Clear Cell Variant of Calcifying Epithelial Odontogenic Tumor: Is It

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J Oral Maxillofac Surg 67:207-211, 2009

Clear Cell Variant of Calcifying Epithelial Odontogenic Tumor: Is It

Locally Aggressive?

Ana Lúcia Carrinho Ayrosa Rangel, DDS, PhD,*

Andréia Aparecida da Silva, DDS, MSc,†

Fábio Augusto Ito, DDS, PhD,‡

Márcio Ajudarte Lopes, DDS, PhD,§

Oslei Paes de Almeida, DDS, PhD,储 and Pablo Agustin Vargas, DDS, PhD¶

The calcifying epithelial odontogenic tumor (CEOT) is a rare benign odontogenic neoplasm of the jaws, accounting for approximately 1% of all intraosseous odontogenic tumors.1-3 Some histologic variants have been described, including CEOT with Langer- hans cells,4,5with cementum-like and bone-like ma- terial, combined epithelial odontogenic tumor and adenomatoid odontogenic tumor, myoepithelial cells, and the clear cell variant of calcifying epithe- lial odontogenic tumor (CCCEOT).6 The diagnosis of CCCEOT is very difficult and other clear cell lesions that affect the oral cavity should be ex- cluded. According to some authors it is more aggressive when compared with other CEOT vari- ants showing a recurrence rate of 10.52%7 and should be considered as a low-grade odontogenic

carcinoma.1,3,6To our knowledge, there are only 19 cases of CCCEOT in the oral cavity published in the English language literature. We report an additional case of CCCEOT affecting the mandible of a 65-year-old male and discuss its clinicopathologic and immunohisto- chemical findings.

Report of a Case

Our biopsy service (Oral Pathology, Piracicaba Dental School-UNICAMP, São Paulo, Brazil) received a specimen from a 65-year-old male of a painless swelling located be- tween the mandibular right lateral incisor and canine that had been growing slowly for about 3 years. The clinical information sent by the private dentist was of a fibrous, firm, sessile, and painless lesion covered by a smooth and regular mucosal surface in the anterior mandibular gingiva between the right lateral incisor and canine, which mea- sured nearly 1.5 cm in its maximum dimension. The periapical radiograph showed a well-defined unilocular radiolucent lesion with radiopacities dispersed through- out the lesion. In addition, there was resorption of the bone crest between the right mandibular lateral incisor and canine; however, the roots of the adjacent teeth were not displaced, and there was no sign of the root resorption (Fig 1). The lesion was removed by complete surgical excision.

Hematoxylin and eosin-stained sections showed multiple mucosal fragments represented by a dense connective tis- sue that was replaced by irregular strands, cords, and nests of epithelial cells. The polyhedral epithelial cells dis- closed an abundant and eosinophilic cytoplasm; round- to-oval relatively large nuclei with dense chromatin, and evident intercellular bridges. These cells showed mild pleomorphic and hyperchromatic nuclei. In significant por- tions, the epithelial cells had a clear, foamy, vacuolated cytoplasm (Figs 2-4). The calcifications areas and Lieseg- ang’s rings were observed, and amyloid-like deposits were not visualized. However, these amyloid-like deposits could be observed in Congo red staining under polarized light (Fig 5). The periodic acid Schiff (PAS) showed numerous glob- ules of positive material, which was removed by prior Received from the Piracicaba Dental School, State University of

Campinas, Piracicaba, São Paulo, Brazil.

*Former PhD Student of Estomatopatologia, Department of Oral Diagnosis, Oral Pathology.

†PhD Student of Estomatopatologia, Department of Oral Diagnosis, Oral Pathology.

‡Former PhD Student of Estomatopatologia, Department of Oral Diagnosis, Oral Pathology.

§Associate Professor, Department of Oral Diagnosis, Oral Semi- ology.

储Head, Department of Oral Diagnosis, Oral Pathology.

¶Associate Professor, Department of Oral Diagnosis, Oral Pathology.

Address correspondence and reprint requests to Dr Vargas: Oral Pathology, Oral Diagnosis Department, Piracicaba-UNICAMP, Av.

Limeira 901, Piracicaba-SP, Brazil. Caixa Postal 52, CEP:13414-903;

e-mail:pavargas@fop.unicamp.br

©2009 American Association of Oral and Maxillofacial Surgeons 0278-2391/09/6701-0031$34.00/0

doi:10.1016/j.joms.2007.11.029

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diastase digestion. Immunohistochemical reactions carried out using avidin-biotin complex technique showed positiv- ity for cytokeratin cocktail (clone: AE1/AE3, Dako, Carpin- teria, CA, dilution 1:500) (Fig 6), ck7 (clone: OV-TL12/30, Dako, dilution 1:400) and ck14 (clone: NCL-L-LL002, Novocastra Laboratories, Newcastle, England, dilution

1:200) in the epithelial neoplastic cells whereas the stromal component was positive for vimentin (clone: Vim 3B4, Dako, dilution 1:400) (Fig 7). The other immunomarkers (1, S-100 protein, Dako, dilution 1:10,000; 2, muscle specific actin, clone: HHF-35, Dako, dilution 1:800; 3, anti-human melano- some, clone: HMB-45, Dako, dilution 1:200; 4, Desmin, clone:

D33, Dako, dilution 1:1,000) were negative in the present case. Analyzing all features described above the final diagnosis of central CCCEOT was established. The patient has been followed for about 24 months with no sign of recurrence observed.

Discussion

The first case of CCCEOT was reported by Abrams and Howell8in 1967. There are currently 20 reported

FIGURE 1. Periapical radiograph showing a well-defined uniloc- ular radiolucent lesion with radiopacities dispersed throughout the radiolucency, with resorption of the bone crest between the right mandibular lateral incisor and canine.

Rangel et al. Clear Cell Variant of Calcifying Epithelial Odonto- genic Tumor. J Oral Maxillofac Surg 2009.

FIGURE 2. Microscopic features of the CCCEOT showing nests of polyhedral epithelial cells with clear cells and calcification (hema- toxylin-eosin stain, original magnification⫻100).

Rangel et al. Clear Cell Variant of Calcifying Epithelial Odonto- genic Tumor. J Oral Maxillofac Surg 2009.

FIGURE 3. High-power view exhibiting mild pleomorphism on polyhedral and clear cells (hematoxylin-eosin stain, original mag- nification⫻400).

Rangel et al. Clear Cell Variant of Calcifying Epithelial Odonto- genic Tumor. J Oral Maxillofac Surg 2009.

FIGURE 4. Microscopic features of the CCCEOT showing nests of polyhedral epithelial cells compounded by large and dark nucleus and clear cells with foamy and clear cytoplasm (hematoxylin-eosin stain, original magnification⫻200).

Rangel et al. Clear Cell Variant of Calcifying Epithelial Odonto- genic Tumor. J Oral Maxillofac Surg 2009.

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cases (including the present one) in the English-lan- guage literature (Table 1). Of these 20 cases, 12 were central and 8 peripheral lesions. The male:female ra- tio was 1:1.2 for the central and 1.66:1 for the periph- eral lesions. Overall ages ranged from 14 to 68 years with a mean age of 40.84 years. The mean age for the intraosseous CCCEOT is, however, considerably higher (46.36 years) than for the extraosseous variant (33.25 years). The surgical management modalities in the 20 cases were as follows: complete or partial resection in 6 patients (30%), excision in 10 (50%), enucleation in 3 (15%), and curettage in 1 (5%). The follow-up ranged from 4 months to 13 years (mean, 3.6 years), and it was not available in 1 case. Recur- rence was reported in 2 cases of central CCCEOT (10.52%) that occurred 4 months after curettage in 1

case, and 13 years after partial resection in the other.

None of the peripheral lesions recurred.

The diagnosis of CCCEOT is usually based on the finding of some areas of typical epithelial clear cells within the tumor. The nuclei show considerable vari- ation in size and shape, with rare mitotic figures. In addition, the CCCEOT can present irregular strands, cords, and nests of the polyhedral epithelial cells with abundant, eosinophilic cytoplasm, round to oval rel- atively large nuclei with dense chromatin, and evident intercellular bridging in association with clear epithe- lial cells.9Deposition of extracellular amyloid-like ma- terial and calcifications are also typical.10

Tumors with a conspicuous clear cell component in the head and neck region can impose serious prob- lems with respect to differential diagnoses. Tumors constituted by clear cells are most often of epithelial origin but can also be present in melanocytic and mesenchymal neoplasms.2Clear cells are characteris- tic cellular components of the epithelial lining of most lateral periodontal cyst and gingival cysts in adults, or they may be found as clear cell rests of the dental lamina within the connective tissue of these cysts.1 With considerably less frequency clear cells may oc- cur in certain odontogenic epithelial tumor entities such as ameloblastoma, calcifying odontogenic cyst and calcifying odontogenic tumor.11-13 Clear cells have also been described in other lesions of the jaw, including salivary gland tumors such as mucoepider- moid carcinoma and acinic cell carcinoma, and met- astatic disease originating from kidney, thyroid, and lung carcinomas.6,14,15 Carcinoma of salivary gland origin is ruled out by the absence of actin and S-100 expression, and clear cell odontogenic carcinoma is excluded by the minor degree of atypia, good circum- scription of the lesion, and presence of calcified and

FIGURE 5. Amyloid-like material stained by Congo red (A) and shown by polarized light showing the characteristic green birefrin- gence in a darkened background (B) (Congo red, original magni- fication⫻200).

Rangel et al. Clear Cell Variant of Calcifying Epithelial Odonto- genic Tumor. J Oral Maxillofac Surg 2009.

FIGURE 6. Epithelial, polyhedral, and clear cells displaying im- munopositivity for cytokeratin cocktail (AE1/AE3) (immunohisto- chemical stain, original magnification⫻100).

Rangel et al. Clear Cell Variant of Calcifying Epithelial Odonto- genic Tumor. J Oral Maxillofac Surg 2009.

FIGURE 7. Stromal cells showing immunoreactivity for vimentin (immunohistochemical stain, original magnification⫻100).

Rangel et al. Clear Cell Variant of Calcifying Epithelial Odonto- genic Tumor. J Oral Maxillofac Surg 2009.

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amyloid-like material.10Moreover, most clear cell sal- ivary gland tumors are positive for PAS reaction with diastase digestion and most of them are malignant.

Occasionally, melanocytic tumors may show a pre- dominant clear cell component, but most of these tumors arise in the soft tissue and they have been described only rarely in the head and neck region. In addition, they show positivity for S-100 protein and melanoma associated antigen (HMB-45). Although metastatic disease originating from thyroid, kidney, and lungs may present clear cells, the absence of PAS positivity excluded metastatic renal cell carcinoma.10 The lack of mitotic figures and the generally good circumscription of the lesion are not typical of meta- static disease of any origin. The diagnosis of CCCEOT in our case was supported by microscopically bipha- sic pattern, presence of apple-green birefringent/

Congo red-positive material between tumor islands, small calcifications, good circumscription of the le- sion, and lack of mitotic figures.

There are few reports about immunohistochemical findings in CCCEOT.3,9,14 Kumamoto et al9 found immunoreactivity of the tumor cells for all wide-spec- trum cytokeratins (CKs), CK 8, 13, and 19 but were negative for CK 10 and 20. For Anavi et al7the tumor cells were positive for cytokeratin cocktail only. For Mesquita et al16 all epithelial cells (polyhedral and clear) strongly expressed CK AE1/AE3 and CK14. In the present case, the immunohistochemical findings

were similar to those other cases published in the literature.3,9,14 Our analysis showed that all cells (polyhedral and clear) strongly expressed CK AE1/

AE3, CK7, and CK14 but were immunonegatives for S-100, muscle specific actin, desmin, and anti-human melanosome. The stromal component, however, was positive for vimentin.

Although considered benign in nature, CCCEOT is designed as locally aggressive for some investigators because its moderate recurrence rate. Some authors report that the presence of clear cells may indicate increased tumor aggressiveness.7,13,17-19 Anavi et al7 described the clinical and radiographic features of CCCEOT and compared them with those reported for CEOT without clear cell component, and concluded that there is evidence to support the classification of CCCEOT as a distinct, more aggressive variant of CEOT but not as a separate entity. This assumption may have been influenced by described cases of clear cell odontogenic tumor with local bone invasion and metastatic spread. In addition, Veness et al20 de- scribed initially a case of CEOT that recurred twice after excision, with a progressive increase in the cel- lularity, loss of differentiation, and presence of vascu- lar and lymph node metastasis, suggesting a malignant transformation process. Kumar et al15reported a case with initial diagnosis of CEOT that showed posterior widespread infiltration, necrosis, and metastatic le- sion in vertebrae and hip. Final diagnosis was metas-

Table 1. WELL-DOCUMENTED REPORTED CASES OF CCCEOT*

Authors Age (yr) Gender Site Size (cm) Treatment Follow-Up

Abrams and Howell8 16 F Gingiva 0.5 Excision FOD 3 yr

50 M Intraosseous 1.2 Enucleation FOD 3 yr

Anderson et al6 68 F Intraosseous 3.0 Curettage Recurrence at 4 mo

Wallace and MacDonald13 65 M Intraosseous NR Excision FOD 22 mo

Greer and Richardson5 37 F Intraosseous 0.5 Enucleation FOD 13 mo

Oikarinen et al3 36 F Intraosseous 10.0 Enucleation FOD 2 yr

Wertheimer et al22 20 M Gingiva 1.5 Excision NR

Yamaguchi et al23 36 M Intraosseous 2.5 Partial resection FOD 2 yr

Ai-Ru et al24 32 F Gingiva NR Partial resection FOD 10 yr

42 F Intraosseous NR Resection FOD 2 yr

Schmidt-Westhausen et al14 38 M Intraosseous 2.5 Resection FOD 2 yr

Hicks et al21 59 F Intraosseous 3.8 Resection FOD 3 yr

Houston and Fowler25 64 M Gingiva 1.5 Excision FOD 4 yr

27 M Gingiva 1.4 Excision FOD 4 yr

Kumamoto et al9 14 F Intraosseous NR Partial resection Recurrence at 13 yr

Orsini et al12 32 M Gingiva NR Excision FOD 4 yr

Mesquita et al16 48 F Gingiva 2.0 Excision FOD 30 mo

Anavi et al7 27 M Gingiva 1.0 Excision FOD 1 yr

Germanier et al11 44 F Intraosseous 3.0 Enucleation FOD 1 yr

Rangel et al† 65 M Intraosseous 1.0 Excision FOD 1 yr

Abbreviations: CCCEOT, clear-cell calcifying epithelial odontogenic tumor; F, female; FOD, free of disease; M, male; NA, not available; NR, not reported.

*Eighteen cases were reported in 16 articles.

†Present report.

Rangel et al. Clear Cell Variant of Calcifying Epithelial Odontogenic Tumor. J Oral Maxillofac Surg 2009.

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tasizing clear cell odontogenic carcinoma. Therefore, it is unknown whether this is attributable to sampling error, or to clear cell change predominating during the natural history of the tumor.

Treatment of CCCEOT involves surgery; enucle- ation of involved tooth, or “in bloc resection” in some cases including any associated soft tissue mass. Tu- mor-free surgical margins should be obtained to re- duce the risk of local recurrences. Analyzing the lit- erature, we observed that the recurrent cases of CCCEOT occurred probably because of inadequate treatment.9,13 On the other hand, the follow-up of some CCCEOT cases is short, not permitting concise conclusions of biological behavior of these tumors.

The clinical course of the present case did not show recurrence after 24 months. Based on our findings and the literature review, we can state that CCCEOT is not locally aggressive as mentioned previously be- cause the cases reported have generally shown little evidence of aggressiveness even years after relatively conservative treatment. Moreover, Hicks et al21 re- ported recurrence rates of 14% for CEOT and our literature review (n ⫽ 19) has detected 10.5% for CCCEOT. Further CCCEOT cases should be reported to increase our knowledge about this rare lesion and to confirm our findings.

References

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