G I S T

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


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


History

Epidemiology

■ 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

■ 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

① CT: Standard. Extraluminal mass + central necrosis

② MRI ③ Barium & Endoscopy ④ Biopsy/ FNA: Peritoneal seeding. Only

unresectable⑤ 18FDG-PET: Follow-up⑥ Surgery: well defined extraluminal mass,

frequently lobulated


Schematic structure of the c-Kit tyrosine kinase

• .


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.


Pathology

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

■ +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

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


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


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


The two most easily applicable criteria for predicting recurrence:

Size and Mitosis


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


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


Bucher et al 2004

Both scales need to be Validated in large prospective GIST trials


Treatment

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

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


Lymph node dissection

GIST, even with high malignant potential, metastasise to lymph nodes Infrequently to warrant

node dissection


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

Unresponsive


Molecular targeted therapy

■ Several protein kinases are overexpressed due to gene mutations

■ Targeted for selective pharmacological inhibitors

Breakthrough

Imatinib mesylate (Glivec)


■ 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

■ 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


■ 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



G I S T

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