TFEB-amplified Renal Cell Carcinomas

Abstract

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 years) compared with unamplified t(6;11) RCC (median age 31 years). 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, while 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 two 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.

Translocation Renal Cell Carcinoma: An Update on Clinicopathological and Molecular Features

“…The RCCs with these three fusions had not only TFEB rearrangement but also amplification of 6p, which is where TFEB is located. Recently, RCC with 6p amplification was shown to be a unique RCC subtype with characteristic histological features and aggressive behavior [ 26 , 27 , 28 ].…”

“…One of these mechanisms is chromosome amplification. Indeed, RCCs with TFE3 or TFEB overexpression caused by genetic or chromosome amplification were reported to behave aggressively with a poor prognosis [ 26 , 27 , 28 , 44 ]. Furthermore, RCCs with ALK fusion often show positive nuclear TFE3 immunostaining by the method using automated immunostaining machine [ 45 ].…”

Molecular Genetics of Renal Cell Tumors: A Practical Diagnostic Approach

“…[149] in 2017. It appears that tumors from this group show amplification of chromosome 6p21 with changes in TFEB and VEGFA [149][150][151][152][153][154][155][156]. So far the described cases show variable morphology with shared positivity for melan-A and/or HMB45.…”

“…So far the described cases show variable morphology with shared positivity for melan-A and/or HMB45. Cathepsin K is usually positive [149,150]. RCC with TFEB/6p21/VEGFA amplification exhibit papillary architecture, however tumors resembling CCRCC or ChRCC were also documented.…”

The morphological characteristics and immunophenotype of renal cell carcinomas with eosinophilic cytoplasm

“…ПКК с t(6;11) транслокацией и слиянием гена TFE-B. Эта опухоль встречается менее часто, чем ПКК с транслокацией в хромосоме Хр11 [24,25] . В нашем исследовании у 1 (0,3%) пациента мужского пола в возрасте 17 лет в левой почке опухоль достигала 4,2 см в диаметре и микроскопически была представлена солидными полями клеток с онкоцитарной дифференцировкой .…”