Transcript Gastrointestinal Stromal Tumours(GIST)

Gastrointestinal Stromal
Tumours(GIST)
INTRODUCTION :
• Stromal or mesenchymal tumors of the GI tract are
divided into two groups:
– 1. Those identical to tumors of the soft tissue arising in the
rest of the body (Lipomas, Schwannomas, Hemangiomas,
Usual Leiomyomas, etc.)
– 2. Stromal tumors arising from the smooth muscle of the
alimentary tract: GIST
• The term “GIST” was applied by Mazur and Clark in 1983 to
define intra-abdominal tumors that were not carcinomas .
EPIDEMIOLOGY
• Most common non epithelial benign neoplasm of the GI tract .
• GIST represents a form of sarcoma that comprises approx. 1%
to 3% of all malignant GI tumors.
• GIST occurs predominantly in adults .
• The incidence has been slightly higher in men than women.
• Small asymptomatic GISTs are found at autopsy in more than
50 % of individuals over the age of 50
• GIST treatment trials estimate an annual incidence of 4,500 –
6,000 new cases
MOLECULAR PATHOBIOLOGY
GIST
• GIST represents a form of sarcoma.
• GISTs originally thought to derive from smooth
muscle, but only rarely showed clear-cut features of
complete muscle differentiation.
• Work in the 1990s: Some tumors classified as GIST
were truly myogenic, some neural, others bidirectional
and some had the ‘null’ phenotype
• Up to two-thirds were CD34 positive
• Unfortunately, Schwannomas and a proportion of true
smooth muscle tumors were also CD 34 positive
ENTER :Membrane (Receptor)
Tyrosine Kinase
• PTKs are involved in cellular
signaling pathways and regulate
key cell functions such as
proliferation, differentiation,
anti-apoptotic signaling and
neurite outgrowth.
• Unregulated activation of these
enzymes can lead to various
forms of cancer as well as
benign proliferative conditions.
•Nishida T, Hirota S, Taniguchi M, et al: Familial gastrointestinal stromal tumours
with germline mutation of the KIT gene
GIST and C-kit
• The c-kit receptor is one of many membrane tyrosine
kinase receptors involved in cellular signaling
pathways.
• CD117 molecule (or antigen) is part of the c-kit
receptor, a membrane tyrosine kinase.
• The c-kit receptor is a product of the c-kit or KIT
protooncogene.
• The CD117 antigen is expressed by almost all GISTs
in contrast to other spindle-cell tumors of the GI tract
UNCONTROLLED KINASE
ACTIVATION (THE MOLECULAR
ETIOLOGY)
• In normal cells activation of the of the c-kit tyrosine kinase
requires the presence of an endogenous ligand (KIT ligand, ckit ligand, or stem cell factor)
• Approx 80 % of GISTs have KIT protooncogene mutations
that lead to activation of the c-kit receptor resulting in
spontaneous receptor activation not requiring a ligand
• Observed both in sporadic and hereditary cases
• A subset of GISTs lacking c-kit mutations have activating
mutations in the PGFRa gene (platelet derived growth factor
receptor alpha), another tyrosine kinase
GISTs are identified by:
• either c-kit immunoreactivity (detection of the CD117
antigen) or
• the presence of activating mutations in KIT or PDGFRa
Are GISTs derived from ICCs?
• Interstitial cells of Cajal (ICC) form the interface between the
autonomic innervation of the bowel wall and the smooth
muscle itself.
• The KIT RTK plays essential roles in the development and
maintenance of normal ICCs .
• Ultrastructural and immunophenotypic features of both
neuronal and smooth muscle differentiation (just like GISTs)
• It is postulated that GISTs originate from CD34 positive stem
cells within the wall of the gut and differentiate toward the
pacemaker cell phenotype (ICC)
• Malignant GISTs may represent dedifferentiated ICCs that
maintain a CD34-positive stem cell phenotype
• Attractive hypothesis but still open to question
LOCATION :
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Stomach – 50 percent
Small bowel – 25 percent
Colon/ Rectum– 10 percent
Omentum/mesentery 7 – percent
Esophagus – 5 percent
CELLULAR MORPHOLOGY
• Three relatively distinctive types
– Spindle cell type – 70 percent
– Epithelioid type – 20 percent, more commonly ckit negative and found in omentum and mesentery
– Mixed type – 10 percent Histologic type may be
of prognostic significance, worse with epitheloid
HISTOPATHOLOGY
• Differential Diagnosis
– H&E stain: Melanoma, leiomyoma/sarcoma,
peripheral nerve sheath tumor, desmoid
– Histology difficult
– Immunophenotyping crucial
• 95 % are positive for C-kit (CD117)
• 60-70 % positive for CD34
• Negative for alpha-smooth muscle actin (SMA)
(leiomyoma)
• Negative for S100 protein (Schwannoma)
• Negative for Desmin (desmoids)
H&E stain
C-kit(CD 117)
Determinants of Malignant
Behavior
• Size: More than 3 cm in diameter(most
malignant GISTs are larger than 10 cm at
diagnosis)
• Mitotic rate: > 25 mitoses per 50 high power
fields
• Warning: Even very small lesions (< 2 cm)
with a low mitotic rate occasionally
metastasize
Approach for defining Risk of
Aggressive Behavior in Gastrointestinal
Stromal Tumors
Metastasis
• GISTs behave differently than other soft tissue
sarcomas:
– GISTs frequently metastasize to the liver and
rarely to regional lymph nodes
– GISTs virtually never metastasize to lungs whereas
this is the most common site of metastasis for
leiomyosarcomas
CLINICAL MANIFESTATIONS
• Mesenchymal tumors of the GI tract are often
asymptomatic and discovered incidentally
during endoscopic or barium studies.
• Overt GI bleeding — 40 percent
• Abdominal mass — 40 percent
• Abdominal pain — 20 percent
– The vast majority of GIST metastases at
presentation are intra-abdominal, either with
metastases to the liver, omentum, or peritoneal
cavity .
Diagnosis :
• CT scan
– Leiomyomas: solid hypodense lesions
– GISTs: typically enhance with IV contrast
• Endoscopy
• Smoothly contoured submucosal mass, possible
central umbilication
• EUS
• Hypoechoic mass arising from muscularis propria
CT scan
Endoscopy
•
PET scan and CT scans in a patient with a GIST metastatic to the liver, before
(left) and after treatment with imatinib mesylate
Management :
• European Consensus Conference Recommendations
(Meeting in Lugano Mar 2004) pub in Ann Oncol.
2005 Apr;16(4):566-78.
• NCCN Sarcoma Guideline (GIST chapter) updated in
2005
Imatinib (Gleevec) a Tyrosine
Kinase Inhibitor
• Imatinib mesylate is a protein-tyrosine kinase
inhibitor that inhibits the Bcr-Abl tyrosine
kinase.
• Imatinib is also an inhibitor PDGF and c-kit,
and inhibits PDGF- and SCF-mediated cellular
events. In vitro, imatinib inhibits proliferation
and induces apoptosis in (GIST) cells, which
express an activating c-kit mutation
Imatinib (Gleevec) a Tyrosine
Kinase Inhibitor
• Imatinib (Gleevec) is very effective for CD114
positive GISTs
• It also has antitumor effficacy in tumors that
lack KIT mutations but have alterations in the
PDGF pathway
• Some PDGFRa mutations are imatinibsensitive, others not therefore, patients with
advanced tumors that are histologically c/w
GIST should not be denied a trial of imatinib if
they are c-kit negative.
Management
PRIMARY, LOCALIZED DISEASE (EARLY-STAGE GIST)
• Surgery remains the mainstay of treatment for patients with
primary localized GIST
• GIST lesions are highly vascularized and often exhibit a
fragile pseudocapsule; therefore, surgeons should be careful
to minimize the risk of tumor rupture.
• GIST rarely involves the locoregional lymph nodes.
• Adjuvant Therapy :At present, it is unclear whether the
administration of imatinib in the postresection adjuvant
setting would confer significant clinical benefits on patients.
MANAGEMENT OF ADV. GIST
MANAGEMENT OF UNRESECTABLE GIST
:
MANAGEMENT OF METASTATIC GIST :
The incidental (asymptomatic) UGI
subepithelial mass
• No firm clinical guidelines or consensus
• Surface Endoscopy can establish a lipomatous nature of the
mass
• If mass is > 1 cm referral for EUS, if < 1 cm repeat EGD in
one year, if stable probably no follow-up
• If mass arises from muscle layer (4th EUS layer mass) and
is > 3 cm referral for surgery (likely GIST)
• Clinical conundrum: The 1 - 3 cm mass
• 4th layer mass should undergo EUS-FNA and c-kit staining
• If a GIST is found discuss management strategies, esp.
surgery
• If results are indeterminate or patient does not wish
(or is not a candidate for) resection, endoscopic
follow up
• Recommendations depend on the age of the patient,
index of suspicion, etc.
• One reasonable strategy: EUS follow-up a year later
and if lesion is stable for two consecutive follow-up
periods, lengthening of the follow-up period.