Features associated with a more aggressive behavior include a high mitotic rate (>5/per 50 hpf), large size (>5 cm), invasion, location within the fundus or gastrointestinal junction, coagulative necrosis, ulceration and epithelioid morphology (55,56). The vast majority of GISTs show a diffuse cytoplasmic staining with membranous accentuation of CD117 (KIT) (Figure 4A). CD117 is the product of the c-kit gene and is

a type-3 tyrosine kinase receptor which is normally expressed in the interstitial cells of Cajal, mast cells, melanocytes, fetal endothelial cells and CD34-positive hematopoietic stem cells. CD117 is also positive in a variety of tumors such as mastocytoma, seminoma, Inhibitors,research,lifescience,medical pulmonary small cell carcinoma and blastic types of myeloid sarcoma just to name a few (57). Although CD117 positivity is present in most GIST, Inhibitors,research,lifescience,medical it is not required for diagnosis (58), since 5-10% of gastric GIST and 4% of small intestinal GIST may be negative for CD117 (57). Most CD117 negative GISTs are positive for another GIST marker-DOG-1 (Figure 4B). The diagnosis of GIST then requires examination of the morphologic, immunohistochemical and molecular PDGRFRA mutation analysis. Other immunohistochemical markers which may be positive in GIST include PDGFRA5, CD34 (80%), SMA (20%) (55),

DOG1 (79%), and CK18 Inhibitors,research,lifescience,medical (59). Antibody cocktails for keratin such as AE1/AE3 are generally negative in gastric GIST as they are negative for CK7, CK17, CK19 and CK20. S-100 is also only positive in <1% of gastric

GISTs (57). GFAP is negative in GIST and thus helps in differentiating from gastrointestinal schwannoma which is GFAP positive. Figure 4 Immunohistochemical features of gastrointestinal stromal tumors (GIST). A. CD117 shows diffuse cytoplasmic staining with membranous accentuation; B. DOG-1 also shows Inhibitors,research,lifescience,medical diffuse positivity Extranodal marginal Inhibitors,research,lifescience,medical zone lymphoma of mucosa-associated lymphoid tissue (MALT) MALT is the most common type of lymphoma to occur in the stomach (60). Development of MALT has been associated with Helicobacter PLX4032 molecular weight pylori infection with induction of remission reported by antibiotic treatment of the H. pylori (61). The lymphoma cells are B-cells and infiltrate the marginal zone around the preserved follicles. The cells are small to medium in size with a monocytoid appearance. Plasmacytic unless differentiation is often present in gastric MALT lymphomas (60). Tumor cells are positive for CD20, CD79a and Pax-5 but negative for CD5, CD10, and CD23. Aberrant CD5 co-expression has been described while co-expression of CD43 has been reported in one-third of cases (62). Cytogenetic abnormalities in MALT include t[11;18], t[1;14], t[14;18] and t[3;14] with t[11;18] being the most common translocation in MALT lymphomas involving the stomach (63,64). Small intestine The small intestine includes the duodenum, jejunum and ileum extending from the pylorus to ileocecal valve, yet neoplasms in the small intestine are extremely rare.