Clinicopathologic and Molecular Analysis of the TFEB Fusion Variant Reveals New Members of TFEB Translocation Renal Cell Carcinomas (RCCs): Expanding the Genomic Spectrum.

Xp11 renal cell carcinoma (RCC) with different gene fusions may have different clinicopathologic features. We sought to identify variant fusions in TFEB translocation RCC. A total of 31 cases of TFEB RCCs were selected for the current study; MALAT1-TFEB fusion 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 TFEB gene, consistent with "negative" TFEB split FISH result, and advising a potential diagnostic pitfall in detecting TFEB gene 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 TFEB RCCs 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-TFEB fusion demonstrated variable morphologies, all 9 cases featuring typical biphasic morphology were associated with MALAT1-TFEB genotype. Accordingly, typical biphasic morphology suggests MALAT1-TFEB fusion, whereas atypical morphology did not suggest the specific type of fusion. Isolated or clustered eosinophilic cells were a common feature in TFEB RCCs, which may be a useful morphology diagnostic clue for TFEB RCCs. Clinicopathologic variables assessment showed that necrosis was the only morphologic feature that correlated with the aggressive behavior of TFEB RCC (P=0.004). In summary, our study expands the genomic spectrum and the clinicopathologic features of TFEB RCCs, and highlights the challenges of diagnosis and the importance of subtyping of this tumor by combining morphology and multiple molecular techniques.

The American journal of surgical pathology. 2019 Nov 22 [Epub ahead of print]

Qiu-Yuan Xia, Xiao-Tong Wang, Ru Fang, Zhe Wang, Ming Zhao, Hong Chen, Ni Chen, Xiao-Dong Teng, Xuan Wang, Xue Wei, Sheng-Bing Ye, Rui Li, Heng-Hui Ma, Zhen-Feng Lu, Xiao-Jun Zhou, Qiu Rao

Department of Pathology, Nanjing Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu Province., State Key Laboratory of Cancer Biology, Department of Pathology, Xi Jing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province., Department of Pathology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College., Department of Pathology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian Province., Department of Pathology, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan Province, China., Department of Pathology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province.