Autoimmune Pancreatitis Giuseppe Zamboni University of Verona IRCS-Ospedale SC Don Calabria, Negrar [email protected]
Autoimmune Pancreatitis
Giuseppe Zamboni
University of VeronaIRCS-Ospedale SC Don Calabria, Negrar
• Increasingly better recognized
• Different clinical profiles by subtype
• Extra-pancreatic involvement
• Differential diagnosis
• Steroid treatment
• Increased risk of malignancy
AUTOIMMUNE PANCREATITIS
Fibro-inflammatory condition, often mistaken for malignancy, that affect virtually any organs, characterized by a dense lymphoplasmacytic infiltrate, storiform fibrosis, obliterative phlebitis, frequent elevation of serum and tissutal IgG4 and initial response to glucocorticoid.
IgG4-Related DiseaseDefinition
• Increasingly better recognized
• Different clinical profiles by subtype
• Extra-pancreatic involvement
• Differential diagnosis
• Steroid treatment
• Increased risk of malignancy
AUTOIMMUNE PANCREATITIS
Periductal inflammation Storiform fibrosis
Venulitis
Diffuse LPC infiltration
Type 1 AIP
SMA
Obliterative phlebitis
IgG4 IgG
414 534IgG4/IgG 78%
Type 1 AIP, IgG4-RD
Granulocytic Epithelial Lesions (GELs)
Acinar GEL
Type 2 AIP (GELs-pos)
Serum IgG4: low
Tissue IgG4: 0 /< 5
Type 2 AIPYounger age (mean 40), equal M/F ratio
High coincidence of UC or Crohn’s disease
Few IgG4 / GELs
Storiform fibrosis: mild
Obliterative phlebitis: unusual
Recurrence: uncommon
Type 1 AIP, IgG4-RD Older age (mean 64), M preponderance
Any organ system can be affected
Storiform fibrosis: very common
Obliterative phlebitis: very common
Many IgG4 / no GELs
Recurrence: frequent, multiple lesions
IgG4
Two Clinico-Pathologic Subtypes
GELs
Conclusions:
Type 2 AIP in histologically confirmed AIP cases in Korea may not be as rare as originally thought, with an estimated prevalence rate of 28.8% (15/52)
Young IBD (specially UC) patients who present with clinical acute
pancreatitis are clinically suspicious for type 2 AIP
12 (44%) with UC
(8 before, 4 simultaneously)
Definition of AIP-NOS (ICDC):
1- the absence of conclusive criteria for AIP type 1 (probable or definitive)
2- the absence of suggestive histology (definitive) for AIP type 2 or in the
presence of concurrent IBD (probable)
8 pts (17.4%) reclassified as AIP type 2 because developed UC
Autoimmune PancreatitisRisk of Relapse by AIP Subtype
Type 1
Type NOS
Type 2
Verona AIP database, 23.2.2018
• Increasingly better recognized
• Different clinical profiles by subtype
• Extra-pancreatic involvement
• Differential diagnosis
• Steroid treatment
• Increased risk of malignancy
AUTOIMMUNE PANCREATITIS
AIP: ANATOMIC DISTRIBUTION OF LESIONS
1a. PANCREATICOCENTRIC
1b. PANCREATICOBILIARYCENTRIC
2a. EXTRAPANCREATICOBILIARYCENTRIC
Type 2 AIP-Ulcerative Colitis
Type 1 AIP-IgG4-RD
• Increasingly better recognized
• Different clinical profiles by subtype
• Extra-pancreatic involvement
• Differential diagnosis
• Steroid treatment
• Increased risk of malignancy
AUTOIMMUNE PANCREATITIS
AUTOIMMUNE PANCREATITISDifferential Diagnosis
1.“Inflammatory” lesions
2. Pancreatic carcinoma
• 50% of pts are asymptomatic
• Not associated with IgG4, IgG4-RDs or IBD
• Mainly affects hilar BD and pancreatic head
• The potential response to steroids remains to be explored
Follicular Pancreatitis and Cholangitis
CD 20
Female, 58yrs, ? Head PDCA
Follicular PancreatitisMale, 70yrs, ? PNET, uncinate process
Follicular PancreatitisMale, 70yrs, ? PNET, uncinate process
Follicular Pancreatitis
Differential Diagnosis
Male, 62yrs, pancreatic head mass
Mono-Clonal peak
Low Grade B-cell Lymphoma
Male, 62yrs, pancreatic head mass
AUTOIMMUNE PANCREATITISDifferential Diagnosis
1. “Inflammatory” lesions
2.Pancreatic carcinoma
Autoimmune PancreatitisSurgery over the time in Verona
AIP Database of Verona Pancreas Center, 2014
Retrospective
on surgical specimens
AIP-FNACytology
PancreatitisCarcinoma AIP
Established criteria
sensitivity: 80-90%specificity: ~100%
Established criteria
mixed inflammationfibrosis
acinar disruptionbland ductal cells
Criteria
Low specificity
Type1-IgG4+cellular stroma
lymphocytic backgroundrare ductal cells
?IgG4-ICC
Type2-GEL+neutrophils infiltration
ductal/acinar intraepithelialneutrophils
cellular stroma
Extremely difficult/Impossible
Important to exclude neoplasia
AIP-FNACytologic diagnosis
A distinct entity with characteristic
The knwoledge of the full range of
morphology of AIP is crucial in the
interpretation of biopsy specimens
AUTOIMMUNE PANCREATITIS
Biopsy diagnosis
Feature Clinically
suggestive of
AIP
Clinically
suggestive of
Non-AIP CP
Granulocytic
epithelial lesion (GEL)
48.3% (14/29) 0% (0/15)
>10 IgG4 positive
plasma cells/HPF
41.4% (12/29) 13.3% (2/15)
>10 eosinophilic
granulocytes/HPF
62.1% (18/29) 33.3% (5/15)
Cellular fibrosis with
inflammation
96.6% (28/29) 40.0% (6/15)
Lymphoplasmacytic
infiltration
93.1% (27/29) 33.3% (5/15)
Venulitis 65.5% (19/29) 26.7% (4/15)
71% of AIP recognized, if 4/6 microscopic features are
present (sensitivity of 76%, with GEL 86%)
Detlefsen-Klöppel, 2009
Storiform fibrosis
Venulitis
1. AIP type 1: Core Biopsy
IgG4
IgG
GEL
2. AIP type 2: Core Biopsy
Storiform Fibrosis
IL-8 immunostaining or IL-8/CD3 double staining may become an ancillary diagnostic tools
Am J Surg Pathol 2017;41:1129
* IL-8 expression in UC suggests a pathogenetic link between the 2 conditions
Am J Surg Pathol 2019;43:898–906
In a subset cases (n=20), 47% of
PD-L1-positive ducts were not
associated with GELs
PD-L1-positivity in 24/35 AIP-2 (69%)
PD-L1-negativity in all 14 AIP-1
*PD-L1-positivity in:
3% PDCA and other type CP
PD-L1-positivity in 8/11 AIP-2
PD-L1-negativity in 7 AIP-1
PD-L1-negativity in 17 PDCA
Validation of PD-L1 Stain in Type 2 AIP on EUS-guided Biopsies
PD-L1 positivity may serve as an ancillary test for the
diagnosis of AIP-2
• Not in isolation, but in the larger clinical and
histologic context
Am J Surg Pathol 2019;43:898–906
* No PD-L1-positivity observed in UC
• Increasingly better recognized
• Different clinical profiles by subtype
• Extra-pancreatic involvement
• Differential diagnosis
• Steroid treatment
• Increased risk of malignancy
AUTOIMMUNE PANCREATITIS
Autoimmune PancreatitisResponse to Steroids and Relapse
August 2003 December 2003 (after steroids)
October 2006 December 2006 (after steroids)
Rituximab in AIP Type 1Pancreatic Relapses, Azathioprine Intolerant
Before RXT 6 month after RXT (2 infusions)
June 2014
• Increasingly better recognized
• Different clinical profiles by subtype
• Extra-pancreatic involvement
• Differential diagnosis
• Steroid treatment
• Increased risk of malignancy
AUTOIMMUNE PANCREATITIS
Intern Med 2019 - Advance Publication DOI: 10.2169 / internalmedicine.2210-18
Two proposed mechanisms
1.Inflammation/CA development:
- the risk increases with duration
2.CA induces AIP (paraneoplastic syndrome)
- the highest risk < 1 years
- clinical improvement after successfultreatment of CA
AIP-INCREASED RISK OF MALIGNANCY
• Increasingly better recognized: worldwide
• Different clinical profiles by subtype:AIPtype1-2,NOS
• Extra-pancreatic involvement: IgG4-RD vs IBD
• Differential diagnosis: inflammatory lesions/neoplasms
• Steroid treatment:Azathioprine/Rituximab in relapse
• Increased risk of malignancy: extrapancreatic>pancreatic
AUTOIMMUNE PANCREATITIS
Many thanks to:
VERONA PANCREATIC TEAM
Günter Klöppel
www.valpolicella.it