Gastrointestinal Stromal Tumors - GIST

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal (GI) tract, representing ~20% of all sarcomas. Common mutations occurring in KIT and PGFRA, which are both highly expressed in these tumors, result in constitutive tyrosine kinase activity and make the tumors sensitive to tyrosine kinase inhibitors (TKIs), with some exceptions.

  • Key Points
  • Diagnosis
  • Background
  • Pediatrics
  • Lab Tests
  • References
  • Related Topics
  • Videos
Primary Authors: Grossman, Allie, MD, PhD. Samowitz, Wade S., MD. Wallander, Michelle L., PhD.

The use of tyrosine kinase inhibitor (TKI) therapy for the treatment of advanced 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. When TKIs are considered for unresectable or metastatic disease in tumors that test negative for CD117 or DOG1 by IHC, mutational analysis is necessary to identify patients who will likely demonstrate TKI resistance (National Comprehensive Cancer Network [NCCN], 2017). 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.



CD117 (c-Kit) by Immunohistochemistry 2003806


  • 97% of adult GISTs (NCCN, 2017)
  • Excellent screen for KIT mutation


  • 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 must be correlated with IHC


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


DOG1 by Immunohistochemistry 2010168


  • 99% of adult GISTs (NCCN, 2017)


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


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


CD34, QBEnd/10 by Immunohistochemistry 2003556


  • 81% of adult GISTs (NCCN, 2017)

Smooth Muscle Actin

Smooth Muscle Actin (SMA) by Immunohistochemistry 2004130


  • 30-40% of adult GISTs


  • Weak pattern with focal staining
aAll linked tests are offered by ARUP Laboratories


Molecular Mutationsa

KIT gene

Gastrointestinal Stromal Tumor Mutation 2002674


  • Mutations cluster on several exons
    • Exon 11 – most common
    • Exons 9, 13, 14, 17, 18 – less common
      • D816V mutation on exon 17 – rarely detected
    • Exons 8, 12 – most rare
  • Acquired mutations occur during TKI treatment
    • Exons 13,14, 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
    • Primaryb – TKI sensitivity
    • Secondaryc – TKI resistance
  • Exon 14 mutations
    • Secondaryc – TKI resistance
  • Exon 17 mutations
    • Primary – TKI sensitivity
    • D816V – TKI resistance
    • Secondary – TKI resistance
  • Exon 18 mutations
    • Rare
    • Secondaryc – TKI resistance


Gastrointestinal Stromal Tumor Mutation 2002674


  • Mutations cluster on exons 12, 14, 18
    • Exon 18 – most common
      • D842V – imatinib resistance
      • D846V – TKI sensitive

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

BRAF gene

BRAF Codon 600 Mutation Detection by Pyrosequencing 2002498


  • ~10% of wild type GISTs (lacking KIT/PDGFRA)
  • V600E; usually exon 15

Therapeutic implications

  • Clinical trials with BRAF inhibitors in place

SDH gene

SDHB with Interpretation by Immunohistochemistry 2006948


  • ~40% of wild type GISTs (lacking KIT/PDGFRA)
  • SDHB IHC – screens for mutations

Therapeutic implications

Clinical trials in place to evaluate other therapies (eg, anti-EGFR agents)

aAll linked tests are offered by ARUP Laboratories

bNontherapy associated

cMutation acquired during therapy

Indications for Testing

  • Gastrointestinal (GI) symptoms
    • Satiety
    • GI bleed
    • Abdominal discomfort or acute abdomen
    • GI obstruction
    • Dysphagia
  • Suspicious mass on endoscopy or scanning
  • Incidentally noted gastrointestinal lesion

Criteria for diagnosis

  • Dependent on tumor morphology and immunohistochemistry (ESMO, 2014)

Laboratory Testing

  • Nonspecific testing – CBC, liver function tests


  • Gastrointestinal stromal tumors (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

Familial Genetic Testing

  • Should be considered when (ACMG, 2015)
    • ≥3 close relatives with GIST
    • Wild-type GIST
    • ≥3 primary GISTs in same person
  • Testing for KIT/PDGFRA suggested (ACMG, 2015)

Imaging Studies

  • Abdominal/pelvic CT with contrast – preferred imaging
  • Magnetic resonance imaging (MRI) of abdomen – alternative to CT, especially for rectal
  • Endoscopic ultrasound
    • High-risk features include irregular border, cystic spaces, ulceration, echogenic foci, and heterogeneity
  • Fluorodeoxyglucose positron emission tomography (FDG-PET) scan (not a substitute for CT but may clarify ambiguous CT or MRI findings) may help differentiate
    • Active tumor from necrotic or inactive scar tissue
    • Malignant from benign tissue
    • Recurrent tumor from nondescript benign changes


Differential Diagnosis

  • Desmoid fibromatosis
  • Leiomyoma
  • Schwannoma
  • Leiomyosarcoma
  • Neurofibroma
  • Inflammatory fibroid polyps
  • Inflammatory myofibroblastic tumors
  • Ischemic bowel
  • Other gastrointestinal adenocarcinoma  – colorectal, gastric, pancreatic
  • Neuroendocrine tumor
  • Solitary fibrous tumor
  • Malignant peripheral-nerve sheath tumor
  • Inflammatory myofibroblastic tumor
  • Fibromatosis
  • Synovial sarcoma
  • Gastric glomus tumor
  • Malignant mesothelioma
  • Angiosarcoma
  • Sarcomatoid carcinom


  • Incidence – ~ 6.8/1,000,000 in the U.S. (NIH/NCI, 2017)
  • Age – median is 60-65 years
    • Rare in children, adolescents – frequently associated with a syndrome
  • Sex – M:F, equal



  • 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 (Demetri, 2010)
    • Variable malignant potential from low to highly aggressive
    • Most common sites are stomach (~60%) and small intestine (30%) (Demetri, 2010)
      • 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 immunohistochemistry [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 (<2 cm), indolent, benign tumors
  • 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, distention (~10% of cases)
    • Esophageal GIST – odynophagia, dysphagia, retrosternal chest pain, hematemesis (<1% of cases)
  • Carney triad – GIST, paraganglioma, pulmonary chondroma
    • Indolent course with high rate of recurrence

Clinical Background


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


  • 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 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 (GI) bleeding
  • Fatigue, pallor, and weakness – due to anemia
  • While inherited syndromes are rare, they are more commonly found in pediatric GISTs


Indications for Testing

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

Laboratory Testing

  • Nonspecific testing – CBC, liver function tests


  • Pathologic criteria for predicting malignancy (eg, size, mitotic activity) do not apply in pediatric GISTs
  • Immunohistochemistry (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


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 tyrosine kinase inhibitor (TKI) therapy


Molecular testing required to confirm KIT mutations

DOG1 by Immunohistochemistry 2010168
Method: Immunohistochemistry


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


Molecular testing for PDGFRA to confirm mutation

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

SDHB with Interpretation by Immunohistochemistry 2006948
Method: Immunohistochemistry

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


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, 16 Genes 2013449
Method: Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray/Sequencing/Multiplex Ligation-dependent Probe Amplification


Diagnostic errors can occur due to rare sequence variations

Not determined or evaluated variants in genes not included on the panel; deep intronic and regulatory region variants; breakpoints for large deletions/duplications; sequence changes in EPCAM gene

Deletions/duplications may not be detected in exon 9 in BMPR1A gene; exon 1 in CDH1 and MSH2 genes; exon 8 in PMS2 gene; exons 4, 6, and 7 in STK11 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; not all predisposing genes are analyzed


Demetri GD, von Mehren M, Antonescu CR, DeMatteo RP, Ganjoo KN, Maki RG, Pisters PW, 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, Version 2.2017. National Comprehensive Cancer Network. Fort Washington, PA [Accessed: Jun 2017]

Protocol for the Examination of Specimens from Patients with Gastrointestinal Stromal Tumor (GIST). Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: Dec 2014. College of American Pathologists (CAP). Northfield, IL [Revised: Dec 2014; Accessed: Dec 2016]

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

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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.

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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 JA. 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.

Smith SM, Coleman J, Bridge JA, Iwenofu H. Molecular diagnostics in soft tissue sarcomas and gastrointestinal stromal tumors J Surg Oncol. 2015; 111(5): 520-31. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

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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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Medical Reviewers

Content Reviewed: 
June 2017

Last Update: October 2017