Gastrointestinal Stromal TumoursGIST INTRODUCTION Stromal or mesenchymal tumors

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 1990 s: Some tumors classified as GIST were truly myogenic, some neural, others bidirectional and some had the ‘null’ phenotype • Up to two-thirds were CD 34 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. • CD 117 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 CD 117 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 c-kit tyrosine kinase requires the presence of an endogenous ligand (KIT ligand, ckit 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 CD 117 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 CD 34 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 CD 34 -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 ckit 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 (CD 117) • 60 -70 % positive for CD 34 • Negative for alpha-smooth muscle actin (SMA) (leiomyoma) • Negative for S 100 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 CD 114 positive GISTs • It also has antitumor effficacy in tumors that lack KIT mutations but have alterations in the PDGF pathway • Some PDGFRa mutations are imatinibsensitive, 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 (4 th EUS layer mass) and is > 3 cm referral for surgery (likely GIST) • Clinical conundrum: The 1 - 3 cm mass • 4 th 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.