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Gastro Intestinal Stromal Tumour (GIST)

What is GIST?

It is an uncommon mesenchymal tumour of GIT, arising from interstitial cells of Cajal. They express CD34, Actin and recently recognized as almost uniformly c-kit (CD117) +
Histologic subtypes include spindle, epitheloid and mixed. Until recently, there were no appropriate diagnostic tests. CD 117 is now used as a diagnostic tool.

Discuss the pathogenesis of GIST?

  • C-Kit or KIT proto-oncogene-àc-kit receptor (memb TK)
  • CD117 molecule is part of C-kit receptor.
  • Normally, this receptor is activated by stem cell factor
  • In GIST- c-kit receptor is permanently switched on– unregulated cell proliferation

Discuss the epidemiology of GIST?

  • 0.1-3% of all GI cancers
  • Incidence 1-2/100,000 based on historical data (difficult to interpret due to changing diagnostic criteria in the past)
  • Estimates now of 200-2000 new cases/year in England and Wales with updated diagnostic criteria.

Discuss the clinical presentation of GIST?

  • Abdominal pain, GI bleed, mass, Obstruction.
  • Site of primary tumour- Stomach (50%), Small bowel (25%), Colon (10%), Oesophagus (5%), Extraintestinal (7%)
  • Primary tumour only (46%), metastatic disease (47%)
  • Frequently metastases to liver, rarely to regional lymph nodes and virtually never to lungs.

Discuss the diagnosis of GIST?

  • Endoscopy- subepithelial mass
  • CT scan- Solid mass that enhances brightly with IV contrast
  • EUS- most accurate
  • EUS FNA/ biopsy- used selectively

Discuss the clinical Behaviour of GIST?

  • All GISTs are potentially malignant
  • Any symptomatic GIST is potentially aggressive
  • No uniform prognostic guidelines. Poor prognosis is associated with-
    • Increasing tumour size
    • GIST with high mitotic rate
    • Metastatic disease at presentation

Discuss the management of GIST?

  • Surgical resection is the treatment of choice. 67% of primary tumours are resectable. However 50% recur in 5 years (most often: intraabdominal, liver)
  • Recurrent disease treated as metastatic disease i.e. no role of further surgery
  • Continued surveillance may be needed after surgery
  • Advanced or metastatic disease- NICE recommends;
    • Imatinib (Gleevac) – 400mg/day first line treatment in CD117+unresectable or metastatic disease. Rapid dramatic response
    • Assess responders every 12 weeks. Continue therapy until tumour ceases to respond.
    • Side effects- nausea and vomiting, fluid retention, cramps, fatigue, GI or intraabdominal bleed- 5%
    • 2 year survival nearly 80%. 2year progression free survival 50%

Discuss stomach GIST?

  • Most common in Fundus
  • Small lesions <1cm with EUS benign- F/U repeat OGD &EUS at 6m and 12m
  • Surgery- if tumour becomes symptomatic, shows structural changes or enlarges >1cm.

Discuss pre Imatinib outcomes for GIST?

  • All GIST
    • 5year survival 28-43%
    • Median survival 19 months
  • Single primary tumour completely resected
    • 5year survival 50-65%
    • Median survival 66months
  • Metastatic disease or recurrent disease
    • Median survival 9-12 months
  • Chemotherapy- not effective

Discuss the mutated Tyrosine kinases in GIST: PDGFRa (platelet derived growth factor receptor)?

  • Subset of GIST tumour without kit mutations (KIT-WT)
  • PDGFRa was constitutively phosphorylated in KIT-WT GIST
  • Approximately 30% of KIT-WT GIST had PDGFRa mutation

Is an identified KIT mutation requisite to treat GIST with Imatinib?
Studies have correlated response to Imatinib to the presence of kit mutation, however not absolute

What about the minority of GIST tumours that do not have kit or PDGFRa mutation? Should they be offered Imatinib?

Imatinib may have an indirect mode of action by boosting NK cell activation in pts with GIST (ass with prolonged progression free survival)


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