What is a Gastrointestinal Stromal Tumor (GIST)?

From the Guidelines

Gastrointestinal Stromal Tumors (GISTs) are the most common soft tissue sarcomas of the gastrointestinal tract, primarily caused by activating mutations in the KIT or PDGFRA genes.

Characteristics of GISTs

• They have a characteristic morphology and are generally positive for CD117 (c-kit) 1
• They can occur in the digestive tract, as well as in extra-visceral locations such as the omentum, mesentery, pelvis, and retroperitoneum 1
• The incidence of GIST is rare, with significant variations in reported incidence, but recent data suggest an incidence of about eight cases per million per year 1

Causes and Associated Syndromes

• GISTs are primarily caused by activating mutations in the KIT or PDGFRA genes 1
• They can be associated with certain syndromes, such as:

• Carney triad syndrome, marked by hypermethylation of the SDHC gene and clinically characterized by multifocal gastric GISTs, paraganglioma, and pulmonary chondromas 1
• Carney-Stratakis syndrome, marked by a germline mutation of one of the subunit genes of the SDH enzyme complex and clinically characterized by a dyad of multifocal gastric GIST and paraganglioma 1
• Type 1 neurofibromatosis (NF1), marked by a germline mutation of the NF1 gene, possibly leading to often multicentric GIST, predominantly located in the small bowel 1

Treatment and Prognosis

• Targeted therapy, such as imatinib, has revolutionized the treatment of advanced GIST and has increased median survival from 18 to more than 60 months 1
• Surgery remains a mainstay of treatment to obtain a permanent cure for GIST, even in the era of targeted therapy 1
• Other drugs, such as sunitinib and regorafenib, have been registered as second- and third-line treatment for metastatic GIST 1

From the Research

Definition and Characteristics of GIST

• Gastrointestinal Stromal Tumors (GISTs) are the most common mesenchymal tumors of the GI tract, arising from the interstitial cells of Cajal, primarily in the stomach and small intestine 2, 3, 4.
• GISTs manifest a wide range of morphologies, from spindle cell to epithelioid, but are immunopositive for KIT (CD117) and/or DOG1 in essentially all cases 2.
• The growth of most GISTs is driven by oncogenic mutations in either of two receptor tyrosine kinases: KIT (75% of cases) or PDGFRA (10%) 2, 5.

Clinical Presentation and Treatment

• Although most tumors are localized at presentation, up to half will recur in the abdomen or spread to the liver 2.
• Treatment with tyrosine kinase inhibitors (TKIs) such as imatinib, sunitinib, and regorafenib is effective in controlling unresectable disease 2, 5, 6.
• Adjuvant therapy with imatinib is commonly used to reduce the likelihood of disease recurrence after primary surgery 2.
• Surgery is the only curative treatment for localized disease, and several targeted therapies have also improved survival in GIST patients after progression on imatinib 6.

Prognostic Factors and Survival

• Tumor size and mitotic count are important prognostic parameters 3.
• The 5-year survival rate for GIST patients is 74%, and the 5-year cause-specific survival rate is 82% 4.
• Factors associated with worse overall survival include tumor size > 5 cm, poorly and undifferentiated grade, age > 60, and distant metastases at presentation 4.

Molecular Genetics and Targeted Therapy

• Routine genotyping is strongly recommended for optimal management of GISTs, as the type and dose of TKI used for treatment is dependent on the mutation identified 2.
• Approximately 15% of GISTs are negative for mutations in KIT and PDGFRA, and recent studies have uncovered other oncogenic drivers, including mutations in neurofibromatosis type I, RAS genes, BRAF, and subunits of the succinate dehydrogenase complex 2.
• New tyrosine kinase inhibitors, such as avapritinib and ripretinib, have been approved for the treatment of heavily pretreated advanced/unresectable GIST 6.