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TFEB-amplified Renal Cell Carcinomas

An Aggressive Molecular Subset Demonstrating Variable Melanocytic Marker Expression and Morphologic Heterogeneity

Argani, Pedram MD; Reuter, Victor E. MD; Zhang, Lei MD; Sung, Yun-Shao MS; Ning, Yi PhD; Epstein, Jonathan I. MD; Netto, George J. MD; Antonescu, Cristina R. MD

The American Journal of Surgical Pathology: November 2016 - Volume 40 - Issue 11 - p 1484–1495
doi: 10.1097/PAS.0000000000000720
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Renal cell carcinomas (RCCs) with the t(6;11)(p21;q12) chromosome translocation are low-grade RCC which often occur in young patients. They typically feature an unusual biphasic morphology characterized by nests of larger epithelioid cells surrounding intraluminal collections of smaller cells clustered around basement membrane material. The t(6;11)(p21;q12) translocation fuses the Alpha (MALAT1) gene with the TFEB transcription factor gene, resulting in upregulated expression of intact native TFEB that drives the aberrant expression of melanocytic markers which is a hallmark of this distinctive neoplasm. We now report 8 cases of RCC, which demonstrate TFEB gene amplification (6 without TFEB rearrangement, 2 with concurrent TFEB rearrangement) and demonstrate downstream consequences of TFEB overexpression. Like the unamplified t(6;11) RCC, all TFEB-amplified RCC were associated with aberrant melanocytic marker expression. However, several differences between TFEB-amplified RCC and the usual unamplified t(6;11) RCC are evident. First, TFEB-amplified RCC occurred in older patients (median age, 64.5 y) compared with unamplified t(6;11) RCC (median age, 31 y). Second, the morphology of TFEB-amplified RCC is not entirely distinctive, frequently featuring nests of high-grade epithelioid cells with eosinophilic cytoplasm associated with pseudopapillary formation and necrosis, or true papillary formations. These patterns raise the differential diagnosis of high-grade clear cell and papillary RCC. Third, TFEB and melanocytic marker expression was more variable within the TFEB-amplified RCC. TFEB protein expression by immunohistochemistry was detectable in 6 of 8 cases. While all 8 cases expressed melan-A, only 5 of 8 expressed cathepsin K and only 3 of 8 expressed HMB45. Fourth, the TFEB-amplified RCC were associated with a more aggressive clinical course; 3 of 8 cases presented with advanced stage or metastatic disease, 2 subsequently developed metastatic disease, whereas the other 3 cases had minimal/no follow-up. Our results are corroborated by scant data reported on 6 TFEB-amplified RCC in the literature, gleaned from 1 case report, 1 abstract, and 4 individual cases identified within 2 genomic studies of large cohorts of RCC. In summary, TFEB-amplified RCC represent a distinct molecular subtype of high-grade adult RCC associated with aggressive clinical behavior, variable morphology, and aberrant melanocytic marker expression.

Departments of *Pathology

Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD

Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY

Conflicts of Interest and Sources of Funding: Supported in part by: P50 CA 140146-01 (CRA), Cycle for Survival (CRA), Kristin Ann Carr Foundation (CRA), Dahan Translocation Carcinoma Fund and Joey’s Wings (PA). The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

Correspondence: Pedram Argani, MD, Department of Surgical Pathology, The Johns Hopkins Hospital, Weinberg Building, Room 2242, 401 N. Broadway, Baltimore, MD 21231-2410 (e-mail: pargani@jhmi.edu).

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