Detection of 6 TFEB-amplified renal cell carcinomas and 25 renal cell carcinomas with MITF translocations: systematic morphologic analysis of 85 cases evaluated by clinical TFE3 and TFEB FISH assays

Abstract

Renal cell carcinomas with MITF aberrations demonstrate a wide morphologic spectrum, highlighting the need to consider these entities within the differential diagnosis of renal tumors encountered in clinical practice. Herein, we describe our experience with application of clinical fluorescence in situ hybridization (FISH) assays for detection of TFE3 and TFEB gene aberrations from 85 consecutive renal cell carcinoma cases submitted to our genitourinary FISH service. Results from 170 FISH assays performed on these tumors were correlated with available clinicopathologic findings. Ninety-eight percent of renal tumors submitted for FISH evaluation were from adult patients. Thirty-one (37%) tumors were confirmed to demonstrate MITF aberrations (21 TFE3 translocation, 4 TFEB translocation, and 6 TFEB amplification cases). Overall, renal cell carcinomas with MITF aberrations demonstrated morphologic features overlapping with clear cell, papillary, or clear cell papillary renal cell carcinomas. Renal cell carcinomas with MITF aberrations were significantly more likely to demonstrate dual (eosinophilic and clear) cytoplasmic tones (P=0.030), biphasic TFEB translocation renal cell carcinoma-like morphology (P=0.002), psammomatous calcifications (P=0.002), and nuclear pseudoinclusions (P=0.001) than renal cell carcinomas without MITF aberrations. Notably, 7/9 (78%) renal cell carcinomas exhibiting subnuclear clearing and linear nuclear array (6 of which showed high World Health Organization/International Society of Urological Pathology nucleolar grade) demonstrated TFE3 translocation, an association that was statistically significant when compared with renal cell carcinomas without MITF aberrations (P=0.009). In this cohort comprising consecutive cases, TFEB-amplified renal cell carcinomas were more commonly identified than renal cell carcinomas with TFEB translocations, and four (67%) of these previously unreported TFEB-amplified renal cell carcinomas demonstrated oncocytic and papillary features with a high World Health Organization/International Society of Urological Pathology nucleolar grade. In summary, TFE3 and TFEB FISH evaluation aids in identification and accurate classification of renal cell carcinomas with MITF aberrations, including TFEB-amplified renal cell carcinoma, which may demonstrate aggressive behavior.

Clues to recognition of fumarate hydratase‐deficient renal cell carcinoma: Findings from cytologic and limited biopsy samples

“…Although decreased expression of pancytokeratins and melanocytic markers in translocation RCCs is characteristic and distinctive from FH‐deficient RCCs (and other RCC types), these features are neither sufficiently sensitive nor specific to establish reliably the diagnosis of translocation RCC. Because the available antibodies against transcription factor E3 (TFE3) and transcription factor EB (TFEB) often are technically challenging, contemporary workup emphasizes the use of break‐apart fluorescence in situ hybridization for the TFE3 locus (or the TFEB locus for the less common t[6,11] translocation RCCs) as a definitive molecular test …”

“…Because the available antibodies against transcription factor E3 (TFE3) and transcription factor EB (TFEB) often are technically challenging, contemporary workup emphasizes the use of break-apart fluorescence in situ hybridization for the TFE3 locus (or the TFEB locus for the less common t [6,11] translocation RCCs) as a definitive molecular test. 20 Given the frequent clustering and papillary architecture observed in most of our samples, the cytologic differential with conventional papillary RCC deserves mention. Although the presence of true fibrovascular cores may be shared, in no case of FH-deficient RCC did we observe distention of cores with foamy macrophages, nor was the characteristic monomorphous appearance of conventional papillary RCC cytology 16,21 or clear cell papillary RCC 22 simulated by any FHdeficient RCC.…”

“…This latter finding emphasizes the importance of clinical correlation and the use of immunostains for triage, including FH and 2SC, which frequently are lost/reduced and strongly positive, respectively, in FH-deficient tumors. It also emphasizes consideration of emerging entities, such as a group of unclassified RCCs with TFEB amplification and melanocytic differentiation, 20,[24][25][26] which, in our experience, can strongly simulate the nucleolar features of FH-deficient RCCs.…”

Reactivity of CK7 across the spectrum of renal cell carcinomas with clear cells

“…There have been several cases of Xp11.2 described in the literature with more diverse morphology. In such cases, immunohistochemical reaction with TFE3, cathepsin K or fluorescence in‐situ hybridisation (FISH) analysis can solve the differential diagnostic problem …”

“…In such cases, immunohistochemical reaction with TFE3, cathepsin K or fluorescence in-situ hybridisation (FISH) analysis can solve the differential diagnostic problem. 20,21 Translocation t(6;11) RCCs are typically composed of large eosinophilic cells with formation of pseudorosettes. These tumours are immunoreactive for HMB45, Melan A and TFEB, and the diagnosis can be further confirmed by molecular genetic analysis of TFEB (break or protein expression).…”