Stomach

• 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 - 10 mm) 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)

• 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)
    • 1 - 2% of all GIST in pediatric patients (J Pediatr Hematol Oncol 2005;27:179, Cancer Res 2007;67:9084)
  • 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 4 subunits (SDHA, SDHB, SDHC, SDHD)
    • In the Krebs cycle, SDH catalyzes oxidation of succinate to fumarate
    • Mutations in 1 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)

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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

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Contributed by Riki Turri, PA (ASCP)

Contributed by Phoenix D. Bell, M.S., M.D.

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



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


Contributed by Raul S. Gonzalez, M.D. (Case #523)

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

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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

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)

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)

D. They sometimes metastasize to lymph nodes. SDH deficient GISTs may metastasize to lymph nodes, which almost never happens in GISTs that arise through other molecular pathways. Despite this behavior, they have a relatively good prognosis. SDH deficient GISTs almost always arise in the stomach, not the colon. They are positive for KIT and DOG1 by immunohistochemistry, facilitating the diagnosis of GIST. They have a moderate prognosis, and patients often have a protracted clinical course with metastases to lymph nodes and distant organs.

Comment Here

Reference: Gastrointestinal stromal tumor (GIST)