Autoimmune Pancreatitis - a diagnostic challenge

1. Autoimmune Pancreatitis- a diagnostic challenge Dr. Lee Ka Yan Tuen Mun Hospital

2. Autoimmune Pancreatitis • Introduction • A case with autoimmune pancreatitis • Diagnostic features and criteria • Differentiation from Pancreatic Cancer • Summary

3. Autoimmune Pancreatitis (AIP) • A special type of chronic pancreatitis with distinct features • pathological • radiological • Immunological • Extremely difficult to distinguish from malignancy • Obstructive jaundice • Weight loss • Mass in head of pancreas • Prompts a number of major resections (up to 20% in one Japanese Study) • Response to steroid treatment, some with complete disease remission

4. Epidemiology • Prevalence 4-6% of chronic pancreatitis (as high as 11%, Pearson et al. Pancreas 2003) • Male predominance • Age > 45 (youngest 10 years old) • Absence of gallstone or excess alcohol consumption

5. A case with Autoimmune Pancreatitis

6. Mr. Lee • M/68 • Presented with obstructive jaundice • Deranged LFT • TB 80 ALP 352 ALT 355

7. USG abdomen • CBD 9mm and prominent IHDs • ERCP • lower CBD stricture and proximal dilatation, plastic stent inserted • MRCP • intrahepatic duct dilatations • Contrast CT abdomen • Biliary tract obstruction with stent in common duct

8. EUS Pancreas • mildly dilated CBD down to lower end • bulky pancreatic head but no obvious lesion seen • a 7mm retropancreatic LN • Ca19.9 – 5.6

9. Exploratory Laparotomy + Whipple Operation • PANCREATITIS • Increased IgG4 plasma cell infiltration, suggestive of autoimmune pancreatitis • IgG4 600 (0-291) • ANCA, ANA positive Pathology

10. Autoimmune Pancreatitis

11. Clinical Features • Mild abdominal pain • Obstructive jaundice – 70-80% • Anorexia and weight loss • Diabetes Mellitus -- up to 76%

12. Extra-Pancreatic involvement Chronic sclerosing sialadenitis Inflammatory aortic aneurysm Interstitial pneumonia IgG4-associated Tubulointerstitial nephritis IgG4-associated cholangitis Retroperitoneal fibrosis

13. Diagnostic Criteria • Japan Pancreas Society (JPS) Criteria • 2002 and revised 2006 • Kim Criteria (Korea) • HISORt Critera (Mayo Clinic)

14. Kim Criteria (Korea)

15. Radiological Features – CT • Uniform or focal (Up to 80% involves head of pancreas) enlargement of pancreas • Sharp outline, homogenous decreased enhancement • Capsule like rim • Minimal peripancreatic strands • Diffuse pancreatic ductal narrowing

17. Radiological Features – ERCP/MRCP • - Diffuse or segmental narrowing of main pancreatic duct

18. Radiological Features – PET-CT • Intense uptake • Disappear after steroid treatment

19. Kim Criteria (Korea)

20. Laboratory Features • Serum IgG4 -- raised in up to 94% (Hirano et al.) • >135mg/dl (Hamano et al.) • Accuracy 97% • Sensitivity 95% • Specificity 97% • Autoimmune antibodies

21. Kim Criteria (Korea)

22. EUS guided biopsy • Sensitivity and accuracy >80% • Lymphoplasmatic infiltrate • Immunostaining – IgG4 positive plasma cells • Absence of malignant cells • Avoid unnecessary surgery

23. Kim Criteria (Korea)

24. Response to Steroid Therapy • Moon et al. Gut 2008 • 22 patients with clinically suspected AIP • 2 weeks course of steroid therapy (prednisolone 0.5mg/kg/day) • FU CT and ERCP/MRCP • Positive steroid response • Complete resolution or marked improvement of main pancreatic ductal narrowing +/- reduction in size of pancreatic mass

25. Response to Steroid Therapy • Positive steroid response : 15 / 22 patients • gradual taper and stopped • No malignancy • Negative steroid response : 7 / 22 patients • Pancreatic surgery (except one refused) • All 6 patients -- pancreatic head cancer • Complete resection possible without operation-related morbidity or mortality

26. Diagnostic algorithm Clinical young, minimal weight loss, mild abdominal pain Radiological Lack features of pancreatic cancer Extrapancreatic lesions Pancreatic biopsy IgG4 Lymphoplasmacytic infiltration No malignancy cells Serology IgG4, autoantibodies Steroid Responsiveness Continue Steroid - + Resection

27. Summary • Autoimmune Pancreatitis is a challenging diagnosis to make and is difficult to differentiate from Pancreatic cancer • Investigate more for possibility of Autoimmune Pancreatitis if features compatible • Proceed to exploratory laparotomy +/- resection if cannot exclude malignancy

28. THE END

29. Diagnostic algorithm Clinical young, minimal weight loss, mild abdominal pain Radiological Lack features of pancreatic cancer Extrapancreatic lesions Pancreatic biopsy IgG4 Lymphoplasmacytic infiltration No malignancy cells Serology IgG4, autoantibodies Steroid Responsiveness Continue Steroid - + Resection

33. HISORt Criteria

34. Japanese Criteria

35. Italian Criteria

36. Results of Surgery • Hardacreet al. Annuals of Surgery 2003 • Surgery for AIP associated with •  difficulty in dissecting pancreas from SMV/portal vein • Significant  blood loss •  operating time • No difference in LOS and overall complication rate • 68% reported improved quality of life • 37% developed DM ; 35% diarrhoea

37. Radiological Features – USG/EUS • Hypoechoic • No calcification or cysts

38. Laboratory Features • Serum IgG4 -- raised in up to 94% (Hirano et al.) • >135mg/dl (Hamano et al.) • Accuracy 97% • Sensitivity 95% • Specificity 97% • >280mg/dl (Ghazale et al.) • AIP 53% • Pancreatic cancer patient 1% • Autoimmune antibodies

39. Treatment • Steroid • Oral prednisolone 30-40mg/day for 3-4 weeks  tapering of various duration +/- maintainence therapy • No consensus of dosage and duration • Immunomodulatory medications • Azathioprine • Mycophenolate mofetil

40. Pathogenesis • Unclear • Autoimmune • Elevated IgG4 level with lymphoplasmacytic infiltrates involving IgG4-positive plasma cells in affected organs • Autoantibodies against carbonic anhydrase, lactoferrin and other antigens • T helper Type 2 (Th2) cells and T regulatory (Tregs) cells predominate the immune reaction • Strong association with other autoimmune conditions e.g Sjogren’s syndrome, PSC, IBD, SLE, retroperitoneal fibrosis, Hashimoto’s thyroiditis, etc • Dramatic response to steroid

41. Gross Pathology

42. Histopathology • Lymhoplasmacytic sclerosing pancreatitis (LPSP) • Infiltration of IgG4-positive plasma cells (>10/HPF) Periductal lymphoplasma infiltration with a storiform pattern Obliterative phlebitis fibrosis

43. EUS-guided Trucut Biopsy • Levy et al, Gastrointestinal Endoscopy 2005 • 3 patients with suspected AIP • Results: • 2 patients -- AIP • 1 patient -- non-specific changes of chronic pancreatitis • Managed conservatively with close monitoring • Avoidance of surgery

44. EUS-guided Trucut Biopsy • Advantages • Larger biopsy specimen • EUS with superior resolution that can improve accuracy of lesion targeting • Risk of seeding is lower than transabdominal biopsy • Drawbacks • Technically difficult (especially when lesion at pancreatic head) due to angulation • Patchy distributions of AIP may lead to false negative

45. Infiltration of IgG4-positive plasma cells • Kamisawa et al. Gastrointestinal Endoscopy 2008 • Biopsy of major duodenal papilla • 10 AIP, 10 pancreatic cancer and 10 papillitis patients • Immunostaining using anti-IgG4 antibodies • IgG4-positive plasma cells per high-power field (HPF)

47.  Sensitivity under influence of specimen size