Renal clear cell carcinoma metastasis to salivary glands – a series of 9 cases: clinico-pathological study

Introduction

Metastatic disease to salivary glands is uncommon representing approximately 5% of all malignant tumors at this site [1, 2]. The parotid gland is most frequently affected, whereas involvement of the submandibular and sublingual glands is less common [1, 3]. Both regional and distant metastatic disease should always be considered in the work-up of these histologically variable and heterogeneous tumors. Metastases to salivary glands most often (in about 80%) originate from squamous cell carcinomas of the head and neck region [4], followed by cutaneous as well as mucosal melanomas [1]. Carcinomas of the breast, lung, kidney and prostate are those primaries that may also potentially metastasize to salivary glands [4, 5, 6, 7, 8].
Renal cell carcinoma (RCC) comprises about 4% of all cancers in the USA and its incidence is still rising [9]. Renal cell carcinoma is known for its high propensity for metastasis to unusual localizations, such that any anatomical site may be affected [10]. About one third of patients with RCC present with metastatic disease [10] and the high metastatic potential accounts for the unpredictable clinical behavior of this malignancy. It is estimated that 30% of organ-confined RCCs will develop metastatic disease after local treatment [11]. Non-central nervous system (non-CNS) head and neck metastases from RCC are uncommon, comprising approximately 15% of tumors [12], but are not infrequently identified in the skin, nasal cavity, lips, hard palate, tongue, sinuses, and tonsils [6, 10, 13, 14]. The thyroid gland is the most common site of head and neck metastasis for RCC [15].
Metastasis of RCC to major salivary glands is extremely rare. Since the initial report of Patey et al. [16], 46 cases with a predominance of parotid gland metastases have been published [14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46]. Among them, two reports contained detailed and full reviews of the literature [14, 46]. Renal cell carcinoma metastases to the submandibular gland were reported in seven cases [47, 48, 49, 50, 51, 52]. Only one case of metastasis to the sublingual gland was found in the current literature [52].
We report a series of 9 cases of renal cell carcinoma metastases to salivary glands. Although metastatic spread to salivary glands is uncommon, it should be taken into consideration in the differential diagnosis of salivary gland tumors. To our best knowledge, this is the largest series presenting such a pattern of dissemination. Finally, we consider the differential diagnosis of clear cell variants of primary salivary gland carcinomas with the emphasis on ancillary immunohistochemical and molecular methods.

Material and methods

The material consisted of 9 cases which came from the pathology archives of two institutions. Five cases of metastatic clear RCC were selected from the historic files of salivary gland neoplasms operated on between 1992 and 2015 in the Departments of Otolaryngology and Maxillofacial Surgery, Medical University of Gdańsk, Poland (HM). Four cases were selected from consultation archives from the Department of Pathology, Charles University in Prague, Faculty of Medicine in Plzen, Czech Republic (AS). Clinical data and follow-up were obtained from medical records (DS, CS). Paraffin blocks and recuts were available for histological and immunohistochemical analysis and reclassification in all studied cases.

Clinical data

The group of patients included 6 females and 3 males (Table I). Their age ranged from 60 to 97 years (mean 72.6 years); the age of 3 patients from consultation material was unknown (cases 6-8). All the patients presented with unilateral metastasis: one tumor was found in the submandibular gland, one in the retromolar region of the oral cavity, and the other 7 cases were located in the parotid gland. All the patients presented with a palpable lesion, but only in three cases the lesions were associated with symptoms suggesting malignancy, i.e., palsy of the facial nerve and immobility of the mass. In one case (9) a multinodular palpable mass was found in the scar after prior parotidectomy due to a benign lesion 16 years earlier.
The parotid tumor was the initial manifestation of renal malignancy in 4 cases. The remaining five patients had been diagnosed and treated for RCC prior to salivary gland metastases, which developed in a time interval from 11 months to 13 years after the primary treatment and was the first sign of metastatic disease. Only in one case the dissemination to lungs had developed prior to salivary gland metastasis (case 6).
All patients underwent surgical treatment: total parotidectomy with selective neck dissection (4 cases), superficial parotidectomy (1 case) or simple resection of the tumor (3 cases); the type of surgery in 1 patient is unknown. The size of tumors ranged from 0.4 to 5 cm (unknown in 3 patients).

Histopathological findings

The tumors revealed multinodular arrangement (cases 3 and 4) or constituted a single round nodule with nested or tubular structure (case 5) (Fig. 1A, B). Unless fragmented, as occurred in cases 1 and 2, they were covered with a thin fibrous pseudocapsule. Histologically, all the tumors were composed of clear cells arranged in small nests divided by a regular network of small thin-walled blood vessels (Fig. 2). The capillary network was rich and associated with areas of extravasated erythrocytes and small hemorrhages. In some alveolar structures the lumen was filled with erythrocytes (Fig. 2). Hemosiderophages were found in the stroma at the periphery (Fig. 1A). The clear cytoplasm was surrounded by distinct cell membrane and contained small round or oval nuclei with evenly distributed chromatin or slightly vesicular nuclei. The nucleoli varied from small and inconspicuous to large and prominent. Mitotic figures were absent.
In seven out of nine cases the origin of tumors was confirmed by at least two antibodies: vimentin, CD10, renal cell carcinoma monoclonal antibody (RCCma) and paired box gene 8 (PAX8). All the tumor cells were negative for S100, p63, and mucin.
Case 9 presented with a most unusual coincidence of recurrent pleomorphic adenoma and RCC. The former was composed of multiple foci of predominantly myxoid hypocellular tumor permeating the residual tissue of parotid gland and extraglandular tissues. Adjacent to one such nodule, a well-circumscribed, non-encapsulated RCC metastasis was identified (Fig. 3). It co-expressed vimentin, cytokeratin AE1/AE3, EMA, and CD10 and was negative for CK7, CK20, and S100 protein. S100 protein was positive in the pleomorphic adenoma component.
Histologically, all the tumors were diagnosed as clear cell renal carcinoma.

Discussion

Salivary gland involvement by dissemination of renal malignancy is uncommon. However, correct diagnosis in such cases is important since the treatment of primary malignancies of the salivary glands differs from the treatment of metastases.
Parotid metastasis may be the initial sign of malignancy in the kidney, as evidenced in 19 of the historical cases and four patients from our series. A previous history of nephrectomy for RCC was known in 20 and 5 patients, respectively; the time interval of presentation spanned from 2 to 19 years and from 11 months to 13 years, respectively. Therefore, the time lag from the original diagnosis of RCC until salivary gland involvement may appear to be less than one year but it may also take decades. Similarly, the size may vary, and, as shown in our series, it may be found accidentally within the confines of the primary salivary gland tumor such as pleomorphic adenoma.
Epidemiological data show that cases in male patients predominated (2 : 1) in the published cases [14, 46], reflecting the epidemiology of this malignancy [11, 14, 46], whereas in our series the reverse was observed (M : F = 1 : 2). The peak incidence occurs in the 7th to 8th decade. The vast majority of patients in the literature (32/46 cases) presented with unilateral parotid metastasis [46], with similar presentation in our group. All the patients had a palpable mass that was occasionally accompanied by pain, tenderness, pulsation, tinnitus, and/or ipsilateral facial weakness. In our series only one case (1) presented with facial nerve palsy and two others (cases 2 and 3) showed immobility of the mass.
The differential diagnosis of a clear cell neoplasm of the salivary gland includes clear cell myoepithelial tumors, oncocytic lesions, clear cell variants of mucoepidermoid carcinoma, acinic cell carcinoma, epithelial-myoepithelial carcinoma, and hyalinizing clear cell carcinoma. Secondary tumors should always be taken into consideration, as the clinical information may not be available or the underlying cancer may be asymptomatic and salivary gland tumor is the first manifestation of the disease.
It is difficult to separate histologically metastatic RCC from benign and malignant oncocytic lesions. Typically metastatic RCC presents characteristic prominent vascular stroma with erythrocytes in the lumina or between nests formed by clear cells. However, there is a significant morphologic overlap between oncocytic neoplasms and RCC, as 37% of RCC present a predominantly oncocytic component and 26% of oncocytomas and 36% of oncocytosis cases show clear cell areas [2, 53]. As neither vimentin nor CD10 is specific, the immunohistochemical staining for p63 proved to be the most reliable single marker for distinguishing RCC (negative) and oncocytic lesions (positive) [2].
In most instances of primary salivary gland lesions clear or oncocytic cells compromise only a minor cellular component and the diagnosis can be rendered based upon identification of classic histomorphological features. However, in the series presented by Skálová et. al. a prominent clear cell component was found in only 39% of de novo clear cell myoepithelial carcinomas (CCMC) and in 24% of clear cell myoepithelial carcinomas ex pleomorphic adenoma (CCMCexPA) [54]. This subset of tumors was arranged in nodules composed of compact nests of large polyhedral cells with abundant clear cytoplasm. Moreover, these tumors showed EWSR1 rearrangement, thus clear cell myoepithelial carcinomas may represent distinctive aggressive variant composed predominantly of clear cells with frequent necrosis [54, 55]. Renal cell carcinoma does not show expression of any myoepithelial markers, e.g., smooth muscle actin (SMA), glial fibrillary acidic protein (GFAP), p63 and S100. On the other hand, CCMCs are usually negative for vimentin and co-express cytokeratin/EMA, S-100 protein and/or at least one other myoepithelial marker: SMA, muscle specific antigen (MSA), calponin, p63, and/or GFAP [54, 55, 56].
Clear myoepithelial cells may also predominate in epithelial-myoepithelial carcinoma (EMC), thus including it in the group of clear cell tumors. In these cases and in small biopsies immunohistochemistry is extremely helpful in identifying biphasic architecture of EMC: the inner abluminal epithelial cells (CK7+, Cam5.2+) and the outer myoepithelial layer (p63+, calponin+, SMA+) [57, 58, 59].
In mucoepidermoid carcinomas (MEC), clear cells comprise approximately 10% of the tumor cells [59]. However, they may occasionally form large aggregates, as clear morphology may be seen not only in the mucinous but also in the intermediate and epidermoid components [57]. As mucinous cells contain mucin, they stain positively with PASD (PAS with predigestion with diastase), mucicarmine, and alcian blue, contrary to glycogen-rich RCC, which is revealed by PAS staining [55]. Schwartz et al. found that the clear cell variant of MEC is the least common pattern [60]. Nevertheless all these cases, like most low-grade MEC, harbored recurrent translocations CRTC1/3-MAML2 [60]. This translocation appears to be specific for MEC and might be helpful in the differential diagnosis.
The historically oldest two cases (no. 1 and 2) in our series had been diagnosed as acinic cell carcinoma (AciCC) and were reclassified retrospectively [61]. Clear cells were found in approximately 6% of AciCC, but in about 1% of cases they predominate [59]. The identification of PAS-positive diastase-resistant zymogen granules in the cytoplasm is crucial for establishing the diagnosis. Positive staining for S-100, CEA, and GFAP in AciCC may prove to be helpful in contrast to vimentin.
Despite minimal morphological similarity [62], hyalinizing clear cell carcinoma (HCCC) must also be taken into account in the differential diagnosis. This unique salivary gland tumor develops predominantly in the minor salivary glands of oral cavity and is composed of nests, cords and trabeculae of clear and eosinophilic cells in a hyalinized stroma [62, 63]. Immunohistochemically, HCCC is diffusely positive for pancytokeratin and p63 but negative for S100, SMA, MSA, calponin, GFAP [2, 62]. Renal cell carcinoma never expresses p63 [2]. Recently, it was demonstrated that more than 80% of HCCC harbor recurrent EWSR1-ATF1 fusion [63].
As tissue evaluation by light microscopy does not always guarantee proper identification of the tumor type, especially in the overlapping and rare entities, the role of molecular markers is expanding in the diagnostic algorithm. The relatively novel but widely used immunohistochemical markers paired box gene 2 and 8 (PAX2 and PAX8) are promising. PAX8 proved to be very useful in primary and metastatic sites of RCC [64]. Nuclear PAX8 positivity was found in 90% of metastatic clear cell RCC [64], whereas the nuclear positivity of PAX2 was shown in 81% of primary and 85% of metastatic clear cell RCC [65, 66]. However, they are not specific to renal epithelium, as both are positive in cancers of Müllerian (endometrial and ovarian) origin, and PAX8 also in thyroid carcinomas [65, 66].

Conclusions

Distinction between metastasis and primary tumor is crucial as management of metastatic renal cell carcinoma and primary carcinoma of salivary gland origin requires different therapeutic decisions. Meta-static disease should always be kept in mind when evaluating a major salivary gland lesion. Metastasis may develop after a long time interval, occasionally even more than 10 years after nephrectomy.

Acknowledgements

The authors are grateful to the following physicians for submission the cases to consultation: dr Romuald Curik, Ostrava, Czech Republic (case 7), dr Horava, Frydek-Místek, Czech Republic (case 8), dr Fero Ondriaš, Bratislava, Slovakia (case 9).
The preliminary results were presented at the poster session under a title “Metastasis of renal cell carcinoma to large salivary glands – description of 4 cases” at 25th European Congress of Pathology in Lisbon, Portugal, 31st August-4th September 2013 (HM, KR). Moreover, the case no 9 was presented during slide seminar of Head and Neck Pathology Session at EScoP in Belgrade, 7-9th April 2011, Serbia (AS).
The publication of this article was supported by the institutional grant of Medical University of Gdańsk, Poland (ST-95).

The authors declare no conflict of interests.

References

1. Barnes, Leon, Eveson, et al. WHO Organization Classification of Tumors. Pathology and Genetics of Head and Neck Tumors. In Kleihues P, Sobin L (eds). IARC Press, Lyon 2005; 430.
2. McHugh JB, Hoschar AP, Dvorakova M, et al. p63 immunohistochemistry differentiates salivary gland oncocytoma and oncocytic carcinoma from metastatic renal cell carcinoma. Head Neck Pathol 2007; 1: 123-131.
3. Wenig, Bruce M. Atlas of head and neck pathology. In: Schmitt, Wiliam (eds.). 2nd ed. Saunders Elsevier 2008; 1139.
4. Bron LP, Traynor SJ, McNeil EB, O’Brien CJ. Primary and metastatic cancer of the parotid: Comparison of clinical behavior in 232 cases. Laryngoscope 2003; 113: 1070-1075.
5. Nuyens M, Schupbach J, Stauffer E, Zbaren P. Metastatic disease to the parotid gland. Otolaryngol Head Neck Surg 2006; 135: 844-848.
6. Pritchyk KM, Schiff BA, Newkirk KA, et al. Metastatic renal cell carcinoma to the head and neck. Laryngoscope 2002; 112: 1598-1602.
7. Rees R, Maples M, Lynch JB, Rosenfeld L. Malignant secondary parotid tumors. South Med J 1981; 74: 1050-1052.
8. Yarington CT. Metastatic malignant disease to the parotid-gland. Laryngoscope 1981; 91: 517-519.
9. Chow W-H, Devesa SS. Contemporary epidemiology of renal cell cancer. Cancer J 2008; 14: 288-301.
10. Marioni G, Gaio E, Poletti A, et al. Uncommon metastatic site of renal adenocarcinoma: The oral tongue. Acta Otolaryngol 2004; 124: 197-201.
11. Protzel C, Maruschke M, Hakenberg OW. Epidemiology, Aetiology, and pathogenesis of renal cell carcinoma. European Urology Supplements 2012; 11: 52-59.
12. Cheng ET, Greene D, Koch RJ. Metastatic renal cell carcinoma to the nose. Otolaryngol Head Neck Surg 2000; 122: 464-464.
13. Altuntaş O, Petekkaya İ, Süslü N, Güllü İ. Renal cell carcinoma metastatic to the tongue: a case report and review of the literature. J Oral and Maxillofac Surg 2015; 73: 1227-1230.
14. Lawlor CM. Parotid metastasis of renal cell carcinoma: a case report and review of the literature. In Wein RO (ed). J Cancer Ter Res 2012; 1: 15.
15. Miyamoto R, Helmus C. Hypernephroma metastatic to head and neck. Laryngoscope 1973; 83: 898-905.
16. Patey DH, Thackray AC, Keeling DH. Malignant disease of parotid. Br J Cancer 1965; 19: 712-737.
17. Adil G, Murat D, Ayhan O, et al. Renal cell carcinoma metastasis to the parotid gland. BJU Int 1999; 83: 861-862.
18. Andreadis D, Nomikos A, Barbatis C. Metastatic renal clear cell carcinoma in the parotid gland: A study of immunohistochemical profile and cell adhesion molecules (CAMs) expression in two cases. Pathol Oncol Res 2007; 13: 161-165.
19. Borghi L, Bianchini E, Ballotta MR, Reale D. Metastatic renal cell carcinoma presenting as a parotid tumor: a case report. Pathologica 1995; 87: 168-170.
20. Chai Y, Song L, Che S, Liu Z. Metastasis to the parotid region as an initial presentation of renal cell carcinoma: A case report. Oncol Lett 2013; 5: 997-999.
21. Coppa GF, Oszczakiewicz M. Parotid-gland metastasis from renal-carcinoma. Int Surg 1990; 75: 198-202.
22. Deeb R, Zhang Z, Kini S, Ghanem T. Metastatic renal cell carcinoma to the parotid gland presenting 19 years after nephrectomy: case report and review of literature. Laryngoscope 2010; 120 Suppl 4: S128-S128.
23. Gangopadhyay K, Abuzeid MO, Martin JM, Saleem M. Metastatic renal cell carcinoma of the parotid gland presenting as a neck mass. Int J Clin Pract 1998; 52: 196-198.
24. Göğüş C, Kilic O, Tulunay O, Beduk Y. Solitary metastasis of renal cell carcinoma to the parotid gland 10 years after radical nephrectomy. Int J Urol 2004; 11: 894-896.
25. Günbay MU, Ceryan K, Küpelioğlu AA. Metastatic renal-carcinoma to the parotid-gland. J Laryngol Otol 1989; 103: 417-418.
26. Harrison DJ, McLaren K, Tennant W. A clear cell tumor of the parotid. J Laryngol Otol 1987; 101: 633-635.
27. Hessan H, Strauss M, Sharkey FE. Urogenital tract carcinoma metastatic to the head and neck. Laryngoscope 1986; 96: 1352-1356.
28. Ito S, Sato I, Ishida E, et al. Case report of mammary analog secretory carcinoma of the parotid gland. Pathol Int 2012; 62: 149-152.
29. Ito R, Nishiike S, Tomiyama Y, et al. Three cases of renal cell carcinoma metastasizing to the head and neck. Nihon Jibiinkoka Gakkai Kaiho 2011; 114: 864-868.
30. Kucan JO, Frank DH, Robson MC. Tumors metastatic to the parotid-gland. Br J Plast Surg 1981; 34: 299-301.
31. Melnick SJ, Amazon K, Dembrow V. Metastatic renal-cell carcinoma presenting as a parotid tumor - a case-report with immunohistochemical findings and a review of the literature. Hum Pathol 1989; 20: 195-197.
32. Mrena R, Leivo I, Passador-Santos F, et al. Histopathological findings in parotid gland metastases from renal cell carcinoma. Eur Arch Otorhinolaryngol 2008; 265: 1005-1009.
33. Newton JR, O’Donnell M, Samuel PR. A case of renal cell carcinoma metastasizing to the parotid gland. Otolaryngol Head Neck Surg 2007; 136 (4 Suppl): S65-S67.
34. Owens RM, Friedman CD, Becker SP. Renal-cell carcinoma with metastasis to the parotid-gland – case-reports and review of the literature. Head Neck 1989; 11: 174-178.
35. Park YW, Hlivko TJ. Parotid gland metastasis from renal cell carcinoma. Laryngoscope 2002; 112: 453-456.
36. Percival RC, Curt JRN. Metastatic hyper-nephroma of the parotid-gland. Postgraduate Medical Journal 1982; 58: 167-168.
37. Pisani P, Angeli G, Krengli M, Pia F. Renal-carcinoma metastasis to the parotid-gland. J Laryngol Otol 1990; 104: 352-354.
38. Ravi R, Tongaonkar HB, Kulkarni JN, Kamat MR. Synchronous bilateral parotid metastases from renal cell carcinoma. A case report. Indian J Cancer 1992; 29: 40-42.
39. Sarangi PP, Hameed B. Bilateral parotid gland metastases from a hypernephroma. J R Coll Surg Edinb 1991; 36: 128-128.
40. Seijas BP, Franco FL, Sastre RM, et al. Metastatic renal cell carcinoma presenting as a parotid tumor. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005; 99: 554-557.
41. Sist TC, Marchetta FC, Milley PC. Renal-cell carcinoma presenting as a primary parotid-gland tumor. Oral Surg Oral Med Oral Pathol 1982; 53: 499-502.
42. Spreafico R, Nicoletti G, Ferrario F, et al. Parotid metastasis from renal cell carcinoma: a case report and review of the literature. Acta Otorhinolaryngol Ital 2008; 28: 266-268.
43. Sykes TCF, Patel A, Archer D, et al. Parotid metastasis from renal-cell carcinoma. Br J Urol 1995; 76: 398-399.
44. Vara A, Madrigal B, del Rio MJP, et al. Parotid metastasis from renal clear cell adenocarcinoma – An unusual site for metastasis. Urol Int 1998; 61: 196-198.
45. Wayne M, Wang W, Bratcher J, et al. Renal cell cancer without a renal primary. World J Surg Oncol 2010; 8: 18.
46. Udager AM, Rungta SA. Metastatic renal cell carcinoma, clear cell type, of the parotid gland: a case report, review of literature, and proposed algorithmic approach to salivary gland clear cell neoplasms in fine-needle aspiration biopsies. Diagn Cytopathol 2014; 42: 974-983.
47. Bedrosian SA, Goldman RL, Dekelboum AM. Renal-carcinoma presenting as a primary submandibular-gland tumor. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1984; 58: 699-701.
48. Miah MS, White SJ, Oommen G, et al. Late simultaneous metastasis of renal cell carcinoma to the submandibular and thyroid glands seven years after radical nephrectomy. Int J Otolaryngol 2010; 2010: pii 69804.
49. Serouya SM, Dultz LA, Concors SJ, et al. Late solitary metastasis of renal cell carcinoma to the submandibular gland. J Oral Maxillofac Surg 2012; 70: 2356-2359.
50. Smits JG, Slootweg PJ. Renal-cell carcinoma with metastasis to the submandibular and parotid-glands – a case-report. J Maxillofac Surg 1984; 12: 235-236.
51. Zoltie N. Pulsatile secondary from renal cell carcinoma presenting in the submandibular gland. J R Coll Surg Edinb 1986; 31: 236-236.
52. Ficarra G, Pierleoni L, Panzoni E. Metastatic renal cell carcinoma involving Wharton’s duct – A case report. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996; 81: 580-583.
53. Okon K. Pathology of renal tumors in adults. Molecular biology, histopathological diagnosis and prognosis. Pol J Pathol 2008; 59: 129-176.
54. Skalova A, Weinreb I, Hyrcza M, et al. Clear cell myoepithelial carcinoma of salivary glands showing EWSR1 rearrangement molecular analysis of 94 salivary gland carcinomas with prominent clear cell component. Am J Surg Pathol 2015; 39: 338-348.
55. Said-Al-Naief N, Klein MJ. Clear cell entities of the head and neck: a selective review of clear cell tumors of the salivary glands. Head Neck Pathol 2008; 2: 111-115.
56. Michal M, Skalova A, Simpson RH, et al. Clear cell malignant myoepithelioma of the salivary glands. Histopathology 1996; 28: 309-315.
57. Simpson RH, Skalova A, Di Palma S, Leivo I. Recent advances in the diagnostic pathology of salivary carcinomas. Virchows Arch 2014; 465: 371-384.
58. Dimitrijevic MV, Tomanovic NR, Jesic SD, et al. Epithelial-myoepithelial carcinoma – review of clinicopathological and immunohistochemical features. Arch Iran Med 2015; 18: 218-222.
59. Ellis GL. Clear cell neoplasms in salivary glands: clearly a diagnostic challenge. Ann Diagn Pathol 1998; 2: 61-78.
60. Schwarz S, Stiegler C, Mueller M, et al. Salivary gland mucoepidermoid carcinoma is a clinically, morphologically and genetically heterogeneous entity: a clinicopathological study of 40 cases with emphasis on grading, histological variants and presence of the t(11;19) translocation. Histopathology 2011; 58: 557-570.
61. Majewska H, Skalova A, Stodulski D, et al. Mammary analogue secretory carcinoma of salivary glands: a new entity associated with ETV6 gene rearrangement. Virchows Archiv 2015; 466: 245-254.
62. Weinreb I. Hyalinizing clear cell carcinoma of salivary gland: a review and update. Head Neck Pathol 2013; 7 Suppl 1: S20-29.
63. Antonescu CR, Katabi N, Zhang L, et al. EWSR1-ATF1 Fusion is a novel and consistent finding in hyalinizing clear-cell carcinoma of salivary gland. Genes Chromosomes Cancer 2011; 50: 559-570.
64. Barr ML, Jilaveanu LB, Camp RL, et al. PAX-8 expression in renal tumours and distant sites: A useful marker of primary and metastatic renal cell carcinoma? J Clin Pathol 2015; 68: 12-17.
65. Gokden N, Gokden M, Phan DC, MeKenney JK. The utility of PAX-2 in distinguishing metastatic clear cell renal cell carcinoma from its morphologic mimics: an immunohistochemical study with comparison to renal cell carcinoma marker. Am J Surg Pathol 2008; 32: 1462-1467.
66. Mentrikoski MJ, Wendroth SM, Wick MR. Immunohistochemical distinction of renal cell carcinoma from other carcinomas with clear-cell histomorphology: Utility of CD10 and CA-125 in addition to PAX-2, PAX-8, RCCma, and adipophilin. Appl Immunohistochem Mol Morphol 2014; 22: 635-641.

Address for correspondence

Hanna Majewska MD, PhD
Department of Pathology
Medical University of Gdansk,
Dębinki 7
80-211 Gdansk, Poland
tel. +48 601 762 460
fax +48 58 349 37 45
e-mail: hania.majewska@gumed.edu.pl