleation REC (3 y), enucleation with radical resection of the tongue tumor Enucleation REC (1 y), enucleation REC (1 y), block resection REC (3 y), wide resection Partial maxillectomy REC (4 y), resection REC (8 y), resection Submandibular lymph node metastasis Direct invasion to the tongue base Died with tumor 4 y after initial diagnosis 7 y following the last surgery, no recurrence 1 y following the last surgery, no recurrence 2 y following the last surgery, no recurrence Semimaxillectomy 2 y following initial surgery, no recurrence * Times cited within parentheses indicate the interval following the previous surgery. REC indicates recurrence. maxilla. Four of the 5 tumors occurred in the anterior or premolar areas of the jaws, with only 1 tumor (case 2) involving the mandibular molar and ramus region, which is the most common site for conventional ameloblastomas. Radiographically, the tumors presented as poorly marginated radiolucencies (Figure 1). Case 1 involved a 31-year-old woman who presented with a painful swelling in the anterior part of the mandible and an unhealing wound after extraction of the lower incisors. Radiographic examination revealed an irregular radiolucency in the mandible symphyseal region between the right and left premolars (Figure 1, a). An incisional biopsy was performed, and a diagnosis of clear cell odontogenic tumor was established at the time. Due to the massive destruction of the anterior mandible, a full-thickness block resection extending from the right first premolar to the left first premolar was carried out and the mandible was immediately reconstructed with a titanium plate. One year later, a recurrent lesion was noted in the remaining anterior mandible with multiple left submandibular and cervical lymphadenopathy. The patient underwent a radical surgical procedure, including wide resection of the mandible and neck dissection. Two years later recurrent tumor growth accelerated, resulting in destruction of the skin and soft tissues of the left side of the patient s face, the lower lip, and neck. Her general condition precluded further surgery. Uncontrolled local tumor growth continued, and the patient became seriously debilitated and died with tumor 1 year later. Case 2 involved a 42-year-old woman who was referred to our hospital for removal of a recurrent mandibular tumor. The lesion was initially treated by enucleation in another hospital 4 years earlier under a working diagnosis of atypical ameloblastoma. The tumor recurred 1 year Arch Pathol Lab Med Vol 125, December 2001 Clear Cell Odontogenic Carcinoma Li et al 1567

3 1568 Arch Pathol Lab Med Vol 125, December 2001 Clear Cell Odontogenic Carcinoma Li et al

4 later and was enucleated again at the local hospital. This time, the patient presented with a swelling in the molar area of the right mandible. The mandibular tumor had destroyed the lingual cortex, and a solid mass measuring 3 cm in diameter was noted on the right side of the tongue base in direct contact with the mandibular lesion. After reviewing the histology of specimens from the previous surgical procedures, a diagnosis of clear cell odontogenic tumor was confirmed. Wide resection of both the mandibular and tongue base lesions was performed, and the pathologic diagnosis was clear cell odontogenic carcinoma. Postoperative radiation therapy was carried out to obviate the possibility of residual disease. The patient has been monitored postoperatively, and there has been no evidence of recurrence or metastasis during the 7 years following surgery. Case 3 involved a 58-year-old woman who came to our hospital with recurrent mandibular swelling 5 years after her third operation for recurrent ameloblastoma. The mandibular tumor was first seen 7 years earlier and was enucleated in another hospital under a diagnosis of ameloblastoma. The tumor recurred twice, both times at 1- year intervals, and the recurrences were resected in local hospitals. Radiographic examination revealed an ill-defined radiolucent lesion at the joint area of the previous bone graft and the right mandibular angle. Histologic review of the previously removed tumors demonstrated features identical to clear cell odontogenic tumors. Thus, the recurrent tumor was excised with a wide margin. No recurrence or metastasis was detected 1 year after the surgery. Case 4 involved a 32-year-old man who presented with a swelling of the right maxilla extending from the lateral incisor to first molar; the swelling had been present for 2 years. Radiographic examination demonstrated an expansile lytic lesion with destruction of the maxillary sinus floor. The lesion was provisionally diagnosed as a lowgrade malignancy. Partial maxillectomy was carried out to remove the tumor, and the pathologic diagnosis was low-grade malignant clear cell odontogenic tumor. Two recurrences were recorded (4 years after initial surgery and 8 years following the second operation), and the diagnosis now was clear cell odontogenic carcinoma. The patient remains under close follow-up 2 years after the last surgery, and there has been no evidence of recurrence or metastasis. Case 5 involved a 49-year-old woman who was referred to our hospital for treatment of a swelling of the right maxilla. The lesion involved the alveolar process of the premolar region, and the radiolucent lesion demonstrated irregular margins with marked destruction of the posteroinferior wall of the sinus (Figure 1, b). The provisional clinical diagnosis was squamous cell carcinoma of the gingiva. A semimaxillectomy was performed, and the postsurgical diagnosis was clear cell odontogenic carcinoma. The patient was monitored for 2 years after the surgery and showed no sign of disease. Pathologic Findings Microscopic examination of all primary tumors revealed a similar histologic pattern that consisted of islands and sheets of clear cells surrounded by a thin fibrous stroma. The tumor cells were characterized by abundant clear cytoplasm and distinct cytoplasmic membranes. The cells were oval or polyhedral in shape and had small, darkstaining, eccentric nuclei (Figures 2 and 3). In areas, solid cords of small basaloid cells with scanty eosinophilic cytoplasm were also commonly found (Figure 4). Pleomorphism and mitotic activity were generally unremarkable. All tumors contained a few to numerous nests that demonstrated palisading of the peripheral cells with the nuclei showing reversed polarity (Figure 2). The typical stellate reticulum and microcyst formation often seen in follicular ameloblastoma, however, was rarely encountered. There were areas in which epithelial nests were mainly composed of large clear or faintly granular cells, and peripheral palisading and reversed nuclear polarity were essentially absent (Figure 3). The tumor stroma was usually mature and fibrous with variable cellularity. Dense fibrous tissue with partial hyalinization was occasionally seen at the peripheral areas of the tumors, especially in recurrent lesions (Figure 4). In the primary tumors of cases 4 and 5, eosinophilic hyaline deposits reminiscent of osteoid or dentinoid structures were formed within the connective tissue stroma in direct contact with the epithelial nests (Figure 5). The tumors were unencapsulated and showed invasion of the surrounding tissues. Perineural invasion was noted in cases 1, 2, and 5 (Figure 6). The recurrent mandibular tumor of case 2 showed extensive infiltration into the adjacent tongue base. Metastasis of submandibular lymph node was histologically identified in case 1. In recurrent tumors, sections from the subsequent surgical procedures showed essentially similar features to their previous lesions, but in cases 1, 2, and 4, the frequency of mitosis appeared to be successively greater in material removed at each procedure. Most of the clear cells in tumors Figure 1. Radiographs of intraosseous tumors in the mandible (a, case 1) and in the maxilla (b, case 5) show lytic changes with ill-defined margins. Note the maxillary tumor (b) causing marked destruction of the sinus wall. Figure 2. Primary tumor of case 1. The tumor nests are composed of clear cells with well-defined cell borders and are separated by a thin fibrous stroma. Peripheral columnar cells with nuclear palisading are evident in some tumor nests (hematoxylin-eosin, original magnification 100). Figure 3. Primary tumor of case 3. Islands of large clear cells with little evidence of peripheral nuclear palisading (hematoxylin-eosin, original magnification 100). Figure 4. Recurrent tumor of case 2. Solid cords of small basaloid cells with scanty eosinophilic cytoplasm are seen at the peripheral areas of the tumor (hematoxylin-eosin, original magnification 100). Figure 5. Primary tumor of case 4. Eosinophilic fibrillar dentin/bonelike structures containing mesenchymal cells are seen in close contact with epithelial tumor nests (hematoxylin-eosin, original magnification 100). Figure 6. Case 5. Perineural infiltration by the tumor cell nests (hematoxylin-eosin, original magnification 100). Figure 7. Most of the clear cells contain cytoplasmic periodic acid Schiff (PAS)-positive granules (a, case 2) and show intense immunoreactivity for cytokeratin 19 (b, case 5) (PAS, original magnification 150 [a]; streptavidin-biotin, original magnification 150 [b]). Arch Pathol Lab Med Vol 125, December 2001 Clear Cell Odontogenic Carcinoma Li et al 1569

5 of all 5 cases were positive for PAS staining and were digested by diastase (Figure 7, a). However, the tumor cells were negative for Alcian blue. Eosinophilic hyaline deposits among the tumor nests were not stained with Congo red. The results of immunocytochemical staining are shown in Table 1. The tumor cells were strongly positive for pan-keratin (AE1/AE3) and cytokeratin 19 (Figure 7, b). Patchy positive staining for epithelial membrane antigen was also noted in all cases. The tumor cells were negative for vimentin, S100 protein, desmin, smooth muscle actin, human melanoma antigen (HMB-45), and 1 -antichymotrypsin. COMMENT Odontogenic tumors of the jaws with a predominant component of clear cells are exceedingly rare. Since the first reports of aggressive and malignant clear cell odontogenic tumors by Hansen et al 6 and Waldron et al, 11 very few additional cases have been documented. 2 5,7 10 The clinicopathologic features of this entity were analyzed by Muramatsu et al, 9 who reported 1 case with a review of an additional 18 cases from the literature. Of the 19 patients described, 12 were female and 7 were male. The patients ages ranged from 14 to 89 years (mean 55.6 years), with a peak frequency in the sixth decade of life. Seventy-four percent (14/19) of the lesions occurred in the mandible, most commonly in the anterior portion (10/14). The clinical features of the present series were in general agreement with those of the previous reports. Our data, however, showed a relatively younger age (mean 42.4 years) of the patients at diagnosis and a more apparent predilection for females (4:1). The most common location of the tumor was the anterior or premolar areas of the jaws (4 of 5 cases), with only 1 case occurring in the mandibular molar and ramus region, the typical site for conventional ameloblastomas. Hansen et al 6 fell short of calling their cases carcinomas because none had metastasized. They called them clear cell odontogenic tumors and considered them to be distinct from ameloblastomas. They nevertheless recognized the aggressive growth pattern. 6 Subsequently, similar cases showing aggressive growth, recurrent behavior, and metastatic spread were reported and were therefore designated as clear cell odontogenic carcinoma. 2,4,5,8,10 The present series confirms the opinions of previous authors, who regarded clear cell differentiation as an ominous sign in an odontogenic tumor. Local recurrence was a common finding in our patients, with 4 of 5 tumors (80%) recurring following the initial surgery. The only nonrecurrent tumor (case 5) was a more recent case and has been followed for only 2 years after a relatively radical removal of the primary tumor. Its clinical behavior is yet to be determined. Furthermore, of the 4 cases with recurrences, 3 (cases 1, 2, and 4) recurred twice and 1 (case 3) recurred 3 times over various time intervals (Table 2). One patient (case 2) developed extension into the tongue base during the second recurrence. With time, the recurrent tumors appeared to assume progressively worsening cytologic atypia. Regional lymph node metastasis was histologically verified in case 1, when the tumor recurred 1 year after the original excision. This patient had a second recurrence 2 years later and subsequently died of general debilitation and extensive local tumor growth. These data, together with the frequently reported nodal and pulmonary metastases 2,4,5,8,10 and the recorded deaths related to tumor progression, 2,4,11 strongly indicate that odontogenic clear cell neoplasms should be classified as at least low-grade malignancies. Tumors with a conspicuous clear cell component in the head and neck region can impose serious problems with respect to differential diagnosis. They can originate from various sources, including salivary gland tumors, metastatic renal cell carcinoma, melanotic tumors, and other odontogenic tumors, such as ameloblastoma and calcifying epithelial odontogenic tumor. 12 Intraosseous mucoepidermoid carcinomas of the jaws are unusual but are not rare, 11 and selected tumors that are almost exclusively composed of clear cell elements may be encountered. 13 Accurate differential diagnosis with other clear cell tumors depends on an exhaustive search for intermediate cells and Alcian blue/pas-positive mucin-producing cells. Immunocytochemical staining is useful in the differential diagnosis with myoepithelial cell containing clear cell salivary gland tumors. Cytokeratin, vimentin, S100 protein, and muscle actin are readily demonstrable in the latter group of tumors. 14,15 Myoepithelial carcinomas of the salivary glands, including clear cell type, have been shown to stain with calponin, a newly identified smooth muscle protein. 16 Carcinomas from the kidney, liver, prostate, and thyroid are known to have the potential for clear cell differentiation, and all of these carcinomas are able to metastasize to the maxillofacial area, with renal cell carcinoma doing so most frequently The metastatic deposits containing clear cells may morphologically mimic salivary gland tumors as well as odontogenic tumors, but renal cell carcinoma is characterized by a prominent sinusoidal vascular component with hemorrhagic foci. 17 Immunocytochemical evaluation (for -fetoprotein, thyroglobulin, and prostate-specific antigen) may be useful in distinguishing metastases from primary tumors Occasionally, melanocytic tumors may show a predominant clear cell component, but most of these tumors arise in the soft tissues and they have been described only rarely in the head and neck. 20,21 In addition, these tumors show typical immunocytochemical expression of S100 protein and melanoma-associated antigen (HMB-45). Clear cell odontogenic carcinoma can be distinguished from the clear cell variant of calcifying epithelial odontogenic tumor because it lacks the characteristic calcifications and amyloid deposition. 22,23 Typical ameloblastomas containing clear cells but not showing features of malignancy or an unusual degree of aggressiveness may arise both centrally and peripherally. 24,25 It is uncertain whether these tumors are related to clear cell odontogenic carcinomas, many of which also show a degree of ameloblastomatous differentiation. 11 Although some authors use the terms clear cell ameloblastoma and clear cell odontogenic carcinoma synonymously, 3,7,11 we do not believe that there are, as yet, sufficient data to substantiate this point of view and concur that they should be regarded as separate lesions at this stage. In the tumors of the present series, most of the clear cells contained diastase-digestible, PAS-positive granules, whereas none of the tumor cells stained with Alcian blue, indicating the presence of glycogen rather than mucin within the cytoplasm. Negative Congo red reactivity indicated that the hyaline osteoid/dentinoid structures in the lesion were different from amyloid deposits. Immunocytochemically, the tumor cells showed positive staining for wide-spectrum cytokeratin, CK-19, and epithelial membrane antigen, but negative staining for vimentin, 1570 Arch Pathol Lab Med Vol 125, December 2001 Clear Cell Odontogenic Carcinoma Li et al

6 S100 protein, desmin, smooth muscle actin, human melanoma antigen (HMB-45), and 1 -antichymotrypsin. Expression of cytokeratin and epithelial membrane antigen has been assessed in various odontogenic lesions, 26,27 and CK-19 has been shown to react with all kinds of odontogenic epithelial cells. 28,29 In salivary glands and their tumors, however, only ductal cells exhibit focal expression of CK Thus, the immunocytochemical profile of the present group of tumors suggests that they are of odontogenic epithelial origin. In addition, the presence of eosinophilic, hyaline, fibrillar, dentin/bonelike structures between tumor cell nests and fibrous stroma also suggests that some of the tumors possess epithelial-mesenchymal inductive capacity, a feature shared by many odontogenic epithelial tumors. 1 In conclusion, we reiterate that caution needs to be exercised when a primary intraosseous tumor of the jaws containing a conspicuous clear cell component is being interpreted, according to the World Health Organization classification, as clear cell odontogenic tumor. The histologic evidence of tumor invasion, frequent or multiple local recurrences, regional and/or distant metastatic potential, and an occasional fatal clinical course, as demonstrated here and in previous reports, 2,4,5,8,10,11 all indicate that this group of clear cell odontogenic tumors should be considered as, at least, low-grade malignancies, and the designation of carcinoma for the condition seems justified. On the basis of experience with the present 5 cases, it appears that the primary surgical management of the tumor should be aggressive and that careful postoperative follow-up is mandatory. References 1. Kramer IRH, Pindborg JJ, Shear M. WHO Histological Typing of Odontogenic Tumors. 2nd ed. Berlin, Germany: Springer Verlag; 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: de Aguiar MC, Gomez RS, Silva EC, de Araujo VC. Clear-cell ameloblastoma (clear-cell odontogenic carcinoma): report of a case. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996;81: Eversole LR, Duffey DC, Powell NB. Clear cell odontogenic carcinoma: a clinicopathologic analysis. Arch Otolaryngol Head Neck Surg. 1995;121: Fan J, Kubota E, Imamura H, et al. Clear cell odontogenic carcinoma: a case report with massive invasion of neighboring organs and lymph node metastasis. 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