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Korean J Pancreas Biliary Tract > Volume 19(1):2014 > Article
1형 자가면역췌장염의 진단기준에서 논란이 되는 쟁점

Abstract

The diagnosis of autoimmune pancreatitis (AIP) is clinically challenging because it is a rare disease, which closely mimics more common pancreaticobiliary malignancies in its presentation such as obstructive jaundice and pancreatic mass. The price of misdiagnosis is high because AIP diagnosed as pancreatic cancer can lead to unnecessary surgery for the benign disease, and cancer diagnosed as AIP can delay potentially curative surgery. There is no single ideal diagnostic test for AIP; hence one has to use a set of diagnostic criteria to distinguish it from other diseases. International consensus diagnostic criteria (ICDC) and algorithm for AIP have been proposed by a consensus of expert opinion in 2011. The concept of the Japan pancreas society (JPS) 2011 criteria took basic concepts of both the Japanese previous criteria and type 1 in the ICDC as much as possible. However, the ICDC are very complex to remember and definition of level 1 and 2 are not evidence based in some criteria. The revised JPS criteria are simpler than ICDC but further evaluation is necessary in other than Japan. So, further research is required to establish easy, ideal and practical diagnostic criteria.

INTRODUCTION

Autoimmune pancreatitis (AIP) is recognized as a distinct clinical entity, and it is also identified as a chronic inflammatory process of the pancreas in which the autoimmune mechanism is involved. The diagnosis of AIP is clinically challenging because it is a rare disease, which closely mimics more common pancreaticobiliary malignancies in its presentation such as obstructive jaundice and pancreatic mass. Since Yoshida et al.[1] proposed the concept of AIP in 1995, the first Korean case of AIP was reported in 2002[2]. According to a nationwide multi-center study in Korea, the prevalence of AIP was 2.0% among 814 patients with chronic pancreatitis[3]. According to the American single center report, 2.5% of patients undergoing pancreaticoduodenectomy were identified as AIP before 2002[4]. Korean multi-center study also showed that 12 (18%) AIP patients among 67 were misdiagnosed as periampullary cancer between 2002 and 2007 because of the unfamiliarity to the concept of AIP or suspicion of pancreatic cancer[5]. The price of misdiagnosis is high because AIP diagnosed as pancreatic cancer can lead to unnecessary surgery for the benign disease, and cancer diagnosed as AIP can delay potentially curative surgery. There is no single ideal diagnostic test for AIP; hence one has to use a set of diagnostic criteria to distinguish it from other diseases. Since the 1st diagnostic criteria for AIP were established by Japan Pancreas Society (JPS) in 2002[6], several diagnostic criteria were proposed including Korean[5,7], revised Japan[8], HISORt[9,10], Asian criteria[11], the international consensus diagnostic criteria (ICDC)[12] and revised Japan 2011[13].
In this review, I will introduce two recent diagnostic criteria of type 1 AIP and issues that remain controversial areas where further research is required.

RECENT DIAGNOSTIC CRITERIA

International consensus diagnostic criteria

International consensus diagnostic criteria (ICDC) and algorithm for AIP have been proposed by a consensus of expert opinion in 2011[12]. The goals of the ICDC for AIP are to develop criteria that can be applied world widely, taking into consideration the marked differences in clinical practice patterns, to safely diagnose AIP and avoid misdiagnosis of pancreatobiliary malignancies as AIP.
ICDC include separate criteria for type 1 and type 2 AIP. The diagnosis of type 1 AIP usually is made on the basis of a combination of 5 cardinal features: (1) imaging (pancreatic parenchyma and direct pancreatogram), (2) serology (serum IgG4), (3) other organ involvement (OOI), (4) histology of the pancreas, and (5) response to steroid (Table 1). Each feature has been categorized as level 1 and 2 findings depending on the diagnostic reliability except response to steroid (Table 2). The diagnoses of Type 1 AIP can be definitive or probable.
In parencymal imaging criterion, level 1 is typical diffuse enlargement with delayed enhancement. Level 2 includes not only segmental enlargement but also atypical form (low density mass). Ductal imaging criterion also includes level 1 and level 2. Level 1 is long or multiple narrowing without marked upstream dilatation and level 2 is segmental or focal narrowing without marked upstream dilatation. In a typical diffuse type, pancreatogram shows level 1 criterion and in non diffuse type, the pancreatogram shows segmental or focal narrowing without marked upstream dilatation.
For the serological criterion, level 1 is a marked elevation of serum IgG4 levels (more than double upper limit of normal value), and level 2 is a mild elevation of serum IgG4 levels. For OOI criterion, level 1 is either histological findings in extrapancreatic organs or typical radiological evidence (proximal bile duct stricture or retroperitoneal fibrosis), and level 2 is histological findings or physical or radiological evidence (symmetrically enlarged salivary/ lacrimal glands or renal involvement).

Revised Japan 2011 diagnostic criteria

The concept of the JPS 2011 criteria took basic concepts of both the Japanese previous criteria and type 1 in the ICDC as much as possible (Table 3): (1) simple for general physicians’ use; (2) diffuse/segmental/focal classification on pancreatic imaging; (3) IgG4 alone as a serological marker; (4) sclerosing cholangitis, sclerosing sialadenitis, and retroperitoneal fibrosis as OOIs; (5) no classifications of level 1/2 in serum IgG4 and OOI; and (6) optional steroid trial only after denying malignancy by endosonographyguided fine needle aspiration (EUS-FNA)[13]. Different from the previous Japanese guidelines, the pancreatic parenchyma on computed tomography/magnetic resonance imaging is separated from the ductal image on endoscopic retrograde pancreatography (ERP). Endoscopic retrograde cholangiopancreatography is basically required in the focal/ segmental type, but not in the typical diffuse type of AIP. Among many OOIs previously reported, sclerosing cholangitis, sclerosing sialoadenitis, and retroperitoneal fibrosis are recommended as the typical OOI in JPS 2011, which follows the ICDC. As the same as Asian criteria or ICDC, an optional steroid trial was included in diagnostic criterion only after denying malignancy using EUS-FNA by experts. Different from the previous Japanese criteria, the patients with AIP are diagnosed as having definitive, probable, or possible AIP by a combination with criteria, similar to the concept of the ICDC.

Comparison of diagnostic criteria and areas where further research is required

The reliable diagnosis of AIP requires a multidisciplinary team of radiologists, pathologists and gastroenterologists familiar with the disease. The Japanese study showed that ICDC is the most sensitive and useful for diagnosing AIP. The sensitivities of 5 major criteria were 95.1% (ICDC), 90.2% (Korean), 86.9% (Japanese), 83.6% (Asian), and 83.6% (HISORt) with 100% of specificity in each[14].
The recent Japanese study retrospectively investigated the usefulness of ICDC in comparison with JPS 2011 in 64 patients with AIP and 90 patients with pancreatic cancer[15]. They concluded that the sensitivity of ICDC (98.4%) is higher than that of JPS 2011 (84.4%) with 100% of specificity in each.
The main cause of the lower sensitivity of the JPS 2011 is the fact that enlargement of the pancreas is an essential component in the JPS 2011. However, in the ICDC, level 2 for parenchymal imaging includes atypical imaging which includes low-density mass, pancreatic ductal dilatation, or distal atrophy.
ICDC is relatively accurate criteria which include separate criteria of type 1 and type 2 AIP, but the main drawback is a complexity.
In ICDC, ERP is necessary for ductal imaging criterion. However, incremental benefit of ERP was little when there were CT features typical of AIP. Magnetic resonance image with MRP can be replaced for ERP in patients without jaundice. Of course, additional ERP was helpful in identifying patients with AIP when CT findings were atypical. Korean study suggested that CT and ERP had better diagnostic performance than CT alone in the differential diagnosis of AIP and pancreatic cancer[16]. The study suggested that making the choice for performance of ERP, therefore, may be tailored to findings on CT. For the serological criterion, level 1 is a marked elevation of serum IgG4 levels (more than double upper limit of normal value), and level 2 is a mild elevation of serum IgG4 levels. High cut off value of serum IgG4 can increase specificity but decrease sensitivity. In JPS 2011, there are no classifications of level 1/2 in serum IgG4. The evidence of level 1 serum IgG4 value is not enough. Multi center data are necessary to determine the ideal cut off value of serum IgG4.
For OOI criterion, level 1 is either histological findings in extrapancreatic organs or typical radiological evidence (proximal bile duct stricture or retroperitoneal fibrosis), and level 2 is histological findings or physical or radiological evidence (symmetrically enlarged salivary/lacrimal glands or renal involvement). In Korean AIP patients, sclerosing cholangitis is the most common extrapancreatic lesion and retroperitoneal fibrosis and renal involvement were relatively common[17]. In Japan, sclerosing cholangitis is also the most common extrapancreatic lesion, and sclerosing sialoadenitis (Mikulicz’s disease) is a relatively common OOI. It is not clear why Mikulicz’s disease and renal involvement are classified as level 2 OOI.

CONCLUSIONS

Even though AIP is a rare disease compared with pancreatic cancer, the gastroenterologists and pancreatic surgeons should keep in mind the concept of AIP for the prevention of unnecessary pancreatic resection. There are several diagnostic criteria of AIP which have their own strong and weak points. The ICDC are very complex to remember and definition of level 1 and 2 are not evidence based in some criteria. The revised JPS criteria are simpler than ICDC but further evaluation is necessary in other than Japan. Therefore, further research is required to establish easy, ideal and practical diagnostic criteria.

Notes

The author has no conflicts to disclose.

REFERENCES

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Table 1.
Diagnosis of defnitive and probable type 1 AIP using ICDC
Diagnosis Primary basis for diagnosis Imaging evidence Collateral evidence
Definitive type 1 AIP Histology Typical/indeterminate Histologically confirmed LPSP (level 1 H)
Imaging Typical indeterminate Any non-D level 1/level 2
Two or more from level 1 (+level 2 D*)
Response to steroid Indeterminate Level 1 S/OOI 十 Rt or level 1 D 十 level 2 S/OOI/H 十 Rt
Probable type 1 AIP Indeterminate Level 2 S/OOI/H 十 Rt

* Level 2 D is counted as level 1 in this setting.

Table 2.
Level 1 and level 2 criteria for type 1 AIP
Criterion Level 1 Level 2
P Parenchymal imaging Typical:
Diffuse enlargement with delayed enhancement (sometimes associated with rim-like enhancement)
Indeterminate (including atypical): 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 lgG4, >2 × upper limit of normal value IgG4, 1-2 × upper limit of normal value
001 Other organ involvement a or b
a. Histology of extrapancreatic organs
Any three of the following:
(1) marked lymphoplasmacytic infiltration with fibrosis and without granulocytic infiltration
(2) Storiform fibrosis
(3) Obliterative phlebitis
(4) Abundant (>10 cells/HPF) IgG4-positive cells
b. Typical radiological evidence
At least one of the following:
(1) Segmental/multiple proximal (hilar/intrahepatic) or proximal and distal bile duct stricture
(2) Retroperitoneal fibrosis
a or b
a. Histology of extrapancreatic organs including endoscopic biopsies of bile duct:
Both of the following:
(1) Marked lymphoplasmacytic infiltration without granulocytic infiltration
(2) Abundant (>10 cells/HPF) IgG4-positive cells
b. Physical or radiological evidence
At least one of the following:
(1) Symmetrically enlarged salivary/lachrymal glands
(2) Radiological evidence of renal involvement described in association with AIP
H Histology of the pancreas LPSP (core biopsy/resection)
At least 3 of the following:
(1) Periductal lymphoplasmacytic infiltrate without granulocytic infiltration
(2) Obliterative phlebitis
(3) storiform fibrosis
(4) Abundant (>10 cells/HPF) IgG4-positive cells
LPSP (core biopsy)
Any 2 of the following:
(1) Periductal lymphoplasmacytic infiltrate without granulocytic infiltration
(2) Obliterative phlebitis
(3) Storiform fibrosis
(4) Abundant (>10 cells/HPF) IgG4-positive cells
Diagnostic steroid trial
Response to steroid (Rt)* Rapid (≤2 wk) radiologically demonstrable resolution or marked improvement in pancreatic/extrapancreatic manifestations

* Diagnostic 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;

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);

Endoscopic biopsy of duodenal papilla is a useful adjunctive method because ampulla often is involved pathologically in AIP.

Table 3.
Japanese clinical diagnostic criteria for autoimmune pancreatitis 2011
A. Diagnostic criterion
 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 levels of serum IgG4 (≥135 mg/dL)
 IV. Pathological findings: among i)~iv) listed below,
  a. Three or more are observed
  b. Two are observed
   i) Prominent infiltration and fibrosis of lymphocytes and plasmacytes
   ii) Ten or more diffuse IgG4-positive plasmacytes per high-power microscope field
   iii) Storiform fibrosis
   iv) Obliterative phlebitis
 V. Other organ involvement (OOI): sclerosing cholangitis, sclerosing dacryoadenitis/ sialoadenitis, retroperitoneal fibrosis
 a. Clinical lesions
  Extra-pancreatic sclerosing cholangitis, sclerosing dacryoadenitis/sialoadenitis (Mikulicz disease), or retroperitoneal fibrosis can be diagnosed with clinical and image findings.
 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
  Diffuse type
    I a + <III / IVb / V(a/b)>
  Segmental/focal type
    I b + II + two or more of <III / IV b / V (a/b)>
    I b + II + <III / IV b / V (a/b)>+ Option
  Definite diagnosis by histopathological study
    IV a
 II. Probable diagnosis
  Segmental/focal type: I b+ II + <III / IV b / V (a/b)>
 III. Possible diagnosis*
  Diffuse type: I a + II + Option
  Segmental/focal type: I b + 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) criteria, he/she can be diagnosed as possible AIP only after the negative workup for malignancy by EUS-FNA, and confirmed as probable one by an optional steroid response.

* A case may be possibly type 2, although it is extremely rare in Japan. “+” refers to “and”, and “/” refers to “or”.

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