2023 GEIS Guidelines for gastrointestinal stromal tumors

Abstract

Gastrointestinal stromal tumor (GIST) is the most common malignant neoplasm of mesenchymal origin. GIST spans a wide clinical spectrum that ranges from tumors with essentially no metastatic potential to malignant and life-threatening spread diseases. Gain-of-function mutations in KIT or PDGFRA receptor tyrosine kinases are the crucial drivers of most GISTs, responsible for tumor initiation and evolution throughout the entire course of the disease. The introduction of tyrosine kinase inhibitors targeting these receptors has substantially improved the outcomes in this formerly chemoresistant cancer. As of today, five agents hold regulatory approval for the treatment of GIST: imatinib, sunitinib, regorafenib, ripretinib, and avapritinib. This, in turn, represents a success for a rare neoplasm. During the past two decades, GIST has become a paradigmatic model in cancer for multidisciplinary work, given the disease-specific particularities regarding tumor biology and tumor evolution. Herein, we review currently available evidence for the management of GIST. This clinical practice guideline has been developed by a multidisciplinary expert panel (oncologist, pathologist, surgeon, molecular biologist, radiologist, and representative of patients' advocacy groups) from the Spanish Group for Sarcoma Research, and it is conceived to provide, from a critical perspective, the standard approach for diagnosis, treatment, and follow-up.

Keywords: KIT; PDGFRA; avapritinib; gastrointestinal stromal tumor; imatinib; regorafenib; ripretinib; sunitinib; surgery.

Figure 1.

Molecular alterations in sporadic and familial GIST. GISTs are classified into KIT/PDGFRA mutant and KIT/PDGFRA WT. WT GISTs are divided into SDH deficient and SDH competent according to SDHB IHC expression. Most of the mutations reported in GIST are sporadic, although a minority are germline mutations related to specific syndromes or familial GISTs. The prevalence of molecular categories is expressed in percentages. GIST, gastrointestinal stromal tumor; IHC, immunohistochemistry; SDH, succinate dehydrogenase; WT, wild type.

Figure 2.

KIT- and PDGFRA-mutant GIST. KIT primary mutations commonly affect exons 9 and 11, and less often 17 and 18, while KIT secondary mutations cluster in the ATP-binding pocket and the activation loop; the most common amino acid affected are displayed. Primary mutations in PDGFRA emerge from similar regions. The prevalence of molecular categories of KIT and PDGFRA primary mutations is expressed in percentages. Ex, exon; GIST, gastrointestinal stromal tumor.