Gastrointestinal Stromal Tumours(GIST)

INTRODUCTION :

• Stromal or mesenchymal tumors of the GI tract are divided into two groups: – 1. Those identical to tumors of the soft tissue arising in the rest of the body (Lipomas, Schwannomas, Hemangiomas, Usual Leiomyomas, etc.) – 2. Stromal tumors arising from the smooth muscle of the alimentary tract: GIST • The term “GIST” was applied by Mazur and Clark in 1983 to define intra-abdominal tumors that were not carcinomas .

EPIDEMIOLOGY

• • • • • • Most common non epithelial benign neoplasm of the GI tract . GIST represents a form of sarcoma that comprises approx. 1% to 3% of all malignant GI tumors.

GIST occurs predominantly in adults . The incidence has been slightly higher in men than women. Small asymptomatic GISTs are found at autopsy in more than 50 % of individuals over the age of 50 GIST treatment trials estimate an annual incidence of 4,500 – 6,000 new cases

MOLECULAR PATHOBIOLOGY GIST

• • • • • GIST represents a form of sarcoma.

GISTs originally thought to derive from smooth muscle, but only rarely showed clear-cut features of complete muscle differentiation.

Work in the 1990s: Some tumors classified as GIST were truly myogenic, some neural, others bidirectional and some had the ‘null’ phenotype Up to two-thirds were CD34 positive Unfortunately, Schwannomas and a proportion of true smooth muscle tumors were also CD 34 positive

ENTER :Membrane (Receptor) Tyrosine Kinase

• • PTKs are involved in cellular signaling pathways and regulate key cell functions such as proliferation, differentiation, anti-apoptotic signaling and neurite outgrowth. Unregulated activation of these enzymes can lead to various forms of cancer as well as benign proliferative conditions. •Nishida T, Hirota S, Taniguchi M, et al: Familial gastrointestinal stromal tumours with germline mutation of the KIT gene

GIST and C-kit

• • • • The c-kit receptor is one of many membrane tyrosine kinase receptors involved in cellular signaling pathways.

CD117 molecule (or antigen) is part of the c-kit receptor, a membrane tyrosine kinase.

The c-kit receptor is a product of the c-kit or KIT protooncogene.

The CD117 antigen is expressed by almost all GISTs in contrast to other spindle-cell tumors of the GI tract

UNCONTROLLED KINASE ACTIVATION (THE MOLECULAR ETIOLOGY)

• • In normal cells activation of the of the c-kit tyrosine kinase requires the presence of an endogenous ligand (KIT ligand, c kit ligand, or stem cell factor) Approx 80 % of GISTs have KIT protooncogene mutations that lead to activation of the c-kit receptor resulting in spontaneous receptor activation not requiring a ligand • • Observed both in sporadic and hereditary cases A subset of GISTs lacking c-kit mutations have activating mutations in the

PGFRa

gene (platelet derived growth factor receptor alpha), another tyrosine kinase

GISTs are identified by:

• either c-kit immunoreactivity (detection of the CD117 antigen) or • the presence of activating mutations in KIT or PDGFRa

Are GISTs derived from ICCs?

• • • • • • Interstitial cells of Cajal (ICC) form the interface between the autonomic innervation of the bowel wall and the smooth muscle itself.

The KIT RTK plays essential roles in the development and maintenance of normal ICCs . Ultrastructural and immunophenotypic features of both neuronal and smooth muscle differentiation (just like GISTs) It is postulated that GISTs originate from CD34 positive stem cells within the wall of the gut and differentiate toward the pacemaker cell phenotype (ICC) Malignant GISTs may represent dedifferentiated ICCs that maintain a CD34-positive stem cell phenotype Attractive hypothesis but still open to question

LOCATION :

• • • • • Stomach – 50 percent Small bowel – 25 percent Colon/ Rectum– 10 percent Omentum/mesentery 7 – percent Esophagus – 5 percent

CELLULAR MORPHOLOGY

• Three relatively distinctive types –

Spindle cell type

– 70 percent –

Epithelioid type

– 20 percent, more commonly c kit negative and found in omentum and mesentery –

Mixed type

– 10 percent Histologic type may be of prognostic significance, worse with epitheloid

HISTOPATHOLOGY

• Differential Diagnosis – H&E stain: Melanoma, leiomyoma/sarcoma, peripheral nerve sheath tumor, desmoid – Histology difficult – Immunophenotyping • crucial 95 % are positive for C-kit (CD117) • • 60-70 % positive for CD34 Negative for alpha-smooth muscle actin (SMA) (leiomyoma) • • Negative for S100 protein (Schwannoma) Negative for Desmin (desmoids)

H&E stain C-kit(CD 117)

Determinants of Malignant Behavior

• • Size: More than 3 cm in diameter(most malignant GISTs are larger than 10 cm at diagnosis) • Mitotic rate: > 25 mitoses per 50 high power fields Warning: Even very small lesions (< 2 cm) with a low mitotic rate occasionally metastasize

Approach for defining Risk of Aggressive Behavior in Gastrointestinal Stromal Tumors

Metastasis

• GISTs behave differently than other soft tissue sarcomas: – GISTs frequently metastasize to the liver and rarely to regional lymph nodes – GISTs virtually never metastasize to lungs whereas this is the most common site of metastasis for leiomyosarcomas

CLINICAL MANIFESTATIONS

• • • • Mesenchymal tumors of the GI tract are often asymptomatic and discovered incidentally during endoscopic or barium studies. Overt GI bleeding — 40 percent Abdominal mass — 40 percent Abdominal pain — 20 percent – The vast majority of GIST metastases at presentation are intra-abdominal, either with metastases to the liver, omentum, or peritoneal cavity .

Diagnosis :

• CT scan – Leiomyomas: solid hypodense lesions – GISTs: typically enhance with IV contrast • Endoscopy • Smoothly contoured submucosal mass, possible central umbilication • EUS • Hypoechoic mass arising from muscularis propria

CT scan

Endoscopy

• PET scan and CT scans in a patient with a GIST metastatic to the liver, before (left) and after treatment with imatinib mesylate

Management :

• • European Consensus Conference Recommendations (Meeting in Lugano Mar 2004) pub in Ann Oncol. 2005 Apr;16(4):566-78.

NCCN Sarcoma Guideline (GIST chapter) updated in 2005

Imatinib (Gleevec) a Tyrosine Kinase Inhibitor

• • Imatinib mesylate is a protein-tyrosine kinase inhibitor that inhibits the Bcr-Abl tyrosine kinase. Imatinib is also an inhibitor PDGF and c-kit , and inhibits PDGF- and SCF-mediated cellular events. In vitro, imatinib inhibits proliferation and induces apoptosis in (GIST) cells, which express an activating c-kit mutation

Imatinib (Gleevec) a Tyrosine Kinase Inhibitor

• • • Imatinib (Gleevec) is very effective for CD114 positive GISTs It also has antitumor effficacy in tumors that lack KIT mutations but have alterations in the PDGF pathway Some PDGFRa mutations are imatinib sensitive, others not therefore, patients with advanced tumors that are histologically c/w GIST should not be denied a trial of imatinib if they are c-kit negative.

Management

PRIMARY, LOCALIZED DISEASE (EARLY-STAGE GIST) • • • • Surgery remains the mainstay of treatment for patients with primary localized GIST GIST lesions are highly vascularized and often exhibit a fragile pseudocapsule; therefore, surgeons should be careful to minimize the risk of tumor rupture.

GIST rarely involves the locoregional lymph nodes. Adjuvant Therapy :At present, it is unclear whether the administration of imatinib in the postresection adjuvant setting would confer significant clinical benefits on patients.

MANAGEMENT OF ADV. GIST

MANAGEMENT OF UNRESECTABLE GIST :

MANAGEMENT OF METASTATIC GIST :

The incidental (asymptomatic) UGI subepithelial mass

• • • • • • • No firm clinical guidelines or consensus Surface Endoscopy can establish a lipomatous nature of the mass If mass is > 1 cm referral for EUS, if < 1 cm repeat EGD in one year, if stable probably no follow-up If mass arises from muscle layer (4th EUS layer mass) and is > 3 cm referral for surgery (likely GIST) Clinical conundrum: The 1 - 3 cm mass 4th layer mass should undergo EUS-FNA and c-kit staining If a GIST is found discuss management strategies, esp. surgery

• • • If results are indeterminate or patient does not wish (or is not a candidate for) resection, endoscopic follow up Recommendations depend on the age of the patient, index of suspicion, etc. One reasonable strategy: EUS follow-up a year later and if lesion is stable for two consecutive follow-up periods, lengthening of the follow-up period.