1. Gastrointestinal Stromal Cell Tumors Joshua D. I. Ellenhorn, M.D. Clinical Professor of Surgery GIST

2. 46 year-old female presented with a 20 pound weight loss melena and dyspnea. Abdominal exam revealed an ill defined left upper quadrant mass. Hgb 4.9 Case Presentation 3. The patient was transfused up to a Hgb of 11 Abdominal CT scan was performed 4. mass 1 mass 3 mass 2 5. H&E c-Kit CT guided core biopsy of the mid-abdominal mass revealed a spindle cell neoplasm which was positive for c-Kit by immunohistochemistry 6. How would you treat this patient? 7. How would you treat this patient? 8. How would you treat this patient? 9. GIST Near GEJ How would you treat this patient? 10. How would you treat this patient? 11. GIST Is a Rare Gastrointestinal Sarcoma 4000 - 6000 new cases/year in US 1500 - 2000 cases/year in Japan Most common GI mesenchymal neoplasm 5%-6% of all sarcomas Wide age range 75% of patients >50 years Median age: ~58 years No gender predilection 12. GISTs Present With Variable Symptoms Often asymptomatic, especially when small Symptoms nonspecific GI bleeding (53%) Abdominal pain (32%) Palpable mass (13%) Other symptoms may include Early satiety Fatigue from anemia Rare obstruction 13. GISTs Occur Mainly in the Stomach Occur anywhere along the GI tract or elsewhere in the abdomen or retroperitoneum Corless CL J Clin Oncol. 22:3813-3825 2004 Miettinen M J Arch Pathol Lab Med. 130:1466-1478 2006 14. Arise From Interstitial Cells of Cajal Interstitial cells of Cajal (ICC)1 Pacemaker cells associated with Auerbachs plexus GISTs share several characteristics with ICC1 CD117 (c-KIT) expression, structural similarities Other markers often positive in GIST2 CD34 (60%-70%), muscle actin (SMA), S- 100 ~4%-5% of GISTs are KIT-negative 1. Kindblom L-G et al. Am J Pathol. 1998;152:1259-1269 2. Fletcher CDM et al. Hum Pathol. 2002;33:459-65 c-KIT Staining Cells of Cajal GIST 15. Structure of KIT Receptor Type III receptor tyrosine kinase Extracellular domain binds ligand: stem cell factor (SCF) Downstream effects of SCF binding to KIT are proliferative and antiapoptotic Intracellular domain has 2 tyrosine kinase domains Multiple autophosphorylation sites SCF binding site 5 IgG domains Cell membrane Tyrosine kinase domains Taylor and Metcalfe. Hematol Oncol Clin North Am. 2000;14:517. 16. Normal KIT Signaling PP P ADP P P PP P ATP SIGNALING Kinase domains Substrate Effector The KIT kinase domain activates a substrate protein This activated substrate initiates a signaling cascade culminating in cell proliferation and survival Savage and Antman. N Engl J Med. 2002;346:683. Scheijen and Griffin. Oncogene. 2002;21:3314. 17. Mutations in GIST PDGFRA 5% 18. Patient Workup Guides Surgical Procedure Initial patient workup should include Complete lab studies CT of abdomen and pelvis with oral IV contrast Selective use of tissue biopsy EUS or CT-FNA Cytology/pathology for spindle cell morphology, CD117(c-KIT) Comorbidity assessment 19. Surgical Treatment of GISTs Surgery optimal for resectable GIST Goals of surgery Complete gross resection Negative microscopic margins (R0 resection) If recurrence develops after surgery, disease is usually not curable 20. Important Surgical Considerations for the Treatment of GIST Metastasis commonly develop in liver and peritoneum1,2 Liver (65%-72%) Peritoneum (21%-64%) Bone (4%-6%) Lung (2%-4%) Lymph node metastases are rare Tumors typically grow extraluminal3 Careful tumor handling is critical Soft fragile tumors that may rupture during surgery Rupturing of pseudocapsule may cause tumor bleeding and/or dissemination 1. DeMatteo RP et al. Ann Surg. 2000;231:51-58. 2. Burkill GJC et al. Radiology. 2003;226:527-532. 3. Corless CL et al. J Clin Oncol. 2004;22(18):3813-3825. 21. Important to Differentiate Between Adenocarcinoma and GIST Small Proximal Gastric GIST Infiltrating adenocarcinoma 22. GIST vs Adenocarcinoma Resections Entail Different Considerations GIST Adenocarcinoma Margins Wide margins not required For clear margins, need a 4-cm distance from tumor Need 10-cm margins for diffuse-type tumors Gastrectomy Wedge or segmental resection often sufficient Formal gastrectomy for large proximal gastric GISTs Total gastrectomy for tumors in proximal third of stomach Lymphadenectomy Lymphadenectomy unnecessary Lymphadenectomy for staging and therapeutic purposes 23. No difference in OR time No difference in margin clearance or recurrence Less blood loss (25 vs. 100 ml) Shorter hospital stay (4 vs. 7 days) Laparoscopic Resection of Gastric GIST Size Matched comparison to Open ( 5cm; median 9 cm. Metastatic/recurrent Kit+ GIST > 2cm Treatment: 600 mg imatinib/day for 8-12 weeks prior to surgery Resume imatinib post-op for 2 years adjuvantly Eisenberg BL et al. J Surg Oncol 2009; 99:42-47.Eisenberg BL et al. J Surg Oncol 2009; 99:42-47. 45. Neoadjuvant Imatinib for GIST (RTOG 0132/ACRIN 6665) Results: 63 patients enrolled; 52 analyzable Locally advanced (PR 7%; SD 83%; unknown 10%) Surgery: R0 (77%); R1 (15%); R2 (8%) Recurrent/Metastatic (PR 4.5%; SD 91%; PD 4.5%) Surgery: R0 (58%); R1 (5%); R2 (32%); unspecified (5%) 2 yr PFS: Loc Advanced (82.7%), Rec/Met (77.3%) 2 yr OS: Loc Advanced (93.3%), Rec/Met (90.9%) Eisenberg BL et al. J Surg Oncol 2009; 99:42-47.Eisenberg BL et al. J Surg Oncol 2009; 99:42-47. 46. Unresectable or metastatic GIST Marginally resectable GIST Surgical morbidity could be improved by preoperative reduction of tumor size Recommended starting dose is 400 mg/day dose of 800 mg/day for patients with KIT exon 9 mutations Dosing can be stopped right before surgery and restarted as soon as the patient is able to tolerate oral medications Neoadjuvant Imatinib 47. Anemia and Neutropenia Nausea and vomiting Edema (swelling of the face, feet, hands) Muscle cramps and bone pain Diarrhea Hemorrhage Skin rash Fever Imatinib Side Effects 48. 46 year-old female presented with a 20 pound weight loss melena and dyspnea. Abdominal exam revealed an ill defined left upper quadrant mass. Hgb 4.9 Case Presentation 49. The patient was transfused up to a Hgb of 11 Abdominal CT scan was performed 50. mass 1 mass 3 mass 2 51. H&E c-Kit CT guided core biopsy of the mid-abdominal mass revealed a spindle cell neoplasm which was positive for c-Kit by immunohistochemistry 52. Day 0 Day 60 Imatinib Day 5 Imatinib 53. 10 weeks 54. At the time of operation the patient was found to have a bilobed mass involving the third portion of the duodenum and an additional lesion involving segments 2/3 of the liver. She underwent resection of the third portion of the duodenum along with the proximal jejunum. A left lateral segmentectomy of the liver was performed. 55. Pathology revealed an 8 cm GIST in the liver and two separate GIST tumors adjacent to the duodenum 7.5 and 10 cm in size. All lesions were resected with negative margins She is currently 4 years postop and has no evidence of disease. She remains on 400 mg of imatinib daily. 56. Day 1 Day 4 Day 45 57. Patient Case Example: How Would You Treat This Patient? 58. GIST Near GEJ 59. GIST Near GEJ 60. Conclusions Surgery is first-line treatment for patients with resectable GISTs Up to 50% patients have recurrence after complete resection Tyrosine kinase inhibitor imatinib now standard treatment for unresectable or metastatic or advanced GIST Adjuvant Imatinib now standard treatment for high risk GIST Neoadjuvant Imatinib for locally advanced GIST