Concept of AIP
AIP is a unique form of pancreatitis in which autoimmune mechanisms are suspected to be involved in the pathogenesis. AIP has many clinical, radiological, serological, and histopathological characteristics as follows: (1) elderly male preponderance; (2) frequent initial symptom of obstructive jaundice without pain; (3) occasional association with impaired pancreatic endocrine or exocrine function and various extrapancreatic lesions; (4) a favorable response to steroid therapy; (5) radiological findings of irregular narrowing of the main pancreatic duct and enlargement of the pancreas; (6) serological findings of elevation of serum γ-globulin, IgG, or IgG4 levels, along with the presence of some autoantibodies; and (7) histopathological findings of dense lymphoplasmacytic infiltration with fibrosis and obliterative phlebitis in the pancreas.15–17 Typical AIP shows diffuse changes of the pancreas, but several cases have shown segmental changes. Localized AIP may extend progressively to the whole pancreas.18,19 The current concept of AIP, including associated extrapancreatic lesions, suggests that AIP may be a systemic disease.7,8,20,21
AIP has been described by various names reflecting different aspects of the entity and each emphasizing the clinical, radiological, or histological findings: for example, chronic inflammatory sclerosis of the pancreas,1 duct-narrowing chronic pancreatitis (DNCP),2 lymphoplasmacytic sclerosing pancreatitis,22 nonalcoholic duct destructive chronic pancreatitis,23 and idiopathic tumefactive chronic pancreatitis.24
Prevalence
AIP is a rare disorder, but its exact incidence is unknown. In a nationwide survey conducted in Japan, 900 patients with AIP were identified,25 and the total number of patients treated for chronic pancreatitis in a year was estimated as 44 700.26 The prevalence rate of AIP among patients with chronic pancreatitis was 1.95% in this survey. We encountered 32 patients (8.4%) with AIP out of 380 patients with chronic pancreatitis clinically diagnosed in our institute. Other reported prevalence rates of AIP among chronic pancreatitis cases are 4.6% (21/451) in Japan,27 5.4% (17/315) in Korea,16 and 6.0% (23/383) in Italy.27 In North America, about 2.5% of pancreatoduodenectomies are performed for AIP because of a mistaken diagnosis of pancreatic cancer,28 and AIP cases represent between 21%29 and 23%28 of pancreatoduodenectomies performed for benign conditions. Reported AIP cases are increasing with the growing awareness of this entity around the world.
Pathogenesis
Serum IgG4 is a subtype of IgG, and its levels are frequently elevated and particularly high in AIP.30,31 Dense infiltration of IgG4-positive plasma cells is seen in various organs of AIP patients.7,8,32–34 These results suggest that IgG4 plays a major role in the pathogenesis of AIP, although the trigger for the IgG4 elevation or its pathogenetic role in AIP has not been clearly disclosed. Antilactoferrin and anti-carbonic anhydrase II (CA-II) antibodies are frequently detected in AIP patients.35 Therefore, lactoferrin and CA-II have been proposed as the target antigens, but this has not yet been fully confirmed. Although the actual effector cells of AIP have not been clearly delineated, the number of activated CD4- and CD8-positive T cells bearing HLADR is increased among the peripheral blood lymphocytes and in the pancreas of AIP patients.35 It has also been reported that this disease is closely associated with the HLA DRB1*0405-DQB1*0401 haplotype, suggesting that the specific peptide presented by these HLA molecules triggers the pathological process of the autoimmunity.36
Although the many above-mentioned findings support an immunologic mechanism of AIP, target antigens for AIP have not been detected. Its preponderant occurrence in elderly men and markedly dramatic response to oral steroid therapy suggest that the pathogenesis of AIP might not be by an autoimmune mechanism but by some other mechanism such as an allergic reaction.
Clinical manifestations
AIP occurs predominantly in elderly men.37 In our series, the mean age of the patients was 68.3 years (range, 29–83 years) and the male-to-female ratio was 4 : 1. In a study in Korea, the mean age was 59.1 years (45–75 years), and the male-to-female ratio was 15:2.16 Patients rarely show typical features of pancreatitis, and the major presenting complaint is painless obstructive jaundice due to associated sclerosing cholangitis (65%16 or 86%38 of cases). The jaundice sometimes fluctuates. Diabetes mellitus, usually type 2, is often (41%39 or 76%16 of cases) observed. In many cases, the diagnoses of diabetes mellitus and AIP are made simultaneously; some patients show exacerbation of preexisting diabetes mellitus with the onset of AIP.40 Tanaka et al.41,42 reported that diabetes mellitus with AIP was caused by T-cell-mediated mechanisms primarily involving islet β-cells as well as pancreatic duct cells. Pancreatic exocrine function is frequently impaired, but marked pancreatic insufficiency is uncommon.43 Some patients have other symptoms related to associated diseases, including salivary gland swelling due to sclerosing sialadenitis, hydronephrosis due to retroperitoneal fibrosis, and lymphadenopathy.44
Laboratory findings
Few patients show marked elevation of serum pancreatic enzymes. The patients with biliary lesions show elevation of serum bilirubin and hepatobiliary enzymes. Some patients show peripheral eosinophilia or elevation of serum IgE levels. Hypergammaglobulinemia (>2.0 g/dl) and elevated serum IgG levels (>1800 mg/dl) are detected in 59%–76%45–47 and 53%16–71%45 of AIP patients, respectively. A diagnostic autoantibody for AIP has not been detected. Autoantibodies including antinuclear antibody and rheumatoid factor are present in 43%–75%39,46,47 and 13%–30%39,46,47 of patients, respectively. Serological findings may change spontaneously during the course of AIP.48 In 2001, Hamano et al.30 reported that serum IgG4 levels are significantly and specifically high in AIP patients and are closely associated with disease activity. According to their report, the use of a cutoff value of 135 mg/dl for the serum IgG4 level resulted in a high rate of accuracy (97%), sensitivity (95%), and specificity (97%) for differentiating AIP from pancreatic cancer. Some AIP patients show elevated serum IgG4 levels in spite of normal IgG levels. However, the sensitivity of elevated serum IgG4 levels is 63%–68% in other reports.15,16,49 Elevation of serum IgG4 levels has been reported in a patient with pancreatic cancer.50
Radiological findings
Typical cases of AIP show diffuse enlargement of the pancreas, the so-called sausage-like appearance, on computed tomography (CT), ultrasonography (US), and magnetic resonance image (MRI). On dynamic CT and MRI, there is delayed enhancement of the swollen pancreatic parenchyma (Fig. 1a).47,51–53 The affected pancreatic lesion shows decreased intensity on the T1-weighted image and increased intensity on the T2-weighted image compared with the signal intensity in the liver.51,53,54 Since inflammatory and fibrous changes involve the peripancreatic adipose tissue, a capsule-like rim surrounding the pancreas, which appears as a low-density area on CT and as a hypointense area on a T2-weighted MRI (Fig. 1b), is detected in some cases.47,51–54 US shows an enlarged hypoechoic pancreas with hyperechoic spots (Fig. 1c).47,51,53 Pancreatic calcification or pseudocyst is uncommon. Some cases show a focal enlargement of the pancreas, similar to that seen with pancreatic cancer.47,55–57 On endoscopic retrograde cholangiopancreatography, an irregular, narrow main pancreatic duct is seen diffusely throughout the pancreas in typical cases. The degree of narrowing of the main pancreatic duct varies in the same patient (Fig. 1d). In some cases, there is segmental narrowing of the main pancreatic duct, but upstream dilatation of the distal pancreatic duct is less often noted than in pancreatic cancer (Fig. 1e).47,57 In a majority of AIP patients, both the ventral and dorsal pancreatic ducts are involved, while some patients show the involvement of only the dorsal pancreatic duct. Patients without involvement of the ventral pancreas tend rarely to present with obstructive jaundice.58,59 Stenosis of the extrahepatic or intrahepatic bile duct is frequently observed (Fig. 1e). Marked wall thickening of the extrahepatic bile duct or gallbladder is sometimes detected on US or endoscopic ultrasonography (EUS).53,60,61 Magnetic resonance cholangiopancreatography does not adequately show the narrow portion of the main pancreatic duct,54 but it can adequately demonstrate stenosis of the bile duct with dilatation of the upper biliary tract.53 Cervical, hilar, and abdominal lymphadenopathy is sometimes detected on CT.47,49 On angiography, encasement of the peripancreatic arteries and stenosis of the portal vein are sometimes observed.47,62 F-18 fluorodeoxyglucose (FDG) positron emission tomography occasionally demonstrates intense FDG uptake in the pancreas of AIP patients.63–65
Histopathological and immunohistochemical findings
In gross appearance, the pancreas in AIP shows firm and mass-like enlargement with a thick capsule. The hallmark of the histological findings in the pancreas of AIP patients is dense inflammatory cell infiltration and fibrosis in a periductal and interlobular distribution (Fig. 2a). The inflammatory infiltrate consists mainly of lymphocytes and plasma cells with occasional formation of lymphoid follicles. Perineural infiltration is sometimes detected. Fibrosis is usually diffuse and dense, but loose with stromal edema in some cases. The acinar cells are then more or less replaced by inflammatory cells and fibrosis, and the lobular architecture of the pancreas is almost lost. The pancreatic duct is narrowed by periductal fibrosis and lymphoplasmacytic infiltration (Fig. 2b). The infiltrate is primarily subepithelial, and the ductal epithelium is usually preserved except for sparse infiltration by lymphocytes. This is appropriately labeled as lymphoplasmacytic sclerosing pancreatitis. Another highly characteristic histological finding is obliterative phlebitis of the variably sized pancreatic veins and involvement of the portal vein with lymphoplasmacytic infiltrate and proliferation of fibroblasts in and around the wall of the vein (Fig. 2c). Such an inflammatory process widely and intensely involves the contiguous soft tissue and peripancreatic retroperitoneal tissue.22,32,66–69 Saito et al.70 reported that histological recovery of the pancreas, including amelioration of the fibrosis and infiltration of inflammatory cells and a substantial increase in the number of acinar cells, was detected in a patient with AIP after steroid therapy. The wall of the bile duct and gallbladder thickens, histologically showing the same inflammatory process as that of the pancreas. Regional lymph nodes are swollen up to 2.0 cm in diameter, and show histologically marked follicular hyperplasia and dense plasmacytic infiltration in the paracortical and medullary regions.22,32
These characteristic histological findings of AIP are detected during its active phase, and may be a gold standard for diagnosing AIP.71 However, diagnosing AIP on the basis of a biopsy or an EUS-guided fine-needle aspiration biopsy is sometimes difficult, because of the small sample size.
Immunohistochemically, infiltrating inflammatory cells in the pancreas consist of CD4- or CD8-positive T lymphocytes and IgG4-positive plasma cells (Fig. 3a). Dense infiltration [>30/high-power field (hpf)] of IgG4-positive plasma cells in the pancreas is not observed in chronic alcoholic pancreatitis or pancreatic cancer. Infiltration of abundant IgG4-positive plasma cells is also detected in various organs such as the peripancreatic retroperitoneal tissue, major duodenal papilla, biliary tract, intrahepatic periportal area (Fig. 3b), salivary glands (Fig. 3c), gastric mucosa, colonic mucosa, lymph nodes (Fig. 3d), or bone marrow of AIP patients.7,8,32–34
Diagnostic criteria and differential diagnosis
As it is usually difficult to take specimens from the pancreas, currently, AIP should be diagnosed on the basis of combination with clinical, laboratory, and imaging studies. The Japan Pancreas Society has proposed “Diagnostic Criteria for Autoimmune Pancreatitis, 2002,” containing three items: (1) radiological imaging showing diffuse enlargement of the pancreas and diffuse irregular narrowing of the main pancreatic duct (more than one-third the length of the entire pancreas); (2) laboratory data demonstrating abnormally elevated levels of serum γ-globulin or IgG, or the presence of autoantibodies; and (3) histological examination of the pancreas showing lymphoplasmacytic infiltration and fibrosis. For the diagnosis of AIP, either all of the criteria should be present or criterion 1 together with either criterion 2 or criterion 3. The presence of the imaging criterion is essential for diagnosing AIP.27,72 These criteria are based on the minimum consensus features of AIP to avoid a misdiagnosis pancreatic cancer as far as possible. However, the accumulation of many AIP cases has revealed several diagnostic limitations to these criteria, and revised criteria has been proposed in 2006.73 According to these new criteria, cases showing localized ductal narrowing over less than one-third the length of the pancreas can be diagnosed, and serological findings showing elevation of the serum IgG4 level is included as one diagnostic factor. Recently, new diagnostic criteria have been proposed in Korea74 and the United States75 that include two more factors: response to steroid therapy and other-organ involvement.
The most important disease that should be differentiated from AIP is pancreatic cancer. Clinically, patients with pancreatic cancer and AIP share many features, such as being elderly, having painless jaundice, developing new-onset diabetes mellitus, and having elevated tumor markers.47 Radiologically, focal swelling of the pancreas, the “double-duct sign,” representing strictures in both the biliary and pancreatic ducts, as well as angiographic abnormalities can sometimes be seen in both pancreatic cancer and AIP. As AIP responds dramatically to steroid therapy, accurate diagnosis of AIP can avoid unnecessary laparotomy or pancreatic resection. Imaging findings, such as a mass showing delayed enhancement and a capsule-like rim on dynamic CT or MRI, and segmental narrowing of the main pancreatic duct associated with a less-dilated upstream pancreatic duct, are all useful in differentiating pancreatic cancer from AIP. Measurement of serum IgG4 levels is a useful tool for differentiating between the two diseases. We preliminarily reported that IgG4-immunostaining of biopsy specimens taken from the major duodenal papilla of AIP patients may support the diagnosis of AIP.76 Although improvement in clinical findings with steroid therapy may be useful in the differential diagnosis of AIP from pancreatic cancer, empiric administration of steroids should be avoided in order not to misdiagnose pancreatic cancer as AIP.
It is of uppermost importance to consider the possible presence of AIP in elderly patients presenting with obstructive jaundice and a pancreatic mass.
Treatment and prognosis
Some AIP patients improve spontaneously.77,78 Steroid therapy is clinically, morphologically, and serologically effective in AIP patients (Fig. 1e,1f). In cases with obstructive jaundice, endoscopic or percutaneous transhepatic biliary drainage must be done, and in cases of diabetes mellitus, glucose levels must be controlled before steroid therapy is started. The preferred initial dose of prednisolone is 30–40 mg/day, and it is tapered by 5 mg every 1–2 weeks. Serological and imaging tests are performed periodically after commencement of steroid therapy. Usually, pancreatic size is normalized within a few weeks, and biliary drainage becomes unnecessary within 1–2 months. Patients in whom complete radiological improvement is documented can stop their medication, but most other patients require continued maintenance therapy with prednisolone 5 mg/day.78 In half of steroid-treated patients, impaired exocrine or endocrine function improves.40,43 Some AIP patients relapse during maintenance therapy or after stopping steroid medication and should be retreated with high-dose steroid therapy. The indications for steroid therapy in AIP include obstructive jaundice due to stenosis of the bile duct or the presence of other associated systemic diseases, such as retroperitoneal fibrosis.79 Steroid therapy is also effective for sclerosing cholangitis that relapses after surgery.80,81
The long-term prognosis of AIP is not well known. In our 1- to 22-year follow-up study of AIP patients, the prognosis was almost always good, except in two patients who progressed to pancreatic insufficiency after resection.82 It has been reported that recurrent attacks of AIP result in pancreatic stone formation in some cases.38
Clinical subtype
Some young patients suffer from AIP. These young AIP patients are more likely to have abdominal pain and serum amylase elevation than middle-aged or elderly patients.83 According to American66 and Italian67 reports, AIP patients with neutrophilic infiltration in the epithelium of the pancreatic duct are younger, more commonly have inflammatory bowel disease, and have a weaker association with sialadenitis than patients without neutrophilic infiltration. AIP might be a heterogeneous disease with different clinical aspects, and these patients with young onset might be another subtype from the usual AIP as defined in Japan.84 Further international study of a larger series of clinically relevant subtypes of AIP is necessary.