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Gastrointestinal stromal tumors (GISTs) are rare neoplasms. Although they represent only 0.1% to 3% of all gastrointestinal malignancies,1–4 they account for 80% of gastrointestinal mesenchymal neoplasms.5 Approximately 5000 to 6000 new cases are diagnosed per year in the United States, for an annual incidence of 14.5 per million and prevalence of 129 per million.6 In the last 15 years, the understanding and treatment of GIST has witnessed remarkable advances due to two key developments: (1) the identification of constitutively active signals (oncogenic mutation of the c-KIT and platelet-derived growth factor alpha [PDGFRA] gene-encoding receptor tyrosine kinases) and (2) the development of therapeutic agents that suppress tumor growth by specifically targeting and inhibiting these signals. These developments in the management of GIST illustrate the principle of translational therapeutics in oncology, confirming that specific inhibition of tumor-associated receptor tyrosine kinase activity is an effective cancer treatment. The advent of effective targeted medical therapy for GIST has increased the complexity of management and opened new dialogues regarding the need for integrated multimodality therapy. This chapter reviews the biology, treatment, and emerging clinical challenges of these mesenchymal neoplasms.
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Historical Background
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The term “GIST” was initially coined in 1983 by Mazur and Clark to describe intra-abdominal nonepithelial neoplasms which lacked the ultrastructural features of smooth muscle cells and the immunohistochemical characteristics of Schwann cells.7 GISTs typically exhibit heterogeneous histologic features. They are most commonly composed of long fascicles of spindle cells with pale to eosinophilic cytoplasm and rare nuclear pleomorphism, but may occasionally exhibit epithelioid characteristics, including sheets of round- to oval-shaped cells with abundant eosinophilic cytoplasm and nuclear atypia (Fig. 33-1). As such, they are typically classified as spindle cell type, epithelioid type, or mixed type. The majority of GISTs are of spindle cell appearance (70%), while epithelioid (20%) and mixed (10%) cell morphology are less common.
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In 1995, Miettinen and colleagues discovered that 70% of GISTs were positive for CD34 by immunohistochemistry, a myeloid progenitor cell antigen also present in endothelial cells and fibroblasts.8 Based upon their histologic features, GISTs are believed to arise from the interstitial cells of Cajal, components of the intestinal autonomic nervous system that serve as intestinal pacemakers and also express CD34.9 Nonetheless, until the late 1990s, there were no objective criteria to classify GISTs. They were frequently misclassified as leiomyomas, leiomyoblastomas, leiomyosarcomas, Schwannomas, gastrointestinal autonomic nerve tumors, or other similar soft tissue histologies.10 Consequently, interpretation of clinical results for reports on “GISTs” published before 2000 is challenging.