Gastrointestinal Stromal Tumors - GIST

Diagnosis

Indications for Testing

• Patient with gastrointestinal symptoms (satiety, abdominal discomfort due to pain or swelling, intra-peritoneal hemorrhage) and suspicious mass on endoscopy or scanning

Laboratory Testing

• CBC – may demonstrate anemia
• Liver function tests

Histology

• GISTs are soft and fragile tumors; biopsy may cause tumor hemorrhage and possible increased risk for tumor dissemination
  • Consideration of biopsy should be based on extent of disease and suspicion of a given histologic subtype
• Immunohistochemistry
  • CD117 (KIT)
    • Most demonstrate strong and diffuse cytoplasmic staining; may have membranous or paranuclear stain
    • 5-10% are KIT negative (half of these cases show KIT or PDGFRA genetic mutations)
      • KIT-negative GISTs typically occur in the stomach
    • KIT positivity alone does not confirm diagnosis; other spindle cell neoplasms may be KIT positive
    • Tissue examination
      • Classic spindle or epithelioid histology
        • KIT-negative tumor typically shows epithelioid or mixed pattern
          • KIT or PDGFRA mutations are characteristic of GIST
    • CD117 stains may become weaker after imatinib therapy
  • Others
    • • CD34 – positive in 80%
      • Caldesmon – positive in up to 85%
      • Smooth muscle actin (SMA) – positive in up to 30%
        • Smooth muscle phenotype becomes more common after TKI therapy
  • Differential markers
    • Desmin – rarely seen in GIST; usually indicates smooth muscle tumor
    • S-100 protein, glial fibrillary acidic protein (GFAP) – seen in schwannomas
    • Beta-catenin-1 – seen in desmoid fibromatosis
• Other
  • Patient should be evaluated by a multidisciplinary team with expertise in sarcoma

Imaging Studies

• Tumor is often discovered incidentally on imaging
• Ultrasound – endoscopic ultrasound demonstrates hypoechoic mass that is contiguous with the muscularis propria
  • High-risk features include irregular border, cystic spaces, ulceration, echogenic foci, and heterogeneity
• MRI and/or abdominal/pelvic CT with contrast – demonstrates mass and helps define extension of tumor
• PET scan – may help differentiate active tumor from necrotic or inactive scar tissue, malignant from benign tissue, and recurrent tumor from nondescript benign changes
  • PET is not a substitute for CT but may clarify ambiguous CT or MRI findings

Prognosis

• Adverse tumor prognosis based on high mitotic cell count, large size, site
• Gastric GISTs have more favorable prognosis than intestinal GISTs
• Refer to the National Cancer Institute's risk stratification of primary GIST by mitotic index, size, and site  
• Molecular genetics
  • Mutational status has both prognostic/diagnostic significance and impact on response to TKI therapy (might be negative after therapy)
  • Primary mutations (detected prior to therapy)
    • KIT exons 11, 9, 13, 17
    • PDGFRA exons 18, 12, 14
  • Acquired resistance to TKIs
    • KIT exons 13, 14, 17
    • PDGFRA exon 18
  • Exon 11 of KIT – mutation in 70-75% of GISTs
    • Better response to imatinib therapy
  • Exon 9 of KIT – mutation in 9-20% of GISTs
    • Related to highly malignant behavior
    • Increased dosage to imatinib probably necessary
    • Best response to sunitinib therapy
  • Exon 13 of KIT – mutation in 0.8-4.1% of GISTs
  • Exon 17 of KIT – mutation in 1% of GISTs
  • Primary resistance to imatinib is seen in ~10% of GISTs
  • Mutation type is therapeutically predictive
    • TKI binding and inactivation of KIT is maximal for exon 11 mutations and intermediate for exon 9 mutations; other mutations show little or no response to imatinib

Differential Diagnosis

• Desmoid fibromatosis
• Leiomyoma
• Schwannoma
• Leiomyosarcoma
• Neurofibroma
• Inflammatory fibroid polyps
• Inflammatory myofibroblastic tumors
• Ischemic bowel
• Other gastrointestinal cancer – colorectal, gastric, pancreatic
• Solitary fibrous tumor

Clinical Background

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal (GI) tract. They represent about 5% of all sarcomas.  These tumors were historically identified as leiomyomas, leiomyosarcomas, leiomyoblastomas and peripheral nerve sheath tumors.

Epidemiology

• Incidence – 5,000 annually in the U.S.
• Age – median age is 60-70 years; rare <21 years
• Sex – M:F, equal

Inheritance

• Most tumors are sporadic
  • Carney triad – KIT or PDGFRA mutations rare
    • More common in women
    • Multifocal disease within stomach
    • Affects <100 people globally
    • Not inherited
    • Shares features similar to pediatric GISTs (lacks defined mechanism of KIT activation)
• Inherited tumors
  • Familial tumors (germline KIT or PDGFRA mutations most common)
    • Median age of onset is 47 years
    • 90% chance of GIST diagnosis by age 70
  • Neurofibromatosis type 1 (strongly KIT positive by immunohistochemistry but wild-type KIT genetically)
    • 25% chance of developing GIST
  • Carney dyad (Carney-Stratakis GISTs) – KIT or PDGFRA mutations rare
    • GIST and paraganglioma dominantly inherited (SDH gene mutation)

Pathophysiology

• Tumor originates from the interstitial cells of Cajal, which are the gastrointestinal pacemaker cells
  • Classified as spindle cell (70%), epithelioid cell (20%), and occasionally mixed tumors of the GI tract that express the KIT gene protein (CD117, stem cell factor receptor), or CD34 (sialylated transmembrane glycoprotein) on immunohistochemistry
  • Mutations involve KIT and PDGFRA genes (maps to chromosome 4q12)
    • ~80% of GISTs have mutation in the gene encoding the KIT receptor tyrosine kinase
    • 5-10% of GISTs have mutation in the gene encoding the related PDGFRA receptor tyrosine kinase
    • 10-15% of GISTs have no detectable KIT or PDGFRA mutation; however, absence of mutation does not rule out diagnosis of GIST
• Variable malignant potential from low to highly aggressive
• Most common sites are stomach (60%) and small intestine (30%)
• 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 (60% of cases)
• Small bowel GIST – melena, abdominal pain (30% of cases)
• Colorectal GIST – change in bowel habits, hematochezia, abdominal pain and distention (~10% of cases)
• Esophageal GIST – odynophagia, dysphagia, retrosternal chest pain, hematemesis (<1% of cases)
• Carney triad – paraganglioma, pulmonary chondroma and GIST
  • Indolent course with high rate of recurrence

Pediatrics

Clinical Background

Epidemiology

• Prevalence – 1-2% of GISTs
• Age – 10-20 years
• Sex – M<F (marked)

Pathophysiology

• Fundamentally different clinicopathologic entity from adult GISTs
• Most tumors are in the stomach or small intestine
• Predominant epithelioid morphology is spindle cell, but epithelioid variants predominate in stomach
• Tumors often spread to liver and peritoneum
• 90% of pediatric GISTs lack KIT or PDGFRA mutations; tyrosine kinase inhibitors (TKIs) are generally less effective

Clinical Presentation

• Pediatric GISTs are generally more indolent than adult type
• Abdominal symptoms – nausea, emesis, abdominal pain, gastrointestinal bleeding
• Fatigue, pallor, weakness-due to anemia
• May be associated with pulmonary chondromas or paragangliomas (Carney triad)

Treatment

• Treatment algorithms for adults do not apply

Diagnosis

Indications for Testing

• Patient with gastrointestinal symptoms and suspicious mass on endoscopy or scanning

Laboratory Testing

• CBC – may demonstrate anemia
• Liver function tests
• Mutation analysis is required for all pediatric GISTs, especially those in young adults

Histology

• Pathologic criteria for predicting malignancy (ie, size, mitotic activity) do not apply in pediatric GISTs
• Immunohistochemistry – stains for KIT immunoreactivity
• Tissue – spindle or epithelioid tumor histology; often have low-grade histologic features
• Mutation detection – presence of KIT or PDGFRA mutations supports the diagnosis of GIST and aids in the prediction of response to imatinib
• Lymph node metastases are not common (in contrast to adults)

Imaging Studies

• Refer to Diagnosis tab

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