Oral Presentation 5th International Symposium on Phaeochromocytoma and Paraganglioma 2017

The succinate dehydrogenase (SDH) complex is a key respiratory enzyme composed of four subunits SDHA, SDHB, SDHC and SDHD. Remarkably immunohistochemistry for SDHB becomes negative whenever there is bialleic inactivation of any component of SDH which is very rare in the absence of syndromic disease. Therefore loss of SDHB immunohistochemistry serves as a marker of syndromic disease, usually germline mutation of one of the SDH subunits. Tumours which show loss of SDHB expression are termed succinate dehydrogenase deficient. In addition to loss of SDHB, tumours associated with SDHA mutation also show loss of SDHA expression.  The identification of succinate dehydrogenase deficient neoplasm facilitates genetic testing and risk reduction strategies.

15% of pheochromocytoma and paraganglioma (PHEO/PGL) are associated with germline SDH mutation and therefore SDH deficient.  We recommend screening SDHB immunohistochemistry for all PHEO/PGL.

SDH deficient Gastrointestinal Stromal Tumours (GISTs) show distinctive features including absent KIT/PDGFRA mutations (but positive staining for cKIT and DOG1), virtually exclusive gastric location, lobulated growth, multifocality, a prognosis not predicted by size and mitotic rate, metastasis to lymph nodes and primary resistance to imatinib therapy. 30% are associated with SDHA germline mutation. 50% are associated with SDHC epimutation (post zygotic promoter hypermethylation) - the hallmark of the syndromic but non-hereditary Carney Triad (SDH deficient GIST, SDH deficient paraganglioma and pulmonary chondroma).

SDH deficient renal carcinoma is newly recognised under the WHO 2016 classification and usually demonstrates characteristic morphology including vacuolated eosinophilic cytoplasmic and cytoplasmic inclusions. SDH deficient renal carcinoma is particularly associated with SDHB mutation, although SDHC and SDHA mutation occur.  SDH deficient pituitary adenomas are recognised but appear to be the least common SDH deficient neoplasm.

Table 1: SDH abnormalities in Phaeochromocytoma and Paraganglioma

 Table 2: Phenotype-Genotype correlations in SDH deficient neoplasia