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Clear cell odontogenic carcinoma
Oral Oncology 38 (2002) 209–213 www.elsevier.com/locate/oraloncology
Case report
Clear cell odontogenic carcinoma G. Iezzi a, C. Rubini b, M. Fioroni c, A. Piattelli a,d,* b
a Dental School, University of Chieti, Italy Institute of Pathologic Anatomy and Histopathology, University of Ancona, Italy c Dental School, University of Ancona, Italy d Eastman Dental Institute for Oral Health Care Sciences, London, UK
Received 17 January 2001; accepted 19 February 2001
Abstract Clear cell tumours, in the head and neck region, are usually derived from salivary or odontogenic tissues, or may be metastatic. A few clear cells may be present in odontogenic cysts, while, odontogenic neoplasms composed predominantly of clear cells are quite rare. They include calcifying epithelial odontogenic tumours (CEOT), ameloblastoma and odontogenic carcinoma. Clear cell odontogenic tumour (CCOT) has been classified in the last WHO classification as a benign tumour, but it is now recognized as a more sinister lesion and current opinion is that CCOT should be designated as a carcinoma. These tumours are characterized by aggressive growth, recurrences, and metastatic disease. A recent review of the literature has yielded 30 cases of tumours with similar characteristics. These tumours have a peak incidence in the 5–7th decades, with a female predilection. The anterior portions of the jaws, especially the mandible, are most frequently affected. The aggressive potential of these neoplasms is well documented by the extensive invasion of adjacent tissues, multiple recurrences and regional or distant metastases. # 2002 Elsevier Science Ltd. All rights reserved. Keywords: Clear cell tumours; Clear cell odontogenic tumour; Clear cell odontogenic carcinoma
1. Introduction Clear cells may be present in several different tumours, and usually are the result of fixation artefacts, intracellular storage of several substances, i.e glycogen, mucin, lipid, or from a paucity of organelles. Clear cell tumours, in the head and neck region, are usually derived from salivary or odontogenic tissues, but also metastatic tumours need to be taken into consideration [1]. A few clear cells may be present in odontogenic cysts, while, odontogenic neoplasms composed entirely or predominantly of clear cells are quite rare [2,3]. They include calcifying epithelial odontogenic tumours (CEOT) [4,5], ameloblastoma and odontogenic carcinoma [6,7]. The presence of clear cells in odontogenic tumours is certainly not surprising due to their origin from the dental lamina, which presents clear cells as a component [8]. Clear cells may be encountered in other head and neck neoplasms, such as salivary gland tumours, * Corresponding author. Present address: Via F. Sciucchi 63, 66100 Chieti, Italy. Tel.: +39-0871-3554073; fax: +39-0871-3554076. E-mail address: [email protected] (A. Piattelli).
metastatic renal cell carcinoma, and melanotic tumours [9]. Due to the limited number of clear cell odontogenic carcinomas reported so far, only incomplete data are available on their clinical, immunohistochemical and prognostic features [10]. The close resemblance of odontogenic clear cell neoplasms to ameloblastoma is a further complication in the differential diagnosis of these lesions [11]. The issue of the biologic behaviour of clear cell odontogenic carcinomas (CCOCs), however, is complicated by the confounding terminology and classification, with some authors using terms such as clear cell ameloblastoma and clear cell odontogenic carcinoma synonymously [11]. Clear cell odontogenic tumour (CCOT) has been classified in the last WHO classification as benign [12], but it is now being increasingly recognized as a more sinister lesion and current opinion is that CCOT should be designated as a carcinoma [1,10]. These tumours are characterized by aggressive growth, recurrences, and metastatic disease, and several deaths have been reported due to the tumour progression [9,13,14]. It remains to be determined whether or not a benign variety exists [1]. Whereas the CCOC is of putative odontogenic origin,
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histologic similarities to the developing tooth germ are lacking in most instances [14].
2. Case report A 62-year-old female patient was referred for an illdefined radiolucent lesion of the right maxilla (Fig. 1). Radiography showed a radiolucency with indistinct margins, located in the lateral incisor region. No radiopaque foci or impacted teeth were present inside the lesion. A biopsy showed large and irregular sheets or cords of neoplastic clear cells in a cellular, collagenous stroma. The tumour cells were cuboidal or polyhedral, with centrally placed, rounded nuclei. The patient underwent a complete check-up to exclude the possibility of an occult primary malignancy. All the results were negative. A diagnosis of clear cell odontogenic carcinoma was made and the patient underwent a right maxillectomy. The patient is alive and well, at a 4-year follow-up, with no evidence of recurrences or of regional or distant metastases. The surgical specimen was fixed in 10% buffered formalin. Five-micron sections were cut and stained with hematoxylin–eosin, periodic acid–Schiff (PAS) with and without diastase treatment, alcian blue at pH 2.5, mucicarmine, Congo red and toluidine blue (for examination under polarized light) and Gomori’s reticulin. Immunohistochemical studies, performed with an peroxidase-anti-peroxidase (APAAP) method were made
Fig. 1. Radiographic aspect of the lesion at first presentation: an illdefined radiolucency of the right maxilla is present.
using AE1/AE3 cytokeratins, CAM 5.2, epithelial membrane antigen (EMA). Before the incubations with the specific primary antibodies, the sections were treated with 0.01% Pronase E in phosphate buffered saline (PBS), for 15 min at room temperature, or subjected to a 45 min microwave irradiation, following immersion in 0.1 M Citrate buffer, pH 6.0, in a microwave oven, set at 750 W. All the incubations lasted 30 min at room temperature, and were followed by 33 min washings in PBS. Appropriate positive controls were included in the procedures, along with negative controls, which were achieved by substituting the primary specific antibodies with non-immune serum.
3. Results It was possible to observe that the tumour (Fig. 2) was composed mainly of three components: clear cells, cells with an eosinophilic cytoplasm, and squamoid cells. The growth of the eosinophilic cell component was trabecular, while the clear cells were arranged in solid nests and the squamoid cells in a way similar to that observed in plexiform ameloblastoma. Occasionally, psudocysts or duct-like structures (Fig. 3), lined predominantly by flattened or cuboidal eosinophilic cells were present. All these cells were immersed in a collagenous stroma. Nuclear pleomorphism was present both in the clear cell and in the eosinophilic cell component. Mitotic activity was observed in the clear cell and squamoid component. Most neoplastic cells contained intracytoplasmic, PAS-positive, diastasesensitive, granules (Fig. 4). The stromal component was always abundant in the squamoid and clear cell component, and areas with prominent cellularity, consisting of mature fibroblasts, were intermingled with hyalinized areas. The stroma contained scattered and small capillary blood vessels. In addition, the tumour islands had invaded the adjacent bone and soft tissues, including muscles; vascular invasion was also present (Fig. 5).
Fig. 2. The tumour is composed by a clear cell component (right side) and by a basaloid cell component (left side). Hematoxylin–Eosin 16.
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Fig. 3. Some pseudoglandular aspects are present in this field. Hematoxylin–Eosin 20.
Fig. 5. It is possible to observe a vascular invasion by the tumour cells. Hematoxylin–Eosin 20. (Arrow.)
Fig. 4. The clear cell component shows the presence of PAS-positive cytoplasmic granules. PAS 20.
Fig. 6. Membrane positivity to CAM 5.2 of the neoplastic clear cells. APAAP 20.
Immunohistochemistry showed that the clear cells showed a non homogeneous membrane positivity for the wide spectrum cytokeratins (AE1/AE3), cytokeratin 19 and EMA (Fig. 6), while, the eosinophilic cells were consistently and strongly immunoreactive for the same antigens (Fig. 7). The squamoid component, on the other hand, reacted negatively (Fig. 8). Some focal positivity was present only rarely (Fig. 9). All the cellular components were consistently negative for vimentin, smooth-muscle actin, S-100 protein Glial Fibulary Acidic Protein (GFAP).
lar bone loss is present and perforation of the cortical bone and invasion into neighbouring tissues is frequently observed [24]. Histologically, three patterns are present [14]. Most commonly these tumours 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, while the least common variant is characterized by clear cell nests with an ameloblastomatous pattern with palisading around the periphery [1,11,13]. A minor subpopulation of small eosinophilic cells, arranged in a double layer and centrally located within the clear cell clusters, with a resemblance to duct structures, can be also present. The proportion of clear cells in these tumours has been different, varying from tumours that are composed almost entirely of clear cells to tumours made up in a significant way by other cellular elements like areas similar to ameloblastoma, basaloid cells or islands of squamous cells [8]. There are no amyloid, calcifications or mucus production [1]. Glycogen storage is quite common in these tumours [9,13,14,27] and consistent cytokeratins immunoreactivity, specifically
4. Discussion A recent review of the literature has yielded 30 cases of tumours with similar characteristics [6,7,15–28]. These tumours have a peak incidence in the 5–7th decades, with a female predilection. The anterior portions of the jaws, especially the mandible, are most frequently affected [1]. Patients usually complain of tooth mobility or swelling of the jaws [24]. Radiologically, these tumours present as ill-defined radiolucent lesions with root resorption present in the majority of cases. Alveo-
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Fig. 7. Strong positivity to AE1/AE3 cytokeratins of the neoplastic eosinophilic cells. APAAP 20.
Fig. 8. Focal positivity of squamoid cells to AE1/AE3 cytokeratins. APAAP 16. (Arrow.)
for cytokeratins 8, 13 and 19, has been reported [9,13,27]. Occasionally EMA, S-100 protein and antiameloblastoma antigen positivity have also been demonstrated [9,27]. We could identify intracellular glycogen, by means of PAS-positive, diastase-sensitive granules accumulation in the tumour cells, whereas mucin and amyloid production could be excluded, due to absence of mucicarmine, alcian blue, Congo red and toluidine blue positivity. These immunohistochemical results confirm the epithelial nature of the tumour cells [8], and they help in the differential diagnosis. It has been pointed out that the presence of two cell populations, i.e. clear and polygonal cells and separation of tumour islands by a mature fibrous stroma could help in distinguishing CCOT from other types of clear cell tumours [10,11]. Calcifying epithelial odontogenic tumour may show a prominent but not predominant clear cell component [4,5]. In this tumour it is possible to find a prominent amyloid and calcium deposition in the stroma, a feature never reported in CCOC. Mucoepidermoid carcinoma commonly shows clear cell changes and may arise as an intra-osseous tumour in the jaws. In central mucoepidermoid carcinoma, glandular or luminal structures and mucus-producing cells are
Fig. 9. Focal positivity of some central squamoid cells to CAM 5.2. APAAP 20. (Arrow.)
observed. Moreover, in this tumour another distinguishing feature is the presence of squamoid cells that appear to be condensed around the periphery of the tumour islands and adjacent to the vascular septae [9,10]. Other types of salivary gland carcinomas, i.e. acinic cell carcinoma, clear cell myoepithelial carcinoma and epithelial-myoepithelial carcinoma only rarely have an intra-osseous origin. Hyalinizing clear cell carcinoma has similar features to CCOC [29] including prominent hyalinization of the stroma, immunoreactivity for cytokeratins and EMA and lack of S-100 protein; these tumours have, however, not been reported to be primarily located in bone. Metastatic tumours to the jaws may also exhibit prominent clear cell features [30]. Metastatic renal cell carcinoma usually presents intratumoural haemorrhage and typical sinusoidal vascularity [31]. Other possible origins, such as from liver, prostate and thyroid can be excluded due to the lack of hepatocyte antigen, prostate specific antigen and thyroglobulin immunoreactivities, and by a complete clinical and radiological work up of the patients. Malignant melanoma may be excluded by the absence of S-100 protein and melanoma antigen HMB45 [32]. About one quarter of the patients, suffering from CCOC and with clinical follow-up, died of tumour, two were alive with persistent disease and 13 are alive without evidence of residual tumour. Recently, it has been proposed that clear cell tumours, showing histologically benign or malignant features, are part of a continuous spectrum and should not be considered distinct entities [33]. Some clear cell odontogenic carcinomas show an ameloblastomatous pattern while others do not. Whether such a distinction is of relevance remains to be elucidated. Moreover, some doubt may exist as to whether the clear cell ameloblastoma and the clear cell odontogenic carcinoma are distinct entities. It must be considered that, by definition, clear cell ameloblastoma presents some features of typical ameloblastoma and a follicular or plexiform configuration, is less aggressive and has little or no tendency to metastasize [34].
G. Iezzi et al. / Oral Oncology 38 (2002) 209–213
The aggressive potential of CCOC is, on the contrary, well documented by the extensive invasion of adjacent tissues, multiple recurrences [5,21,23] and regional [9,12,14,15] or distant metastases [9,15]. Pulmonary metastases have been reported particularly in cases with multiple recurrences, and more than one surgical intervention [1]. Whether or not they are to be considered as true hematogenous metastases is still in doubt [1].
References [1] MacDonald DG, Browne RM. Tumours of odontogenic epithelium. In: Anthony PA, Macsween RNM, Lowe DG, editors. Recent advances in histopathology. Edinburgh: ChurchillLivingstone, 1997. p. 139–66. [2] Ng KH, Siar CH. Clear cell change in a calcifying odontogenic cyst. Oral Surg Oral Med Oral Pathol 1985;60:417–9. [3] Maiorano E, Altini M, Favia G. Clear cell tumours of the salivary glands, jaws and oral mucosa. Semin Diagn Pathol 1997;14:203–12. [4] Schmidt-Westhausen A, Philipsen HP, Reichart PA. Clear cell calcifying epithelial odontogenic tumour. A case report. Int J Oral Maxillofac Surg 1992;21:47–9. [5] Hicks MJ, Flaitz CM, Wong MEK, McDaniel RK, Cagle PT. Clear cell variant of calcifying epithelial odontogenic tumour: case report and review of the literature. Head Neck Surg 1994;16:272–7. [6] Hansen LS, Eversole LR, Green TL, Powell NB. Clear cell odontogenic tumour — a new histologic variant with aggressive potential. Head Neck Surg 1985;8:115–23. [7] Waldron CA, Small IA, Silverman H. Clear cell ameloblastoma: an odontogenic carcinoma. J Oral Maxilofac Surg 1985;43: 701–17. [8] de Aguiar MCF, 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;81:79–83. [9] Muramatsu T, Hashimoto S, Inoue T, Shimono M, Noma H, Shigematsu T. Clear cell odontogenic carcinoma in the mandible: histochemical and immunohistochemical observations with a review of the literature. J Oral Pathol Med 1996;25:516–21. [10] Miyauchi M, Ogawa I, Takata T, Ito H, Nikai H, Ijuhin N, Tanimoto K, Itoh Y. Clear cell odontogenic tumour: a case with induction of dentin-like structures? J Oral Pathol Med 1998;27:220–4. [11] Yamamoto H, Inui M, Mori A, Tagawa T. Clear cell odontogenic carcinoma. A case report and literature review of odontogenic tumours with clear cells. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;86:86–9. [12] Kramer IRH, Pindborg JJ, Shear M. Histological typing of odontogenic tumours. WHO international histological classification of tumours. 2nd ed. Berlin, Germany: Springer-Verlag, 1992. [13] Kumamoto H, Yamazaki S, Sato A, Yamaguchi T, Tezuka F, Ooya K. Clear cell odontogenic tumour in the mandible: report of a case with duct-like appearances and dentinoid induction. J Oral Pathol Med 2000;29:43–7. [14] Eversole LR. Malignant epithelial odontogenic tumours. Semin Diagn Pathol 1999;16:317–24.
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[15] Muller H, Slootweg P. Clear cell differentiation in an ameloblastoma. J Maxillofac Surg 1986;14:158–60. [16] Bang G, Koppang HS, Hansen LS, Gilhuus-Moe O, Aksdal E, Persson PG, Lundgren J. Clear cell odontogenic carcinoma: report of three cases with pulmonary and lymph node metastases. J Oral Pathol Med 1989;18:113–8. [17] Ng KH, Siar CH. Peripheral ameloblastoma with clear cell differentiation. Oral Surg Oral Med Oral Pathol 1990;70:210–3. [18] Guilbert F, Auriol M, Chomette G. Une forme rare d’epitheliome primitif de la mandibule: le carcinome odontogenique a cellules claires. Etude clinique et morphologique. Rev Stomatol Chir Maxillofac 1991;92:277–80. [19] Fan J, Kubota K, Imamura H, Shimokama T, Tokunaga O, Katsuki T, Watanabe T. Clear cell odontogenic carcinoma: a case report with massive invasion of neighboring organs and lymph node metastases. Oral Surg Oral Med Oral Pathol 1992;74: 768–75. [20] Odukoya O, Arole O. Clear cell ameloblastoma of the mandible (a case report). Int J Oral Maxillofac Surg 1992;21:358–9. [21] Milles M, Doyle JL, Mesa M, Raz S. Clear cell odontogenic carcinoma with lymph node metastases. Oral Surg Oral Med Oral Pathol 1993;76:82–9. [22] Piattelli A, Sesenna E, Trisi P. Clear cell odontogenic carcinoma — report of a case with lymph node and pulmonary metastases. Oral Oncol — Eur J Cancer Part B 1994;30B:278–80. [23] Eversole LR, Duffey DC, Powell MB. Clear cell odontogenic carcinoma. A clinico-pathologic analysis. Arch Otolaryngol Head Neck Surg 1995;121:685–9. [24] Sadeghi EM, Levin S. Clear cell odontogenic carcinoma of the mandible: report of a case. J Oral Maxillofac Surg 1995;53:613–6. [25] Duffey DC, Bailet JW, Newman A. Ameloblastoma of the mandible with cervical lymph node metastasis. Am J Otolaryngol 1995;16:66–73. [26] Mari A, Escutia E, Carrera M, Pericot J. Clear cell ameloblastoma or odontogenic carcinoma — a case report. J Craniomaxillofac Surg 1995;23:387–90. [27] Kumamoto H, Kawamura H, Ooya K. Clear cell odontogenic tumour in the mandible: report of a case with immunohistochemical study of epithelial cell markers. Pathol Int 1998;48: 618–22. [28] Eversole LR, Belton CM, Hansen LS. Clear cell odontogenic tumour: histochemical and ultrastructural features. J Oral Pathol 1985;14:603–14. [29] 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. [30] Hirshberg A, Leibovich P, Buchner A. Metastatic tumours to the jawbones: analysis of 390 cases. J Oral Pathol Med 1994;23:337–41. [31] Seifert G, Hennings K, Caselitz J. Metastatic tumours to the parotid and submandibular glands — analysis and differential diagnosis of 108 cases. Pathol Res Pract 1986;181:684–92. [32] Hicks MJ, Saldivar VA, Chintagumpala MM, Horowitz ME, Cooley LA, Barrish JP, et al. Malignant melanoma of soft parts involving the head and neck region: review of literature and case report. Ultrastruct Pathol 1995;19:395–400. [33] Gardner DG. Some current concepts on the pathology of ameloblastomas. Oral Surg Oral Med Oral Pathol Oral Radiol Endodon 1996;82:660–9. [34] Cawson RA, Binnie WH, Speight P, Barrett AW, Wright JM. Lucas’ pathology of tumours of the oral tissues. London: Churchill-Livingstone, 1998.
Case report
Clear cell odontogenic carcinoma G. Iezzi a, C. Rubini b, M. Fioroni c, A. Piattelli a,d,* b
a Dental School, University of Chieti, Italy Institute of Pathologic Anatomy and Histopathology, University of Ancona, Italy c Dental School, University of Ancona, Italy d Eastman Dental Institute for Oral Health Care Sciences, London, UK
Received 17 January 2001; accepted 19 February 2001
Abstract Clear cell tumours, in the head and neck region, are usually derived from salivary or odontogenic tissues, or may be metastatic. A few clear cells may be present in odontogenic cysts, while, odontogenic neoplasms composed predominantly of clear cells are quite rare. They include calcifying epithelial odontogenic tumours (CEOT), ameloblastoma and odontogenic carcinoma. Clear cell odontogenic tumour (CCOT) has been classified in the last WHO classification as a benign tumour, but it is now recognized as a more sinister lesion and current opinion is that CCOT should be designated as a carcinoma. These tumours are characterized by aggressive growth, recurrences, and metastatic disease. A recent review of the literature has yielded 30 cases of tumours with similar characteristics. These tumours have a peak incidence in the 5–7th decades, with a female predilection. The anterior portions of the jaws, especially the mandible, are most frequently affected. The aggressive potential of these neoplasms is well documented by the extensive invasion of adjacent tissues, multiple recurrences and regional or distant metastases. # 2002 Elsevier Science Ltd. All rights reserved. Keywords: Clear cell tumours; Clear cell odontogenic tumour; Clear cell odontogenic carcinoma
1. Introduction Clear cells may be present in several different tumours, and usually are the result of fixation artefacts, intracellular storage of several substances, i.e glycogen, mucin, lipid, or from a paucity of organelles. Clear cell tumours, in the head and neck region, are usually derived from salivary or odontogenic tissues, but also metastatic tumours need to be taken into consideration [1]. A few clear cells may be present in odontogenic cysts, while, odontogenic neoplasms composed entirely or predominantly of clear cells are quite rare [2,3]. They include calcifying epithelial odontogenic tumours (CEOT) [4,5], ameloblastoma and odontogenic carcinoma [6,7]. The presence of clear cells in odontogenic tumours is certainly not surprising due to their origin from the dental lamina, which presents clear cells as a component [8]. Clear cells may be encountered in other head and neck neoplasms, such as salivary gland tumours, * Corresponding author. Present address: Via F. Sciucchi 63, 66100 Chieti, Italy. Tel.: +39-0871-3554073; fax: +39-0871-3554076. E-mail address: [email protected] (A. Piattelli).
metastatic renal cell carcinoma, and melanotic tumours [9]. Due to the limited number of clear cell odontogenic carcinomas reported so far, only incomplete data are available on their clinical, immunohistochemical and prognostic features [10]. The close resemblance of odontogenic clear cell neoplasms to ameloblastoma is a further complication in the differential diagnosis of these lesions [11]. The issue of the biologic behaviour of clear cell odontogenic carcinomas (CCOCs), however, is complicated by the confounding terminology and classification, with some authors using terms such as clear cell ameloblastoma and clear cell odontogenic carcinoma synonymously [11]. Clear cell odontogenic tumour (CCOT) has been classified in the last WHO classification as benign [12], but it is now being increasingly recognized as a more sinister lesion and current opinion is that CCOT should be designated as a carcinoma [1,10]. These tumours are characterized by aggressive growth, recurrences, and metastatic disease, and several deaths have been reported due to the tumour progression [9,13,14]. It remains to be determined whether or not a benign variety exists [1]. Whereas the CCOC is of putative odontogenic origin,
1368-8375/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved. PII: S1368-8375(01)00038-0
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histologic similarities to the developing tooth germ are lacking in most instances [14].
2. Case report A 62-year-old female patient was referred for an illdefined radiolucent lesion of the right maxilla (Fig. 1). Radiography showed a radiolucency with indistinct margins, located in the lateral incisor region. No radiopaque foci or impacted teeth were present inside the lesion. A biopsy showed large and irregular sheets or cords of neoplastic clear cells in a cellular, collagenous stroma. The tumour cells were cuboidal or polyhedral, with centrally placed, rounded nuclei. The patient underwent a complete check-up to exclude the possibility of an occult primary malignancy. All the results were negative. A diagnosis of clear cell odontogenic carcinoma was made and the patient underwent a right maxillectomy. The patient is alive and well, at a 4-year follow-up, with no evidence of recurrences or of regional or distant metastases. The surgical specimen was fixed in 10% buffered formalin. Five-micron sections were cut and stained with hematoxylin–eosin, periodic acid–Schiff (PAS) with and without diastase treatment, alcian blue at pH 2.5, mucicarmine, Congo red and toluidine blue (for examination under polarized light) and Gomori’s reticulin. Immunohistochemical studies, performed with an peroxidase-anti-peroxidase (APAAP) method were made
Fig. 1. Radiographic aspect of the lesion at first presentation: an illdefined radiolucency of the right maxilla is present.
using AE1/AE3 cytokeratins, CAM 5.2, epithelial membrane antigen (EMA). Before the incubations with the specific primary antibodies, the sections were treated with 0.01% Pronase E in phosphate buffered saline (PBS), for 15 min at room temperature, or subjected to a 45 min microwave irradiation, following immersion in 0.1 M Citrate buffer, pH 6.0, in a microwave oven, set at 750 W. All the incubations lasted 30 min at room temperature, and were followed by 33 min washings in PBS. Appropriate positive controls were included in the procedures, along with negative controls, which were achieved by substituting the primary specific antibodies with non-immune serum.
3. Results It was possible to observe that the tumour (Fig. 2) was composed mainly of three components: clear cells, cells with an eosinophilic cytoplasm, and squamoid cells. The growth of the eosinophilic cell component was trabecular, while the clear cells were arranged in solid nests and the squamoid cells in a way similar to that observed in plexiform ameloblastoma. Occasionally, psudocysts or duct-like structures (Fig. 3), lined predominantly by flattened or cuboidal eosinophilic cells were present. All these cells were immersed in a collagenous stroma. Nuclear pleomorphism was present both in the clear cell and in the eosinophilic cell component. Mitotic activity was observed in the clear cell and squamoid component. Most neoplastic cells contained intracytoplasmic, PAS-positive, diastasesensitive, granules (Fig. 4). The stromal component was always abundant in the squamoid and clear cell component, and areas with prominent cellularity, consisting of mature fibroblasts, were intermingled with hyalinized areas. The stroma contained scattered and small capillary blood vessels. In addition, the tumour islands had invaded the adjacent bone and soft tissues, including muscles; vascular invasion was also present (Fig. 5).
Fig. 2. The tumour is composed by a clear cell component (right side) and by a basaloid cell component (left side). Hematoxylin–Eosin 16.
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Fig. 3. Some pseudoglandular aspects are present in this field. Hematoxylin–Eosin 20.
Fig. 5. It is possible to observe a vascular invasion by the tumour cells. Hematoxylin–Eosin 20. (Arrow.)
Fig. 4. The clear cell component shows the presence of PAS-positive cytoplasmic granules. PAS 20.
Fig. 6. Membrane positivity to CAM 5.2 of the neoplastic clear cells. APAAP 20.
Immunohistochemistry showed that the clear cells showed a non homogeneous membrane positivity for the wide spectrum cytokeratins (AE1/AE3), cytokeratin 19 and EMA (Fig. 6), while, the eosinophilic cells were consistently and strongly immunoreactive for the same antigens (Fig. 7). The squamoid component, on the other hand, reacted negatively (Fig. 8). Some focal positivity was present only rarely (Fig. 9). All the cellular components were consistently negative for vimentin, smooth-muscle actin, S-100 protein Glial Fibulary Acidic Protein (GFAP).
lar bone loss is present and perforation of the cortical bone and invasion into neighbouring tissues is frequently observed [24]. Histologically, three patterns are present [14]. Most commonly these tumours 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, while the least common variant is characterized by clear cell nests with an ameloblastomatous pattern with palisading around the periphery [1,11,13]. A minor subpopulation of small eosinophilic cells, arranged in a double layer and centrally located within the clear cell clusters, with a resemblance to duct structures, can be also present. The proportion of clear cells in these tumours has been different, varying from tumours that are composed almost entirely of clear cells to tumours made up in a significant way by other cellular elements like areas similar to ameloblastoma, basaloid cells or islands of squamous cells [8]. There are no amyloid, calcifications or mucus production [1]. Glycogen storage is quite common in these tumours [9,13,14,27] and consistent cytokeratins immunoreactivity, specifically
4. Discussion A recent review of the literature has yielded 30 cases of tumours with similar characteristics [6,7,15–28]. These tumours have a peak incidence in the 5–7th decades, with a female predilection. The anterior portions of the jaws, especially the mandible, are most frequently affected [1]. Patients usually complain of tooth mobility or swelling of the jaws [24]. Radiologically, these tumours present as ill-defined radiolucent lesions with root resorption present in the majority of cases. Alveo-
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Fig. 7. Strong positivity to AE1/AE3 cytokeratins of the neoplastic eosinophilic cells. APAAP 20.
Fig. 8. Focal positivity of squamoid cells to AE1/AE3 cytokeratins. APAAP 16. (Arrow.)
for cytokeratins 8, 13 and 19, has been reported [9,13,27]. Occasionally EMA, S-100 protein and antiameloblastoma antigen positivity have also been demonstrated [9,27]. We could identify intracellular glycogen, by means of PAS-positive, diastase-sensitive granules accumulation in the tumour cells, whereas mucin and amyloid production could be excluded, due to absence of mucicarmine, alcian blue, Congo red and toluidine blue positivity. These immunohistochemical results confirm the epithelial nature of the tumour cells [8], and they help in the differential diagnosis. It has been pointed out that the presence of two cell populations, i.e. clear and polygonal cells and separation of tumour islands by a mature fibrous stroma could help in distinguishing CCOT from other types of clear cell tumours [10,11]. Calcifying epithelial odontogenic tumour may show a prominent but not predominant clear cell component [4,5]. In this tumour it is possible to find a prominent amyloid and calcium deposition in the stroma, a feature never reported in CCOC. Mucoepidermoid carcinoma commonly shows clear cell changes and may arise as an intra-osseous tumour in the jaws. In central mucoepidermoid carcinoma, glandular or luminal structures and mucus-producing cells are
Fig. 9. Focal positivity of some central squamoid cells to CAM 5.2. APAAP 20. (Arrow.)
observed. Moreover, in this tumour another distinguishing feature is the presence of squamoid cells that appear to be condensed around the periphery of the tumour islands and adjacent to the vascular septae [9,10]. Other types of salivary gland carcinomas, i.e. acinic cell carcinoma, clear cell myoepithelial carcinoma and epithelial-myoepithelial carcinoma only rarely have an intra-osseous origin. Hyalinizing clear cell carcinoma has similar features to CCOC [29] including prominent hyalinization of the stroma, immunoreactivity for cytokeratins and EMA and lack of S-100 protein; these tumours have, however, not been reported to be primarily located in bone. Metastatic tumours to the jaws may also exhibit prominent clear cell features [30]. Metastatic renal cell carcinoma usually presents intratumoural haemorrhage and typical sinusoidal vascularity [31]. Other possible origins, such as from liver, prostate and thyroid can be excluded due to the lack of hepatocyte antigen, prostate specific antigen and thyroglobulin immunoreactivities, and by a complete clinical and radiological work up of the patients. Malignant melanoma may be excluded by the absence of S-100 protein and melanoma antigen HMB45 [32]. About one quarter of the patients, suffering from CCOC and with clinical follow-up, died of tumour, two were alive with persistent disease and 13 are alive without evidence of residual tumour. Recently, it has been proposed that clear cell tumours, showing histologically benign or malignant features, are part of a continuous spectrum and should not be considered distinct entities [33]. Some clear cell odontogenic carcinomas show an ameloblastomatous pattern while others do not. Whether such a distinction is of relevance remains to be elucidated. Moreover, some doubt may exist as to whether the clear cell ameloblastoma and the clear cell odontogenic carcinoma are distinct entities. It must be considered that, by definition, clear cell ameloblastoma presents some features of typical ameloblastoma and a follicular or plexiform configuration, is less aggressive and has little or no tendency to metastasize [34].
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The aggressive potential of CCOC is, on the contrary, well documented by the extensive invasion of adjacent tissues, multiple recurrences [5,21,23] and regional [9,12,14,15] or distant metastases [9,15]. Pulmonary metastases have been reported particularly in cases with multiple recurrences, and more than one surgical intervention [1]. Whether or not they are to be considered as true hematogenous metastases is still in doubt [1].
References [1] MacDonald DG, Browne RM. Tumours of odontogenic epithelium. In: Anthony PA, Macsween RNM, Lowe DG, editors. Recent advances in histopathology. Edinburgh: ChurchillLivingstone, 1997. p. 139–66. [2] Ng KH, Siar CH. Clear cell change in a calcifying odontogenic cyst. Oral Surg Oral Med Oral Pathol 1985;60:417–9. [3] Maiorano E, Altini M, Favia G. Clear cell tumours of the salivary glands, jaws and oral mucosa. Semin Diagn Pathol 1997;14:203–12. [4] Schmidt-Westhausen A, Philipsen HP, Reichart PA. Clear cell calcifying epithelial odontogenic tumour. A case report. Int J Oral Maxillofac Surg 1992;21:47–9. [5] Hicks MJ, Flaitz CM, Wong MEK, McDaniel RK, Cagle PT. Clear cell variant of calcifying epithelial odontogenic tumour: case report and review of the literature. Head Neck Surg 1994;16:272–7. [6] Hansen LS, Eversole LR, Green TL, Powell NB. Clear cell odontogenic tumour — a new histologic variant with aggressive potential. Head Neck Surg 1985;8:115–23. [7] Waldron CA, Small IA, Silverman H. Clear cell ameloblastoma: an odontogenic carcinoma. J Oral Maxilofac Surg 1985;43: 701–17. [8] de Aguiar MCF, 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;81:79–83. [9] Muramatsu T, Hashimoto S, Inoue T, Shimono M, Noma H, Shigematsu T. Clear cell odontogenic carcinoma in the mandible: histochemical and immunohistochemical observations with a review of the literature. J Oral Pathol Med 1996;25:516–21. [10] Miyauchi M, Ogawa I, Takata T, Ito H, Nikai H, Ijuhin N, Tanimoto K, Itoh Y. Clear cell odontogenic tumour: a case with induction of dentin-like structures? J Oral Pathol Med 1998;27:220–4. [11] Yamamoto H, Inui M, Mori A, Tagawa T. Clear cell odontogenic carcinoma. A case report and literature review of odontogenic tumours with clear cells. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;86:86–9. [12] Kramer IRH, Pindborg JJ, Shear M. Histological typing of odontogenic tumours. WHO international histological classification of tumours. 2nd ed. Berlin, Germany: Springer-Verlag, 1992. [13] Kumamoto H, Yamazaki S, Sato A, Yamaguchi T, Tezuka F, Ooya K. Clear cell odontogenic tumour in the mandible: report of a case with duct-like appearances and dentinoid induction. J Oral Pathol Med 2000;29:43–7. [14] Eversole LR. Malignant epithelial odontogenic tumours. Semin Diagn Pathol 1999;16:317–24.
213
[15] Muller H, Slootweg P. Clear cell differentiation in an ameloblastoma. J Maxillofac Surg 1986;14:158–60. [16] Bang G, Koppang HS, Hansen LS, Gilhuus-Moe O, Aksdal E, Persson PG, Lundgren J. Clear cell odontogenic carcinoma: report of three cases with pulmonary and lymph node metastases. J Oral Pathol Med 1989;18:113–8. [17] Ng KH, Siar CH. Peripheral ameloblastoma with clear cell differentiation. Oral Surg Oral Med Oral Pathol 1990;70:210–3. [18] Guilbert F, Auriol M, Chomette G. Une forme rare d’epitheliome primitif de la mandibule: le carcinome odontogenique a cellules claires. Etude clinique et morphologique. Rev Stomatol Chir Maxillofac 1991;92:277–80. [19] Fan J, Kubota K, Imamura H, Shimokama T, Tokunaga O, Katsuki T, Watanabe T. Clear cell odontogenic carcinoma: a case report with massive invasion of neighboring organs and lymph node metastases. Oral Surg Oral Med Oral Pathol 1992;74: 768–75. [20] Odukoya O, Arole O. Clear cell ameloblastoma of the mandible (a case report). Int J Oral Maxillofac Surg 1992;21:358–9. [21] Milles M, Doyle JL, Mesa M, Raz S. Clear cell odontogenic carcinoma with lymph node metastases. Oral Surg Oral Med Oral Pathol 1993;76:82–9. [22] Piattelli A, Sesenna E, Trisi P. Clear cell odontogenic carcinoma — report of a case with lymph node and pulmonary metastases. Oral Oncol — Eur J Cancer Part B 1994;30B:278–80. [23] Eversole LR, Duffey DC, Powell MB. Clear cell odontogenic carcinoma. A clinico-pathologic analysis. Arch Otolaryngol Head Neck Surg 1995;121:685–9. [24] Sadeghi EM, Levin S. Clear cell odontogenic carcinoma of the mandible: report of a case. J Oral Maxillofac Surg 1995;53:613–6. [25] Duffey DC, Bailet JW, Newman A. Ameloblastoma of the mandible with cervical lymph node metastasis. Am J Otolaryngol 1995;16:66–73. [26] Mari A, Escutia E, Carrera M, Pericot J. Clear cell ameloblastoma or odontogenic carcinoma — a case report. J Craniomaxillofac Surg 1995;23:387–90. [27] Kumamoto H, Kawamura H, Ooya K. Clear cell odontogenic tumour in the mandible: report of a case with immunohistochemical study of epithelial cell markers. Pathol Int 1998;48: 618–22. [28] Eversole LR, Belton CM, Hansen LS. Clear cell odontogenic tumour: histochemical and ultrastructural features. J Oral Pathol 1985;14:603–14. [29] 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. [30] Hirshberg A, Leibovich P, Buchner A. Metastatic tumours to the jawbones: analysis of 390 cases. J Oral Pathol Med 1994;23:337–41. [31] Seifert G, Hennings K, Caselitz J. Metastatic tumours to the parotid and submandibular glands — analysis and differential diagnosis of 108 cases. Pathol Res Pract 1986;181:684–92. [32] Hicks MJ, Saldivar VA, Chintagumpala MM, Horowitz ME, Cooley LA, Barrish JP, et al. Malignant melanoma of soft parts involving the head and neck region: review of literature and case report. Ultrastruct Pathol 1995;19:395–400. [33] Gardner DG. Some current concepts on the pathology of ameloblastomas. Oral Surg Oral Med Oral Pathol Oral Radiol Endodon 1996;82:660–9. [34] Cawson RA, Binnie WH, Speight P, Barrett AW, Wright JM. Lucas’ pathology of tumours of the oral tissues. London: Churchill-Livingstone, 1998.