Treatment Options for Gastrointestinal Stromal Tumors

Abstract

The term gastrointestinal stromal tumor (GIST) in the description of a specific group of gastrointestinal nonepithelial tumors lacking the microscopic evidence of smooth muscle or characteristics of neural immunoreactivity was first introduced by Mazur and Clark (Mazur & Clark, 1983). The common origin of GIST and interstitial cell of Cajal (ICC), the pacemaker cells in the digestive tract, was proposed due to their immunohistochemical and ultrastructural similarities. The definition of GISTs as tumors originating from ICC was further confirmed according to the findings that both GIST and ICC express KIT and that most GISTs have gain-of-function mutations of KIT, the proto-oncogene that encodes a 145 kDa transmembrane tyrosine kinase KIT receptor. Mutation of different exons of the KIT oncogene results in activation of the tyrosine kinase activity of KIT, leading to ligandindependent kinase activity and uncontrolled cell proliferation as well as resistance to apoptosis (Demetri et al., 2002; Hirota et al., 1998; Kindblom et al., 1998; Savage & Antman, 2002). More than 90% of GIST have constitutive activation of the KIT protein as a result of KIT mutation and in GIST without KIT mutations, gain-of-function of platelet derived growth factor receptor α (PDGFRA) are present in about one-third of cases. It was recently proposed that ETV1, one of the ETS family transcription factor, can be a lineage survival factor that cooperates with KIT in gastrointestinal stromal tumours. GIST arises from ICCs with high levels of endogenous ETV1 expression that, when coupled with an activating KIT mutation, drives an oncogenic ETS transcriptional program (Chi et al., 2010; Roberts & Eisenberg, 2002; Rubin et al., 2001). GIST was estimated to occur in about 14.5 cases per million and was the most common mesenchymal tumor of the gastrointestinal tract. The most common locations of GIST are the stomach (50-60%), small intestine (20-30%), colon and rectum (10%), and esophagus (5%). Patients mostly present with nonspecific symptoms and signs (69%) and initial metastasis was noted in about 15-50% of GISTs (DeMatteo et al., 2000; Fletcher et al., 2002; Nilsson et al., 2005; Roberts & Eisenberg, 2002; Shinomura et al., 2005). The accurate diagnosis of GIST should be based on tumor morphology and immunohistochemistry. GIST tumors grossly appear as well-defined submucosal lesion with prominent vasculature and occasional hemorrhage or ulceration (Fig. 1A and 1B.). Under morphologic examination in the immunohistochemical analysis, GIST tumor cells are