GIST cology Oncology Oncology F ALMashat Dep of

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GIST cology @@@@@ Oncology @@@@@ Oncology @@@@ F. AL-Mashat Dep of surgery Kauh &

GIST cology @@@@@ Oncology @@@@@ Oncology @@@@ F. AL-Mashat Dep of surgery Kauh & Kahoc

Definition cology @@@@@ Oncology @@@@@ Oncology @@@@ c-Kit–positive mesenchymal tumours (MT) with specific histological

Definition cology @@@@@ Oncology @@@@@ Oncology @@@@ c-Kit–positive mesenchymal tumours (MT) with specific histological & IHC characteristics occuring in GIT

History cology @@@@@ Oncology @@@@@ Oncology @@@@ ① 20 y most MT of gut

History cology @@@@@ Oncology @@@@@ Oncology @@@@ ① 20 y most MT of gut were considered to be of smooth muscle or perineural origin ② Mazur & Clark (1983): GIST ③ Kindblom(1998): Interstitial cell of Cajal GIPACT ④ Today, most gut MT previously designated leiomyomas, leiomyoblastomas & leiomyosarcomas are GIST ⑤ True gut leiomyomas & schwannomas remain to be identified

Epidemiology cology @@@@@ Oncology @@@@@ Oncology @@@@ ■ The most common MT of gut

Epidemiology cology @@@@@ Oncology @@@@@ Oncology @@@@ ■ The most common MT of gut ■ 0. 1 - 3% of gut cancers ■ Incidence: 20/10 people/year ■♂=♀ ■ Predominantly 5 - 7 decades. Rare < 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

Manifestations cology @@@@@ Oncology @@@@@ Oncology @@@@ ■ Difficult early diagnosis, often asymptomatic ■

Manifestations cology @@@@@ Oncology @@@@@ Oncology @@@@ ■ 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

Diagnosis cology @@@@@ Oncology @@@@@ Oncology @@@@ ① CT: Standard. Extraluminal mass + central

Diagnosis cology @@@@@ Oncology @@@@@ Oncology @@@@ ① CT: Standard. Extraluminal mass + central necrosis ② MRI ③ Barium & Endoscopy ④ Biopsy/ FNA: Peritoneal seeding. Only unresectable ⑤ 18 FDG-PET: Follow-up ⑥ Surgery: well defined extraluminal mass, frequently lobulated

Schematic structure of the c-Kit tyrosine kinase cology @@@@@ • . Oncology @@@@@ Oncology

Schematic structure of the c-Kit tyrosine kinase cology @@@@@ • . Oncology @@@@@ Oncology @@@@@ Oncology @@@@ 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

c-Kit signal transduction cology @@@@@ Oncology @@@@@ Oncology @@@@ Binding of the ligand SCF

c-Kit signal transduction cology @@@@@ Oncology @@@@@ Oncology @@@@ 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.

Pathology cology @@@@@ Oncology @@@@@ Oncology @@@@ ① Cells may resemble mesenchymal, neural, &

Pathology cology @@@@@ Oncology @@@@@ Oncology @@@@ ① Cells may resemble mesenchymal, neural, & smooth muscle ② Spindle cell (70%) , less commonlly Epithelioid or Mixed cell phenotype ① 1 cm to > 40 cm ② extraluminal with frequent mucosal ulceration ③ well circumscribed & pseudo-encapsulation ④ frequent necrosis, cystic degeneration & focal haem

Immunohistochemistry cology @@@@@ Oncology @@@@@ Oncology @@@@ ■ +ve c-Kit (90 – 100 %)

Immunohistochemistry cology @@@@@ Oncology @@@@@ Oncology @@@@ ■ +ve c-Kit (90 – 100 %) ■ recommended: c-Kit be performed on all intraabdominal sarcoma-like tumours ■ performed on fixed paraffin or frozen ■ CD 34: 70% - 80%. expressed in many tumours, so modestly specific ■ Actin (30 %) & Keratin (<10 %) ■ Desmin & S-100: -ve ■ Vimentin: +ve ■ Ki 67: may aid in prognosis and monitoring

cology @@@@@ Oncology @@@@@ Oncology @@@@ Histological & I H C ( KIT, CD

cology @@@@@ Oncology @@@@@ Oncology @@@@ Histological & I H C ( KIT, CD 34) are the defining features of GIST

Treatment cology @@@@@ Oncology @@@@@ Oncology @@@@ • • Until now limited treatment options,

Treatment cology @@@@@ Oncology @@@@@ Oncology @@@@ • • 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 (CD 117), 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

Prognostic factors cology @@@@@ Oncology @@@@@ Oncology @@@@ ■ Display gifferent degrees of aggressiveness

Prognostic factors cology @@@@@ Oncology @@@@@ Oncology @@@@ ■ Display gifferent degrees of aggressiveness ■ Biological behaviour prediction: conflicting reports ■ Criteria: ① Siz: <5 cm ② Mitosis: >5/hpf ③ Necrosis ④ Mi. B 1: >10% ⑤ Invasive character ⑥ Symptoms ⑦ Histology ⑧ IHC ⑨ Met ⑩ Node invasion

cology @@@@@ Oncology @@@@@ Oncology @@@@ The two most easily applicable criteria for predicting

cology @@@@@ Oncology @@@@@ Oncology @@@@ The two most easily applicable criteria for predicting recurrence: Size and Mitosis

Fletcher et al 2002 cology @@@@@ Oncology @@@@@ Oncology @@@@ ① Very low risk:

Fletcher et al 2002 cology @@@@@ Oncology @@@@@ Oncology @@@@ ① Very low risk: <2 cm <5/50 HPF ② Low risk Excellent : 2– 5 cm <5/50 HPF ③ Intermediate: <5 cm 6– 10/50 HPF 5– 10 cm <5/50 HPF ④ High risk : >5 cm >5/50 HPF >10 cm any mitotic rate any size >10/50 HPF Recurrence

Bucher et al 2004 cology @@@@@ Oncology @@@@@ Oncology @@@@ Minor criteria ① Size

Bucher et al 2004 cology @@@@@ Oncology @@@@@ Oncology @@@@ Minor criteria ① Size ≥ 5 cm ② Mitosis ≥ 5 /50 hpf ③ Necrosis ④ Infiltration of adjacent structures (i. e. mucosa or serosa) ⑤ Mi. B 1 index ≥ 10% Major criteria ① Node invasion ② Met Low malignant potential (LMP): 5 -y - 95% < 4 minor criteria High malignant potential (HMP): 5 -y - <20% 4 or 5 minor or 1 major

cology @@@@@ Oncology @@@@@ Oncology @@@@ Both scales need to be Validated in large

cology @@@@@ Oncology @@@@@ Oncology @@@@ Both scales need to be Validated in large prospective GIST trials

Treatment cology @@@@@ Oncology @@@@@ Oncology @@@@ Surgical resection: Choice ■ Resectability rate (RR):

Treatment cology @@@@@ Oncology @@@@@ Oncology @@@@ Surgical resection: Choice ■ Resectability rate (RR): 50 – 90 % ? ? Non specialised centres: high RR Specialised centres: advanced ■ Completeness of resection correlates with survival

Extent of resection cology @@@@@ Oncology @@@@@ Oncology @@@@ ① En bloc (R 0)

Extent of resection cology @@@@@ Oncology @@@@@ Oncology @@@@ ① En bloc (R 0) ② ≤ 2 cm: Wedge(gastric) or Segmental(bowel) ③ Large: extensive en bloc including adjacent structures / organs ④ Incomplete: Palliative. Risk of bleeding

Synchronous liver met cology @@@@@ Oncology @@@@@ Oncology @@@@ ■ Resection advocated when applicable,

Synchronous liver met cology @@@@@ Oncology @@@@@ Oncology @@@@ ■ 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

Lymph node dissection cology @@@@@ Oncology @@@@@ Oncology @@@@ GIST, even with high malignant

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

cology @@@@@ Oncology @@@@@ Oncology @@@@ There is no indication for Chemo & Radio

cology @@@@@ Oncology @@@@@ Oncology @@@@ There is no indication for Chemo & Radio after resection because: Unresponsive

Molecular targeted therapy cology @@@@@ Oncology @@@@@ Oncology @@@@ ■ Several protein kinases are

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

cology @@@@@ Oncology @@@@@ Oncology @@@@ ■ Glivec: powerful & selective inhibitor of all

cology @@@@@ Oncology @@@@@ Oncology @@@@ ■ 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

Prognosis cology @@@@@ Oncology @@@@@ Oncology @@@@ ■ Overall 5 y surv: 48 -

Prognosis cology @@@@@ Oncology @@@@@ Oncology @@@@ ■ 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 < 50% before Glivec

cology @@@@@ Oncology @@@@@ Oncology @@@@ ■ Recurrence: LMP: extremly rare HMP: > 80

cology @@@@@ Oncology @@@@@ Oncology @@@@ ■ Recurrence: LMP: extremly rare HMP: > 80 % ■ Follow - up: ☊ LMP: yearly ☊ HMP: closer. 50% recur during 1 year ☊ PET: The most reliable ☊ CT: Valuable for recur

cology @@@@@ Oncology @@@@@ Oncology @@@@

cology @@@@@ Oncology @@@@@ Oncology @@@@