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Gastrointestinal Stromal Tumors: A Review of the Literature

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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.

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									                                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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