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

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

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

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

A case with Autoimmune Pancreatitis

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

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

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

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

Autoimmune Pancreatitis

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

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

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

Kim Criteria (Korea)

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

Autoimmune Pancreatitis Pancreatic Cancer Diffuse enlargement of pancreasParenchymal atrophy above stricture Delayed enhancement of pancreatic mass Poor enhancement Diffuse narrowing main pancreatic duct Single localized stricture Minimal upstream duct dilatationMarked upstream duct dilatation Other organs involvement (kidney, retroperitoneal fibrosis) No other organ involvement

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

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

Kim Criteria (Korea)

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

Kim Criteria (Korea)

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

Kim Criteria (Korea)

Response to Steroid Therapy Moon et al. Gut 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

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

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

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

THE END

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

JPSKimHISORtItalian Imaging * Essential Not essentialNot included LaboratoryElevated IgG4 Elevated IgG4/IgG or autoantibodies Elevated IgG4 Not included HistopathologyMarked lympho- plasmacytic infiltration and fibrosis Lympho- Plasmacytic infiltration and fibrosis * LPSP IgG4 plasma cells * Histology or cytology Response to Steroid Not includedIncluded Other organ involvement Not included Included

HISORt Criteria

Japanese Criteria

Italian Criteria

Results of Surgery Hardacre et 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

Radiological Features – USG/EUS Hypoechoic No calcification or cysts

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

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

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

Gross Pathology

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

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

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

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)

IgG4 plasma cells Significant  10/HPF Moderate 4-9/HPF Rare  3/HPF Autoimmune Pancreatitis 82 (body/tail) Pancreatic Cancer 019 Papillitis 0010

Detection RateCore BiopsyResection Bang et al. Pancreas %100% Zamboni et al. Virchows Arch %90% Chari et al. Clin Gastroenterol Hepatol %92%  Sensitivity under influence of specimen size