TFEB-amplified Renal Cell Carcinomas: An Aggressive Molecular Subset Demonstrating Variable Melanocytic Marker Expression and Morphologic Heterogeneity

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 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.

Figure 1

(case 1). The tumor shows a solid to nested architecture with areas of pseudopapillary growth (A). The neoplastic cells show prominent eosinophilic nucleoli surrounded by a clear halo (B). The neoplastic cells demonstrate diffuse nuclear immunoreactivity for PAX8 (C) and patchy immunoreactivity for cytokeratin Cam5.2 (D). The tumors cells show moderate nuclear labeling for TFEB protein (E) and diffuse immunoreactivity for melan-A (F).

Figure 2

(case 2). This neoplasm demonstrates papillary (A) and nested (B) architecture. The papillary areas are associated with abundant psammoma bodies (C). The cytoplasm is pale and nuclei have coarse chromatin (D). The neoplastic cells are diffusely immunoreactive for PAX8 (E) and multifocally immunoreactive for melan-A (F).

Figure 3

(case 3). The neoplasm has a solid nested architecture (A). The neoplastic cells have eosinophilic cytoplasm and prominent eosinophilic nucleoli surrounded by a clear halo (B). The neoplastic cells label strongly for PAX8 (C). The neoplastic cells demonstrate moderate immunoreactivity for TFEB (D). The neoplastic cells demonstrate diffuse immunoreactivity for melan-A (E) and cathepsin K (F).

Figure 4

(case 4). This neoplasm had predominantly solid nested architecture (A) with smaller areas of acinar architecture with small abortive papillae (B). The neoplasm showed weak nuclear labeling for TFEB (C). The neoplasm demonstrated patchy immunoreactivity for both melan-A (D) and cathepsin K (E), and multifocal labeling for HMB45 in the form of dispersed individual positive cells (F).

Figure 5

(case 8). This neoplasm has an unusual biphasic appearance, with smaller paler epithelioid cells forming acinar structures and larger epithelioid cells with more abundant eosinophilic cytoplasm often clustered within the lumen of these acini (A, B). The neoplastic cells are diffusely immunoreactive for PAX8 (C). They show moderate nuclear labeling for TFEB (D). The neoplasm demonstrates patchy immunoreactivity for melan-A (E) and cathepsin K (F), with immunoreactivity preferentially seen in the larger epithelioid cells with eosinophilic cytoplasm.

Figure 6

TFEB FISH analysis. (A) Case 1: High level of TFEB gene amplification showing innumerable red (centromeric) and green (telomeric) signals of TFEB, some condensed in larger blobs. For comparison a normal cell depicted at 12 o’clock for comparison with 2 copies each. B, C (Case 2). High level of TFEB amplification (typically defined as >10) consisting of both centromeric and telomeric parts of TFEB (no gene break-apart). D (Case 8). Unbalanced TFEB break-apart with subsequent amplification of the centromeric part (red) and deletion of the telomeric (green) signal (remaining of 1X normal red-green pair of TFEB allele).