Autoimmune Pancreatitis

Giuseppe Zamboni

University of VeronaIRCS-Ospedale SC Don Calabria, Negrar

giuseppe.zamboni@univr.it

• 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