Molecularly Targeted Therapy: Imatinib and Beyond

Abstract

Gastrointestinal stromal tumors (GISTs) are rare tumors, with an estimated incidence of 1.5/100,000 persons per year (Nilsson, 2005). This number accounts for clinically relevant tumors, there is a much higher number of microscopic lesions that can be detected on pathologic specimens. The incidence of such microscopic subclinical lesions approaches 20% in surgical and autopsy specimens (Agaimy, 2007). GISTs account for the overwhelming majority of mesenchymal tumors arising in the GI tract. GISTs arise most frequently in the stomach (approximately 60%), and small bowel (30%), but these tumors can arise anywhere in the GI tract (DeiTos, 2011). GISTs are thought to originate from the interstitial cells of Cajal (GI pacemaker cells). These subepithelial neoplasms share a unique molecular and immunohistochemical signature. Morphologically, GISTs are subdivided into spindle cell, epithelioid cell, and mixed types, but these distinctions have little clinical relevance. Overt cytologic atypia and dedifferentiation are quite rare, and should lead to considerations of alternative diagnoses (DeiTos, 2011). Nearly all GISTs express immunoreactivity to c-KIT, also known as CD117 or stem cell growth factor receptor (SCFR). The KIT receptor is a membrane-bound class III receptor tyrosine kinase (RTK) encoded by the KIT protooncogene. This RTK is activated by the binding of mast cell growth factor (MGF), also known as stem cell factor. About 95% of GISTs overexpress KIT. DOG1 has also been used as a very sensitive and specific immunomarker. In a large pathology series, the overall sensitivity of DOG1 and KIT in GISTs was nearly identical: 94.4% and 94.7%, and results in GISTs were generally concordant. Gastric spindle cell GISTs were nearly uniformly positive for both markers, whereas DOG1 performed slightly better in gastric epithelioid GISTs that included a higher percentage of platelet derived growth factor receptor alpha (PDGFRA)mutant GISTs. In the intestinal GISTs, KIT was slightly more sensitive than DOG1. Negativity for both DOG1 and KIT was observed in 2.6% of GISTs (Miettinen, 2009). In 80%