Pathology of gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors in the gastrointestinal tract. It was found that most GIST expressed KIT, a receptor tyrosine kinase encoded by protooncogene c‐kit. In normal gastrointestinal wall, KIT is expressed by interstitial cells of Cajal (ICC), which are a pacemaker for autonomous gastrointestinal movement. Because both GIST and ICC are double‐positive for KIT and CD34, and because familial and multiple GIST appear to develop from diffuse hyperplasia of ICC, GIST are considered to originate from ICC or their precursor cells. It was also found that approximately 90% of the sporadic GIST have somatic gain‐of‐function mutations of the c‐kitgene, and that the patients with familial and multiple GIST have germline gain‐of‐function mutations of the c‐kitgene. These facts strongly suggest that the c‐kitgene mutations are a cause of GIST. Approximately half of the sporadic GIST without c‐kitgene mutations were demonstrated to have gain‐of‐function mutations in platelet‐derived growth factor receptor‐α (PDGFRA) gene that encodes another receptor tyrosine kinase. Because KIT is immunohistochemically negative in a minority of GIST, especially inPDGFRAgene mutation‐harboring GIST, mutational analyses of c‐kitandPDGFRAgenes may be required to diagnose such GIST definitely. Imatinib mesylate was developed as a selective tyrosine kinase inhibitor. It inhibits constitutive activation of mutated KIT and PDGFRA, and is now being used for KIT‐positive metastatic or unresectable GIST as a molecular target drug. Confirmation of KIT expression by immunohistochemistry is necessary for application of the drug. The effect of imatinib mesylate is different in various types of c‐kitandPDGFRAgene mutations, and the secondary resistance against imatinib mesylate is often acquired by the second mutation of the identical genes. Mutational analyses of c‐kitandPDGFRAgenes are also significant for prediction of effectiveness of drugs including newly developed agents.