Gastrointestinal Stromal Tumours(GIST)

1. Gastrointestinal Stromal Tumours(GIST)

2. 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 .

3. 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

4. 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

5. 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

6. 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

7. 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

8. GISTs are identified by: • either c-kit immunoreactivity (detection of the CD117 antigen) or • the presence of activating mutations in KIT or PDGFRa

9. 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

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

11. 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

12. 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)

13. H&E stain C-kit(CD 117)

14. 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

15. Approach for defining Risk of Aggressive Behavior in Gastrointestinal Stromal Tumors

16. 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

17. 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 .

18. 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

19. CT scan

20. Endoscopy

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

23. 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

24. 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

25. 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.

26. 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.

27. MANAGEMENT OF ADV. GIST

28. MANAGEMENT OF UNRESECTABLE GIST :

29. MANAGEMENT OF METASTATIC GIST : 

30. 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

31. 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.