Gastrointestinal Stromal Tumors - GIST

Diagnostic Algorithm

Clinical Background

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal (GI) tract. These tumors were historically classified as leiomyomas, leiomyosarcomas, leiomyoblastomas and peripheral nerve sheath tumors.

Epidemiology

• Incidence – 10-20/1,000,000
• Age – median age is 60-70 years; rare <21 years
• Sex – M:F equal

Inheritance

• Most tumors are sporadic
• Inherited tumors
  • Familial tumors (patients have c-KIT or platelet-derived growth factor receptor, alpha polypeptide [PDGFRA] mutations most commonly)
  • Neurofibromatosis type 1 (strongly c-KIT positive)
  • Carney triad (rarely c-KIT or PDGFRA mutations)

Pathophysiology

• Tumor originates from the interstitial cells of Cajal, which are the gastrointestinal pacemaker cells
  • Classified as spindle cell, epithelioid cell, and occasionally pleomorphic mesenchymal tumors of the GI tract that express the c-KIT protein (CD117, stem cell factor receptor) or CD34 (sialylated transmembrane glycoprotein) on immunohistochemistry
  • Most common KIT mutation is on exon 11
• Variable malignant potential from low to highly aggressive
• Most common sites are stomach (40-60%) and small intestine (25-40%)
• Tumors usually involve the outer muscular layer; growth tends to be exophytic
• Rarely found extragastrointestinally
  • Known as extragastrointestinal stromal tumors (EGIST)
  • Sites include uterus, vagina, mesentery, omentum, retroperitoneum
• Rare lymph node metastases, distant metastases to liver, and rarely lung or bone

Clinical Presentation

• 30% are asymptomatic – usually small tumors (<2 cm)
• Most common symptom is GI bleeding due to mucosal ulceration
• Gastric GIST – nausea, emesis, weight loss, abdominal discomfort
• Esophageal GIST – odynophagia, dysphagia, retrosternal chest pain, hematemesis
• Small bowel GIST – melena, abdominal pain
• Colorectal GIST – change in bowel habits, hematochezia, abdominal pain and distention
• Carney triad – gastric epithelioid leiomyosarcoma, paraganglioma, pulmonary chondroma
  • Indolent course with high rate of recurrence

Diagnosis

• Indications for testing – patient with gastrointestinal symptoms and suspicious mass on endoscopy or scanning
• Laboratory testing
  • CBC – may demonstrate anemia
• Histology
  • Immunohistochemistry – stains on tissue for KIT immunoreactivity
    • 5-10% are KIT negative
    • KIT positivity alone does not confirm the diagnosis as other spindle cell neoplasms may be KIT positive
    • Classic spindle or epithelioid histology on tissue examination   
• Imaging studies
  • Tumor is often discovered incidentally on imaging
  • Ultrasound – endoscopic ultrasound demonstrates hypoechoic mass that is contiguous with the muscularis propria
  • MRI/CT – demonstrates mass and helps define extension of the tumor

Prognosis

• Adverse tumor prognosis – high mitotic cell count, DNA aneuploidy, c-KIT 11 exon, presence of telomerase activity, large size
• Best response to imatinib therapy – presence of c-KIT 11 exon mutation

Differential Diagnosis

• Desmoid tumor
• Leiomyoma
• Schwannoma
• Leiomyosarcoma
• Neurofibroma
• Inflammatory fibroid polyps
• Ischemic bowel
• Other gastrointestinal cancer
• Solitary fibrous tumor

Pharmacogenetics and Therapeutic Drug Monitoring

Screening

Monitoring

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory

General References

References from the ARUP Institute for Clinical and Experimental Pathology®