Gastrointestinal stromal tumor (GIST) is a type of sarcoma (i.e., a connective tissue neoplasia). GIST is a rare cancer affecting the digestive tract or nearby structures within the abdomen.
Epidemiology and Clinical-Pathological Features of GIST
GISTs are believed to arise from the interstitial cells of Cajal (ICCs), the pacemaker cells for the autonomous movement of the GI tract. Other studies have suggested that GISTs arise from interstitial mesenchymal precursor stem cells; however, pinpointing the progenitor cell has been difficult. Although it is considered a rare tumor, nearly 4,500–6,000 new cases are diagnosed annually in the USA. The peak incidence of GIST occurs later in life with a median age of 58 years; however, there are also reports of pediatric GISTs. The most common sites of origin for GIST are the stomach (39–70%) and small intestine (31–45%). Other primary sites include the large bowel, rectum, appendix, and rarely the esophagus. A small percentage of GISTs arise outside the tubal gut, i.e., within the mesentery, gallbladder, and omentum. These tumors are known as extra-gastrointestinal GIST. The symptoms of GIST include bloating, gastrointestinal bleeding, or fatigue related to anemia. The common metastatic sites for GIST include the liver and omentum, and less frequently, the lung and bone.
Oncogenic Signaling Pathways in GIST
KIT gain-of-function mutations result in autoactivation of the receptor and consequently transmit the KIT oncogenic signal to downstream targets such as phosphatidylinositol 3-kinase (PI3K), AKT (also known as protein kinase B), and mitogen-activated protein kinases (MAPK). These signaling proteins influence proliferation, apoptosis, differentiation, and/or cell adhesion (Fig. 2b). Clinical observations and laboratory research have shown that different gain-of-function mutations within the same receptor can affect different downstream pathways and clinical response to therapy.
Cytogenetics and Molecular Cytogenetic Alterations
Even though mutations in KIT or PDGFRα appear to be the primary driving force in the pathogenesis of GIST, several other genetic and genomic changes have been documented which contribute to the development of this disease. Monosomy for chromosome 14 is one of the most frequent (>60%) genomic alterations detected in GISTs. Other common changes in metastatic GISTs include loss of chromosome arms 1p, 9p, 10, 14q, 15q, and 22 and gains involving 5p and 20q.
Cytoreductive surgery is the standard of care for patient with primary GIST. This surgery seeks to remove the entire gross tumor and may require total or subtotal organ resection, depending on tumor location and size. However, surgery has limited success for locally recurrent or metastatic GIST and clinical response of patients to systemic therapy using conventional chemotherapies is abysmal. Chemotherapy response rates in patients with metastatic disease are less than 5% for all tested cytotoxic agents with a median survival of 10–20 months.
Imatinib mesylate (STI-571 or Gleevec™) is an oral 2-phenylaminopyrimidine derivative that acts as a selective inhibitor against several receptor tyrosine kinases including KIT, PDGFRα, and BCR-ABL (which is the causative chromosomal translocation in chronic myelogenous leukemia). Based on a high percentage of metastatic GIST patients demonstrating clinical response to imatinib in phase I/II clinical trials, the FDA granted Novartis approval of imatinib for the treatment of advanced GIST in 2001. Clinically, it has been reported that patients with metastatic or localized GIST possessing a mutation in exon 11 (i.e., involving the juxtamembrane domain of the receptor) of c-KIT mutations have a longer progression free survival and overall survival when treated with imatinib as compared to patients with tumors with other types of c-KIT mutations. Likewise, mutations in exon 12 (juxtamembrane domain) of PDGFRα are more sensitive to imatinib treatment than patients with other types of mutations in PGDFRα.
In summary, GISTs are the most common mesenchymal tumors of the digestive tract and possess mutations in either c-KIT or PDGFRα. For patients with localized resectable GIST, surgery remains the treatment of choice, whereas, for patients with metastatic disease, imatinib-based therapy is providing benefit for long-term disease control.