Stomach
Stromal / other tumors
Gastrointestinal stromal tumor (GIST)


Topic Completed: 25 November 2019

Revised: 5 December 2019

Copyright: 2012-2019, PathologyOutlines.com, Inc.

PubMed Search: Gastrointestinal stromal tumor [title](GIST[title]) stomach

Phoenix D. Bell, M.S., M.D.
Jennifer Findeis-Hosey, M.D.
Page views in 2018: 34,515
Page views in 2019 to date: 25,886
Cite this page: Bell P, Findeis-Hosey J. Gastrointestinal stromal tumor (GIST). PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/stomachGIST.html. Accessed December 13th, 2019.
Definition / general
  • Most common mesenchymal tumor of the gastrointestinal tract
  • Arises from the interstitial cells of Cajal within the myenteric plexus of the muscularis propria
  • Micro / mini / subclinical GIST: minute growths (1-10mm) of interstitial cells of Cajal / GIST-like cells (Am J Pathol 2002;160:1567)
  • Extragastrointestinal GIST: GIST arising outside of the gastrointestinal tract (omentum, mesentery, retroperitoneum or pleura)
Essential features
  • Most common in stomach
  • Most due to mutations in proto-oncogene KIT (exon 11)
  • 3 histologic types: spindle, epithelioid and mixed
  • Prognosis: depends on tumor size, mitotic rate and site of origin
  • Treatment: surgical excision or imatinib
Terminology
  • Gastrointestinal stromal tumor (GIST)
  • Historic terms:
    • Gastrointestinal smooth muscle tumor
    • Gastrointestinal autonomic nerve tumor
    • Leiomyoblastoma
    • Smooth muscle tumour of uncertain malignant potential
    • Gastrointestinal pacemaker cell tumour
ICD coding
Epidemiology
Sites
  • Can occur anywhere along the tubular gastrointestinal tract
  • Stomach (60%) > jejunum and ileum (30%) > duodenum (4 - 5%) > rectum (4%) > colon and appendix (1 - 2%) > esophagus (< 1%) (Semin Diagn Pathol 2006;23:70)
Pathophysiology
  • Activating mutations in the proto-oncogene KIT (~75%) (Science 1998;279:577) or platelet derived growth factor receptor-α (PDGFR-α) (~10%) (Science 2003;299:708)
    • Leads to constitutive phosphorylation of the receptor tyrosine kinase and activation of downstream pathways → cell proliferation and survival
    • KIT and PDGFRA mutations are mutually exclusive in GIST
  • Succinate dehydrogenase deficient GIST (Am J Surg Pathol 2010;34:636)
    • Young adults (before age 40)
    • Female preponderance (> 2:1)
    • Almost exclusively in stomach (predilection for distal stomach and antrum)
    • Pathophysiology:
      • SDH is an enzyme complex in the electron transport chain and Krebs (citric acid) cycle, composed of four subunits (SDHA, SDHB, SDHC, SDHD)
      • In the Krebs cycle, SDH catalyzes oxidation of succinate to fumarate
      • Mutations in one of the subunits (most commonly SDHA) results in succinate accumulation, increased transcription of HIF1α-regulated genes and decreased DNA methylation
    • Loss of SDHB immunoexpression
  • Recently identified, less well understood mutations
    • NF1 mutation
    • Mutations in the RAS / RAF / MEK pathway (ex. ETV1 transcription factor associated with GIST formation)
Etiology
  • Unknown at this time
  • Most are sporadic
  • Small percentage are familial
Diagrams / tables

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KIT and PDGFRA tyrosine kinase receptors

Clinical features
  • SDH deficient GIST
    • Carney triad: GIST, pulmonary chondroma, paraganglioma
      • Nonhereditary
      • SDHC promoter hypermethylation
      • Small percentage have germline SDH mutations
    • Carney-Stratakis syndrome: GIST and paraganglioma
      • Hereditary, autosomal dominant
      • Germline mutations in SDHB, SDHC or SDHD subunit
  • Neurofibromatosis (NF): 7% of patients with NF1 develop one or more GIST, usually in small bowel (Am J Surg Pathol 2005;29:1170, Am J Surg Pathol 2006;30:90, Hum Mol Genet 2006;15:1015)
  • Familial: germline mutations in KIT or PDGFRα autosomal dominant
    • Immunopositive for SDHB
Diagnosis
  • Patients most commonly present with gastrointestinal bleeding or abdominal pain
  • May be an incidental finding during radiologic or endoscopic workup for other clinical issues
    • Endoscopy show as a subepithelial lesion
  • Definitive diagnosis cannot be made without histologic examination
Laboratory
  • No significant laboratory findings
Radiology description
  • Radiologic findings are variable, depending on size and time of presentation
  • CT usually shows a solid, heterogeneous mass (reflecting the presence of hemorrhage or cystic degeneration)
  • Endoscopic ultrasound reveals a hypoechoic solid mass
Radiology images

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Gastric GIST

Prognostic factors
  • GIST can have clinically malignant behavior
  • Prognosis depends upon tumor size, mitotic rate and site of origin (Semin Diagn Pathol 2006;23:70)
  • Intraoperative tumor rupture is also associated with poorer prognosis
  • Compete surgical resection: improved local recurrence rate and overall survival
    • Incomplete resection particularly in the area of the rectum, is associated with a higher risk of recurrence
  • 60 - 80% of patients with SDH deficient GIST developed distant metastasis; however, the NIH risk stratification criteria may not be appropriate for this subtype (Am J Surg Pathol 2016;40:1616)
Gastric GIST: Risk of Disease Progression (Semin Diagn Pathol 2006;23:70)

Size ≤ 5 mitoses per 50 HPF > 5 mitoses per 50 HPF
 > 10 cm   Moderate   High 
 > 5 to ≤ 10 cm   Low   High 
 > 2 to ≤ 5 cm   Very low   Moderate 
 ≤ 2 cm   No   No 
Case reports
Treatment
  • Most GIST are treated with surgical resection
  • Imatinib mesylate (Gleevec): tyrosine kinase inhibitor of KIT and PDGFRα
    • Metastatic / recurrent GIST
  • Sunitinib malate (Sutent): a tyrosine kinase inhibitor of KIT, PDGFRα, VEGFR
    • Imatinib resistant GIST
  • SDH deficient tumors are less responsive to tyrosine kinase inhibitor
Clinical images

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Endoscopy

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Intraoperative mass

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Gastroscopy

Gross description
  • Well circumscribed, intramural lesion, centered within the muscularis propria
  • Fleshy, tan-pink cut surfaces, which may show hemorrhage or cystic degeneration
  • Mean size 6 cm (0.4 – 40 cm) (Am J Surg Pathol 2005;29:52)
Gross images

Contributed by Riki Turri, P.A. (ASCP)
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Stomach GIST, cross section

Frozen section description
  • Spindle cell neoplasm
Frozen section images

Contributed by Phoenix D. Bell, M.S., M.D.
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Bland spindle cells on frozen section

Microscopic (histologic) description
  • 3 morphologic types: spindle (70%), epithelioid (20%), mixed (10%) (WHO Classification of Tumours Editorial Board: Digestive System Tumours (Medicine), 5th Edition, 2019)
    • Spindle:
      • Bland spindle cells with faintly eosinophilic cytoplasm in a syncytial pattern; elongated nuclei with inconspicuous nucleoli; artifactual paranuclear vacuoles common in stomach GIST"
      • Subtypes: sclerosing, palisaded, vacuolated, diffuse hypercellular, sarcomatoid features with significant nuclear atypia and mitotic activity
    • Epithelioid:
      • Round cells with clear to eosinophilic cytoplasm in sheets or nests; increased tendency for pleomorphism versus spindle type
      • Subtypes: sclerosing, discohesive, hypercellular, sarcomatous with significant atypia and mitotic activity
    • Mixed:
      • Tumor is composed of cells with spindle and epithelioid morphology
  • SDH deficient: epithelioid or mixed epithelioid / spindle cell morphology, multinodular pattern, minimal nuclear pleomorphism, occasional atypical mitoses
  • Dedifferentiated: anaplastic appearance with an unusual phenotype (may lose expression of KIT or may aberrantly express other markers such as cytokeratin)
Microscopic (histologic) images

Contributed by Phoenix D. Bell, M.S., M.D. and Jennifer Findeis-Hosey, M.D.
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Spindle cell type

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Stomach GIST (mixed type)

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Evidence of mitotic activity

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Prominent paranuclear vacuoles


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Stomach GIST, epithelioid type

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Stomach GIST, spindle cell type



Contributed by Andrey Bychkov, M.D., Ph.D.
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Core biopsy

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Core biopsy with IHC

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CD34

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c-kit / CD117

Virtual slides

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Gastric GIST

Cytology description
  • Endoscopic ultrasound guided fine needle aspiration may lend a preliminary diagnosis
    • Bland spindle to epithelioid cells arranged in fascicles
Cytology images

Contributed by Andrey Bychkov, M.D., Ph.D.
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Highly cellular

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Spindled

Positive stains
Negative stains
  • S100
  • SDHB (in SDH deficient GIST, loss of retention is an abnormal finding)
Molecular / cytogenetics description
Molecular / cytogenetics images

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c-kit mutations

Sample pathology report
  • Stomach, fundus, partial gastrectomy:
    • Gastrointestinal stromal tumor (GIST), mixed spindle cell and epithelioid type (see synoptic report)
Differential diagnosis
Board review question #1

    The image above demonstrates a gastric mass in a 20 year old woman. Which of the following mutations is most likely seen in this entity?

  1. KIT
  2. NF1
  3. PDGFRA
  4. SDHA
  5. SDHC
Board review answer #1
D. The image shows cells with round nuclei, abundant eosinophilic cytoplasm, inconspicuous nucleoli and minimal pleomorphism, representative of an epithelioid type GIST. This subtype is commonly seen in patients with an SDH deficient GIST, which are most often due to mutations in the SDHA subunit; however, rare mutations in the other subunits have also been identified. The majority of GIST result from mutations in the KIT (75%) or PDGFR-α (10%) proto-oncogenes. They are usually found in the stomach and are composed of a spindle, versus epithelioid, population. More recently, there have been reports suggesting patients with neurofibromatosis 1 (NF1) mutations are predisposed to GIST development.

Comment Here

Reference: Gastrointestinal stromal tumor (GIST)
Board review question #2
    A 60 year old man presents with abdominal pain and a CT reveals a mass within the gastrointestinal system, which is resected. Histopathologic examination reveals a submucosal mass composed of spindle cells with lightly eosinophilic cytoplasm arranged in a syncytial pattern. The pathologic diagnosis is a GIST, spindle cell type. Which of the following answer choices correlates with the most favorable prognosis for this patient?

  1. KIT mutation present
  2. Mass 11 cm in greatest dimension
  3. Mass located in the jejunum
  4. Mitotic rate ≥ 5 per 50 HPF
  5. R1 resection
Board review answer #2
A. The main prognostic factors associated with GIST are mitotic rate, tumor size and tumor location. The extent of surgical resection and the presence of a KIT mutation also affect prognosis. GIST findings suggesting a more favorable prognosis include: stomach location, tumor size ≤ 2 cm, mitotic rate < 5 per 50 HPF, R0 (a resection with negative margins) and the presence of a KIT mutation.

Comment Here

Reference: Gastrointestinal stromal tumor (GIST)
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