Fig. 3

Hypothetical underlying molecular defect in SDHB immunostaining positive SDH–deficient RCC. Chromosome 1 is depicted. a Non-tumor tissue in patients with a germline pathogenic SDHB mutation. The disease is inherited in an autosomal dominant fashion and the wild-type allele is able to form functioning SDH complexes that are detected by immunostaining as granular (mitochondrial): cytoplasmic SDHB staining. b SDH–deficient RCC, classical concept. A somatic SDHB mutation associated with SDH–deficient RCC will result in non-formation of SDH complexes and in negative SDHB staining, as recognized by the 2016 WHO classification of tumors of the urinary system and male genital organs [1]. c SDH-deficient RCC, new hypothesis. Given the overall morphological similarity between the present case report and SDH–deficient RCC, we hypothesize that some somatic mutations may still result in SDH dysfunction but are associated with formation of SDH complexes and positive SDHB staining. The clinical impact would be that RCC that are stained positive for SDHB may still be observed in patients with SDHB mutations and that SDHB positivity in RCC does not exclude the existence of syndromic RCC due to SDHB mutations. Drawn by using the genome decoration page (https://www.ncbi.nlm.nih.gov/genome/tools/gdp)