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Gastrointestinal stromal tumors (GISTs) are rare neoplasms. Although they represent only 0.1–3% of all gastrointestinal (GI) malignancies,1–4 they account for 80% of gastrointestinal mesenchymal neoplasms.5 Approximately 5000–6000 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 12 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 receptor alpha[PDGFRA] gene-encoding receptor tyrosine kinases) and (2) the development of therapeutic agents that suppress tumor growth by specifically targeting and inhibiting this signal (imatinib mesylate, sunitinib malate). These developments in the management of GIST represent a proof of the principle of translational therapeutics in oncology, confirming that specific inhibition of tumor-associated receptor tyrosine kinase activity may be an effective cancer treatment. The advent of effective therapy for GIST has not diminished but rather redefined the role of surgery for this disease. This chapter reviews the biology, treatment, and emerging clinical challenges of these mesenchymal neoplasms.

Historical Background

The term “GIST” was initially coined in 1983 by Mazur and Clark to describe intra-abdominal nonepithelial neoplasms that 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. 24-1). Based on their histologic and immunohistochemical features, GISTs are believed to arise from the interstitial cells of Cajal, components of the intestinal autonomic nervous system that serve as intestinal pacemakers.8 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.9 Consequently, interpreting clinical results for reports on “GISTs” published before 2000 can be challenging.

Figure 24-1

Gastrointestinal stromal tumor (GIST) histology. Staining of tumor paraffin sections with hematoxylin and eosin (H&E) reveals three patterns of GIST histology: (A) spindle cell, (B) mixed cell, and (C) epithelioid cell type.

Receptor Tyrosine Kinase Mutations

In a landmark publication in 1998, Hirota and colleagues reported two critical findings: (1) near-universal expression of the transmembrane receptor tyrosine kinase KIT in GIST, and (2) presence of gain-of-function mutations in the corresponding c-kit proto-oncogene.10 The KIT receptor is activated by binding its cytokine ligand known as steel factor or stem cell factor.11 KIT plays a critical role in the development and maintenance of components of hematopoiesis, gametogenesis, and intestinal pacemaker ...

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