Gastrointestinal stromal tumor (GIST) is defined as a specific mesenchymal tumor of the gastrointestinal (GI) tract that has a characteristic histologic spectrum, is generally KIT (CD117) positive, and is driven by oncogenic KIT or platelet-derived growth factor receptor α (PDGFRA) mutations. This definition of GIST excludes GI smooth muscle and nerve sheath tumors. Availability of KIT tyrosine kinase inhibitor drug therapy (imatinib mesylate and second-generation inhibitors) has greatly magnified the interest in GIST and vastly increased the importance of its specific diagnosis.

GISTs occur along the entire length of the GI tract, from the esophagus to the anus, and similar tumors can occur anywhere in the abdomen, usually representing metastases or tumors detached from their GI tract site of origin. GISTs have a wide clinical spectrum, ranging from benign, small incidentally detected nodules to massive, frankly malignant tumors that can fill the entire abdomen.

This chapter summarizes the clinical, pathologic, and molecular genetic features of GISTs. Although all GISTs share many features, tumors at each site have distinctive clinicopathologic and prognostic differences and are therefore reviewed site by site. Small intestinal GISTs in particular show malignant behavior more frequently than the gastric tumors do. The unique clinicopathologic features of pediatric GISTs, those occurring in Carney triad, neurofibromatosis 1, and familial GIST syndrome, are discussed separately.

Tumor size (preferably in three dimensions), mitotic rate per 50 HPFs, and tumor margin status should be included in the pathology report.