Molecular and clinicopathological features of KIT/PDGFRAwild‐type gastrointestinal stromal tumors

AbstractApproximately 10% of gastrointestinal stromal tumors (GISTs) harbor reportedly no KIT and PDGFRA mutations (wild‐type GISTs). The clinicopathological features and oncologic outcomes of wild‐type GISTs based on molecular profiles are unknown. We recruited 35 wild‐type GIST patients from the two registry studies of high‐risk GISTs between 2012 and 2015 and primary GISTs between 2003 and 2014. Molecular profiling of wild‐type GISTs was performed by targeted next‐generation sequencing (NGS) using formalin‐fixed paraffin‐embedded tumor samples. Among 35 wild‐type GISTs, targeted NGS analysis detected NF1, SDH, or BRAF mutation: 16 NF1‐GISTs with various NF1 mutations, 12 SDH‐GISTs (4 with SDHA mutations, 4 with SDHB mutations, and 4 with SDHB‐negative staining), and 5 BRAF‐GISTs with the V600E mutation. Two GISTs showed no mutations based on our targeted NGS analysis. Additional gene mutations were infrequent in primary wild‐type GISTs and found in TP53, CREBBP, CDKN2A, and CHEK2. Most NF1‐GISTs were located in the small intestine (N = 12; 75%) and showed spindle cell features (N = 15; 94%) and multiple tumors (N = 6, 38%) with modest proliferation activities. In contrast, SDH‐GISTs were predominantly found in the stomach (N = 11; 92%), exhibiting epithelioid cell (N = 6; 50%) and multiple (N = 6, 50%) features. The overall survival of patients with SDH‐GISTs appeared to be better than that of BRAF‐GISTs (p = 0.0107) or NF1‐GISTs (p = 0.0754), respectively. In conclusion, major molecular changes in wild‐type GISTs include NF1, SDH, and BRAF. NF1‐GISTs involved multifocal spindle cell tumors in the small intestine. SDH‐GISTs occurred in young patients and were multifocal in the stomach and clinically indolent.