Diagnosis of autoimmune pancreatitis

Table 1 Clinical diagnostic criteria for autoimmune pancreatitis in 2011 by Japan Pancreas Society (JPS-2011)[16]

A: Diagnostic items

I: Enlargement of the pancreas:

(a) Diffuse enlargement

(b) Segmental/focal enlargement

II: ERP (endoscopic retrograde pancreatography) shows irregular narrowing of the main pancreatic duct

III: Serological findings

Elevated level of serum IgG4 (≥ 135 mg/dL)

IV: Pathological findings: Among (1)-(4) listed below

(a) Three or more are observed

(b) Two are observed

(1) Prominent infiltration of lymphocytes and plasmacytes and fibrosis

(2) More than 10 IgG4-positive plasmacytes per high-power microscope field

(3) Storiform fibrosis

(4) Obliterative phlebitis

V: Extra-pancreatic lesions: sclerosing cholangitis, sclerosing dacryoadenitis/sialoadenitis/retroperitoneal fibrosis

(a) Clinical lesions

Extrapancreatic sclerosing cholangitis, sclerosing dacryoadenitis/ sialoadenitis (Mikulicz disease) or/retroperitoneal fibrosis

(b) Pathological lesions

Pathological examination shows characteristic features of sclerosing cholangitis, sclerosing dacryoadenitis sialoadenitis or/retroperitoneal fibrosis

<Option> Effectiveness of steroid therapy

A specialized facility may include in its diagnosis the effectiveness of steroid therapy, once pancreatic or bile duct cancers have been ruled out. When it is difficult to differentiate from malignant conditions, it is desirable to perform cytological examination using an endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). Facile therapeutic diagnosis by steroids should be avoided unless the possibility of malignant tumor has been ruled out by pathological diagnosis.

B: Diagnosis

I: Definite diagnosis

(1) Diffuse type

Ia + III/IVb/V (a/b)

(2) Segmental/focal type

Ib + II + two or more of < III/IVb/V (a/b) >

or

Ib + II + < III/IVb/V (a/b) > + Option

(3) Definite diagnosis by histopathological study

IVa

II: Probable diagnosis

Segmental/focal type: Ib + II + < III/IVb/V(a/b) >

III: Possible diagnosis1

Diffuse type: Ia + II + Option

Segmental/focal type: Ib + II + Option

When a patient with a focal/segmental image of AIP on CT/MRI without ERCP findings fulfill more than one of III, Ivb and V (a/b) ERP criteria, he/she can be diagnosed as probable AIP only after the negative workup for malignancy by EUS-FNA, and confirmed as definitive one by an optional steroid response.

¹Possible diagnosis: A case may possibly be type 2, although it is extremely rare in Japan. AIP: Autoimmune pancreatitis; CT: Computed tomography; MRI: Magnetic resonance image.

Table 2 Diagnosis of definitive and probable type 1 autoimmune pancreatitis using international consensus diagnostic criteria[25]

Diagnosis	Primary basis for diagnosis	Imaging evidence	Collateral evidence
Definitive type 1 AIP	Histology	Typical/indeterminate	Histologically confirmed LPSP (level 1 H)
	Imaging	Typical	Any non-D level 1/level 2
		Indeterminate	Two or more from level 1 (+ level 2 D1)
	Response to steroid	Indeterminate	Level 1 S/OOI + Rt or level 1 D +
			Level 2 S/OOI/H + Rt
Probable type 1 AIP		Indeterminate	Level 2 S/OOI/H + Rt
Criterion	Level 1		Level 2
P: Parenchymal imaging	Typical:		Indeterminate (including atypical3):
	Diffuse enlargement with delayed enhancement (sometimes associated with rim-like enhancement)		Segmental/focal enlargement with delayed enhancement
D: Ductal imaging (ERP)	Long (> 1/3 length of the main pancreatic duct) or multiple strictures without marked upstream dilatation		Segmental/focal narrowing without marked upstream dilatation (duct size, < 5 mm)
S: Serology	IgG4, > 2 × upper limit of normal value		IgG4, 1-2 × upper limit of normal value
OOI: Other organ involvement	a or b		a or b
	a: Histology of extrapancreatic organs		a: Histology of extrapancreatic organs including endoscopic biopsies of bile duct4:
	Any three of the following:		Both of the following:
	(1) Marked lymphoplasmacytic infiltration with fibrosis and without granulocytic infiltration		(1) Marked lymphoplasmacytic infiltration without granulocytic infiltration
	(2) Storiform fibrosis		(2) Abundant (> 10 cells/HPF) IgG4-positive cells
	(3) Obliterative phlebitis
	(4) Abundant (> 10 cells/HPF) IgG4-positive cells
	b: Typical radiological evidence		b: Physical or radiological evidence
	At least one of the following:		At least one of the following
	(1) Segmental/multiple proximal (hilar/intrahepatic) or proximal and distal bile duct stricture		(1) Symmetrically enlarged salivary/lachrymal glands
	(2) Retroperitoneal fibrosis		(2) Radiological evidence of renal involvement described in association with AIP
H: Histology of the pancreas	LPSP (core biopsy/resection)		LPSP (core biopsy)
	At least 3 of the following:		Any 2 of the following:
	(1) Periductal lymphoplasmacytic infiltrate without granulocytic infiltration		(1) Periductal lymphoplasmacytic infiltrate without granulocytic infiltration
	(2) Obliterative phlebitis		(2) Obliterative phlebitis
	(3) Storiform fibrosis		(3) Storiform fibrosis
	(4) Abundant (> 10 cells/HPF) IgG4-positive cells		(4) Abundant (> 10 cells/HPF) IgG4-positive cells
Response to steroid (Rt)2		Diagnostic steroid trial
	Rapid ( ≤ 2 wk) radiologically demonstrable resolution or marked improvement in pancreatic/extrapancreatic manifestations

¹Level 2 D is counted as level 1 in this setting;

²Diagnostic steroid trial should be conducted carefully by pancreatologists with caveats (see text) only after negative workup for cancer including endoscopic ultrasound-guided fine needle aspiration;

³Atypical: Some AIP cases may show low-density mass, pancreatic ductal dilatation, or distal atrophy. Such atypical imaging findings in patients with obstructive jaundice and/or pancreatic mass are highly suggestive of pancreatic cancer. Such patients should be managed as pancreatic cancer unless there is strong collateral evidence for AIP, and a thorough workup for cancer is negative (see algorithm);

⁴Endoscopic biopsy of duodenal papilla is a useful adjunctive method because ampulla often is involved pathologically in AIP. AIP: Autoimmune pancreatitis; ICDC: International consensus diagnostic criteria; HPF: High power field; LPSP: Lymphplasmacytic sclerosing; OOI: Other organ involvement.

Table 3 Diagnosis of definitive and probable type 2 autoimmune pancreatitis using international consensus diagnostic criteria[25]

Diagnosis	Imaging evidence	Collateral evidence
Definitive type 2 AIP	Typical/indeterminate	Histologically confirmed IDCP (level 1 H) or clinical inflammatory bowel disease + level 2 H + Rt
Probable type 2 AIP	Typical/indeterminate	Level 2 H/clinical inflammatory bowel disease + Rt
Criterion	Level 1	Level 2
P: Parenchymal imaging	Typical:	Indeterminate (including atypical2):
	Diffuse enlargement with delayed enhancement (sometimes associated with rim-like enhancement)	Segmental/focal enlargement with delayed enhancement
D: Ductal imaging (ERP)	Long (> 1/3 length of the main pancreatic duct) or multiple strictures without marked upstream dilatation	Segmental/focal narrowing without marked upstream dilatation (duct size, < 5 mm)
OOI: Other organ involvement		Clinically diagnosed inflammatory bowel disease
H: Histology of the pancreas (core biopsy/resection)	IDCP
	Both of the following:	Both of the following:
	(1) Granulocytic infiltration of duct wall (GEL) with or without granulocytic acinar inflammation	(1) Granulocytic and lymphoplasmacytic acinar infiltrate
	(2) Absent or scant (0-10 cells/HPF) IgG4-positive cells	(2) Absent or scant (0-10 cells/HPF) IgG4-positive cells
Response to steroid (Rt)1	Diagnostic steroid trial
	Rapid ( ≤ 2 wk) radiologically demonstrable resolution or marked improvement in manifestations

¹Diagnostic steroid trial should be conducted carefully by pancreatologists with caveats (see text) only after negative workup for cancer including endoscopic ultrasound-guided fine needle aspiration;

²Atypical: Some AIP cases may show low-density mass, pancreatic ductal dilatation, or distal atrophy. Such atypical imaging findings in patients with obstructive jaundice and/or pancreatic mass are highly suggestive of pancreatic cancer. Such patients should be managed as pancreatic cancer unless there is strong collateral evidence for AIP, and a thorough workup for cancer is negative (see algorithm). AIP: Autoimmune pancreatitis; ICDC: International consensus diagnostic criteria; IDCP: Idiopathic duct-centritic pancreatitis.

Table 4 Diagnosis of autoimmune pancreatitis-not otherwise specified using international consensus diagnostic criteria[25]

Diagnosis	Collateral evidence (case with only D1/2)
AIP-not otherwise specified	D1/2 + Rt

Table 5 Characteristics of clinicopathological findings in type 1 and type 2 autoimmune pancreatitis

	Type 1 AIP	Type 2 AIP
Geographical distributuion	Asia > United States, Europe	Europe > United States > Asia
Age at presentation	60-70 s	40-50 s
Gender	Male >> Female	Male = Female
Symptoms	Jaundice, Abdominal pain	Jaundice, Abdominal pain
Serology	IgG4, IgG, Autoantibodies	Usually negative
Pancreatic images	Enlarged (focal, diffuse)	Enlarged (focal, diffuse)
Pancreatic histology	LPSP	IDCP with GEL
Extrapancreatic lesions	Sclerosing cholangitis, sialoadenitis, retroperitoneal fibrosis, interstitional nephritis, etc.	Inflammatory bowel disease
Steroid response	Excellent	Excellent
Relapse	High rate	Rare

AIP: Autoimmune pancreatitis; LPSP: Lymphoplasmacytic sclerosing pancreatitis; IDCP with GEL: Idiopathic duct-centritic pancreatitis with granulocyte epithelial lesion.

Table 6 Extrapancreatic lesions associated with type 1 autoimmune pancreatitis

Close association	Possible association
Lachrymal gland inflammation	Hypophysitis
Sialoadenitis	Autoimmune neurosensory hearing loss
Hilar lymphadenopathy	Uveitis
Interstitial pneumonitis	Chronic thyroiditis
Sclerosing cholangitis	Pseudotumor (breast, lung, liver)
Retroperitoneal fibrosis	Gastric ulcer
Tubulointestinal nephritis	Swelling of Papilla of Vater
	IgG4 hepatopathy
	Periaortitis
	Prostatitis
	Schonlein-Henoch purpura
	Autoimmune thrombocytopenia