Succinate dehydrogenase-deficient GISTs: a clinicopathologic, immunohistochemical, and molecular genetic study of 66 gastric GISTs with predilection to young age

Abstract

Most gastrointestinal stromal tumors (GISTs) are driven by KIT or PDGFRA-activating mutations, but a small subset is associated with loss of function of the succinate dehydrogenase (SDH) complex of mitochondrial inner membrane proteins. This occurs by germline mutations of the SDH subunit genes and hitherto unknown mechanisms. SDH-deficient GISTs especially include pediatric GISTs and those associated with Carney triad (CT) or Carney-Stratakis syndromes (CSSs); the latter 2 also include paraganglioma as a component. SDH-deficient GISTs were identified in this study on the basis of immunohistochemical loss of succinate dehydrogenase subunit B (SDHB), which signals functional loss of the SDH complex. We found 66 SDH-deficient GISTs among 756 gastric GISTs, with an estimated frequency of 7.5% of unselected cases. Nearly, all gastric GISTs in patients <20 years, and a substantial percentage of those in patients <40 years, but only rare GISTs in older adults were SDH deficient. There was a female predominance of over 2:1. Two patients each had either pulmonary chondroma or paraganglioma (CT), but none of the examined cases had SDH germline mutations (CSS) or somatic KIT/PDGFRA or BRAF mutations. SDH-deficient GISTs were often multiple and typically showed plexiform muscularis propria involvement and epithelioid hypercellular morphology. They were consistently KIT-positive and DOG1/Ano 1-positive and almost always smooth muscle actin negative. Tumor size and mitotic activity varied, and the tumors were somewhat unpredictable with low mitotic rates developing metastases. Gastric recurrences occurred in 11 patients, and peritoneal and liver metastases occurred in 8 and 10 patients, respectively. Lymph node metastases were detected in 5 patients, but lymphovascular invasion was present in >50% of cases studied; these 2 were not related to adverse outcome. Seven patients died of disease, but many had long survivals, even with peritoneal or liver metastases. All 378 nongastric GISTs and 34 gastric non-GIST mesenchymal tumors were SDHB positive. SDH-deficient GISTs constitute a small subgroup of gastric GISTs; they usually occur in children and young adults, often have a chronic course similar to that of pediatric and CT GISTs, and have potential association with paraganglioma, necessitating long-term follow-up.

Fig. 1

Frequency of SDHB-negative and positive gastric GISTs as a function of patient age.

Fig. 2

Examples of immunohistochemically SDHB-negative and positive gastric GISTs. A-D. SDHB- negative cases with staining limited to blood vessels, lymphohistiocytic infiltration, smooth muscle, or hepatocytes. C. Liver metastasis with positive hepatocytes. Note a faint cytoplasmic blush in panel D. E–H. SDHB- positive spindle cell and epithelioid GISTs with granular cytoplasmic staining of various intensities in tumor cells and vessel walls.

Fig. 3

Subtotal gastrectomy specimen contains a multinodular SDHB-negative GIST with a mucosal ulceration.

Fig. 4

Histologic features typical of SDH-deficient GISTs. A. Multinodular, “plexiform” muscularis propria involvement. B. An example showing an organoid pattern with mixed epithelioid and spindled cytology. C. Epithelioid hypercellular cytology was the predominant finding. D. Marked nuclear pleomorphism was a rare finding. An atypical mitotic figure is seen right to the center.

Fig. 5

A. Peritoneal GIST micrometastasis. B. Lymph node metastasis of a SDH-deficient GIST. This tumor shows spindle cell morphology, seen in a minority of cases. C, D. Lymphovascular invasion was a common feature seen in half of the cases.