Identifying and managing rare subtypes of gastrointestinal stromal tumors

Introduction A subset of gastrointestinal stromal tumors (GISTs) lack the common mutations in KIT/PDGFRa genes. This is a rare and heterogeneous group of challenging GISTs due to their diversity and absence of sensitivity to the tyrosine kinase inhibitor (TKI) imatinib.Areas covered In this manscript, we review the pathogenesis, natural history, diagnostic features and management of KIT/PDGFRa wild-type (WT) GISTs, including SDH-deficient GISTs, GISTs with mutations in the RAS/RAF pathway, quadruple WT GISTs which lack mutations in either KIT/PDGFRa and SDH genes or components of the RAS/RAF pathway, syndromic GISTs as well as GISTs with rare KIT/PDGFRa mutations.Expert opinion Patients should be managed in referrence centers. There is progress in the understanding of the biology of these GISTs and promising therapeutic targets have been identified. In SDH-deficient GISTs, the TKI olverembatinib has shown encouraging clinical activity but requires further clinical validation, while the HIF2a inhibitor bezultifan and temozolomide alone or in combination with the death receptor agonist 5 are under clinical investigation. Targeting the RAS/RAF pathway in RAS/RAF-mutated GISTs warrants evaluation in clinical trials. Rare molecular alterations in quadruple WT GISTs require investigation for their oncogenic potential. Collaborative research and patient advocacy is critical for these extremely rare tumors.