Gastrointestinal Stromal Tumors - GIST

Key Points

The advent of tyrosine kinase inhibitor (TKI) therapy for the treatment of gastrointestinal stromal tumors (GISTs) makes it imperative to distinguish GISTs from histologic mimics (eg, leiomyoma, leiomyosarcoma, schwannoma, high grade sarcomas and desmoid fibromatosis).

Immunohistochemistry staining for c-KIT identifies most GISTs. Mutational analysis is most helpful if TKIs are considered for unresectable or metastatic disease, in tumors which test negative for CD117 by immunohistochemistry or to identify patients who will likely demonstrate TKI resistance (NCCN 2010). 90-95% of GISTS will have a mutation (the majority of mutations are KIT); PDGFRA and KIT gene mutations are mutually exclusive. KIT and PDGFRA mutations cause ligand-independent activation of signal transduction pathways. TKI therapy competitively inhibits the ATP-binding pocket of KIT and PDGFRA.

• Immunohistochemistry (see table below)

• Molecular mutations in KIT and PDGFRA (see table below)

Diagnosis

Indications for Testing

• Patient with gastrointestinal symptoms (satiety, abdominal discomfort due to pain or swelling, intraperitoneal 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
    • 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 tyrosine kinase inhibitor (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
• Molecular testing – GIST mutation analysis
  • KIT or PDGFRA mutations are characteristic of GIST
  • KIT immunohistochemistry positivity alone does not confirm diagnosis; other spindle cell neoplasms may be KIT positive
  • 5-10% are KIT negative (half of these cases show KIT or PDGFRA genetic mutations)
    • KIT-negative GISTs typically occur in the stomach and show epithelioid or mixed pattern
• 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
• Percutaneous image-guided biopsy may be appropriate for confirmations of metastatic disease

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
  • Primary mutations (detected prior to therapy)
    • KIT exons 11, 9, 13, 17
      • Exon 11 – 70-75% of GISTs
      • Exon 9 – 9-20% of GISTs
      • Exon 13 – 0.8-4.1% of GISTs
      • Exon 17 – 1% of GISTs
    • PDGFRA exons 18, 12, 14
  • Acquired resistance to TKIs
    • KIT exons 13, 14, 17
    • PDGFRA exon 18
  • Exon mutation is therapeutically predictive for response to TKIs (might become negative after therapy)
    • Primary resistance to imatinib is seen in ~10% of GISTs
    • TKI binding and inactivation of KIT is maximal for exon 11 mutations, intermediate for exon 9 mutations; other mutations show little or no response to imatinib
      • Exon 9
        • Related to highly malignant behavior
        • Increased dosage with imatinib usually necessary for therapeutic response
        • Best response to sunitinib therapy

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 ~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

• Sporadic tumors (most common)
  • 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 or 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
• Metastases
  • 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 – 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

Histology

• Pathologic criteria for predicting malignancy (ie, size, mitotic activity) do not apply in pediatric GISTs
• Immunohistochemistry – stain for KIT immunoreactivity
• Tissue – spindle or epithelioid tumor histology; often have low-grade histologic features
• Mutation analysis – required for all pediatric GISTs, especially those in young adults
  • 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

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
CBC with Platelet Count and Automated Differential 0040003 Method: Automated Cell Count/Differential	Use to determine presence of anemia
Hepatic Function Panel 0020416 Method: Quantitative Enzymatic/Quantitative Spectrophotometry	Use to monitor liver function
Solid Tumor Mutation Panel by Next Generation Sequencing 2007991 Method: Massively Parallel Sequencing	Prognosis/treatment of individuals with solid tumor cancers at initial diagnosis or with refractory disease