Posted June 4, 2013
Nicole Riddle, MD
Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors almost exclusively occurring along the GI tract: stomach (50%–70%), small intestine (25%–40%), colorectal (<10%), esophagus (rare). These types of tumor represent about 1% of all GI tumors and over 75% are considered benign.1-3 However, the system for determining the nature of the lesions is complex, and they are not always predictable. Most commonly occurring in middle-aged adults, they have been reported in children, usually with a more aggressive nature and more frequent metastasis but with a good long-term prognosis.4 Believed to arise from the interstitial cells of Cajal, GISTs form in the wall of the GI tract and push outward.
Histologically, GISTs may have a varied appearance, though approximately 70% are spindled and 20% are epithelioid; and other patterns are described as organoid, pleomorphic, and mixed.3 Rarely, a GIST may dedifferentiate and appear, as well as stain, like an undifferentiated pleomorphic sarcoma (malignant fibrous histiocytoma). One helpful feature, especially in small intestinal GISTs, are the skeinoid fibers; PAS+ aggregates of extracellular collagen that imply a more favorable prognosis.3,4
As with most spindle cell/epithelioid neoplasms, immunohistochemical studies remain an important part of the diagnosis. Between 85%–95% of GISTs will show positivity for CD117/c-kit; however, there is low specificity.4,5 A recent marker, DOG-1, has been shown to be more sensitive and more specific.3 Of the C-kit negative GISTs, most are PDGFRa positive and many will also have DOG-1. This immunohistochemical pattern is more common with the epithelioid subtypes from the stomach or omentum. Other stains that are often positive are bcl-2 (80%), CD34 (60%), and smooth muscle actin (SMA, 50%). Rare cases have focal S100 and Desmin.2
As mentioned above, the process by which the prognostic nature of a GIST is complicated and there are no set rules assigned; however, the general principles are the same. In general, intestinal GISTs tend to be more aggressive than their gastric counterparts.3 For each individual lesion the risk is defined by the size of the tumor and the number of mitosis per high-power field. The greater the size or mitotic count, the more aggressive is the lesion. But depending on which resource the pathologist uses, the cut-offs between low-, moderate-, and high-risk may differ.2,3,5
Treatment of GISTs usually consists of a medical treatment to decrease the size of the tumor, often followed by surgery for complete removal. The first line treatment is Imatinib (Gleevac), a tyrosine kinase inhibitor.7 However, Imatinib only works on cases with specific c-kit mutations (eg, exon 11, ~70% of cases), but upwards of 30% may have specific mutational loci that are resistant (eg, exon 9). In these cases, physicians either use increased doses of Imatinib, or move on to a second-line treatment, like Sunitinib.8. It is important to note that the Imatinib-resistant exon 9 mutation is more frequently seen in small intestinal lesions. As described above, 5%–10% of GISTs will have a PDGFRa mutation; again the loci of the mutation is important because certain ones are more sensitive than others. It is for this reason that many physicians send GISTs for molecular analysis to accurately identify the specific mutation. Communication between the clinicians and the pathologist is important to assure that all appropriate variables affecting the patient’s prognosis and potential treatment for GISTs are conveyed in the pathology report.
- Nilsson B, Bümming P, Meis-Kindblom JM, et al. Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era—a population-based study in western Sweden. Cancer. 2005;103(4):821–829.
- Fletcher CD, Berman JJ, Corless C, et al. Diagnosis of gastrointestinal stromal tumors: a consensus approach. Hum. Pathol. 2002; 33(5);459–465.
- Miettinen M, Lasota J. Gastrointestinal stromal tumors: pathology and prognosis at different sites. Semin Diagn Pathol. 2006;23(2); 70–83.
- Corless CL, Fletcher JA, Heinrich MC. Biology of gastrointestinal stromal tumors. J Clin Oncol. 2004;22(18):3813–3825.
- Dematteo RP, Gold JS, Saran L, et al. Tumor mitotic rate, size, and location independently predict recurrence after resection of primary gastrointestinal stromal tumor (GIST). Cancer. 2008;112(3):608–615.
- West RB, Corless CL, Chen X, et al. The novel marker, DOG1, is expressed ubiquitously in gastrointestinal stromal tumors irrespective of KIT or PDGFRA mutation status. Am J Pathol. 2004;165(1):107–113.
- Blanke CD, Rankin C, Demetri GD, et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol. 2008.26(4):626–632. doi: 10.1200/JCO.2007.13.4452.
- Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy and safety of sunitinib in patients with advanced gastrointest-inal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006;368(9544):1329–1338.
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