Xp11 translocation renal cell carcinoma (RCC): extended immunohistochemical profile emphasizing novel RCC markers

Abstract

Xp11 translocation renal cell carcinoma (RCC) harbor various TFE3 gene fusions, and are known to underexpress epithelial immunohistochemical (IHC) markers such as cytokeratin and EMA relative to usual adult type RCC; however, their profile in reference to other IHC markers that are differentially expressed in other subtypes of RCC has not been systematically assessed. Few therapeutic targets have been identified in these aggressive cancers. We created 2 tissue microarrays (TMA) containing five 1.4-mm cores from each of 21 Xp11 translocation RCC (all confirmed by TFE3 IHC, 6 further confirmed by genetics), 7 clear cell RCC (CCRCC), and 6 papillary RCC (PRCC). These TMA were labeled for a panel of IHC markers. In contrast to earlier published data, Xp11 translocation RCC frequently expressed renal transcription factors PAX8 (16/21 cases) and PAX2 (14/21 cases), whereas only 1 of 21 cases focally expressed MiTF and only 5 of 21 overexpressed p21. Although experimental data suggest otherwise, Xp11 translocation RCC did not express WT-1 (0/21 cases). Although 24% of Xp11 translocation RCC expressed HIF-1alpha (like CCRCC), unlike CCRCC CA IX expression was characteristically only focal (mean 6% cell labeling) in Xp11 translocation RCC. Other markers preferentially expressed in CCRCC or PRCC, such as HIG-2, claudin 7, and EpCAM, yielded inconsistent results in Xp11 translocation RCC. Xp11 translocation RCC infrequently expressed Ksp-cadherin (3/21 cases) and c-kit (0/21 cases), markers frequently expressed in chromophobe RCC. Using an H-score that is the product of intensity and percentage labeling, Xp11 translocation RCC expressed higher levels of phosphorylated S6, a measure of mTOR pathway activation (mean H score=88), than did CCRCC (mean H score=54) or PRCC (mean H score=44). In conclusion, in contrast to prior reports, Xp11 translocation RCC usually express PAX2 and PAX8 but do not usually express MiTF. Although they may express HIF-1alpha, they only focally express the downstream target CA IX. They inconsistently express markers associated with other RCC subtypes, further highlighting the lack of specificity of the latter markers. TFE3 and Cathepsin K remain the most sensitive and specific markers of these neoplasms. Elevated expression of phosphorylated S6 in Xp11 translocation RCC suggests the mTOR pathway as an attractive potential therapeutic target for these neoplasms.

FIGURE 1

Expression of Transcription Factors in Xp11 Translocation Renal Cell Carcinoma (RCC). A, Hematoxylin and Eosin stain of genetically-confirmed PSF-TFE3 RCC. The neoplasm shows strong nuclear labeling for PAX8 (B) and PAX2 (C), whereas only rare cells label for MiTF (D). All other cases were completely negative for MiTF. All images are 400× magnification.

FIGURE 2

Expression of HIF-1α and CA IX in Xp11 Translocation RCC versus Clear Cell RCC. This genetically-confirmed PRCC-TFE3 RCC (A, Hematoxylin and Eosin stain) shows strong difuse nuclear labeling for HIF-1α (B) but is negative for CA IX (C). In contrast, a conventional (clear cell) adult RCC (D, Hematoxylin and Eosin stain) shows strong diffuse nuclear labeling for HIF-1α (E) and strong diffuse cytoplasmic labeling for the downstream target CA IX (F). All images are 400× magnification.

FIGURE 3

Miscellaneous RCC markers in Xp11 translocation RCC. PSF-TFE3 RCC shows patchy membranous labeling for claudin 7 (A) and cytoplasmic labeling for napsin A (B), accentuated in papillary areas. PRCC-TFE3 RCC shows cytoplasmic labeling for HIG2 (C). Xp11 translocation RCC shows incomplete membranous labeling for Ksp-cadherin (D). All images are 400× magnification.

FIGURE 4

Expression of phosphorylated S6 (pS6), a marker of mTOR pathway activation, in genetically confirmed Xp11 translocation RCC. Hematoxylin and Eosin stain of t(X;3)(pll;q23) RCC (A) and corresponding pS6 immunohistochemistry (B). Hematoxylin and Eosin stain of PRCC-TFE3 RCC (C) and corresponding pS6 immunohistochemistry (D). All images are 400× magnification.