Published online Feb 28, 2015. doi: 10.3748/wjg.v21.i8.2303
Peer-review started: July 25, 2014
First decision: August 27, 2014
Revised: October 29, 2014
Accepted: December 16, 2014
Article in press: December 16, 2014
Published online: February 28, 2015
Processing time: 219 Days and 5.5 Hours
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.
Core tip: Succinate dehydrogenase (SDH) deficiency occurs in about 5%-7.5% of gastrointestinal stromal tumors (GISTs). These so-called SDH-deficient GISTs lack KIT and PDGFRA mutations. Such type of GISTs has its own clinical, morphological and molecular characteristics. The accumulation of hypoxia-inducible factor 1α and the upregulation of its downstream molecules, such as insulin-like growth factor 1 and vascular endothelial growth factor receptor, may play important roles in the tumorigenesis of SDH-deficient GISTs. They are promising to be the novel therapeutic targets of GISTs.