Succinate dehydrogenase-deficient gastrointestinal stromal tumors

Abstract

Most gastrointestinal stromal tumors (GISTs) are characterized by KIT or platelet-derived growth factor alpha (PDGFRA) activating mutations. However, there are still 10%-15% of GISTs lacking KIT and PDGFRA mutations, called wild-type GISTs (WT GISTs). Among these so-called WT GISTs, a small subset is associated with succinate dehydrogenase (SDH) deficiency, known as SDH-deficient GISTs. In addition, GISTs that occur in Carney triad and Carney-Stratakis syndrome represent specific examples of SDH-deficient GISTs. SDH-deficient GISTs locate exclusively in the stomach, showing predilection for children and young adults with female preponderance. The tumor generally pursues an indolent course and exhibits primary resistance to imatinib therapy in most cases. Loss of succinate dehydrogenase subunit B expression and overexpression of insulin-like growth factor 1 receptor (IGF1R) are common features of SDH-deficient GISTs. In WT GISTs without succinate dehydrogenase activity, upregulation of hypoxia-inducible factor 1α may lead to increased growth signaling through IGF1R and vascular endothelial growth factor receptor (VEGFR). As a result, IGF1R and VEGFR are promising to be the novel therapeutic targets of GISTs. This review will update the current knowledge on characteristics of SDH-deficient GISTs and further discuss the possible mechanisms of tumorigenesis and clinical management of SDH-deficient GISTs.

Keywords: Gastrointestinal stromal tumors; Hypoxia-inducible factor 1α; Insulin-like growth factor 1 receptor; Succinate dehydrogenase; Vascular endothelial growth factor receptor.

Figure 1

Histological features of succinate dehydrogenase-deficient gastrointestinal stromal tumors. A: Multinodular architecture; B: Lymphovascular invasion; C: Lymph node metastasis; D: Liver metastasis with a multinodular/lobulated architecture similar to that seen in gastric primary SDH-deficient tumors. Data adapted from Barletta et al[50].

Figure 2

Morphological features of succinate dehydrogenase-deficient gastrointestinal stromal tumor cells. A: Epithelioid gastrointestinal stromal tumor (GIST) cells (HE staining); B: Loss of expression of succinate dehydrogenase subunit B (SDHB, immunohistochemistry); C: Mixed epithelioid and spindle GIST cells (HE staining); D: Loss of expression of SDHB (immunohistochemistry). Data adapted from Wagner et al[25].

Figure 3

Role of succinate dehydrogenase deficiency in the tumorigenesis of succinate dehydrogenase-deficient gastrointestinal stromal tumors. SDH complex dysfunction within mitochondria leads to increased levels of succinate, which in turn inhibits PHD activity. Non-hydroxylated HIF1α is resistant to VHL-mediated targeting for degradation and stimulates transcription of VEGF and IGF. SDH: Succinate dehydrogenase; HIF1α: Hypoxia-inducible factor α; PHD: Prolyl hydroxylase; E3 complex: Ubiquitin ligase complex; VHL: Von Hippel-Lindau; VEGF: Vascular endothelial growth factor; IGF: Insulin-like growth factor; PI3K: Phosphatidylinositol 3-kinase; mTOR: Mammalian target of rapamycin.