G I S T

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G I S T
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• F. AL-Mashat
• Dep of surgery
• Kauh Kahoc

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Definition
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• c-Kitpositive mesenchymal tumours (MT) with
  specific histological IHC characteristics
  occuring in GIT

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History
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• ? 20 y most MT of gut were considered to be of
  smooth muscle or perineural origin
• ? Mazur Clark (1983) GIST
• ? Kindblom(1998)Interstitial cell of Cajal
  GIPACT
• ? Today,most gut MT previously designated
  leiomyomas, leiomyoblastomas leiomyosarcomas
  are GIST
• ? True gut leiomyomas schwannomas remain to be
  identified

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Epidemiology
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• The most common MT of gut
• 0.1 - 3 of gut cancers
• Incidence 20/10 people/year
• ? ?
• Predominantly 5 - 7 decades. Rare lt 40 y

• Spectrum Benign - highly Malignant
• Majority Benign. 10 30 Malignant
• Currently many clinicians and pathologists
  believe that all GISTs have at least some
  malignant potential

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Manifestations
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• Difficult early diagnosis, often asymptomatic
• Small asymptomatic and discovered incidentally
  (1/3)
• Many silent until they grow large enough to
  bleed or rupture
• Stomach (60 - 70) and small intestine (20 -
  30)
• Other sites oesophagus, omentum, mesentery,
  colon, and rectum
• 30 malignant metastatic or infiltrating
• Met usually to liver. Peritonium infrequent.
  Nodes extra-abdominal rare
• 
  
  
•  

• Symptoms location , size growth pattern
• Most common palpable abdominal mass( 50 to
  70) , may be associated with vague G I pain and
  discomfort.
• The second G I haemorrhage (one third).
• Less common, non-specific anorexia, weight
  loss, nausea, bowel obstruction , obstructive
  jaundice ,
• 10 present with met

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Diagnosis
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• ? CT Standard. Extraluminal mass central
  necrosis
• ? MRI
• ? Barium Endoscopy
• ? Biopsy/ FNA Peritoneal seeding. Only
  unresectable
• ? 18FDG-PET Follow-up
• ? Surgery well defined extraluminal mass,
  frequently lobulated

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Schematic structure of the c-Kit tyrosine kinase

• .

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The extracellular domain of the c-Kit receptor
binds to the ligand SCF. Tyrosine protein, which
is where Glivec binds to c-Kit kinase activity
resides in the intracellular domain of the
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c-Kit signal transduction
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• Binding of the ligand SCF to the c-Kit
  tyrosine kinase receptor causes the receptor to
  dimerise, auto-phosphorylate, and become
  activated. Recruitment of other signalling
  proteins into a signalling complex then initiates
  a signal transduction cascade with some final
  steps occurring in the nucleus.

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Pathology
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• ? Cells may resemble mesenchymal, neural,
  smooth muscle
• ? Spindle cell (70) , less commonlly Epithelioid
  or Mixed cell phenotype

? 1 cm to gt 40 cm ? extraluminal with frequent
mucosal ulceration ? well circumscribed
pseudo-encapsulation ? frequent necrosis, cystic
degeneration focal haem
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Immunohistochemistry
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• ve c-Kit (90 100 )
• recommended c-Kit be performed on all
  intra-abdominal sarcoma-like tumours
• performed on fixed paraffin or frozen
• 
  

• CD 34 70 - 80.expressed in many tumours, so
  modestly specific
• Actin (30 ) Keratin (lt10 )
• Desmin S-100 -ve
• Vimentin ve
• Ki67 may aid in prognosis and monitoring

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• Histological I H C ( KIT,CD34) are the
  defining features of GIST

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Treatment
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• Until now limited treatment options, such as
  radiation and surgery, which have shown only
  limited success.
• The recent introduction of Glivec (imatinib)
  molecularly targeted therapy for treatment of
  patients with unresectable or metastatic GISTs
  has led to significantly better outcomes and
  helped spur renewed interest in reliable and
  accurate diagnosis of this difficult malignancy.
  Glivec specifically targets the surface tyrosine
  kinase receptor c-Kit (CD117), which is now
  recognised as the hallmark immunohistochemical
  cell marker of GIST.
• Before Glivec
• The majority of GISTs (95) are highly resistant
  to radiation and systemic therapy, and, until
  now, surgery has been the only effective
  treatment option. Unfortunately, many GISTs are
  unresectable, and metastatic GISTs are
  essentially incurable, with a median survival of
  10 to 21 months, and for these tumours,
  palliative surgery or chemotherapy has been the
  only therapeutic option

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Prognostic factors
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• Display gifferent degrees of aggressiveness
• Biological behaviour prediction conflicting
  reports
• Criteria
• ? Siz lt5cm
• ? Mitosis gt5/hpf
• ? Necrosis
• ? MiB1 gt10
• ? Invasive character
• ? Symptoms
• ? Histology
• ? IHC
• ? Met
• ? Node invasion

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• The two most easily applicable criteria for
  predicting recurrence
• Size and Mitosis

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Fletcher et al 2002
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• ? Very low risk lt2 cm lt5/50 HPF
  Excellent
• ? Low risk 25 cm lt5/50 HPF
• ? Intermediate lt5 cm 610/50 HPF
• 510 cm lt5/50
  HPF
• ? High risk gt5 cm gt5/50 HPF
• gt10 cm any
  mitotic rate Recurrence
• any size gt10/50
  HPF

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Bucher et al 2004
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• Minor criteria
• ? Size 5 cm
• ? Mitosis 5 /50 hpf
• ? Necrosis
• ? Infiltration of adjacent structures (i.e.
  mucosa or serosa)
• ? MiB1 index 10
• Major criteria
• ? Node invasion
• ? Met
• Low malignant potential (LMP) 5-y - 95
• lt 4 minor criteria
• High malignant potential (HMP) 5-y - lt20
• 4 or 5 minor or 1 major

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• Both scales need to be Validated in large
  prospective GIST trials

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Treatment
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• Surgical resection Choice
• Resectability rate (RR) 50 90 ??
• Non specialised centres high RR
• Specialised centres advanced
• Completeness of resection correlates with
  survival

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Extent of resection
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• ? En bloc (R0)
• ? 2 cm Wedge(gastric) or Segmental(bowel)
• ? Large extensive en bloc including adjacent
  structures / organs
• ? Incomplete Palliative. Risk of bleeding

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Synchronous liver met
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• Resection advocated when applicable, since a
  complete long term response to Glivec not
  demonstrated
• Non-resectable complementary resection should
  be done after response to Glivec

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Lymph node dissection
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• GIST, even with high malignant potential,
  metastasise to lymph nodes Infrequently to
  warrant node dissection

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• There is no indication for Chemo Radio after
  resection because Unresponsive

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Molecular targeted therapy
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• Several protein kinases are overexpressed due
  to gene mutations
• Targeted for selective pharmacological
  inhibitors
• Breakthrough
• Imatinib mesylate (Glivec)
• 
  

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• Glivec powerful selective inhibitor of all
  ABL tyrosine kinases c-kit, c-ABL, bcr-ABL
  PDGFRA
• Efficacy assessed in CML
• Mechanism
• A- Inhibits KIT PDGFRA by reversible
  binding (vast majority of KIT mutants wild KIT
  are sensitive)
• B- Inhibits ligand-stimulated native PDGFRA
  PDGFRA mutant
• 
  

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Prognosis
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• Overall 5 y surv 48 - 80
• LMP 95
• HMP 0 30
• No long-term surv data available for malignant
  GIST in Glivec era
• Major improvement 1 y 90 vs lt 50 before
  Glivec
• 
  

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• Recurrence
• LMP extremly rare
• HMP gt 80
• Follow - up
• ? LMP yearly
• ? HMP closer. 50 recur during 1 year
• ? PET The most reliable
• ? CT Valuable for recur

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