XP11 Translocation Renal Cell Carcinoma (RCC): Extended Immunohistochemical (IHC) Profile Emphasizing Novel RCC Markers
P Argani, J Hicks, A De Marzo, R Albadine, P Illei, M Ladanyi, VE Reuter, G Netto. The Johns Hopkins Medical Institutions, Baltimore, MD; Memorial Sloan-Kettering Cancer Center, New York, NY
Background: Xp11 translocation RCC (Xp11 RCC) harbor various TFE3 gene fusions. Translocation associated RCC are known to underexpress epithelial IHC markers such as cytokeratin and EMA relative to usual adult type RCC; however, their profile in reference to other IHC markers which are differentially expressed in other subtypes of RCC has not been systematically assessed. Few therapeutic targets have been identified in these aggressive cancers.
Design: We created two tissue microarrays (TMA) containing five 1.4 mm cores from each of 21 Xp11 RCC (all confirmed by TFE3 IHC, 6 further confirmed by genetics), 7 clear cell RCC (CC RCC) and 6 papillary RCC (PRCC). These TMA were labeled for a panel of IHC markers.
Results: In contrast to previously published data, Xp11 RCC frequently expressed renal transcription factors PAX8 (16/21 cases) and PAX2 (14/21 cases), while only 1 of 21 cases focally expressed MiTF and only 4 of 21 overexpressed p21. While experimental data suggests otherwise, Xp11 RCC did not express WT-1 (0/21 cases). While 24% of Xp11 RCC expressed HIF 1α (like CCRCC), unlike CCRCC CAIX expression was characteristically only focal (mean 6% cell labeling) in Xp11 RCC. Other markers preferentially expressed in CCRCC or PRCC yielded inconsistent results in Xp11 RCC; while 42% of Xp11 RCC expressed HIG2 (similar to CCRCC), 33% expressed claudin 7 and 38% expressed EpCAM (similar to PRCC). Xp11 RCC infrequently expressed Ksp-cadherin (3/21 cases) and c-kit (0/21 cases), markers frequently expressed in chromophobe RCC. Using an H-score which is the product of intensity and percentage labeling, Xp11 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).
Conclusions: In contrast to prior reports, Xp11 RCC usually express PAX2 and PAX8 but do not usually express MiTF. While they frequently express HIF 1α, they only focally express the downstream target CAIX. 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 RCC suggests the mTOR pathway as an attractive potential therapeutic target for these neoplasms.
Category: Genitourinary (including renal tumors)
Tuesday, March 23, 2010 9:30 AM
Poster Session III # 154, Tuesday Morning