Gastrointestinal stromal tumors (GISTs) are transmural mesenchymal tumors with differentiation towards the interstitial cells of Cajal. (2,3) These tumors can arise in any part of the gastrointestinal tract; the most common location is the stomach (54%), followed by the small bowel (30%), the colon and rectum (5%), and the esophagus (1%). (4) Sporadic GISTs most often occur in adults older than 50 (median age 55-60). (5,6) The patients can present with vague abdominal symptoms, gastrointestinal bleeding, symptoms of obstruction, or could be incidentally detected during endoscopy or imaging studies. (6,7)

On cytopathology, GISTs can be encountered on submucosal samples obtained by endoscopic fine needle aspiration procedure of the gastrointestinal tract. Most frequently, GISTs aspirates are composed of fragments of crowded spindle-shaped cells, although some can show an epithelioid morphology. (8) Other findings include a wispy cytoplasm with long extensions, individual cells with stripped nuclei, perinuclear or paranuclear vacuoles, and nuclear palisading. Mitosis and necrosis can also be observed. (9-12) By immunohistochemistry, most GISTs are immunoreactive for CD117 (KIT) and DOG1. (13-17) CD34 is often positive, especially in spindle cell GISTs of the stomach. GISTS can rarely express h-caldesmon, SMA, desmin, keratins (CK18), and S100. (18)

Most GISTs harbor a KIT activating (approximately 75%) mutation, and a small fraction harbors PDGFRA activating (approximately 10%) mutation. (19-24) Tyrosine kinase inhibitors target KIT and PDGFRA mutations, and these are particularly helpful in metastatic or inoperable cases. The first line Tyrosine inhibitor is imatinib; sunitinib and regorafenib are the second and third lines of treatment in patients that develop resistance to imatinib. (25) GISTs can show variable behavior but all are considered potentially malignant. The risk of progression is assessed based on location, size, and mitotic rate. (26)

A subset of GISTs are SDH-deficient; these usually arise in the stomach of young individuals, predominantly in females, have an epithelioid morphology, lack KIT or PDGFRA mutations, and show loss of SDHB protein expression. (27,28) SDH-deficient GISTs more often present with lymphovascular invasion and lymph node metastases; a higher rate of distant metastases has been observed on these tumors. (29) Lastly, GISTs can be found in non-hereditary Carney triad (GIST, paranganglioma, and pulmonary chondroma), Carney-Stratakis syndrome (GIST and paraganglioma), neurofibromatosis type 1, and in familial germline mutation of KIT or PDGFRA. (30-34)