Gastrointestinal Stromal Tumor (GIST)

Gastrointestinal stromal tumors (GISTs) are soft-tissue sarcomas that may arise anywhere along the gastrointestinal tract.1 The most common site is the stomach (50%to 60%) followed by the small intestine (30% to 35%), being less frequent in the colon and rectum (5%), and the oesophagus (<1%).2 On rare occasions (<5%), GISTs are found in extra-visceral locations such as the omentum, mesentery, pelvis and retroperitoneum, although these can be originated from metastases of an undetected primary tumor.2,3

The scientific community collectively recognizes that GISTs originate from interstitial cells of Cajal (ICC) or a common progenitor cell.1,4 ICCs are present throughout the gastrointestinal (GI) tract where they generate spontaneous electrical slow waves to coordinate peristalsis. GISTs develop through oncogenic gain of function mutations in KIT or platelet-derived growth factor receptor (PDGFR) genes that lead to constitutive oncogenic activation of the tyrosine kinase receptor.5 As a result, there is physiological deregulation of cell proliferation or prevention of sensitivity toward apoptotic stimuli.

Several clinical practice guidelines by the National Comprehensive Cancer Network (NCCN),6 the European Society for Medical Oncology (ESMO)7 or from other countries8–10 have been published and updated regularly in order to provide reliable diagnosis and treatment pipelines aiming to improve the prognosis of patients and the quality of medical care, as well as control medical costs.

Clinical Presentation

Although GISTs are usually asymptomatic until they enlarge more than 5 cm,11 clinical identification may occur due to presentation of symptoms, such as gastrointestinal bleeding and subsequent anemia, early satiety, and abdominal pain due to tumor compression.12,13 Nevertheless, around 25% of these tumors are incidentally discovered during imaging studies (endoscopy or radiography) or surgery for other disorders, whereas only a few (about 5%) are found at autopsy.13,14

Diagnostic Imaging

Several imaging methods have been used to diagnose GISTs, including computed tomography (CT scan), magnetic resonance imaging (MRI), positron emission tomography (PET) scan, and ultrasound.15,16 Radiological tests, such as CT scan and MRI are usually the first choice to further evaluate the cause of nonspecific abdominal symptoms or abdominal mass.8,17 When using CT with contrast, GISTs usually appear as hyperdense enhancing solid mass lesions, while a non-contrast CT-scan allows identification of haemorrhage or intratumoral calcification.

By providing better soft-tissue contrast, MRI allows visualization of the mesenteric and peritoneal tumor extension and central necrosis, including hemorrhage, being useful for the local study of tumors, particularly in the pelvic area.18,19 On MRI, small GISTs tend to be round and with increased vascularity, whereas large GISTs appear as lobulated tumors and usually show mild, heterogeneous, gradual enhancement with intratumoral cystic change.

PET scan can provide further information on tumor metabolic activity, as GISTS typically exhibit strong F-fluorodeoxyglucose (FDG) uptake. FDG-PET has high sensitivity in detecting metastases or an otherwise unknown primary site, and for assessing response to tyrosine kinase inhibitor therapy.16 Therefore, the use of PET is usually suggested for baseline staging in patients with a large mass who are at high risk of metastases. Additionally, the use of morphological information provided by CT with PET may be useful for differentiating viable tumors from necrotic tissue, malignant from benign tissue, and recurrent tumor from scar tissue.

Endoscopic contrast-enhanced ultrasound (CE-EUS) is especially valuable for discriminating GIST from benign lesions,20 and in the detection of liver metastases.21 In EUS images, GISTs are usually hypoechoic masses that originate from the proper muscle layer.  Moreover, endoscopic US is a useful method for diagnosing small (<2 cm), incidentally detected submucosal GISTs, by clearly determining the gut wall layers and also allowing EUS-guided tissue acquisition for histological analysis.22

Although imaging tests are useful for narrowing down the differential diagnoses of subepithelial tumors, these techniques are unable to provide a conclusive diagnosis. Thus, a reliable preoperative immunohistological test is necessary. An echoendoscopy-guided-biopsy or a EUS fine needle aspiration endoscopy are usually the techniques of choice for providing a tissue sample for immunohistochemical analysis.23,24 These biopsy sample methods are recommended over transcutaneous biopsy because of the lower risk of perforation and tumor spillage into the abdominal cavity.

Pathological Diagnosis

The pathological diagnosis of GIST depends on the morphology and immunohistochemical findings. GISTs are morphologically defined as spindle cell type (70 % of the cases), epithelioid cell type (20 %), or sometimes pleomorphic tumors arising from the gastrointestinal (GI) stroma/mesenchyma (10%).9,17 These patterns overlap with various other tumours affecting the gastrointestinal tract, including leiomyoma, leiomyosarcoma, desmoid tumor, schwannoma, malignant peripheral nerve sheath tumor, sarcomatoid carcinomas, and even metastatic melanoma. Therefore, immunohistochemical stains are needed to confirm a suspected diagnosis.

GISTs, however, have a characteristic immunohistochemical pattern in that almost all (95%) express the CD117 antigen, which is part of the c-kit tyrosine kinase receptor, and/or Discovered on GIST-1 (DOG1), that encodes the chloride channel protein anoctamin 1.9,17 Some GISTs also stain positive for other markers such as CD34 (60% to 70%) and smooth muscle actin (30% to 40%). Most other GI mesenchymal tumors are negative for CD117, although some sarcomas (angiosarcomas, Ewing’s sarcoma), seminomas, and metastatic melanoma and small cell lung carcinoma can also be immunopositive for c-kit. A small percentage of GISTs (∼5%) will be CD117 negative.

The diagnosis of GIST in these cases is more challenging, and clinical factors such as tumor location and morphology are strongly considered. In addition, some GISTs also stain positive for other markers such as CD34 (60% to 70%) and smooth muscle actin (30% to 40%). Lastly, gene mutation testing can be useful in the diagnosis of GISTS, as nearly 80% and 10 % of GISTs are positive for KIT gene and for the PDGFRA gene, respectively. Approximately 10% of GISTs lack activating mutations in the KIT and PDGFRA genes, being referred to as wild-type GISTs. Wild-type GISTs are heterogeneous in genotype and may include mutations in HRAS, NRAS, BRAF, NF1 or the SDH complex.


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Reviewed by Harshi Dhingra, MD, on 7/1/2021.