Prognostic Markers in Gastrointestinal Stromal Tumors – We Are Not There Yet

index have been known to metastasize. This has prompted the development of guidelines for defining risk of aggressive behavior rather than classifying lesions as either benign or malignant [10] . These guidelines, which were developed during a NIH consensus conference in 2001, are based on the idea that all GISTs have some potential for aggressive clinical behavior. Other pathological features of GISTs, in addition to mitotic index and tumor size, such as cellularity, mucosal invasion and ulceration, were also evaluated for prognostic significance, but have not gained wide acceptance [11] . Kit mutation status has also been evaluated in terms of prognosis. However, since approximately 90% of GISTs contain either Kit or PDGFR
mutations, the presence or absence of a mutation does not, by itself, distinguish between benign and malignant GISTs [12, 13] . Preliminary studies indicate that accumulation of secondary cytogenetic abnormalities/ molecular alterations [12] , Ki-67 proliferative index and telomerase activity are associated with clinically aggressive behavior [14] . Aberration of the cell cycle regulators is a frequent finding and may be a contributing factor in the pathogenesis of GIST. Indeed, malignant GISTs are more likely to be associated with a positive E2F1 and p53 phenotype and a negative p16 and p27 kip1 phenotype [15– 17] . For p27 kip1 , a member of the Cip/Kip family, a tumor suppressor role was demonstrated in mice, and a decrease or loss of the p27 kip1 protein was found to be a predictor of poor prognosis in many human cancers, including gasGastrointestinal stromal tumors (GISTs) comprise the largest subset of mesenchymal tumors of the digestive tract. It has been suggested that these tumors originate from the interstitial cells of Cajal or from their stem celllike precursors [1] . Most GISTs have an activating mutation in the c-kit protooncogene that leads to constitutive expression of Kit protein, a tyrosine kinase specific to the stem cell factor [2] . Therefore, in the context of appropriate morphology, these tumors are best defined by Kit (CD-117)-positive immunostaining. Recently, an activating mutation of platelet-derived growth factor receptor(PDGFR ) was identified to comprise 5% of GISTs [3, 4] . GISTs have a wide range of biological behaviors, including benign, borderline and malignant variants. Approximately 20–25% of gastric and 40–50% of small intestinal GISTs are clinically malignant [5] . The treatment of GIST is complete excision when possible, and treatment with Kit/PDGFR tyrosine kinase inhibitors, such as imatinib, when the tumor is unresectable or in the metastatic setting. The majority of patients can achieve complete or partial remission. Long-term success is limited by the development of imatinib resistance, usually based on secondary mutations in the Kit or PDGFR
tyrosine kinase domains [6, 7] . The most widely examined criteria for evaluating biologic potential of GISTs are tumor size and mitotic activity [8, 9] . Unfortunately, these indices do not guarantee a benign clinical course, as small GISTs with a low mitotic Published online: March 30, 2007