termsTerm

SDH deficiency (SDHB immunohistochemistry loss)

aka SDH-deficient, SDH-deficient GIST, SDHB immunohistochemistry, SDHB loss, SDHB-negative, SDHx, SDHx mutation, SDHA, SDHC epimutation, SDHC promoter methylation, succinate dehydrogenase deficiency, Carney-Stratakis syndrome, Carney triad, KIT/PDGFRA wild-type GIST, hereditary paraganglioma syndrome, SDH-deficient renal cell carcinoma

Loss of the succinate dehydrogenase enzyme, shown by a negative SDHB stain, marks a small family of tumours (some stomach GISTs, paragangliomas and phaeochromocytomas, a rare kidney cancer) that are often inherited, occur in young people, ignore imatinib and grow slowly; the stain is the trigger for germline testing of the whole family.

What is measured: loss of the mitochondrial succinate dehydrogenase complex. How: SDHB immunohistochemistry on the tumour (loss of granular cytoplasmic staining whichever subunit is mutated; SDHA staining is lost only with SDHA mutation), followed by germline and tumour sequencing of SDHA, SDHB, SDHC, SDHD and SDHAF2 and, if negative, testing for SDHC promoter methylation (the epimutation behind the Carney triad). Where it occurs: 5 to 7 percent of GISTs (almost all gastric, in young and often female patients, multifocal, epithelioid, with nodal metastases and an indolent course; Carney-Stratakis syndrome pairs them with paragangliomas), 30 to 40 percent of paragangliomas and phaeochromocytomas (SDHB carriers have the highest metastatic risk), SDH-deficient renal cell carcinoma and some pituitary adenomas. What a result changes: an SDH-deficient GIST does not respond to imatinib because it does not depend on KIT, sunitinib and regorafenib help modestly, temozolomide is under study because of the tumours' hypermethylation, surgery is kept conservative because multifocality and nodal disease are the rule, and follow-up is lifelong; a germline finding leads to cascade testing, whole-body MRI surveillance every two to three years and plasma metanephrines; metastatic paraganglioma is treated with lutetium-177 DOTATATE or iodine-131 MIBG, and HIF-2 alpha inhibitors such as belzutifan are in trials. Where it matters: GIST, imatinib-resistant GIST and the rare childhood cancers page.