Supplementary mutations involve exon 18 (Asp842Val). with KIT and PDGFRA receptors or with the downstream-signalling proteins. or activating mutations [1C6]. Recent population-based studies in Europe revealed annual incidences of 10C20 per million, and the prevalence was estimated at 129 per million [7C9]. About 4500C6000 new cases of GIST are diagnosed each year in the USA . GISTs have an equal sex predilection, and most tumours occur in individuals over the age of 50. GISTs are very rare in children (<1%) [1, 2, 11, 12]. GIST occurs throughout Ophiopogonin D' the gastrointestinal tract. The most common sites are the stomach (50%) and small bowel (25%). Approximately 10% of GISTs arise in the colon and rectum and 5% within the oesophagus. About 10% of the cases occur outside of the Ophiopogonin D' gastrointestinal tract (extra-gastrointestinal GISTs), mainly in the mesentery, omentum, Ophiopogonin D’ retroperitoneum and pelvis [1, 2, 13C20]. The most common clinical presentation of GIST is gastrointestinal bleeding. Acute abdomen due to tumour rupture, obstruction, appendicitis-like pain, early satiety, bloating or fatigue related to anaemia can occur. Smaller GISTs are often incidental findings during surgery, radiologic studies or endoscopic procedures. Aggressive tumours generally metastasize to the liver or disseminate throughout the abdomen, and they rarely metastasize to lymph nodes or spread outside of the abdominal cavity [1, 2, 13]. GISTs range in Ophiopogonin D’ size from less than 10 mm (GIST tumorlets) to very large lesions (>350 mm), and the median size is approximately 50 mm. Small GISTs often form solid subserosal, intramural or polypoid intraluminal masses. Larger GISTs form external, pedunculated masses attached to outer aspect of gastrointestinal structures. They are usually uninodular but multiple nodules may occur. Cystic degeneration, haemorrhage or necrosis can be found, generally in larger tumours [1, 2]. GISTs are usually cytologically monomorphic and exhibit spindle cell or epithelioid cell cytomorphology, as well as a mixed pattern consisting of both spindle and epithelioid cells . Epithelioid and mixed spindle and epithelioid GISTs are more common in the stomach . Spindle cell GISTs are generally arranged in fascicles, and epithelioid tumours are often arranged in nests or sheets. The stroma can be hyalinized or myxoid. Histological features that can be seen in GISTs are paranuclear vacuoles, nuclear palisading mimicking schwannoma, neuroendocrine-like morphology mimicking paraganglioma or carcinoid tumour, and skeinoid fibres, MMP19 hyaline eosinophilic cytoplasmic structures that are found predominantly in small bowel GISTs [1, 2, 13]. Approximately 96% of GISTs are positive for KIT (CD117) by immunohistochemistry. CD34 can be expressed by 60C70% of the tumours, and smooth muscle actin (SMA) expression is detected in 30C40% of the cases. S100 protein, keratins and desmin are rarely expressed in GISTs (up to 5%) [1C3, 10, 13, 21C23]. Recently, gene expression profiling studies found that the DOG1 (Discovered On GIST-1) protein was ubiquitously expressed in GISTs, regardless of mutation status . Subsequently, several studies found that DOG1 is a sensitive immunohistochemical marker for GIST, being rarely expressed in other mesenchymal tumours [25C27]. The main differential diagnosis of GIST includes smooth muscle tumours (leiomyoma and leiomyosarcoma), nerve sheath tumours (schwannoma and neurofibroma), inflammatory fibroid polyp and desmoid fibromatosis. These tumours are almost invariably negative for KIT (CD117) by immunohistochemistry. Moreover, smooth muscle tumours and nerve sheath tumours are diffusely positive for desmin and S100 protein, respectively. Inflammatory fibroid polyp can be positive for CD34, but.