Clinicopathologic and Molecular Analysis of the TFEBFusion Variant Reveals New Members of TFEBTranslocation Renal Cell Carcinomas (RCCs)

Supplemental Digital Content is available in the text.Xp11 renal cell carcinoma (RCC) with different gene fusions may have different clinicopathologic features. We sought to identify variant fusions in TFEBtranslocation RCC. A total of 31 cases of TFEBRCCs were selected for the current study; MALAT1-TFEBfusion was identified in 25 cases (81%, 25/31) using fusion probes. The remaining 6 cases (19%, 6/31) were further analyzed by RNA sequencing and 5 of them were detected with TFEB-associated gene fusions, including 2 ACTB-TFEB, 1 EWSR1-TFEB, 1 CLTC-TFEB, and 1 potential PPP1R10-TFEB(a paracentric inversion of the TFEBgene, consistent with “negative” TFEBsplit FISH result, and advising a potential diagnostic pitfall in detecting TFEBgene rearrangement). Four of the 5 fusion transcripts were successfully validated by reverse transcription-polymerase chain reaction and Sanger sequencing. Morphologically, approximately one third (29%, 9/31) of TFEBRCCs showed typical biphasic morphology. The remaining two thirds of the cases (71%, 22/31) exhibited nonspecific morphology, with nested, sheet-like, or papillary architecture, resembling other types of renal neoplasms, such as clear cell RCC, Xp11 RCC, perivascular epithelioid cell tumor (PEComa), or papillary RCC. Although cases bearing a MALAT1-TFEBfusion demonstrated variable morphologies, all 9 cases featuring typical biphasic morphology were associated with MALAT1-TFEBgenotype. Accordingly, typical biphasic morphology suggests MALAT1-TFEBfusion, whereas atypical morphology did not suggest the specific type of fusion. Isolated or clustered eosinophilic cells were a common feature in TFEBRCCs, which may be a useful morphology diagnostic clue for TFEBRCCs. Clinicopathologic variables assessment showed that necrosis was the only morphologic feature that correlated with the aggressive behavior of TFEBRCC (P=0.004). In summary, our study expands the genomic spectrum and the clinicopathologic features of TFEBRCCs, and highlights the challenges of diagnosis and the importance of subtyping of this tumor by combining morphology and multiple molecular techniques.