Both sporadic and germ line mutations result in constitutively active KIT or PDGFRA receptor tyrosine kinases and produce intracellular signals that promote tumor cell proliferation and survival (Chapter 6). In GISTs without KIT or PDGFRA mutations, genes encoding components of the mitochondrial succinate dehydrogenase (SDH) complex are most commonly affected. These mutations result in loss of SDH function and confer increased risk for both GIST and paraganglioma. One mutant allele is often inherited, with the second copy of the gene being either mutated or otherwise lost in the tumor. The loss of SDH causes a number of metabolic changes, including increased production of reactive oxygen species, activation of hypoxia induced factor (HIF), and increased dependency on glycolysis for ATP production, but how these alterations lead to transformation is uncertain.
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MORPHOLOGYPrimarygastricGISTsusuallyformasolitary,well-circumscribed,fleshy,submucosalmass.Metastasesmayformmultiplesmallserosalnodulesorfewerlargenodulesintheliver;spreadoutsideoftheabdomenisuncommon.GISTscanbecomposedofthin,elongatedspindle cells orplumperepithelioid cells. ThemostusefuldiagnosticmarkerisKIT,whichisimmunohistochemicallydetectablein95%ofthesetumors.
The peak incidence of gastric GIST is around 60 years of age, with less than 10% occurring in individuals younger than 40 years of age. Overall, GISTs are slightly more common in males. Small GISTs may come to clinical attention incidentally during work-up of other GI symptoms, which are common. Larger GISTs may present with symptoms related to mass effects or mucosal ulceration, such as intestinal obstruction or gastrointestinal bleeding. Complete surgical resection is the primary treatment for localized gastric GIST. The prognosis correlates with tumor size, mitotic index, and location, with gastric GISTs being somewhat less aggressive than those arising in the small intestine. Recurrence or metastasis is rare for gastric GISTs less than 5 cm in diameter but common for mitotically active tumors larger than 10 cm. Tumors that are unresectable or metastatic often respond, sometimes for years, to tyrosine kinase inhibitors that are active against KIT and PDGFRA, such as imatinib. Unfortunately, as in chronic myeloid leukemia (Chapter 12), resistance to imatinib eventually arises due to outgrowth of subclones with additional mutations in KIT or PDGFRA. In some instances, these tumors respond to other tyrosine kinase inhibitors that retain activity against KIT and PDGFRA.
Inflammatory and hyperplastic gastric polyps arereactivelesionsassociatedwithchronicgastritis.Riskfordevelopmentofdysplasiaincreaseswithpolypsize.
Gastric adenomas developinabackgroundofchronicgastritisandareparticularlyassociatedwithintestinalmetaplasiaandmucosal(glandular)atrophy.Adenocarcinomafrequentlyarisesingastricadenomas,whichthereforerequirecompleteexcisionandsurveillancetodetectrecurrence.
Gastric adenocarcinomas areclassifiedaccordingtolocationandgrossandhistologicmorphology.Thosewithanintestinalhistologicpatterntendtoformbulkytumorsandmaybeulcerated,whereasthosecomposedofmucus-filledsignetringcellstypicallydisplayadiffuseinfiltrativegrowthpatternthatmaythickenthegastricwall(linitisplastica)withoutformingadiscretemass.
H. pylori infectionisthemostcommonetiologicagentforgastricadenocarcinoma,butotherassociations,includingchronicatrophicgastritisandEBVinfection,suggestseveralpossiblepathwaysofneoplastictransformation.