Gastrointestinal stromal tumour

The gastrointestinal stromal tumour, abbreviated GIST, is an uncommon tumour of the gastrointestinal tract.

Gastrointestinal stromal tumour
Diagnosis in short
Gastrointestinal stromal tumour. H&E stain.
LM	spindle or epithelioid or mixed morphology, usu. centred on the muscularis propria
LM DDx	schwannoma, leiomyoma, leiomyosarcoma, neurofibroma, desmoid-type fibromatosis
IHC	CD117 +ve, DOG1 +ve, CD34 +ve, S-100 -ve
Molecular	mutation in KIT gene or PDGFRA gene
Staging	gastrointestinal stromal tumour staging
Site	stomach, small intestine, other sites
Syndromes	Neurofibromatosis type 1, Carney triad, Carney-Stratakis syndrome
Prognosis	good to poor - dependent on size, site & mitotic rate

General

Definition

• Tumour resulting from a mutation in the KIT gene or PDGFRA (Platelet-derived growth factor receptor, alpha polypeptide) gene.
• Cases wild-type for KIT or PDFGRA may harbour defects in the succinate dehydrogenase complex, NF-1, BRAF, or extremely rarely KRAS.

Epidemiology

• Arise from Interstitial cells of Cajal.

May be familial/syndromic:

• Neurofibromatosis 1 (von Recklinghausen's disease).
• Carney triad.
• Carney-Stratakis syndrome - GISTs and paraganglioma - due to mutation in the genes for succinate dehydrogenase.

Treatment

• Imatinib (Gleevec) - drug was developed for chronic myelogenous leukemia.
  • There are other similar drugs, e.g. nilotinib and dasatinib.

Factors predictive of malignant behaviour

Features suggesting a bad prognosis:

• Large size.
  • Often benign if small size.
• High mitotic rate (for area 5mm²).
• Site - small intestine GISTs worse than stomach GISTs.

Small intestine bad prognosis:

• >5 mitoses/5 mm² or size >10 cm.

Stomach bad prognosis:

• >5 mitoses/5 mm² and size >5 cm.

Location

Most common locations in order:

• 60% in stomach.
• 35% in small intestine.
• 5% elsewhere.

Notes:

• Small intestinal GISTs have a worse prognosis than gastric ones.
• GISTs almost never metastasize to the lymph nodes (except for SDH-B deficient epithelioid GISTs)
  • Most common metastasis locations: liver, abdominal soft tissue.

Microscopic

Features:

• Classically, spindle cell morphology ~ 50% of tumours.
  • May be epithelioid (round) ~40% of tumours.
  • Mixed epithelioid and spindle cell tumours ~10% tumours.
• +/-Cytoplasmic inclusions - perinuclear.
• Classically splits the layers of the muscularis propria - as this is where the interstitial cells of Cajal are located.
• +/-Skenoid fibres - extracellular collagen bundles ~ 2-5 x 60 micrometers - uncommon finding.
  • Not seen in gastric GISTs.
  • High specificity for GIST.

DDx

• Leiomyosarcoma.
• Leiomyoma - esp. in the esophagus.
• Neural tumours.
  • Neurofibroma.
  • Schwannoma (GFAP +ve).
    • GFAP uniformly neg. in GISTs.
• Desmoid-type fibromatosis.
• Epstein-Barr virus-associated smooth muscle tumour - very uncommon, in immunoincompetent individuals.

Images

• www:
  • GIST (radiographics.rsna.org).
  • GIST with skenoid fibres (radiographics.rsna.org).
  • GIST with skenoid fibres (nature.com).

• 

  GIST - low mag. (WC/KGH)

• 

  GIST - high mag. (WC/KGH)

• 

  Intestinal spindle cell GIST - very low mag. (WC/Nephron)

• 

  Intestinal spindle cell GIST - low mag. (WC/Nephron)

• 

  Intestinal spindle cell GIST - intermed. mag. (WC/Nephron)

• 

  Intestinal spindle cell GIST - high mag. (WC/Nephron)

• 

  Intestinal spindle cell GIST - very high mag. (WC/Nephron)

• 

  Epithelioid GIST - intermed. mag. (WC/Nephron)

IHC

• CD117 +ve in 95%.
  • Mast cells are the internal positive control.
• DOG1 +ve.

Others:

• CD34 +ve in 70%.
• Desmin +ve in 5%.
• WT1 +ve -- cytoplasmic (28/28 cases).

IHC work-up panel

• S-100 (neural tumours, rarely +ve in GISTs).
• CD34, CD117 (GIST).
• Desmin (muscle tumours).

Molecular tests

See Molecular_pathology_tests#Other.

• Sequence Kit gene, PDGFRA gene.
  • Kit gene sequencing is being done more frequently as of late-- if a mutation is found it suggest the drug imatinib will be effective.
  • Exon 11 mutation associated with malignant behaviour.
  • Secondary mutations of c-kit lead to imatinib resistance, and resistance to other similar inhibitors.

Gastrointestinal stromal tumour staging

Main article: Gastrointestinal stromal tumour staging

GIST has its own staging.

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STOMACH (MASS), LESSER CURVE, WEDGE RESECTION:
- GASTROINTESTINAL STROMAL TUMOUR (GIST).
-- MARGINS NEGATIVE FOR GIST.

COMMENT:
The tumour stains as follows:
POSITIVE: CD117, CD34.
NEGATIVE: Desmin, S-100.

SMALL BOWEL (ILEUM), RESECTION:
- GASTROINTESTINAL STROMAL TUMOUR (GIST), LOW-GRADE, NO RISK OF 
  PROGRESSIVE DISEASE.
-- MARGINS NEGATIVE FOR GIST.
-- PLEASE SEE TUMOUR SUMMARY.
- THREE BENIGN LYMPH NODES.

COMMENT:
The tumour stains as follows:
POSITIVE: CD117, CD34.
NEGATIVE: Desmin, S-100.
PROLIFERATION (Ki-67): <1%.

Incidental GIST

Partial Stomach, Sleeve Gastrectomy:
	- Stomach wall with incidental GASTROINTESTINAL STROMAL TUMOUR (GIST), 2 mm in maximal dimension.
	-- Margin clear.
	- Gastric mucosa within normal limits.

Comment:
The tumour stains as follows:
POSITIVE: DOG1, CD117, CD34.
NEGATIVE: desmin, S-100.
PROLIFERATION (Ki-67): <2%.

Staging

• The stage is primarily determined by the tumour size and mitotic grade.
  • In the stomach, the mitotic grade determines whether a given tumour is Stage I or Stage III.

Micro

The sections show a spindle cell lesion that is well-circumscribed and without significant nuclear pleomorphism. No lymphocytic cuff is surrounding the lesion. The lesion is focally seen at the inked soft tissue margin. Three mitoses are seen in 5 mm*mm.

See also

• Stomach.
• Small bowel.
• Gastrointestinal pathology.