Download
g i s t n.
Skip this Video
Loading SlideShow in 5 Seconds..
G I S T PowerPoint Presentation

G I S T

336 Views Download Presentation
Download Presentation

G I S T

- - - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript

  1. G I S T Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ F. AL-Mashat Dep of surgery Kauh & Kahoc

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

  3. History Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ 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

  4. Epidemiology Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ 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

  5. Manifestations Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ 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

  6. Diagnosis Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ ①CT: Standard. Extraluminal mass + central necrosis ②MRI ③Barium & Endoscopy ④Biopsy/ FNA: Peritoneal seeding. Only unresectable ⑤18FDG-PET: Follow-up ⑥Surgery: well defined extraluminal mass, frequently lobulated

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

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

  9. Pathology Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ ①Cells may resemble mesenchymal, neural, & smooth muscle ②Spindle cell (70%) , less commonlly Epithelioid or Mixed cell phenotype ①1 cm to > 40 cm ②extraluminal with frequent mucosal ulceration ③well circumscribed & pseudo-encapsulation ④frequent necrosis, cystic degeneration & focal haem

  10. Immunohistochemistry Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ ■ +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 (<10 %) ■ Desmin & S-100: -ve ■ Vimentin: +ve ■ Ki67: may aid in prognosis and monitoring

  11. Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Histological & I H C ( KIT,CD34) are the defining features of GIST

  12. Treatment Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ 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 (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

  13. Prognostic factors Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ ■ Display gifferent degrees of aggressiveness ■ Biological behaviour prediction: conflicting reports ■ Criteria: ① Siz: <5cm ②Mitosis: >5/hpf ③ Necrosis ④MiB1: >10% ⑤ Invasive character ⑥ Symptoms ⑦ Histology ⑧IHC ⑨ Met ⑩ Node invasion

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

  15. Fletcher et al 2002 Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ ① Very low risk:<2 cm <5/50 HPF Excellent ② Low risk :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 Recurrence any size >10/50 HPF

  16. Bucher et al 2004 Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Minor criteria ①Size ≥5 cm ②Mitosis ≥5 /50 hpf ③Necrosis ④Infiltration of adjacent structures (i.e. mucosa or serosa) ⑤MiB1 index ≥10% Major criteria ①Node invasion ②Met Low malignant potential (LMP):5-y - 95% < 4 minor criteria High malignant potential (HMP):5-y - <20% 4 or 5 minor or 1 major

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

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

  19. Extent of resection Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ ①En bloc (R0) ②≤ 2 cm: Wedge(gastric) or Segmental(bowel) ③Large: extensive en bloc including adjacent structures / organs ④ Incomplete: Palliative. Risk of bleeding

  20. Synchronous liver met Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ 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

  21. Lymph node dissection Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ GIST, even with high malignant potential, metastasise to lymph nodes Infrequentlyto warrant node dissection

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

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

  24. Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ 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

  25. Prognosis Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ 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

  26. Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ 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

  27. Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@ Oncology @@@@@