Renal Cell Carcinoma With Concurrent Loss of SMARCB1/INI-1 and Fumarate Hydratase By Immunohistochemistry: A Case Report With Review of the Literature

Both SMARCB1(INI-1)-deficient and FH (fumarate hydratase)-deficient renal cell carcinoma (RCC) have a male predominance, potentially overlapping high-grade histologic features, and typically poor clinical outcomes. SMARCB1(INI-1) deficiency is the characteristic pathogenic alteration in medullary (or medullary-like) RCC, which is aggressively treated with chemotherapy, primarily platinum-based. In contrast, a distinct set of agents, such as the combination of bevacizumab and erlotinib, is the principal systemic therapy consideration for FH-deficient RCC. SMARCB1 (INI-1) is a core subunit of the SWI/SNF complex, regulating chromatin remodeling and gene transcription through epigenetics. The accumulation of fumarate, resulting from the loss of FH, can alter DNA methylation and promote a CpG island methylator phenotype (CIMP), silencing tumor suppressor genes. Rare case reports of FH-deficient RCC with concurrent loss of SMARCB1 (INI-1) have been reported, which is likely due to secondary epigenetic silencing of SMARCB1. Herein, we report a unique RCC case with concurrent loss of SMARCB1 (INI-1) and FH expression by immunohistochemistry. Molecular studies demonstrated a SMARCB1 mutation, but no FH mutation was identified. Relatively low FH transcription was detected in the case, which raises the possibility of a pathogenic loss of SMARCB1 (INI-1), accompanied by a potential secondary, epigenetic loss of FH expression. Therefore, FH loss by IHC does not necessarily always indicate a pathogenic FH mutation. Further molecular studies are critical in determining the underlying pathogenic mutation.