Sporadic Oncocytic Tumors with Features Intermediate between Oncocytoma and Chromophobe Renal Cell Carcinoma: Comprehensive Clinico-Pathological and Genomic Profiling

ABSTRACTBackgroundMorphology, clinical behavior, and genomic profiles of renal oncocytoma (RO) and its malignant counterpart chromophobe renal cell carcinoma (ChRCC) are distinctly different. However, there is a substantial group of sporadic oncocytic tumors with peculiar hybrid phenotypes as well as a perplexing degree of morphologic and immunohistochemical overlap between classic RO and ChRCC with eosinophilic cytoplasm. The aim of this study is to provide detailed characterization of these hybrid tumors.DesignThirty eight sporadic oncocytic neoplasms with ambiguous morphology from two institutions were reviewed by 4 pathologists. CKIT positivity was used as a selection criterion. We correlated CK7 and S100A1 immunostaining and detailed morphologic features with cytogenetic profiles. DNA from the FFPE tissues was extracted and analyzed using Cytogenomic Microarray Analysis (CMA) to evaluate copy number alterations and ploidy.ResultsCMA categorized cases into 3 groups: RO (N=21), RO variant (N=7) and ChRCC (N=10). Cytogenetic RO had either no CNA (48%) or loss of chromosome 1p, X or Y (52%). RO-variant had additional chromosomal losses [-9q, –14 (n=2), –13] and chromosomal gains [+1q (n=2), +4, +7 (n=2), +13, +19, +20, and +22]. ChRCC were either hypodiploid with numerous monosomies (40%) or hypotetraploid with multiple relative losses (60%). RO, RO-variant and ChRCC groups differed significantly in tumor architecture (p<0.01), stroma (p=0.013), presence of nuclear wrinkling, perinuclear halos and well-defined cell borders in >5% cells (p<0.01), focal cell clearing (p=0.048) and CK7 expression (p<0.02). Pathologic prediction of cytogenetic subtype using only two categories (benign RO or malignant ChRCC) would overcall or undercall up to 40% of tumors that were ChRCC based on cytogenetics. This finding provides the rationale for an intermediate diagnostic category of so-called hybrid tumors (HOCT). HOCT was a heterogeneous group enriched for cytogenetic RO-variant. Other HOCTs have a profile of either RO or ChRCC.ConclusionsGenomic profile allows classification of oncocytic tumors with ambiguous morphology into RO, RO-variant and ChRCC. Several architectural and cytologic features combined with CK7 expression are significantly associated with cytogenetic RO, RO-variant or ChRCC tumors. Doubled hypodiploidy by whole genome endoduplication is a common phenomenon in eosinophilic ChRCC.Parts of this study were presented in an abstract form at the 104th annual meeting of the United Stated and Canadian Academy of Pathology, Boston, March 21–27, 2015