GIST can develop anywhere along the GI tract, from the esophagus to the rectum; however, Gastric (50%), small-intestine (25%), and colorectal (10%) GIST are most common. Only 15% of GIST are found in the esophagus, mesentery, or omentum. Depending on the tumor site, over 30% of GIST exhibit high-risk (malignant) behavior, such as metastasis and infiltration. The majority of esophageal and colon GIST are malignant, while only 25% of gastric GIST are overtly malignant. The metastatic pattern is predominantly intra-abdominal, with spread throughout the peritoneal cavity and to the liver. Lymph nodal invasion is uncommon. True smooth muscle tumors—leiomyomas—also occur throughout the GI tract but are now thought to be rare in comparison with GIST, except in the esophagus, where they are more common. Emory TS, Sobin LH, Lukes L, Lee DH, O’Leary TJ. Prognosis of gastrointestinal smooth muscle (stromal) tumors: dependence on anatomic site . Am J Surg Pathol . 1999;23:82-87. Hatch KF, Blanchard DK, Hatch GF, et al. Tumors of the rectum and anal canal. World J Surg. 2000;24:437-443. Pidhorecky I, Cheney RT, Kraybill WG, Gibbs JF. Gastrointestinal stromal tumors: current diagnosis, biologic behavior, and management. Ann Surg Oncol . 2000;7:705-712. Kindblom LG, Meis-Kindblom J, B ümming P, et al . Incidence, prevalence, phenotype and biologic spectrum of gastrointestinal stromal cell tumors (GIST) – a population-based study of 600 cases. Ann Oncol. 2002;13:157. Abstract 5770.
An alarming 72% of GI tumors now verified as GIST originally had been classified as other tumors. 34% were classified as leiomyoma. 18% were classified as leiomyosarcoma. 13% were classified as leiomyoblastoma. 7% were classified as other tumors. Clearly, the incidence of GIST is much higher than previously believed. Variable disease criteria and confusing nomenclature often led to misclassification and underdiagnosis of GIST. Kindblom LG, Meis-Kindblom J, B ü mming P, et al. Incidence, prevalence, phenotype and biologic spectrum of gastrointestinal stromal cell tumors (GIST) – a population-based study of 600 cases. Ann Oncol. 2002;13:157. Abstract 577O. Kindblom LG . New tests reveal GIST more common, more aggressive than earlier thought. Available at: www.peerviewpress.com/asco2003c. Accessed March 9, 2004.
GIST cannot always be distinguished from smooth muscle tumors using basic histologic methods—light microscopy and hematoxylin-eosin (H-E) staining. Advances in modern immunohistochemistry (IHC) and other techniques now allow GIST to be distinguished from other histopathologic subtypes of GI sarcomas and mesenchymal cell proliferations. Miettinen M, Lasota J. Gastrointestinal stromal tumors (GISTs): definition, occurrence, pathology, differential diagnosis and molecular genetics. Pol J Pathol . 2003;54:3-24.
Over 80% of GIST have KIT gene mutations. Exon 11: Mutations in the intracellular juxtamembrane region occur in mast cell tumors and GIST. Comprise ~70% of all mutations in GIST Are generally point mutations (missense), in-frame deletions, or duplications Are associated with constitutive ligand-independent receptor dimerization and activation of the kinase domain (gain-of-function mutations) Occur more frequently in high-risk GIST than in intermediate-risk GIST (and are rarely or never found in leiomyomas or leiomyosarcomas) Predict a poor prognosis: 49% 5-year patient survival rate vs 86% 5-year survival rate of patients with non – exon 11 mutations Exon 9: Mutations in the extracellular juxtamembrane region involve a similar activation mechanism. Exon 13: Mutations in the split tyrosine kinase domain also occur in GIST. Other KIT mutations have been identified in other diseases. Exon 17: Mutations in the phosphotransferase domain occur in mast cell and germ cell tumors and result in tyrosine kinase activation that requires no dimerization. Exon 17 mutations render these tumors resistant to imatinib mesylate. Exon 2: A mutation in the proximal extracellular domain has been identified in 2 hematologic disorders: myelofibrosis and chronic myeloid leukemia (CML). Seven percent of GIST have PDGFRA gain-of-function intragenic mutations. Taniguchi M, Nishida T, Hirota S, et al. Effect of c-kit mutation on prognosis of gastrointestinal stromal tumors. Cancer Res. 1999;59:4297-4300. Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279:577-580. Lasota J, Jasinski M, Sarlomo-Rikala M, Miettinen M. Mutations in exon 11 of c-Kit occur preferentially in malignant versus benign gastrointestinal stromal tumors and do not occur in leiomyomas or leiomyosarcomas. Am J Pathol. 1999;154:53-60. Heinrich MC, Rubin BP, Longley BJ, Fletcher JA. Biology and genetic aspects of gastrointestinal stromal tumors: KIT activation and cytogenetic alterations. Hum Pathol. 2002;33:484-495. Corless CL, Heinrich MC, Duensing A, et al. PDGFRA and KIT gain-of-function mutations are alternative oncogenic mechanisms in gastrointestinal stromal tumors (GIST). Proc Am Assoc Cancer Res. 2003;44. Abstract R4447.
The major histologic patterns of GIST are spindle cell and epithelioid. GIST with a spindle cell morphology often will appear syncytial while clear cell borders are common in epithelioid GIST. Gastric GIST are often of spindle cell morphology, with the epithelioid GIST often historically misclassified as myoblastomas. GIST of the small intestine are primarily of spindle cell morphology. A salient feature of small intestine GIST, especially those of lower risk, is the presence of aggregates of collagen fibers known as skeinoid fibers. In contrast, epithelioid GIST of the small intestine are generally of high risk. Spindle cell morphologies dominate GIST at other sites. Miettinen M, Lasota J. Gastrointestinal stromal tumors (GISTs): definition, occurrence, pathology, differential diagnosis and molecular genetics. Pol J Pathol . 2003;54:3-24.
GIST are often defined as KIT - positive mesenchymal tumors of the GI tract. Over 90% of reported cases (but not all GIST) express KIT. KIT is a type III transmembrane receptor tyrosine kinase, the protein product of the KIT proto-oncogene. KIT is the single most common tumor marker for GIST. CD34 is a mesenchymal and hematopoietic precursor cell marker that is positive in many tumors of mesenchymal origin. It is expressed in 60% to 70% of GIST, making it a modestly sensitive and specific diagnostic GIST marker. Vimentin and smooth-muscle actin are variably expressed by GIST. Desmin is rarely present in GIST. In contrast, true smooth-muscle tumors often express high levels of desmin and smooth-muscle actin. S-100 is used to distinguish tumors of neural crest origin, such as schwannomas and melanomas, and it is particularly useful for differentiating GIST with neural phenotype (formerly GANT) from primary schwannomas. Miettinen M, Lasota J. Gastrointestinal stromal tumors—definition, clinical, histological, immunohistochemical, and molecular genetic features and differential diagnosis. Virchows Arch . 2001;438:1-12. Miettinen M, Sobin LH, Sarlomo-Rikala M. Immunohistochemical spectrum of GIST at different sites and their differential diagnosis with a reference to CD117 (KIT). Mod Pathol. 2000;13:1134-1142. Sarlomo-Rikala M, Kovatich AJ, Barusevicius A, Miettinen M. CD117: a sensitive marker for gastrointestinal stromal tumors that is more specific than CD34. Mod Pathol . 1998;11:728-734. Wang L, Vargas H, French SW. Cellular origin of gastrointestinal stromal tumors: a study of 27 cases. Arch Pathol Lab Med. 2000;124:1471-1475.
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