Section 4 -

Translocation Carcinomas of the Kidney Pedram Argani The Johns Hopkins Hospital Baltimore, Maryland

Xp11.2 Translocation Renal Carcinomas Renal cell carcinomas (RCC) with chromosome translocations involving Xp11.2 and resulting gene fusions involving the TFE3 transcription factor gene are newly recognized entities in the 2004 WHO Renal Tumor Classification. These neoplasms tend to affect younger patients. One distinctive subtype bears a t(X;17)(p11;q25), which results in the identical ASPL-TFE3 gene fusion as was initially identified in alveolar soft part sarcoma (ASPS). Other subtypes are listed in Table 1. The ASPL-TFE3 RCC characteristically present at advanced stage and virtually all neoplasms (even small ones) have presented with lymph node metastases at diagnosis, despite the often small size of the primary. While the ASPL-TFE3 RCC usually present at advanced stage, their clinical course has been indolent in some cases, though other patients have done poorly. Some Xp11-translocation RCC have recurred 20 or 30 years after initial diagnosis. Approximately 10-15% of Xp11-translocation RCC have arisen in patients previously treated with chemotherapy, including a unique case in which a child with a prior ASPL-TFE3 RCC developed a PRCC-TFE3 RCC in the opposite kidney. Xp11.2 translocation RCC closely resemble conventional (clear cell) renal carcinomas on gross examination, usually being tan-yellow, and often necrotic and hemorrhagic. A papillary carcinoma comprised of clear cells is the most distinctive histopathologic appearance, since this combination is uncommon in other defined types of renal carcinomas. However, the Xp11.2-translocation RCC often have nested architecture, and often contain cells with granular eosinophilic cytoplasm. The histologies of Xp11-translocation RCC associated with different TFE3 gene fusions differ. The ASPL-TFE3 renal carcinomas feature cells with voluminous, clear to eosinophilic cytoplasm, discrete cell borders, vesicular nuclear chromatin and prominent nucleoli. In contrast, the PRCC-TFE3 renal carcinomas typically have less abundant cytoplasm, fewer psammoma bodies, fewer hyaline nodules, and a more nested, compact architecture Renal carcinomas with Xp11.2-associated translocations characteristically underexpress epithelial immunohistochemical markers such as cytokeratin and epithelial membrane antigen. Only approximately one half of cases will be positive with these markers, and the labelling is often focal. Vimentin immunoreactivity is also often focal compared to the adjacent blood vessels; this also differs from conventional RCC which are diffusely positive. Rare Xp11.2-translocation carcinomas, specifically ones with variant gene fusions such as PSF-TFE3 and CLTC-TFE3, have labelled for melanocytic markers HMB45 and Melan A. The most distinctive immunohistochemical feature of these neoplasms is nuclear labelling for TFE3 protein using an antibody to the C-terminal portion of TFE3, which is retained in the gene fusions. Nuclear labelling for TFE3 is a common feature of all Xp11.2-translocation RCC and ASPS but does not occur in clear cell or papillary RCC. Since native TFE3 is known to be ubiquitously expressed but is not detectable in normal tissues by immunohistochemistry, we suspect that the different TFE3 gene fusions consistently lead to overexpression of the fusion protein relative to native TFE3, such that the protein becomes detectable by this assay. t(6;11)(p21;q12) Renal Carcinomas Another distinctive type of RCC bears a t(6;11)(p21;q12). The distinctive clinicopathologic features of these neoplasms were not described until 2001. Of the 12 cases with clinical history available, the median age has been 18 years (range: 6-53 years). One patient has developed metastases and died in the limited follow-up. On microscopic examination, these neoplasms usually feature nests and tubules of polygonal epithelioid cells, separated by thin capillaries. Some cases have had papillary formations. The majority of the tumor cells have abundant clear to granular eosinophilic cytoplasm, well-defined cell borders and round nuclei with small nucleoli. However, a second population of smaller epithelioid cells is also characteristic, typically (but not always) clustered around nodules of hyaline basement membrane material within larger acini. The cases examined have generally been negative for cytokeratins by immunohistochemistry, but all have labelled at least focally for HMB45 and Melan A. The t(6;11)(p21;q12) has been shown to result in a fusion of the intronless, untranslated Alpha gene with TFEB, a gene belonging to the same transcription factor family as TFE3. The consequence of the Alpha-TFEB fusion is dysregulated expression of the normal full-length TFEB protein. Along these lines, we have found that the t(6;11) RCC (also known as Alpha-TFEB RCC) demonstrate specific nuclear labelling for TFEB protein by IHC while other neoplasms and normal tissues do not. Hence, nuclear labelling for TFEB is a sensitive and specific diagnostic marker for this neoplasm with a TFEB gene fusion, just as nuclear labelling for TFE3 is a sensitive and specific marker for neoplasms bearing TFE3 gene fusions. While the t(6;11) RCC features a distinctive dimorphic cytology and labels for melanocytic markers immunohistochemically, it shares clinical, morphologic, immunohistochemical and molecular features with the Xp11 translocation RCC, such that we propose to group both of them under the broader category of "MiTF/TFE translocation renal cell carcinomas". The recognition of these carcinomas as distinct from usual RCC, a distinction facilitated by the application of immunohistochemistry for TFE3 and TFEB, will be critical in defining their clinical behavior and, consequently, the appropriate management of these patients. Table 1: MiTF/TFE Translocation Neoplasms Gene Fusion Chromosome Translocation Age (years) Tumor ASPL-TFE3 der(17)t(X;17)(p11.2;q25) 5-40 ASPS ASPL-TFE3 t(X;17)(p11.2;q25) 2-68 RCC PRCC-TFE3 t(X;1)(p11.2;q21) 2-70 RCC PSF-TFE3 t(X;1)(p11.2;p34) 5-68 RCC NoNo-TFE3 inv(X)(p11;q12) 39 RCC CLTC-TFE3 t(X;17)(p11.2;q23) 14 RCC Alpha-TFEB t(6 ;11)(p21;q12) 6-53 RCC References: Argani P, Antonescu CR, Couturier J, Fournet JC, Sciot R, Debiec-Rychter M, et al. PRCC-TFE3 renal carcinomas. Morphologic, immunohistochemical, ultrastructural, and molecular analysis of an entity associated with the t(X;1)(p11.2;q21). Am J Surg Pathol 2002; 26:1553–66. Argani P, Antonescu CR, Illei PB, Lui MY, Timmons C, Newbury R et al. Primary renal neoplasms with the ASPL-TFE3 gene fusion of alveolar soft part sarcoma. A distinctive tumor entity previously included among renal cell carcinomas of children and adolescents. Am J Pathol 2001; 159: 179–92. Argani P, Hawkins A, Griffin CA, Goldstein J, Haas M, Beckwith JB, et al. A distinctive pediatric renal neoplasm characterized by epithelioid morphology, basement membrane production, focal HMB45 immunoreactivity, and t(6; 11)(p21.1; q12) chromosome translocation. Am J Pathol 2001; 158: 2089–96. Argani P, Ladanyi M. Renal carcinomas associated with Xp11.2 translocations/TFE3 gene fusions. In: Eble JN, Sauter G, Epstein J, Sesterhenn I, editors. Pathology and Genetics of Tumors of the Urinary System & Male Genital Organs. Lyon, France: IARC 2003, 37-8. Argani P, Ladanyi M. Translocation carcinomas of the Kidney. Clin Lab Med 2005;25:363-378. Argani P, Laé M, Ballard ET, Rodriguez M, Hutchinson B, Reuter VE, Ladanyi M. Translocation carcinomas of the kidney following chemotherapy in childhood. J Clin Oncol 2006;24: 1529-1534. Argani P, Laé M, Hutchinson B, Reuter VE, Collins MH, Perentesis J, et al. Renal carcinomas with the t(6;11)(p21;q12). 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