Gastrointestinal stromal tumors: Pathology and prognosis at different sites

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Gastrointestinal (GI) stromal tumors (GISTs) are the most common mesenchymal tumors specific to the GI tract, generally defined as KIT (CD117)-positive tumors with a characteristic set of histologic features. These tumors, derived from Cajal cells or their precursors, most commonly occur at the age >50 years in the stomach (60%), jejunum and ileum (30%), duodenum (4-5%), rectum (4%), colon and appendix (1-2%), and esophagus (<1%), and rarely as apparent primary extragastrointestinal tumors in the vicinity of stomach or intestines. Their overall incidence has been estimated as 10 to 20 per million, including incidental minimal tumors. GISTs are rare in children (<1%) and almost exclusively occur in stomach. They are common in patients with neurofibromatosis 1, who have a predisposition to (multiple) small intestinal GISTs. GISTs contain a spectrum from minute indolent tumors to sarcomas at all sites of occurrence. Their gross patterns are diverse, including nodular, cystic, and diverticular tumors. External involvement of pancreas and liver can simulate primary tumor in these organs. In general, gastric tumors have a more favorable prognosis than the intestinal ones with similar parameters. Gastric GISTs ≤10 cm and ≤5 mitoses per 50 HPFs have a low risk for metastasis, whereas those with >5 per 50 HPFs and >5 cm in diameter have a high risk for metastasis. In contrast, all intestinal GISTs >5 cm independent of mitotic rate have at least moderate risk for metastases, and all >5 mitoses per 50 HPFs have a high risk for metastases. Intestinal GISTs ≤5 cm with ≤5 mitoses per 50 HPFs have a low risk for metastases. Gastric GISTs can be divided into histologic subgroups including 4 spindle cell and 4 epithelioid variants. Intestinal GISTs are a histologically more homogeneous group and often contain distinctive extracellular collagen globules, skeinoid fibers. Immunohistochemical demonstration of KIT, CD34, or protein kinase theta positivity helps to properly identify these tumors.

Section snippets

Esophageal GISTs

In the esophagus, GISTs are rare, and true leiomyomas are the most common mesenchymal tumors by a 3:1 margin. The relative frequency of esophageal GISTs is low, not exceeding 1% to 2% of all GISTs.8, 9 These tumors typically occur in the lower third of esophagus in older adults and vary from small incidental tumors to large masses. The larger tumors often cause dysphagia, but some form mediastinal masses with no apparent esophagus-related symptoms.

Histologically, esophageal GISTs vary from

Gastric GISTs

Gastric GISTs form a large, clinicopathologically complex group comprising a majority of all GISTs. Their relative frequency among all GISTs in three studies, including two population-based ones, varied in a narrow range of 59% to 61%.10, 11, 12 Median or mean ages of patients have varied in a range of 63 to 70 years, and several series have found a mild male predominance of 52% to 55%.13, 14, 15 Less than 1% of gastric GISTs occur in children, and <10% are diagnosed in patients under the age

Duodenal GISTs

Approximately 4% to 5% of all GISTs with specified location originate in the duodenum. They can occur in any part of the duodenum, but are most common in its second part.18, 19 Those tumors that arise in the second part can involve pancreas and clinically simulate a pancreatic tumor. One reported pancreatic GIST that also had duodenal wall involvement20 apparently represents a duodenal GIST with pancreatic extension. Clinicopathologic series have shown 35% to 50% tumor-related mortality.

Small intestinal GISTs

Small intestinal GISTs involving jejunum or ileum comprise approximately 30% of all GISTs with specified location. As a group, these GISTs are more often malignant than gastric GISTs with 40% to 50% tumor-related mortality with mortality being higher with tumors >5 cm or with mitotic rate >5 per 50 HPFs. Location in the jejunum is more common than in the ileum by a factor of 1.6:1, and in 2 studies, ileal tumors were found to be more commonly clinically malignant,12, 21 although in the latter,

Pathology of GIST of colon and appendix

GISTs of colon (excluding rectum) are rare comprising no more than 1% to 2% of all GISTs. They occur throughout the colon but seem to be more common on the left than the right side. Like other GISTs, they usually occur in older adults (median age of two series: 60 years).

A study on 20 colonic GISTs segregated them into 2 groups: those that metastasized, and those that did not. This study did not evaluate KIT expression. The two best predictive adverse prognostic factors were found to be high

Pathology of GISTs of rectum

GISTs of rectum comprise approximately 4% of all GISTs of defined localized origin, based on the AFIP series.28 They vary from incidental minimal tumors to sarcomas.28, 29, 30, 31, 32 Small tumors can be found during prostate or pelvic examination and have been incidentally detected in stapled hemorrhoidopexy specimens.33 Larger tumors are often symptomatic by rectal obstruction, bleeding, or both. Especially those rectal GISTs that involve the anterior rectal wall can extend to posterior

Extragastrointestinal GISTs

GISTs have been reported outside of the tubular GI tract as apparent primary tumors, sometimes designated as “extragastrointestinal GISTs” (EGISTs).34, 35, 36 However, a great majority of GISTs outside the GI tract are metastases from GI primaries. It is important to recognize GIST in this setting, and KIT immunostaining should therefore be performed on unclassified epithelioid and mesenchymal neoplasms in the abdomen, and also on suspected GIST metastases in peripheral tissues.

The frequency of

GISTs in children

Less than 1% of GISTs occur in children in the second decade at or under the age of 16 years, and these tumors have a strong (90%) predilection to stomach and female patients and are more common in antrum.47, 48 The majority of these GISTs (75%) have epithelioid morphology, and few are associated with Carney Triad in combination with pulmonary chondroma, paraganglioma, or both. However, Carney triad is not exclusive to pediatric age.49 Prognosis of pediatric GISTs varies and seems to be

GISTs in neurofibromatosis type 1 (NF1) patients

NF1 patients have a significant predisposition to GISTs.50, 51, 52, 53 In our experience, 5% to 7% of duodenal jejunoileal GISTs occur in the setting of NF1, and GISTs are the most common GI mesenchymal tumors in these patients markedly outnumbering nerve sheath tumors. One study on 100 consecutive GIST patients found the frequency of NF1 to be 5%, a 150-fold enrichment from the overall incidence of NF1, which is 1:3000.51 The NF1-associated GISTs typically occur in small intestine and only

Immunohistochemical features of GIST

The key feature of GIST is positivity for the KIT (CD117), as observed in >95% of cases. Although KIT-positivity is a major defining feature for GIST, it is no longer considered an absolute requirement. Other, commonly expressed but less GIST-specific antigens are CD34, nestin, and protein kinase C theta. GISTs are variably positive for smooth muscle markers but are generally negative for desmin. Positivity for S100 protein is rare, and GFAP is absent. Keratins and neurofilaments are

Evaluation of biologic potential of GISTs

GISTs have a wide spectrum of biologic potential at all sites of their occurrence, ranging from minute nearly uniformly indolent tumors to sarcomas. Older studies on GI smooth muscle tumors (largely reflecting GISTs in modern terminology) often reported separately on benign and malignant tumors creating an illusion of a distinct separation between benign and malignant GISTs. Because criteria of separation were not precisely stated, it is impossible to determine predictive parameters based on

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    The opinions and assertions contained herein are the expressed views of the authors and are not to be construed as official or reflecting the views of the Departments of the Army or Defense.

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