Gastrointestinal Stromal Tumors

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

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 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

Tests generally appear in the order most useful for common clinical situations

Test name: CBC with Platelet Count & Automated Differential

ARUP #: 0040003

Methodology: Automated Cell Count with Flow Cell Differential

Use:

Determine presence of anemia

Test name: Hepatic Function Panel

ARUP #: 0020416

Methodology: Refer to individual components.

Use:

Monitor liver function

Test name: Gastrointestinal Stromal Tumor Mutation

ARUP #: 2002674

Methodology: Polymerase Chain Reaction/High Resolution Melt Analysis

Use:

Determine presence of KIT and PDGFRA mutations

85% of adult GISTs have KIT or PDGFRA mutation

Limitations:

90% of pediatric GISTs are mutation negative

Test name: CD117 (c-Kit) by Immunohistochemistry

ARUP #: 2003806

Methodology: Immunohistochemistry

Use:

Aid in histologic diagnosis of GIST

5-10% of GISTs are CD117 negative by immunohistochemistry (IHC)

Melanoma, angiosarcoma (50%) and Ewing sarcoma (30%) are CD117 positive

Test name: CD34, QBEnd/10 by Immunohistochemistry

ARUP #: 2003556

Methodology: Immunohistochemistry

Use:

Aid in histologic diagnosis of GIST

GISTs are negative for CD34 by IHC in 30% of cases

Test name: Caldesmon by Immunohistochemistry

ARUP #: 2003484

Methodology: Immunohistochemistry

Use:

Aid in histologic diagnosis of GIST

Stained and returned to client pathologist; consultation available if needed

Test name: Smooth Muscle Actin (SMA) by Immunohistochemistry

ARUP #: 2004130

Methodology: Immunohistochemistry

Use:

Aid in histologic diagnosis of GIST

GISTs are positive for SMA in 30% of cases

Test name: Desmin by Immunohistochemistry

ARUP #: 2003863

Methodology: Immunohistochemistry

Use:

Aid in histologic diagnosis of GIST

GISTs are positive for desmin in <5% of cases; useful for differentiating GISTs from smooth muscle tumors

Test name: S-100 Protein by Immunohistochemistry

ARUP #: 2004127

Methodology: Immunohistochemistry

Use:

Aid in histologic diagnosis of GIST

GISTs are positive for S-100 in <5% of cases; useful for differentiating GIST from malignant melanoma and schwannoma

Test name: Glial Fibrillary Acidic Protein (GFAP) by Immunohistochemistry

ARUP #: 2003899

Methodology: Immunohistochemistry

Use:

Aid in histologic diagnosis of GIST

Stained and returned to client pathologist; consultation available if needed

Test name: Beta-Catenin-1 by Immunohistochemistry

ARUP #: 2003454

Methodology: Immunohistochemistry

Use:

Aid in histologic diagnosis of GIST

Differentiate GIST from desmoid-type fibromatosis

Stained and returned to client pathologist; consultation available if needed

Guidelines

General

ARUP Institute for Clinical and Experimental Pathology®

Isaac JC, Willmore C, Holden JA, Layfield LJ. A c-kit-negative gastrointestinal stromal tumor with a platelet-derived growth factor receptor alpha mutation. Appl Immunohistochem Mol Morphol. 2006; 14 (1) :52-56.PubMed

Comprehensive Review: July 2011
Last Update: July 2011

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