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Gastrointestinal stromal tumors are mesenchymal neoplasms with a spectrum of histologic appearances and biologic activity. The morphologic classification of these lesions has evolved over time, and molecular analysis has led to a better understanding of their nature. The histologic differential diagnosis for these lesions is broad and includes many spindle cell lesions of the gastrointestinal tract, including neoplasms of true smooth muscle and neural origin, proliferating fibrous lesions, metastatic neoplasms, and primary sarcomas of vascular and adipose origin. Immunohistochemical studies that include CD117 have become invaluable in the classification of mesenchymal lesions arising in the gastrointestinal tract. Treatment of gastrointestinal stromal tumors has historically been involved surgery, but the use of the chemotherapeutic agent imatinib mesylate for advanced disease has made accurate classification even more important. The molecular features have not only allowed us to understand the pathogenesis of these tumors but also have proven to be associated with response to kinase inhibitors.
Gastrointestinal Stromal Tumors A Review of the Literature Javier A. Laurini, MD; J. Elliot Carter, MD ● Gastrointestinal stromal tumors are mesenchymal neo- CD34 was advocated as a more reproducible marker of plasms with a spectrum of histologic appearances and bi- gastrointestinal stromal tumors (GISTs). However, only ologic activity. The morphologic classiﬁcation of these le- 60% to 70% of GISTs are positive for this marker, and sions has evolved over time, and molecular analysis has led because a broad variety of spindle cell tumors, including to a better understanding of their nature. The histologic smooth muscle and neural cell tumors, also express it, the differential diagnosis for these lesions is broad and includes speciﬁcity of CD34 was signiﬁcantly reduced in the di- many spindle cell lesions of the gastrointestinal tract, in- agnosis of mesenchymal tumors of the gastrointestinal cluding neoplasms of true smooth muscle and neural ori- (GI) tract. gin, proliferating ﬁbrous lesions, metastatic neoplasms, and In the late 1990s, 2 main approaches were available for primary sarcomas of vascular and adipose origin. Immu- dealing with these lesions. One approach classiﬁed all nohistochemical studies that include CD117 have become mesenchymal tumors of the GI tract as GISTs, regardless invaluable in the classiﬁcation of mesenchymal lesions of the immunohistochemical proﬁle. The second approach arising in the gastrointestinal tract. Treatment of gastroin- excluded true smooth muscle and neural tumors in an testinal stromal tumors has historically been involved sur- attempt to identify a subset of mesenchymal tumors with gery, but the use of the chemotherapeutic agent imatinib unique clinicopathologic features. Although the second mesylate for advanced disease has made accurate classiﬁ- approach ultimately proved to be correct, initially its re- cation even more important. The molecular features have producibility was ﬂawed by the lack of a sensitive and not only allowed us to understand the pathogenesis of relatively speciﬁc diagnostic marker.3 these tumors but also have proven to be associated with This situation changed drastically in 1998, when Hirota response to kinase inhibitors. and colleagues6 discovered that most GISTs harbored c-kit (Arch Pathol Lab Med. 2010;134:134–141) mutations that resulted in full-length KIT proteins with ligand-independent activation. Furthermore, the authors6 demonstrated that GISTs were usually positive for CD117 I n 1941, Golden and Stout1 described a set of mesenchy- mal tumors arising in the bowel wall. Under the mis- taken assumption that these tumors originated from (c-kit) by immunohistochemistry. This single discovery changed our understanding of the pathogenesis of GISTs. Later, it became clear that a subset of GISTs harbored mu- smooth muscle cells, they designated them as leiomyo- tations in the platelet-derived growth factor receptor blastoma, leiomyoma, and leiomyosarcoma, based on their (PDGFRA). The term GIST is currently applied to ‘‘spe- morphologic appearance.1 In the late 1960s and early ciﬁc, generally CD117 and KIT or PDGFRA mutation- 1970s, electron microscopy revealed that few of these tu- driven mesenchymal tumors of the gastrointestinal tract mors had evidence of smooth muscle differentiation, an with a set of characteristic histologic features including observation that was corroborated later with the addition spindle cells, epithelioid and rarely pleomorphic mor- of immunohistochemistry in the late 1980s.2,3 Mazur and phology’’ according to the deﬁnition proposed by Mietti- Clark4 proposed the term stromal tumors for these mesen- nen et al7 and agreed upon on the GIST workshop held at chymal lesions because it did not specify a line of differ- the National Institutes of Health in April 2001.3 entiation. In 1984, Herrera et al5 studied a subset of these tumors showing positivity for S100 protein by immuno- CLINICAL FEATURES histochemistry and evidence of schwannian and neuroax- Gastrointestinal stromal tumors constitute approxi- onal differentiation by electron microscopy and proposed mately 2% of all neoplasms of the GI tract, where they the name plexosarcomas for them. Later, they become represent the most common mesenchymal tumor. The an- known as gastrointestinal autonomic nerve tumors. nual incidence is estimated at 4500 to 6000 new cases per year in the United States. These tumors equally affect fe- Accepted for publication May 19, 2009. male and male patients, with a wide age distribution, al- From the Department of Pathology, University of South Alabama though more than 75% of the cases affect patients older Medical Center, Mobile. than 50 years of age8–10; 5% of the lesions arise in the The authors have no relevant ﬁnancial interest in the products or companies described in this article.
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