Gastrointestinal Stromal Tumors Current Concepts 2005

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Gastrointestinal Stromal TumorsCurrent Concepts
2005

• Reviewed byKlaus Gottlieb, MD, FACP, FACG
• Endoscopic Ultrasound and Interventional
  Endoscopy
• Spokane, WA

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In the Beginning

• there were smooth muscle tumors of the
  gastrointestinal tract. And darkness reigned over
  the face of these tumors and there was much
  confusion

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but now there are Guidelines

• European Consensus Conference Recommendations
  (Meeting in Lugano March 2004) just published in
  Ann Oncol. 2005 Apr16(4)566-78.
• NCCN Sarcoma Guideline (GIST chapter) updated in
  2005

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Terminology

• Stromal or mesenchymal tumors of the GI tract
  are divided into two groups
• Those identical to tumors of the soft
  tissuearising in the rest of the body
• Lipomas, Schwannomas, Hemangiomas, Usual
  Leiomyomas, etc.
• Stromal tumors arising from the smooth muscle of
  the alimentary tract GIST

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Gastrointestinal Stromal Tumors

• Most often located in the stomach and proximal
  small intestine
• Can occur in any portion of the GI tract that
  contains smooth muscle
• Occasionally found in the omentum, mesentery and
  peritoneum

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GIST

• Most common benign non-epithelial tumor of the GI
  tract
• 1 of primary GI cancers
• Small asymptomatic GISTs are found at autopsy in
  more than 50 percent of individuals over the age
  of 50
• GIST treatment trials estimate an annual
  incidence of 4,500 6,000 new cases

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Evolution of our Understanding

• GISTs originally thought to derive from smooth
  muscle, but only rarely showed clear-cut features
  of complete muscle differentiation
• Some stromal tumors had ultrastructural evidence
  of autonomic neural differentiation
  (gastrointestinal autonomic nerve tumors, GANTs)

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Immunophenotyping

• 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

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Enter CD117

• 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
• In 80 percent of GISTs c-kit activation is the
  result of an activating KIT mutation

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Membrane (Receptor) Tyrosine Kinase
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A Tyrosine Kinase primer

• Protein tyrosine kinases (PTKs) catalyze the
  phosphorylation of tyrosine residues.
• the total number of PTKs does not exceed 1000
  (human genome project)
• two main classes of PTKs receptor PTKs and
  cellular, or non-receptor, PTKs.
• Of the 91 protein tyrosine kinases identified
  thus far, 59 are receptor tyrosine kinases and 32
  are non-receptor tyrosine kinases.
• 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, through
  mechanisms such as point mutations or
  over-expression, can lead to various forms of
  cancer as well as benign proliferative
  conditions.
• more than 70 of the known oncogenes and
  proto-oncogenes involved in cancer code for PTKs.
  
• existence of aberrations in PTK signaling
  occurring in inflammatory diseases and diabetes.

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Membrane (Receptor) Tyrosine Kinase Families
Adapted from Hubbard,1999
Extracellular
Intracellular
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Membrane (Receptor) Tyrosine Kinase Families
Adapted from Hubbard,1999
Extracellular
Intracellular
Epidermal Growth Factor Receptor Family
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Membrane (Receptor) Tyrosine Kinase Families
Adapted from Hubbard,1999
Extracellular
Intracellular
Insulin Receptor Family
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Membrane (Receptor) Tyrosine Kinase Families
Adapted from Hubbard,1999
Extracellular
Intracellular
Platelet-Derived Growth Factor Receptor Family
including KIT
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Membrane (Receptor) Tyrosine Kinase Families
Adapted from Hubbard,1999
Extracellular
Intracellular
Vascular Endothelial Growth Factor Receptor
Family
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Membrane (Receptor) Tyrosine Kinase Families
Adapted from Hubbard,1999
Extracellular
Intracellular
Fibroblast Growth Factor Receptor Family
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Membrane (Receptor) Tyrosine Kinase Families
Adapted from Hubbard,1999
Extracellular
Intracellular
Hepatocyte Growth Factor Receptor Family
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Membrane (Receptor) Tyrosine Kinase Families
Adapted from Hubbard,1999
Extracellular
Intracellular
Ret Receptor (Orphan)
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TK Receptor Activation and Signal Transduction
Ligand
Extracellular
Intracellular
Inactive Receptor
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TK Receptor Activation and Signal Transduction
Ligand
Extracellular
Intracellular
Receptor Dimerization
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TK Receptor Activation and Signal Transduction
Extracellular
P
P
Intracellular
P
P
P
P
Receptor Auto-Phosphorylationand Activation
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TK Receptor Activation and Signal Transduction
Ligand
Extracellular
P
P
Intracellular
P
P
P
P
24
TK Receptor Activation and Signal Transduction
Ligand
Extracellular
P
P
Intracellular
Y
P
P
P
P
Intracellular SignalingMolecule
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TK Receptor Activation and Signal Transduction
Ligand
Extracellular
P
P
Intracellular
Y
Y
P
P
P
P
Recruitment and Phosphorylationof Signaling
Molecule
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TK Receptor Activation and Signal Transduction
Ligand
Extracellular
P
P
Intracellular
Y
Y
P
P
P
P
ATP
ADP
Recruitment and Phosphorylationof Signaling
Molecule
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TK Receptor Activation and Signal Transduction
Ligand
Extracellular
P
P
Intracellular
Y
Y
P
Y
P
P
P
P
Activation of SignalingMolecule
anddownstreamSignaling Pathway
ATP
ADP
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GIST and c-kit

• Reminder the c-kit receptor is one of many
  membrane tyrosine kinase receptors involved in
  cellular signaling pathways
• GISTs are identified by
• either c-kit immunoreactivity (detection of the
  CD117 antigen)
• or the presence of activating mutations in KIT or
  PDGFRa (more about PDGFRa in a minute)

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C-kit gain-of-function mutations

• In normal cells activation of the of the c-kit
  tyrosine kinase requires the presence of an
  endogenous ligand (KIT ligand, c-kit 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

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KIT mutations

• Approx 80 of GISTs have KIT protooncogene
  mutations
• Observed both in sporadic and hereditary cases
• At least six families with germ line mutations in
  KIT autosomal dominant predisposition to GISTs
  with hyperpigmentation, urticaria pigmentosa, and
  dysphagia in some members

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Not straightforward

• C-kit activation normally associated with KIT
  mutations
• C-kit activation sometimes without KIT mutations
• Some c-kit negative tumors have KIT mutations
• Some c-kit negative GISTs have activating
  mutations in a different TK (tyrosine kinase),
  PDGFRa

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PDGFR alpha mutations

• A subset of GISTs lacking c-kit mutations have
  activating mutations in the PGFRa gene (platelet
  derived growth factor receptor alpha), another
  tyrosine kinase
• In one series such mutations were found in 14 of
  40 KIT-mutation negative GIST tumors and
  activation of downstream signaling intermediates
  were indistinguishable from those with
  KIT-mutations

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Clinical Relevance

• 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 imatinib-sensitive,
  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

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Interstitial Cells of Cajal

• Interstitial cells of Cajal (ICC) form the
  interface between the autonomic innervation of
  the bowel wall and the smooth muscle itself
• GI pacemaker cells
• Ultrastructural and immunophenotypic features of
  both neuronal and smooth muscle differentiation
  (just like GISTs)

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An ICC in action
Note contractions of the triangularly shaped ICC,
note that processes contact smooth muscle cells.
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Are GISTs derived from ICCs?

• 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)
• Benign GISTs which tend to lack expression of
  CD34 may be composed of more mature ICCs
• Malignant GISTs may represent dedifferentiated
  ICCs that maintain a CD34-positive stem cell
  phenotype
• Attractive hypothesis but still open to question

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Histopathology

• Differential Diagnosis
• HE 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)

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C-kit (CD117)
HE stain
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Spindle-cell tumor with High mitotic rate
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GIST Cellular Morphology

• Three relatively distinctive types
• Spindle cell type 70 percent
• Epithelioid type 20 percent, more commonly
  c-kit negative and found in omentum and mesentery
• Mixed type 10 percent
• Histologic type may be of prognostic
  significance, worse with epitheloid

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Determinants of Malignant Behavior

• Size More than 3 cm in diameter(most malignant
  GISTs are larger than 10 cm at diagnosis)
• Mitotic rate gt 25 mitoses per 50 high power
  fields
• Caveat Even very small lesions (lt 2 cm) with a
  low mitotic rate occasionally metastasize

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Other factors

• Site of origin better prognosis for gastric
  GISTs (?)
• Imaging characteristics EUS and CT
• Tumor biology
• C-kit mutations
• Chromosomal gains and losses
• DNA ploidy

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KIT mutations

• Most KIT mutations effect exon 11, others 9,13,17
• The type of exon 11 deletion may affect
  prognosis deletions of codons 562 to 579
  (563-569 always malignant)
• Exon 11 mutations are more likely to respond to
  iminitab

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Imatinib (Gleevec) a Tyrosine Kinase Inhibitor

• Imatinib mesylate is a protein-tyrosine kinase
  inhibitor that inhibits the Bcr-Abl tyrosine
  kinase, the constitutive abnormal tyrosine kinase
  created by the Philadelphia chromosome
  abnormality in chronic myeloid leukemia (CML).
• Imatinib is also an inhibitor of the receptor
  tyrosine kinases for platelet-derived growth
  factor (PDGF) and stem cell factor (SCF), c-kit,
  and inhibits PDGF- and SCF-mediated cellular
  events. In vitro, imatinib inhibits proliferation
  and induces apoptosis in gastrointestinal stromal
  tumor (GIST) cells, which express an activating
  c-kit mutation

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Action on Bcr-Abl TK similar to c-kit TK
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Clinical Manifestations

• Major presentations
• Overt GI bleeding 40 percent
• Abdominal mass 40 percent
• Abdominal pain 20 percent
• Location
• Stomach 50 percent
• Small bowel 25 percent
• Colon 10 percent
• Omentum/mesentery 7 percent
• Esophagus 5 percent

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Metastatic spread

• 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

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Diagnostic Work-Up

• 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

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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 gt 1 cm referral for EUS, if lt 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 gt 3 cm referral for surgery (likely
  GIST)

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The incidental (asymptomatic) UGI subepithelial
mass

• 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

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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

Adapted from Hwang JH, Kimmey MB.The incidental
upper gastrointestinal subepithelial
mass.Gastroenterology. 2004 Jan126(1)301-7.
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Questions?