Chromophobe renal cell carcinoma (RCC) is a form of renal cancer that may be confused with other eosinophilic renal tumors, including oncocytoma, type 2 papillary RCC, and clear-cell RCC with eosinophilic features. There are currently no robust markers to distinguish these neoplasms. Chromophobe RCC and renal oncocytoma are presumably derived from the distal nephron. FXYD2 is a distal tubule regulator of the trimeric Na(+/)K(+)-transporting ATPase that is enriched in kidney tissue. In this study, we investigated the expression of FXYD2 in normal human kidney, 27 chromophobe RCCs, 30 oncocytomas, 15 clear-cell RCCs, and 11 papillary RCCs. Immunohistochemical staining for FXYD2 showed diffuse, strong immunoreactivity in the basolateral membrane of distal tubules of normal human kidney. Ninety-six percent (26/27) of chromophobe RCCs were immunoreactive for FXYD2 in a distinctly membranous pattern. Twenty-five of these tumors showed at least focal 2+ staining. In contrast, only 17% (5/30) of renal oncocytomas, 11% (2/15) of clear-cell RCCs, and 0% (0/11) of papillary RCCs displayed FXYD2 immunoreactivity. None of these cases showed ≥2+ FXYD2 staining. A subset of cases was confirmed as oncocytoma or chromophobe RCC using cytokeratin 7, colloidal iron, and interphase fluorescence in situ hybridization analysis of chromosomes 1, 2, 6, 10, and 17. Among this subset, 100% (7/7) of chromophobe RCCs were FXYD2 positive, whereas 17% (2/12) of oncocytomas were stained with FXYD2. The oncocytomas that stained with FXYD2 did so in a weak (1+), patchy manner. In contrast, chromophobe RCCs showed ≥2+ staining in 86% (6/7) of these tumors. For comparison, this subset was also stained for kidney-specific cadherin (Ksp-cadherin). Ksp-cadherin showed positive staining in 100% (7/7) of chromophobe RCCs and 33% (4/12) of oncocytomas. This is the first report demonstrating the potential utility of FXYD2 immunohistochemistry in the diagnosis of chromophobe RCC.
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