From the Armed Forces Institute of Pathology (AFIP) series, 6% of duodenal GISTs belong to patients with NF1 (14). Although NF1 patients can have GISTs elsewhere, the great majority occur in the small bowel in this population. The tumors are frequently multiple, small, and indolent with a low mitotic activity. However, NF1 patients can go on to develop malignant GISTs, which can be confused with malignant schwannomas if immunohistochemical

studies are not carried out. Interestingly, GISTs in NF1 patients likely have a different pathogenic pathway, since they rarely if ever have the c-kit and PDGFRA mutations as seen in sporadic GISTs (16) (Table 2). Table 2 The Inhibitors,research,lifescience,medical incidence mutations of KIT and PDGFA in GIST The Carney triad includes gastric GIST, paraganglioma, and pulmonary chondroma. These GISTs are usually epithelioid. They often occur in children and have a strong female predominance (85%) and the Inhibitors,research,lifescience,medical majority are indolent, even in the setting of metastatic disease (14). Rare cases of familial GIST syndrome have been reported (14). Usually, they show autosomal dominant transmission of activating KIT or PDGFRA mutations. Patients with germline KIT or PDGFRA mutations have

shown Cajal cell hyperplasia and progression to discrete GISTs (17). Tumors are typically multiple with biological behavior Inhibitors,research,lifescience,medical that varies from indolent to malignant. These individuals also develop cutaneous hyperpigmentation and mastocytosis (18). A Inhibitors,research,lifescience,medical study using PCR for clonality analysis showed that diffuse Cajal cell proliferations seen in these patients are polyclonal, whereas the GIST tumors are monoclonal

(18). This suggests that additional genetic alterations are required before clonal expansion and malignant transformation can occur (14). The therapeutic drug of choice for unresectable, metastatic, or recurrent GISTs Inhibitors,research,lifescience,medical is imatinib, a competitive antagonist of the ATP binding site of tyrosine kinases such as KIT, platelet growth factor receptors alpha and beta, ABL, and ABL-related gene product. It causes interruption of the until downstream signaling process that leads to cellular proliferation. Ten to twenty percent of GISTs exhibit click here Resistance to imatinib (10). This resistance has been associated with selection of mutations that in some cases interrupt the binding site of imatinib (19). Patients with the Kit exon 9 mutations often require a higher dose of imatinib, often double the starting dose recommended for exon 11 mutants (10). Resistance is also thought to result from secondary mutations in the KIT and/or PDGFRA kinase domain. Several other inhibitors are being developed for resistant tumors. Surgery however, remains the only curative treatment for GISTs. Molecular pathology of gastric neuroendocrinetumors Gastric neuroendocrine tumors are being diagnosed with higher and higher frequency than previously reported (20).