1. Painless obstructive jaundice - think beyond malignancy
Lorraine Ma
Ruttonjee Hospital

2. Patient 56/M , Good past health , Non-smoker , non-drinker
Presented with on and off epigastric discomfort, bloating sensation for 2 weeks
No abdominal pain
Seen private practitioners and given antacids with no relieve
Clinically jaundice, vague epigastric ?mass
WCC normal
Bil 102 / ALP 629 / ALT 313 / Amylase 247
?malignant biliary obstruction
- ?cholangiocarcinoma ?Ca pancreas

3. CT Arterial Portal-venous Proceeded with CT scan
Diffusely enlarged pancreas with delayed enhancement
No dilated main pancreatic duct
Arterial
Portal-venous

4. In addition…
Thickening around the aorta
Dilated biliary tree

5. Diffuse marked enlargement of the pancreas with compression and marked narrowing of upper SMV and medial splenic vein
Obliteration of the distal CBD with moderate dilatation of the biliary tree.
Minimal rind of enhancing soft-tissue densities are also seen around the lower abdominal aorta just above IMA origin.
Represent IgG4-related disease with autoimmune pancreatitis and minimal periaortitis / retroperitoneal fibrosis.
It was reported that

6. Autoimmune pancreatitis
First described in 1961
Raised gammaglobin in chronic idiopathic pancreatitis
Suspecting autoimmune involvement
2 distinctive forms denoted in 2003
Type 1 AIP – lymphoplasmacytic sclerosing pancreatitis
Part of IgG4-related diseases
Type 2 AIP – idiopathic duct-centric chronic pancreatitis
Sarles H, et al. Chronic inflammatory sclerosing of the pancreas-An autonomous pancreatic disease? Am J Dis 1961;6:688-98
Notohara K, et al. Idiopathic chronic pancreatitis with periductal lymphoplamacytic infiltration. Clinicopathologic features of 35 cases. Am J Surg Pathol 2003;27:

7. Autoimmune pancreatitis (AIP)
Frequently presents as painless obstructive jaundice with or without epigastric mass
Mimicking malignancy biliary obstruction, specifically cancer of the pancreas
Others may present as acute/ chronic pancreatitis

8. Lymphoplasmacytic sclerosing pancreatitis
Subtype of AIP
Type 1
Type 2
Synonym
Lymphoplasmacytic sclerosing pancreatitis
Idiopathic duct-centric choronic pancreatitis
Prevalence
Asia > EU/ US
EU > US > Asia
Age
Older
Younger
Sex
Male >> Female
Male ~ Female
Symptoms
- Obstructive jaundice
- Abdominal pain
- Pancreatic swelling
Often
Rare
Common
Serology
High IgG/IgG4
AutoAb (+)
Normal IgG/ IgG4
AutoAb (-)
Other organ involvement
Sclerosing cholangitis
Sclerosing sialadenitis
Retroperitoneal fibrosis
Unrelated with ulcerative colitis
Unrelated with other organ involvement
Related with Ulcerative colits
Steroid
Responsive
Relapse
High
Type 1 AIP more common than Type 2 , especially in Asia, hence I will be focusing today’s presentation on Type1 AIP
Affects male yrs of age
Male > Female, 3:1 in AIP vs 9:1 in other autoimmune conditions
Other organ involvement like sclerosing cholangitis in AIP1, ulcerative colitis in AIP2
Kamisawa T, et al. Recent advances in autoimmune pancreatitis: type1 and type . Gut 2013;62:
Kanno A, et al, and the Research Committee on Intractable Diseases of Pancreas. Nationwide epidemiological survey of autoimmune pancreatitis in Japan. In 2011 Pancreas 2015; 44: 535–39.

9. Diagnosing of AIP – type 1
Imaging
Parenchymal – CT / MRI
Ductal – ERCP / MRCP
Serology – IgG / IgG4
Histology
FNAC
Core biopsy
Resection
Other organ involvement
Response to steroids
Internation Association of Pancreatology
International Consensus Diagnostic Criteria for Autoimmune Pancreatitis
Shimosegawa T, Chari ST, Frulloni L, et al. Guidelines of the International Association of Pancreatology
International Consensus Diagnostic Criteria for Autoimmune Pancreatitis. Pancreas 2011; 40:

10. Imaging – Parenchymal - CT / MRI
Diffuse enlargement - ‘sausage-shaped’ pancreas
Delayed enhancement
>90% AIP
Low levels of enhancement in adenocarcinomas / lymphomas (>70%)
Pancreatic ‘envelope’
Hypoattenuating / hypointense capsule –like peripheral rim
Proctor RD, et al. Autoimmune pancreatitis: An illustrated guide to diagnosis. Clinical Radiology 68 (2013)

11. CT Arterial Portal-venous
AIP: classical, diffuse enlargement of the pancreas on arterial(a) and portal venous-phase images (b) axial CT images showing mildly bulky pancreas with delayed enhancement.
Also note the thickening of the pancreatic envelope and the paucity of peripancreatic stranding.
Shows delay enhancement on venous phase
Arterial
Portal-venous
Proctor RD, et al. Autoimmune pancreatitis: An illustrated guide to diagnosis. Clinical Radiology 68 (2013)

12. MRI
(a) AIP: MRI image of the pancreas demonstrates the bulky head of the pancreas on the T1-weighted image (arrow).
(b) Bulky pancreas with thickening of the pancreatic envelope on the T2-weighted image (arrow). T1 T2
Proctor RD, et al. Autoimmune pancreatitis: An illustrated guide to diagnosis. Clinical Radiology 68 (2013)

13. Imaging – Ductal – ERCP / MRCP
Long Irregular narrowing of the main pancreatic duct (MPD)
Lack of upstream dilatation from narrowing
Multiple strictures
Side branches from narrowing
MRCP preferred in the absence of symptomatic biliary obstruction that requires intervention
But ERCP shows the pancreatic strictures clearer
Sugumar A, Levy MJ, Kamisawa T, et al. Endoscopic retrograde pancreatography criteria to diagnose autoimmune pancreatitis: an international multicentre study. Gut 2011; 60:

14. Lack upstream dilatation
Long stricture
Lack upstream dilatation
ERCP
Multiple strictures
Side branching
Key features of autoimmune pancreatitis in a pancreatogram.
Feature 1: long (>1/3 the length of the pancreatic duct) narrow stricture. Feature 2: lack of upstream dilatation from the stricture (<5 mm).
Feature 3: multiple strictures. Feature 4: side branches arising from the stricture site.
Sugumar A, Levy MJ, Kamisawa T, et al. Endoscopic retrograde pancreatography criteria to diagnose autoimmune pancreatitis: an international multicentre study. Gut 2011; 60:

15. Serology – IgG4 High IgG4 levels in autoimmune pancreatitis
2001; 344:732-8
High IgG4 levels in autoimmune pancreatitis
Sensitivity 95% specificity 97%
Levels corresponds to disease activity

16. AIP vs pancreatic cancers (n=434)
J Gastroenterol Hepatol Jan;24(1):15-36
AIP vs control (n=1258)
Sensitivity: 82.4% (P=0.078)
Specificity: 94.6% (P<0.001)
AIP vs pancreatic cancers (n=434)
Sensitivity: 82.3% (P=0.043)
Specificity: 95.4% (P=0.001)

17. ICDC recommends 2x upper normal limit as evidence for definite AIP
et al. Am J Gastroenterol 2007;102:1646–1653)
AIP (N = 45)
Pancreatic Cancer (N = 135)
P Value
CA 19-9 >37
9/33 (27%)
100/126 (79%)
<0.001
CA 19-9 >100
3/33 (9%)
91/126 (71%)
% with  total IgG
19/45 (42%)
7/135 (5%)
% with serum IgG4 >140 mg/dL
34/45 (76%)
13/135 (10%)
% with serum IgG4 >280 mg/dL
24/45 (53%)
2/135 (1%)
ICDC recommends 2x upper normal limit as evidence for definite AIP
Paper that looks at the value of IgG4 in diagnosing AIP vs Ca pancreas
Not surprisingly, Ca19.9 is increased in Ca pancreas
But when looking at mildly elevated IgG4 , although significantly different, there are 10% pancreatic cancer patients with this finding
When the cut-off bar is raised to 280mg/dL, there are only 1% pancreatic cancer paitents

18. In the absence of histology / ductal imaging (ERP/MRP)
Typical parenchymal imaging & significantly elevated IgG4 sufficient in making diagnosis in Type 1 autoimmune pancreatitis
In the absence of histology / ductal imaging (ERP/MRP)

19. ?Autoimmune pancreatitis
? Pancreatic cancer
?Autoimmune pancreatitis
Focal / segmengtal autoimmune pancreatitis
Compromises >40% AIP

20. Histology Collection method: Findings: Ampullary biopsies
Useful in diffuse type / pancreatic head AIP
EUS-guided core biopsy / FNA
Focal type AIP
Resection
Findings:
Periductal lymphoplasmacytic infiltrate without granulocytic infiltration
Obliterative phlebitis
Storiform fibrosis
Abundant (>10cells/HPF) IgG4-postives cells
K Terumi. et al. Role of endoscopy in the diagnosis of autoimmune pancreatitis and immunoglobulin G4-related sclerosing cholangitis Digestive Endoscopy 2014; 26: 627–635

21. Other organ involvement

22. IgG4-associated cholangitis
Intrapancreatic biliary strictures - resembles Ca Pancreas
Proximal extrahepatic biliary strictures -mimick cholangiocarcinoma
Intrahepatic strictures - similar to primary sclerosing cholangitis
Multifocal strictures.
Diagnosing IgG4 associated cholangitis poses difficulties as it may mimick many other coniditions like
Ca pancreas – intrapancreatic biliary strictures
Cholangiocarcinoma – proximal extrahepatic biliary strictures
Primary sclerosing cholangitis – intrahepatic strictures
Ghazale A, et al. Immunoglobulin G4-Associated Cholangitis: Clinical Profile and Response to Therapy. Gastroenterology 2008;134:

23. Treatment for AIP Steroids (Prednisolone) Induction: Maintenance
0.6mg/kg/day for 2-4 weeks initially
then tapered by 5 mg every 1–2 weeks
Maintenance
2.5-5mg/day for 6-12 months
Withdrawal
Depends on disease activity
Within 3 years
Kamisawa T, Okazaki K, Kawa S, et al.
Research Committee for Intractable Pancreatic Disease and Japan Pancreas Society
Japanese consensus guidelines for management of autoimmune pancreatitis. III. Treatment and prognosis of AIP.
J Gastroenterol 2010;45:471-7.

24. Treatment of AIP Relapses Immunomodulators
Azathioprine, mycophenolate mofetil (MMF), and methotrexate
Commonly used as maintenance but no clinical trials
Rituximab (CD-20 monoclonal antibody)
Usefulness still not proven
Kamisawa T, et al. Japanese consensus guidelines for management of autoimmune pancreatitis. III. Treatment and prognosis of AIP. J Gastroenterol 2010;45:471-7.
Kamisawa T, et al. IgG4-related diasease. Lancet 2015; 385:
Stone JH , et al. IgG4-Related Disease . N Engl J Med 2012;366:

25. Type 1 autoimmune pancreatitis
Back to our patient
Fluctuating liver enzymes and bilirubin levels between
Epigastric mass subsided
No enlarged salivary glands
Ca19.9 normal (18.6) , AFP/CEA also normal
IgG 21g/L (upper normal limit 15.6)
IgG4 1092mg/dL (upper normal limit 100)
Type 1 autoimmune pancreatitis
Steroid therapy

26. Take-home message
Autoimmune pancreatitis as an uncommon but important differential diagnosis of painless obstructive jaundice
Can be diagnosed with TYPICAL imaging findings with positive serology results
Look out for other organ involvement

27. Thank you

28. Shimosegawa T, et al. International Consensus Diagnostic Criteria for Autoimmune Pancreatitis. Pancreas 2011; 40:

29. Kanno A, et al, and the Research Committee on Intractable Diseases of Pancreas. Nationwide epidemiological survey of autoimmune pancreatitis in Japan. In 2011 Pancreas 2015; 44: 535–39

30. Mikulicz’s disease
Kamisawa T, et al. IgG4-related diasease. Lancet 2015; 385:

31. PET-CT Not as a diagnostic tool
Helps in locating other organ involvement
Monitor disease progresss
Ozaki et al.11 studied 15 patients with AIP and 26 patients with pancreatic cancer and stated that the maximum standardized uptake value (SUV) did not differ significantly in either the early or delayed phase between AIP (the median max SUV was 4.6 in the early phase and 5.4 in the delayed phase) and pancreatic cancer (the median max SUV was 5.3 in the early phase and 6.5 in the delayed phase).11 However, they stated that multiple foci in the pancreas were significantly more often observed in AIP (eight of 15 cases) than in pancreatic cancer (one of 19 cases). Also, hilar lymphadenopathy was significantly more frequent in patients with AIP (n
K. Nakatani et al. Utility of FDG PET/CT in IgG4-related systemic disease
Clinical Radiology :

32. Relapses & Prognosis Recurrence in 22.2 % patients (193/869)
55% pancreas (107)
Same area 72% , different 28%
Sclerosing cholangitis
14% porta hepatis
14% intrapancreatic
8% lacrimal/salivary glands inflammation
5.7% retroperitoneal fibrosis
17 of 903 patients died , only 7 (0.8%) died of pancreatic cancer
Relapse
During the course of observation ( [976.8] days), recurrence developed in 193 (22.2%) of 869 patients, including the pancreas in 107, sclerosing cholangitis at the porta hepatis in 27, intrapancreatic sclerosing cholangitis in 27, lacrimal glands/sialadenitis in 16, and retroperitoneal fibrosis in 11 (including overlapping cases). Of the 107 patients with recurrent swelling of the pancreas, recurrent swelling appeared in the same area in 59 (72.0%) of 82 patients and at a different site in 23 (28.0%) of 82. There were no data for 25 patients.
Prognosis
During the mean (SD) observation period of (1089.9) days, 17 of the 903 patients whose prognosis was provided died. The cause of death was cancer in 4 patients (pancreatic cancer in 2, lung cancer in one, and bile duct cancer in one), pneumonia in 2 patients, respiratory failure in one, and an accident in one. The cause was unknown in 2, and there were no data for 7 patients.
Malignant tumors were detected in 109 (11.8%) of 923 patients. There were 21 patients with gastric cancer, 16 with colorectal cancer, 2 with lung cancer, 5 with bile duct cancer, 6 with thyroid cancer, 9 with bladder cancer, 7 with renal cell cancer, and 7 with pancreatic cancer. In 36 patients, malignant tumors were detected, but the origins of the tumors were not described (Table 6).
Steroid therapy is the first-line and mainstay treatment for AIP, but relapse is frequent upon steroid withdrawal.15 In this study, more than 80% of patients were treated with steroids, and the efficacy was as high as 96.3%. Recent reports in Western countries have described the use of immunomodulatory drugs for the treatment of AIP in those for whom steroid tapering fails,16–18 but there were only 10 patients who received immunomodulatory drugs in this survey.

33. References
Sarles H, et al. Chronic inflammatory sclerosing of the pancreas-An autonomous pancreatic disease? Am J Dis 1961;6:688-98
Notohara K, et al. Idiopathic chronic pancreatitis with periductal lymphoplamacytic infiltration. Clinicopathologic features of 35 cases. Am J Surg Pathol 2003;27:
Kamisawa T, et al. Recent advances in autoimmune pancreatitis: type1 and type . Gut 2013;62:
Proctor RD, et al. Autoimmune pancreatitis: An illustrated guide to diagnosis. Clinical Radiology 68 (2013)
Sugumar A, Levy MJ, Kamisawa T, et al. Endoscopic retrograde pancreatography criteria to dianose autoimmune pancreatitis: an international multicentre study. Gut 2011; 60:
Hamano H, et al. High serum IgG4 concentrations in patient with sclerosing pancreatitis. N Eng J Med 2001; 344:732-8
Vlachou PA, et al. IgG4-related Sclerosing Disease: Autoimmune Pancreatitis and Extrapancreatic Manifestations. RadioGraphics :5,
Ghazale A, et al. Immunoglobulin G4-Associated Cholangitis: Clinical Profile and Response to Therapy. Gastroenterology 2008;134:
Shimosegawa T, et al. International Consensus Diagnostic Criteria for Autoimmune Pancreatitis. Pancreas 2011; 40:
Kamisawa T, et al. IgG4-related diasease. Lancet 2015; 385:
Okazaki K, et al. Autoimmune Pancreatitis The Past, Present, and Future. Pancreas ; 44(7):

34. Rind The tough outer skin of certain fruit, especially citrus fruit:
Oxford Advanced Learner's Dictionary