Differential immunohistochemical and molecular profiling of conventional and aggressive components of chromophobe renal cell carcinoma: pitfalls for diagnosis

Chromophobe renal cell carcinoma (ChRCC) is a relatively rare subtype of RCC with a characteristic histologic appearance. Most ChRCCs are slow growing, but sarcomatoid differentiation and metastases can occur, indicative of aggressive behavior and poor prognosis. Herein, we characterize ten ChRCCs with aggressive components, defined as sarcomatoid change and/or metastasis. Immunohistochemistry (IHC) and next-generation sequencing were performed on available formalin-fixed paraffin-embedded tissue, with differential profiling of conventional and aggressive components. All ten cases showed a conventional component of renal tumor morphologically consistent with ChRCC: three had sarcomatoid change, four had metastases, and three had both sarcomatoid change and metastases. In the primary conventional components, a typical ChRCC IHC pattern (CK7+, CD117+, and CAIX-) was observed in 8 of 10 cases; 2 cases had rare CK7 staining. In the aggressive components, CD117 and/or CK7 was lost in 7 of 10 cases; 3 cases showed loss of both. Two of 10 cases showed significant CAIX staining in the aggressive component. All 7 cases that had molecular profiling performed showed characteristic chromosomal losses reported for ChRCC, with the aggressive components generally demonstrating more copy number complexity. Recurrent TP53 mutations (TP53m) were also seen; however, surprisingly, the conventional and aggressive components had no shared TP53m: a TP53m was private to aggressive components in 2 cases and to the conventional component in 1 case, and in 4 cases, components demonstrated different TP53m. Of the 21 pathogenic alterations identified in 7 tumors, only a PTEN splicing alteration was shared between both components in one case. In conclusion, ChRCC can have IHC staining patterns and molecular profile that differ between conventional and aggressive components. Interpretation of stains on metastases or small biopsies to determine histologic subtype can be misleading. The lack of shared pathogenic mutations between the two components supports a model in which aggressive ChRCC can have convergent subclones with different TP53m.