Gastrointestinal Stromal Tumors - GIST

Primary Authors: Grossman, Allie, MD, PhD. Samowitz, Wade S., MD. Wallander, Michelle L., PhD.

  • Key Points
  • Diagnosis
  • Background
  • Pediatrics
  • Lab Tests
  • References
  • Related Topics
  • Videos

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 sarcoma, and desmoid fibromatosis).

Immunohistochemistry (IHC) staining for KIT (CD117) identifies most GISTs; the remainders are frequently identified by DOG1 staining. Mutational analysis is most helpful if TKIs are considered for unresectable or metastatic disease, in tumors that test negative for CD117 or DOG1 by IHC, or to identify patients who will likely demonstrate TKI resistance (National Comprehensive Cancer Network [NCCN], 2015). The vast majority (90-95%) of GISTs have a gene mutation (primarily in the KIT gene). PDGFRA and KIT gene mutations are mutually exclusive and cause ligand-independent activation of signal transduction pathways. TKI therapy competitively inhibits the ATP-binding pocket at the catalytic binding site of tyrosine kinase.

Immunohistochemistry

CD117

ARUP Test

CD117 (c-Kit) by Immunohistochemistry 2003806

Occurrence

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

Characteristics

  • Strong staining with diffuse pattern in cytoplasm is typical – may also be dot-like, perinuclear, membranous, or combination pattern
    • 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 IHC

Limitations

  • Does not identify type of mutation – crucial for predicting responsiveness to TKI therapy

DOG1 (ANO1)

ARUP Test

DOG1 by Immunohistochemistry 2010168

Occurrence

  • >90% of adult GISTs

Characteristics

  • Most sensitive in spindle cell subtypes
  • Most useful in KIT-negative tumors – likely to harbor a PDGFRA mutation
    • Staining does not correlate with mutational status

Limitations

  • Does not identify type of PDGFRA gene 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 adult GISTs

Smooth Muscle Actin

ARUP Test

Smooth Muscle Actin (SMA) by Immunohistochemistry 2004130

Occurrence

  • 30-40% of adult GISTs

Characteristics

  • Weak pattern with focal staining

 

Molecular Mutations in KIT and PDGFRA

KIT gene

ARUP Test

Gastrointestinal Stromal Tumor Mutation 2002674

Characteristics

  • Mutations cluster on several exons
    • Exon 11 – most common
    • Exons 9, 13, 14, 17, and 18 – less common
      • D816V mutation on exon 17 – rarely detected
    • Exons 8, 12 – most rare
  • Acquired mutations occur during TKI treatment
    • Exons 13,14, and 17 – most common
    • Exon 18 – less common
    • Mutations decrease binding capacity of TKIs

Therapeutic implications (usual pattern of TKI response)

  • Wild-type KIT GISTs
    • More responsive to sunitinib
  • Exon 9 mutations
    • Requires escalated dose of TKI for response
    • Better response to sunitinib than imatinib
  • Exon 11 mutations
    • TKI sensitivity
  • Exon 13 mutations
    • Primary* – TKI sensitivity
    • Secondary** – TKI resistance
  • Exon 14 mutations
    • Secondary** – TKI resistance
  • Exon 17 mutations
    • Primary* – TKI sensitivity
    • D816V – TKI resistance
    • Secondary** – TKI resistance
  • Exon 18 mutations
    • Rare
    • Secondary** – TKI resistance

*Non-therapy associated

**Mutation acquired during therapy

PDGFRA gene

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 (usual pattern of TKI response)

  • Wild-type PDGFRA
    • TKI resistance
    • More responsive to sunitinib
  • Exons 12, 14 mutations
    • TKI sensitivity
  • Exon 18 mutations
    • TKI resistance

Indications for Testing

  • Gastrointestinal symptoms (satiety, abdominal discomfort due to pain or swelling, intraperitoneal hemorrhage) and suspicious mass on endoscopy or scanning

Laboratory Testing

  • Nonspecific testing – CBC, 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 and molecular testing
    • See Key Points
    • Molecular testing should be performed to confirm mutation suspected based on IHC stain results
    • Tumors lacking KIT or PDGFRA gene mutations (so-called wild type GIST) should be considered for the following
      • BRAF gene mutation
        • BRAF V600, usually exon 15
      • SDH-deficient GIST testing (~40% of all wild type GISTs)
        • SDHB IHC – screen for SDH mutations
        • SDH gene mutation testing confirms mutation type (A, B, C, D)

Genetic Testing

  • Should be considered when (ACMG, 2015)
    • ≥3 close relatives with GIST
    • Wild type GIST
    • ≥3 primary GISTs in same person

Imaging Studies

  • Tumor is often discovered incidentally on imaging
  • Ultrasound
    • High-risk features include irregular border, cystic spaces, ulceration, echogenic foci, and heterogeneity
  • MRI and/or abdominal/pelvic CT with contrast – helps to define extension of tumor
  • PET scan may help differentiate
    • Active tumor from necrotic or inactive scar tissue
    • Malignant from benign tissue
    • 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 confirmation 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

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal (GI) tract, representing ~20% of all sarcomas. These tumors were historically identified as leiomyomas, leiomyosarcomas, leiomyoblastomas, and peripheral nerve sheath tumors.

Epidemiology

  • Incidence – <1/100,000 in the U.S.
  • Age – median is 60-65 years
    • Rarely in children, adolescents – frequently associated with a syndrome
  • Sex – M:F, equal

Inheritance

Pathophysiology

  • Tumor originates from the interstitial cells of Cajal – pacemaker cells that regulate peristalsis in the GI tract
    • Classified as spindle cell (70%), epithelioid cell (20%), and occasionally mixed tumors of the GI tract
    • Variable malignant potential from low to highly aggressive
    • Most common sites are stomach (~60%) and small intestine (30%) (NCCN, 2015)
      • Small number are extraintestinal (omentum, mesentery, retroperitoneal, perineal)
    • Tumors usually involve the outer muscular layer; growth tends to be exophytic
  • Mutations most often involve KIT or PDGFRA genes
    • ~80% of adult GISTs have mutation in the gene encoding the KIT receptor tyrosine kinase
    • 5-10% of adult GISTs have mutation in the gene encoding the related PDGFRA receptor tyrosine kinase
    • 10-15% of adult GISTs have no detectable KIT or PDGFRA mutation
      • Absence of mutation does not rule out diagnosis of GIST
      • Small number of wild-type GISTs (lacking KIT/PDGFRA) have SDH or (SDH deficiency by IHC), or BRAF V600E mutations
        • SDH-deficient tumors tend to metastasize in 50% of time
  • Characteristic patterns of metastases
    • Do not metastasize to lymph nodes (except SDH-deficient GISTs)
    • Frequently metastasize to liver
    • Unusual to metastasize outside of abdomen

Clinical Presentation

  • Asymptomatic
    • ~30% of GISTs
    • Usually small tumors (<2 cm)
  • Most common symptom – GI bleeding due to mucosal ulceration
  • GIST symptoms by subtype
    • 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, and hematemesis (<1% of cases)
  • Carney triad – GIST, paraganglioma, pulmonary chondroma
    • Indolent course with high rate of recurrence

Clinical Background

Epidemiology

  • Prevalence – <1% of GISTs
  • Age – 10-20 years
  • Sex – M<F (marked)
    • In males, tumor aggressiveness tends to follow adult GIST course

Pathophysiology

  • Fundamentally different clinicopathologic entity from adult GISTs
    • Majority have SDH gene mutations
    • 85-90% of pediatric GISTs lack KIT or PDGFRA gene mutations
      • Tyrosine kinase inhibitors (TKIs) are generally less effective
  • Most tumors are in the stomach or small intestine
  • Predominant epithelioid morphology
  • Tumors often spread to liver and peritoneum – neither feature necessarily worsens prognosis

Clinical Presentation

  • Pediatric GISTs usually more indolent than adult GISTs in spite of metastatic disease
  • Abdominal symptoms – nausea, emesis, abdominal pain, and gastrointestinal bleeding
  • Fatigue, pallor, and weakness – due to anemia
  • While inherited syndromes are rare, they are more commonly found in pediatric GISTs

Diagnosis

Indications for Testing

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

Laboratory Testing

  • Nonspecific testing – CBC, liver function tests

Histology

  • Pathologic criteria for predicting malignancy (eg, size, mitotic activity) do not apply in pediatric GISTs
  • IHC – stain for KIT immunoreactivity and SDH mutation, which can be screened for by SDH IHC (usually has loss of expression of SDHA or SDHB)
  • Tissue – epithelioid histology most common; often has low-grade histologic features
  • Mutation analysis – required for all pediatric GISTs, especially those in young adults
    • Presence of KIT or PDGFRA gene mutations supports the diagnosis of GIST and aids in the prediction of response to imatinib
      • KIT and PDGFRA mutations are uncommon in pediatric patients
    • In KIT and PDGFRA negative tumors, SDH gene mutation is necessary
    Lymph node metastasis more common when compared to adults GISTs

Imaging Studies

  • Refer to Diagnosis tab

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.

CD117 (c-Kit) by Immunohistochemistry 2003806
Method: Immunohistochemistry

Limitations

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

GISTs with PDGFRA mutation may have weak KIT IHC staining

Does not identify type of mutation, which is crucial for predicting responsiveness to TKI therapy

Follow Up

Molecular testing required to confirm KIT mutations

DOG1 by Immunohistochemistry 2010168
Method: Immunohistochemistry

Limitations

Does not identify type of mutation – crucial for predicting responsiveness to TKI therapy

Follow Up

Molecular testing for PDGFRA to confirm mutation

SDHB with Interpretation by Immunohistochemistry 2006948
Method: Immunohistochemistry

BRAF Codon 600 Mutation Detection by Pyrosequencing 2002498
Method: Polymerase Chain Reaction/Pyrosequencing

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

Limitations

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

Caldesmon by Immunohistochemistry 2003484
Method: Immunohistochemistry

Smooth Muscle Actin (SMA) by Immunohistochemistry 2004130
Method: Immunohistochemistry

Desmin by Immunohistochemistry 2003863
Method: Immunohistochemistry

S-100 Protein by Immunohistochemistry 2004127
Method: Immunohistochemistry

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

Beta-Catenin-1 by Immunohistochemistry 2003454
Method: Immunohistochemistry

Gastrointestinal Hereditary Cancer Panel, Sequencing and Deletion/Duplication, 15 Genes 2010198
Method: Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray

Limitations

Diagnostic errors can occur due to rare sequence variations

Not determined or evaluated

  • Mutations in genes not included on the panel
  • Deep intronic and regulatory region mutations
  • Breakpoints for large deletions/duplications
  • PMS2 gene (associated with Lynch syndrome) is not included on this panel
  • Sequence changes in EPCAM will not be evaluated

Deletions/duplications may not be detected in exon 1 in CDH1 and MSH2 genes, exons 4, 6, and 7 in STK11 gene, exon 8 in PTEN gene, exon 9 in BMPR1A gene

Individuals with hematological malignancy and/or a previous allogenic bone marrow transplant should not undergo molecular genetic testing on peripheral blood specimen; testing of cultured fibroblasts or buccal specimen is required for accurate interpretation of test results

Lack of a detectable gene mutation does not exclude a diagnosis of hereditary GI cancer syndrome; not all predisposing genes are analyzed

Related Tests

Guidelines

Demetri GD, von Mehren M, Antonescu CR, DeMatteo RP, Ganjoo KN, Maki RG, Pisters PW T, Raut CP, Riedel RF, Schuetze S, Sundar HM, Trent JC, Wayne JD. NCCN Task Force report: update on the management of patients with gastrointestinal stromal tumors. J Natl Compr Canc Netw. 2010; 8 Suppl 2: S1-41; quiz S42-4. PubMed

ESMO/European Sarcoma Network Working Group. Gastrointestinal stromal tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014; 25 Suppl 3: iii21-6. PubMed

Hampel H, Bennett RL, Buchanan A, Pearlman R, Wiesner GL, Guideline Development Group, American College of Medical Genetics and Genomics Professional Practice and Guidelines Committee and National Society of Genetic Counselors Practice Guidelines Committee. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2015; 17(1): 70-87. PubMed

NCCN Clinical Practice Guidelines in Oncology, Soft Tissue Sarcomas. National Comprehensive Cancer Network. Fort Washington, PA [Accessed: Jun 2015]

Protocol for the Examination of Specimens from Patients with Gastrointestinal Stromal Tumor (GIST). Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: February 2010. College of American Pathologists (CAP). Northfield, IL [Accessed: Jun 2015]

General References

Badalamenti G, Rodolico V, Fulfaro F, Cascio S, Cipolla C, Cicero G, Incorvaia L, Sanfilippo M, Intrivici C, Sandonato L, Pantuso G, Latteri MA, Gebbia N, Russo A. Gastrointestinal stromal tumors (GISTs): focus on histopathological diagnosis and biomolecular features. Ann Oncol. 2007; 18 Suppl 6: vi136-40. PubMed

Bayraktar UD, Bayraktar S, Rocha-Lima CM. Molecular basis and management of gastrointestinal stromal tumors. World J Gastroenterol. 2010; 16(22): 2726-34. PubMed

Boikos SA, Stratakis CA. The genetic landscape of gastrointestinal stromal tumor lacking KIT and PDGFRA mutations. Endocrine. 2014; 47(2): 401-8. PubMed

Folpe A, Gown A. Immunohistochemistry for Analysis of Soft Tissue Tumors, Ch 7. In Goldblum JR, Folpe AL, Weiss SW, eds. Enzinger and Weiss's Soft Tissue Tumors, 6th ed. Philadelphia, PA: Elsevier, 2014.

Goldblum J, Folpe A, Weiss S. Approach to the Diagnosis of Soft Tissue Tumors, Ch 6. In Goldblum JR, Folpe AL, Weiss SW, eds. Enzinger and Weiss's Soft Tissue Tumors, 6th ed. Philadelphia, PA: Elsevier, 2014.

Gupta P, Tewari M, Shukla HS. Gastrointestinal stromal tumor. Surg Oncol. 2008; 17(2): 129-38. PubMed

Janeway KA, Weldon CB. Pediatric gastrointestinal stromal tumor. Semin Pediatr Surg. 2012; 21(1): 31-43. PubMed

Joensuu H, Hohenberger P, Corless CL. Gastrointestinal stromal tumour. Lancet. 2013; 382(9896): 973-83. PubMed

Jones DH, Caracciolo JT, Hodul PJ, Strosberg JR, Coppola D, Bui MM. Familial gastrointestinal stromal tumor syndrome: report of 2 cases with KIT exon 11 mutation. Cancer Control. 2015; 22(1): 102-8. PubMed

Ladanyi M, Fletcher J, Cin P. Cytogenetic and Molecular Genetic Pathology of Soft Tissue Tumors, Ch 4. In Goldblum JR, Folpe AL, Weiss SW, eds. Enzinger and Weiss's Soft Tissue Tumors, 6th ed. Philadelphia, PA: Elsevier, 2014.

Laurini JA, Carter E. Gastrointestinal stromal tumors: a review of the literature. Arch Pathol Lab Med. 2010; 134(1): 134-41. PubMed

Layfield LJ, Wallander ML. Diagnosis of gastrointestinal stromal tumors from minute specimens: cytomorphology, immunohistochemistry, and molecular diagnostic findings. Diagn Cytopathol. 2012; 40(6): 484-90. PubMed

Martín-Broto J, Rubio L, Alemany R, López-Guerrero JAntonio. Clinical implications of KIT and PDGFRA genotyping in GIST. Clin Transl Oncol. 2010; 12(10): 670-6. PubMed

Miettinen M, Lasota J. Gastrointestinal stromal tumors. Gastroenterol Clin North Am. 2013; 42(2): 399-415. PubMed

Patil DT, Rubin BP. Gastrointestinal stromal tumor: advances in diagnosis and management. Arch Pathol Lab Med. 2011; 135(10): 1298-310. PubMed

Postow MA, Robson ME. Inherited gastrointestinal stromal tumor syndromes: mutations, clinical features, and therapeutic implications. Clin Sarcoma Res. 2012; 2(1): 16. PubMed

Rubin B. GIST and EGIST, Ch 18. In Goldblum JR, Folpe AL, Weiss SW. Enzinger and Weiss's Soft Tissue Tumors, 6th ed. Philadelphia, PA: Elsevier, 2014.

References from the ARUP Institute for Clinical and Experimental Pathology®

Chen LL, Chen X, Choi H, Sang H, Chen LC, Zhang H, Gouw L, Andtbacka RH, Chan BK, Rodesch CK, Jimenez A, Cano P, Jones KA, Oyedeji CO, Martins T, Hill HR, Schumacher J, Willmore C, Scaife CL, Ward JH, Morton K, Randall L, Lazar AJ, Patel S, Trent JC, Frazier ML, Lin P, Jensen P, Benjamin RS. Exploiting antitumor immunity to overcome relapse and improve remission duration. Cancer Immunol Immunother. 2012; 61(7): 1113-24. PubMed

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): 52-6. PubMed

Layfield LJ, Wallander ML. Diagnosis of gastrointestinal stromal tumors from minute specimens: cytomorphology, immunohistochemistry, and molecular diagnostic findings. Diagn Cytopathol. 2012; 40(6): 484-90. PubMed

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Last Update: April 2016