GIST

DEFINITION
Gastrointestinal Stromal Tumor
A paradigm for molecular targeted therapy of cancer.
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EPIDEMIOLOGY

Incidence

Rare overall; 1% of gastric neoplasms.
But most common mesenchymal one.
~60s.
Slightly M>F.
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AETIOLOGY

Pathogenesis
ICC-derived tumor.
Gain of function mutation in the CD117 (KIT) proto-oncogene.
- codes a transmembrane tyrosine kinase receptor, whose activation initiates intracellular signalling for proliferation, differentiation and adhesion.
- hence response to Gleevec / imatinib mesylate.
A small percentage of GIST harbour PDGFR-alpha mutations.
- sumitinib better option.

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BIOLOGICAL BEHAVIOUR

Natural History
60% gastric, 25% small intestine, 10% oesophagus / rectum; rarly in colon & mesentery.

Gastric

Usually arises in the proximal stomach
May grow into the gastric lumen; remain serosal, or pedunculate within the abdominal cavity.
Spreads via invasion or blood-born mets; lymph rare in adults (kids have a different GIST biology).
- liver and peritoneum are most frequent sites
Recurrence same, lung or bone rare.
- median time to recurrence 18-24 months.

Small Bowel

Most duodenal are in 2nd portion.
Grow into mucosa and ulcerate
Or protrude toward serosal aspect.
Aggressive GISTS metastasise to liver by blood
- also spread locally throughout abdomen and develop serosal nodules.
Rarely go to lymph nodes, extra-abdominal spread unusual.

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MANIFESTATIONS

Symptoms

Small (<2cm) tumours are often discovered incidentally.

Gastric

Local
Vague abdominal pain
Notice an abdominal mass
25% will get bleeding

Metastatic / Complications
Like most sarcomas tend not to obstruct, but rather displace other tissues.
Obstruction, dysphagia and jaundice are rare.

Small bowel

May obstruct, abdo discomfort, early satiety.
Blood loss if bleed, often intra-peritoneally.


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INVESTIGATIONS

Endoscopy
Submucosal mass, less commonly ulcerated.

Biopsy?

FNA sensitivity is good (80%)
But biopsy generally discouraged, especially if resectable
- increases risk of haemorrhage, seeding and dissemination
Only need perc biopsy if considered unresectable
Else proceed to surgery based on radiology +/- FNA if available.

Histopath
Conventional staining and immunohistochemistry.
CD117 is found in 95%, i.e. the product of the KIT protooncogene.
Three most important (independently) predictive factors for recurrence are:
- mitotic rate (<5/50 HPF is good, >5 is bad)
- tumour size (>5cm is getting bad)
- tumour location (stomach better than colon/rectum, s.i. worse).
Nomogram is good (Lancet Oncol 10:1045-1052, 2009).

Imaging
CT (or MRI) with IV contrast shows a hypervascular mass associated with the GI tract.
Often exophytic growth, larger ones may show central necrosis or haemorrhage
Shows disease extension.
PET - often FDG-PET avid, may help show extent in suspected mets and imatinib mesylate response.

Staging
CT first, examination at exploration.

TNM
T1 = 2cm or less
T2 = 2-5cm
T3 = 5-10cm
T4 = >10cm
N / M
TNM used with mitotic rate for stage grouping and prognostication.

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MANAGEMENT

Depends on extent of disease
Thoroughly evaluate before and during op for Mets.

Medical
Glivec.
- 80% response
(cf only 5% with previous chemotherapy agents)
- has shifted survival from 15 months to >5 yrs.

Operative
Take great care not to disrupt these often friable tumours
- else can cause bleeding or intraperitoneal dissemination.
- some evidence this reduces survival.
Principles
Limited resection of the area of origin is often sufficient.
Complete gross resection with intact pseudocapsule
- 1-2cm margin adequate.
- Wedge resection adequate.
R0 resection = good.
En-bloc resection may be needed due to location or invasion.
Exceedingly low rate of nodal mets means no routine regional node dissection required.

Small intestine GIST
Segmental resection of involved bowel.
Periampullary tumours may require a pancreaticoduodenectomy

Laparoscopic?
Evolving role.
Successful for wedge resection of tumours <5cm
Limited data on SB gist.

What if the resection was R1?
Microscopically positive margins.
As a principle would be good to return for clear margins.
However, tempered by difficulty in identifying which area is involved
- and lack of evidence for microscopically positive margins being associated with poorer outcomes.
Large tumours can shed cells intra-abdominally

Role of adjuvant Imatinib?

Large double-blind RCT from US (ACS Oncology Group >700 pts):
- 400 mg daily = 1 yr recurrence-free survival of 98% cf 83% for placebo.
--> hence FDA approved.
Give it when tumours >3cm (or intermediate-to-high risk GISTS) for at least 1 yr (lack of evidence beyond that).

Neoadjuvant?
Safe and has a role in large GISTs with extensive organ involvement, duodenal or low rectal, or near GOJ, when downsizing relevant to safe effective resection.
- will see a decrease in tumour density first if Gleevec working, before size reduction.
But monitor closely as disease may rapidly progress, rendering disease unresectable and reversing what was achieved.
Baseline and follow up CT with or without PET can monitor efficacy.
Follow up scan for 2-r weeks after initial scan for less extensive GIST and 3 months if was initially unresectable.

Follow up?
CT every 3-6mo for 5yr, then annually.
Less frequent if tumour <2cm, though natural history ill defined here.

Side effects of imatinib?
Usually well tolerated.
Diarrhoea, abdo discomfort, dermatitis, peripheral / periorbital oedema.

Recurrent disease?
Up to 50% get recurrence within 5y and eventually succumb.
If not on Gleevec
--> put on Gleevec and assess response.
- ~80% of patients with metastatic disease will partly response (50-60%) or respond.
- 2-yr survival now 75% cf 40% pre-imitinab.
If Gleevec responsive:
- continue gleevac, often best response after 2-6 mo.
- then consider surgery or RFA liver ablation if liver mets.
--> high majority of patients eventually become resistant to Gleevec; typically following new mutations in KIT.
If Gleevec resistant / progression:
- surgery not recommended for multifocal resistant disease as survival benefit poor.
- escalate dose of imatinib if tolerated
- or move to sumatinib (KIT and PDGFR-alpha receptr selective inhibitor with broader activity).
--> 40% response to this alternative agent.
If continued progression
- med onc for consideration of other inhibitors or chemotherapeutics.

Prognosis?

Overall 5-yr survival is 40%.
Negative factors:
- age >55
- tumour size, mitotic index
- males
- poorly differentiated
- R1 resection
- small bowel tumours

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REFERENCES
Cameron 10th.
Doherty