Download GIST -2010

Gastrointestinal Stromal Tumors
(GISTs)
Efraim Idelevich, MD, PhD
Gastro-Intestinal Oncology Unit
Kaplan Medical Center
GISTs
 Originally classified as other tumors: leiomyoma,
leiomyoblastoma, leiomyosarcoma or schwannomas
 1998- the discovery of gain-of-function mutations in the
c-KIT proto-oncogene in GISTs that allowed GISTs to be
distinguished reliably from these other histopathological
subtypes of GI tumors
GISTs
 The most common mesenchymal neoplasm of the
GI tract.
 0.1%-3% of GI malignant tumors
 Recently described as a distinct clinical and
histopathological entity:
Type of sarcoma, a tumor of mesenchymal
(connective tissue) origin
Epidemiology
 4000-6000 new cases in the USA each year with annual incidence of
11-14 per 106
 Occur mostly in patients with a median age of 60 years (40-80)
 No predilection for either gender
 Familial GISTs- autosomal dominant
Type I neurofibromatosis (7% mostly in the small intestine without
KIT mutations)
Carney triad (GISTs + paraganglioma +pulmonary chondroma)
GIST: Involved Sites
 Occurs anywhere in GI tract/abdomen
Site
Incidence %
Gastric
60-70
Small intestine
20-30
Colon
<5
Other (omentum, mesentery,
esophagus)
<5
Clinical Presentation
 Often asymptomatic, especially early in tumor
development, discovered incidentally by CT or
endoscopy
 Symptomatic:
Signs/symptoms related to location of tumor
– Vague GI pain or discomfort
– GI hemorrhage
– Anorexia, weight loss, nausea, anemia, and
additional GI complaints
Diagnostic studies
 CT – for initial evaluation and surveillance for recurrence
 EUS – determines size and extent of the tumor
 FDG-PET – reveals small metastases and establish baseline
metabolic activity and assess therapy response
 Routine use of PET for surveillance after resection is not yet
recommended
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Histopathology of GIST:
Biological Markers Used in Diagnosis of GIST
 GISTs positive for
– CD117 (c-Kit receptor tyrosine kinase)
• Positive in >95%
– CD34 (mesenchymal/haematopoietic
precursor cell marker)
• Positive in 60% to 70%
– Vimentin and smooth muscle actin
• Positive in 15% to 60%
• DOG1
– Desmin
– S-100 (rare- in small intestine 10%)
– Keratin (rare 10%)
CD117 (c-Kit)–positive
staining GIST
The need for a biopsy is debatable
 FNA- cytologic morphology
immunohistochemistry
PCR analysis for KIT mutations
 FNA- not consistently diagnostic
 FNA- controversial due to risk of rupture and dissemination
Resectable lesion in the absence of metastatic diseasea preoperative diagnosis may be unnecessary
 If diagnosis would impact the extent of resection or if
unresectable or metastatic disease is present , biopsy is
warrant
 Biopsy should be open or by endoscopy and not percutaneous
Traditional Treatment Options
Pre-Imatinib Mesylate (Glivec)
 Surgery is primary treatment modality for GISTs
– 5-year survival 50% to 65%
– Recurrence have been reported up to 20 years after surgery
 If incomplete resection/metastatic at presentation
– Median survival <1 year
– 5-year survival <35%
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Management of localized disease
 Surgical resection – complete gross resection with preservation
of an intact pseudocapsule without any tumor rupture
 Segmental resection with negative microscopic margins is the
preferred intervention
 Laparoscopic resection cannot be recommended routinely yet
 Routine lymphadenectomy is not recommended
 Endoscopic resection of small GISTs is still controversial due
to its inherent risks of positive margins and tumor spillage
 Is adjuvant treatment recommended?
Imatinib (Glivec)
 Small molecule tyrosine kinase inhibitor with activity
against ABL , BCR-ABL , KIT , PDGFRA , PDGFRB and
CSF1R
 Its structure mimics ATP
and it binds competitively
to the ATP binding site of
the target kinases
Imatinib Mesylate: Mechanism of Action
Imatinib mesylate occupies
the ATP binding pocket of the
c KIT kinase domain
c KIT
This prevents substrate
phosphorylation and signaling
A lack of signaling inhibits
Imatinib
mesylate
P
ATP
P P P
proliferation and survival
SIGNALING
Savage and Antman. N Engl J Med. 2002;346:683.
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Survival
according to tumor size
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Neoadjuvant Imatinib in primary GISTs
 Still investigational
 May be use to downstage primary or metastatic disease
before surgery
 many reports have been published of this approach to
convert an unresectable mass to one that is surgically
approachable, or to reduce the morbidity of a procedure
 The use of neoadjuvant imatinib, with or without adjuvant
imatinib, to reduce or eradicate micrometastatic disease is
also being assessed
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Conclusions
 Surgery in M1 patients still an individual decision.
 No data from randomized or prospectively controlled
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yet available
Residual tumor resection is safe
Resection of progressive tumor is less rewarding
Multifocal resection is not recommended without
considering the patient’s personal situation
Our experience with systemic therapy is: it more
often avoids emergency surgery
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Resistance to Imatinib
 Primary resistance : no achievement of stable disease or progressing
disease within 6 months of an initial clinical response (KIT exon 9
mutation or no detectable kinase mutation – wild-type tumors)
 Secondary resistance: disease progression after more than 6 months
clinical response (new acquired kinase mutation in KIT or PDGF-R that
interfere with Imatinib activity)
 Dose escalation of imatinib is the first step
 Use of other kinase inhibitors (Sunitinib)
 Surgery, radiofrequency ablation or hepatic artery chemoembolisation
Continuous vs. Intermittent Imatinib in Advanced GIST
 Prospective multicenter phase III Imatinib treatment
study: continuous vs. interrupted (46 patients randomized
to two groups)
 After 3 months: 0 and 5 (21%) patients had reprogression respectively
 Conclusion: Advanced GIST patients stopping Glivec
experience frequent re-progression at 3 months
 Based on these results imatinib should not be
discontinued
ASCO 2004
SUTENT (Sunitinib Malate) Capsules
Conclusions: SUTENT in GIST
Final thoughts
 Neoadjuvant treatment with IM is still investigational
 Adjuvant treatment with IM is “standard of care” for high
(moderate) risk recurrence GIST (3 year and >)
 Metastatic and unresectable GIST should be treated with
IM (genotype evaluation is suggested)
 Retrospective studies have defined the subset of pts
most likely to potentially benefit from “adjuvant
cytoreductive surgery”
 Benefit of cytoreductive surgery in pts on SU is less clear
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Thank you