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

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

Epidemiology ■ The most common MT of gut ■ % of gut cancers ■ Incidence: 20/10 people/year ■ ♂ = ♀ ■ Predominantly decades. Rare < 40 y Oncology Oncology Oncology Oncology Oncology Oncology Oncology ■ 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 ■ 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 Oncology Oncology Oncology Oncology Oncology Oncology Oncology ■ 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 ① CT: Standard. Extraluminal mass + central necrosis ② MRI ③ Barium & Endoscopy ④ Biopsy/ FNA: Peritoneal seeding. Only unresectable ⑤ 18FDG-PET: Follow-up ⑥ Surgery: well defined extraluminal mass, frequently lobulated Oncology Oncology Oncology Oncology Oncology Oncology Oncology

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

c-Kit signal transduction 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. Oncology Oncology Oncology Oncology Oncology Oncology Oncology

Pathology ① Cells may resemble mesenchymal, neural, & smooth muscle ② Spindle cell (70%), less commonlly Epithelioid or Mixed cell phenotype Oncology Oncology Oncology Oncology Oncology Oncology Oncology 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 ■ +ve c-Kit (90 – 100 %) ■ recommended: c-Kit be performed on all intra- abdominal sarcoma-like tumours ■ performed on fixed paraffin or frozen Oncology Oncology Oncology Oncology Oncology Oncology Oncology ■ 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

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

Treatment 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 Oncology Oncology Oncology Oncology Oncology Oncology Oncology

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

The two most easily applicable criteria for predicting recurrence: Size and Mitosis 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 Oncology Oncology Oncology Oncology Oncology Oncology Oncology Fletcher et al 2002

Minor criteria ① Size ≥5 cm ② Mitosis ≥5 /50 hpf ③ Necrosis ④ Infiltration of adjacent structures (i.e. mucosa or serosa) ⑤ MiB1 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 Oncology Oncology Oncology Oncology Oncology Oncology Oncology Bucher et al 2004

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

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

Extent of resection ① En bloc (R0) 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 ■ 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 Oncology Oncology Oncology Oncology Oncology Oncology Oncology

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

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

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

Prognosis ■ Overall 5 y surv: % 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 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 Oncology Oncology Oncology Oncology Oncology Oncology Oncology