The majority of renal cell carcinomas (RCCs) in adults are readily classified into one of several well-defined categories under the 2004 World Health Organization classification, a classification based on morphologic features and genetics. 1 The types of RCC include clear cell (conventional), papillary, chromophobe, collecting duct, and the recently described mucinous tubular and spindle cell carcinoma. Many of these morphologically defined entities are associated with specific genetic

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... ns (ie, chromosome 3p deletion in clear cell RCC and trisomy of chromosome 7 and 17 in papillary RCC), further validating the classification. Only approximately 5% of adult RCCs remain unclassifiable. In contrast, pediatric RCCs have been more difficult to categorize. Early studies recognized that pediatric RCCs were more frequently papillary than their adult counterparts, and subtle morphologic differences were noted. 2 Dr J. Bruce Beckwith (personal communication) often noted that pediatric RCCs were more frequently negative for cytokeratins by immunohistochemical analysis compared with adult RCCs. However, the biologic basis for these distinctions remained unclear. In the past 5 years, it has become apparent that approximately one third of pediatric RCCs belong to the newly recognized family of Xp11 translocation RCCs. 3 These RCCs are characterized by various chromosome translocations, all of which involve a breakpoint at Xp11.2 and all of which result in fusions involving the TFE3 transcription factor gene that maps to this locus. Five distinct gene fusions involving TFE3 have been characterized ❚Table 1❚. 4-6 These include an ASPL-TFE3 gene fusion identical to the gene fusion first identified in alveolar soft part sarcoma (ASPS), 7 resulting from a t(X;17)(p11.2;q25) chromosome translocation. Xp11 translocation RCCs typically have a nested to papillary architecture and are composed of clear cells with frequent associated psammomatous calcifications. Tumors with different specific gene fusions may have slightly different clinical manifestations and morphologic features. For example, the RCCs associated with the ASPL-TFE3 gene fusion (so-called ASPL-TFE3 RCC) frequently present at an advanced stage and have voluminous cytoplasm with extensive psammomatous calcifications. In contrast with clear cell and papillary RCCs usually seen in adults, the Xp11 translocation RCCs underexpress vimentin and cytokeratins on immunohistochemical analysis, the latter fact providing at least part of the explanation for Dr Beckwith's astute observations more than a decade ago. Occasional Xp11 translocation RCCs express melanocytic markers by immunohistochemical analysis. Ultrastructurally, despite the unusual immunophenotype, these neoplasms show predominantly epithelial features. Aside from molecular genetic analysis, the most sensitive and specific assay for the Xp11 translocation RCCs is nuclear labeling with antibodies to the retained C-terminal portion of the TFE3 protein. 8 TFE3 protein is expressed ubiquitously, but, like most transcription factors, its levels are tightly regulated so that it is undetectable by routine immunohistochemical analysis in normal tissues and almost all other neoplasms. All TFE3 fusion proteins retain the C-terminal portion of TFE3, including its leucine-zipper dimerization domain, nuclear localization signal, and DNA binding domain. It is likely that the genes fused 5' to TFE3 contribute strong promoters that cause overexpression of the TFE3 fusion protein such that it now becomes detectable by immunohistochemical analysis. Therefore, TFE3 immunohistochemical analysis allows these tumors to be delineated in archival paraffinembedded material when frozen tissue samples for molecular analysis are not available.