Chapter 118: Gastrointestinal Stromal Tumors

BACKGROUND

Gastrointestinal stromal tumor (GIST) is a rare malignancy of mesenchymal origin. The true incidence of GIST has historically been underestimated as these tumors were commonly misclassified as leiomyomas, leiomyosarcomas, and leiomyoblastomas.¹ The term gastric stromal tumor was first proposed in 1983 to describe gastric wall tumors that lacked the ultrastructural features of smooth muscle cells and the immunohistochemical characteristics of Schwann cells.² Mazur and Clark² examined 28 gastric wall tumors that were originally classified by light microscopy as leiomyomas or leiomyosarcomas and, using electron microscopy, determined that some of these tumors lacked features expected in cells derived from smooth muscle. Additionally, using immunohistochemistry to identify the neuroectoderm marker S-100, they found that the majority of tumors failed to show evidence of a nerve sheath origin. They postulated that this subset of tumors that did not appear from a smooth muscle origin or peripheral nerve origin may arise from the myenteric nervous system.

In the early 1990s, confusion persisted as to the lines of differentiation of these stromal tumors which prevented accurate determination of their biologic behavior. Continued investigation into the immunophenotype demonstrated that some of these stromal tumors showed neural, smooth muscle, bidirectional differentiation, or neither.³ In 1995, Miettinen et al⁴ discovered that 70% of GISTs were positive for CD34, a myeloid progenitor cell antigen also present in endothelial cells and fibroblasts. This approach was, however, imperfect as no more than 60% to 70% of GISTs are CD34 positive, and Schwann cell neoplasms and some smooth muscle tumors are also CD34 positive.¹

It was not until the late 1990s when Hirota et al⁵ discovered that GISTs express KIT (CD117), a receptor tyrosine kinase encoded by the proto-oncogene c-kit. It was also discovered that interstitial cells of Cajal, which are considered the pacemaker cells of the gastrointestinal tract, were positive for both KIT and CD34 and are the most likely cell of origin of GISTs.^5-8 In subsequent studies, the gain-of-function mutation of c-kit that results in ligand-independent tyrosine kinase activity was identified in 85% to 100% of so-called “benign” and “malignant” GISTs but not in gastrointestinal leiomyomas or leiomyosarcomas.^6,9

This discovery not only impacted the ability to accurately identify GISTs, but also led to a breakthrough in management. The receptor tyrosine kinase KIT was found to have a similar structure to ABL, a tyrosine kinase implicated in chronic myelogenous leukemia. Imatinib mesylate (Gleevec, Novartis, Basel, Switzerland) is a tyrosine kinase inhibitor that had been shown to be successful in the treatment of chronic myelogenous leukemia and was also found to selectively inhibit KIT. In 2001, a 50-year-old woman with rapidly progressing metastatic GIST was treated with imatinib and within 1 month of treatment had a complete metabolic response by [¹⁸F]fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) and a 50% decrease in tumor volume on MRI.¹⁰ This ...