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Gastrinoma. Zollinger-Ellison syndrome

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Gastrinoma. Zollinger-Ellison syndrome

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Gastrinoma. Zollinger-Ellison syndrome

  1. 1. Zollinger – Ellison Syndrome Eduardo A. Guzman MD
  2. 2. Robert Milton Zollinger 1903 - 1992 • Giant of american surgery • “He was respected by his peers, feared by his students and loved by his patients”
  3. 3. Robert Milton Zollinger • Born on September 4, 1903 in Millersport, Ohio • He attended grade school in a one room schoolhouse • Graduated in medicine from the Ohio State University
  4. 4. Robert Milton Zollinger • Internship at Peter Bent Brigham Hospital • Interns were not allowed to get married • In 1929 he married Louise Kiewet at the conclusion of his internship
  5. 5. Robert Milton Zollinger • Residency at Western Reserve University • Chief resident at Harvard with Dr Elliot Cutler • Cutler and Zollinger published the first edition of the ¨Atlas of Surgical Operations¨
  6. 6. Robert Milton Zollinger Military • Joined the army in 1941 • Commanded the 5th general hospital • Legion of Merit Award – Mobile surgical teams • Battle Stars – Normandy – Northern France – Rhineland
  7. 7. Robert Milton Zollinger • Ohio State • Chief of Surgery
  8. 8. Robert Milton Zollinger • President – American Board of Surgery – American Surgical Association – American College of Surgeons • Sheen Award – Highest honor of the AMA • Offered the presidency of the Ohio State University which he turned down • Training Dr Sirinek
  9. 9. Robert Milton Zollinger • Perfectionist • Competitive • Humane • Died in 1992 of pancreatic cancer
  10. 10. GASTRINOMA Recent advances and ongoing controversies
  11. 11. • 1954 • Ohio State University • Dr Robert Zollinger • Dr Edwin Ellison Discovery
  12. 12. Southern Surgical Association • 1955 • 2 patients with a clinical triad of – Benign jejunal ulcers – Extreme acid hyper secretion – Non β Islet cell pancreatic tumors
  13. 13. Gastrin • Gregory 1960 • G cells • Gastric antrum • Acid release • 1976 Gastrin Radioimmunoassay
  14. 14. • Tumor – ¾ malignant • Incidence – 2 per million population – 0.1 % of patients with duodenal ulcers – 2 % of patients with recurrent ulcers • 80 % sporadic • 20 % as part of the MEN 1 syndrome Gastrinoma
  15. 15. Identification Treat Localize Diagnose Identify
  16. 16. ↑ Gastrin ↑ Gastric acid Duodenal ulcer Bowel mucosal injury Bleeding Diarrhea Pain Malabsorption Complications Pathophysiology
  17. 17. Clinical syndrome • Manifestations of peptic ulcer disease – Pain – Bleeding – Obstruction – Perforation • Diarrhea • Malabsorption
  18. 18. Diarrhea • Not typical for ulcer disease • A prominent feature of Zollinger Ellison syndrome
  19. 19. Clinical syndrome • Patients are often times misdiagnosed – Crohn’s – Irritable bowel syndrome – Celiac sprue – Lactose intolerance • A high index of suspicion is required to make the diagnosis
  20. 20. Clues • Diarrhea • Ulcers in atypical locations – Distal duodenum – Jejunum • H Pylori negative • Failure of medical management • Recurrent ulcers • Hyperparathyroidism
  21. 21. Impact of antacid therapy on the presentation of gastrinomas • Less dramatic presentation • Complicating the diagnosis of gastrinoma • More patients with advanced disease • Lower survival C. Ellison. The American Journal of Surgery 2003
  22. 22. Study Period 1955–65 Discovery 1966–75 Recognition 1976–85 Gastrin RIA 1986–98 Medical tx p value Patients (n) 11 27 21 49 Metastasis 45% 56% 19% 55% 0.030 5-year survival 45% 74% 90% 69% 0.052 5-year disease free survival 0% 4% 29% 2% 0.003 The American Journal of Surgery. 2003
  23. 23. Diagnosis • ↑ Gastric acid • ↑ Gastrin Treat Localize Diagnose Identify
  24. 24. Diferential diagnosis for hypergastrinemia • Gastrinoma • Pernicious anemia • Renal failure • G cell hyperplasia • Atrophic gastritis • Retained gastric antrum • Gastric outlet obstruction • Use of acid suppression medications
  25. 25. Gastrin Radioimmunoassay • Off acid suppressing medicines for 48 hours JE McGuigan. New England Journal of Medicine 1968 < 200 pg/ml Normal 200 – 1000 pg/ml Confirmatory test (70%) >1000 pg/ml Gastrinoma (30%)
  26. 26. Secretin stimulation test (Confirmatory test) • Normally, secretin ↓ gastrin • In gastrinoma, secretin ↑ gastrin • Intravenous secretin • Measure serum gastrin at regular intervals • A rise of 200 pg / ml confirms the diagnosis CW Deveney. Annals of Internal Medicine 1977 H Frucht. Annals of Internal Medicine 1989
  27. 27. Tests for gastric hypersecretion • Basal gastric output – >15 mEq/h if no previous surgery • Maximal gastric outupt • BAO/ MAO ratio – > 0.6 = ZES
  28. 28. Localization Treat Localize Diagnose Identify
  29. 29. Gastrinoma triangle • A – Junction of cystic duct and CBD • B – Junction of second and third portion of duodenum • C – Junction of body and neck of pancreas
  30. 30. Location, location, location JA Norton. The New England Journal of Medicine 1999 • National Institutes of health • 123 patients • Duodenum 47 % • Pancreas 14% • Lymph node 13% • Other locations 9 % • Unknown 16%
  31. 31. Localization Can be found anywhere in the body • CT • MRI • US • Angiography • Somatostation Receptor Scintigraphy
  32. 32. Somatostatin Receptor Scintigraphy “Ocreotide scan” • Gastrinomas have somatostatin receptors • Radioactively labeled ocreotide • Single most sensitive study • Misses small duodenal gastrinomas B Termanini. Gastroenterology 1997
  33. 33. Somatostatin Receptor Scintigraphy Sensitivity SRS CT MRI Angio US SRS + CT 0% 20% 40% 60% 80% 100% Primary tumor JA Norton. The New England Journal of Medicine 1999
  34. 34. Somatostatin Receptor Scintigraphy: Its Sensitivity Compared with That of Other Imaging Methods in Detecting Primary and Metastatic Gastrinomas: A Prospective Study F Gibril. Annals of internal medicine 1996
  35. 35. Operative exploration • 70 % preoperative localization • 20 % Intraoperative localization • 90 % succesful localization
  36. 36. Conduct of the operation • Thorough abdominal exploration • Liver ultrasound • Bimanual palpation of pancreatic head and uncinate • Pancreas ultrasound • Anterolateral duodenotomy with mucosal palpation • Removal of peripancreatic and periduodenal lymph nodes • Frozen section analysis
  37. 37. Treatment Treat Localize Diagnose Identify
  38. 38. Tumor resection • Pancreas head – Enucleation • Pancreas Body or tail – Distal pancreatectomy • Duodenum – Full thickness excision • Gastrectomy not required
  39. 39. Annals of Surgery 2006
  40. 40. Duodenotomy • Dr Norman Thompson • University of Michigan • The primary location for gastrinomas is in the duodenum • Imaging studies miss small duodenal gastrinomas
  41. 41. Annals of Surgery 2004
  42. 42. Postoperative management • Standard postoperative care • At least 2 serum gastrin levels • Secretin stimulation test • Fasting serum gastrin and secretin stimulation test in 6 months
  43. 43. Metastases • 60 – 85 % of gastrinomas are malignant • Hepatic metastases predicts survival • Localized liver metastasis should be considered for surgery
  44. 44. Effect of liver metastases on survival • Liver metastases are the #1 predictor of overall survival • Patients with diffuse liver involvement do worse F Yu. Journal of Clinical Oncology 1999
  45. 45. S Musunuru. Archives of Surgery 2006
  46. 46. Prognosis • Extent of disease – Large tumors – Metastases • Biologic characteristics – Benign / malignant – Aggressive / Non aggressive – MEN 1 syndrome • Surgical therapy – Complete / Incomplete resection
  47. 47. Journal of the American college of surgeons 2005
  48. 48. Summary • Monterrey is a nice place to live • Dr Zollinger was a good man • Gastrinoma is a malignancy • A high index of suspicion is required for diagnosis • More common in the duodenum • A duodenotomy should be routinely performed • Tumor resection improves survival • Liver metastatectomy should be considered • Prognosis is good if completely resected
  49. 49. Controversy 1 What is the role of Endoscopic Ultrasound as preoperative localization method? FOR • It can identify depth of invasion and obtain tissue diagnosis AGAINST • Sensitivity – Pancreas 75% – Dudenum 46 % • Misses small duodenal gastrinomas (same as SRS) • Pancreatic gastrinomas would have been detected by conventional imaging MY ANSWER •Only in MEN 1 patients (multiple tumors)
  50. 50. Controversy 2 Should patients with gastrinoma and MEN1 syndrome undergo routine surgical resection? FOR • Metastatic neuroendocrine tumors are the predominant cause of death in patients with MEN1 AGAINST • Cure is rare in patients with MEN1 – Multiple tumors • Less aggressive nature of tumors • 100 % 15 year survival if tumor < 2.5 cm and no surgical exploration MY ANSWER •No •Surgery if greater than 2.5 cm only
  51. 51. Controversy 3 What is the role of endoscopic resection of small duodenal gastrinomas? FOR • Biochemical cure can occur AGAINST • Misses lymph nodes • Risk of duodenal perforation MY ANSWER •Do not try it
  52. 52. Controversy 4 Should a Whipple procedure be performed for the Zollinger Ellison syndrome? FOR • Whipple may provide a better chance of cure and increased survival since it removes all the nodes. • For MEN 1 AGAINST • Survival already good after current surgery – Sporadic 10 yr 95% – MEN 10 yr 86% • Makes reoperations more difficult • Negates hepatic chemoembolization if liver mets develop MY ANSWER •No •Only for patients that cannot be treated by simple enucleation
  53. 53. Controversy 5 What is the role of surgery for advanced disease? FOR • Liver metastasis is the most important predictor of survival • Patients with diffuse liver metastasis have significantly worse prognosis • Slow tumor growth • May improve symptoms • May increase survival AGAINST • Does not provide cure • Surgical morbidity MY ANSWER •Yes •In selected patients •Limited to one lobe or less than 5 mets
  54. 54. Conclusions • During the last decade has been significant improvements in the surgical treatment of gastrinoma that have had an impact on its localization and survival • Gastrinoma remains a challenging and interesting disease to treat by the surgeon

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