Gastrointestinal stromal tumours. On diagnosis and treatment

Abstract: Gastrointestinal stromal tumours (GIST) are thought to originate from the interstitial cells of Cajal, which show many properties in common with neurons of the gastrointestinal tract. High-risk GIST has a very poor prognosis and tumour recurrence is common after intentionally curative surgery. With recent advances in our understanding of the molecular pathology of this disease and now that a specific KIT tyrosine kinase inhibitor, imatinib, is available, the prognosis for these patients has dramatically changed. A population-based study from western Sweden with a total population of approximately 1.5 million was conducted, and 259 patients with clinically detected GIST were included. The annual incidence of GIST in the region was estimated to be 14.5 per million inhabitants. The majority of patients with high-risk GIST and all those with overtly malignant tumours experienced recurrence after complete (R0) resection. Tumour size, proliferative index (Ki67 max%), R0 resection, and KIT exon 11 deletion were independent prognostic factors. Prediction of prognosis for patients with GIST was simplified by a risk score based on tumour size and Ki67 max%. Early on, we treated patients with high-risk or overtly malignant GIST with imatinib in three different clinical settings (neoadjuvant, adjuvant and palliative) and response to treatment was found to be correlated with KIT mutational status and tumour regression. The response to treatment was studied by functional imaging of tumour glucose uptake using 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET). In one patient, neoadjuvant treatment facilitated later surgical treatment. Adjuvant imatinib seemed promising, but long-term effects on survival must be evaluated in randomised clinical trials. Palliative imatinib was safe and effective, particularly in patients with KIT exon 11 mutations. A 2-tracer PET, using 18F-FDG and 11C-hydroxyephedrine, was used to simultaneously detect GIST and pheochromocytoma in patients with neuroendocrine (NE) tumour syndromes, e.g. Carney triad and neurofibromatosis type 1. GISTs were examined for a possible NE phenotype by immunohistochemistry, western blot and quantitative gene expression studies. GIST showed an abundant expression of synaptic-like microvesicle (SLMV) proteins both at the transcriptional and the translational level. Subsets of GIST appear to express peptide hormone receptors, which may be used for receptor-based radionuclide therapy.In summary, the incidence of GIST was shown to be higher than previously estimated. Radical surgery and KIT exon 11 mutation were important prognosticators. Adjuvant treatment with imatinib seems to be promising in patients with high-risk GIST. Pre-treatment with imatinib is an attractive option in patients with tumours that are non-resectable initially. The 2-tracer PET technique may be useful in patients with NE tumour syndromes. The expression of SLMV proteins in GIST indicates a certain degree of NE differentiation, which has possible potential therapeutic implications.