gastrointestinal stromal tumors (gists) efraim idelevich, md, phd gastro-intestinal oncology unit...
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Gastrointestinal Stromal TumorsGastrointestinal Stromal Tumors
(GISTs)(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
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)–positivestaining 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 disease-a 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%
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
This prevents substrate phosphorylation and signaling
A lack of signaling inhibits proliferation and survival
P
PP P
ATP
SIGNALING
Imatinib mesylate
c KIT
Savage and Antman. N Engl J Med. 2002;346:683.
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
Conclusions
Surgery in M1 patients still an individual decision. No data from randomized or prospectively controlled
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
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 re-progression 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
55
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