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  1. 1. <ul><li>62yr old male pt with pmh of HTN, ESRD, with severe headache , chest pain and nausea since last 3 days </li></ul><ul><li>Pt was medically stabilized transferred to medicine floor for further management </li></ul><ul><li>Hgb between 7-9 and FOBT was positive </li></ul>
  2. 2. <ul><li>-GI consulted , recommended endoscopy </li></ul><ul><li>- Endoscopy revealed 3cm sub mucosal mass in proximal body stomach </li></ul><ul><li>Multiple biopsies were taken </li></ul>
  3. 3. <ul><li>Spindle cells from biopsy specimen were positive for CD117 and CD 34 </li></ul>
  4. 5. Epidemiology <ul><li>The most common nonepithelial benign neoplasm involving the GI tract </li></ul><ul><li>the annual incidence of GIST in the United States is at least 4000 to 6000 new cases </li></ul><ul><li>  Although the majority of GISTs appear to be sporadic, several kindreds with heritable mutations in the KIT gene have been identified. </li></ul>
  5. 6. MOLECULAR PATHOLOGY <ul><li>They are characterized by expression of a tyrosine kinase growth factor receptor, also called kit receptor or CD117. </li></ul><ul><li>This expression allows unchecked growth of tumor and resistance to apoptosis. </li></ul><ul><li>KIT gene mutations is present in exon 9, 13, or 17, that results in uncontrolled KIT signaling </li></ul>
  6. 7. - These tumors differ immunohistologically and behaviorally from other mesenchymal tumors such as leiomyosarcomas, which do not express kit antigen
  7. 8. Cellular origin of GISTs <ul><li>Interstitial cells of Cajal (ICC) </li></ul><ul><li>GI pacemaker cells </li></ul><ul><li>form the interface between the autonomic innervation of the bowel wall and the smooth muscle itself </li></ul><ul><li>immunophenotypic and ultrastructural features of both smooth muscle and neuronal differentiation and serve to regulate peristalsis </li></ul>
  8. 9. Histopathology <ul><li>Spindle cell type — 70 percent </li></ul><ul><li>Epithelioid type — 20 percent </li></ul><ul><li>Mixed type — 10 percent </li></ul>
  9. 10. <ul><li>(upper panel) is composed of spindle cells with elongated nuclei and eosinophilic cytoplasm </li></ul><ul><li>(lower panel) consist of epithelioid cells having round central nuclei within eosinophilic or clear cytoplasm. </li></ul>
  10. 11. TNM staging Primary tumor (T) TX Primary tumor cannot be assessed T0 No evidence for primary tumor T1 Tumor 2 cm or less T2 Tumor more than 2 cm but not more than 5 cm T3 Tumor more than 5 cm but not more than 10 cm T4 Tumor more than 10 cm in greatest dimension Regional lymph nodes (N) N0 No regional lymph node metastasis* N1 Regional lymph node metastasis Distant metastasis (M) M0 No distant metastasis M1 Distant metastasis
  11. 12. <ul><li>Features favoring benign lesions in general like: </li></ul><ul><ul><li>Size less than 5 cm </li></ul></ul><ul><ul><li>Low number of mitosis per HPF </li></ul></ul><ul><ul><li>No mucosal invasion </li></ul></ul><ul><ul><li>Low cellularity </li></ul></ul><ul><ul><li>Low markers of cell proliferation </li></ul></ul><ul><li>The above have shown to be associated with malignant behavior in some but not in other studies. </li></ul><ul><li>With prolonged follow up any GIST has the potential to behave in a malignant fashion. </li></ul><ul><li>50% of primary localized tumors that are resected relapse after 5 years of follow up </li></ul>
  12. 13. CLINICAL MANIFESTATIONS  <ul><li>Overt GI bleeding — 40 percent </li></ul><ul><li>Abdominal mass — 40 percent </li></ul><ul><li>Abdominal pain — 20 percent </li></ul><ul><li>GISTs frequently metastasize to liver and peritoneum and rarely to regional lymph nodes. </li></ul>
  13. 14. DIAGNOSTIC WORK-UP  <ul><li>CT scan : to characterize an abdominal mass, evaluate its extent, and the presence or absence of metastatic disease. </li></ul><ul><li>The usual CT appearance of a GIST is that of a solid smoothly contoured mass that enhances brightly with IV contrast. </li></ul>
  14. 15. Tumor arising from gastric wall
  15. 16. Upper endoscopy  <ul><li>Endoscopy may be useful to further characterize the lesion if a gastric mass is identified </li></ul><ul><li>Endoscopic biopsies using standard techniques usually do not obtain sufficient tissue for a definite diagnosis </li></ul>
  16. 17. Endoscopic view of an actively oozing 20mm by 30mm submucosal mass in the body of the stomach body (left panel). Bleeding was controlled by injection of a 1:10,000 epiniphrine solution and bioploar electrocautery (right panel).
  17. 18. Endoscopic ultrasonography  <ul><li>EUS-guided fine-needle aspiration — for cytologic analysis, immunohistochemistry, and KIT mutations </li></ul><ul><li>If metastatic disease is suspected or if preoperative imatinib is considered prior to attempted resection </li></ul>
  18. 19. First patient to be treated with Imatinib <ul><li>54 year old female with metastatic GIST diagnosed in 1996 </li></ul><ul><li>Liver metastases and multiple small intra-abdominal metastases were excised in February 1998 and in September 1998 </li></ul><ul><li>Seven cycles of chemotherapy with doxorubicin, </li></ul><ul><li>ifosfamide, and dacarbazine with no response </li></ul>
  19. 20. <ul><li>In March 1999 had bowel obstruction and on laparotomy had diffuse intraabdominal mets. </li></ul><ul><li>Received thalidomide and interferon with no response </li></ul><ul><li>Treatment with 400 mg Imatinib once daily was started in March 2000. </li></ul>
  20. 22. Before and after im
  21. 23. IMATINIB FOR GIST <ul><li>Imatinib is approved in the United States for use as adjuvant therapy for any primary GIST ≥3 cm. </li></ul><ul><li>tyrosine kinase inhibitors such as imatinib block signaling via KIT and PDGFRA, thus halting tumor proliferation. </li></ul><ul><li>median survival of patients with advanced GIST increased from an average of 18 to 57 months in the trial with the longest follow-up to date </li></ul>
  22. 24.   Assessing response <ul><li>PET scanning : responses can be observed within 24 hours of starting therapy. </li></ul><ul><li>Rarely used to assess the response of therapy </li></ul><ul><li>Can be used for a patient with a borderline resectable GIST or a potentially resectable tumor that requires extensive organ disruption who is being treated with initial imatinib </li></ul>
  23. 25. contd….. <ul><li>CT scan: re-evaluation should be done two to three months after starting therapy </li></ul>
  24. 26. Side effects: <ul><li>fluid retention: diuretics useless, upright during day </li></ul><ul><li>diarrhea: loperamide, atropine </li></ul><ul><li>nausea:antacid, proton pump inhibitor </li></ul><ul><li>muscle cramps: Ca or Mg supplements </li></ul><ul><li>Rash: resolves with continued treatment </li></ul>
  25. 27. MANAGEMENT OF REFRACTORY OR INTOLERANT PATIENTS <ul><li>Switching to an alternative TKI, sunitinib </li></ul><ul><li>Dose escalation may be considered in patients started on imatinib 400 mg daily who, after careful review of radiologic studies, are judged to have clear evidence of disease progression. </li></ul>
  26. 28. GENERAL SURGICAL PRINCIPLES  <ul><li>Preoperative biopsy:biopsy is preferred to confirm the diagnosis if metastatic disease is suspected or if preoperative imatinib is considered prior to attempted resection in a patient who has a large locally advanced lesion thought to represent a GIST. </li></ul><ul><li>All GISTs ≥2 cm in size should be resected. </li></ul>
  27. 29. <ul><li>The natural history of these and other GISTs between 1 and 2 cm, including their growth rate and metastatic potential, remains unknown. </li></ul><ul><li>initial therapy with imatinib may be preferred if a tumor is borderline resectable, or if resection would necessitate extensive organ disruption. </li></ul>
  28. 30. Management of gastrointestinal stromal cell tumors
  29. 31. POSTTREATMENT FOLLOW-UP <ul><li>completely resected GIST tumor: every three to six months for five years, then annually. </li></ul><ul><li>locally advanced or metastatic disease who are receiving imatinib: every three to six months. </li></ul>
  30. 32. Further reading <ul><li>Abeloff: Abeloff's Clinical Oncology, 4th ed. </li></ul><ul><li>Feldman: Sleisenger & Fordtran's Gastrointestinal and Liver Disease, 9th ed. </li></ul><ul><li>Quek R - Hematol Oncol Clin North Am - 01-FEB-2009; 23(1): 69-78, viii </li></ul>