FH-deficient renal cell carcinoma expands the spectrum of renal papillary tumors

Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) is a distinct entity, which shows a biallelic inactivation of the FH gene that consequently leads to FH protein expression and function loss, respectively. This alteration leads to an accumulation of the oncometabolite fumarate in the citrate cycle and various disorders of the cell balance and DNA processing. FH-deficient RCC often shows a morphologically overlapping spectrum with papillary renal cell carcinoma (type 2), whereby a typical mixture of growth patterns including tubulo-cystic, cribriform, and/or solid differentiation can be observed. A characteristic but non-specific morphological feature is prominent eosinophilic, virus-inclusion body-like nucleoli with perinucleolar halos. Tumoral immunohistochemical loss of FH expression supports the diagnosis but may be preserved in rare cases. Most FH-deficient RCCs show very aggressive biological behavior and are often metastasized at the time of diagnosis. The initial description encompassed RCC in association with the hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome, which also includes cutaneous and uterine leiomyomas. However, current data also show an increasing proportion of sporadic cases, so that a distinction (hereditary vs. sporadic) seems appropriate. So far, few but promising data on effective systemic therapeutic options have been reported. In summary, precise diagnosis is of great importance due to the frequent aggressive biological behavior, potential need to deviate from the therapeutic standard, and the possible indicator of a hereditary disease.