Gastrointestinal Stromal Tumors - GIST

Primary Author Wallander, Michelle, PhD.

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)
IMMUNOHISTOCHEMISTRY

CD117 (c-Kit)

ARUP test: 

CD117 (c-Kit) by Immunohistochemistry 2003806

Occurrence

  • 90-95% of GISTs
  • Excellent screen for KIT mutation

Characteristics

  • Strong staining with diffuse pattern in cytoplasm typical; may also be dot-like, perinuclear, or membranous
    • Staining intensity does not correlate with treatment sensitivity or mutational status
  • Other tumors (eg, melanoma, synovial sarcoma) may also stain positive, so histology should be correlated with immunohistochemistry

Limitations

  • Does not identify type of mutation – crucial for predicting responsiveness to TKI therapy
Other markers (may be helpful in questionable histology)

CD34

ARUP test:

CD34, QBEnd/10 by Immunohistochemistry 2003556

Occurrence

  • 60-70% of GISTs

Smooth Muscle Actin

ARUP test:

Smooth Muscle Actin (SMA) by Immunohistochemistry 2004130

Occurrence

  • 30-40% of GISTs

Characteristics

  • Weak pattern with focal staining
DOG1 (ANO1)

Occurrence

  • >75% of GISTs

Characteristics

  • Most sensitive in spindle cell subtypes
  • Frequently positive in c-Kit negative tumors that harbor a PDGFRA mutation
  • Molecular mutations in KIT and PDGFRA (see table below)
MOLECULAR MUTATIONS IN KIT AND PDGFRA

KIT gene (type 3 membrane tyrosine kinase receptor)

ARUP test:

Gastrointestinal Stromal Tumor Mutation 2002674

Characteristics

  • Mutations cluster most commonly on exon 11; less commonly on exons 9, 13, and 17
    • D816V mutation on exon 17 rarely detected
  • Acquired mutations occur during TKI treatment on exons 13,14, and 17
    • Mutations decrease binding capacity of TKIs

Therapeutic implications

  • Exon 11 mutation
    • Associated with TKI sensitivity
  • Exon 13 mutation
    • Primary (non-therapy associated) – associated with TKI sensitivity
    • Secondary (acquired during therapy) – associated with TKI resistance
  • Exon 9 mutation
    • Requires escalated dose of TKI for response
    • Better response to sunitinib than imatinib
  • Exon 17 mutation
    • Primary – associated with TKI sensitivity
    • D816V – associated with TKI resistance
    • Secondary – associated with TKI resistance 
  • Wild-type-KIT GISTs
    • More responsive to sunitinib

PDGFRA gene (platelet-derived growth factor receptor alpha)

ARUP test:

Gastrointestinal Stromal Tumor Mutation 2002674

Characteristics

  • Mutations cluster on exons 12, 14, and 18
    • Exon 18 most common
      • D842V and D846V mutations

Therapeutic implications

  • Wild-type PDGFRA – associated with TKI resistance
  • Wild-type PDGFRA GISTs – more responsive to sunitinib

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
    • Necessary for therapeutic decisions
  • 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

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
Test Name and Number Recommended Use Limitations Follow Up
CD117 (c-Kit) by Immunohistochemistry 2003806
Method: Immunohistochemistry
Initial screening test in tumor that is morphologically and clinically suspicious for GIST

Not specific for GIST; may also be found in melanoma, angiosarcoma, and Ewing sarcoma

Molecular testing for KIT required to confirm mutations

Gastrointestinal Stromal Tumor Mutation 2002674
Method: Polymerase Chain Reaction/Sequencing

Diagnostic evaluation for all GISTs

Provide prognostic and predictive information for tyrosine kinase inhibitor (TKI) therapy planning

Clinical sensitivity – mutations detected in >85% of GISTs (70% KIT and 15% PDGFRA)

Analytical sensitivity – 25% mutant alleles (50% tumor)

Mutations outside of targeted exons are not detected

Test alone cannot be used for diagnosis of malignancy

 
CD34, QBEnd/10 by Immunohistochemistry 2003556
Method: Immunohistochemistry
Aid in histologic diagnosis of GIST    
Caldesmon by Immunohistochemistry 2003484
Method: Immunohistochemistry

Aid in histologic diagnosis of GIST

Stained and returned to client pathologist; consultation available if needed

   
Smooth Muscle Actin (SMA) by Immunohistochemistry 2004130
Method: Immunohistochemistry
Aid in histologic diagnosis of GIST    
Desmin by Immunohistochemistry 2003863
Method: Immunohistochemistry

Aid in histologic diagnosis of GIST

Use to differentiate GISTs from smooth muscle tumors

   
S-100 Protein by Immunohistochemistry 2004127
Method: Immunohistochemistry

Aid in histologic diagnosis of GIST

Use to differentiate GIST from malignant melanoma and schwannoma

   
Glial Fibrillary Acidic Protein (GFAP) by Immunohistochemistry 2003899
Method: Immunohistochemistry

Aid in histologic diagnosis of GIST

Stained and returned to client pathologist; consultation available if needed

   
Beta-Catenin-1 by Immunohistochemistry 2003454
Method: Immunohistochemistry

Aid in histologic diagnosis of GIST

Differentiate GIST from desmoid-type fibromatosis

Stained and returned to client pathologist; consultation available if needed

   
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
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